| 1. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693-699. |
Observational-Tx |
48 patients |
To evaluate the role of OLT in the treatment of patients with cirrhosis and HCC. |
Median follow-up 26 months. The overall mortality rate was 17%. After 4 years, the actuarial survival rate was 75% and the rate of recurrence-free survival was 83%. HCC recurred in 4 patients (8%). The OS and recurrence-free survival rates at 4 years among the 35 patients (73% of the total) who met the predetermined criteria for the selection of small HCC at pathological review of the explanted liver were 85% and 92%, respectively, whereas the rates in the 13 patients (27%) whose tumors exceeded these limits were 50% and 59%, respectively (P=0.01 for OS; P=0.002 for recurrence-free survival). In this group of 48 patients with early-stage tumors, tumor-node-metastasis status, the number of tumors, the serum AFP concentration, and treatment received before transplantation, and 10 other variables were not significantly correlated with survival. Liver transplantation is an effective treatment for small, unresectable HCC in patients with cirrhosis. |
2 |
| 2. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999;19:329-38. |
Review/Other-Tx |
N/A |
To discuss the new staging system to be proposed, the Barcelona Clinic Liver Cancer (BCLC) staging classification, that comprises four stages that select the best candidates for the best therapies currently available. |
No results in abstract. |
4 |
| 3. Toso C, Mentha G, Kneteman NM, Majno P. The place of downstaging for hepatocellular carcinoma. J Hepatol 2010;52:930-6. |
Review/Other-Tx |
N/A |
To discuss which treatments and strategies are available for downstaging hepatocellular carcinoma (HCC) on the basis of the published literature |
No results in abstract. |
4 |
| 4. Teh SH, Christein J, Donohue J, et al. Hepatic resection of hepatocellular carcinoma in patients with cirrhosis: Model of End-Stage Liver Disease (MELD) score predicts perioperative mortality. J Gastrointest Surg 2005;9:1207-15; discussion 15. |
Observational-Tx |
82 patients |
To examine whether MELD was predictive of perioperative mortality and correlated MELD with other potential clinicopathologic factors to overall survival in patients with cirrhosis undergoing hepatic resection for HCC |
Forty-five patients had MELD score > or =9 (range, 9-15) and CTP score ranged from 5 to 9 points. Fifty-nine patients underwent minor (<3 segments) hepatic resections (MELD < or =8, n = 29; MELD > or =9, n = 30) and 23 underwent major (> or =3 segments) hepatic resections (MELD < or =8, n = 8; MELD > or =9, n = 15). Perioperative mortality rate was 16%. MELD score < or =8 was associated with no perioperative mortality versus 29% for patients with an MELD score > or =9 (P < 0.01). Multivariate analysis demonstrated that MELD score > or =9 (P < 0.01), clinical tumor symptoms (P < 0.01), and ASA score (P = 0.046) are independent predictors of perioperative mortality. Multivariate analysis showed MELD > or =9 (P < 0.01), tumor size >5 cm (P < 0.01), high tumor grade (P = 0.03), and absence of tumor capsule (P < 0.01) as independent predictors of decreased long-term survival. MELD score was a strong predictor of both perioperative mortality and long-term survival in patients with cirrhosis undergoing hepatic resection for HCC. In patients with cirrhosis, hepatic resection (minor or major) for HCC is recommended if the MELD score is < or =8. In patients with MELD score > or =9, other treatment modalities should be considered. |
3 |
| 5. Yamashita Y, Taketomi A, Itoh S, et al. Longterm favorable results of limited hepatic resections for patients with hepatocellular carcinoma: 20 years of experience. J Am Coll Surg. 2007;205(1):19-26. |
Observational-Tx |
321 patients |
To report the effectiveness of limited hepatic resection for cirrhotic patients with HCC. |
Anatomic resection did not influence overall and recurrence-free survival rates after hepatic resection. In the liver damage A group (n=215), both 5-year overall and recurrence-free survival rates in the anatomic resection group were considerably better than those in the limited resection group (87% vs 76%, P=0.02, and 63% vs 35%, P<0.01, respectively). In the liver damage B group (n=106), both 5-year overall and recurrence-free survival rates in the anatomic resection group were substantially worse than those in the limited resection group (48% vs 72%, P<0.01, and 28% vs 43%, P=0.01, respectively). The results of multivariate analysis revealed that anatomic resection was a notably poor factor in promoting recurrence-free survival in patients with liver damage B. |
2 |
| 6. Sapisochin G, Bruix J. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol 2017;14:203-17. |
Review/Other-Tx |
N/A |
To provide a comprehensive overview of the outcomes after liver transplantation for hepatocellular carcinoma (HCC), focusing on tumour recurrence in terms of surveillance, prevention and treatment. |
No results in abstract. |
4 |
| 7. Akoad ME, Pomfret EA. Surgical resection and liver transplantation for hepatocellular carcinoma. [Review]. Clin Liver Dis. 19(2):381-99, 2015 May. |
Review/Other-Tx |
N/A |
To discuss the role of surgical resection and liver transplantation in the management of hepatocellular carcinoma (HCC). |
No results in abstract. |
4 |
| 8. Taura K, Ikai I, Hatano E, et al. Influence of coexisting cirrhosis on outcomes after partial hepatic resection for hepatocellular carcinoma fulfilling the Milan criteria: an analysis of 293 patients. Surgery 2007;142:685-94. |
Observational-Tx |
293 HCC patients (both with and without cirrhosis) |
To examine whether OLT is the best treatment strategy for patients with resectable hepatocellular carcinoma (HCC) . |
There were 127 noncirrhotic, 129 Child-Pugh A cirrhotic, and 37 Child-Pugh B cirrhotic patients. Five-year survival rates in each population were 81%, 54%, and 28%, respectively. Coexisting cirrhosis, Child-Pugh classification, alpha-fetoprotein value, tumor burden, and vascular invasion by the tumor were identified as significant prognostic factors. Among these factors, coexisting cirrhosis was the most crucial variable by multivariate analysis. During the initial 3 postoperative years, yearly tumor recurrence rate was 22% in cirrhotic patients and 15% in noncirrhotic patients. In cirrhotic patients, the recurrence rate did not decrease even after three years of tumor-free survival post-resection, whereas in noncirrhotic patients the recurrence rate decreased to 9%. Cirrhosis was associated with a higher probability of recurrence exceeding the Milan criteria. |
3 |
| 9. Meloni MF, Chiang J, Laeseke PF, et al. Microwave ablation in primary and secondary liver tumours: technical and clinical approaches. Int J Hyperthermia 2017;33:15-24. |
Review/Other-Tx |
N/A |
To discuss the relevant physics, review current clinical outcomes and then describe the current techniques used to optimise patient care when using microwave ablation systems. |
No results in abstract. |
4 |
| 10. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908-943. |
Review/Other-Tx |
N/A |
To provide EASL–EORTC Clinical Practice Guidelines for the management of hepatocellular carcinoma. |
n/a |
4 |
| 11. Jiang L, Liao A, Wen T, Yan L, Li B, Yang J. Living donor liver transplantation or resection for Child-Pugh A hepatocellular carcinoma patients with multiple nodules meeting the Milan criteria. Transpl Int. 27(6):562-9, 2014 Jun. |
Observational-Tx |
257 patients (131 underwent transplant, 126 underwent resection) |
To compare outcomes for patients undergoing transplant versus resection at a single institution in a UNOS region with short wait times for organ availability. |
Two hundred fifty-seven patients were analyzed, of whom 131 underwent transplant and 126 underwent resection. All transplant patients met MC; 45 (36%) resection patients met MC. Median follow-up time was 30 months. Median wait time to transplant was 55 days; no patients dropped off the waitlist while awaiting an organ. Among patients meeting MC, transplant demonstrated significantly greater 5-year OS (65.7% vs. 43.8%; P = 0.005) and RFS (85.3% vs. 22.7%; P < 0.001) versus resection. For patients with hepatitis C, transplant (n = 87) demonstrated significantly improved 5-year outcomes compared to patients meeting MC who underwent resection (n = 21; OS: 63.5% vs. 23.3%; P = 0.001; RFS: 83.5% vs. 23.7%; P < 0.001). |
2 |
| 12. Squires MH 3rd, Hanish SI, Fisher SB, et al. Transplant versus resection for the management of hepatocellular carcinoma meeting Milan Criteria in the MELD exception era at a single institution in a UNOS region with short wait times. J Surg Oncol. 109(6):533-41, 2014 May. |
Observational-Tx |
67 patients with early HCC (LDLT = 34 patients, LR = 33 patients) |
To compare the outcomes of living donor liver transplantation (LDLT) with that of liver resection (LR) for early Child-Pugh A HCC patients with multiple nodules meeting the Milan criteria. |
The postoperative mortality and rate of major complications were similar in both groups. The 5-year overall survival (OS; 76.5% vs. 51.2%, P = 0.046) and recurrence-free survival (RFS;72.0% vs. 19.8%, P = 0.000) were better in group LDLT than that in group LR. The 5-year OS and RFS were similar between patients with tumours located in the same lobe (TSL) and those in the different lobes (TDL) after LDLT, whereas the5-year RFS was better in patients with tumours in TSL (30.6% vs. 0%, P = 0.012)after LR. In conclusion, primary LDLT might be the optimum treatment for early HCC patients with multiple nodules meeting the Milan criteria. |
3 |
| 13. Majumdar A, Roccarina D, Thorburn D, Davidson BR, Tsochatzis E, Gurusamy KS. Management of people with early- or very early-stage hepatocellular carcinoma: an attempted network meta-analysis. Cochrane Database Syst Rev 2017;3:CD011650. |
Meta-analysis |
18 trials |
To assess the comparative benefits and harms of different interventions used in the treatment of early or very early hepatocellular carcinoma through a network meta-analysis and to generate rankings of the available interventions according to their safety and efficacy. |
Eighteen trials met the inclusion criteria for this review. Four trials (593 participants; 574 participants included for one or more analyses) compared surgery versus radiofrequency ablation in people with early hepatocellular carcinoma, eligible to undergo surgery. Fourteen trials (2533 participants; 2494 participants included for various analyses) compared different non-surgical interventions in people with early hepatocellular carcinoma, not eligible to undergo surgery. Overall, the quality of evidence was low or very low for all outcomes for both comparisons. Surgery versus radiofrequency ablation. The majority of participants had cirrhotic livers, and the hepatocellular carcinoma was of viral aetiology. The trials did not report the participants' portal hypertension status or whether they received adjuvant antiviral treatment or adjuvant immunotherapy. The average follow-up ranged from 29 months to 42 months (3 trials).There was no evidence of a difference in all-cause mortality at maximal follow-up for surgery versus radiofrequency ablation (hazard ratio 0.80, 95% confidence interval (CI) 0.60 to 1.08; 574 participants; 4 trials; I2 = 68). Cancer-related mortality was lower in the surgery group (20/115 (17.4%)) than in the radiofrequency ablation group (43/115 (37.4%)) (odds ratio 0.35, 95% CI 0.19 to 0.65; 230 participants; 1 trial). Serious adverse events (number of participants) was higher in the surgery group (14/60 (23.3%)) than in the radiofrequency ablation group (1/60 (1.7%)) (odds ratio 17.96, 95% CI 2.28 to 141.60; 120 participants; 1 trial). The number of serious adverse events was higher in the surgery group (adjusted rate 11.3 events per 100 participants) than in the radiofrequency ablation group (3/186 (1.6 events per 100 participants)) (rate ratio 7.02, 95% CI 2.29 to 21.46; 391 participants; 2 trials; I2 = 0%). None of the trials reported health-related quality of life. One trial was funded by a party with vested interests; three trials were funded by parties without any vested. Non-surgical interventions. The majority of participants had cirrhotic livers, and the hepatocellular carcinoma was of viral aetiology. Most trials did not report the portal hypertension status of the participants, and none of the trials reported whether the participants received adjuvant antiviral treatment or adjuvant immunotherapy. The average follow-up ranged from 6 months to 37 months (11 trials). Trial participants, who were not eligible for surgery, were treated with radiofrequency ablation, laser ablation, microwave ablation, percutaneous acetic acid injection, percutaneous alcohol injection, a combination of radiofrequency ablation with systemic chemotherapy, a combination of radiofrequency ablation with percutaneous alcohol injection, a combination of transarterial chemoembolisation with percutaneous alcohol injection, or a combination of transarterial chemoembolisation with radiofrequency ablation. The mortality at maximal follow-up was higher in the percutaneous acetic acid injection (hazard ratio 1.77, 95% CI 1.12 to 2.79; 125 participants; 1 trial) and percutaneous alcohol injection (hazard ratio 1.49, 95% CI 1.18 to 1.88; 882 participants; 5 trials; I2 = 57%) groups compared with the radiofrequency ablation group. There was no evidence of a difference in all-cause mortality at maximal follow-up for any of the other comparisons. The proportion of people with cancer-related mortality at maximal follow-up was higher in the percutaneous alcohol injection group (adjusted proportion 16.8%) compared with the radiofrequency ablation group (20/232 (8.6%)) (odds ratio 2.18, 95% CI 1.22 to 3.89; 458 participants; 3 trials; I2 = 0%). There was no evidence of a difference in any of the comparisons that reported serious adverse events (number of participants or number of events). None of the trials reported health-related quality of life. Five trials were funded by parties without any vested interest; the source of funding was not available in the remaining trials. |
Not Assessed |
| 14. Orlando A, Leandro G, Olivo M, Andriulli A, Cottone M. Radiofrequency thermal ablation vs. percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials. Am J Gastroenterol. 2009;104(2):514-524. |
Meta-analysis |
701 patients; 5 randomized controlled trials |
To review the available evidence comparing RFA to PEI for small HCC. |
The OS was significantly higher in patients treated with RFA than in those treated with PEI (risk differences 0.116, 95% CI, 0.173/0.060; heterogeneity not present). LR rate is significantly higher in patients treated with PEI than in those treated with RFA. In the RFA group the 1, 2, and 3 years cancer-free survival rates were significantly better than in the PEI-treated patients (respectively: risk differences 0.098, 95% CI, 0.006/0.189; heterogeneity P=0.57; risk differences 0.187, 95% CI, 0.082/0.293; heterogeneity P=0.98; risk differences 0.210, 95% CI, 0.095/0.325; heterogeneity P=0.78). A small number of adverse events were reported in the 2 treatments. RFA is superior to PEI in the treatment of small HCC with respect to OS, 1, 2, and 3 years survival rates, 1, 2, and 3 cancer-free survival rates, and tumor response. RFA shows a significantly smaller risk of LR. |
M |
| 15. Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg. 2006;243(3):321-328. |
Experimental-Tx |
180 total patients: 90 received percutaneous local ablative therapy; 90 received surgical resection |
Randomized trial to compare the results of percutaneous local ablative therapy with surgical resection in the treatment of solitary and small HCC. |
The 1-, 2-, 3-, and 4-year OS rates after percutaneous local ablative therapy and surgery were 95.8%, 82.1%, 71.4%, 67.9% and 93.3%, 82.3%, 73.4%, 64.0%, respectively. The corresponding DFS rates were 85.9%, 69.3%, 64.1%, 46.4% and 86.6%, 76.8%, 69%, 51.6%, respectively. Statistically, there was no difference between these 2 treatments. Percutaneous local ablative therapy was as effective as surgical resection in the treatment of solitary and small HCC. Percutaneous local ablative therapy had the advantage over surgical resection in being less invasive. |
1 |
| 16. Feng K, Yan J, Li X, et al. A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. J Hepatol. 2012;57(4):794-802. |
Experimental-Tx |
168 patients |
To compare the efficacy of RFA with surgical resection in the treatment of small HCC. |
The 1-, 2-, and 3-year survival rates for the surgical resection and RFA groups were 96.0%, 87.6%, 74.8% and 93.1%, 83.1%, 67.2%, respectively. The corresponding recurrence-free survival rates for the 2 groups were 90.6%, 76.7%, 61.1% and 86.2%, 66.6%, 49.6%, respectively. There were no statistically significant differences between the 2 groups in OS rate (P=0.342) or recurrence-free survival rate (P=0.122). Multivariate analysis demonstrated that the independent risk factors associated with survival were multiple occurrences of tumors at different hepatic locations (relative risk of 2.696; 95% CI: 1.189–6.117; P=0.018) and preoperative indocyanine green retention rate at 15 min (relative risk of 3.853; 95% CI: 1.647–9.015; P=0.002). |
1 |
| 17. Fujimori M, Takaki H, Nakatsuka A, et al. Survival with up to 10-year follow-up after combination therapy of chemoembolization and radiofrequency ablation for the treatment of hepatocellular carcinoma: single-center experience. J Vasc Interv Radiol. 2013;24(5):655-666. |
Observational-Tx |
277 patients with 382 treatment-naive HCCs |
To report 10-year outcomes of treating HCCs by combination therapy of chemoembolization and RFA. |
Tumor enhancement disappeared after 466 RFA sessions in all tumors, resulting in a complete response rate of 100% (277/277) based on modified Response Evaluation Criteria In Solid Tumors. Local tumor progression developed in 15 patients (5.4%; 15/277) during the mean follow-up of 44.9 months +/- 29.1 (range, 6.0–134.4 months). OS and recurrence-free survival rates were 56.3% (95% CI, 52.5%–60.2%) and 22.5% (95% CI, 19.3%–25.6%) at 5 years and 23.5% (95% CI, 17.7%–29.2%) and 9.3% (95% CI, 6.3%–12.4%) at 10 years. The Child-Pugh class was the only significant prognostic factor detected in both the univariate (P<.001) and the multivariate analyses (HR, 3.8; 95% CI, 2.5–5.6; P<.001). The 5-year and 10-year OS rates were 66.4% (95% CI, 62.0%–70.8%) and 30.6% (95% CI, 23.3%–37.9%) in 210 Child-Pugh class A patients. In addition to the Child-Pugh class, the maximum tumor diameter (=3 cm vs >3 cm) and the tumor number (single vs multiple) were significant independent factors affecting recurrence-free survival. No death was related to the combination therapy. The major complication rate was 3.2% (15/466). |
2 |
| 18. Huang J, Yan L, Cheng Z, et al. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg. 2010;252(6):903-912. |
Experimental-Tx |
230 patients |
To compare the long-term outcomes of surgical resection and RFA for the treatment of small HCC. |
The 1-, 2-, 3-, 4- and 5-year OS rates for the RFA group and the surgical resection group were 86.96%, 76.52%, 69.57%, 66.09%, 54.78% and 98.26%, 96.52%, 92.17%, 82.60%, 75.65%, respectively. The corresponding recurrence-free survival rates for the 2 groups were 81.74%, 59.13%, 46.08%, 33.91%, 28.69% and 85.22%, 73.92%, 60.87%, 54.78%, 51.30%, respectively. OS and recurrence-free survival were significantly lower in the RFA group than in the surgical resection group (P=0.001 and P=0.017). The 1-, 2-, 3-, 4-, and 5-year overall recurrence rates were 16.52%, 38.26%, 49.57%, 59.13%, and 63.48% for the RFA group and 12.17%, 22.60%, 33.91%, 39.13%, and 41.74% for the surgical resection group. The overall recurrence was higher in the RFA group than in the surgical resection group (P=0.024). |
1 |
| 19. Livraghi T, Meloni F, Di Stasi M, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology. 2008;47(1):82-89. |
Observational-Tx |
218 patients |
To assess the response and complications rates after RFA of very early HCC in cirrhosis compared to results achieved with resection. |
After a median follow-up of 31 months, sustained complete response was observed in 216 patients (97.2%). In the remaining 6, PEI, selective intra-arterial chemoembolization, or resection were used as salvage therapy. Perioperative mortality, major complication, and 5-year survival rates were 0%, 1.8%, and 68.5%, respectively. Conclusion: Compared with resection, RFA is less invasive and associated with lower complication rate and lower costs. RFA is also just as effective for ensuring local control of stage T1 HCC, and it is associated with similar survival rates (as recently demonstrated by 2 randomized trials). These data indicate that RFA can be considered the treatment of choice for patients with single HCC =2.0 cm, even when surgical resection is possible. Other approaches can be used as salvage therapy for the few cases in which RFA is unsuccessful or unfeasible. |
2 |
| 20. Peng ZW, Lin XJ, Zhang YJ, et al. Radiofrequency ablation versus hepatic resection for the treatment of hepatocellular carcinomas 2 cm or smaller: a retrospective comparative study. Radiology. 2012;262(3):1022-1033. |
Observational-Tx |
145 patients |
To compare retrospectively the effects of percutaneous RFA with those of hepatic resection in the treatment of HCC measuring 2 cm or smaller. |
One death was considered to be related to treatment after surgical resection. Major complications occurred significantly more often in the surgical resection group (38/74 patients) than in the RFA group (14/71 patients) (P=.009). The 1-, 3-, and 5-year OS rates were 98.5%, 87.7%, and 71.9%, respectively, with RFA and 90.5%, 70.9%, and 62.1% with surgical resection (P=.048). The corresponding recurrence-free survival rates were 76.4%, 65.2%, and 59.8% with RFA and 75.6%, 56.1%, and 51.3% with surgical resection (P=.548). At subgroup analysis of patients with central HCC, 1-, 3-, and 5-year OS rates were 96.6%, 93.0%, and 79.9% with RFA and 92.0%, 71.6%, and 61.5% with surgical resection (P=.020). The corresponding recurrence-free survival rates were 86.5%, 74.0%, and 67.0% with RFA and 68.0%, 40.0%, and 40.0% with surgical resection (P=.033). For patients with peripheral HCC, 1-, 3-, and 5-year OS rates were 97.3%, 83.3%, and 65.1% with RFA and 87.8%, 68.4%, and 62.9% with surgical resection (P=.464). The corresponding recurrence-free survival rates were 68.7%, 59.2%, and 54.9% with RFA and 82.9%, 66.6%, and 52.9% with surgical resection (P=.351). |
2 |
| 21. Tohme S, Geller DA, Cardinal JS, et al. Radiofrequency ablation compared to resection in early-stage hepatocellular carcinoma. HPB. 15(3):210-7, 2013 Mar. |
Observational-Tx |
110 patients |
To compare survival outcomes after hepatic resection and RFA in early-stage HCC at a Western hepatobiliary centre. |
Patients who underwent hepatic resection had larger tumors, a longer length of stay and a higher rate of postoperative complications. After a median follow-up of 29 months, there were no significant differences between the treatment groups in 1-, 3- and 5-year OS [RFA group: 86%, 50%, 35%, respectively; hepatic resection group: 88%, 68%, 47%, respectively (P= 0.222)] or DFS [RFA group: 68%, 42%, 28%, respectively; hepatic resection group: 66%, 42%, 34%, respectively (P= 0.823)]. The 58 patients who underwent RFA demonstrated ablation success on follow-up CT at 3 months. Of these, 96.5% of patients showed sustained ablation success over the entire follow-up period. In a subgroup analysis of patients with tumors measuring 2–5 cm, no differences in OS or DFS emerged between the hepatic resection and RFA groups. Similarly, no significant differences in outcomes in patients with Child-Pugh class A cirrhosis were seen between the RFA and hepatic resection groups. |
2 |
| 22. Schaub SK, Hartvigson PE, Lock MI, et al. Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Current Trends and Controversies. Technol Cancer Res Treat 2018;17:1533033818790217. |
Review/Other-Tx |
N/A |
To highlight future possible research and clinical directions. |
N/A |
4 |
| 23. Andolino DL, Johnson CS, Maluccio M, et al. Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2011;81(4):e447-453. |
Observational-Tx |
60 patients |
To evaluate the safety and efficacy of SBRT for the treatment of primary HCC. |
The median follow-up time was 27 months, and the median tumor diameter was 3.2 cm. The 2-year LC, PFS, and OS were 90%, 48%, and 67%, respectively, with median TTP of 47.8 months. Subsequently, 23 patients underwent transplant, with a median time to transplant of 7 months. There were no =Grade 3 nonhematologic toxicities. 13% of patients experienced an increase in hematologic/hepatic dysfunction >1 grade, and 20% experienced progression in Child-Turcotte-Pugh class within 3 months of treatment. |
2 |
| 24. Bujold A, Massey CA, Kim JJ, et al. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol. 2013;31(13):1631-1639. |
Observational-Tx |
102 patients |
To describe outcomes of prospective trials of SBRT for HCC. |
A total of 102 patients were evaluable (Trial 1, 2004 to 2007: n = 50; Trial 2, 2007 to 2010: n = 52). Underlying liver disease was hepatitis B in 38% of patients, hepatitis C in 38%, alcohol related in 25%, other in 14%, and none in 7%. 52% received prior therapies (no prior sorafenib). TNM stage was III in 66%, and 61% had multiple lesions. Median gross tumor volume was 117.0 mL (range, 1.3 to 1,913.4 mL). Tumor vascular thrombosis was present in 55%, and extrahepatic disease was present in 12%. Local control at 1-year was 87% (95% CI, 78% to 93%). SBRT dose (HR = 0.96; P=.02) and being in Trial 2 (HR = 0.38; P=.03) were associated with local control at 1-year on univariate analysis. Toxicity = grade 3 was seen in 30% of patients. In 7 patients (2 with tumor vascular thrombosis progressive disease), death was possibly related to treatment (1.1 to 7.7 months after SBRT). Median OS was 17.0 months (95% CI, 10.4 to 21.3 months), for which only tumor vascular thrombosis (HR = 2.47; P=.01) and being in Trial 2 (HR = 0.49; P=.01) were significant on multivariate analysis. |
