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1. Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual (7th Edition). New York, NY: Springer; 2010. Review/Other-Dx N/A Cancer staging manual. n/a 4
2. American College of Radiology. ACR Appropriateness Criteria®: Local Regional Recurrence and Salvage Surgery-Breast Cancer. Available at: https://acsearch.acr.org/docs/69387/Narrative/. Review/Other-Tx N/A Evidence-based guidelines to assist referring physicians and other providers in making the most appropriate imaging or treatment decision for a specific clinical condition. N/A 4
3. American College of Radiology. ACR Appropriateness Criteria®: Postmastectomy Radiotherapy. Available at: https://acsearch.acr.org/docs/69347/Narrative/. Review/Other-Tx N/A Evidence-based guidelines to assist referring physicians and other providers in making the most appropriate imaging or treatment decision for a specific clinical condition. N/A 4
4. Buchholz TA, Lehman CD, Harris JR, et al. Statement of the science concerning locoregional treatments after preoperative chemotherapy for breast cancer: a National Cancer Institute conference. J Clin Oncol. 2008;26(5):791-797. Review/Other-Tx N/A To review the state of the science with respect to diagnostic imaging and locoregional therapy for patients with breast cancer receiving preoperative chemotherapy. Loco-regional therapy decisions should be based on the pretreatment clinical extent of disease and the pathologic extent of the disease after chemotherapy. Physical examination and imaging studies that accurately define the initial extent of disease are required before treatment. Increased use of preoperative chemotherapy has raised questions concerning optimal methods to stage and monitor disease response to treatment and how to optimize loco-regional treatment. Multidisciplinary approach improves outcomes. 4
5. Liberman L, Morris EA, Dershaw DD, Abramson AF, Tan LK. MR imaging of the ipsilateral breast in women with percutaneously proven breast cancer. AJR Am J Roentgenol. 2003;180(4):901-910. Observational-Dx 70 consecutive patients Retrospective review of MRI findings in the ipsilateral breast in women with percutaneously proven breast cancer. MRI identified mammographically and clinically occult cancer other than the index lesion in the ipsilateral breast in 19 women (27%), including infiltrating cancer in 11 women (16%) and ductal carcinoma in situ in 8 women (11%). MRI identified additional sites of ipsilateral cancer in 27% of women with percutaneously proven breast cancer. The yield was highest in women with a family history of breast cancer or infiltrating lobular histology in the index cancer. 3
6. Liberman L, Morris EA, Kim CM, et al. MR imaging findings in the contralateral breast of women with recently diagnosed breast cancer. AJR Am J Roentgenol. 2003;180(2):333-341. Observational-Dx 1,336 consecutive patients Retrospective review to determine the frequency and positive predictive value of biopsy performed on the basis of MRI findings in the contralateral breast in women with recently diagnosed breast cancer. Contralateral breast biopsy was recommended in 32% of women. Cancer occult to mammography and physical examination was detected by MRI in 12 women, constituting 20% of women who underwent contralateral biopsy and 5% of women who underwent contralateral breast MRI. 3
7. Rosen EL, Blackwell KL, Baker JA, et al. Accuracy of MRI in the detection of residual breast cancer after neoadjuvant chemotherapy. AJR Am J Roentgenol. 2003;181(5):1275-1282. Observational-Dx 21 patients To evaluate the ability of MRI to accurately show residual primary breast malignancy in women treated with neoadjuvant chemotherapy. MRI after chemotherapy showed a correlation coefficient of 0.75 with histology, which was better than physical examination (r = 0.61). MRI underestimated the extent of residual tumor in 2 patients by >1 cm (including 1 false-negative examination), was within 1 cm in 12/21 patients, and overestimated tumor extent by >1 cm in 7/21 patients. MRI can show residual malignancy after neoadjuvant chemotherapy better than physical examination, particularly in patients who have not had a complete clinical response to therapy. 3
8. Yeh E, Slanetz P, Kopans DB, et al. Prospective comparison of mammography, sonography, and MRI in patients undergoing neoadjuvant chemotherapy for palpable breast cancer. AJR Am J Roentgenol. 2005;184(3):868-877. Observational-Dx 31 patients Prospective study to determine the relative accuracy of mammography, US, and MRI in predicting residual tumor after neoadjuvant chemotherapy for breast cancer as compared with the gold standards of physical examination and pathology. Agreement rates about the degree of response were 32%, 48%, and 55%, respectively, for mammography, US, and MRI compared with clinical evaluation and did not differ statistically. Agreement about the rate of response as measured by clinical examination, mammography, US, and MRI compared with the gold standard (pathology) was 19%, 26%, 35%, and 71%, respectively. MRI agreed with the gold standard significantly more often (P<0.002 for all 3 paired comparisons with MRI). 2
9. Dose-Schwarz J, Tiling R, Avril-Sassen S, et al. Assessment of residual tumour by FDG-PET: conventional imaging and clinical examination following primary chemotherapy of large and locally advanced breast cancer. Br J Cancer. 2010;102(1):35-41. Experimental-Dx 99 patients To evaluate FDG-PET (2-(fluorine-18)-fluoro-2-deoxy-D-glucose positron emission tomography) for assessment of residual tumour after primary chemotherapy of large and locally advanced breast cancer in comparison with conventional imaging modalities. By applying a threshold SUV of 2.0, the sensitivity of FDG-PET for residual tumour was 32.9% (specificity, 87.5%) and increased to 57.5% (specificity, 62.5%) at a threshold SUV of 1.5. Conventional imaging modalities were more sensitive in identifying residual tumour, but had a low corresponding specificity; sensitivity and specificity were as follows: MRI 97.6 and 40.0%, mammography 92.5 and 57.1%, ultrasound 92.0 and 37.5%, respectively. Breast MRI provided the highest accuracy (91.3%), whereas FDG-PET had the lowest accuracy (42.7%). 2
10. Groheux D, Espie M, Giacchetti S, Hindie E. Performance of FDG PET/CT in the clinical management of breast cancer. [Review]. Radiology. 266(2):388-405, 2013 Feb. Review/Other-Dx N/A To review the role of metabolic imaging with fluorine 18 fluorodeoxyglucose (FDG) in breast cancer. FDG PET/CT is very useful for restaging of cancer in patients with documented breast cancer recurrence or in those who are suspected of having breast cancer recurrence and is more efficient than PET alone and conventional imaging methods. FDG PET/CT is also efficient to perform the staging of locally advanced and inflammatory breast cancer. It allows detection of extraaxillary lymph nodes and distant metastases. PET/CT also brings valuable information in the staging of clinical stage IIB and primary operable stage IIIA breast carcinoma. In contrast, the spatial resolution of PET (approximately 5–6 mm) is not sufficient to allow the detection of early axillary node involvement and micrometastases. PET/CT cannot replace staging by using the sentinel node procedure. Also, PET is not recommended for the initial assessment of stage I breast cancer. The metabolic information provided by using PET has been shown to be valuable for the early assessment of response to chemotherapy (at the neoadjuvant and metastasis settings), but this indication remains to be validated. 4
11. Karlsson P, Cole BF, Chua BH, et al. Patterns and risk factors for locoregional failures after mastectomy for breast cancer: an International Breast Cancer Study Group report. Ann Oncol. 2012;23(11):2852-2858. Review/Other-Tx 8,106 patients enrolled in 13 randomized trials To study the rates and risk factors of local, axillary and supraclavicular recurrences separately, not only to guide patient selection for PMRT but also to guide radiation target volume when radiotherapy is indicated. Ten-year cumulative incidence for chest wall recurrence of >15% was seen in patients aged <40 years (16.1%), with >/=4 positive nodes (16.5%) or 0-7 uninvolved nodes (15.1%); for supraclavicular failures >10%: >/=4 positive nodes (10.2%); for axillary failures of >5%: aged <40 years (5.1%), unknown primary tumor size (5.2%), 0-7 uninvolved nodes (5.2%). In patients with 1-3 positive nodes, 10-year cumulative incidence for chest wall recurrence of >15% were age <40, peritumoral vessel invasion or 0-7 uninvolved nodes. Age, number of positive nodes and number of uninvolved nodes were significant parameters for each locoregional relapse site. 4
12. Whitman GJ, Strom EA. Workup and staging of locally advanced breast cancer. Semin Radiat Oncol. 2009;19(4):211-221. Review/Other-Dx N/A To review current approaches for workup and staging in patients with locally advanced breast cancer (LABC). In patients with LABC, accurate workup and staging evaluations are extremely important in facilitating appropriate multidisciplinary treatment. Careful clinical evaluation should be followed with mammography. Thereafter, sonography is particularly helpful in showing multifocal and/or multicentric disease and regional lymph node involvement. Ultrasoundguided biopsy can be performed to document the presence of additional tumor foci in the breast and regional lymph node metastases. MRI plays a role in some cases, and it is especially useful in showing multifocal and multicentric disease and chest wall involvement in the ipsilateral breast as well as disease in the contralateral breast. Conventional imaging used to evaluate for distant metastatic disease includes chest radiography, bone scan, and abdominal CT. PET and PET/CT scans have been shown to be useful in identifying distant metastatic disease not identified on conventional imaging. In the future, with developments in radiopharmaceuticals and imaging detectors, it is likely that PET/CT will play a greater role in regional lymph node staging. At the current time, because PET and PET/CT scans are unable to identify microscopic metastatic deposits, PET and PET/CT scans should not be used instead of axillary lymph node biopsy or sentinel lymph node biopsy in patients with LABC. If sentinel lymph node biopsy is being considered in a LABC patient, it is suggested that sentinel lymph node biopsy be performed before the initiation of neoadjuvant chemotherapy. 4
13. Haagensen CD, Stout AP. Carcinoma of the breast. III. Results of treatment, 1935-1942. Ann Surg. 1951;134(2):151-172. Review/Other-Tx N/A To review the results of radical mastectomy from 1935-1942. Recent improvement in results of radical mastectomy is partly due to: 1) Adoption of a more radical surgical attack embodying the principle of a more extensive sacrifice of skin over the breast, 2) Dissection of thin skin flaps, 3) Use of skin graft to cover defect, and 4) Willingness of surgeons to devote more time and care to the operation. End results are better in patients who had biopsy than in those in which no biopsy was done. From 1935-1942, local recurrence rate following radical mastectomy has decreased, and both relative and absolute cure rates have improved. 4
14. Arriagada R, Mouriesse H, Sarrazin D, Clark RM, Deboer G. Radiotherapy alone in breast cancer. I. Analysis of tumor parameters, tumor dose and local control: the experience of the Gustave-Roussy Institute and the Princess Margaret Hospital. Int J Radiat Oncol Biol Phys. 1985;11(10):1751-1757. Observational-Tx 463 patients Retrospective study to analyze tumor parameters, tumor dose and local control in breast cancer patients treated by RT. Statistical analysis of local control showed 2 significant factors: tumor dose and tumor size. Multivariate analysis permitted to define an "individual risk" of local recurrence according to 3 independent factors: tumor size, tumor fixation, and nodal fixation. "Individual risk" was a good prognostic factor for local control. Tumor dose was the most significant independent factor on local control, able to produce up to a 10-fold increase compared to 2-fold decrease for tumor size. 2