1 |
| 25. Mendez Romero A, Wunderink W, Hussain SM, et al. Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-ii study. Acta Oncol 2006;45:831-7. |
Observational-Tx |
25 patients (45 lesions) |
To investigate the feasibility, toxicity and tumor response of stereotactic body radiation therapy (SBRT) for treatment of primary and metastastic liver tumors. |
In total 45 lesions were treated, 34 metastases and 11 hepatocellular carcinoma (HCC). Median follow-up was 12.9 months (range 0.5-31). Median lesion size was 3.2 cm (range 0.5-7.2) and median volume 22.2 cm3 (range 1.1-322). Patients with metastases, HCC without cirrhosis, and HCC < 4 cm with cirrhosis were mostly treated with 3 x 12.5 Gy. Patients with HCC > or =4 cm and cirrhosis received 5 x 5 Gy or 3 x 10 Gy. The prescription isodose was 65%. Acute toxicity was scored following the Common Toxicity Criteria and late toxicity with the SOMA/LENT classification. Local failures were observed in two HCC and two metastases. Local control rates at 1 and 2 years for the whole group were 94% and 82%. Acute toxicity grade > or =3 was seen in four patients; one HCC patient with Child B developed a liver failure together with an infection and died (grade 5), two metastases patients presented elevation of gamma glutamyl transferase (grade 3) and another asthenia (grade 3). Late toxicity was observed in one metastases patient who developed a portal hypertension syndrome with melena (grade 3). |
2 |
| 26. Cardenes HR, Price TR, Perkins SM, et al. Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma. Clin Transl Oncol 2010;12:218-25. |
Observational-Tx |
17 patients (25 lesions) |
To determine the feasibility and toxicity of stereotactic body radiation therapy (SBRT) for primary hepatocellular carcinoma (HCC). |
Seventeen patients with 25 lesions were enrolled. Dose was escalated to 48 Gy (16 Gy/fraction) in CTP-A patients without DLT. Two patients with CPC-B disease developed grade 3 hepatic toxicity at the 42-Gy (14 Gy/fraction) level. The protocol was amended for subsequent CTP-B patients to receive a regimen of 5 fractions starting at 40 Gy (8 Gy/fraction) with one patient experiencing progressive liver failure. Four additional patients were enrolled (one died of unrelated causes after an incomplete SBRT course) without DLT. The only factor related to more than one grade 3 or greater liver toxicity or death within 6 months was the CTP score (p=0.03). Six patients underwent a liver transplant. Ten patients are alive without progression with a median FU of 24 months (10-42 months), with local control/stabilisation of the disease of 100%. One and two-year Kaplan-Meier estimates for overall survival are 75% and 60%, respectively. |
2 |
| 27. Eriguchi T, Takeda A, Tateishi Y, et al. Comparison of stereotactic body radiotherapy and radiofrequency ablation for hepatocellular carcinoma: Systematic review and meta-analysis of propensity score studies. Hepatol Res 2021;51:813-22. |
Meta-analysis |
3 studies |
To perform a systematic review and meta-analyses of the studies focusing on BCLC-factors matching. |
Stereotactic body radiotherapy led to comparable OS (HR, 0.89; 95% CI, 0.74-1.08; p = 0.24; I(2) = 0%; p for heterogeneity, 0.56) and significantly better LC (HR, 0.39; 95% CI, 0.30-0.51; p < 0.001; I(2) = 0%; p for heterogeneity, 0.67). We also identified three additional BCLC-factor-unmatched studies (HR of OS, 1.41; 95% CI, 1.21-1.65; p < 0.0001; I(2) = 0%; p for heterogeneity, 0.63). However, considerable heterogeneity was observed for HR of OS between BCLC-factor-matched and -unmatched studies (I(2) = 92.6%; p for heterogeneity, 0.0002). |
Good |
| 28. Pan YX, Fu YZ, Hu DD, et al. Stereotactic Body Radiotherapy vs. Radiofrequency Ablation in the Treatment of Hepatocellular Carcinoma: A Meta-Analysis. Front Oncol 2020;10:1639. |
Meta-analysis |
10 retrospective studies |
To compare the treatment outcomes of SBRT with RFA as curable or bridge intention. |
As no randomized clinical trials met the criteria, 10 retrospective studies with a total of 2,732 patients were included. Two studies were in favor of SBRT in local control, two studies preferred RFA in OS, and others reported comparable outcomes for both. SBRT demonstrated significantly higher 1- and 3-year local control than RFA [odds ratio (OR) 0.42, 95% CI 0.24–0.74, P = 0.003; and OR 0.54, 95% CI 0.37–0.80, P = 0.002, respectively]. However, SBRT reported significantly shorter 1- and 2-year OS (OR 1.52, 95% CI 1.21–1.90, P = 0.0003; and OR 1.66, 95% CI 1.38–2.01, P < 0.00001, respectively). As bridge treatment, no significant difference was shown in transplant rate and post-transplant pathological necrosis rate (OR 0.57, 95% |
Good |
| 29. Parikh ND, Marshall VD, Green M, et al. Effectiveness and cost of radiofrequency ablation and stereotactic body radiotherapy for treatment of early-stage hepatocellular carcinoma: An analysis of SEER-medicare. J Med Imaging Radiat Oncol 2018;62:673-81. |
Observational-Tx |
408 RFA patients and 32 SBRT patients |
To characterize the comparative outcomes and cost between the two 22 treatment strategies. |
440 patients were identified, 408 treated with RFA and 32 SBRT. In the overall 34 cohort, 90-day hospitalization and 1-year mortality were similar between groups but RFA 35 patients had better overall survival (p<0.001). Multivariate analysis showed advanced 36 age, higher stage, decompensated cirrhosis, and treatment with SBRT (HR 1.80; 95%CI: 37 1.15-2.82) were associated with worse survival, but in the PS adjusted analysis, survival 38 and costs were similar between the two groups. |
2 |
| 30. Rajyaguru DJ, Borgert AJ, Smith AL, et al. Radiofrequency Ablation Versus Stereotactic Body Radiotherapy for Localized Hepatocellular Carcinoma in Nonsurgically Managed Patients: Analysis of the National Cancer Database. J Clin Oncol 2018;36:600-08. |
Observational-Tx |
3,684 RFA patients; 296 SBRT patients |
To compare the effectiveness of radiofrequency ablation (RFA) versus stereotactic body radiotherapy (SBRT) by using the National Cancer Database. |
Overall, 3,684 (92.6%) and 296 (7.4%) nonsurgically managed patients with stage I or II HCC received RFA or SBRT, respectively. After propensity matching, 5-year overall survival was 29.8% (95% CI, 24.5% to 35.3%) in the RFA group versus 19.3% (95% CI, 13.5% to 25.9%) in the SBRT group (P , .001). Inverse probability–weighted analysis yielded similar results. The benefit of RFA was consistent across all subgroups examined and was robust to the effects of severe fibrosis/ cirrhosis. |
2 |
| 31. Seo YS, Kim MS, Yoo HJ, et al. Radiofrequency ablation versus stereotactic body radiotherapy for small hepatocellular carcinoma: a Markov model-based analysis. Cancer Med 2016;5:3094-101. |
Observational-Tx |
20,000 patients |
To compare radiofrequency ablation (RFA) with stereotactic body radiotherapy (SBRT) for hepatocellular carcinomas (HCC) smaller than 3 cm. |
The probability distributions of the expected overall survival were nearly identical. The 95% confidence intervals were 6.25-6.66 and 6.17-6.58 years for RFA and SBRT, respectively. The difference between RFA and SBRT was insignificant (P = 0.2884). Two-way sensitivity analysis demonstrated that if the tumor is 2-3 cm, SBRT is the preferred treatment option. |
3 |
| 32. Lewandowski RJ, Kulik LM, Riaz A, et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant. 2009;9(8):1920-1928. |
Observational-Tx |
86 total patients: 43 TACE; 43 TARE Y-90 |
To compare the downstaging efficacy of TACE vs transarterial radioembolization. |
Median tumor size was similar (TACE: 5.7 cm, TARE-Y-90: 5.6 cm). Partial response rates favored TARE-Y-90 vs TACE (61% vs 37%). Downstaging to UNOS T2 was achieved in 31% of TACE and 58% of TARE-Y-90 patients. TTP according to UNOS criteria was similar for both groups (18.2 months for TACE vs 33.3 months for TARE-Y-90, P=0.098). Event-free survival was significantly greater for TARE-Y-90 than TACE (17.7 vs 7.1 months, P= 0.0017). OS favored TARE-Y-90 compared to TACE (censored 35.7/18.7 months; P=0.18; uncensored 41.6/19.2 months; P=0.008). In conclusion, TARE-Y-90 appears to outperform TACE for downstaging HCC from UNOS T3 to T2. |
2 |
| 33. Katz AW, Chawla S, Qu Z, Kashyap R, Milano MT, Hezel AF. Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular carcinoma: clinical outcome and pathologic correlation. International journal of radiation oncology, biology, physics 2012;83:895-900. |
Observational-Tx |
18 patients (21 lesions) |
To determine efficacy, safety, and outcome of stereotactic hypofractionated radiation therapy (SHORT) as a suitable bridging therapy for patients awaiting liver transplantation (LT) for hepatocellular carcinoma (HCC).To examine histological response to radiation in the resected or explanted livers. |
Six of 18 patients were delisted because of progression (n = 3) or other causes (n = 3). Twelve patients successfully underwent major hepatic resection (n = 1) or LT (n = 11) at a median follow-up of 6.3 months (range, 0.6-11.6 months) after completion of SHORT. No patient developed gastrointestinal toxicity Grade =3 or radiation-induced liver disease. Ten patients with 11 lesions were evaluable for pathological response. Two lesions had 100% necrosis, three lesions had =50% necrosis, four lesions had =50% necrosis, and two lesions had no necrosis. All patients were alive after LT and/or major hepatic resection at a median follow-up of 19.6 months. |
3 |
| 34. O'Connor JK, Trotter J, Davis GL, Dempster J, Klintmalm GB, Goldstein RM. Long-term outcomes of stereotactic body radiation therapy in the treatment of hepatocellular cancer as a bridge to transplantation. Liver Transpl. 2012;18(8):949-954. |
Observational-Tx |
10 patients |
To report the safety and efficacy of SBRT, the explant pathology findings and survival of patients treated with SBRT as a bridge to transplantation for HCC. |
At 5 years, the OS rate and the DFS rate were both 100%. Overall, 4 of the 10 patients (40%) experienced acute toxicity. Most toxicities were grade 1, and they included nausea, fatigue, and abdominal discomfort. One patient had grade 2 nausea/vomiting. Explant pathology revealed no viable tumor in 3 of the 11 tumors for a complete response rate of 27%. The remaining 8 tumors decreased or remained stable in size. |
3 |
| 35. Mohamed M, Katz AW, Tejani MA, et al. Comparison of outcomes between SBRT, yttrium-90 radioembolization, transarterial chemoembolization, and radiofrequency ablation as bridge to transplant for hepatocellular carcinoma. Adv Radiat Oncol 2016;1:35-42. |
Observational-Tx |
60 patients |
To evaluate and compare outcome of stereotactic body radiation therapy (SBRT), yttrium-90 radioembolization, radiofrequency ablation (RFA), or transarterial chemoembolization (TACE) as bridge to liver transplant (LT) in patients with hepatocellular carcinoma. |
Sixty patients with a median age 57.5 years (range, 44-70) met inclusion criteria. Thirty-one patients (50.7%) had hepatitis C cirrhosis, 14 (23%) alcoholic cirrhosis, and 8 (13%) nonalcoholic steatohepatitis cirrhosis. Patients received a total of 79 bridge therapies: SBRT (n = 24), TACE (n = 37), RFA (n = 9), and Y90 (n = 9). Complete response (CR) was 25% for TACE, 8.6% for SBRT, 22% for RFA, and 33% for Y90. Grade 3 or 4 acute toxicity occurred following TACE (n = 4) and RFA (n = 2). Transplant occurred at a median of 7.4 months after bridge therapy. Pathological response among 57 patients was 100% necrosis (n = 23, 40%), >50% necrosis (n = 20, 35%), <50% necrosis (n = 9, 16%), and no necrosis (n = 5, 9%). Pathologic complete response was as follows: SBRT (28.5%), TACE (41%), RFA (60%), Y90 (75%), and multiple modalities (33%). At a median follow-up of 35 months, 7 patients had recurrence after LT. DFS was 85.8% and overall survival was 79% at 5 years. |
2 |
| 36. Bryce K, Tsochatzis EA. Downstaging for hepatocellular cancer: harm or benefit? Transl Gastroenterol Hepatol 2017;2:106. |
Review/Other-Tx |
N/A |
To review the literature and evidence for downstaging, as well as considering its drawbacks. |
N/A |
4 |
| 37. Zheng XH, Guan YS, Zhou XP, et al. Detection of hypervascular hepatocellular carcinoma: Comparison of multi-detector CT with digital subtraction angiography and Lipiodol CT. World J Gastroenterol 2005;11:200-3. |
Observational-Tx |
28 patients with nodular HCC |
To compare the diagnostic accuracy of biphasic multi-detector row helical computed tomography (MDCT), digital subtraction angiography (DSA) and Lipiodol computed tomography (CT) in detection of hypervascular hepatocellular carcinoma (HCC). |
The three imaging techniques had the same sensitivity in detecting nodules >20 mm in diameter. There was no significant difference in the sensitivity among HAP-MDCT, Lipiodol CT and DSA for nodules of 10-20 mm in diameter. For the nodules <10 mm in diameter, HAP-MDCT identified 47, Lipiodol CT detected 27 (chi2 = 11.3, P = 0.005<0.01, HAP-MDCT vs Lipiodol CT) and DSA detected 16 (chi2 = 9.09, P = 0.005<0.01 vs Lipiodol CT and chi2 = 29.03, P = 0.005<0.01vs HAP-MDCT). However, six nodules <10 mm in diameter were detected only by Lipiodol CT. |
2 |
| 38. Gandhi S, Iannitti DA, Mayo-Smith WW, Dupuy DE. Technical report: Lipiodol-guided computed tomography for radiofrequency ablation of hepatocellular carcinoma. Clin Radiol 2006;61:888-91. |
Review/Other-Tx |
N/A |
No abstract available. |
N/A |
4 |
| 39. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology. 2010;138(1):52-64. |
Observational-Tx |
291 patients |
To assess clinical outcomes of patients treated with intra-arterial Y-90 microspheres. |
A total of 526 treatments were administered (mean, 1.8; range, 1–5). Toxicities included fatigue (57%), pain (23%), and nausea/vomiting (20%); 19% exhibited grade 3/4 bilirubin toxicity. The 30-day mortality rate was 3%. Response rates were 42% and 57% based on WHO and EASL criteria, respectively. The overall TTP was 7.9 months (95% CI, 6–10.3). Survival times differed between patients with Child-Pugh A and B disease (A, 17.2 months; B, 7.7 months; P=.002). Patients with Child-Pugh B disease who had portal vein thrombosis survived 5.6 months (95% CI, 4.5–6.7). Baseline age; sex; performance status; presence of portal hypertension; tumor distribution; levels of bilirubin, albumin, and AFP; and WHO/EASL response rate predicted survival. |
2 |
| 40. Mazzaferro V, Sposito C, Bhoori S, et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study. Hepatology 2013;57:1826-37. |
Observational-Tx |
52 patients |
To assess the ef?cacy and safety of Y90RE—as for variations in TTP and overall survival (OS)—in a prospective cohort of intermediate and advanced HCC: namely, in a population of patients with well-compensated cirrhosis and cancer, associated or not with tumoral invasion of the portal system. |
Fifty-eight treatments were performed on 52 patients. The median follow-up was 36 months. The median TTP was 11 months with no significant difference between portal vein thrombosis (PVT) versus no PVT (7 versus 13 months). The median OS was 15 months (95% confidence interval [CI], 12-18 months) with a nonsignificant trend in favor of non-PVT versus PVT patients (18 versus 13 months). Five complete responses occurred (9.6%), and the 2 year-progression rate was 62%. Objective response was 40.4%, whereas the disease control rate (78.8%) significantly affected survival (responders versus nonresponders: 18.4% versus 9.1%; P = 0.009). Tumor response significantly correlated with absorbed dose in target lesions (r = 0.60, 95% CI, 0.41-0.74, P < 0.001) and a threshold of 500 Gy predicted response (area under the curve, 0.78). Mortality at 30-90 days was 0%-3.8%. Various grades of reduction in liver function occurred within 6 months in 36.5% of patients, with no differences among stages. On multivariate analysis, tumor response was the sole variable affecting TTP (P < 0.001) and the second affecting survival (after Child-Pugh class). |
2 |
| 41. Titano J, Voutsinas N, Kim E. The Role of Radioembolization in Bridging and Downstaging Hepatocellular Carcinoma to Curative Therapy. Semin Nucl Med 2019;49:189-96. |
Review/Other-Tx |
N/A |
To discuss how radioembolization applications combine to augment the treatment options available to hepatocellular carcinoma patients both within and beyond transplantation criteria. |
N/A |
4 |
| 42. Lewandowski RJ, Gabr A, Abouchaleh N, et al. Radiation Segmentectomy: Potential Curative Therapy for Early Hepatocellular Carcinoma. Radiology 2018;287:1050-58. |
Observational-Tx |
70 patients with solitary HCC |
To report long-term outcomes of radiation segmentectomy (RS) for early hepatocellular carcinoma (HCC). |
Seventy patients were treated with RS over 14 years. Sixty-three patients (90%) showed response by using EASL criteria, of which 41 (59%) showed complete response. Fifty patients (71%) achieved response by using WHO criteria, of which 11 (16%) achieved complete response. Response rates at 6 months were 86% and 49% by using EASL and WHO criteria, respectively. Median time to progression was 2.4 years (95% confidence interval: 2.1, 5.7), with 72% of patients having no target lesion progression at 5 years. Median overall survival was 6.7 years (95% confidence interval: 3.1, 6.7); survival probability at 1, 3, and 5 years was 98%, 66%, and 57%, respectively. Overall survival probability at 1, 3, and 5 years was 100%, 82%, and 75%, respectively, in patients with baseline tumor size less than or equal to 3 cm (n = 45) and was significantly longer than in patients with tumors greater than 3 cm (P = .026). |
2 |
| 43. Vouche M, Habib A, Ward TJ, et al. Unresectable solitary hepatocellular carcinoma not amenable to radiofrequency ablation: multicenter radiology-pathology correlation and survival of radiation segmentectomy. Hepatology 2014;60:192-201. |
Observational-Tx |
102 patients |
To assess the efficacy (response, radiology-pathology correlation, survival) of radiation segmentectomy in solitary HCC not amenable to RFA or resection. |
In all, 102 patients were included in this study. mRECIST complete response (CR), partial response (PR), and stable disease (SD) were 47/99 (47%), 39/99 (39%), and 12/99 (12%), respectively. Median time-to-disease-progression was 33.1 months. In all, 33/102 (32%) patients were transplanted with a median (interquartile range [IQR]) time-to-transplantation of 6.3 months (3.6-9.7). Pathology revealed 100% and 50-99% necrosis in 17/33 (52%) and 16/33 (48%), respectively. Median overall survival was 53.4 months. Univariate analysis demonstrated a survival benefit for Eastern Cooperative Oncology Group (ECOG) 0 patients. In the multivariate model, age <65, ECOG 0, and Child-Pugh A were characteristics associated with longer survival. |
2 |
| 44. Riaz A, Gates VL, Atassi B, et al. Radiation segmentectomy: a novel approach to increase safety and efficacy of radioembolization. International journal of radiation oncology, biology, physics 2011;79:163-71. |
Observational-Tx |
84 patients with HCC treated with (90)Y radioembolization |
To describe a technique of segmental radioembolization for the treatment of patients with unresectable hepatocellular carcinoma (HCC). |
The median treatment volume was 110 cm(3). The median radiation-naïve liver volume was 1403 cm(3). The median dose delivered to the segment(s) assuming uniform distribution was 521 Gy. Taking into account tumor hypervascularity (nonuniform distribution), the median dose delivered to the tumor and normal infused hepatic volume was 1214 Gy and 210 Gy, respectively. Response by size and necrosis guidelines was seen in 59% and 81% of patients. Grade 3/4 biochemical toxicities were observed in 8 patients (9%). Median time to progression was 13.6 months (95% confidence interval, 9.3-18.7 months); median survival was 26.9 months (95% confidence interval, 20.5-30.2 months). |
3 |
| 45. Gabr A, Abouchaleh N, Ali R, et al. Comparative study of post-transplant outcomes in hepatocellular carcinoma patients treated with chemoembolization or radioembolization. Eur J Radiol. 93:100-106, 2017 Aug. |
Observational-Tx |
172 HCC patients who underwent OLT after being treated with LDTs |
To analyze long-term outcomes in patients bridged/downstaged to orthotopic liver transplantation (OLT) by transarterial chemoembolization (TACE) or yttrium-90 radioembolization (Y90) for hepatocellular carcinoma (HCC). |
Time-to-OLT was longer in the Y90 group (Y90: 6.5 months; TACE: 4.8 months; p=0.02). With a median post-OLT follow-up of 26.1 months (IQR: 11.1-49.7), tumor recurrence was found in 6/79 (8%) TACE and 8/93 (9%) Y90 patients. Time-to-recurrence was 26.6 (CI: 7.0-49.5) and 15.9 months (CI: 7.8-46.8) for TACE and Y90, respectively (p=0.48). RFS (Y90: 79 months; TACE: 77 months; p=0.84) and OS (Y90: 57% alive at 100 months; TACE: 84.2 months; p=0.57) were similar. 54/155 patients (Y90: 29; TACE: 25) were downstaged to UNOS T2 or less. RFS hazard ratios for patients downstaged to =T2 versus those that were not were 0.6 (CI: 0.33-1.1) and 1.7 (CI: 0.9-3.1) respectively (p=0.13). 17/155 patients (Y90: 8; TACE: 9) that were >T2 were downstaged to UNOS T2 or less (within transplant criteria). Distribution (unilobar/bilobar), AFP, and pre-transplant UNOS stage affected RFS on univariate analyses. |
2 |
| 46. Kulik LM, Atassi B, van Holsbeeck L, et al. Yttrium-90 microspheres (TheraSphere) treatment of unresectable hepatocellular carcinoma: downstaging to resection, RFA and bridge to transplantation. J Surg Oncol. 2006;94(7):572-586. |
Observational-Tx |
150 patients |
To present the clinical data of 35 patients with T3 unresectable HCC that were treated with Y-90 with the specific intent of downstaging to resection, RFA candidate, United Network for Organ Sharing (UNOS) stage T2 or liver transplantation. |
19/34 patients (56%) were successfully downstaged from T3 to T2 following treatment. 11/34 (32%) patients treated were downstaged to target lesions measuring =3.0 cm. 23/35 (66%) were downstaged to either T2 status, lesion <3.0 cm (RFA candidate), or resection. 17/34 (50%) had an objective tumor response by WHO criteria. 8 patients (23%) were successfully downstaged and underwent OLT following treatment. 1, 2, and 3-year survival was 84%, 54%, and 27%, respectively. Median survival by Kaplan-Meier analysis for the entire cohort was 800 days. These data suggest that intra-arterial Y-90 microspheres can be used as a bridge to transplantation, surgical resection, or RFA. |
3 |
| 47. Salem R, Gabr A, Riaz A, et al. Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience. Hepatology 2018;68:1429-40. |
Observational-Tx |
1,000 patients with HCC treated with TARE |
To present overall survival (OS) outcomes in a 1,000-patient cohort acquired over a 15-year period. |
All treatments were outpatient, with a median one treatment per patient. Five hundred six (51%) were CP A, 450 (45%) CP B, and 44 (4%) CP C. Two hundred sixty-three (26%) patients were BCLC A, 152 (15%) B, 541 (54%) C, and 44 (4%) D. Three hundred sixty-eight (37%) were UNOS T1/T2, 169 (17%) T3, 147 (15%) T4a, 223 (22%) T4b, and 93 (9%) N/M. In CP A patients, censored OS for BCLC A was 47.3 (confidence interval [CI], 39.5-80.3) months, BCLC B 25.0 (CI, 17.3-30.5) months, and BCLC C 15.0 (CI, 13.8-17.7) months. In CP B patients, censored OS for BCLC A was 27 (CI, 21-30.2) months, BCLC B 15.0 (CI, 12.3-19.0) months, and BCLC C 8.0 (CI, 6.8-9.5) months. Forty-nine (5%) and 110 (11%) patients developed grade 3/4 albumin and bilirubin toxicities, respectively. |
2 |
| 48. Parikh ND, Waljee AK, Singal AG. Downstaging hepatocellular carcinoma: A systematic review and pooled analysis. Liver Transpl 2015;21:1142-52. |
Review/Other-Tx |
13 studies (950 patients) |
To characterize rates of successful downstaging to within Milan criteria and post-LT recurrence and survival among patients who underwent downstaging. |
We performed a systematic literature review using the MEDLINE and Embase databases from January 1996 through March 2015 and a search of national meeting abstracts from 2010 to 2014. Rates of downstaging success (defined as a decrease of tumor burden to within Milan) and post-LT recurrence with 95% confidence intervals (CIs) were calculated. Prespecified subgroup analyses were conducted by treatment modality, study design, and patient characteristics. Thirteen studies (n = 950 patients) evaluating downstaging success had a pooled success rate of 0.48 (95% CI, 0.39-0.58%). In subgroup analyses, there was no significant difference comparing transarterial chemoembolization (TACE) versus transarterial radioembolization (TARE; P = 0.51), but there were higher success rates in prospective versus retrospective studies (0.68 versus 0.44; P < 0.001). The 12 studies (n = 320 patients) evaluating post-LT HCC recurrence had a pooled recurrence rate of 0.16 (95% CI, 0.11-0.23). There was no significant difference in recurrence rates between TACE and TARE (P = 0.33). Post-LT survival could not be aggregated because of heterogeneity in survival data reporting. Current data have heterogeneity in baseline tumor burden, waiting time, downstaging protocols, and treatment response assessments. There are also notable limitations including inconsistent reporting of inclusion criteria, downstaging protocols, and outcome assessment criteria. |
4 |
| 49. Bharadwaz A, Bak-Fredslund KP, Villadsen GE, et al. Combination of radiofrequency ablation with transarterial chemoembolization for treatment of hepatocellular carcinoma: experience from a Danish tertiary liver center. Acta Radiol. 57(7):844-51, 2016 Jul. |
Observational-Tx |
18 patients with RFA+TACE; 18 patients with TACE (control) |
To study the effectiveness of combination therapy with RFA and TACE compared to that of TACE alone in a Scandinavian tertiary liver cancer center. |
Each group consisted of 14 patients with cirrhosis and four without. There were no significant differences between the groups regarding age, gender, tumor characteristics, causes of cirrhosis, levels of bilirubin, creatinine, prothrombin time, Child Pugh score, or World Health Organization (WHO) performance status. The median survival of patients in the RFA + TACE combination group was 586 days compared to 296 days in the control group. The difference was not statistically significant (P = 0.26). However, when we stratified the data for cirrhosis and WHO performance status, patients in the combination group had significantly better survival (P = 0.024). |
2 |
| 50. Iezzi R, Pompili M, La Torre MF, et al. Radiofrequency ablation plus drug-eluting beads transcatheter arterial chemoembolization for the treatment of single large hepatocellular carcinoma. Dig Liver Dis. 47(3):242-8, 2015 Mar. |
Observational-Tx |
40 cirrhotic patients with single HCC |
To evaluate the effectiveness of the single-step combined therapy with radiofrequency ablation and drug-eluting beads transarterial chemoembolization in single hepatocellular carcinoma (HCC) larger than 3cm.To compare the results with those obtained in a matched population treated with drug-eluting beads transarterial chemoembolization alone. |
Complete response at 1 month was achieved in 32/40 tumours (80%). During follow-up, complete response was maintained in 25 patients (25/40, 62.5%), and this rate was higher in Group A (69.6% vs 53%, p=0.008). The group treated with combined therapy showed a significantly lower 2-year recurrence (48.1% vs 78.2%, p<0.001) and significantly higher survival (91.1% vs 60.6%, p=0.004) than the group treated with chemoembolization alone. |
1 |
| 51. Lu Z, Wen F, Guo Q, Liang H, Mao X, Sun H. Radiofrequency ablation plus chemoembolization versus radiofrequency ablation alone for hepatocellular carcinoma: a meta-analysis of randomized-controlled trials. Eur J Gastroenterol Hepatol. 2013;25(2):187-194. |
Meta-analysis |
7 randomized-controlled trials |
A meta-analysis of randomized-controlled trials was performed to provide greater clarity on whether RFA plus TACE was more effective than RFA alone for HCC. |
Meta-analysis showed that RFA plus TACE significantly improved the survival rates of patients with HCC at 1 and 3 years (for the 1-survival rate, fixed-effects OR=2.71, 95% CI 1.65–4.43, P<0.0001; for the 3-survival rate, fixed-effects OR=2.27, 95% CI 1.57–3.27, P<0.0001) compared with RFA alone. There was no difference in terms of major complications (fixed-effects OR=1.26, 95% CI 0.33–4.77, P=0.73). Subgroup analyses by tumor size showed that RFA plus TACE significantly improved the survival rates at 1, 3, and 5 years compared with RFA alone in patients with HCC larger than 3 cm; however, there was no advantage of TACE plus RFA over RFA alone for patients with HCC >3 cm. The quality of evidence was high for the 1-year survival rate, the 3-year survival rate, and major complications. No evidence of publication bias was observed. |
M |
| 52. Peng ZW, Zhang YJ, Liang HH, Lin XJ, Guo RP, Chen MS. Recurrent hepatocellular carcinoma treated with sequential transcatheter arterial chemoembolization and RF ablation versus RF ablation alone: a prospective randomized trial. Radiology 2012;262:689-700. |
Experimental-Tx |
139 patients with recurrent HCC (69 sequential treatment group, 70 ablation group) |
To compare prospectively the effects of radiofrequency (RF) ablation after transcatheter arterial chemoembolization (TACE) with those of RF ablation alone in the treatment of recurrent hepatocellular carcinoma (HCC). |
The 1-, 3-, and 5-year overall survival rates were 94%, 69%, and 46 %, respectively, for the sequential treatment group and 82%, 47%, and 36% for the RF ablation group ( P = .037). The corresponding recurrence-free survival rates were 80%, 45%, and 40% for the sequential treatment group and 64%, 18%, and 18% for the ablation group ( P = .005). At subgroup analyses, the overall survival for the sequential treatment group was better than that for the RF ablation group for patients with tumor recurrence 1 year or less after initial treatment ( P = .004) and those with tumors measuring 3.1–5.0 cm ( P = .002) but not for those with tumor recurrence more than 1 year after initial treatment ( P = .421) and those with tumors 3.0 cm or smaller ( P = .478). The recurrence-free survival in the sequential treatment group was better than that in the RF ablation group for patients with tumors measuring 3.1–5.0 cm ( P , .001) but not for those with tumors 3.0 cm or smaller ( P = .204). For recurrence-free survival, there was no signifi cant difference between the two groups for patients with tumor recurrence 1 year or less or more than 1 year after initial treatment ( P = .020 and P = .111, respectively). Logistic regression analysis showed that treatment allocation and the interval between initial treatment and tumor recurrence were signifi cant prognostic factors for overall survival, whereas the interval between initial treatment and tumor recurrence, treatment allocation, and tumor size were signifi cant prognostic factors for recurrence-free survival. |
1 |
| 53. Sheta E, El-Kalla F, El-Gharib M, et al. Comparison of single-session transarterial chemoembolization combined with microwave ablation or radiofrequency ablation in the treatment of hepatocellular carcinoma: a randomized-controlled study. European journal of gastroenterology & hepatology 2016;28:1198-203. |
Experimental-Tx |
50 patients with nonresectable single-lesion HCC (divided into 3 groups) |
To compare combination treatment with radiofrequency or MWA, followed by transarterial chemoembolization, and performed in a single session. |
Group A included 20 patients treated by transcatheter hepatic arterial chemoembolization, group B included 20 patients treated by radiofrequency thermal ablation combined with transcatheter arterial chemoembolization, and group C included 10 patients treated by MWA combined with transcatheter arterial chemoembolization. The combined treatments were performed in a single session, with the ablation performed first. The total success rate in this study at 6 months following the procedure was 50% in group A, 70% in group B, and 80% in group C. Major complications were recorded in 22% of patients. The number of complications was the highest in group A. |
1 |
| 54. Yao FY, Kerlan RK, Jr., Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 2008;48:819-27. |
Observational-Tx |
61 patients with tumor stage exceeding T2 criteria |
To report longer follow-up data in a larger cohort. The primary study endpoints are intention-to-treat survival, dropout, and post-transplantation tumor recurrence after down-staging. We also examine factors that may influence response to down-staging treatments. |
A minimum observation period of 3 months after down-staging was required before OLT. Tumor down-staging was successful in 43 patients (70.5%). Thirty-five patients (57.4%) had received OLT, including two who had undergone live-donor liver transplantation. Treatment failure was observed in 18 patients (29.5%), primarily due to tumor progression. In the explant of 35 patients who underwent OLT, 13 had complete tumor necrosis, 17 met T2 criteria, and five exceeded T2 criteria. The Kaplan-Meier intention-to-treat survival at 1 and 4 years after down-staging were 87.5% and 69.3%, respectively. The 1-year and 4-year posttransplantation survival rates were 96.2% and 92.1%, respectively. No patient had HCC recurrence after a median posttransplantation follow-up of 25 months. The only factor predicting treatment failure was pretreatment alphafetoprotein > 1,000 ng/mL. |
2 |
| 55. Yin X, Zhang L, Wang YH, et al. Transcatheter arterial chemoembolization combined with radiofrequency ablation delays tumor progression and prolongs overall survival in patients with intermediate (BCLC B) hepatocellular carcinoma. BMC Cancer 2014;14:849. |
Observational-Tx |
211 patients with intermediate stage HCC |
To evaluate the effectiveness of radiofrequency ablation in patients with intermediate (BCLC B) stage hepatocellular carcinoma who underwent transcatheter arterial chemoembolization. |
The complete tumor necrosis rate after treatment was 76.9% in combination group vs. 46.5% in transcatheter arterial chemoembolization alone group (P = 0.02). The major complication rate was 1.8% in combination group vs. 2.6% in transcatheter arterial chemoembolization alone group. Follow-up observation showed that the total tumor control rate was 74.5% in combination group versus 54.5% in transcatheter arterial chemoembolization alone group (P < 0.001). The 1-, 3- and 5-year survival rates in combination group were significantly higher than those in TACE alone group (P = 0.01). |
2 |
| 56. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 67(1):358-380, 2018 01. |
Review/Other-Dx |
N/A |
To present official recommendations of the American Association for the Study of Liver Diseases (AASLD) on the surveillance, diagnosis, and treatment of hepatocellular carcinoma (HCC) occurring in the setting of adults with cirrhosis. |
No abstract available. |
4 |
| 57. Mazzaferro V, Bhoori S, Sposito C, et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl 2011;17 Suppl 2:S44-57. |
Review/Other-Tx |
N/A |
No abstract available. |
No abstract available. |
4 |
| 58. Zhang NN, Lu W, Cheng XJ, Liu JY, Zhou YH, Li F. High-powered microwave ablation of larger hepatocellular carcinoma: evaluation of recurrence rate and factors related to recurrence. Clin Radiol 2015;70:1237-43. |
Observational-Tx |
45 patients (60 lesions) |
To evaluate the safety and efficacy of high-powered (80-100 W) percutaneous microwave ablation (MWA) at a frequency of 2450±10 MHz for treating larger hepatocellular carcinoma (HCC) and to predict the risk factors of local recurrence after high-powered MWA. |
The complete ablation rates were 82.61% for the first ablation and 100% for the second ablation for 3-5 cm lesions. The complete ablation rates were 64.29% (82.61% versus 64.29%, p=0.037) for the first ablation and 85.71% (100% versus 85.71%, p=0.055) for the second ablation for 5-8 cm lesions. Local recurrence was observed in 11 out of the 45 (24.44%) successfully treated patients. The 1-year and 2-year survival rates were 95.56% (43/45) and 86.67% (39/45), respectively. No procedure-related mortality was observed and no major bleeding, liver rupture, or liver abscesses occurred. Univariate analysis showed that a positive correlation existed between the number of lesions (p=0.022), proximity to the risk area (p=0.001), pre-ablation alpha-fetoprotein (AFP) levels (p=0.025), hepatitis B virus (HBV)-DNA replication (p=0.027) and local recurrence. Multivariate analysis identified HBV-DNA (p=0.031) and proximity to the risk area (p=0.039) as the independent prognosis factors causing postoperative HCC local recurrence. |
2 |
| 59. Medhat E, Abdel Aziz A, Nabeel M, et al. Value of microwave ablation in treatment of large lesions of hepatocellular carcinoma. J Dig Dis 2015;16:456-63. |
Observational-Tx |
26 patients with large HCC lesions |
To evaluate microwave ablation in the treatment of large HCC (5-7 cm) and to assess its effect on local tumor progression, prognostic outcome and patients' survival. |
Complete ablation was achieved in 19/26 (73.1%). Local tumor progression was recorded in five treated lesions (19.2%). Distant tumor progression within the liver was recorded in six patients (23.1%), with a mean survival of 21.5 months. No procedure-related major complications or deaths were observed. |
2 |
| 60. Brown KT, Do RK, Gonen M, et al. Randomized Trial of Hepatic Artery Embolization for Hepatocellular Carcinoma Using Doxorubicin-Eluting Microspheres Compared With Embolization With Microspheres Alone. J Clin Oncol 2016;34:2046-53. |
Experimental-Tx |
101 patients |
To compare the outcome of embolization using microspheres alone with chemoembolization using doxorubicin-eluting microspheres. |
Between December 2007 and April 2012, 101 patients were randomly assigned: 51 to BB and 50 to LCB. Demographics were comparable: median age, 67 years; 77% male; and 22% Barcelona Clinic Liver Cancer stage A and 78% stage B or C. Adverse events occurred with similar frequency in both groups: BB, 19 of 51 patients (38%); LCB, 20 of 50 patients (40%; P = .48), with no difference in RECIST response: BB, 5.9% versus LCB, 6.0% (difference, -0.1%; 95% CI, -9% to 9%). Median PFS was 6.2 versus 2.8 months (hazard ratio, 1.36; 95% CI, 0.91 to 2.05; P = .11), and overall survival, 19.6 versus 20.8 months (hazard ratio, 1.11; 95% CI, 0.71 to 1.76; P = .64) for BB and LCB, respectively. |
1 |
| 61. Kluger MD, Halazun KJ, Barroso RT, et al. Bland embolization versus chemoembolization of hepatocellular carcinoma before transplantation. Liver Transpl. 2014;20(5):536-543. |
Observational-Tx |
25 TAE patients matched in a 1:2 ratio with TACE patients |
A retrospective, matched case-control study of patients undergoing TAE and TACE while awaiting transplantation was performed. Equivalency between treatments was hypothesized. |
The mean adjusted MELD scores at transplantation and waiting times were not significantly different between the TAE and TACE patients (MELD scores: 26 +/- 3 vs 24 +/- 3 points, P=0.12; waiting times: 13 +/- 8 vs 11 +/- 10 months, P=0.43). TAE patients (16%) were less likely than TACE patients (40%) to require 2 procedures (P=0.04). Explant tumors were completely necrotic for 36% of the TAE patients and for 26% of the TACE patients. The 3-year OS rates were 78% for the TAE patients and 74% for the TACE patients (P=0.66), and the 3-year recurrence-free survival rates were 72% for the TAE patients and 68% for the TACE patients (P=0.67). On an intention-to-treat basis, there was no significant risk of wait-list dropout associated with TAE or TACE (P=0.83). |
2 |
| 62. Maluccio MA, Covey AM, Porat LB, et al. Transcatheter arterial embolization with only particles for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2008;19(6):862-869. |
Observational-Tx |
322 patients |
Retrospective study to determine the survival of patients with HCC treated with a standardized method of transcatheter arterial embolization with small embolic particles intended to impart terminal vessel blockade, and to evaluate prognostic factors that impact OS. |
The median survival time was 21 months, with 1-, 2-, and 3-year OS rates of 66%, 46%, and 33%, respectively. In patients without extrahepatic disease or portal vein involvement by tumor, the overall 1-, 2-, and 3-year survival rates increased to 84%, 66%, and 51%, respectively. Okuda stage, extrahepatic disease, diffuse disease (=5 tumors), and tumor size were independent predictors of survival on multivariate analysis. There were 90 complications (11.9%) in 75 patients, including 8 deaths (2.5%), within 30 days of embolization. Hepatic arterial embolization with small particles to cause terminal vessel blockade is an effective treatment method for patients with unresectable HCC. These data support the hypothesis that particles alone may be the critical component of catheter-directed embolotherapy. |
2 |
| 63. Marelli L, Stigliano R, Triantos C, et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol. 2007;30(1):6-25. |
Review/Other-Tx |
9 randomized control trials |
To evaluate whether specific patient characteristics and/or radiological transarterial techniques result in better outcomes. |
Anticancer drugs were used as sole agent in 75% of cases (double 15% and triple 6%): doxorubicin (36%), cisplatin (31%), epirubicin (12%), mitoxantrone (8%), mitomycin (8%), and SMANCS (5%). Embolizing agents used were: gelatin sponge particles (71%), polyvinyl alcohol particles (8%), degradable starch microspheres (4%), and embospheres (4%). Sessions per patient were 2.5 +/- 1.5 (interval: 2 months). Objective response was 40 +/- 20%; survival rates at 1, 2, 3, and 5 years were: 62 +/- 20%, 42 +/- 17%, 30 +/- 15%, and 19 +/- 16%, respectively, and survival time was 18 +/- 9.5 months. The post-TACE complications were: acute liver failure, 7.5% (range 0%–49%); acute renal failure, 1.8% (0%–13%); encephalopathy, 1.8% (0%–16%); ascites, 8.3% (0%–52%); upper gastrointestinal bleeding; 3% (0%–22%); and hepatic or splenic abscess, 1.3% (0%–2.5%). Treatment-related mortality was 2.4% (0%–9.5%), mainly due to acute liver failure. |
4 |
| 64. Dhanasekaran R, Kooby DA, Staley CA, Kauh JS, Khanna V, Kim HS. Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC). J Surg Oncol. 2010;101(6):476-480. |
Observational-Tx |
71 consecutive patients: Group A - 45 received therapy with drug eluting beads; Group B - 26 underwent chemoembolization |
To explore long-term survival benefits of TACE and chemoembolization with doxorubicin drug eluting beads for unresectable HCC. |
Median survival from diagnosis of HCC in groups A and B were 610 (351–868) and 284 days (4–563; P=0.03), respectively. In Okuda stage I, survival in groups A and B were 501 (421–528) and 354 days (148–560, P=0.02). In Child-Pugh classes A and B, survival in groups A and B were 641 (471–810) and 323 days (161–485, P=0.002). Median survival in patients with Cancer of Liver Italian Program score =3 in groups A and B were 469 (358-581) and 373 days (195–551, P=0.03). NCI CTCAEv3 Grade 5 clinical toxicity was similar. Transcatheter therapy with drug eluting beads offers a survival advantage over conventional chemoembolization for patients with unresectable HCC. |
2 |
| 65. Huang K, Zhou Q, Wang R, Cheng D, Ma Y. Doxorubicin-eluting Bead versus Conventional Transarterial Chemoembolization for the Treatment of HCC: a Meta-Analysis. J Gastroenterol Hepatol. 2013. |
Meta-analysis |
7 clinical studies with 700 participants |
To evaluate the efficacy and safety of the 2 treatments for patients with unresectable HCC. |
Significantly better objective tumor response was found following DEB-TACE over conventional TACE (OR=1.92, 95%CI [1.34, 2.77]; P=0.0004) with relative risk difference of 0.15 [0.07, 0.24] (P=0.0003). 1-year, 2-year survival rates were statistically significant higher in DEB-TACE group compared with conventional TACE group (Peto OR, 95% CI: 0.64 [0.46, 0.89], P=0.007; 0.61 [0.47, 0.80], P=0.0003; respectively). Peto OR of 6-month and 3-year survival were 0.72 [0.46, 1.14] (P=0.16) and 0.77 [0.55, 1.06] (P=0.11) respectively; showing no difference statistically. But we could still find tendency that favors DEB-TACE group. Adverse side effects were similar in both groups and post-embolization syndrome existed most commonly. |
M |
| 66. Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33(1):41-52. |
Experimental-Tx |
212 patients |
To compare conventional TACE with TACE with drug-eluting bead for the treatment of cirrhotic patients with HCC. |
The primary endpoint was tumor response (EASL) at 6 months following independent, blinded review of MRI studies. The drug-eluting bead group showed higher rates of complete response, objective response, and disease control compared with the conventional TACE group (27% vs 22%, 52% vs 44%, and 63% vs 52%, respectively). The hypothesis of superiority was not met (one-sided P=0.11). However, patients with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease showed a significant increase in objective response (P=0.038) compared to conventional TACE. Drug-eluting bead was associated with improved tolerability, with a significant reduction in serious liver toxicity (P<0.001) and a significantly lower rate of doxorubicin-related side effects (P=0.0001). TACE with drug-eluting bead and doxorubicin is safe and effective in the treatment of HCC and offers a benefit to patients with more advanced disease. |
1 |
| 67. Martin R, Geller D, Espat J, et al. Safety and efficacy of trans arterial chemoembolization with drug-eluting beads in hepatocellular cancer: a systematic review. Hepatogastroenterology. 2012;59(113):255-260. |
Review/Other-Tx |
N/A |
To compare current conventional TACE to the drug eluting beads loaded with doxorubicin device in the treatment of HCC. |
The drug eluting beads loaded with doxorubicin are an effective therapy with a favorable pharmacokinetic profile with significantly less systemic doxorubicin exposure when compared to conventional TACE. The drug eluting beads loaded with doxorubicin had a significant (P<0.05) advantage in objective response in the more advanced patients (defined as Child-Pugh B, ECOG 1, recurrent disease and bilobar disease; P=0.038) and overall disease control in the more advanced patients (P=0.026). The drug eluting beads loaded with doxorubicin was also found to have a highly significant (P<0.01) advantage in the reduction of doxorubicin associated side effects (P=0.0001) in all patients. |
4 |
| 68. Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359(9319):1734-1739. |
Experimental-Tx |
903 patients assessed; 112 patients included |
Randomized controlled trial to assess the survival benefits of regularly repeated arterial embolization (gelatin sponge) or chemoembolization (gelatin sponge plus doxorubicin) compared with conservative treatment. |
25/37 patient’s assigned embolization. 21/40 assigned chemoembolization, and 25/35 assigned conservative treatment died. Survival probabilities at 1 year and 2 years were 75% and 50% for embolization; 82% and 63% for chemoembolization, and 63% and 27% for control (chemoembolization vs control P=0.009). Chemoembolization induced objective responses sustained for at least 6 months in 35% (14) of cases, and was associated with a significantly lower rate of portal-vein invasion than conservative treatment. Treatment allocation was the only variable independently related to survival (OR 0.45 [95% CI, 0.25–0.81], P=0.02). Chemoembolization improved survival of stringently selected patients with unresectable HCC. |
1 |
| 69. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35(5):1164-1171. |
Experimental-Tx |
79 total patients: 40 chemoembolization; 39 controls |
Randomized trial to assess the efficacy of transarterial Lipiodol chemoembolization in patients with unresectable HCC. |
Chemoembolization resulted in a marked tumor response, and the actuarial survival was significantly better in the chemoembolization group (1 year, 57%; 2 years, 31%; 3 years, 26%) than in the control group (1 year, 32%; 2 years, 11%; 3 years, 3%; P=.002). When adjustments for baseline variables that were prognostic on univariate analysis were made with a multivariate Cox model, the survival benefit of chemoembolization remained significant (relative risk of death, 0.49; 95% CI, 0.29-0.81; P=.006). Although death from liver failure was more frequent in patients who received chemoembolization, the liver functions of the survivors were not significantly different. In conclusion, in Asian patients with unresectable HCC, transarterial Lipiodol chemoembolization significantly improves survival and is an effective form of treatment. |
1 |
| 70. Doffoel M, Bonnetain F, Bouche O, et al. Multicentre randomised phase III trial comparing Tamoxifen alone or with Transarterial Lipiodol Chemoembolisation for unresectable hepatocellular carcinoma in cirrhotic patients (Federation Francophone de Cancerologie Digestive 9402). Eur J Cancer 2008;44:528-38. |
Experimental-Tx |
61 patients-Tamoxifen group and 62 patients-TACE group |
To compare the effects of the combination of Transarterial Lipiodol Chemoembolisation (TACE) and tamoxifen with tamoxifen alone on overall survival and quality of life in the palliative treatment of hepatocellular carcinoma with cirrhosis. |
Baseline characteristics were similar: Child-Pugh class A: 70%, alcoholic cirrhosis: 76%, Okuda stage I: 71%, multinodular tumour: 70% and segmental portal vein thrombosis: 10%. At 2years, the overall survival was 22% and 25% in the Tamoxifen and TACE groups (P=.68), respectively. Multivariate analysis identified four independent prognostic factors for survival: alpha-fetoprotein (AFP)>400ng/mL (P=.008), abdominal pain (P=.011), hepatomegaly (P=.023) and Child-Pugh score (P=.032). The Spitzer Index level assessing the quality of life during follow-up did not differ between the two groups (P=.70). Amongst patients with stage Okuda I, the 2-year overall survival was 28% in the Tamoxifen group and 32% in the TACE group (P=.58). In this subgroup, two prognostic factors were statistically significant for survival: AFP>400ng/mL (P=.004) and Spitzer Index (P=.013) as shown by multivariable analysis. In conclusion, this study suggests that TACE improves neither the survival nor the quality of life in patients with HCC and cirrhosis. |
1 |
| 71. Pelletier G, Ducreux M, Gay F, et al. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe CHC. J Hepatol 1998;29:129-34. |
Experimental-Tx |
37 patients-lipiodol chemoembolization group, 36 patients-tamoxifen group |
To assess the efficacy of lipiodol chemoembolization in patients with unresectable hepatocellular carcinoma. |