15. Fletcher GH, Montague ED. Radical Irradiation of Advanced Breast Cancer. Am J Roentgenol Radium Ther Nucl Med. 1965;93:573-584. Review/Other-Tx N/A Review survival rates of radical irradiation in patients with advanced breast cancer. Ultraprotracted irradiation technique is an effective means of obtaining high percentage of permanent controls of inoperable breast cancers. 4
16. Zucali R, Uslenghi C, Kenda R, Bonadonna G. Natural history and survival of inoperable breast cancer treated with radiotherapy and radiotherapy followed by radical mastectomy. Cancer. 1976;37(3):1422-1431. Observational-Tx 454 consecutive patients: 321 RT alone 133 RT + radical mastectomy To evaluate the time and site of relapse as well as the median survival of patients with T3-T4 Nx Mo breast cancer treated with RT. Incidence of relapse was higher in presence than in absence of regional adenopathy, with no statistical difference between T3 and T4. Inflammatory carcinoma showed highest percent of relapse during the first 12 months (48%). Site of first relapse occurred more often (68%) in areas distant from irradiation fields. Median survival for the whole series was 2.5 years, with no significant difference between roentgen therapy (3 years) and cobalt (2.5 years). Patients treated with RT followed by surgery showed a median survival of 3.9 years compared to 2.1 years for those given only irradiation. 2
17. Huang CJ, Hou MF, Lin SD, et al. Comparison of local recurrence and distant metastases between breast cancer patients after postmastectomy radiotherapy with and without immediate TRAM flap reconstruction. Plast Reconstr Surg. 2006;118(5):1079-1086; discussion 1087-1078. Observational-Tx 191 patients 82 TRAM flap group 109 non-TRAM flap group To compare the local recurrence and distant metastasis of PMRT for breast cancer patients with and without immediate TRAM flap reconstruction. Median follow-up period 40 months. Percentages of chest wall recurrence were 3.7% (3/82) in TRAM flap group and 1.8% (2/109) in non-TRAM flap group (P=0.653). Percentages of distant metastases were 12.2% (10/82) in TRAM group and 15.6% (17/109) for non-TRAM group (P=0.67). Percentages of acute radiation dermatitis according to RTOG scoring criteria (TRAM flap group vs non-TRAM flap group) were as follows: Grade I, 74/82 (90%) vs 93/109 (85%). Grade II, 7/82 (9%) vs 13/109 (12%). Grade III, 1/82 (1%) vs 3/109 (3%) (P=0.558). There were no significant differences in the incidences of complication, locoregional recurrence, and distant metastasis between TRAM flap and non-TRAM flap patients. Results suggest that immediate TRAM flap reconstruction can be considered a feasible treatment for breast cancer patients requiring PMRT. 2
18. Formenti SC, Volm M, Skinner KA, et al. Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: a phase I/II trial. J Clin Oncol. 2003;21(5):864-870. Experimental-Tx 44 patients Phase I/II trial to examine the safety and efficacy of primary twice-weekly paclitaxel and concurrent RT before MRM followed by adjuvant doxorubicin-based chemotherapy. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in 6 patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. 34% of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (<10 residual microscopic foci of invasive breast cancer). Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for locally advanced breast cancer. 1
19. Lerouge D, Touboul E, Lefranc JP, Genestie C, Moureau-Zabotto L, Blondon J. Combined chemotherapy and preoperative irradiation for locally advanced noninflammatory breast cancer: updated results in a series of 120 patients. Int J Radiat Oncol Biol Phys. 2004;59(4):1062-1073. Observational-Tx 120 patients To evaluate updated data concerning survival and locoregional control in a prospective study of LABC after primary chemotherapy followed by external preoperative RT. Median follow-up 140 months. 10-year actuarial local failure rate was 13% after RT alone, 23% after wide excision and RT, and 4% after mastectomy (P=0.1). Possibility of BCT was related to initial tumor size (<6 cm vs >6 cm in diameter, P=0.002). 10-year overall metastatic DFS rate was 61%. In nonconservative breast treatment group, of 32 patients with no change in clinical tumor size after induction chemotherapy, 10-year metastatic DFS rate was 59% with only one local relapse. 1
20. Recht A, Gray R, Davidson NE, et al. Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: experience of the Eastern Cooperative Oncology Group. J Clin Oncol. 1999;17(6):1689-1700. Review/Other-Tx 2,016 patients entered onto 4 randomized prospective trials To assess patterns of failure and how selected prognostic and treatment factors affect the risks of locoregional failure after mastectomy in breast cancer patients with histologically involved axillary nodes treated with chemotherapy with or without tamoxifen without RT. 1,099 patients (55%) experienced disease recurrence. The first sites of failure were as follows: isolated locoregional failure, 254 (13%); locoregional failure with simultaneous distant failure, 166 (8%); and distant only, 679 (34%). The risk of locoregional failure with or without simultaneous distant failure at 10 years was 12.9% in patients with 1 to 3 positive nodes and 28.7% for patients with 4 or more positive nodes. Multivariate analysis showed that increasing tumor size, increasing numbers of involved nodes, negative ER protein status, and decreasing number of nodes examined were significant for increasing the rate of locoregional failure with or without simultaneous distant failure. Locoregional failure after mastectomy is a substantial clinical problem, despite the use of chemotherapy with or without tamoxifen. Prospective randomized trials will be necessary to estimate accurately the potential disease-free and OS benefits of PMRT for patient’s in particular prognostic subgroups treated with presently used and future systemic therapy regimens. 4
21. Taghian A, Jeong JH, Mamounas E, et al. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004;22(21):4247-4254. Observational-Tx 5,758 patients To assess patterns of LRF in LN-positive breast cancer patients treated with mastectomy and adjuvant chemotherapy (+/- tamoxifen) and without postmastectomy RT in five National Surgical Adjuvant Breast and Bowel Project trials. The overall 10-year cumulative incidences of isolated LRF, LRF with or without distant failure, and distant failure alone as first event were 12.2%, 19.8%, and 43.3%, respectively. Cumulative incidences for LRF as first event with or without distant failure for patients with 1-3, 4-9, and =10 LN-positive were 13.0%, 24.4%, and 31.9%, respectively (P<.0001). In patients with large tumors and 4 or more LN-positive, LRF as first event remains a significant problem. Although postmastectomy RT is currently recommended for patients with four or more LN-positive, it may also have value in selected patients with 1-3 LN-positive. However, in the absence of a randomized trial examining the worth of RT in this group of patients, the value of postmastectomy RT remains unknown. 2
22. Childs SK, Chen YH, Duggan MM, et al. Surgical margins and the risk of local-regional recurrence after mastectomy without radiation therapy. Int J Radiat Oncol Biol Phys. 2012;84(5):1133-1138. Observational-Tx 397 women To clarify the influence of the mastectomy margin on the risk of LRR. The median follow-up was 6.7 years (range, 0.5-12.8 years). The superficial margin was positive in 41 patients (10%) and close (</=2 mm) in 56 (14%). The deep margin was positive in 23 patients (6%) and close in 34 (9%). The 5-year LRR and DM rates for all patients were 2.4% (95% confidence interval, 0.9-4.0) and 3.5% (95% confidence interval, 1.6-5.3) respectively. Fourteen patients had an LRR. Margin status was significantly associated with time to isolated LRR (P=.04); patients with positive margins had a 5-year LRR of 6.2%, whereas patients with close margins and negative margins had 5-year LRRs of 1.5% and 1.9%, respectively. On univariate analysis, positive margins, positive nodes, lymphovascular invasion, grade 3 histology, and triple-negative subtype were associated with significantly higher rates of LRR. When these factors were included in a multivariate analysis, only positive margins and triple-negative subtype were associated with the risk of LRR. 2
23. Sheikh F, Rebecca A, Pockaj B, et al. Inadequate margins of excision when undergoing mastectomy for breast cancer: which patients are at risk? Ann Surg Oncol. 2011;18(4):952-956. Observational-Tx 426 patients To analyze the margin status and risk factors for inadequate margins among patients who underwent skin-sparing mastectomies (SSM) and traditional total mastectomies (TM). A total of 426 patients were identified. The mean age was 60 years and 90% were white. Mean tumor size was 2.6 cm and 44% had multiple ipsilateral carcinomas. Of 426 patients, 177 (42%) underwent SSM with reconstruction and 249 (58%) TM. The rate of positive or close margins on the initial specimen was 29% for SSM vs. 12% for TM (P < 0.01), and the rate of reoperation for margins was 7% for SSM vs. 2% for TM (P < 0.01). Logistic regression analysis revealed that independent risk factors for initial close or positive margins included SSM (odds ratio 2.36, 95% confidence interval [95% CI] 1.05-5.30), multiple ipsilateral tumors (OR 2.12, 95% CI 1.05-4.24), and upper-inner quadrant location (OR 2.58, 95% CI 1.07-6.19). Mean follow-up time was 28 months, and the local recurrence rate was 0.9%. Local recurrence rates were not different for those undergoing SSM (1.1%) vs. TM (0.8%, P = NS). 2
24. Matsunuma R, Oguchi M, Fujikane T, et al. Influence of lymphatic invasion on locoregional recurrence following mastectomy: indication for postmastectomy radiotherapy for breast cancer patients with one to three positive nodes. Int J Radiat Oncol Biol Phys. 2012;83(3):845-852. Observational-Tx 1,994 node-positive patients To identify patient groups for whom PMRT may be indicated, focusing on varied locoregional recurrence rates depending on lymphatic invasion (ly) status. Multivariate analysis showed that the lymphatic invasion status affected the locoregional recurrence rate to as great a degree as the number of positive lymph nodes (p < 0.001). Especially for patients with one to three positive nodes, extensive lymphatic invasion was a more significant factor than stage T3 in the TNM staging system for locoregional recurrence (p < 0.001 vs. p = 0.295). 3
25. Mamounas EP, Anderson SJ, Dignam JJ, et al. Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27. J Clin Oncol. 2012;30(32):3960-3966. Review/Other-Tx 3,088 patients To examine the rates and patterns of LRR in patients treated with neoadjuvant chemotherapy and to identify independent predictors ofLRRin this setting. In 3,088 patients, 335 LRR events had occurred after 10 years of follow-up. The 10-year cumulative incidence of LRR was 12.3% for mastectomy patients (8.9% local; 3.4% regional) and 10.3% for lumpectomy plus breast radiotherapy patients (8.1% local; 2.2% regional). Independent predictors of LRR in lumpectomy patients were age, clinical nodal status (before NC), and pathologic nodal status/breast tumor response; in mastectomy patients, they were clinical tumor size (before NC), clinical nodal status (before NC), and pathologic nodal status/breast tumor response. By using these independent predictors, groups at low, intermediate, and high risk of LRR could be identified. Nomograms that incorporate these independent predictors were created. 4
26. Wang SL, Li YX, Song YW, et al. Triple-negative or HER2-positive status predicts higher rates of locoregional recurrence in node-positive breast cancer patients after mastectomy. Int J Radiat Oncol Biol Phys. 2011;80(4):1095-1101. Observational-Tx 835 patients To evaluate the prognostic value of determining estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression in node-positive breast cancer patients treated with mastectomy. Patients with triple-negative, Rec-/HER2+, and Rec+/HER2+ expression profiles had a significantly lower 5-year locoregional recurrence-free survival than those with Rec+/HER2- profiles (86.5% vs. 93.6%, p = 0.002). Compared with those with Rec+/HER2+ and Rec+/HER2- profiles, patients with Rec-/HER2- and Rec-/HER2+ profiles had significantly lower 5-year distant metastasis-free survival (69.1% vs. 78.5%, p = 0.000), lower disease-free survival (66.6% vs. 75.6%, p = 0.000), and lower overall survival (71.4% vs. 84.2%, p = 0.000). Triple-negative or Rec-/HER2+ breast cancers had an increased likelihood of relapse and death within the first 3 years after treatment. 2
27. Allis S, Reali A, Mortellaro G, Arcadipane F, Bartoncini S, Ruo Redda MG. Should radiotherapy after primary systemic therapy be administered with the same recommendations made for operable breast cancer patients who receive surgery as first treatment? A critical review. Tumori. 2012;98(5):543-549. Review/Other-Tx N/A To provide a comprehensive discussion of how primary systemic therapy in operable breast cancer patients could affect the indications of radiotherapy to optimize local-regional treatment and to discussavailable literature data regarding neoadjuvant treatment and radiotherapy. No results stated in abstract. 4
28. Montagna E, Bagnardi V, Rotmensz N, et al. Pathological complete response after preoperative systemic therapy and outcome: relevance of clinical and biologic baseline features. Breast Cancer Res Treat. 2010;124(3):689-699. Observational-Tx 687 patients To evaluate, in a large series of patients who were homogeneously diagnosed and treated in a single institution, the outcome of patients who achieved pCR or presented residual disease (RD) at final surgery, according to the clinical and biologic baseline features. Of the 687 patients treated with preoperative therapy, we identified 82 patients who achieved pCR (12%) and 605 patients with RD (88%). A statistically significant difference in disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) was observed for patients with pCR compared with those who had RD (5 year DFS 73% vs. 59% P = 0.029; 5 year DDFS 81% vs. 72% P = 0.085; 5 year OS 88% vs. 77% P = 0.033). At the multivariate analysis, for patients achieving pCR, large tumor size (> 5 cm) correlated with worse DFS (HR 3.18; 95% CI 1.34-7.51); clinical nodal involvement was associated with poorer DFS and DDFS (HR 6.94; 95% CI 1.62-29.73 and HR 9.87 95% CI 1.29-75.53, respectively). pCR after preoperative systemic therapy correlated with significant improved outcome. 2
29. Floyd SR, Buchholz TA, Haffty BG, et al. Low local recurrence rate without postmastectomy radiation in node-negative breast cancer patients with tumors 5 cm and larger. Int J Radiat Oncol Biol Phys. 2006;66(2):358-364. Observational-Tx 70 patients To assess the need for adjuvant radiotherapy following mastectomy for patients with node-negative breast tumors 5 cm or larger. With a median follow-up of 85 months, the 5-year actuarial LRF rate was 7.6% (95% confidence interval, 3%-16%). LRF was primarily in the chest wall (4/5 local failures), and lymphatic-vascular invasion (LVI) was statistically significantly associated with LRF risk by the log-rank test (p=0.017) and in Cox proportional hazards analysis (p=0.038). The 5-year OS and DFS rates were 83% and 86% respectively. LVI was also significantly associated with OS and DFS in both univariate and multivariate analysis. 2
30. Taghian AG, Jeong JH, Mamounas EP, et al. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006;24(24):3927-3932. Observational-Tx 313 patients To assess patterns of locoregional failure (LRF) in LN-negative patients who underwent mastectomy, either with or without adjuvant chemotherapy or hormonal therapy and without postmastectomy radiation therapy (PMRT). Twenty-eight patients experienced LRF. The overall 10-year cumulative incidences of isolated LRF, LRF with and without distant failure (DF), and DF alone as first event were 7.1%, 10.0%, and 23.6%, respectively. Cumulative incidences for isolated LRF as first event for patients with tumors of 5 cm or more than 5 cm were 7.0% and 7.2%, respectively (P = .9). For patients who underwent no systemic treatment, chemotherapy alone, tamoxifen alone, or chemotherapy plus tamoxifen, the incidences were 12.6%, 5.6%, 4.6%, and 5.3%, respectively (P = .2). The majority of failures occurred on the chest wall (24 of 28 patients). Multivariate analysis did not identify significant prognostic factors for LRF. 2
31. McGale P, Taylor C, Correa C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383(9935):2127-2135. Meta-analysis 8,135 patients; 22 trials To assess the effect of radiotherapy in these women after mastectomy and axillary dissection. 3786 women had axillary dissection to at least level II and had zero, one to three, or four or more positive nodes. All were in trials in which radiotherapy included the chest wall, supraclavicular or axillary fossa (or both), and internal mammary chain. For 700 women with axillary dissection and no positive nodes, radiotherapy had no significant effect on locoregional recurrence (two-sided significance level [2p]>0.1), overall recurrence (rate ratio [RR], irradiated vs not, 1.06, 95% CI 0.76-1.48, 2p>0.1), or breast cancer mortality (RR 1.18, 95% CI 0.89-1.55, 2p>0.1). For 1314 women with axillary dissection and one to three positive nodes, radiotherapy reduced locoregional recurrence (2p<0.00001), overall recurrence (RR 0.68, 95% CI 0.57-0.82, 2p=0.00006), and breast cancer mortality (RR 0.80, 95% CI 0.67-0.95, 2p=0.01). 1133 of these 1314 women were in trials in which systemic therapy (cyclophosphamide, methotrexate, and fluorouracil, or tamoxifen) was given in both trial groups and, for them, radiotherapy again reduced locoregional recurrence (2p<0.00001), overall recurrence (RR 0.67, 95% CI 0.55-0.82, 2p=0.00009), and breast cancer mortality (RR 0.78, 95% CI 0.64-0.94, 2p=0.01). For 1772 women with axillary dissection and four or more positive nodes, radiotherapy reduced locoregional recurrence (2p<0.00001), overall recurrence (RR 0.79, 95% CI 0.69-0.90, 2p=0.0003), and breast cancer mortality (RR 0.87, 95% CI 0.77-0.99, 2p=0.04). M
32. Shirvani SM, Pan IW, Buchholz TA, et al. Impact of evidence-based clinical guidelines on the adoption of postmastectomy radiation in older women. Cancer. 2011;117(20):4595-4605. Observational-Tx 38,322 women To determine the temporal association between guideline publication and changes in the receipt of PMRT by older women with breast cancer stratified according to their risk group. The receipt of PMRT by patients with high-risk breast cancer increased from 36.5% (95% confidence interval, 26%-46.9%) to 57.7% (95% confidence interval, 46.9%-68.4%) between 1996 and 1998 with the publication of landmark clinical trials. However no further increase in PMRT use was observed between 1999 and 2005 despite publication of multiple guidelines endorsing its use; during this period, only 54.8% (2729 of 4978) of high-risk patients received PMRT. Within this high-risk group, patients with smaller tumors or less advanced lymph node disease were at risk for PMRT omission. 2
33. Adams S, Chakravarthy AB, Donach M, et al. Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: pathologic response correlates with five-year overall survival. Breast Cancer Res Treat. 2010;124(3):723-732. Experimental-Tx 105 patients To report the 5-year results of the patients accrued to the trial, and analyze outcomes in the context of pathologic response and original tumor characteristics. Patients were treated with paclitaxel (30 mg/m(2) intravenously twice a week) for 10-12 weeks. Daily radiotherapy was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2-7 of paclitaxel treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Pathological complete response (pCR) was defined as the absence of invasive cancer in breast and lymph nodes and pathological partial response (pPR) as the persistence of <10 microscopic foci of invasive carcinoma in breast or lymph nodes. Pathologic response (pCR and pPR) after neoadjuvant chemoradiation was achieved in 36/105 patients (34%) and was associated with significantly better DFS and OS. Pathological responders had a lower risk of recurrence or death (HR = 0.35, P = 0.01) and a longer OS (HR = 4.27, P = 0.01) compared with non-responders. Median DFS and OS were 57 and 84 months for non-responders, respectively, and have not yet been reached for responders. Importantly, pathologic response was achieved in 54% of patients with HR negative tumors (26/48). 1
34. Fowble BL, Einck JP, Kim DN, et al. Role of postmastectomy radiation after neoadjuvant chemotherapy in stage II-III breast cancer. Int J Radiat Oncol Biol Phys. 2012;83(2):494-503. Review/Other-Tx 24 studies To identify a cohort of women treated with neoadjuvant chemotherapy and mastectomy for whom postmastectomy radiation therapy (PMRT) may be omitted according to the projected risk of local-regional failure (LRF). Of 24 sources identified, 23 were retrospective studies from single institutions. Consensus on the appropriateness rating, defined as 80% agreement in a category, was achieved for 86% of the cases. Distinct LRF risk categories emerged. Clinical stage II (T1-2N0-1) patients, aged >40 years, estrogen receptor-positive subtype, with pathologic complete response or 0-3 positive nodes without lymphovascular invasion or extracapsular extension, were identified as having </= 10% risk of LRF without radiation. 4
35. Hortobagyi GN, Ames FC, Buzdar AU, et al. Management of stage III primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer. 1988;62(12):2507-2516. Experimental-Tx 174 patients To describe the results of treatment in patients with Stage 111, noninflammatory, primary breast cancer. There were 48 patients with Stage IIIA, and 126 patients with Stage IIIB disease. A complete remission was achieved in 16.7% of the patients, and 70.7% achieved a partial remission after the initial three cycles of FAC. The complete response rate was higher for patients with Stage IIIA, than for patients with Stage IIIB disease. All but six of the 174 patients treated were rendered disease-free after induction chemotherapy and local treatment. The median follow-up of this group of patients is 59 months. The 5-year disease-free survival rates were 84% for patients with Stage IIIA, and 33% for patients with Stage IIIB disease. The 5-year survival rate for, patients with Stage IIIA was 84%, and for patients with Stage IIIB 44%. At 10 years, 56% of patients with Stage IIIA and 26% of patients with Stage IIIB disease are projected to be alive. Younger patients, and those with estrogen receptor-positive tumors, had a trend for better survival than older patients and those with estrogen receptor-negative tumors. The quality of response to induction chemotherapy correlated prominently with prognosis, as did compliance with treatment. Twenty-six patients (15.3%) had locoregional recurrence. 1
36. Karlsson YA, Malmstrom PO, Hatschek T, et al. Multimodality treatment of 128 patients with locally advanced breast carcinoma in the era of mammography screening using standard polychemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide: prognostic and therapeutic implications. Cancer. 1998;83(5):936-947. Experimental-Tx 128 patients To determine the objective response rate and to study the frequency of local relapse as well as disease free survival (DFS) and overall survival (OS) in subsets of patients with LABC. Clinical responses were observed in 60% of the patients; 5% had complete responses (CR) and 55% had partial responses (PR). Stable disease (SD) was observed in 40%. No patient had progressive disease (PD) preoperatively. With a median follow-up of 37 months, the median disease free survival (DFS) and median overall survival (OS) were 29 and 54 months, respectively. The actuarial 5-year DFS and OS were 36% and 49%, respectively. The locoregional recurrence rate was 20%, and 53% of the patients experienced systemic relapse. Univariate analysis revealed a significant prognostic difference according to clinical stage of LABC in favor of less advanced stages. Clinical and biologic parameters linked to a significantly worse prognosis were the presence of inflammatory breast carcinoma and peau d'orange. There was a significant trend of worse prognosis for patients receiving below 60% and 75% of the intended dose intensity with reference to DFS and OS, respectively. 1