The 37 patients in the lipiodol chemoembolization group received 104 courses (median 3 per patient). By 1 September 1996, 58 patients had died: 30 in the lipiodol chemoembolization group and 28 in the tamoxifen group. There was no difference in survival between the two groups (p=0.77). The relative risk of death in the lipiodol chemoembolization plus tamoxifen group as compared to the tamoxifen group was 0.92 (95% confidence interval 0.55 to 1.56). At 1 year, survival was 51% and 55%, respectively. An objective tumoral response was more frequently observed in the lipiodol chemoembolization group than in the tamoxifen group (24 versus 5.5%, respectively, p=0.046). Lipiodol chemoembolization caused two deaths and induced signs of liver failure in 51% of the patients assigned to this treatment. |
1 |
| 72. Groupe d'Etude et de Traitement du Carcinome H. A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. N Engl J Med 1995;332:1256-61. |
Experimental-Dx |
47 patients-chemoembolization
group, 45 patients-conservative management group |
To test the hypothesis that Lipiodol chemoembolization would result in a 75 percent rate of survival after eight months, as compared with the 50 percent rate associated with conservative management by comparing four courses of Lipiodol chemoembolization with conservative treatment in patients who had unresectable hepatocellular carcinoma but not severe liver disease. |
The study was stopped in December, 1992, after a sequential analysis showed the lack of the expected benefit from chemoembolization. As of October 1, 1994, 39 of the 50 patients assigned to chemoembolization and 40 of the 46 patients assigned to conservative management had died. Twenty-six patients assigned to chemoembolization received all four courses of treatment. There was no significant difference in survival between the two groups, although there was a trend favoring the chemoembolization group (estimated relative risk of death in the control group, 1.4; 95 percent confidence interval, 0.9 to 2.2; P = 0.13). The comparison of survival between the two groups was not substantially changed by adjustments for differences in base-line and prognostic characteristics (adjusted relative risk, 1.3; 95 percent confidence interval, 0.8 to 2.1; P = 0.31). At one year, the estimated survival rates were 62 percent in the chemoembolization group (95 percent confidence interval, 48.6 to 75.4 percent) and 43.5 percent in the conservative-management group (95 percent confidence interval, 29.2 to 57.8 percent). In the chemoembolization group, tumor growth, as assessed by tumor size and serum alpha-fetoprotein concentration, was reduced and the incidence of portal obstruction was lower than in the conservative-management group. Liver failure occurred after 47 courses of treatment in 30 patients assigned to chemoembolization. |
1 |
| 73. Martin RC, Joshi J, Robbins K, et al. Hepatic intra-arterial injection of drug-eluting bead, irinotecan (DEBIRI) in unresectable colorectal liver metastases refractory to systemic chemotherapy: results of multi-institutional study. Ann Surg Oncol. 2011;18(1):192-198. |
Observational-Tx |
55 patients |
To evaluate the efficacy of hepatic arterial sulfonate hydrogel microsphere (drug-eluting beads), irinotecan preloaded therapy in metastatic CRC refractory to systemic chemotherapy. |
The median number of drug-eluting bead, irinotecan treatments was 2 (range 1–5), median treatment dose was 100 mg (range 100–200 mg), with total hepatic treatment of 200 mg (range 200–650 mg), with 86% of treatments performed as lobar infusion and 30% of patients treated with concurrent simultaneous chemotherapy. Adverse events occurred in 28% of patients with median grade of 2 (range 1–3) with no deaths at 30 days post procedure. Response rates were 66% at 6 months and 75% at 12 months. OS in these patients was 19 months, with PFS of 11 months. |
2 |
| 74. Cescon M, Cucchetti A, Ravaioli M, Pinna AD. Hepatocellular carcinoma locoregional therapies for patients in the waiting list. Impact on transplantability and recurrence rate. J Hepatol. 2013;58(3):609-618. |
Review/Other-Tx |
N/A |
To review HCC locoregional therapies for patients in the waiting list. |
With a persistent scarcity of organ donors, neo-adjuvant treatments can help identify patients with different probabilities of cancer progression, and consequently balance the priority of HCC and non-HCC candidates through revised additional scores for HCC. |
4 |
| 75. Chapman WC, Majella Doyle MB, Stuart JE, et al. Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation. Ann Surg. 2008;248(4):617-625. |
Observational-Tx |
202 patients referred for transplant |
To evaluate outcomes of downstaging patients with advanced (American liver tumor study group stage III/IV) HCC with TACE to allow eligibility for OLT. |
18/76 (23.7%) patients had adequate downstaging to qualify for OLT under the Milan criteria. By Response Evaluation Criteria in Solid Tumors, 27/76 (35.5%) patients had a partial response, 22/76 (29%) had stable disease, and 27/76 (35.5%) had progressive disease. 17/76 (22.4%) patients who met other qualifications underwent OLT after successful downstaging (13/38 stage III; 4/38 stage IV). Explant review demonstrated 28 identifiable tumors in which post-TACE necrosis was greater than 90% in 21 (75%). At a median of 19.6 months (range 3.6-104.7), 16/17 (94.1%) patients who underwent OLT are alive. Selected patients with stage III/IV HCC can be downstaged to Milan criteria with TACE. Importantly, patients who are successfully downstaged and transplanted have excellent midterm DFS and OS, similar to stage II HCC. |
2 |
| 76. Chua TC, Liauw W, Saxena A, et al. Systematic review of neoadjuvant transarterial chemoembolization for resectable hepatocellular carcinoma. Liver Int. 2010;30(2):166-174. |
Review/Other-Tx |
3,927 patients: 1,293 underwent neoadjuvant TACE; 18 studies; 3 randomized trials; 15 observational trials |
To identify published studies of TACE administered preoperatively as a neoadjuvant treatment for resectable HCC. |
The median DFS in the TACE and non-TACE group ranged from 10 to 46 and 8 to 52 months. 67% of studies reporting similar DFS between groups despite higher extent of tumor necrosis from the resected specimens indicating a higher rate of pathological response (partial TACE 27%–72% vs non-TACE 23%–52%). Complete TACE 0%–28% vs non-TACE 0%), with no difference in surgical morbidity and mortality outcome. No conclusion could be drawn with respect to OS. Both randomized and non-randomized trials suggest the use of TACE preoperatively as a neoadjuvant treatment in resectable HCC is a safe and efficacious procedure with high rates of pathological responses. However, it does not appear to improve DFS. |
4 |
| 77. De Giorgio M, Vezzoli S, Cohen E, et al. Prediction of progression-free survival in patients presenting with hepatocellular carcinoma within the Milan criteria. Liver Transpl. 2010;16(4):503-512. |
Observational-Tx |
206 patients |
To retrospectively analyze the risk of progression of HCC (death or progression outside United Network of Organ Sharing stage T2) in a consecutive cohort of prospectively followed patients that presented within the Milan criteria. |
Progression occurred in 84 patients, and 8 patients died. Risk factors for the time to disease progression (death or progression beyond T2) were analyzed in 170 patients with a complete data set. Risk factors with the strongest relationship to progression included tumor diameter and tumor persistence/recurrence after local therapy (HRs of 1.51 and 2.75, respectively, when transplanted patients were censored at the time of transplantation and HRs of 1.53 and 3.66, respectively, when transplantation was counted as an event; P=0.0001). To evaluate the current MELD exception, we compared the expected progression rate with our observed progression rate in 133 stage T2 patients. The current policy resulted in a large overestimation of the progression rate for T2 HCC and an unsatisfactory performance [Harrell's concordance index (C index) = 0.60, transplant censored; C index = 0.55, transplant as progression]. Risk factors for progression that were identified by univariate analysis were considered for multivariate analysis. With these risk factors and the patients’ natural MELD scores, an adjusted model applicable to organ allocation was generated, and this decreased the discrepancy between the expected and observed progression rates (C index = 0.66, transplant censored; C index = 0.69, transplant as progression). |
2 |
| 78. Heckman JT, Devera MB, Marsh JW, et al. Bridging locoregional therapy for hepatocellular carcinoma prior to liver transplantation. Ann Surg Oncol. 2008;15(11):3169-3177. |
Observational-Tx |
123 total patients: 50 patients received therapy (20 TACE, 16 Y-90,13 RFA, 3 resections); 73 patients transplanted without therapy |
To examine locoregional therapies and their effect on survival compared with transplantation alone. |
Median list time was 28 days (range 2–260 days) in group I, and 24 days (range 1–380 days) in group II. Median time from therapy to OLT was 3.8 months (range 9 days to 68 months). 12 patients (24%) were successfully downstaged (8 TACE, 2 Y-90, 2 RFA/resection). Overall 1-, 3-, and 5-year survival were 81%, 74%, and 74%, respectively. Survival was not statistically significantly different between the 2 groups (P=0.53). The 12 patients downstaged did not have a significant difference in survival as compared with the patients who received therapy but did not respond or the patients who were transplanted without therapy (P=0.76). Report addresses locoregional therapy for HCC as a bridge to transplant. There was no statistical difference in OS between patients treated and those not treated prior to transplant. Locoregional therapy is a safe tool for patients on the transplant list, does not impact survival, and can downstage selected patients to allow life-saving liver transplantation. |
2 |
| 79. Lesurtel M, Mullhaupt B, Pestalozzi BC, Pfammatter T, Clavien PA. Transarterial chemoembolization as a bridge to liver transplantation for hepatocellular carcinoma: an evidence-based analysis. Am J Transplant. 2006;6(11):2644-2650. |
Review/Other-Tx |
N/A |
To assess the impact of TACE as a neoadjuvant therapy prior to OLT for HCC. |
There is currently no convincing evidence that TACE allows to expand the current selection criteria for OLT, nor that TACE decreases dropout rates on the waiting list (grade C). However, TACE does not increase the risk for postoperative complications (grade C). There is insufficient evidence that TACE offers any benefit when used prior to OLT, neither for early nor for advanced HCC. Well-designed randomized controlled trials are needed to define the role of TACE in OLT patients. |
4 |
| 80. Maddala YK, Stadheim L, Andrews JC, et al. Drop-out rates of patients with hepatocellular cancer listed for liver transplantation: outcome with chemoembolization. Liver Transpl. 2004;10(3):449-455. |
Review/Other-Tx |
54 patients |
To analyze drop-out rates on the waiting list for patients with HCC. |
Between January 1994 and August 2001, 54 patients with HCC were listed for liver transplantation. Patients underwent chemoembolization prior to liver transplantation, and were assessed every 3 months for disease progression until LT. Two patients were stage T1, 45 patients were stage T2, and 7 patients were stage T3 at time of first chemoembolization. Median time was 211 days (range 28–1,099 days) for patients that were eventually transplanted. 8 patients were removed from the list. Cumulative probability of drop out on the waiting list, assessed by Kaplan-Meier analysis, was 15% and 25% at 6 and 12 months, respectively. There were no significant differences in age, gender, initial tumor stage, or serum AFP levels in those who eventually underwent liver transplantation vs those who dropped out. |
4 |
| 81. Habib A, Desai K, Hickey R, Thornburg B, Lewandowski R, Salem R. Locoregional therapy of hepatocellular carcinoma. [Review]. Clin Liver Dis. 19(2):401-20, 2015 May. |
Review/Other-Tx |
N/A |
To discuss key data regarding the effectiveness of locoregional therapies in treating these patients |
No results provided in abstract. |
4 |
| 82. Victor DW, 3rd, Monsour HP, Jr., Boktour M, et al. Outcomes of Liver Transplantation for Hepatocellular Carcinoma Beyond the University of California San Francisco Criteria: A Single-center Experience. Transplantation 2020;104:113-21. |
Observational-Tx |
220 patients with HCC |
To determine the survival of patients outside UCSF criteria, inside UCSF but outside Milan, and inside Milan criteria. |
Two hundred twenty HCC patients were transplanted, 138 inside Milan, 23 inside UCSF, and 59 beyond UCSF criteria. Patient survival was equivalent at 1, 3, or 5 years despite pathologic tumor size. Waiting time to transplantation was not significantly different at an average of 344 days. In patients outside UCSF, tumor recurrence was equivalent to Milan and UCSF criteria recipients who waited >9 months from LRT. Although tumor recurrence was more likely in outside of UCSF patients (3% versus 9% versus 15%; P = 0.02), recurrence-free survival only trended toward significance among the groups (P = 0.053). |
2 |
| 83. Xu LF, Sun HL, Chen YT, et al. Large primary hepatocellular carcinoma: transarterial chemoembolization monotherapy versus combined transarterial chemoembolization-percutaneous microwave coagulation therapy. J Gastroenterol Hepatol 2013;28:456-63. |
Observational-Tx |
136 patients with unresectable large HCC |
To evaluate the clinical benefits of transarterial chemoembolization (TACE) monotherapy or TACE combined with percutaneous microwave coagulation therapy (PMCT) and the long-term survival rate of patients with large primary hepatocellular carcinoma (HCC) treated with these techniques. |
All patients successfully underwent TACE alone or TACE with PMCT with no serious complications. The median survival time was 13 months (range, 3-84 months) for the TACE group and 25 months (range, 7-96 months) for the TACE-PMCT group. The 1-year, 3-year, and 5-year OS rates were 62.5%, 17.5%, and 5.0% in the TACE group, respectively. In contrast, in the TACE-PMCT group, the 1-year, 3-year, and 5-year OS rates were 87.5%, 50.0%, and 10.0%, respectively. This difference was statistically significant between the groups (P < 0.001). |
2 |
| 84. Liu C, Liang P, Liu F, et al. MWA combined with TACE as a combined therapy for unresectable large-sized hepotocellular carcinoma. Int J Hyperthermia 2011;27:654-62. |
Observational-Tx |
34 patients (18 TACE, 16 percutaneous ablation & microwave ablation after TACE) |
To evaluate the efficacy and safety of microwave ablation combined with transcatheter arterial chemoembolization for unresectable large-sized hepotocellular carcinoma. |
Follow-up images showed reduction in tumor size was seen in 21 patients (61.7%; 7/18 in group 1, 14/16 in group 2), survival rates were better in group 2 than in group 1 (P = 0.003), during the median follow-up of 8 months, 10 patients (62.5%) remained alive in group 2, whereas 6 patients (33.3%) remained alive in group 1, the mean survival times were 6.13 months ± 0.83 in group 1 and 11.61 months ± 1.59 in group 2. |
2 |
| 85. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. |
Experimental-Tx |
602 patients |
To evaluate the effectiveness of sorafenib in advanced HCC. |
Median OS was 10.7 months in the sorafenib group and 7.9 months in the placebo group (HR in the sorafenib group, 0.69; 95% CI, 0.55 to 0.87; P<0.001). There was no significant difference between the 2 groups in the median time to symptomatic progression (4.1 months vs 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). 7 patients in the sorafenib group (2%) and 2 patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. In patients with advanced HCC, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. |
1 |
| 86. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. The Lancet. Oncology 2009;10:25-34. |
Experimental-Tx |
271 patients (150=experimental group, 76=placebo group) |
To assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. |
271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% CI 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; p=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.79]; p=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation. |
1 |
| 87. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020;382:1894-905. |
Observational-Tx |
336 patients (atezolizumab–bevacizumab group); 165 patients (sorafenib group) |
To determine the safety and efficacy of atezolizumab plus bevacizumab as compared with sorafenib in patients with unresectable hepatocellular carcinoma who had not previously received systemic therapy |
The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent. |
1 |
| 88. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56-66. |
Experimental-Tx |
379 patients-regorafenib group, 194 patients-placebo group |
To assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. |
Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50-0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1-12·1) for regorafenib versus 7·8 months (6·3-8·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand-foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group. |
1 |
| 89. Kelley RK, Ryoo BY, Merle P, et al. Second-line cabozantinib after sorafenib treatment for advanced hepatocellular carcinoma: a subgroup analysis of the phase 3 CELESTIAL trial. ESMO Open 2020;5. |
Experimental-Tx |
33 patients-cabozantinib group, 164-placebo group |
To evaluate cabozantinib in patients who had received sorafenib as the only prior systemic therapy. |
Of patients who had received only prior sorafenib, 331 were randomised to cabozantinib and 164 to placebo; 136 patients had received sorafenib for <3 months, 141 for 3 to <6 months and 217 for =6 months. Cabozantinib improved OS relative to placebo in the overall second-line population who had received only prior sorafenib (median 11.3 vs 7.2 months; HR=0.70, 95% CI 0.55 to 0.88). This improvement was maintained in analyses by prior sorafenib duration with longer duration generally corresponding to longer median OS-median OS 8.9 vs 6.9 months (HR=0.72, 95% CI 0.47 to 1.10) for prior sorafenib <3 months, 11.5 vs 6.5 months (HR=0.65, 95% CI 0.43 to 1.00) for 3 to <6 months and 12.3 vs 9.2 months (HR=0.82, 95% CI 0.58 to 1.16) for =6 months. Cabozantinib also improved PFS in all duration subgroups. Safety data were consistent with the overall study population. |
1 |
| 90. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. The Lancet. Oncology 2018;19:940-52. |
Observational-Tx |
104 patients |
To assess the efficacy and safety of pembrolizumab in this patient population. |
Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11-26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. |
2 |
| 91. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017;389:2492-502. |
Observational-Tx |
48 patients in dose-escalation phase, 214 patients in dose-expansion phase |
To assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. |
Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. |
2 |
| 92. Bova V, Miraglia R, Maruzzelli L, Vizzini GB, Luca A. Predictive factors of downstaging of hepatocellular carcinoma beyond the Milan criteria treated with intra-arterial therapies. Cardiovasc Intervent Radiol 2013;36:433-9. |
Observational-Tx |
48 patients |
To analyze the clinical results in patients suitable for liver transplantation with hepatocellular carcinoma (HCC) who exceeded Milan criteria, which underwent intra-arterial therapies (IAT), to determine predictive factors of successful downstaging. |
Nineteen patients (39 %) had their tumors successfully downstaged; 29 patients (61 %) did not. Multivariate analysis showed that AFP level <100 ng/mL and 3-year calculated survival probability using the Metroticket calculator were the only independent predictors of successful downstaging (p < 0.023 and p < 0.049 respectively). |
2 |
| 93. DuBay DA, Sandroussi C, Kachura JR, et al. Radiofrequency ablation of hepatocellular carcinoma as a bridge to liver transplantation. HPB (Oxford). 2011;13(1):24-32. |
Observational-Tx |
170 patients: RFA (n= 77) and No Treatment groups (n= 93) |
To measure the effect of RFA on time to drop-off in HCC-listed patients. |
The primary effectiveness of RFA was 83% (complete radiographic response). RFA was associated with a longer median wait time to transplant (9.5 vs 5 months). Tumor-specific drop-off events were equivalent between RFA (21%) and No Treatment (12%) groups (P=0.11). Controlling for wait time, there was no difference in overall (P=0.56) or tumor-specific drop-off (P=0.94). Furthermore, there were no differences in 5-year OS or tumor-free survivals from list date or transplant. Using multivariate analysis, the likelihood of receiving a transplant and patient survivals were associated with tumor characteristics (AFP, tumor number and size) and not with bridge therapy or waiting time. |
2 |
| 94. Graziadei IW, Sandmueller H, Waldenberger P, et al. Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome. Liver Transpl 2003;9:557-63. |
Observational-Tx |
48 patients |
To evaluate the efficacy of preoperative TACE to impede tumor progression in patients fulfilling current selection criteria while waiting for OLT.To analyze the efficacy of TACE in reducing tumor size before OLT as a possibility of expanding selection criteria and its impact on long-term survival in patients with advanced-stage HCC. |
Forty-eight patients met the selection criteria and were eligible for this study. Seven patients are still on the waiting list; 41 underwent OLT. None of these patients had to be removed from the list because of tumor progression after a mean waiting time of 178 days (23 patients > or =180 days). The 1-, 2-, and 5-year intention-to-treat survival was 98%, 98%, and 94%. The outcome after OLT was also excellent with 1-, 2-, and 5-year survival rates of 98%, 98%, and 93%. Tumor recurrence occurred only in 1 patient (2.4%). Fifteen patients with advanced-stage HCC were included in this study. Three developed a tumor progression and had to be removed from the list (20% dropout rate). Despite tumor reduction before OLT, these patients had a significantly less favorable outcome in the intention-to-treat analysis as well as in the posttransplantation survival. Tumor recurrence was seen in 30% of patients after OLT. In conclusion, TACE followed by OLT is associated with an excellent outcome in selected patients. |
2 |
| 95. Lau WY, Lai EC. The current role of radiofrequency ablation in the management of hepatocellular carcinoma: a systematic review. Ann Surg. 2009;249(1):20-25. |
Review/Other-Tx |
N/A |
To review the current status of RFA in the management of HCC. |
The evidence in the medical literature showed RFA was more effective than other local ablative therapies, and supported its use in the treatment of unresectable small HCC, recurrent small HCC, and as bridging therapy before liver transplantation, and as a primary treatment in competition with partial hepatectomy for resectable small HCC. |
4 |
| 96. Ravaioli M, Grazi GL, Piscaglia F, et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am J Transplant 2008;8:2547-57. |
Observational-Tx |
177 patients with HCC |
To assess outcome of patients down-staged was compared to that of Milan criteria after liver transplantation and since the first evaluation according to an intention-to-treat principle. |
From 2003 to 2006, 177 patients with HCC were considered for transplantation: the transplantation rate was comparable between the Milan and down-staging groups: 88/129 cases (68%) versus 32/48 cases (67%), respectively. At a median follow-up of 2.5 years after transplantation, the 1 and 3 years’ disease-free survival rates were comparable: 80% and 71% in theMilan group versus 78% and 71% in the down-staging. The actuarial intention-to-treat survival was 27/48 patients (56.3%) in the down-staging and 81/129 cases (62.8%) in the Milan group, p= n.s. The proposed down-staging criteria provide a comparable outcome to the conventional criteria. |
2 |
| 97. Sun PL, Chen CL, Hsu SL, et al. The significance of transarterial embolization for advanced hepatocellular carcinoma in liver transplantation. Transplant Proc 2004;36:2295-6. |
Review/Other-Tx |
12 cirrhotic patients with HCC |
To evaluate the effect of pretransplantation TAE for treatment of advanced HCC. |
The explanted livers from the 12 patients who had undergone TAE were noted to have extensive tumor necrosis. The pathological specimens at LT showed downstaging of the HCC, which allowed those six patients to meet the Milan criteria. The overall 1- and 2-year survival rates were 92% and 73%, respectively. The overall 1- and 2-year disease-free survival rates were 92% and 73%, respectively. One death unrelated to liver disease at 2 years after LT was noted in the downgraded group. One patient of the initially eligible group developed lung metastasis at 6 months and died at 12 months after LT. |
4 |
| 98. Baumann BC, Wei J, Plastaras JP, et al. Stereotactic Body Radiation Therapy (SBRT) for Hepatocellular Carcinoma: High Rates of Local Control With Low Toxicity. Am J Clin Oncol 2018;41:1118-24. |
Observational-Tx |
37 patients |
To test if SBRT can achieve excellent local control (LC) with acceptable toxicity treating HCC lesions, even in advanced cirrhosis. |
Pre-SBRT mean CP was 6.4 (range, A5 to C11). Nine (24%) had CP>/=B8. Thirty-one of 33 patients (93%) had prior liver-directed therapy (median 2). Seventeen (40%) had solitary lesions. Median lesion diameter was 2.7 cm (range, 1.1 to 5.6). Median follow-up was 14 months (range, 2 to 45). There was 1 local failure (multifocal HCC with 3 prior transarterial chemoembolization). LC, freedom from liver progression, and overall survival at 12 months was 95%, 66%, 87% in the full cohort, and 100%, 76%, 93% for patients with solitary lesions. Four had grade 3 toxicity (ascites [n=2]/gastrointestinal bleed [n=1]/capsular pain [n=1]). Eight of 9 CP>/=B8 patients had no grade >/=3 hepatic toxicity. |