37. Swain SM, Sorace RA, Bagley CS, et al. Neoadjuvant chemotherapy in the combined modality approach of locally advanced nonmetastatic breast cancer. Cancer Res. 1987;47(14):3889-3894. Experimental-Tx 76 patients To report on treating 76 patients with locally advanced breast cancer, 31 with stage IIIA, 41 with stage IIIB, and 4 with stage IV disease, with primary induction chemotherapy including an attempted hormonal synchronization in 70 patients The objective response rate to induction chemotherapy was 93% with 49% complete response (CR), 44% PR, and 7% NC. The median numbers of cycles of chemotherapy to achieve a CR, PR, or NC were 5, 3, and 5, respectively. Three patients who currently have PRs are still on chemotherapy with continued tumor regression. Of 37 patients achieving a CR to chemotherapy, 35 were assessed by biopsies to determine pathological evidence of response. Twenty-three of the 37 patients (62%) were proven to be complete responders with negative biopsies. Twenty-four patients have relapsed, 6 with stage IIIA, 16 with stage IIIB, and 2 with stage IV. Five patients have had locoregional relapses alone, 4 locoregional and distant, and 15 distant alone. Median time to progression is 35.9 months for stage IIIA and 34.2 months for stage IIIB. Median survival is 35.3 months for stage IIIB and is indeterminate for stage IIIA. 2
38. De Lena M, Varini M, Zucali R, et al. Multimodal treatment for locally advanced breast cancer. Result of chemotherapy-radiotherapy versus chemotherapy-surgery. Cancer Clin Trials. 1981;4(3):229-236. Experimental-Tx 132 patients To test the efficacy of two combined modality approaches (chemotherapy + RT or chemotherapy + mastectomy) in women with LABC. Although higher proportion of women achieved complete remission after mastectomy (100%) compared to women given RT (60%), total response rate at end of combined modality was identical (75%). There was no significant difference between the two treatment groups in terms of patterns of treatment failure, median duration of response, and total survival. Results of present study failed to indicate that surgery improved overall results including local control, over RT in a combined modality setting. 1
39. Perloff M, Lesnick GJ, Korzun A, et al. Combination chemotherapy with mastectomy or radiotherapy for stage III breast carcinoma: a Cancer and Leukemia Group B study. J Clin Oncol. 1988;6(2):261-269. Experimental-Tx 113 patients; 91 operable To compare chemotherapy with mastectomy or RT to determine which of these modalities afforded better local tumor control. Median follow-up 37 months. Overall duration of disease control was similar following either modality, with median of 29.2 months for surgery patients and 24.4 months for RT patients. Pre- or perimenopausal status and inflammatory disease were associated with shorter disease control and survival. Prolonged control of stage III breast carcinoma can be achieved with combined modality therapy in which cytotoxic chemotherapy precedes and follows treatment directly primarily at the breast tumor, using either surgery or RT. 1
40. Pierce L, Adler D, Helvie M, Lichter A, Merajver S. The use of mammography in breast preservation in locally advanced breast cancer. Int J Radiat Oncol Biol Phys. 1996;34(3):571-577. Experimental-Dx 91 patients Prospective trial to evaluate the role of mammography in selecting candidates with LABC for conservative local therapy. Among patients with a clinical complete response, positive and negative predictive values for residual cancer using postinduction mammography were 79% and 56%, respectively. Although mammography improved accuracy of noninvasive evaluation with patients with clinical complete response, pathologic assessment was still required to determine appropriate local therapy. 1
41. Hellman S. Improving the therapeutic index in breast cancer treatment: the Richard and Hinda Rosenthal Foundation Award lecture. Cancer Res. 1980;40(12):4335-4342. Review/Other-Tx N/A Lecture. To improve the relationship between desired and undesired effects of therapy (therapeutic index) in breast cancer treatment. Eliminating breast cancer while preserving normal structure and function is the goal of combining RT and tumor excision. Results with this technique are comparable to those following mastectomy without loss of the breast or chest musculature. Hopefully, use of limited surgery, RT with both external beam and interstitial radiation and finally, adjuvant chemotherapy when indicated, will achieve the dual goals of increased patient survival with preservation of function and structure. 4
42. Rutqvist LE, Pettersson D, Johansson H. Adjuvant radiation therapy versus surgery alone in operable breast cancer: long-term follow-up of a randomized clinical trial. Radiother Oncol. 1993;26(2):104-110. Experimental-Tx 960 patients: 316 (preoperative RT); 323 (postoperative RT); 321 surgery alone To present long-term results from randomized trial of pre- or postoperative megavoltage RT vs surgery alone in pre- and postmenopausal women with operable breast cancer. Mean follow-up 16 years. Results showed significant benefit with RT in terms of RFS survival during entire follow-up period. There was OS difference in favor of RT patients which was not statistically significant (P=0.09). Among patients who developed LRR, long-term control was achieved in about one-third of the cases. This was similar among those who received adjuvant RT (34%) compared to those initially treated with surgery alone (32%). This suggests that local undertreatment may be deleterious in subgroups of patients. 1
43. Huang EH, Tucker SL, Strom EA, et al. Postmastectomy radiation improves local-regional control and survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy. J Clin Oncol. 2004;22(23):4691-4699. Observational-Tx 676 patients Retrospective analysis to evaluate the efficacy of radiation in patients treated with neoadjuvant chemotherapy and mastectomy. Median follow-up: Irradiated, 73 months; nonirradiated, 66 months. Irradiated patients had lower rate of LRR (10-year rates: 11% vs 22%, P=.0001). Radiation reduced LRR for patients with clinical T3 or T4 tumors, stage =IIB disease, pathological tumor size >2 cm, or =4 positive nodes (P=.002 for all comparisons). Radiation improved CSS in the following subsets: stage =IIIB disease, clinical T4 tumors, and =4 positive nodes (P=.007 for all comparisons). After neoadjuvant chemotherapy and mastectomy, radiation benefited both local control and survival for patients with clinical T3 tumors or stage III-IV disease and for patients with =4 positive nodes. Radiation should be considered for these patients regardless of their response to initial chemotherapy. 2
44. Nagar H, Mittendorf EA, Strom EA, et al. Local-regional recurrence with and without radiation therapy after neoadjuvant chemotherapy and mastectomy for clinically staged T3N0 breast cancer. Int J Radiat Oncol Biol Phys. 2011;81(3):782-787. Observational-Tx 162 patients To determine local-regional recurrence (LRR) risk according to whether postmastectomy radiation therapy (PMRT) was used to treat breast cancer patients with clinical T3N0 disease who received neoadjuvant chemotherapy (NAC) and mastectomy. At a median follow-up of 75 months, 15 of 162 patients developed LRR. For all patients, the 5-year LRR rate was 9% (95% confidence interval [CI], 4%-14%). The 5-year LRR rate for those who received PMRT was 4% (95% CI, 1%-9%) vs. 24% (95% CI, 10%-39%) for those who did not receive PMRT (p <0.001). A significantly higher proportion of irradiated patients had pathology involved LNs and were </=40 years old. Among patients who had pathology involved LNs, the LRR rate was lower in those who received PMRT (p <0.001). A similar trend was observed for those who did not have pathology involved LN disease. Among nonirradiated patients, the appearance of pathologic LN disease after NAC was the only clinicopathologic factor examined that significantly correlated with the risk of LRR. 2
45. Olson JE, Neuberg D, Pandya KJ, et al. The role of radiotherapy in the management of operable locally advanced breast carcinoma: results of a randomized trial by the Eastern Cooperative Oncology Group. Cancer. 1997;79(6):1138-1149. Experimental-Tx 332 patients randomized to either RT or observation To test the role of RT following total mastectomy, axillary dissection, and adjuvant systemic therapy in the management of operable LABC. Median follow-up period 9.1 years. There were no significant differences in time to relapse and OS between the 2 treatment arms. RT: 60% relapsed, median time to relapse 4.7 years, 46% alive at last follow-up, median survival 8.3 years. Observation: 56% relapsed, median time to relapse 5.2 years, 47% alive at last follow-up, median survival 8.1 years. 2 treatment arms had significantly different patterns of sites of first recurrence. 15% loco-regional first recurrences in RT group vs 24% observation. First relapses at distant sites (50% RT vs 35% observation) (P=0.003). RT for LABC, following mastectomy, axillary dissection, and adjuvant systemic therapy, results in fewer loco-regional but more distant recurrences at first relapse. 1
46. Klefstrom P, Grohn P, Heinonen E, Holsti L, Holsti P. Adjuvant postoperative radiotherapy, chemotherapy, and immunotherapy in stage III breast cancer. II. 5-year results and influence of levamisole. Cancer. 1987;60(5):936-942. Experimental-Tx 120 patients Randomized trial to present 5-year results and influence of levamisole from randomized trial studying preoperative RT, chemotherapy, and immunotherapy in stage III breast cancer patients. RT provided local and chemotherapy systemic control over the tumor, but the best patient-saving results were achieved with a combination of RT and chemotherapy. Levamisole seemed to increase DFS and OS in all 3 treatment arms (RT, chemotherapy, combined treatment). Significance was reached in DFS (P=0.035) and OS, adjusted for all other treatment modalities (P=0.019). 1
47. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med. 1997;337(14):949-955. Experimental-Tx 1,708 women: 852 randomized to receive 8 cycles of CMF plus RT of the chest wall and regional LNs or 9 cycles of CMF alone (856 women) Randomized trial of RT after mastectomy in high-risk premenopausal women, all of whom also received adjuvant systemic chemotherapy with CMF. The frequency of LRR alone or with distant metastases was 9% among the women who received RT plus CMF and 32% among those who received CMF alone (P<0.001). The probability of survival free of disease after 10 years was 48% among the women assigned to RT plus CMF and 34% among those treated only with CMF (P<0.001). OS at 10 years was 54 % among those given RT and CMF and 45 % among those who received CMF alone (P<0.001). Multivariate analysis demonstrated that RT after mastectomy significantly improved DFS and OS, irrespective of tumor size, the number of positive nodes, or the histopathological grade. The addition of postoperative RT to mastectomy and adjuvant chemotherapy reduces LRR and prolongs survival in high-risk premenopausal women with breast cancer. 1
48. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet. 1999;353(9165):1641-1648. Experimental-Tx 1,375 patients randomized to adjuvant tamoxifen (30 mg daily for 1 year) alone (689) or with postoperative RT to the chest wall and regional LNs (686) To compare adjuvant tamoxifen alone with tamoxifen plus postoperative RT in a randomized trial among postmenopausal women who had undergone mastectomy. Median follow-up 123 months. LRR occurred in 52 (8%) of RT plus tamoxifen group and 242 (35%) of tamoxifen only group (P<0.001). DFS: 36% RT plus tamoxifen, 24% tamoxifen alone (P<0.001). OS: higher in RT group (385 vs 434 deaths; survival 45% vs 36% at 10 years, P=0.03). Postoperative RT decreased risk of LRR and was associated with improved survival in high-risk postmenopausal breast-cancer patients after mastectomy and limited axillary dissection. Improved survival in high-risk breast cancer is best achieved by strategy of both loco-regional and systemic tumor control. 1
49. Kyndi M, Sorensen FB, Knudsen H, Overgaard M, Nielsen HM, Overgaard J. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2008; 26(9):1419-1426. Observational-Tx 1,000 patients To examine the importance of ER, PR, HER-2, and constructed subtypes in a large study randomly assigning patients to receive or not receive postmastectomy RT. A significantly improved OS after postmastectomy RT was seen only among patients characterized by good prognostic markers such as hormonal receptor-positive and HER-2- patients (including the two Rec+ subtypes). No significant OS improvement after postmastectomy RT was found among patients with an a priori poor prognosis, the hormonal receptor-negative and HER-2+ patients, and in particular the Rec-/HER-2+ subtype. Hormonal receptor status, HER-2, and the constructed subtypes may be predictive of LRR and survival after postmastectomy RT. 1