3 |
| 99. Jang WI, Bae SH, Kim MS, et al. A phase 2 multicenter study of stereotactic body radiotherapy for hepatocellular carcinoma: Safety and efficacy. Cancer 2020;126:363-72. |
Review/Other-Tx |
74 patients |
To evaluate the safety and efficacy of SBRT for patients with HCC in a hepatitis B virus-endemic area. |
. One patient experienced radiation-induced liver disease with acute grade >/=3 toxicity 1 month after SBRT. In addition, 1 patient had a grade 3 esophageal ulcer with stenosis 5 months after SBRT. The actuarial rate of treatment-related severe toxicity at 1 year was 3%. The pre-SBRT and post-SBRT EGD findings were not significantly different among the 57 evaluable patients who underwent EGD. The 2-year and 3-year local control rates were 97% and 95%, respectively. The progression-free and overall survival rates were 48% and 84% at 2 years, respectively, and 36% and 76% at 3 years, respectively. |
4 |
| 100. Miyayama S, Yamashiro M, Ikuno M, Okumura K, Yoshida M. Ultraselective transcatheter arterial chemoembolization for small hepatocellular carcinoma guided by automated tumor-feeders detection software: technical success and short-term tumor response. Abdom Imaging 2014;39:645-56. |
Observational-Tx |
81 patients (155 HCCs) |
To analyze the technical success and tumor response of ultraselective transcatheter arterial chemoembolization (TACE) for small hepatocellular carcinoma (HCC) using automated tumor-feeders detection (AFD) software. |
One-hundred and twenty-eight (82.6%) tumors were classed as grade A, 17 (11%) as grade B, and 10 (6.5%) as grade C. AFD software could identify 211 (85.4%) of 247 tumor-feeders but not 36 (14.6%). Eighteen (7.9%) were false positive. The tumor response of target lesions in each patient was complete response (CR) in 49 (69%) patients, partial response (PR) in 19 (26.8%), and stable disease (SD) in 3 (4.2%). The overall tumor response was CR in 39 (54.9%) patients, PR in 15 (21.2%), SD in 1 (1.4%), and progressive disease in 16 (22.5%). |
2 |
| 101. Miyayama S, Matsui O, Yamashiro M, et al. Ultraselective transcatheter arterial chemoembolization with a 2-f tip microcatheter for small hepatocellular carcinomas: relationship between local tumor recurrence and visualization of the portal vein with iodized oil. J Vasc Interv Radiol 2007;18:365-76. |
Observational-Tx |
72 patients (123 tumors) |
To retrospectively evaluate the relationship between local tumor recurrence and iodized oil deposition in the portal vein by using ultraselective transcatheter arterial chemoembolization (TACE) for small hepatocellular carcinoma. |
To retrospectively evaluate the relationship between local tumor recurrence and iodized oil deposition in the portal vein by using ultraselective transcatheter arterial chemoembolization (TACE) for small hepatocellular carcinoma. |
2 |
| 102. Carr BI, Kondragunta V, Buch SC, Branch RA. Therapeutic equivalence in survival for hepatic arterial chemoembolization and yttrium 90 microsphere treatments in unresectable hepatocellular carcinoma: a two-cohort study. Cancer. 2010;116(5):1305-1314. |
Observational-Tx |
691 patients |
To evaluate the therapeutic equivalence in survival for hepatic arterial chemoembolization and Y-90 microsphere treatments in unresectable HCC. |
OS was slightly better in the Y-90 group compared with the TACE group (median survival, 11.5 months vs 8.5 months). However, the selection criteria indicated a small but significant bias toward milder disease in the Y-90 group. By using stratification into a 3-tier model with patients dichotomized according to bilirubin levels <1.5 mg/dL, the absence of portal vein thrombosis, and low AFP plasma levels (<25 U/dL), an analysis of survival in clinical subgroups indicated that the 2 treatments resulted in similar survival. In addition, patients who had portal vein thrombosis or high AFP levels also had similar survival in both treatment groups. Given the current evidence of therapeutic equivalence in survival, Y-90 and TACE appeared to be equivalent regional therapies for patients with unresectable, nonmetastatic HCC. |
2 |
| 103. Kooby DA, Egnatashvili V, Srinivasan S, et al. Comparison of yttrium-90 radioembolization and transcatheter arterial chemoembolization for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2010;21(2):224-230. |
Observational-Tx |
71 patients: 44 chemoembolization; 27 radioembolization |
To compare the effectiveness and toxicity of transcatheter arterial chemoembolization and Y-90-labeled microspheres in patients with unresectable HCC. |
Progressive disease at 3 months was observed in 16 (36%) of the 44 patients treated with chemoembolization and 9 (33%) of the 27 patients treated with radioembolization (P=not statistically significant). The median OS was similar for both groups (6 months with chemoembolization vs 6 months with radioembolization, P=.7). Grade 3 or higher toxicity was observed in 24/71 patients (34%). Tumor multifocality, vascular invasion, and hepatitis C seropositivity were independently associated with worse survival, whereas method of treatment was not. In this single-center study, preliminary evidence suggests that chemoembolization and radioembolization provided similar effectiveness and toxicity in patients with unresectable HCC. |
2 |
| 104. Lance C, McLennan G, Obuchowski N, et al. Comparative analysis of the safety and efficacy of transcatheter arterial chemoembolization and yttrium-90 radioembolization in patients with unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2011;22(12):1697-1705. |
Observational-Tx |
73 patients |
To compare retrospectively the safety and efficacy of Y-90 radioembolization with the safety and efficacy of chemoembolization in patients with unresectable HCC. |
This study included 73 patients with HCC who underwent index embolization with radioembolization (n = 38; 52.1%) or chemoembolization (n = 35; 47.9%). The 2 patient populations were similar in terms of demographics, etiology of cirrhosis, functional status, tumor characteristics, Child-Pugh class, previous liver-directed therapy, and number of patients with bilirubin > 2.0 mg/dL. There was no significant difference in survival between the radioembolization (median 8.0 months) and chemoembolization (median 10.3 months) cohorts (P=.33). Postembolization syndrome was significantly more severe in patients who underwent chemoembolization, which led to increased total hospitalization rates in these patients. The rates of other complications and rehospitalization were similar between groups. Increased age, Child-Pugh class B, hepatitis seropositivity, bilobar tumor distribution, tumor vascular invasion, and presence of extrahepatic metastases were associated with reduced patient survival. |
2 |
| 105. Lobo L, Yakoub D, Picado O, et al. Unresectable Hepatocellular Carcinoma: Radioembolization Versus Chemoembolization: A Systematic Review and Meta-analysis. [Review]. Cardiovasc Intervent Radiol. 39(11):1580-1588, 2016 Nov. |
Review/Other-Tx |
5 studies (533 patients) |
To compare clinical outcomes of both the techniques. |
The search strategy yielded 172 studies, five met selection criteria and included 553 patients with unresectable HCC, 284 underwent TACE and 269 underwent TARE. Median ages were 63 and 64 years for TACE and TARE, respectively. Meta-analysis showed no statistically significant difference in survival for up to 4 years between the two groups (HR = 1.06; 95 % CI 0.81-1.46, p = 0.567). TACE required at least one day of hospital stay compared to TARE which was mostly an outpatient procedure. TACE had more post-treatment pain than TARE (RR = 0.51, 95 % CI 0.36-0.72, p < 0.01), but less subjective fatigue (RR = 1.68, 95 % CI 1.08-2.62, p < 0.01). There was no difference between the two groups in the incidence of post-treatment nausea, vomiting, fever, or other complications. In addition, there was no difference in partial or complete response rates between the two groups. |
4 |
| 106. Moreno-Luna LE, Yang JD, Sanchez W, et al. Efficacy and safety of transarterial radioembolization versus chemoembolization in patients with hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2013;36(3):714-723. |
Observational-Tx |
61 TARE group; 55 TACE group |
To compare the outcomes and safety of TARE vs TACE in patients with unresectable HCC |
Complete tumor response was more common after TARE (12%) than after TACE (4%) (P=0.17). When complete response was combined with partial response and stable disease, there was no difference between TARE and TACE. Median survival did not differ between the 2 groups (15.0 months for TARE and 14.4 months for TACE; P=0.47). 2-year survival rates were 30% for TARE and 24% for TACE. TARE patients received fewer treatments (P<0.001). 59 (97%) TARE patients received outpatient treatment. In contrast, 53 (98%) TACE patients were hospitalized for =1 day (P<0.001). Compared with TACE, TARE was more likely to induce fatigue (P=0.003) but less likely to cause fever (P=0.02). |
2 |
| 107. Salem R, Lewandowski RJ, Kulik L, et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2011;140(2):497-507 e492. |
Observational-Tx |
463 patients |
A comparative effectiveness analysis between Y-90 and chemoembolization was performed in patients with HCC. |
Abdominal pain and increased transaminase activity were more frequent following chemoembolization (P<.05). There was a trend that patients treated with radioembolization had a higher response rate than with chemoembolization (49% vs 36%, respectively, P=.104). Although TTP was longer following radioembolization than chemoembolization (13.3 months vs 8.4 months, respectively, P=.046), median survival times were not statistically different (20.5 months vs 17.4 months, respectively, P=.232). Among patients with intermediate-stage disease, survival was similar between groups that received chemoembolization (17.5 months) and radioembolization (17.2 months, P=.42). |
2 |
| 108. Sangro B, Carpanese L, Cianni R, et al. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 2011;54:868-78. |
Observational-Tx |
325 patients |
To evaluate the main prognostic factors driving survival after radioembolization using yttrium-90-labeled resin microspheres in patients with hepatocellular carcinoma at eight European centers. |
In total, 325 patients received a median activity of 1.6 GBq between September 2003 and December 2009, predominantly as whole-liver (45.2%) or right-lobe (38.5%) infusions. Typically, patients were Child-Pugh class A (82.5%), had underlying cirrhosis (78.5%), and had good Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 0-1; 87.7%), but many had multinodular disease (75.9%) invading both lobes (53.1%) and/or portal vein occlusion (13.5% branch; 9.8% main). Over half had advanced Barcelona Clinic Liver Cancer (BCLC) staging (BCLC C, 56.3%) and one quarter had intermediate staging (BCLC B, 26.8%). The median overall survival was 12.8 months (95% confidence interval, 10.9-15.7), which varied significantly by disease stage (BCLC A, 24.4 months [95% CI, 18.6-38.1 months]; BCLC B, 16.9 months [95% CI, 12.8-22.8 months]; BCLC C, 10.0 months [95% CI, 7.7-10.9 months]). Consistent with this finding , survival varied significantly by ECOG status, hepatic function (Child-Pugh class, ascites, and baseline total bilirubin), tumor burden (number of nodules, alpha-fetoprotein), and presence of extrahepatic disease. When considered within the framework of BCLC staging, variables reflecting tumor burden and liver function provided additional prognostic information. The most significant independent prognostic factors for survival upon multivariate analysis were ECOG status, tumor burden (nodules >5), international normalized ratio >1.2, and extrahepatic disease. Common adverse events were: fatigue, nausea/vomiting, and abdominal pain. Grade 3 or higher increases in bilirubin were reported in 5.8% of patients. All-cause mortality was 0.6% and 6.8% at 30 and 90 days, respectively. |
2 |
| 109. Gabr A, Kallini JR, Gates VL, et al. Same-day 90Y radioembolization: implementing a new treatment paradigm. Eur J Nucl Med Mol Imaging. 43(13):2353-2359, 2016 Dec. |
Observational-Tx |
78 patients |
To assess the feasibility of conducting pretreatment mesenteric angiography, coil embolization, 99mTc macroaggregated albumin (99mTc-MAA) scintigraphy, and 90Y radioembolization treatment in a single, same-day, combined outpatient encounter. |
All patients underwent same-day angiography, 99mTc-MAA scintigraphy and 90Y radioembolization. Of the 78 patients, 16 received multiple segmental treatments to both lobes, 44 received treatment to the right lobe, and 18 received treatment to the left lobe. The median dose was 106 Gy. The median number of 90Y vials needed was two (range one to six). The median in-room time was 160 min (75 - 250 min). The residential status of the patients was as follows, 18 % (14/78) were local residents, 55 % (43/78) traveled from outside the city limits, 18 % (14/78) were from out-of-state, and 9 % (7/78) were resident abroad. Of the 78 patients, 61 (77 %) had hepatocellular carcinoma, and 17 (22 %) had liver metastases. The median lung dose was 3.5 Gy. |
3 |
| 110. Gates VL, Marshall KG, Salzig K, Williams M, Lewandowski RJ, Salem R. Outpatient single-session yttrium-90 glass microsphere radioembolization. J Vasc Interv Radiol 2014;25:266-70. |
Observational-Tx |
14 patients |
To investigate the feasibility of yttrium-90 ((90)Y) glass microsphere radioembolization (including angiography, lung shunt assessment, and treatment) as a single-session, outpatient procedure. |
All patients successfully underwent planning angiography with administration of (99m)Tc-MAA and (90)Y radioembolization as a single-session treatment. There were no reportable or recordable medical events; treatment was carried out to the desired dose in all cases. The mean total procedure time was 2.70 hours ± 0.72 (range, 1.63-3.97 h). |
3 |
| 111. Zhong JH, Ke Y, Gong WF, et al. Hepatic resection associated with good survival for selected patients with intermediate and advanced-stage hepatocellular carcinoma. Ann Surg 2014;260:329-40. |
Observational-Tx |
1259 patients with BCLC stage B/C HCC |
To assess the therapeutic value of hepatic resection (HR) and compared it with TACE for treating Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC patients in the Guangxi province of China, where the population shows the highest HCC incidence rates in the world. |
Among our patient sample, the 90-day mortality rate in the HR group was 3.1%. HR provided a survival benefit over TACE at 1, 3, and 5 years (88% vs 81%, 62% vs 33%, and 39% vs 16%, respectively; all P < 0.001). Propensity scoring and subgroup analyses based on tumor size, tumor number, presence or absence of macrovascular invasion, and portal hypertension (PHT) also showed that HR was associated with better longterm survival than TACE. All 36 studies identified in our literature search reported that HR is associated with good long-term survival and low morbidity. Multivariate analyses revealed that alpha-fetoprotein more than or equal to 400 ng/mL, diabetes mellitus, macrovascular invasion, and PHT are independent predictors of poor prognosis in patients with BCLC stage B/C HCC. |
2 |
| 112. Andreou A, Bahra M, Schmelzle M, et al. Predictive factors for extrahepatic recurrence of hepatocellular carcinoma following liver transplantation. Clin Transplant. 30(7):819-27, 2016 Jul. |
Observational-Tx |
364 patients with HCC |
To identify factors associated with the development of extrahepatic tumor recurrence in patients who underwent LT for HCC in a high-volume transplant center aiming to establish prediction tools for such high-risk patients. |
Three hundred and sixty-four patients underwent LT for HCC. After a median follow-up time of 78 months, 93 patients (25%) were diagnosed with a recurrence. Median time to recurrence was 19 months. Recurrence was located exclusively in the liver in 19 cases (20%), and 74 patients (80%) had extrahepatic recurrence. Factors associated with extrahepatic recurrence in multivariate analysis included HCC beyond the Milan criteria (p < 0.0001) and the presence of macrovascular tumor invasion (p = 0.035). In patients with HCC beyond the Milan criteria who developed a recurrence (N = 73), macrovascular invasion was the only positive predictor of extrahepatic recurrence in multivariate analysis (p < 0.0001). In patients with HCC within the Milan criteria who recurred after LT (N = 20), DNA-index >1.5 (p = 0.013) was the only predictive factor for extrahepatic recurrence in multivariate analysis. Conclusions: Advanced HCC beyond the Milan criteria and the presence of macrovascular invasion are associated with an increased risk for extrahepatic recurrence and are currently considered as relative contraindications to LT. In patients with HCC within the Milan criteria, the DNA-index represents a valuable prognostic marker for the development of extrahepatic recurrence and may support the selection of patients for intensified postoperative tumor surveillance. |
2 |
| 113. Finkenstedt A, Vikoler A, Portenkirchner M, et al. Excellent post-transplant survival in patients with intermediate stage hepatocellular carcinoma responding to neoadjuvant therapy. Liver Int 2016;36:688-95. |
Observational-Tx |
174 HCC patients |
To determine stage-dependent HCC recurrence and overall survival rates in transplant recipients and the impact of response to neoadjuvant treatment on outcome. |
Of 174 HCC patients, 48 (28%) were BCLC intermediate stage. Neoadjuvant treatment was performed in 94% of patients. When patients were stratified according to tumour stage, no significant difference in overall survival was observed between very early or early and intermediate stage. When stratified according to treatment response, patients with complete response had a 5-year overall survival of 87%, which was significantly higher than in patients with progressive disease (62%, P = 0.02). HCC recurrence in intermediate stage patients without disease progression after neoadjuvant treatment was equal to that in patients with very early or early stage HCC. Tumour grading, histological and radiological evidence of vascular invasion, but not tumour stage were identified as independent risk factors for HCC recurrence. |
2 |
| 114. Xue TC, Xie XY, Zhang L, Yin X, Zhang BH, Ren ZG. Transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus: a meta-analysis. BMC Gastroenterol 2013;13:60. |
Meta-analysis |
8 studies (1601 HCC patients) |
To evaluate the efficacy and safety of transarterial chemoembolization (TACE) for treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). |
Eight controlled trials involving 1601 HCC patients were included. TACE significantly improved the 6-month (HR, 0.41; 95% CI: 0.32–0.53; z, 6.28; p = 0.000) and 1-year (HR, 0.44; 95% CI: 0.34–0.57; z, 6.22; p = 0.000) overall survival of patients with PVTT compared with conservative treatment. Subgroup analyses showed that TACE was significantly effective in HCC patients whether with main portal vein (MPV) obstruction or with segmental PVTT. Fatal complications were rare, even in patients with MPV obstruction. Temporary liver decompensation and postembolization syndrome occurred frequently. However, they could be treated successfully with conservative treatment. |
Good |
| 115. Niu ZJ, Ma YL, Kang P, et al. Transarterial chemoembolization compared with conservative treatment for advanced hepatocellular carcinoma with portal vein tumor thrombus: using a new classification. Med Oncol |
Observational-Tx |
150 patients (115 = TACE group, 35 = conservative group) |
To compare the survival benefit of transarterial chemoembolization (TACE) with conservative treatment for patients with advanced hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT), furthermore, to reveal which PVTT types benefit from TACE treatment. |
We performed survival analysis of the two treatment groups and then stratified by a new classification of PVTT that was divided into four types. Overall survival was significantly better in the TACE group than in the conservative group (8.67 months vs. 1.4 months, P<0.001). The overall median survival for types I-IV PVTT were 12.0, 8.3, 5.0, and 2.43 months (P<0.01). On subgroup analysis of PVTT, the median survival in the TACE group compared with conservative group for type I, II, III, and IV PVTT was 19.0 months versus 4.0 months, 11.0 months versus 1.43 months, 7.1 months versus 1.3 months, and 4.0 months versus 1.0 months, respectively (P<0.01). The TACE group had significantly better survival than the conservative group for different extent of PVTT. |
2 |
| 116. Luo J, Guo RP, Lai EC, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a prospective comparative study. Ann Surg Oncol 2011;18:413-20. |
Observational-Tx |
164 patients (TACE group = 84; conservative group = 80) |
To determine whether TACE confers a survival benefit to patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT), and to uncover prognostic factors. |
A total of 164 patients were recruited for the study (TACE group, n = 84; conservative treatment group, n = 80). Patients in the TACE group received a mean of 1.9 (range, 1–5) TACE sessions. The overall median survival for all patients was 5.2 months, and the 12- and 24-month overall survival rates were 18.3% and 5.6%, respectively. The 12- and 24-month overall survival rates for the TACE and conservative groups were 30.9%, 9.2%, and 3.8%, 0%, respectively. The TACE group had significantly better survivals than the conservative group (P \ 0.001). On subgroup analysis of segmental and major PVTT, the TACE group also had significantly better survivals (P = 0.002, P = 0.002). The treatment type, PVTT extent, tumor size, and serum bilirubin were independent prognostic factors of survival on multivariate analysis. |
1 |
| 117. Yoon SM, Ryoo BY, Lee SJ, et al. Efficacy and Safety of Transarterial Chemoembolization Plus External Beam Radiotherapy vs Sorafenib in Hepatocellular Carcinoma With Macroscopic Vascular Invasion: A Randomized Clinical Trial. JAMA Oncol 2018;4:661-69. |
Experimental-Tx |
90 patients (45 = sorafenib group, 45 = TACE plus RT group) |
To evaluate the efficacy and safety of TACE plus RT compared with sorafenib for patients with hepatocellular carcinoma and macroscopic vascular invasion. |
Of the 90 patients (median age, 55 years; range, 33-82 years), 77 were men and 13 were women. All patients had portal vein invasion of hepatocellular carcinoma and Child-Pugh class A liver function. The median maximal tumor diameter was 9.7 cm. Most patients (71 [78.9%]) had multiple lesions. At week 12, the progression-free survival rate was significantly higher in the TACE-RT group than the sorafenib group (86.7% vs 34.3%; P?<?.001). The TACE-RT group showed a significantly higher radiologic response rate than the sorafenib group at 24 weeks (15 [33.3%] vs 1 [2.2%]; P?<?.001), a significantly longer median time to progression (31.0 vs 11.7 weeks; P?<?.001), and significantly longer overall survival (55.0 vs 43.0 weeks; P?=?.04). Curative surgical resection was conducted for 5 patients (11.1%) in the TACE-RT group owing to downstaging. No patients in the TACE-RT group discontinued treatment owing to hepatic decompensation. |
1 |
| 118. Valle JW, Furuse J, Jitlal M, et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann Oncol 2014;25:391-8. |
Meta-analysis |
2 studies |
To perform a meta-analysis of individual patient-level data of these studies to establish the effect of CisGem versus Gem on progression-free survival (PFS), overall survival (OS) and carried out exploratory subgroup analyses. |
CisGem demonstrates a significant improvement in PFS [hazard ratio (HR)=0.64, 95% confidence interval (CI) 0.53-0.76, P<0.001] and OS (HR=0.65, 95% CI 0.54-0.78, P<0.001) over Gem. This effect is most marked among patients with good performance status (PS 0-1): HR for PFS is 0.61 (95% CI 0.51-0.74), P<0.001 and OS HR=0.64 (95% CI 0.53-0.77), P<0.001. CisGem resulted in improved PFS and OS for intra- and extra-hepatic cholangiocarcinomas and gallbladder cancer. The treatment effect between UK and Japanese patients was consistent with respect to OS (HR=0.65, 95% CI 0.53-0.79 and 0.65, 95% CI 0.42-1.03, respectively); with similar OS in the combination arms (median 11.7 and 11.1 months, respectively). Subgroups least likely to benefit included patients with ampullary tumours and poor performance status (PS2). |
Inadequate |
| 119. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281. |
Experimental-Tx |
410 patients |
To conduct a randomized trial to compare cisplatin plus gemcitabine with gemcitabine alone. |
After a median follow-up of 8.2 months and 327 deaths, the median OS was 11.7 months among the 204 patients in the cisplatin-gemcitabine group and 8.1 months among the 206 patients in the gemcitabine group (HR, 0.64; 95% CI, 0.52 to 0.80; P<0.001). The median PFS was 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group (P<0.001). In addition, the rate of tumor control among patients in the cisplatin-gemcitabine group was significantly increased (81.4% vs 71.8%, P=0.049). Adverse events were similar in the 2 groups, with the exception of more neutropenia in the cisplatin-gemcitabine group; the number of neutropenia-associated infections was similar in the 2 groups. |
1 |
| 120. Guro H, Kim JW, Choi Y, Cho JY, Yoon YS, Han HS. Multidisciplinary management of intrahepatic cholangiocarcinoma: Current approaches. [Review]. Surg Oncol. 26(2):146-152, 2017 Jun. |
Review/Other-Tx |
N/A |
To discuss multidisciplinary approaches necessary in improving the outcomes of intrahepatic cholangiocarcinoma (ICC). |
No results available. |
4 |
| 121. Squires MH, Cloyd JM, Dillhoff M, Schmidt C, Pawlik TM. Challenges of surgical management of intrahepatic cholangiocarcinoma. [Review]. Expert rev. gastroenterol. hepatol.. 12(7):671-681, 2018 Jul. |
Observational-Tx |
257 patients (131 = transplant, 126 = resection) |
To compare outcomes for patients undergoing transplant versus resection at a single institution in a UNOS region with short wait times for organ availability. |
Two hundred fifty-seven patients were analyzed, of whom 131 underwent transplant and 126 underwent resection. All transplant patients met MC; 45 (36%) resection patients met MC. Median follow-up time was 30 months. Median wait time to transplant was 55 days; no patients dropped off the waitlist while awaiting an organ. |
2 |
| 122. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation. 2000;69(8):1633-1637. |
Review/Other-Tx |
207 patients |
To review results in patients who underwent liver transplantation for otherwise unresectable cholangiocarcinoma or cholangiohepatoma. |
The 1, 2, and 5-year survival estimates using life table analysis were 72%, 48%, and 23%. 51% of patients had recurrence of their tumors after transplantation and 84% of recurrences occurred within 2 years of transplantation. Survival after recurrence was rarely more than 1 year. 47% of recurrences occurred in the allograft and 30% in the lungs. Tumor recurrence, and evidence of tumor spread at the time of surgery, were negative prognostic variables. There were no positive prognostic variables. Patients with incidentally found cholangiocarcinomas did not have improved survival over patients with known or suspected tumors. A small number of patients survived for more than 5 years without recurrence. However, this group had no variable in common that would aid in the selection of similar patients in the future. |
4 |
| 123. Kim JH, Won HJ, Shin YM, Kim KA, Kim PN. Radiofrequency ablation for the treatment of primary intrahepatic cholangiocarcinoma. AJR Am J Roentgenol. 2011;196(2):W205-209. |
Observational-Tx |
13 patients |
To present the results of percutaneous RFA in patients with unresectable primary ICC. |
Technical effectiveness of RFA was achieved for 15 of the 17 tumors (88%), all <5 cm in diameter. Treatment failure occurred in 2 patients with large tumors (7 and 8 cm). After the 17 RFA sessions, 1 major complication (6%), a liver abscess, occurred 1 month later. During follow-up (median, 19.5 months; range, 3.3–82.1 months), 9 patients died and 4 remain alive. Median local PFS and OS periods were 32.2 and 38.5 months, respectively. The 1-, 3-, and 5-year survival rates were 85%, 51%, and 15%, respectively. |
2 |
| 124. Mosconi C, Cappelli A, Ascanio S, et al. Yttrium-90 microsphere radioembolization in unresectable intrahepatic cholangiocarcinoma. Fut Oncol. 13(15):1301-1310, 2017 Jun. |
Review/Other-Tx |
N/A |
To examine preliminary analyses of safety and efficacy that have been reported in some small studies [16–20], with median survival ranging from 9 to 22 months. |
No results available. |
4 |
| 125. Xu HX, Wang Y, Lu MD, Liu LN. Percutaneous ultrasound-guided thermal ablation for intrahepatic cholangiocarcinoma. Br J Radiol. 2012;85(1016):1078-1084. |
Observational-Tx |
18 patients |
To evaluate the treatment efficacy and OS of percutaneous ultrasound-guided thermal ablation by means of microwave ablation or RFA for ICC. |
Complete ablation was achieved in 23 (92.0%, 23/25) nodules (diameter, 0.7–4.3 cm; mean, 2.5 +/- 0.9 cm) and incomplete ablation was found in 2 (8.0%, 2/25) larger tumors (6.4 and 6.9 cm in diameter). No death associated with the treatment was found. The major complication rate was 5.5% (1/18). The follow-up periods ranged from 1.3 to 86.2 months (mean, 20.5 +/- 26.3 months; median, 8.7 months). OS rates for all patients at 6, 12, 36 and 60 months were 66.7%, 36.3%, 30.3% and 30.3%, respectively. By univariate analysis, the patient source (primary or recurrent case) was found to be a significant prognostic factor for OS rates (P=0.001). The patient source (P=0.001) and the number of nodules (P=0.038) were found to be significant prognostic factors for recurrence-free survival. OS rates for the primary ICC at 6, 12, 36 and 60 months were 87.5%, 75.0%, 62.5% and 62.5%, respectively. |
1 |
| 126. Han K, Ko HK, Kim KW, Won HJ, Shin YM, Kim PN. Radiofrequency ablation in the treatment of unresectable intrahepatic cholangiocarcinoma: systematic review and meta-analysis. J Vasc Interv Radiol 2015;26:943-8. |
Meta-analysis |
7 observational studies (84 patients) |
To perform a meta-analysis and systematic review of the clinical efficacy and safety of radiofrequency (RF) ablation in the treatment of intrahepatic cholangiocarcinoma (ICC). |
The pooled 1-year, 3-year, and 5-year survival rates were 82% (95% confidence interval [CI], 72%-90%), 47% (95% CI, 28%-65%), and 24% (95% CI, 11%-40%). One or 2 major complications occurred in 4 studies, and 1 patient died of liver abscess and subsequent sepsis despite treatment with percutaneous drainage and antibiotics. RF ablation is a locoregional treatment option that prolongs survival rates in patients with ICC who are ineligible for surgery. |
Good |
| 127. Saxena A, Bester L, Chua TC, Chu FC, Morris DL. Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg Oncol. 2010;17(2):484-491. |
Observational-Tx |
25 patients |
To present data on the safety and efficacy of a novel treatment option, Y-90 radioembolization for unresectable ICC. |
No patient was lost to follow-up. The median follow-up was 8.1 (range, 0.4–56) months and the median survival after Y-90 radioembolization was 9.3 months. 2 patients died within 1 month of treatment; the median follow-up for the remaining 23 was 8.9 (range, 1.5–56) months. 2 factors were associated with an improved survival: peripheral tumor type (vs infiltrative, P=.004) and ECOG performance status of 0 (vs 1 and 2, P<.001). On imaging follow-up of 23 patients, a partial response to treatment was observed in 6 patients (24%), stable disease in 11 patients (48%), and progressive disease in 5 patients (20%). The most common clinical toxicities were fatigue (64%) and self-limiting abdominal pain (40%). 2 patients (8%) each developed grade III bilirubin and albumin toxicity. One patient (4%) developed grade III alkaline phosphatase toxicity. |
2 |
| 128. Mansour JC, Aloia TA, Crane CH, Heimbach JK, Nagino M, Vauthey JN. Hilar cholangiocarcinoma: expert consensus statement. HPB (Oxford) 2015;17:691-9. |
Review/Other-Tx |
N/A |
To review current evidence on the management of hilar cholangiocarcinoma in order to establish practice guidelines and to agree consensus statements. |
No results stated in abstract. |
4 |
| 129. Hyder O, Marsh JW, Salem R, et al. Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann Surg Oncol 2013;20:3779-86. |
Observational-Tx |
198 patients with advanced ICC treated with IAT |
To assess the safety and efficacy of intra-arterial therapy (IAT) in patients with advanced intrahepatic cholangiocarcinoma (ICC) in a large cohort of patients treated at five major centers. |
Median patient age was 61 years. Median tumor size was 8.1 cm, and 47.5 % patients had a solitary lesion. IAT consisted of conventional transarterial chemoembolization (cTACE) (64.7 %), drug-eluting beads (DEB) (5.6 %), bland embolization (TAE) (6.6 %), or yttrium-90 radioembolization (23.2 %). Median number of IAT sessions was 2 (range 1–8). The median time between IAT sessions was 48 days. The periprocedural morbidity was 29.8 %; most complications were minor (n = 43); however, 16 patients had a grade 3–4 complication. Assessment of tumor response revealed complete or partial response in 25.5 % patients, while 61.5 % had stable disease; 13.0 % had progressive disease. Median overall survival was 13.2 months and did not differ on the basis of the type of IAT (cTACE, 13.4 months vs. DEB 10.5 months vs. TAE, 14.3 months vs. yttrium-90, 11.3 months; P = 0.46). IAT response on modified response evaluation criteria in solid tumors (mRECIST; hazard ratio for complete–partial response 0.49, 95 % confidence interval 0.30–0.81; P\0.001) was independently associated with better survival. |
3 |
| 130. Ray CE, Jr., Edwards A, Smith MT, et al. Metaanalysis of survival, complications, and imaging response following chemotherapy-based transarterial therapy in patients with unresectable intrahepatic cholangiocarcinoma. J Vasc Interv Radiol 2013;24:1218-26. |
Meta-analysis |
16 articles (542 patients) |
To assess primary clinical and imaging outcomes, as well as complication rates, following transarterial interventions in this patient population. |
A total of 16 articles (N = 542 subjects) met the inclusion criteria and are included. Overall survival times were 15.7 months ± 5.8 and 13.4 months ± 6.7 from the time of diagnosis and time of first treatment, respectively. The overall weighted 1-year survival rate was 58.0% ± 14.5. More than three fourths of all subjects (76.8%) exhibited a response or stable disease on postprocedure imaging; 18.9% of all subjects experienced severe toxicities (National Cancer Institute/World Health Organization grade = 3), and most experienced some form of postembolization syndrome. Overall 30-day mortality rate was 0.7%. |
Good |
| 131. Jia Z, Paz-Fumagalli R, Frey G, Sella DM, McKinney JM, Wang W. Resin-based Yttrium-90 microspheres for unresectable and failed first-line chemotherapy intrahepatic cholangiocarcinoma: preliminary results. J Cancer Res Clin Oncol. 143(3):481-489, 2017 Mar. |
Observational-Tx |
24 patients |
To evaluate the value of resin-based yttrium-90 (90Y) radioembolization for unresectable and failed firstline chemotherapy (cisplatin plus gemcitabine) intrahepatic cholangiocarcinoma (ICC). |
Twenty-four patients (eight male and 16 female) were included in this study. Mean 5.6 ± 1.6 cycles of firstline chemotherapy were performed prior to 90Y treatment. The mean delivered activity of 90Y was 1.6 ± 0.4 GBq with a total of 27 treatments. Disease control rate was 81.8% at 3 months after 90Y therapy, with partial response (n = 8, 36.4%), stable disease (n = 10, 45.5%) and progressive disease (n = 6, 18.2%). CA199 changes pre- and 1 month post-treatment were complete (n = 2), partial (n = 2), none (n = 5) and progression (n = 2), respectively. Side effects included fatigue (n = 21, 87.5%), anorexia (n = 19, 79.2%), nausea (n = 15, 62.5%), abdominal pain (n = 10, 58.3%), vomiting (n = 4, 16.7%) and fever (n = 3, 12.5%). Radiation-induced gastrointestinal ulcer was identified in one patient. The mean follow-up was 11.3 ± 6.6 months, and the median survivals from the time of diagnosis of ICC, beginning of first-line chemotherapy and first 90Y procedure were 24.0, 16.0 and 9.0 months, respectively, and the 6-, 12-, 18-, 24- and 30-month survival after 90Y therapy were 69.9, 32.6, 27.2, 20.4 and 20.4%, respectively. ECOG performance status (P = 0.002) and lymph node metastases (P = 0.019) had statistically significant influence on overall survival. |
2 |
| 132. Padia SA. Y90 Clinical Data Update: Cholangiocarcinoma, Neuroendocrine Tumor, Melanoma, and Breast Cancer Metastatic Disease. [Review]. Techniques in Vascular & Interventional Radiology. 22(2):81-86, 2019 Jun. |
Review/Other-Tx |
N/A |
To summarize findings for numerous single-arm studies regarding radioembolization in patients with hepatocellular carcinoma and hepatic metastases. |
No results in abstract. |
4 |
| 133. Jia Z, Paz-Fumagalli R, Frey G, Sella DM, McKinney JM, Wang W. Single-institution experience of radioembolization with yttrium-90 microspheres for unresectable metastatic neuroendocrine liver tumors. J Gastroenterol Hepatol. 32(9):1617-1623, 2017 Sep. |
Observational-Tx |
36 patients |
To assess the effectiveness of yttrium-90 (90 Y) microspheres for the treatment of unresectable metastatic liver neuroendocrine tumors (NET). |
Of the 36 patients, the mean delivered dose of 90 Y was 1.8 ± 0.7 GBq with a total of 40 treatments. Overall disease control rate was 88.9% (32/36) at 3 months following therapy. In 16 patients with carcinoid syndrome, 15 (93.8%) patients had symptomatic improvement. Tumor marker response (5-hydroxyindoleacetic acid [n = 7] and chromogranin A [n = 13]) at 3 months after treatment were as follows: none (n = 0, 4), partial (n = 6, 7), and complete (n = 1, 2). Radiation-induced gastrointestinal ulcers (n = 2, 5.6%) were identified. Side effects included fatigue (n = 31, 86.1%), anorexia (n = 26, 72.2%), nausea (n = 15, 41.7%), vomiting (n = 14, 38.9%), abdominal pain (n = 10, 27.8%), and fever (n = 8, 22.2%). The mean follow-up was 27.0 ± 16.4 months, with a median survival of 41.0 months. Child-Pugh classification (P = 0.008) and lymph node metastases (P = 0.045) had statistically significant influence on overall survival. |
2 |
| 134. Rinke A, Wittenberg M, Schade-Brittinger C, et al. Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival. Neuroendocrinology 2017;104:26-32. |
Experimental-Tx |
85 patients (42 = octreotide LAR, 43 = placebo) |
To analyze the prognostic significance of early treatment with octreotide LAR and of hepatic tumor load in the PROMID trial cohort. |
Forty-eight out of 85 patients (56.5%) died. In 38 patients (79.2%), death was tumor related. The median overall survival (84.7 and 83.7 months) was only slightly different in patients assigned to octreotide and placebo [HR = 0.83 (95% CI: 0.47-1.46); p = 0.51]. The median overall survival was 84.7 months for all 85 patients, 107.6 months in the low-tumor-load (n = 64) and 57.5 months in the high-tumor-load (n = 21) subgroups [HR = 2.49 (95% CI: 1.36-4.55); p = 0.002]. There was a trend towards improved overall survival in patients with a low hepatic tumor load receiving octreotide compared to placebo ['median not reached' and 87.2 months; HR = 0.59 (95% CI: 0.29-1.2); p = 0.142]. |
1 |
| 135. Atwell TD, Charboneau JW, Que FG, et al. Treatment of neuroendocrine cancer metastatic to the liver: the role of ablative techniques. Cardiovasc Intervent Radiol. 2005;28(4):409-421. |
Review/Other-Tx |
N/A |
To review the role of ablative techniques in the treatment of neuroendocrine cancer metastatic to the liver. |
Image-guided ablation, as either an adjunct to surgery or a primary treatment modality, can be used to treat neuroendocrine cancer metastatic to the liver. Image-guided ablative techniques, including RFA, alcohol injection, and cryoablation, can be used in selected patients to debulk hepatic tumors and improve patient symptoms. Although long-term follow-up data are not available, the surgical literature indicates that significant ablative debulking may improve patient survival. In this review, we discuss metastatic neuroendocrine disease and its treatment options, especially image-guided ablative techniques. |
4 |
| 136. Fazio N, Kulke M, Rosbrook B, Fernandez K, Raymond E. Updated Efficacy and Safety Outcomes for Patients with Well-Differentiated Pancreatic Neuroendocrine Tumors Treated with Sunitinib. Target Oncol 2021;16:27-35. |
Observational-Tx |
N/A |
To assess the clinical benefit with sunitinib using the combined data from these trials. |
The updated median OS for the phase IV trial was 54.1 months (95% CI 37.9-not reached). Investigator-assessed median PFS for the combined cohort (n = 102) was 12.9 months (95% CI 7.4-16.7) with a significant benefit versus placebo in the phase III trial (n = 35) (HR 0.429; 95% CI 0.245-0.752; p = 0.001). Median OS could not be calculated for the combined cohort or placebo group due to the high number of patients censored; however, the estimated HR of 0.303 (CI 0.100-0.921; p = 0.013) favored sunitinib. ORR for the combined cohort was 16.7% (95% CI 10.0-25.3). Sunitinib was well tolerated in both trials with a safety profile similar to previously seen in other studies. |
2 |
| 137. Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016;387:968-77. |
Experimental-Tx |
205 everolimus patients; 97 placebo patients |
To assess the efficacy and safety of everolimus compared with placebo in this patient population. |
Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2-13·3) in the everolimus group and 3·9 months (3·6-7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35-0·67], p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40-1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0). |
1 |
| 138. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011;378:2005-12. |
Observational-Tx |
429 patients |
To assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). |
Median progression-free survival by central review was 16.4 (95% CI 13.7-21.2) months in the everolimus plus octreotide LAR group and 11.3 (8.4-14.6) months in the placebo plus octreotide LAR group (hazard ratio 0.77, 95% CI 0.59-1.00; one-sided log-rank test p=0.026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62%vs 14%), rash (37%vs 12%), fatigue (31%vs 23%), and diarrhoea (27%vs 16%). |
2 |
| 139. Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2010;28:69-76. |
Observational-Tx |
115 patients in Stratum1; 45 patients in Stratum 2 |
To assess the clinical benefits of everolimus alone and in combination with octreotide LAR. |
By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. |
1 |
| 140. Que FG, Nagorney DM, Batts KP, Linz LJ, Kvols LK. Hepatic resection for metastatic neuroendocrine carcinomas. Am J Surg 1995;169:36-42; discussion 42-3. |
Observational-Tx |
74 patients |
To review the clinical outcomes of our updated experience with 74 patients and define further guidelines for patient selection. |
There were 50 carcinoid, 23 islet-cell, and 1 atypical neuroendocrine tumors. Resections included 36 hemihepatectomies or extended hepatectomies and 38 nonanatomic resections. Thirty-eight primary tumors were resected concomitantly. Perioperative mortality was 2.7% and morbidity was 24%. Four-year survival was 73%. Overall postoperative symptomatic response rate was 90% with a mean duration of response of 19.3 months. |
3 |
| 141. Sarmiento JM, Heywood G, Rubin J, Ilstrup DM, Nagorney DM, Que FG. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg. 2003;197(1):29-37. |
Observational-Tx |
170 consecutive patients |
To determine outcomes of surgery for neuroendocrine metastases in the liver. |
The postoperative complication rate was 14%, and 2 patients died (1.2%). Operation controlled symptoms in 104/108 patients, but the recurrence rate at 5 years was 59%. Operation decreased 5-hydroxyindoleacetic acid levels considerably, and no patient experienced carcinoid heart disease postoperatively. Recurrence rate was 84% at 5 years. OS was 61% and 35% at 5 and 10 years, respectively, with no difference between carcinoid and islet cell tumors. Hepatic resection for metastatic NETs is safe and achieves symptom control in most patients. Debulking extends survival, although recurrence is expected. Hepatic resection is justified by its effects on survival and quality of life. |
2 |
| 142. Saxena A, Chua TC, Perera M, Chu F, Morris DL. Surgical resection of hepatic metastases from neuroendocrine neoplasms: a systematic review. Surgical oncology 2012;21:e131-41. |
Review/Other-Tx |
29 studies |
To critically appraise the quantity and quality of current clinical evidence and evaluate the clinical efficacy of hepatic resection for NET hepatic metastases (NETHM). |
Twenty-nine included reported survival outcomes with a median 3-, 5- and 10-year overall survival of 83% (range, 63-100%), 70.5% (range, 31-100%), and 42% (range, 0-100%), respectively. The median progression-free survival (PFS) was 21 months (range, 13-46 months) and median 1-,3-,5- and 10-year PFS of 63% (range, 50-80 %), 32% (range, 24-69%), 29% (range, 6-66%) and 1% (range, 0-11%), respectively. Poor histologic grade, extra-hepatic disease and a macroscopically incomplete resection were associated with a poor prognosis. Studies reported a median rate of symptomatic relief from surgery in 95% of patients (range, 50-100%). |
4 |
| 143. Boudreaux JP, Wang YZ, Diebold AE, et al. A single institution's experience with surgical cytoreduction of stage IV, well-differentiated, small bowel neuroendocrine tumors. J Am Coll Surg 2014;218:837-44. |
Observational-Tx |
189 patients |
To evaluate and compare the effectiveness and safety of TAE and TACE in a retrospective series of patients with liver metastases from NET. |
A total of 189 patients underwent 229 cytoreductive operations. Ten percent of patients required an intraoperative blood transfusion and 3% (6 of 229) had other intraoperative complications. For all 229 procedures performed, mean (± SD) stay in the ICU was 4 ± 3 days and in the hospital was 9 ± 10 days. Before discharge, 51% of patients had no postoperative complications and 39% of patients had only minor complications. In a 30-day follow-up period from discharge, 85% of patients had no additional complications and 13% had only minor complications. The 30-day postoperative death rate was 3% (5 of 189). Mean survival from histologic diagnosis of NET was 236 months. The 5-, 10-, and 20-year Kaplan-Meier survival rates from diagnosis were 87%, 77%, and 41%, respectively. |
3 |
| 144. McEntee GP, Nagorney DM, Kvols LK, Moertel CG, Grant CS. Cytoreductive hepatic surgery for neuroendocrine tumors. Surgery 1990;108:1091-6. |
Review/Other-Tx |
37 patients |
To evaluate the role of cytoreductive hepatic surgery in patients with metastatic neuroendocrine tumors (carcinoid, 24; islet cell, 13). |
Seventeen resections were curative (no gross residual tumor); nine patients had symptomatic endocrinopathies and seven patients had symptoms caused by the primary tumor. Eight of nine patients with symptomatic endorcrinopathies obtained complete relief of symptoms; five are alive with no evidence of disease at 2 to 82 months (mean, 26 months). Six of seven patients with symptoms caused by the primary tumor obtained complete relief; five are alive with no evidence of disease at 5 to 28 months (mean, 14 months). One symptom-free patient underwent curative hepatic resection 5 years after abdominoperineal resection for a rectal carcinoid. Twenty resections were palliative (gross residual tumor); 16 patients had symptomatic endocrinopathies and 4 patients had symptoms caused by the primary tumor. Eight of 16 patients with symptomatic endocrinopathies obtained complete relief; five are alive at 2 to 30 months (mean, 11 months), with a mean duration of complete relief of 6 months (3 to 12 months). All four patients who underwent resection for symptoms caused by the primary tumor obtained complete relief; two are alive and symptom free at 10 and 101 months. |
4 |
| 145. Moris D, Tsilimigras DI, Ntanasis-Stathopoulos I, et al. Liver transplantation in patients with liver metastases from neuroendocrine tumors: A systematic review. Surgery 2017;162:525-36. |
Review/Other-Tx |
64 studies |
To perform a systematic review of the current literature to summarize data on patients undergoing liver transplantation with neuroendocrine tumors liver metastases as the indication. |
From the 1,216 records retrieved, 64 studies were eligible. Overall, 4 studies presented data from registries, namely the European Liver Transplant Registry and the United Network for Organ Transplantation/Organ Procurement and Transplantation Network databases, 3 were multicenter studies. The largest cohort of data on patients undergoing liver transplantation for neuroendocrine tumors liver metastasis indication were from single center studies comprising a total of 279 patients. Pancreas was the primary tumor site for most patients followed by the ileum. Several studies reported that more than half of patients presented with synchronous disease (55.9% and 57.7%); in contrast, metachronous neuroendocrine tumors liver metastasis ranged from 17.7% to 38.7%. Overall, recurrence after liver transplantation ranged from 31.3% to 56.8%. Reported 1-, 3-, and 5-year overall survival was 89%, 69%, and 63%, respectively. Several prognostic factors associated with worse long-term survival including transplantation >50% liver tumor involvement, high Ki67, as well as a pancreatic neuroendocrine tumors versus gastrointestinal neuroendocrine tumors tumor location. |
4 |
| 146. Wahl DR, Stenmark MH, Tao Y, et al. Outcomes After Stereotactic Body Radiotherapy or Radiofrequency Ablation for Hepatocellular Carcinoma. J Clin Oncol 2016;34:452-9. |
Observational-Tx |
161 patients in RFA group, 63 patients in image-guided SBRT |
To compare outcomes between stereotactic body radiotherapy (SBRT) and radiofrequency ablation (RFA) for HCC. |
RFA and SBRT groups were similar with respect to number of lesions treated per patient, type of underlying liver disease, and tumor size (median, 1.8 v 2.2 cm in maximum diameter; P = .14). However, the SBRT group had lower pretreatment Child-Pugh scores (P = .003), higher pretreatment alpha-fetoprotein levels (P = .04), and a greater number of prior liver-directed treatments (P < .001). One- and 2-year FFLP for tumors treated with RFA were 83.6% and 80.2% v 97.4% and 83.8% for SBRT. Increasing tumor size predicted for FFLP in patients treated with RFA (hazard ratio [HR], 1.54 per cm; P = .006), but not with SBRT (HR, 1.21 per cm; P = .617). For tumors = 2 cm, there was decreased FFLP for RFA compared with SBRT (HR, 3.35; P = .025). Acute grade 3+ complications occurred after 11% and 5% of RFA and SBRT treatments, respectively (P = .31). Overall survival 1 and 2 years after treatment was 70% and 53% after RFA and 74% and 46% after SBRT. |
2 |