50. Hoffman KE, Mittendorf EA, Buchholz TA. Optimising radiation treatment decisions for patients who receive neoadjuvant chemotherapy and mastectomy. Lancet Oncol. 2012;13(6):e270-276. Review/Other-Tx N/A To review the literature assessing radiation therapy after neoadjuvant chemotherapy and mastectomy, and identify subgroups of women who might benefit from such therapy. Results not stated in abstract. 4
51. Le Scodan R, Selz J, Stevens D, et al. Radiotherapy for stage II and stage III breast cancer patients with negative lymph nodes after preoperative chemotherapy and mastectomy. Int J Radiat Oncol Biol Phys. 2012;82(1):e1-7. Observational-Tx 134 patients To evaluate the effect of postmastectomy radiotherapy (PMRT) in Stage II-III breast cancer patients with negative lymph nodes (pN0) after neoadjuvant chemotherapy (NAC). Of the 134 eligible patients, 78 (58.2%) received PMRT and 56 (41.8%) did not. At a median follow-up time of 91.4 months, the 5-year locoregional recurrence-free survival and OS rate was 96.2% and 88.3% with PMRT and 92.5% and 94.3% without PMRT, respectively (p = NS). The corresponding values at 10 years were 96.2% and 77.2% with PMRT and 86.8% and 87.7% without PMRT (p = NS). On multivariate analysis, PMRT had no effect on either locoregional recurrence-free survival (hazard ratio, 0.37; 95% confidence interval, 0.09-1.61; p = .18) or OS (hazard ratio, 2.06; 95% confidence interval, 0.71-6; p = .18). This remained true in the subgroups of patients with clinical Stage II or Stage III disease at diagnosis. A trend was seen toward poorer OS among patients who had not had a pathologic complete in-breast tumor response after NAC (hazard ratio, 6.65; 95% confidence interval, 0.82-54.12; p = .076). 2
52. Buchholz TA, Tucker SL, Masullo L, et al. Predictors of local-regional recurrence after neoadjuvant chemotherapy and mastectomy without radiation. J Clin Oncol. 2002;20(1):17-23. Observational-Tx 150 breast cancer cases Retrospective analysis to define clinical and pathologic predictors of LRR for patients treated with neoadjuvant chemotherapy and mastectomy without radiation. Median follow-up 4.1 years. 5- and 10-year LRR both 27%. Pathologic and treatment factors that positively correlated with LRR were size of residual primary tumor (P=.0048), increasing number of involved LNs (P<.0001), and no use of tamoxifen (P=.0013). In Cox analysis, clinical stage IIIB or greater (HR of 4.5, P<.001), pathologic involvement of =4 LNs (HR 2.7, P=.008), and no use of tamoxifen (HR 3.9, P=.027) independently predicted for LRR. Advanced disease and positive LNs after chemotherapy predict for clinically significant rates of LRR. 2
53. Beriwal S, Schwartz GF, Komarnicky L, Garcia-Young JA. Breast-conserving therapy after neoadjuvant chemotherapy: long-term results. Breast J. 2006;12(2):159-164. Observational-Tx 153 patients: 67 CMF chemo; 86 Adriamycin chemo To determine patterns of IBTR and LRR after neoadjuvant chemotherapy and BCT. Median follow-up 55 months. 8 patients developed LRR, 5 of which classified as IBTR. 5- and 10-year: loco-regional control (93%, 88%), IBTR-free survival (96%, 91%), distant metastasis-free survival (70%, 58%). IBTR positively correlated with advanced stage (P=0.03) and positive margin (P=0.04). 2
54. Chen AM, Meric-Bernstam F, Hunt KK, et al. Breast conservation after neoadjuvant chemotherapy: the MD Anderson cancer center experience. J Clin Oncol. 2004;22(12):2303-2312. Observational-Tx 340 breast cancer cases Retrospective review to determine patterns of LRR and IBTR among patients treated with breast conservation therapy after neoadjuvant chemotherapy. Median follow-up 60 months. 5-year: IBTR-free survival 95%, LRR-free survival 91%. Variables that positively correlated with IBTR and LRR were: 1) Clinical N2 or N3 disease; 2) Pathologic residual tumor >2 cm; 3) Multifocal pattern of residual disease; and 4) Lymphovascular space invasion in the specimen. Presence of any one factor associated with 5-year IBTR-free and LRR-free survival rates of 87% to 91% and 77% to 84%, respectively. BCT after neoadjuvant chemotherapy results in acceptably low rates of LRR and IBTR in appropriately selected patients, even those with T3 or T4 disease. 2
55. Chen AM, Meric-Bernstam F, Hunt KK, et al. Breast conservation after neoadjuvant chemotherapy. Cancer. 2005;103(4):689-695. Observational-Tx 340 patients To develop a prognostic index to help refine selection criteria and to serve as a general framework for clinical decision-making for patients treated by this multimodality approach. Actuarial 5-year IBTR-free survival rates were 97%, 88%, and 82% for patients in the low MD Anderson Prognostic Index (MDAPI) overall score 0 or 1, n=276), intermediate (MDAPI score 2, n=43), and high (MDAPI score 3 or 4, n=12) risk groups, respectively (P<0.001). Corresponding actuarial 5-year LRR-free survival rates were 94%, 83%, and 58%, respectively (P<0.001). Patients with an MDAPI score of 0 or 1, which made up 81% of the study population, had very low rates of IBTR and LRR. The MDAPI enabled the identification of a small group (4%) of patients who are at high risk for IBTR and LRR and who may benefit from alternative locoregional treatment strategies. 2
56. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008;26(5):778-785. Experimental-Tx 1,493 total patients: 751 preoperative doxorubicin and cyclophosphamide; 742 postoperative doxorubicin and cyclophosphamide To determine whether 4 cycles of doxorubicin and cyclophosphamide administered preoperatively improved breast cancer DFS and OS compared with doxorubicin and cyclophosphamide administered postoperatively. There were trends in favor of preoperative chemotherapy for DFS and OS in women <50 years old (HR = 0.85, P=.09 for DFS; HR = 0.81, P=.06 for OS). DFS conditional on being event free for 5 years also demonstrated a strong trend in favor of the preoperative group (HR = 0.81, P=.053). Protocol B-27 results demonstrated that the addition of docetaxel to doxorubicin and cyclophosphamide did not significantly impact DFS or OS. Preoperative docetaxel added to doxorubicin and cyclophosphamide significantly increased the proportion of patients having pathologic complete responses compared with preoperative doxorubicin and cyclophosphamide alone (26% vs 13%, respectively; P<.0001). In both studies, patients who achieved a pathologic complete response continue to have significantly superior DFS and OS outcomes compared with patients who did not. Protocols B-18 and B-27 demonstrate that preoperative therapy is equivalent to adjuvant therapy. B-27 also showed that the addition of preoperative taxanes to doxorubicin and cyclophosphamide improves response. 1
57. Shen J, Valero V, Buchholz TA, et al. Effective local control and long-term survival in patients with T4 locally advanced breast cancer treated with breast conservation therapy. Ann Surg Oncol. 2004;11(9):854-860. Observational-Tx 33 patients To assess the outcome of a carefully selected group of patients who presented with breast cancer involving the skin and who had BCT following neoadjuvant chemotherapy. Median follow-up 91 months. 5-year: DFS (70%), OS (78%), IBTR (6%). Patients with T4 breast cancer who experience tumor shrinkage and resolution of skin changes with neoadjuvant chemotherapy represent select group of patients who can have BCT. 2
58. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst. 2005;97(3):188-194. Meta-analysis 3,946 patients; 9 randomized studies To compare the clinical end points of patients with breast cancer treated preoperatively with systemic therapy (neoadjuvant therapy) and of those treated postoperatively with the same regimen (adjuvant therapy) in a meta-analysis of randomized trials. We found no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms associated with death (summary risk ratio [RR] = 1.00, 95% confidence interval [CI] = 0.90 to 1.12), disease progression (summary RR = 0.99, 95% CI = 0.91 to 1.07), or distant disease recurrence (summary RR = 0.94, 95% CI = 0.83 to 1.06). However, neoadjuvant therapy was statistically significantly associated with an increased risk of loco-regional disease recurrences (RR = 1.22, 95% CI = 1.04 to 1.43), compared with adjuvant therapy, especially in trials where more patients in the neoadjuvant, than the adjuvant, arm received radiation therapy without surgery (RR = 1.53, 95% CI = 1.11 to 2.10). Across trials, we observed heterogeneity in the rates of complete clinical response (range = 7%-65%; P for heterogeneity of <.001), pathologic response (range = 4%-29%; P for heterogeneity of <.001), and adoption of conservative local treatment (range = 28%-89% in neoadjuvant arms, P for heterogeneity of <.001). M
59. Hance KW, Anderson WF, Devesa SS, Young HA, Levine PH. Trends in inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program at the National Cancer Institute. J Natl Cancer Inst. 2005;97(13):966-975. Review/Other-Tx SEER 9 Registries (n=180,224): IBC (n=3,648), LABC (n=3,636), and non-T4 breast cancer (n=172,940) To examine recent incidence trends for LABC and IBC in the US. Throughout the 1990s, IBC incidence rose (from 2 to 2.5 per 100,000), and survival improved modestly. Incidence for LABC declined (from 2.5 to 2.0). Substantial racial differences were noted in age at diagnosis, age-specific incidence rates, and survival outcomes. 4
60. Baldini E, Gardin G, Evagelista G, Prochilo T, Collecchi P, Lionetto R. Long-term results of combined-modality therapy for inflammatory breast carcinoma. Clin Breast Cancer. 2004;5(5):358-363. Review/Other-Tx 68 patients Review records of patients in two randomized phase III trials of combined-modality therapy in LABC. Both trials included patients with IBC. Records of these patients are reviewed, with a focus on the prognostic factors and long-term results obtained with this therapeutic modality. DFS rates at 5 and 10 years were 29% and 20%, respectively, and median DFS was 2.2 years (range, 3.8 months to 11.5 years). OS rates at 5 and 10 years were 44% and 32%, respectively, and median OS was 4 years (range, 5 months to 14.7 years). Significant prognostic factors for DFS and OS were the number of axillary nodes and residual disease in the breast at surgery. Analysis confirmed that patients with IBC obtained significant long-term survival benefit from combined-modality therapy. 4
61. Dawood S, Lei X, Dent R, et al. Survival of women with inflammatory breast cancer: a large population-based study. Ann Oncol. 2014;25(6):1143-1151. Observational-Tx 7,679 patients To see if there have been improvements in survival among women with stage III IBC, over time. A total of 7679 patients with IBC were identified of whom 1084 patients (14.1%) were diagnosed between 1990 and 1995, 1614 patients (21.0%) between 1996 and 2000, 2683 patients (34.9%) between 2001 and 2005, and 2298 patients (29.9%) between 2006 and 2010. The 2-year BCSS for the whole cohort was 71%. Two-year BCSS were 62%, 67%, 72%, and 76% for patients diagnosed between 1990-1995, 1996-2000, 2001-2005, and 2006-2010, respectively (P < 0.0001). In the multivariable analysis, increasing year of diagnosis (modeled as a continuous variable) was associated with decreasing risks of death from breast cancer (HR = 0.98, 95% confidence interval 0.97-0.99, P < 0.0001). 2