| 147. Hoffe SE, Finkelstein SE, Russell MS, Shridhar R. Nonsurgical options for hepatocellular carcinoma: evolving role of external beam radiotherapy. Cancer control : journal of the Moffitt Cancer Center 2010;17:100-10. |
Review/Other-Tx |
N/A |
To review nonsurgical therapies for hepatocellular carcinoma (HCC) with an exploration of how external beam radiotherapy can be used alone or with other modalities. |
Current data show a promising future for treatment strategies incorporating radiation with high rates of infield tumor control and low rates of radiation-induced liver disease. Radiation can be delivered in conjunction with transarterial catheter embolization for advanced-stage patients. External beam radiotherapy also has a role in the setting of patients with macrovascular tumor thrombus. |
4 |
| 148. Edyta WR, Jakub L, Jerzy W. Whole Liver Palliative Radiotherapy for Patients with Massive Liver Metastases. Asian Pac J Cancer Prev 2015;16:6381-4. |
Observational-Tx |
27 patients with liver metastases |
To examine the effectiveness and tolerability of a radiotherapy technique for the palliation of symptomatic liver metastases. |
Individual symptom response rates were 100% at 4 weeks. Partial or complete global symptomatic responses were noted in 11 patients (40%) after 2 months. After 3 months, 8 patients (28%) reported loss of pain. The treatment was well tolerated with one patient (3%) experiencing grade 3 toxicity (one vomiting and one diarrhoea). Overall the median survival time was 4.9 months (range 1-14 months). One year survival was 39%. |
3 |
| 149. Gupta S, Johnson MM, Murthy R, et al. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival. Cancer. 2005;104(8):1590-1602. |
Observational-Tx |
123 patients: 69 carcinoid tumors; 54 islet cell tumors |
To determine prognostic variables that influence survival and response for carcinoid and islet cell tumors. |
Patients who had carcinoid tumors had a higher response rate (66.7% vs 35.2%; P=0.0001) and had longer PFS (22.7 months vs 16.1 months; P=0.046) and OS (33.8 months vs 23.2 months; P=0.012) compared with patients who had islet cell carcinomas. Patients with carcinoid tumors, multivariate analysis identified male gender as the only independent risk factor for poor survival (P=0.05). Octreotide was predictive marginally for PFS (P=0.06). Patients who were treated with hepatic arterial embolization had a higher response rate than patients who were treated with chemoembolization (P=0.004). For patients with islet cell carcinoma, an intact primary tumor, =75% liver involvement, and extrahepatic metastases were associated with reduced OS in the univariate analysis; the presence of bone metastases was the only risk factor (P=0.031) in the multivariate analysis. Patients treated with chemoembolization had a prolonged OS (31.5 months vs 18.2 months) and improved response (50% vs 25%) than those who were treated with hepatic arterial embolization, although the differences did not reach statistical significance. Patients with carcinoid tumors had better outcomes than patients with islet cell carcinomas. Addition of intra-arterial chemotherapy to hepatic arterial embolization did not improve the outcome of patients with carcinoid tumors, but it seemed to benefit patients with islet cell carcinomas. In patients who had carcinoid tumors, male gender predicted a poor outcome, and a trend toward prolonged PFS was observed in patients who received concomitant octreotide carcinomas. |
2 |
| 150. Ruutiainen AT, Soulen MC, Tuite CM, et al. Chemoembolization and bland embolization of neuroendocrine tumor metastases to the liver. J Vasc Interv Radiol. 2007;18(7):847-855. |
Observational-Tx |
67 total patients: 23 received bland embolization with polyvinyl administration; 44 received chemoembolization with cisplatin |
To assess the toxicity and efficacy of chemoembolization and bland embolization in patients with NET metastases to the liver. |
The mortality rate at 30 days was 1.4%. Toxicities of grade 3 or worse in severity occurred after 25% of chemoembolization procedures and 22% of bland embolization procedures (OR, 1.2; 95% CI, 0.4–4.0). Rates of freedom from progression at 1, 2, and 3 years were 49%, 49%, and 35% after chemoembolization and 0%, 0%, and 0% after bland embolization (log-rank test, P=.16). Among the subgroup with carcinoid tumors, the proportions without progression were 65%, 65%, and 52% after chemoembolization and 0%, 0%, and 0% after bland embolization (log-rank test, P=.08). Patients treated with chemoembolization and bland embolization experienced symptomatic relief for means of 15 and 7.5 months, respectively (P=.14). Survival rates at 1, 3, and 5 years after therapy were 86%, 67%, and 50%, respectively, after chemoembolization and 68%, 46%, and 33%, respectively, after bland embolization (log-rank test, P=.18). Chemoembolization was not associated with a higher degree of toxicity than bland embolization. Chemoembolization demonstrated trends toward improvement in TTP, symptom control, and survival. Based on these results, a multicenter prospective randomized trial is warranted. |
2 |
| 151. Dong XD, Carr BI. Hepatic artery chemoembolization for the treatment of liver metastases from neuroendocrine tumors: a long-term follow-up in 123 patients. Med Oncol 2011;28 Suppl 1:S286-90. |
Observational-Tx |
123 patients |
To review here our experience with chemoembolization therapy for the treatment of metastatic NETs to the liver at a large tertiary referral center over a 15-year period, with a focus on prognostic factors. |
We reviewed our 15-year experience with chemoembolization in 123 patients with unresectable NET liver metastases, whose prognosis was evaluated upon baseline clinical factors. There were 64 males (53%) and 59 females (47%). Average age at presentation was 56 years (range: 14.3-85.5 years). Abdominal pain (44%) was the most common presenting symptom, followed by diarrhea (30%) and weight lost (22%). Patients underwent an average 7.3 cycles of chemoembolization (range 1-32 cycles). Responses: 62% of patients had PR; 24% had stable disease and 14% had tumor progression. Overall 3-, 5- and 10-year survivals were 59, 36 and 20% of patients with a mean follow-up of 3.2 years (range 2 weeks-18.3 years) and mean survival of 3.3 years. Univariate analysis showed that age greater than 60 years had worse outcome (P < 0.01), as did baseline serum albumin of = 3.5 g/dL and prothrombin time >13 s. Location of the primary tumor (P = 0.68), gender (P = 0.4) and serum NET peptide levels did not influence survival. However, multivariate analysis showed that a low baseline serum albumin level was an independent factor for prognosis (P = 0.003). |
2 |
| 152. Bhagat N, Reyes DK, Lin M, et al. Phase II study of chemoembolization with drug-eluting beads in patients with hepatic neuroendocrine metastases: high incidence of biliary injury. Cardiovasc Intervent Radiol. 36(2):449-59, 2013 Apr. |
Observational-Tx |
13 patients |
To evaluate safety in an interim analysis of DEB-TACE in 13 patients with hepatic metastases from NETs as part of a phase II trial. |
DEB-TACE was successfully performed in all 13 patients. At 1 month follow-up, there was a mean 12% decrease in tumor size (P<0.0003) and a 56% decrease in tumor enhancement (P<0.0001). By EASL criteria, the targeted lesion objective response rate was 78%. Grade 3 to 4 toxicities were fatigue (23%), increased alanine amino transferase (15%), hyperglycemia (15%), and abdominal pain (8%). 7 patients developed bilomas (54%); all of these patients had multiple small (<4 cm) lesions. Subsequently, 4 underwent percutaneous drainage, 3 for abscess formation and 1 for symptoms related to mass effect. |
2 |
| 153. Fiore F, Del Prete M, Franco R, et al. Transarterial embolization (TAE) is equally effective and slightly safer than transarterial chemoembolization (TACE) to manage liver metastases in neuroendocrine tumors. Endocrine 2014;47:177-82. |
Observational-Tx |
30 patients |
To compare the effectiveness and safety of TAE-TACE in the treatment of liver metastases in patients with NET. |
Thirty patients with a histologically confirmed gastro-entero-pancreatic NET with liver metastases were retrospectively investigated. Seventeen patients underwent TAE, while 13 patients underwent TACE. Tumor response, degree of devascularization in treated lesions, and progression free survival (PFS) were evaluated in the whole population and then separately in TAE and TACE subgroups. In all patients treated with TAE and TACE, there was a significant size reduction of lesions as compared to baseline. Per lesion reduction was 2.2 ± 1.4 versus 3.3 ± 1.5 cm for TAE (p < 0.001) and 2.2 ± 1.5 versus 3.4 ± 1.7 cm for TACE (p < 0.001). In the whole population, the median PFS for all patients was 36 months (16.2-55.7 CI), without significant difference between TAE and TACE. In no patient did adverse events grade 3 and 4 as well as TAE/TACE-related death occurred, while the post-embolization syndrome occurred in 41 % of patients treated with TAE and 61 % of those treated with TACE. |
2 |
| 154. Devcic Z, Rosenberg J, Braat AJ, et al. The efficacy of hepatic 90Y resin radioembolization for metastatic neuroendocrine tumors: a meta-analysis. J Nucl Med. 55(9):1404-10, 2014 Sep. |
Meta-analysis |
12 studies |
To evaluate the efficacy of this modality in a meta-analysis of the published literature. |
One hundred fifty-six studies were screened; 12 were selected, totaling 435 procedures for response assessment. Funnel plotsshowed no evidence of publication bias (P 5 0.841). Critical appraisal revealed a median of 75% of desired criteria included in selected studies. Very high between study heterogeneity ruled out a fixed-effects model. The random-effects weighted average objective response rate (complete and partial responses, CR and PR, respectively) was 50% (95% confidence interval, 38%–62%), and weighted average disease control rate (CR, PR, and stable disease) was 86% (95% confidence interval, 78%–92%). The percentage of patients with pancreatic mNET was marginally associated with poorer response (P 5 0.030), accounting for approximately 23% of the heterogeneity among studies. The percentage of CR and PR correlated with median survival (R 5 0.85; P 5 0.008). |
Inadequate |
| 155. Pericleous M, Caplin ME, Tsochatzis E, Yu D, Morgan-Rowe L, Toumpanakis C. Hepatic artery embolization in advanced neuroendocrine tumors: Efficacy and long-term outcomes. Asia Pac J Clin Oncol 2016;12:61-9. |
Observational-Tx |
50 patients with NETs |
To assess efficacy, toxicity and survival parameters in NET patients undergoing TAE and TACE. |
Symptomatic improvement was observed in 75% of patients who underwent TAE and 57% of patients who had TACE (P = 0.36). Radiological response was observed following 73% of embolization treatments delivered and specifically in 82% of all TAE and 62% of all TACE procedures (P = 0.46). Plasma Chromogranin A (CgA) levels were reduced in 65% of the patients following embolization. Patients with increasing serum CgA levels after treatment had reduced median overall survival (OS) and progression-free survival (PFS) (P = 0.0001). Patients on somatostatin analogs (SSAs) at the time of treatment had improved OS (P = 0.013), but not PFS (P = 0.216). Overall, the differences in OS (P = 0.21) and PFS (P = 0.19) between one mode of treatment over the other were not found to be statistically significant. One- and 5-year OS were 65% and 41% for TACE and 90% and 57% for TAE, respectively. The commonest complication was postembolization syndrome and mortality was 4%. Overall, the complication (P = 0.18) and mortality rates (P = 0.22) were not significantly different between TAE and TACE. |
2 |
| 156. Fan KY, Wild AT, Halappa VG, et al. Neuroendocrine tumor liver metastases treated with yttrium-90 radioembolization. Contemp Clin Trials. 50:143-9, 2016 09. |
Observational-Tx |
38 patients |
To evaluate the efficacy and tolerability of Y-90 radioembolization and identifies prognostic factors for radiographic response and survival. |
Median length of follow-up was 17.0months (IQR, 9.0-37.0). Median survival was 29.2months. Three patients (9%) had a radiographic complete response to treatment, 6 (17%) had a partial response, 21 (60%) had stable disease, and 5 (14%) developed progressive disease. Two factors were significantly associated with a good radiographic response (complete/partial response): islet cell histological subtype (p=0.043) and hepatic tumor burden =33% (p=0.031). Multivariate analysis revealed that patients requiring multiple Y-90 treatments (HR 2.9, p=0.035) and patients who had previously failed systemic therapy with octreotide/chemotherapy (HR 4.4, p=0.012) had worse survival. Grade 3 serologic toxicity was observed in 2 patients (5%; hyperbilirubinemia, elevated alkaline phosphatase) after treatment. Grade 3 non-serologic toxicities included abdominal pain (11%), fatigue (11%), nausea/vomiting (5%), ascites (5%), dyspnea (3%), diarrhea (3%), and peripheral edema (3%). No grade 4 or 5 toxicity was reported. |
2 |
| 157. Guiu B, Deschamps F, Aho S, et al. Liver/biliary injuries following chemoembolisation of endocrine tumours and hepatocellular carcinoma: lipiodol vs. drug-eluting beads. J Hepatol. 2012;56(3):609-617. |
Observational-Tx |
208 patients (n = 120 in the NET-group); n = 88 in the HCC-group) |
To describe and compare liver/biliary injuries encountered with TACE in tumors developed in HCC and non-cirrhotic (endocrine tumors (NETs)) livers. |
A liver/biliary injury followed 17.2% (82/476) of sessions in 30.8% (64/208) of patients. The occurrence of liver/biliary injury was associated with DEB-TACE (OR=6.63; P<0.001) irrespectively of the tumor type. Biloma/parenchymal infarct was strongly associated with both DEB-TACE (OR=9.78; P=0.002) and NETs (OR: 8.13; P=0.04). Biloma/liver infarcts were managed conservatively but were associated with an increase in serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatases, and gamma glutamyl transpeptidase (P=0.005, P=0.005, P=0.012, and P=0.006, respectively). |
2 |
| 158. Chen JX, Rose S, White SB, et al. Embolotherapy for Neuroendocrine Tumor Liver Metastases: Prognostic Factors for Hepatic Progression-Free Survival and Overall Survival. Cardiovasc Intervent Radiol. 40(1):69-80, 2017 Jan. |
Observational-Tx |
155 patients with NET liver metastases |
To evaluate prognostic factors for survival outcomes following embolotherapy for neuroendocrine tumor (NET) liver metastases. |
Median HPFS and OS were 18.5 and 125.1 months for G1 (n = 75), 12.2 and 33.9 months for G2 (n = 60), and 4.9 and 9.3 months for G3 tumors (n = 20), respectively (p < 0.05). Tumor burden >50 % hepatic volume demonstrated 5.5- and 26.8-month shorter median HPFS and OS, respectively, versus burden =50 % (p < 0.05). There were no significant differences in HPFS or OS between gut or pancreas primaries. In multivariate HPFS analysis, there were no significant differences among embolotherapy modalities. In multivariate OS analysis, TARE had a higher hazard ratio than TACE (unadjusted Cox model: HR 2.1, p = 0.02; propensity score adjusted model: HR 1.8, p = 0.11), while TAE did not differ significantly from TACE. |
2 |
| 159. Tomozawa Y, Jahangiri Y, Pathak P, et al. Long-Term Toxicity after Transarterial Radioembolization with Yttrium-90 Using Resin Microspheres for Neuroendocrine Tumor Liver Metastases. J Vasc Interv Radiol 2018;29:858-65. |
Observational-Tx |
93 patients (48 = unilobar TARE, 45 = bilobar TARE) |
To evaluate long-term effects of yttrium-90 (90Y) transarterial radioembolization (TARE) for unresectable hepatic metastases of neuroendocrine tumors (NETs). |
Unilobar TARE was performed in 48 patients, and staged bilobar TARE was performed in 45 patients. In multivariate analysis, ascites (P = .002) and extrahepatic metastases (P = .038) at baseline were associated with poor survival. Among 52 patients who had > 1 year of follow-up, significant increases in alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase were observed; however, only 4 patients experienced grade 3 serologic toxicities. Imaging signs of cirrhosis-like morphology and portal hypertension were observed in 15 of 52 patients, more frequently in patients treated with bilobar TARE compared with unilobar TARE. Patients treated with bilobar TARE exhibited significantly increased hepatobiliary enzymes and decreased platelet count. Sustained increases in liver enzymes were observed in patients with > 4 years of follow-up. No radioembolization-related liver failure or grade 4 toxicity was observed. |
2 |
| 160. Filice A, Fraternali A, Frasoldati A, et al. Radiolabeled somatostatin analogues therapy in advanced neuroendocrine tumors: a single centre experience. J Oncol 2012;2012:320198. |
Observational-Tx |
65 patients |
To assess the efficacy of PRRT in patients with advanced neuroendocrine tumors (NETs). |
Complete response (CR) was found in 1/59 (2%) patients, partial remission (PR) in 24/59 (40.5%) patients, stable disease (SD) in 24/59 (40.5%), and progression (PD) in 10/59 (17%) patients. The overall tumor response rate (CR + PR) was 42.5%. In 40.5% of patients, the disease could be stabilized. Overall, 49 out of 59 patients had no tumor progression (83%). Twelve patients out of 59 (20%) had grade 2-3 hematological side effects including anemia, thrombocytopenia, and leukopenia. Long-term nephrotoxicity was observed in 3 patients (2 moderate, 1 severe). |
2 |
| 161. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 26(13):2124-30, 2008 May 01. |
Observational-Tx |
504 patients |
To report on the toxicity and efficacy of this treatment, performed in over 500 patients. |
Any hematologic toxicity grade 3 or 4 occurred after 3.6% of administrations. Serious adverse events that were likely attributable to the treatment were myelodysplastic syndrome in three patients, and temporary, nonfatal, liver toxicity in two patients. Complete and partial tumor remissions occurred in 2% and 28% of 310 GEPNET patients, respectively. Minor tumor response (decrease in size > 25% and > 50%) occurred in 16%. Median time to progression was 40 months. Median OS from start of treatment was 46 months, median OS from diagnosis was 128 months. Compared with historical controls, there was a survival benefit of 40 to 72 months from diagnosis. |
2 |
| 162. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med 2017;376:125-35. |
Experimental-Tx |
229 patients (Lu-Dotate = 116, octreotide = 113) |
To evaluate the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. |
At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. |
1 |
| 163. Lin PS, Semrad TJ. Molecular Testing for the Treatment of Advanced Colorectal Cancer: An Overview. [Review]. Methods Mol Biol. 1765:281-297, 2018. |
Review/Other-Tx |
N/A |
To discuss concurrent development of molecular biomarkers with new treatment strategies holds great promise of precision medicine in improving outcomes for patients with advanced CRC. |
No results available. |
4 |
| 164. Sanchez-Gundin J, Fernandez-Carballido AM, Martinez-Valdivieso L, Barreda-Hernandez D, Torres-Suarez AI. New Trends in the Therapeutic Approach to Metastatic Colorectal Cancer. [Review]. Int J Med Sci. 15(7):659-665, 2018. |
Review/Other-Tx |
N/A |
To review important developments in chemotherapy for metastatic colorectal cancer over the last years, with an emphasis on the most recently published data from clinical trials. |
No results available. |
4 |
| 165. Ducreux M, Adenis A, Pignon JP, et al. Efficacy and safety of bevacizumab-based combination regimens in patients with previously untreated metastatic colorectal cancer: final results from a randomised phase II study of bevacizumab plus 5-fluorouracil, leucovorin plus irinotecan versus bevacizumab plus capecitabine plus irinotecan (FNCLCC ACCORD 13/0503 study). Eur J Cancer 2013;49:1236-45. |
Experimental-Tx |
145 patients (bevacizumab-XELIRI = 72; bevacizumab-FOLFIRI = 73) |
To evaluate the efficacy and safety of bevacizumab in combination with either XELIRI or 5-FU/LV plus irinotecan (FOLFIRI) as first-line therapy for mCRC. |
A total of 145 patients were enrolled (bevacizumab-XELIRI, n=72; bevacizumab-FOLFIRI, n=73). The 6-month PFS rate was 82% (95% confidence intervals (CI) 71-90%) in the bevacizumab-XELIRI arm and 85% (95% CI 75-92%) in the bevacizumab-FOLFIRI arm. In both the bevacizumab-XELIRI and bevacizumab-FOLFIRI arms, median PFS and overall survival (OS) were 9 and 23 months, respectively. The most frequent toxicities were grade 3/4 neutropenia (bevacizumab-XELIRI 18%; bevacizumab-FOLFIRI 26%) and grade 3 diarrhoea (12% and 5%, respectively). |
1 |
| 166. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin |
Experimental-Tx |
Period 1: 430 patients; Period 2: 117 patients |
To compare the safety and efficacy of the following three different irinotecan-containing regimens in the first-line treatment of metastatic colorectal cancer: irinotecan plus infusional fluorouracil (FU)/leucovorin (LV) (FOLFIRI), irinotecan plus bolus FU/LV (mIFL), and irinotecan plus oral capecitabine (CapeIRI). |
Median PFS was 7.6 months for FOLFIRI, 5.9 months for mIFL (P = .004 for the comparison with FOLFIRI), and 5.8 months for CapeIRI (P = .015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (P = .09), and 18.9 months for CapeIRI (P = .27). CapeIRI was associated with higher rates of severe vomiting, diarrhea, and dehydration. After the amendment to add bevacizumab, the median survival time has not yet been reached for FOLFIRI+Bev and was 19.2 months for mIFL+Bev (P = .007). FOLFIRI+Bev was associated with a higher rate of > or = grade 3 hypertension than mIFL+Bev. |
1 |
| 167. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23-30. |
Experimental-Tx |
795 patients |
To compare the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. |
A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. |
1 |
| 168. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. The Lancet. Oncology 2015;16:1306-15. |
Experimental-Tx |
508 patients |
To provide mature results for overall survival—a secondary endpoint—and report treatment efficacy in RAS and BRAF molecular subgroups. |
Between July 17, 2008, and May 31, 2011, 508 patients were randomly assigned. At a median follow-up of 48·1 months (IQR 41·7-55·6), median overall survival was 29·8 months (95% CI 26·0-34·3) in the FOLFOXIRI plus bevacizumab group compared with 25·8 months (22·5-29·1) in the FOLFIRI plus bevacizumab group (hazard ratio [HR] 0·80, 95% CI 0·65-0·98; p=0·03). Median overall survival was 37·1 months (95% CI 29·7-42·7) in the RAS and BRAF wild-type subgroup compared with 25·6 months (22·4-28·6) in the RAS-mutation-positive subgroup (HR 1·49, 95% CI 1·11-1·99) and 13·4 months (8·2-24·1) in the BRAF-mutation-positive subgroup (HR 2·79, 95% CI 1·75-4·46; likelihood-ratio test p<0·0001). Treatment effect was not significantly different across molecular subgroups (pinteraction=0·52). |
1 |
| 169. Sag AA, Selcukbiricik F, Mandel NM. Evidence-based medical oncology and interventional radiology paradigms for liver-dominant colorectal cancer metastases. [Review]. World J Gastroenterol. 22(11):3127-49, 2016 Mar 21. |
Review/Other-Tx |
N/A |
To review evidence-based conceptual, pharmacological, and technological paradigm shifts in parenteral and percutaneous treatment strategies as well as forthcoming evidence regarding next-generation systemic, locoregional, and local treatment approaches for this patient population. |
No results available. |
4 |
| 170. Wicherts DA, de Haas RJ, Adam R. Bringing unresectable liver disease to resection with curative intent. Eur J Surg Oncol. 2007;33 Suppl 2:S42-51. |
Review/Other-Tx |
N/A |
To describe all currently available oncological and surgical options to convert patients with technical unresectable liver metastases to a resectable situation. |
Hepatic resection of colorectal liver metastases after downstaging by chemotherapy provides the only chance of long-term survival for patients with initially unresectable disease. |
4 |
| 171. Guglielmi A, Ruzzenente A, Conci S, Valdegamberi A, Iacono C. How much remnant is enough in liver resection? Dig Surg 2012;29:6-17. |
Review/Other-Tx |
N/A |
To investigate the different risk factors related to the occurrence of post-hepatectomy liver failure (PHLF) and to identify the limits for a safe liver resection in patients with normal liver and injured liver (cirrhosis, cholestasis, steatosis and post-chemotherapy liver injury). |
In spite of improvements in surgical and postoperative management, the parameters determining how much liver can be resected are still largely undefined. A number of preoperative, intraoperative and postoperative factors all contribute to the likelihood of liver failure after surgery. The safe limits for liver resection can be estimated from the data of the literature for patients with normal liver and for those with different types of liver injury. |
4 |
| 172. Toso C, Pinto Marques H, Andres A, et al. Liver transplantation for colorectal liver metastasis: Survival without recurrence can be achieved. Liver Transpl 2017;23:1073-76. |
Observational-Tx |
12 patients |
To demonstrate the potential of achieving disease-free survival after transplantation for colorectal metastases in a meaningful proportion of patients. |
No abstract or results available. |
2 |
| 173. Gillams AR, Lees WR. Radio-frequency ablation of colorectal liver metastases in 167 patients. Eur Radiol 2004;14:2261-7. |
Observational-Tx |
167 patients |
To report our results from a prospective study of 167 patients with colorectal liver metastases treated with radio-frequency ablation (RFA). |
The mean number of metastases was 4.1 (1-27). The mean maximum diameter was 3.9 cm (1-12). Fifty-one (31%) had stable/treated extra-hepatic disease. Treatments were performed under general anaesthesia using US and CT guidance and single or cluster water-cooled electrodes (Valleylab, Boulder, CO). All patients had been rejected for or had refused surgical resection. Eighty percent received chemotherapy. Survival data were stratified by tumour burden at the time of first RFA. The mean number of RFA treatments was 2.1 (1-7). During a mean follow-up of 17 months (0-89), 72 developed new liver metastases and 71 developed progressive extra-hepatic disease. There were 14/354 (4%) major local complications and 22/354 (6%) minor local complications. For patients with < or =5 metastases, maximum diameter < or =5 cm and no extra-hepatic disease, the 5-year survival from the time of diagnosis was 30% and from the time of first thermal ablation was 26%. Given that the 5-year survival for operable patients is a median of 32%, our 5-year survival of 30% is promising. |
2 |
| 174. Khajanchee YS, Hammill CW, Cassera MA, Wolf RF, Hansen PD. Hepatic resection vs minimally invasive radiofrequency ablation for the treatment of colorectal liver metastases: a Markov analysis. Arch Surg. 2011;146(12):1416-1423. |
Review/Other-Tx |
30 articles from literature search and 99 patients from database of patients undergoing laparoscopic RFA |
A systematic review of published literature was performed, identifying studies involving patients with colorectal liver metastases treated with RFA or resection. |
The base-case analysis (60-year-old man) demonstrated a mean +/- SD quality-adjusted life expectancy of 5.67 +/- 0.71 years and a 5-year survival of 38.2% following resection. Based on current literature, the mean +/- SD quality-adjusted life expectancy for RFA was 3.61 +/- 0.49 years, with a 5-year survival of 27.2%. Sensitivity analyses demonstrated that RFA becomes the preferred strategy if the median DFS reaches 1.42 years. When limited to patients from our institution with resectable lesions, the quality-adjusted life expectancy for RFA improved to a mean +/- SD of 5.72 +/- 0.50 years. |
4 |
| 175. Lemke J, Cammerer G, Ganser J, et al. Survival and Prognostic Factors of Colorectal Liver Metastases After Surgical and Nonsurgical Treatment. Clin Colorectal Cancer. 15(4):e183-e192, 2016 12. |
Observational-Tx |
506 patients (152 = resection, 354 = no treatment) |
To prospectively analyze the outcome of patients with CRLM in a population-based manner, and thereby, to compare the prognosis of patients undergoing resection with those receiving nonsurgical treatment.To identify and confirm important prognostic factors after resection of CRLM. |
The 5-year overall survival rate (5y-OSR) for patients receiving resection of CRLM (n = 152) was 46% (95% confidence interval (CI), 37%-54%) compared with a 5y-OSR of 6% (95% CI, 4%-9%) for patients treated nonsurgically (n = 354). There was no perioperative mortality. Multivariate analysis revealed, among other factors, good performance status of the patient (low American Society of Anesthesiologists score), the absence of extrahepatic metastases, < 5 metastatic lesions, and a tumor-free resection margin (R0) as important, independent prognostic factors. Importantly, repeated hepatic resections of CRLM performed in 13 patients were associated with an excellent outcome (5y-OSR, 47%; 95% CI, 17%-72%). |
2 |
| 176. Shady W, Petre EN, Gonen M, et al. Percutaneous Radiofrequency Ablation of Colorectal Cancer Liver Metastases: Factors Affecting Outcomes--A 10-year Experience at a Single Center. Radiology 2016;278:601-11. |
Observational-Tx |
162 patients |
To identify predictors of oncologic outcomes after percutaneous radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLMs) and to describe and evaluate a modified clinical risk score (CRS) adapted for ablation as a patient stratification and prognostic tool. |
Technique effectiveness was 94% (218 of 233). Median LTPFS was 26 months. At univariate analysis, predictors of shorter LTPFS were tumor size greater than 3 cm (P < .001), ablation margin size of 5 mm or less (P < .001), high modified CRS (P = .009), male sex (P = .03), and no history of prior hepatectomy (P = .04) or hepatic arterial infusion chemotherapy (P = .01). At multivariate analysis, only tumor size greater than 3 cm (P = .01) and margin size of 5 mm or less (P < .001) were independent predictors of shorter LTPFS. Median and 5-year OS were 36 months and 31%. At univariate analysis, predictors of shorter OS were tumor size larger than 3 cm (P = .005), carcinoembryonic antigen level greater than 30 ng/mL (P = .003), high modified CRS (P = .02), and extrahepatic disease (EHD) (P < .001). At multivariate analysis, tumor size greater than 3 cm (P = .006) and more than one site of EHD (P < .001) were independent predictors of shorter OS. |
2 |
| 177. Franzese C, Comito T, Clerici E, et al. Liver metastases from colorectal cancer: propensity score-based comparison of stereotactic body radiation therapy vs. microwave ablation. J Cancer Res Clin Oncol. 144(9):1777-1783, 2018 Sep. |
Observational-Tx |
135 patients treated with MWA or SBRT |
To compare the disease control in two groups of patients affected by liver metastases from CRC treated with microwave ablation (MWA) or stereotactic body radiation therapy (SBRT). |
A total of 135 patients with 214 lesions were included in the analysis. Median follow-up time was 24.5 months (range 2.4-95.8). The 1-year freedom from local progression (FFLP) was 88% (95%CI 80-92). In the SBRT group, FFLP was statistically longer than MWA group (p = 0.0214); the 1-year FFLP was 91% (95% CI 81-95) in SBRT group and 84% (95% CI 0.72-0.91) in MWA group. Patients treated with SBRT showed a reduce risk of local relapse compared to MWA (adjusted HR 0.31; 95%CI 0.13-0.70, p = 0.005). As expected, analogous result obtained in the inverse probability weighting analysis (HR 0.38; 95%CI 0.18-0.80; p = 0.011). |
2 |
| 178. Ceelen W, Praet M, Villeirs G, et al. Initial experience with the use of preoperative transarterial chemoembolization in the treatment of liver metastasis. Acta Chir Belg 1996;96:37-40. |
Observational-Tx |
14 patients-preoperative TAE group; 9 patients-surgical resection group |
To retrospectively evaluated the influence of preoperative Transarterial Chemoembolization (TAE) on technique and complications, tumour histology, and disease-free survival after surgery for hepatic metastasis. |
Extensive tumour necrosis was seen in the majority of patients treated with TAE; in tumours with an important fibrotic component, embolization was less effective. No significant effect was seen on operating time, transfusion requirement or perioperative complication rate. In the group of patients who underwent TAE, survival rate was 93% after a mean follow-up period of 15.5 months (SD: 12.5); recurrence was seen in only 8% of the survivors. In the second group, however, mortality was 33% after a median follow-up of 17.5 months (SD: 10), and recurrence was present in 66.7% of the survivors. These results indicate that preoperative TAE reduces the recurrence rate in the first postoperative year. Thereby survival may be improved in patients with resectable metastatic liver cancer. |
1 |
| 179. Yamakado K, Inaba Y, Sato Y, et al. Radiofrequency Ablation Combined with Hepatic Arterial Chemoembolization Using Degradable Starch Microsphere Mixed with Mitomycin C for the Treatment of Liver Metastasis from Colorectal Cancer: A Prospective Multicenter Study. Cardiovasc Intervent Radiol. 40(4):560-567, 2017 Apr. |
Observational-Tx |
25 patients |
To investigate possible benefits of radiofrequency ablation (RFA) combined with hepatic arterial chemoembolization using degradable starch microsphere (DSM) mixed with mitomycin C (MMC) in non-surgical candidates with colorectal liver metastases. |
This study examined 25 patients (22 males, 3 females) with 38 tumors of mean maximum diameter of 2.2 ± 0.9 cm (standard deviation) (range 1.0-4.2 cm). Their mean age was 70.2 ± 8.2 years (range 55-82 years). Local tumor progression developed in 3 tumors (7.9%, 3/38) of 3 patients (12%, 3/25) during the mean follow-up of 34.9 ± 9.2 months (range 18.3-50.1 months). The 2-year local tumor control rates were 92.0% [95% confidence interval (CI), 81.4-100%] on a patient basis and 94.6% (95% CI, 87.3-100%) on a tumor basis. The respective 2-year overall and recurrence-free survival rates were 88.0% (95% CI, 75.3-98.5%) and 63.3% (95% CI, 44.2-82.5%), with median survival time of 48.4 months. Fever was the only adverse event requiring treatments in 2 patients (8%). |
2 |
| 180. Folprecht G, Gruenberger T, Bechstein W, et al. Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study). Ann Oncol. 25(5):1018-25, 2014 May. |
Observational-Tx |
56 patients (arm A), 55 patients (arm B) |
To report the longterm outcome for patients with initially unresectable colorectal liver metastases treated with chemotherapy plus cetuximab plus or minus secondary surgical resection of their metastases. |
Between December 2004 and March 2008, 56 patients were randomised to arm A, 55 to arm B. The median OS was 35.7 [95% confidence interval (CI) 27.2-44.2] months [arm A: 35.8 (95% CI 28.1-43.6), arm B: 29.0 (95% CI 16.0-41.9) months, HR 1.03 (95% CI 0.66-1.61), P = 0.9]. The median PFS was 10.8 (95% CI 9.3-12.2) months [arm A: 11.2 (95% CI 7.2-15.3), arm B: 10.5 (95% CI 8.9-12.2) months, HR 1.18 (95% CI 0.79-1.74), P = 0.4]. Patients who underwent R0 resection (n = 36) achieved a better median OS [53.9 (95% CI 35.9-71.9) months] than those who did not [21.9 (95% CI 17.1-26.7) months, P < 0.001]. The median disease-free survival for R0 resected patients was 9.9 (95% CI 5.8-14.0) months, and the 5-year OS rate was 46.2% (95% CI 29.5% to 62.9%). |
2 |
| 181. Ruers T, Van Coevorden F, Punt CJ, et al. Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial. J Natl Cancer Inst 2017;109. |
Experimental-Tx |
119 patients (standard arm= 59, experimental arm = 60) |
To investigate the long-term benefits of tumor ablation employed for unresectable colorectal liver metastases. |
At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm. |
1 |
| 182. Chang DT, Swaminath A, Kozak M, et al. Stereotactic body radiotherapy for colorectal liver metastases: a pooled analysis. Cancer 2011;117:4060-9. |
Observational-Tx |
65 patients |
To determine outcomes of stereotactic body radiotherapy for colorectal liver metastases in a pooled patient cohort. |
Forty-seven (72%) patients had = 1 chemotherapy regimen before stereotactic body radiotherapy, and 27 (42%) patients had = 2 regimens. The median follow-up was 1.2 years (range, 0.3-5.2 years). The median dose was 42 gray (Gy; range, 22-60 Gy). When evaluated separately by multivariate analysis, total dose (P = .0015), dose/fraction (P = .003), and BED (P = .004) all correlated with local control by lesion. On multivariate analysis, nonactive extrahepatic disease was associated with overall survival (OS; P = .046), and sustained local control was closely correlated (P = .06). By using single-fraction equivalent dose, BED, or linear quadratic model-based single-fraction dose in the TCP model, the estimated dose range needed for 1-year local control > 90% is 46 to 52 Gy in 3 fractions. |
2 |
| 183. Lim A, Le Sourd S, Senellart H, et al. Hepatic Arterial Infusion Chemotherapy for Unresectable Liver Metastases of Colorectal Cancer: A Multicenter Retrospective Study. Clin Colorectal Cancer 2017;16:308-15. |
Observational-Tx |
61 patients |
To evaluate its feasibility, efficacy and tolerance in 4 centers. |
Sixty-one patients with unresectable LM from CRC were included. Patients had previously received systemic chemotherapy in 95% of patients and 82.8% had previous oxaliplatin treatment. Oxaliplatin was administered using an intra-arterial route combined with intravenous (I.V.) Five-fluorouracil (5-FU) with leucovorin alone in 43.3% of patients, or combined with other I.V. chemotherapies or monoclonal antibodies in 56.7% of patients. Grade 3 to 4 clinical toxicities were reported in 16% of patients, including 9.8% of neurotoxicity, and Grade 3 to 4 biological toxicities were reported in 24.6% of patients including 22.2% with neutropenia. Catheter-related complications were observed in 31.1%. Tumor response rate in first- and second-line was 26.5% and third- and fourth-line was 11%. Median overall survival (OS) in first- and second-line was 13.5 months and third- and fourth-line was 8.3 months (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.39-1.12; P = .1729). Median progression-free survival (PFS) in first- and second-line was 9 months and third- and fourth-line were 6 months (HR, 0.53; 95% CI, 0.18-0.659; P = .0037). A secondary R0 resection was possible in 10 cases (16.4%) allowing a 2-year survival of 80%. |
2 |
| 184. Guo JH, Zhang HY, Gao S, et al. Hepatic artery infusion with raltitrexed or 5-fluorouracil for colorectal cancer liver metastasis. World J Gastroenterol 2017;23:1406-11. |
Observational-Tx |
24 patients (TOMOX arm = 18, FOLFOX arm = 24) |
To evaluate the efficiency and safety of hepatic artery infusion chemotherapy (HAIC) using raltitrexed or 5-fluorouracil for colorectal cancer (CRC) liver metastasis (CRCLM). |
The median survival time (MST) from diagnosis of CRC was 40.8 mo in the oxaliplatin plus raltitrexed (TOMOX) arm and 33.5 mo in the oxaliplatin plus 5-fluorouracil (FOLFOX) arm (P = 0.802). MST from first HAIC was 20.6 mo in the TOMOX arm and 15.4 mo in the FOLFOX arm (P = 0.734). Median progression-free survival (PFS) from first HAIC was 4.9 mo and 6.6 mo, respectively, in the TOMOX arm and FOLFOX arm (P = 0.215). Leukopenia (P = 0.026) was more common in the FOLFOX arm, and hepatic disorder (P = 0.039) was more common in the TOMOX arm. There were no treatment-related deaths in the TOMOX arm and one treatment-related death in the FOLFOX arm. Analysis of prognostic factors indicated that response to HAIC was a significant factor related to survival. |
2 |
| 185. D'Angelica MI, Correa-Gallego C, Paty PB, et al. Phase II trial of hepatic artery infusional and systemic chemotherapy for patients with unresectable hepatic metastases from colorectal cancer: conversion to resection and long-term outcomes. Ann Surg 2015;261:353-60. |
Observational-Tx |
49 patients |
To evaluate conversion rate of patients with unresectable colorectal-liver metastasis to complete resection with hepatic-arterial infusion plus systemic chemotherapy including bevacizumab (Bev). |
Median number of tumors was 14 and 65% were previously treated patients. A high biliary toxicity rate was found in the first 24 patients whose treatment included Bev. The remaining 25 patients were treated without Bev. Overall response rates were 76% (4 complete responses). Twenty-three patients (47%) achieved conversion to resection at a median of 6 months from treatment initiation. Median OS and progression-free survival for all patients were 38 (95% confidence interval: 28 to not reached) and 13 months (95% confidence interval: 7-16). Bev administration did not impact outcome. Conversion was the only factor associated with prolonged OS and progression-free survival in multivariate analysis. On landmark analysis, patients who had undergone resection had longer OS than those who did not undergo resection (3-year OS: 80% vs 26%). Currently, 10 of 49 (20%) patients have no evidence of disease (NED) at a median follow-up of 39 months (32-65 months). |
2 |
| 186. Chan DL, Alzahrani NA, Morris DL, Chua TC. Systematic review and meta-analysis of hepatic arterial infusion chemotherapy as bridging therapy for colorectal liver metastases. [Review]. Surg Oncol. 24(3):162-71, 2015 Sep. |
Review/Other-Tx |
11 studies |
To evaluate the potential role of HAIC as a neoadjuvant downstaging therapy, prior to hepatic resection with curative intent for initially unresectable CRLM. |
Eleven studies (n = 1514) were included. HAIC response rate was 50% and achieved conversion to surgery rate in 18% of patients. The median overall and 5-year survival for patients who underwent conversion to hepatectomy was 53 months and 49% compared to 16 months and 3% for patients who did not undergo surgery. Meta-analysis demonstrated strong association between hepatectomy and improved 5-year survival (RR 0.56, 95% CI = 0.48-0.65, Z = 7.26, p < 0.00001). |
4 |
| 187. Arai Y, Ohtsu A, Sato Y, et al. Phase I/II study of radiologic hepatic arterial infusion of fluorouracil plus systemic irinotecan for unresectable hepatic metastases from colorectal cancer: Japan Clinical Oncology Group Trial 0208-DI. J Vasc Interv Radiol 2012;23:1261-7. |
Experimental-Tx |
25 patients with unresectable liver metastases |
To assess the combination of image-guided delivery of fluorouracil through HAIC and systemic irinotecan in a multicenter phase I/II study. |
No dose-limiting toxicity was encountered during phase I, and the recommended dose of irinotecan was set at 150 mg/m(2). Grade 3 or higher adverse events included hyperglycemia (15%), elevated ?-glutamyl transpeptidase levels (15%), and neutropenia (9%). The response rate and median survival time were 72% and 49.8 months (95% CI, 27.5-78.1 mo), respectively. |
2 |
| 188. Richardson AJ, Laurence JM, Lam VW. Transarterial chemoembolization with irinotecan beads in the treatment of colorectal liver metastases: systematic review. J Vasc Interv Radiol 2013;24:1209-17. |
Review/Other-Tx |
6 studies |
To evaluate available data on the efficacy and safety of DEBIRI embolization. |
Five observational studies and one randomized controlled trial (RCT) were reviewed. A total of 235 patients were included in the descriptive analysis of observational studies. Postembolization syndrome was the most common adverse event. Peak plasma levels of irinotecan were observed at 1-2 hours after administration. Wide variations in tumor response were observed. The median survival time ranged from 15.2 months to 25 months. In the RCT, treatment with DEBIRI was superior to systemic chemotherapy with 5-fluorouracil/leucovorin/irinotecan in terms of quality of life and progression-free survival. |
4 |
| 189. Albert M, Kiefer MV, Sun W, et al. Chemoembolization of colorectal liver metastases with cisplatin, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol. Cancer. 2011;117(2):343-352. |
Observational-Tx |
121 patients |
To evaluate response and survival after transarterial chemoembolization. |
A total of 245 treatments were performed over 141 cycles on 121 patients. 95/141 treatment cycles were evaluable for response: 2 (2%) partial response, 39 (41%) stable disease, and 54 (57%) progression. Median time to disease progression in the treated liver was 5 months, and median time to disease progression anywhere was 3 months. Median survival was 33 months from diagnosis of the primary colon cancer, 27 months from development of liver metastases, and 9 months from chemoembolization. Survival was significantly better when chemoembolization was performed after first- or second-line systemic therapy (11-12 months) than after third- to fifth-line therapies (6 months) (P=.03). Presence of extrahepatic metastases did not adversely affect survival (P=.48). |
2 |
| 190. Wasan HS, Gibbs P, Sharma NK, et al. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 18(9):1159-1171, 2017 09. |
Experimental-Tx |
549 patients FOLFOX, 554 patients FOLFOX plus SIRT |
To examine the FOXFIRE, SIRFLOX, and FOXFIRE-Global randomised studies evaluating the efficacy of combining first-line chemotherapy with SIRT using yttrium-90 resin microspheres in patients with metastatic colorectal cancer with liver metastases. The studies were designed for combined analysis of overall survival. |
Between Oct 11, 2006, and Dec 23, 2014, 549 patients were randomly assigned to FOLFOX alone and554 patients were assigned FOLFOX plus SIRT. Median follow-up was 43·3 months (IQR 31·6–58·4). There were411 (75%) deaths in 549 patients in the FOLFOX alone group and 433 (78%) deaths in 554 patients in the FOLFOXplus SIRT group. There was no difference in overall survival (hazard ratio [HR] 1·04, 95% CI 0·90–1·19; p=0·61). Themedian survival time in the FOLFOX plus SIRT group was 22·6 months (95% CI 21·0–24·5) compared with23·3 months (21·8–24·7) in the FOLFOX alone group. In the safety population containing patients who received atleast one dose of study treatment, as treated, the most common grade 3–4 adverse event was neutropenia (137 [24%]of 571 patients receiving FOLFOX alone vs 186 (37%) of 507 patients receiving FOLFOX plus SIRT). Serious adverseevents of any grade occurred in 244 (43%) of 571 patients receiving FOLFOX alone and 274 (54%) of 507 patientsreceiving FOLFOX plus SIRT. 10 patients in the FOLFOX plus SIRT group and 11 patients in the FOLFOX alonegroup died due to an adverse event; eight treatment-related deaths occurred in the FOLFOX plus SIRT group andthree treatment-related deaths occurred in the FOLFOX alone group. |
1 |
| 191. van Hazel GA, Heinemann V, Sharma NK, et al. SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer. J Clin Oncol. 34(15):1723-31, 2016 05 20. |
Experimental-Tx |
530 patients (control, 263; SIRT, 267) |
To assess the efficacy and safety of adding selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)-based chemotherapy in patients with previously untreated metastatic colorectal cancer. |
Between October 2006 and April 2013, 530 patients were randomly assigned to treatment (control, 263; SIRT, 267). Median PFS at any site was 10.2 v 10.7 months in control versus SIRT (hazard ratio, 0.93; 95% CI, 0.77 to 1.12; P = .43). Median PFS in the liver by competing risk analysis was 12.6 v 20.5 months in control versus SIRT (hazard ratio, 0.69; 95% CI, 0.55 to 0.90; P = .002). Objective response rates (ORRs) at any site were similar (68.1% v 76.4% in control v SIRT; P = .113). ORR in the liver was improved with the addition of SIRT (68.8% v 78.7% in control v SIRT; P = .042). Grade = 3 adverse events, including recognized SIRT-related effects, were reported in 73.4% and 85.4% of patients in control versus SIRT. |
1 |
| 192. Gibbs P, Heinemann V, Sharma NK, et al. Effect of Primary Tumor Side on Survival Outcomes in Untreated Patients With Metastatic Colorectal Cancer When Selective Internal Radiation Therapy Is Added to Chemotherapy: Combined Analysis of Two Randomized Controlled Studies. Clin Colorectal Cancer. 17(4):e617-e629, 2018 12. |
Observational-Tx |
739 patients |
To examine the survival data from 2 randomized studies to determine whether the outcomes differ between patients with mCRC with right-sided primary (RSP) tumors and those with left-sided primary (LSP) tumors after selective internal radiation therapy (SIRT) plus mFOLFOX6 (folinic acid [leucovorin], 5-fluorouracil, oxaliplatin) chemotherapy, versus chemotherapy alone. |
In the combined analysis of all 739 patients enrolled, SIRT had no effect on OS (median OS, 24.3 vs. 24.6 months; hazard ratio [HR], 1.021; P = .810). For the 179 patients (24.2%) with a RSP tumor, OS was improved with the addition of SIRT (median, 22.0 vs. 17.1 months HR, 0.641; P = .008). The addition of SIRT was not associated with a significant difference in OS among the 540 patients with a LSP tumor (median, 24.6 vs. 26.6 months; HR, 1.120; P = .264). A test of treatment interaction by primary tumor side was statistically significant for RSP and SIRT (P = .002). |
2 |
| 193. Seidensticker R, Denecke T, Kraus P, et al. Matched-pair comparison of radioembolization plus best supportive care versus best supportive care alone for chemotherapy refractory liver-dominant colorectal metastases. Cardiovasc Intervent Radiol 2012;35:1066-73. |
Observational-Tx |
58 patients (29 = radioembolization, 29 = BSC) |
To evaluate overall survival after radioembolization or best supportive care (BSC) in patients with chemotherapy-refractory liver-dominant metastatic colorectal cancer (mCRC). |
Of 29 patients in each study arm, 16 pairs (55.2%) matched for all four criteria, and 11 pairs (37.9%) matched three criteria. Patients in both groups had a similar performance status (Karnofsky index, median 80% [range, 60-100%]). Compared with BSC alone, radioembolization prolonged survival (median, 8.3 vs. 3.5 months; P < 0.001) with a hazard ratio of 0.3 (95% confidence interval, 0.16-0.55; P < 0.001) in a multivariate Cox proportional hazard model. Treatment-related adverse events following radioembolization included: grade 1-2 fatigue (n = 20, 69%), grade 1 abdominal pain/nausea (n = 14, 48.3%), and grade 2 gastrointestinal ulceration (n = 3, 10.3%). Three cases of grade 3 radiation-induced liver disease were symptomatically managed. |
2 |
| 194. Cosimelli M, Golfieri R, Cagol PP, et al. Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases. Br J Cancer 2010;103:324-31. |
Observational-Tx |
50 patients |
To evaluate the radioembolisation of patients with colorectal liver metastases (mCRC) who failed previous oxaliplatin- and irinotecan-based systemic chemotherapy regimens. |
Of 50 eligible patients, 38 (76%) had received > or =4 lines of chemotherapy. Most presented with synchronous disease (72%), >4 hepatic metastases (58%), 25-50% replacement of total liver volume (60%) and bilateral spread (70%). Early and intermediate (>48 h) WHO G1-2 adverse events (mostly fever and pain) were observed in 16 and 22% of patients respectively. Two died due to renal failure at 40 days or liver failure at 60 days respectively. By intention-to-treat analysis using Response Evaluation Criteria in Solid Tumours, 1 patient (2%) had a complete response, 11 (22%) partial response, 12 (24%) stable disease, 22 (44%) progressive disease; 4 (8%) were non-evaluable. Median overall survival was 12.6 months (95% CI, 7.0-18.3); 2-year survival was 19.6%. |
2 |