62. Gonzalez-Angulo AM, Hennessy BT, Broglio K, et al. Trends for inflammatory breast cancer: is survival improving? Oncologist. 2007;12(8):904-912. Observational-Tx 398 patients To evaluate whether the survival of women with inflammatory breast cancer (IBC) treated at our institution has improved over the past 30 years. Three-hundred ninety-eight patients with IBC were treated between 1974 and 2005. Patient characteristics and outcomes were tabulated and compared among decades of diagnosis. Survival outcomes were estimated with the Kaplan-Meier product limit method and compared among groups with the log-rank statistic. Cox proportional hazards models were fit to determine the association between year of diagnosis and survival outcomes after adjustment for patient and disease characteristics and treatments received. The median follow-up was 5.8 years (range, 0.3-23.8 years). There were 238 recurrences and 236 deaths. The median recurrence-free survival (RFS) duration was 2.3 years and the median overall survival (OS) time was 4.2 years. In the models for RFS and OS, after adjustment for patient and disease characteristics, increasing year of diagnosis was not associated with a decrease in the risk for recurrence (hazard ratio, [HR], 1.00; 95% confidence interval [CI], 0.97-1.04) or death (HR, 0.97; 95% CI, 0.94-1.01). 2
63. Smoot RL, Koch CA, Degnim AC, et al. A single-center experience with inflammatory breast cancer, 1985-2003. Arch Surg. 2006;141(6):567-572; discussion 572-563. Observational-Tx 128 patients A single-institution experience with IBC during a 19-year period was examined to determine which prognostic factors might be identified for overall and DFS. Emphasis on the sequence of therapy. Overall median survival was 37 months, with a median disease-free interval of 23 months. 5-year survival was 42%, with a DFS of 21%. Univariate survival analysis highlighted previous hormone therapy (RR, 0.48; P=.04), RT (RR, 0.39; P=.02), sequence of therapy (P=.001), family history (RR, 0.47; P=.01), and palpable adenopathy (RR, 2.22; P<.001) as being important. Multivariate analysis of recurrence identified menopausal status as the key factor. Adenopathy at the initial examination was associated with decreased length of survival, while RT was associated with better survival. 2
64. Hennessy BT, Gonzalez-Angulo AM, Hortobagyi GN, et al. Disease-free and overall survival after pathologic complete disease remission of cytologically proven inflammatory breast carcinoma axillary lymph node metastases after primary systemic chemotherapy. Cancer. 2006;106(5):1000-1006. Observational-Tx 61 patients To determine long-term outcome in patients achieving a pathologic complete response of cytologically proven IBC axillary LN metastases after primary chemotherapy. Patients with cytologically documented axillary LN metastases from IBC were treated in three prospective primary chemotherapy trials. Pathologic complete response of axillary LN metastases is associated with an excellent prognosis in patients with IBC. The rates of axillary LN pathologic complete response are nearly 50% in patients with IBC who are treated with anthracyclines and weekly paclitaxel before surgery. However, those patients with residual axillary LN disease at the time of surgery greatly require the introduction of novel therapeutic strategies. 2
65. Liao Z, Strom EA, Buzdar AU, et al. Locoregional irradiation for inflammatory breast cancer: effectiveness of dose escalation in decreasing recurrence. Int J Radiat Oncol Biol Phys. 2000;47(5):1191-1200. Observational-Tx 115 patients Retrospective study to evaluate the effect of radiation dose escalation on loco-regional control, OS, and long-term complication in patients with IBC. Median follow-up 5.7 years. Entire patient group, 5-year DFS (32%), OS (40.5%). 10-year DFS (28.8%), OS (31.3%). Long-term complications of radiation, such as arm edema >3 cm (7 patients), rib fracture (10 patients), severe chest wall fibrosis (4 patients), and symptomatic pneumonitis (5 patients), were comparable in the 2 groups, indicating that dose escalation did not result in increased morbidity. Significant differences in rates of loco-regional control (P=0.03) and OS (P=0.03), and a trend of better DFS (P=0.06) were observed that favored the recently treated patients receiving the higher doses of irradiation. Twice-daily postmastectomy radiation to total of 66 Gy for patients with IBC resulted in improved loco-regional control, DFS, and OS, and was well tolerated. 2
66. Bristol IJ, Woodward WA, Strom EA, et al. Locoregional treatment outcomes after multimodality management of inflammatory breast cancer. Int J Radiat Oncol Biol Phys. 2008;72(2):474-484. Observational-Tx 192 patients To determine outcomes for patients with inflammatory breast cancer (IBC) treated with multimodality therapy, to identify factors associated with locoregional recurrence, and to determine which patients may benefit from radiation dose escalation. The 192 patients who were able to complete the planned course of chemotherapy, mastectomy, and postmastectomy radiation had significantly better outcomes than the 64 patients who did not. The respective 5-year outcome rates were: locoregional control (84% vs. 51%), distant metastasis-free survival (47% vs. 20%), and overall survival (51% vs. 24%) (p < 0.0001 for all comparisons). Univariate factors significantly associated with locoregional control in the patients who completed plan treatment were response to neoadjuvant chemotherapy, surgical margin status, number of involved lymph nodes, and use of taxanes. Increasing the total chest-wall dose of postmastectomy radiation from 60 Gy to 66 Gy significantly improved locoregional control for patients who experienced less than a partial response to chemotherapy, patients with positive, close, or unknown margins, and patients <45 years of age. 2
67. Damast S, Ho AY, Montgomery L, et al. Locoregional outcomes of inflammatory breast cancer patients treated with standard fractionation radiation and daily skin bolus in the taxane era. Int J Radiat Oncol Biol Phys. 2010;77(4):1105-1112. Observational-Tx 107 patients To assess locoregional outcomes of inflammatory breast cancer (IBC) patients who received standard fractionation radiation with daily skin bolus and taxanes as part of combined-modality therapy (CMT). All patients received chemotherapy (95% anthracycline and 95% taxane), modified radical mastectomy, and RT to the chest wall and regional lymphatics using standard fractionation to 50 Gy and daily skin bolus. The RT to the chest wall was delivered via electrons (55%) or photons (45%) in daily fractions of 180 cGy (73%) or 200 cGy (27%). Scar boost was performed in 11%. A majority (84%) of patients completed the prescribed treatment. Median follow-up was 47 months (range, 10-134 months). Locoregional control (LRC) at 3 years and 5 years was 90% and 87%, respectively. Distant metastases-free survival (DMFS) at 3 years and 5 years was 61% and 47%, respectively. 2
68. Yap ML, Sappiatzer J, Tieu MT, et al. Abstract P5-14-01: Chest wall bolus in post-mastectomy radiotherapy – Is it really necessary? Cancer Research. 2014;73(24 Supplement):P5-14-01-P15-14-01. Observational-Tx 314 patients To report on clinical outcomes for PMRT patients treated without the routine use of bolus. A total of 314 patients were suitable for analysis: 52 received bolus and 262 did not. The median follow up was 4.2 years, with a mean age of 52.7 years. Patients who received bolus had a higher T stage than those without bolus, with T1 tumors 16% vs 26%, T2 tumors 24% vs 40%, T3 tumors 45% vs 27% and T4 tumors 10% vs 1% (p = 0.002). For the whole cohort, 35% had N1 disease and 38% had N2/N3 disease, with no significant differences in N stage between the two groups. There was a higher incidence of dermal invasion for the bolus group compared to non-bolus, 27% vs. 7% (p<0.001), as well as lympho-vascular invasion, 73% vs. 46% (p<0.001) and positive margins, 14% vs. 3% (p = 0.003). There were no significant differences between the 2 groups in terms of ER positivity (58 vs. 76% p = 0.07), HER 2 positivity (17 vs. 9% p = 0.09) or grade 3 disease (75 vs. 67%, p = 0.77). Four-year LRR was 14% in the bolus group and 3% in the non-bolus group. On uni-variate analysis, this resulted in a significant difference in LRR (HR 3.1; CI 1.2-8.3; p = 0.02). However, when adjusting for margin status (HR 5.0; CI 1.5-16.5; p = 0.008), this result was no longer significant (HR = 2.5; CI 0.8-7.5, p = 0.12). Four-year OS was 77% vs. 86% for bolus vs. non-bolus group (p = 0.07). The pattern of failure in this cohort was predominantly distant, with 50/314 patients (16%) developing distant metastases as the first site of failure, 17 patients (5%) in the chest wall and 4 (1%) in regional nodes. There was a significant difference in acute skin toxicity between the bolus vs. non-bolus groups (p = 0.01) with Grade 2 toxicity 37% vs. 21%, grade 3 toxicity 0 vs. 1% and grade 4 toxicity 2% vs. 0%. 2
69. National Cancer Institute (NCI). Clinical Trial of The Use of Bolus in Post Mastectomy Irradiation in Breast Cancer. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). December 4, 2015. Available from: https://clinicaltrials.gov/ct2/show/study/NCT01925651. NLM Identifier: NCT01925651. Review/Other-Tx N/A To evaluate the impact of adding bolus in adjuvant radiotherapy after mastectomy, in relation to the time of treatment interruption and acute effects. This study evaluates whether there is an increase in treatment time with the addition of the bolus, which can overshadow the benefit of increased dose to the skin and subcutaneous tissue. No abstract available. 4
70. Dawood S, Cristofanilli M. Inflammatory breast cancer: what progress have we made? Oncology (Williston Park). 2011;25(3):264-270, 273. Review/Other-Tx N/A Review on the progress made in the field of IBC research over the last decade, with particular attention to advances in the areas of epidemiology, molecular biology, arid clinical management. Inflammatory breast cancer (IBC) is a rare and aggressive subtype of locally advanced breast cancer (LABC). Its diagnosis is primarily clinical; however, a pathological confirmation of invasive cancer is required. Historically, IBC was a uniformly fatal disease. A major advance in the last three decades has been the introduction of a multidisciplinary approach to the management of this aggressive disease, incorporating pre-operative chemotherapy, surgery, and radiation therapy; this approach has significantly improved survival. 4
71. Kao J, Conzen SD, Jaskowiak NT, et al. Concomitant radiation therapy and paclitaxel for unresectable locally advanced breast cancer: results from two consecutive phase I/II trials. Int J Radiat Oncol Biol Phys. 2005;61(4):1045-1053. Experimental-Tx 33 patients subset analysis of 16 patients To examine rates of local control of adverse events associated with concurrent radiation and chemotherapy among unresectable stage III breast patients. Concurrent week-on/week-off RT and paclitaxel +/- vinorelbine is effective locoregional therapy for unresectable LABC with an acceptable toxicity profile. Further investigation of concurrent chemoradiotherapy is warranted. 1
72. Karasawa K, Katsui K, Seki K, et al. Radiotherapy with concurrent docetaxel for advanced and recurrent breast cancer. Breast Cancer. 2003;10(3):268-274. Experimental-Tx 35 patients To examine whether the addition of docetaxel to RT enhanced tumor response in patients with advanced or recurrent breast cancer. Overall response was 95% for irradiated site and complete response was 68%. 17% had Grade 3-4 neutropenia, 6% radiation dermatitis and 3% pneumonitis. Concurrent treatment with docetaxel and radiation is an active and safe regimen and merits further study. 1
73. Burstein HJ, Bellon JR, Galper S, et al. Prospective evaluation of concurrent paclitaxel and radiation therapy after adjuvant doxorubicin and cyclophosphamide chemotherapy for Stage II or III breast cancer. Int J Radiat Oncol Biol Phys. 2006;64(2):496-504. Experimental-Tx 40 patients To evaluate the safety and feasibility of concurrent RT and paclitaxel-based adjuvant chemotherapy, given either weekly or every 3 weeks, after adjuvant doxorubicin and cyclophosphamide. Weekly paclitaxel treatment at 60 mg/m2 per week with concurrent radiation led to dose-limiting toxicity in 4/16 patients (25%), including 3 who developed pneumonitis (either Grade 2 [1 patient] or Grade 3 [2 patients]) requiring steroids. Efforts to eliminate this toxicity in combination with weekly paclitaxel through treatment scheduling and computed tomography-based RT simulation were not successful. By contrast, dose-limiting toxicity was not encountered among patients receiving concurrent radiation with paclitaxel given every 3 weeks at 135-175 mg/m2. However, Grade 2 radiation pneumonitis not requiring steroid therapy was seen in 2/24 patients (8%) treated in such a fashion. Excessive radiation dermatitis was not observed with either paclitaxel schedule. 2
74. Lee BT, T AA, Colakoglu S, et al. Postmastectomy radiation therapy and breast reconstruction: an analysis of complications and patient satisfaction. Ann Plast Surg. 2010;64(5):679-683. Observational-Tx 919 reconstructed breasts in 3 groups To examine PMRT and reconstruction compared with a control group without RT. Overall complication rates for patients undergoing PMRT (before and after reconstruction) were higher than that of the controls (39.66% vs 23.16%, P<0.001). Immediate reconstruction before PMRT had increased overall and late (>90 days) complication rates, compared with controls (47.46% vs 23.16%, P<0.001; 33.90% vs 15.59%, P<0.001, respectively); however general and aesthetic satisfaction was similar. In contrast, PMRT before reconstruction has similar complication rates and general satisfaction with controls, but decreased aesthetic satisfaction (50% vs 66.88%, P<0.035). 2
75. Jones EL, Prosnitz LR, Dewhirst MW, et al. Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer. Clin Cancer Res. 2004;10(13):4287-4293. Experimental-Tx 18 patients To evaluate toxicity, response, and changes in oxygenation in patients with LABC treated with concurrent taxol, hyperthermia, and RT followed by mastectomy. 6 patients had complete response, 9 had partial response. 13 patients underwent mastectomy with tumor hypoxia present in 8 of them. Patients with well oxygenated tumors pre-surgery or those with reoxygenation had better responses. Reoxygenation appeared to be temperature related so hyperthermia may be beneficial 1
76. Welz S, Hehr T, Lamprecht U, Scheithauer H, Budach W, Bamberg M. Thermoradiotherapy of the chest wall in locally advanced or recurrent breast cancer with marginal resection. Int J Hyperthermia. 2005;21(2):159-167. Observational-Tx 50 patients To evaluate the efficacy of combined hyperthermia and RT in high-risk breast cancer patients with microscopic involved margins (R1) after mastectomy or with resected loco-regional, early recurrence with close margins or R1-resection. 13 patients in Group 1 received hyperthermia and RT in high-risk situation (free margins <1cm or involved margins, and N+) and 37 patients in Group 2. Median radiation dose was 60Gy with hyperthermia given twice weekly. OS at 3 years was 89%, DFS was 68% and local control was 80%. Study concludes that hyperthermia and RT offers promising outcomes but longer follow-up is needed. 2
77. Hehr T, Classen J, Huth M, et al. Postmastectomy radiotherapy of the chest wall. Comparison of electron-rotation technique and common tangential photon fields. Strahlenther Onkol. 2004;180(10):629-636. Observational-Tx 287 patients To analyze patterns of LRF after MRM and axillary LN dissection followed by locoregional RT with or without systemic treatment with emphasis on comparison of electron rotation technique with common tangential photon fields. The 5-year locoregional tumor control (LRC), LRC first event, disease-free, and overall survival were 85%, 91%, 61%, and 70% (Kaplan-Meier analysis), respectively. Cox regression analysis showed that stage III (relative risk [RR] 1.7), more than three involved axillary lymph nodes (RR 5.1), and infiltration of the pectoral fascia (RR 3.2) increased the risk of locoregional failure, while positive estrogen receptor status (RR 0.3) was associated with a reduced risk. No statistically significant differences in LRC were observed for patients treated either with the electron-rotation technique (LRC 92%) or with the photon-based technique (LRC 89%; p = 0.9). A subgroup analysis of tumors resected with "close margins" showed a higher LRF rate of 25% after electronbeam-rotation irradiation (n = 180) compared to an LRF of 13% with tangential opposed 6-MV photon fields (n = 107; p < 0.05). Large primary tumors of > or = 5 cm developed LRF in 29% of patients treated with electron-beam-rotation irradiation and in 17% of patients with photon-based irradiation (p = 0.1). 2
78. Strom EA, Woodward WA, Katz A, et al. Clinical investigation: regional nodal failure patterns in breast cancer patients treated with mastectomy without radiotherapy. Int J Radiat Oncol Biol Phys. 2005;63(5):1508-1513. Observational-Tx 1,031 patients To describe regional nodal failure patterns in patients who had undergone mastectomy with axillary dissection to define subgroups of patients who might benefit from supplemental regional nodal radiation to the axilla or supraclavicular fossa/axillary apex. 21 patients recurred within the low-mid axilla (10-year actuarial rate 3%). Of these, 16 were isolated regional failures. 3/100 patients with <10 nodes examined recurred in the low-mid axilla. 77 patients had a recurrence in the supraclavicular fossa/axillary apex (10-year actuarial rate 8%). 49 were isolated regional recurrences. Significant predictors of failures in this region included =4 involved axillary LNs, >20% involved axillary nodes, and the presence of gross extranodal extension (10-year actuarial rates 15%, 14%, and 19%, respectively, P<0.0005). The extent of axillary dissection and the size of the largest involved node were not predictive of failure within the supraclavicular fossa/axillary apex. 2
79. Motwani SB, Strom EA, Schechter NR, et al. The impact of immediate breast reconstruction on the technical delivery of postmastectomy radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66(1):76-82. Observational-Tx 110 patients (112 treatment plans) cohort of 106 stage-matched patients To quantify the impact of immediate breast reconstruction on PMRT planning. Patients who had mastectomy with immediate reconstruction followed by RT were compared with contemporaneous stage-matched patients who had undergone mastectomy without intervening reconstruction. Of 112 PMRT plans scored after reconstruction, 52% had compromises compared with 7% of matched controls (P<0.0001). Of the compromised plans after reconstruction, 33% were considered to be moderately compromised plans and 19% were major compromised treatment plans. Optimal chest wall coverage, treatment of the ipsilateral internal mammary chain, lung minimization, and heart avoidance was achieved in 79%, 45%, 84%, and 84% of the plans in the group undergoing immediate reconstruction, compared respectively with 100%, 93%, 97%, and 92% of the plans in the control group (P<0.0001, P<0.0001, P=0.0015, and P=0.1435). In patients with reconstructions, 67% of the “major” compromised RT plans were left-sided (P<0.16). For patients with LABC, the potential for compromised PMRT planning should be considered when deciding between immediate and delayed reconstruction. 2
80. Pomahac B, Recht A, May JW, Hergrueter CA, Slavin SA. New trends in breast cancer management: is the era of immediate breast reconstruction changing? Ann Surg. 2006;244(2):282-288. Review/Other-Tx N/A Review available literature on the topic of breast reconstruction and radiation. Factors influencing the decision-making process in breast reconstruction are analyzed. New trends of immediate breast reconstruction are presented. When the indications for postoperative RT are unknown, premastectomy sentinel node biopsy, delayed-immediate reconstruction, or delayed reconstruction is preferable. 4
81. Nava MB, Pennati AE, Lozza L, Spano A, Zambetti M, Catanuto G. Outcome of different timings of radiotherapy in implant-based breast reconstructions. Plast Reconstr Surg. 2011;128(2):353-359. Experimental-Tx 257 patients To observe the effects of radiation on temporary expanders and permanent implants. The totally failed reconstruction rate was significantly higher in group 2, with 40 percent of unsuccessful reconstructions compared with 6.4 percent in group 1 and 2.3 percent in the control group (p < 0.0001). The capsular contracture rate was significantly higher for groups 1 and 2 compared with the control group. The shape and symmetry assessment and the patients' opinions demonstrated a higher incidence of good results in group 1 in comparison with group 2. The best scores were always obtained by the control group. 1
82. Russo JK, Armeson KE, Rhome R, Spanos M, Harper JL. Dose to level I and II axillary lymph nodes and lung by tangential field radiation in patients undergoing postmastectomy radiation with tissue expander reconstruction. Radiat Oncol. 2011;6:179. Observational-Tx 23 patients To define the dosimetric coverage of level I/II axillary volumes and the lung volume irradiated in postmastectomy radiotherapy (PMRT) following tissue expander placement. The mean coverage of the level I/II axillary volume by the 95% isodose line (V(D95%)) was 23.9% (range 0.3 - 65.4%). The mean Ipsilateral Lung V(D50%) was 8.8% (2.2-20.9). Ipsilateral and contralateral expander volume correlated to Axillary V(D95%) in patients with bilateral reconstruction (p = 0.01 and 0.006, respectively) but not those with ipsilateral only reconstruction (p = 0.60). Ipsilateral Lung V(D50%) correlated with angle of the expander from midline (p = 0.05). 3
83. Whitfield GA, Horan G, Irwin MS, Malata CM, Wishart GC, Wilson CB. Incidence of severe capsular contracture following implant-based immediate breast reconstruction with or without postoperative chest wall radiotherapy using 40 Gray in 15 fractions. Radiother Oncol. 2009;90(1):141-147. Observational-Tx 120 immediate reconstructions; 41 patients in RT group To determine the incidence of capsular contracture requiring revisional surgery in patients receiving postoperative RT or no RT following mastectomy and immediate breast reconstruction. 110 patients had implant-based reconstructions with a median follow-up of 51 months. In the RT group (41 patients), there were 8 patients with severe capsular contracture requiring revisional surgery, a crude rate of 19.5%, with actuarial rates of 0%, 5%, 5%, 21%, 30% and 30% at 1, 2, 3, 4, 5 and 6 years follow-up. In the unirradiated group, there were no cases of severe capsular contracture. This difference is highly significant (P<0.001). Hormones and chemotherapy were not significantly associated with severe capsular contracture. This series showed a significantly higher rate of severe capsular contracture with postoperative RT. 2
84. Sitathanee C, Puataweepong P, Swangsilpa T, Narkwong L, Kongdan Y, Suvikapakornkul R. Acute effects of postmastectomy radiotherapy after immediate TRAM flap reconstruction in breast cancer patients. J Med Assoc Thai. 2005;88(12):1861-1866. Review/Other-Tx 10 patients To examine the acute effects of RT after mastectomy and immediate TRAM flap reconstruction in breast cancer patients. During radiation, 3 patients developed erythema or mild hyperpigmentation of the skin, and 4 developed moderate hyperpigmentation. Three patients who were treated with Cobalt-60 and/or bolus to the chest wall developed skin desquamation (1 dry desquamation, 2 moist desquamation). No patient required a treatment break because of acute side effects. One patient who received chemotherapy after radiation developed recalled moist desquamation. 4
85. Spear SL, Ducic I, Low M, Cuoco F. The effect of radiation on pedicled TRAM flap breast reconstruction: outcomes and implications. Plast Reconstr Surg. 2005;115(1):84-95. Observational-Tx 171 pedicled TRAM reconstructions done in 150 patients To examine the effect of postreconstruction RT on patients undergoing pedicled TRAM flap breast reconstruction. Post-TRAM radiation patients were compared with patients who received pre-TRAM radiation and a control TRAM-only group who received no radiation. In terms of overall aesthetic outcome, symmetry, and contracture, the control group consistently rated better than the pre-TRAM (P=0.021, P=0.03, P=0.03, respectively) and the post-TRAM (P=0.0001, P=0.0001, and P=0.0001, respectively) radiation groups. The control group had clinically and statistically significant less hyperpigmentation than the post-TRAM radiation group (P=0.0002). Irradiated postreconstruction patients had scores worse than those of irradiated prereconstruction patients. When these two groups were compared with each other, except for contracture, no statistical significance, because of a small patient sample, was found. Neither preoperative nor postoperative radiation increased the risk for flap or donor-site complications. In contrast, radiation of any type did affect aesthetic appearance, symmetry, contracture, and hyperpigmentation. Authors recommend that TRAM flap breast reconstruction be postponed in those patients known or expected to receive PMRT. 2
86. Chang EI, Liu TS, Festekjian JH, Da Lio AL, Crisera CA. Effects of radiation therapy for breast cancer based on type of free flap reconstruction. Plast Reconstr Surg. 2013;131(1):1e-8e. Observational-Tx 363 flaps To analyze free flap types based on postoperative radiation exposure versus no radiation exposure. Three hundred sixty-three of 446 flaps (81 percent) were included in the analysis, with the three most common flaps being the free transverse rectus abdominis myocutaneous (TRAM) flap (7.4 percent), the muscle-sparing free TRAM flap (44 percent), and the deep inferior epigastric perforator flap (41 percent). There were no significant differences in early or late complications among the different flap types or radiation categories. Flaps with prior radiation exposure were associated with higher percentages of contralateral symmetry procedures, whereas flaps with postoperative radiation exposure had a lower incidence of ipsilateral revisions. 2
87. Fowble B, Park C, Wang F, et al. Rates of Reconstruction Failure in Patients Undergoing Immediate Reconstruction With Tissue Expanders and/or Implants and Postmastectomy Radiation Therapy. Int J Radiat Oncol Biol Phys. 2015;92(3):634-641. Observational-Tx 99 patients To examine the rate of TE/I reconstruction failure (ie, removal of the TE or I with the inability to replace it resulting in no final reconstruction or autologous tissue reconstruction) in patients receiving postmastectomy radiation therapy (PMRT). Total TE/I failure was 18% (12% without final reconstruction, 6% converted to autologous reconstruction). In univariate analysis, the strongest predictor of reconstruction failure (RF) was absence of total TE/I coverage (acellular dermal matrix and/or serratus muscle) at the time of radiation. RF occurred in 32.5% of patients without total coverage compared to 9% with coverage (P=.0069). For women with total coverage, the location of the mastectomy scar in the inframammary fold region was associated with higher RF (19% vs 0%, P=.0189). In multivariate analysis, weight was a significant factor for RF, with lower weight associated with a higher RF. Weight appeared to be a surrogate for the interaction of total coverage, thin skin flaps, interval to exchange, and location of the mastectomy scar. 2
88. Matzinger O, Heimsoth I, Poortmans P, et al. Toxicity at three years with and without irradiation of the internal mammary and medial supraclavicular lymph node chain in stage I to III breast cancer (EORTC trial 22922/10925). Acta Oncol. 2010;49(1):24-34. Experimental-Tx 3,866 patients Phase III study to investigate the potential survival benefit and toxicity of elective irradiation of the internal mammary and medial supraclavicular nodes. Only lung (fibrosis; dyspnoea; pneumonitis; any lung toxicities) (4.3% vs 1.3%; P<0.0001) but not cardiac toxicity (0.3% vs 0.4%; P=0.55) significantly increased with internal mammary and medial supraclavicular treatment. Internal mammary and medial supraclavicular irradiation seems well tolerated and does not significantly impair WHO performance status at 3 years. A follow-up period of at least 10 years is needed to determine whether cardiac toxicity is increased after RT. 1
89. Taghian AG, Assaad SI, Niemierko A, et al. Risk of pneumonitis in breast cancer patients treated with radiation therapy and combination chemotherapy with paclitaxel. J Natl Cancer Inst. 2001;93(23):1806-1811. Observational-Tx 41 patients To examine the incidence of pneumonitis among breast cancer patients treated with radiation and paclitaxel. Radiation pneumonitis developed in six of the 41 patients. Three patients received paclitaxel concurrently with RT, and three received it sequentially (P =.95). The mean percentage of lung volume irradiated was 20% in patients who developed radiation pneumonitis and 22% in those who did not (P =.6). For patients treated with CT including paclitaxel, the crude rate of developing radiation pneumonitis was 14.6% (95% confidence interval [CI] = 5.6% to 29.2%). For patients treated with CT without paclitaxel, the crude rate of pneumonitis was 1.1% (95% CI = 0.2% to 2.3%). The difference between the crude rates with or without paclitaxel is highly statistically significant (P<.0001). The mean time to develop radiation pneumonitis in patients treated concurrently with RT and paclitaxel was statistically significantly shorter in patients receiving paclitaxel weekly than in those receiving it every 3 weeks (P =.002). 2
90. Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol. 2005;6(8):557-565. Observational-Tx 308,861 women with early breast cancer of known laterality To assess the long-term heart disease risks associated with RT for early breast cancer. 115,165 (37%) received radiotherapy. Among those who did not, tumour laterality was of little relevance to subsequent mortality. For women diagnosed during 1973-82 and irradiated, the cardiac mortality ratio (left versus right tumour laterality) was 1.20 (95% CI 1.04-1.38) less than 10 years afterwards, 1.42 (1.11-1.82) 10-14 years afterwards, and 1.58 (1.29-1.95) after 15 years or more (trend: 2p=0.03). For women diagnosed during 1983-92 and irradiated, the cardiac mortality ratio was 1.04 (0.91-1.18) less than 10 years afterwards and 1.27 (0.99-1.63) 10 or more years afterwards. For women diagnosed during 1993-2001 and irradiated the cardiac mortality ratio was 0.96 (0.82-1.12), with none yet followed for 10 years. Among women irradiated for breast cancer who subsequently developed an ipsilateral or contralateral lung cancer, the lung cancer mortality ratio (ipsilateral versus contralateral) for women diagnosed during 1973-82 and irradiated was 1.17 (0.62-2.19), 2.00 (1.00-4.00), and 2.71 (1.65-4.48), respectively, less than 10 years, 10-14 years, and 15 or more years afterwards (trend: 2p=0.04). For women irradiated after 1982 there is, as yet, little information on lung cancer risks more than 10 years afterwards. 2
91. Giordano SH, Kuo YF, Freeman JL, Buchholz TA, Hortobagyi GN, Goodwin JS. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst. 2005;97(6):419-424. Observational-Tx 27,283 women treated with adjuvant radiation for breast cancer To examine whether the risk of death from ischemic heart disease after adjuvant breast RT decreased over time. here were no differences in age, race/ethnicity, disease stage, or follow-up time between the 13 998 women with left-sided and 13 285 with right-sided cancer. For women diagnosed in 1973-1979, there was a statistically significant difference in 15-year mortality from ischemic heart disease between patients with left-sided (13.1%, 95% confidence interval [CI] = 11.6 to 14.6) and those with right-sided (10.2%, 95% CI = 8.9 to 11.5) breast cancer (P = .02); no such difference was found for women diagnosed in 1980-1984 (9.4%, [95% CI = 8.1 to 10.6] versus 8.7% [95% CI = 7.4 to 10.0], respectively, P = .64) or 1985-1989 (5.8% [95% CI = 4.8 to 6.8] versus 5.2% [95% CI = 4.4 to 5.9], respectively, P = .98). In the Cox model, the hazard ratio [HR] for ischemic heart disease mortality for women with left-sided versus women with right-sided disease was 1.50 (95% CI = 1.19 to 1.87) in 1979. With each succeeding year after 1979, the hazard of death from ischemic heart disease for women with left-sided versus those with right-sided disease declined by 6% (HR = 0.94, 95% CI = 0.91 to 0.98). 2
92. Chung E, Corbett JR, Moran JM, et al. Is there a dose-response relationship for heart disease with low-dose radiation therapy? Int J Radiat Oncol Biol Phys. 2013;85(4):959-964. Experimental-Tx 32 women To quantify cardiac radiation therapy (RT) exposure using sensitive measures of cardiac dysfunction; and to correlate dysfunction with heart doses, in the setting of adjuvant RT for left-sided breast cancer. The mean difference in pre- and post-RT PD was -0.38% +/- 3.20% (P=.68), with no clinically significant defects. To assess for subclinical effects, PD were also examined using a 1.5-SD below the normal mean threshold, with a mean difference of 2.53% +/- 12.57% (P=.38). The mean differences in SSS and EF before and after RT were 0.78% +/- 2.50% (P=.08) and 1.75% +/- 7.29% (P=.39), respectively. The average heart Dmean and D95 were 2.82 Gy (range, 1.11-6.06 Gy) and 0.90 Gy (range, 0.13-2.17 Gy), respectively. The average Dmean and D95 to the left anterior descending artery were 7.22 Gy (range, 2.58-18.05 Gy) and 3.22 Gy (range, 1.23-6.86 Gy), respectively. No correlations were found between cardiac doses and changes in PD, SSS, and EF. 1
93. Boekel NB, Schaapveld M, Gietema JA, et al. Cardiovascular morbidity and mortality in patients treated for ductal carcinoma in situ of the breast. J Clin Oncol. 2013;31:(suppl 26; abstr 58). Review/Other-Tx 10,468 patients To study cardiovascular morbidity and mortality in a large population-based cohort of DCIS patients. Compared with the general population, five-year survivors of DCIS had a similar risk of dying due to any cause (standardized mortality ratio (SMR)=1.04 95% confidence interval (CI) 0.97-1.11), but a lower risk of dying of CVD (SMR=0.77 95% CI 0.67-0.89). When comparing treatment groups within the cohort, no difference in risk of CVD was found when comparing patients treated with radiotherapy to surgery only. Left- versus right-sided radiotherapy did also not increase this risk (hazard ratio (HR)=0.93 95% CI 0.67-1.30). In a subgroup analysis of patients diagnosed between 1997 and 2005, accounting for overall history of CVD before DCIS diagnosis, we did not observe a risk difference between treatment groups (left- versus right-sided radiotherapy HR=0.95 95% CI 0.69-1.30). When taking into account CVD that occurred two years prior to DCIS diagnosis only, however, a statistically non-significantly increased risk was seen for patients with a history of CVD (HR=1.84 95% CI 0.45-7.50). 4
94. Hojris I, Overgaard M, Christensen JJ, Overgaard J. Morbidity and mortality of ischaemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials. Radiotherapy Committee of the Danish Breast Cancer Cooperative Group. Lancet. 1999;354(9188):1425-1430. Experimental-Tx 3,083 women: RT (n=1,538) no RT (n=1,545) To assess morbidity and mortality from ischemic heart disease in high-risk breast-cancer patients given systemic treatment with or without RT after mastectomy. More women in the no-RT group than in the RT group died of breast cancer (799 [52.5%] vs 674 [44.2%]), whereas similar proportions of each group died from ischemic heart disease (13 [0.9%] vs 12 [0.8%]). The relative hazard of morbidity from ischemic heart disease among patients in the RT compared with the no-RT group was 0.86 (95% CI, 0.6-1.3), and that for death from ischemic heart disease was 0.84 (0.4-1.8). The hazard rate of morbidity from ischemic heart disease in the RT group compared with the no-RT group did not increase with time from treatment. PMRT with this regimen does not increase the actuarial risk of ischemic heart disease after 12 years. 1
95. Nixon AJ, Manola J, Gelman R, et al. No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques. J Clin Oncol. 1998;16(4):1374-1379. Observational-Tx 745 total patients: 365 patients received left-sided irradiation and 380 right-sided irradiation To determine whether left-breast irradiation using modern techniques after BCS leads to an increased risk of cardiac-related mortality. No significant difference in the distribution of clinical, pathologic, or treatment characteristics between the two groups, with the exception of a small difference in pathologic tumor size (medians, left, 2.0 cm, right, 1.5 cm; P=.007). At 12 years, a majority of patients still were alive. Slightly more patients with left-sided tumors had died of breast cancer (31% vs 27%; P=NS). Equivalent proportions from each group died of nonbreast cancer causes (11%), including 9 patients (2%) from each group who died from cardiac causes. The risk of cardiac mortality did not increase as time after treatment increased for patients who received left-sided irradiation compared with right-sided irradiation. Modern breast RT is not associated with an increased risk of cardiac-related mortality within at least the first 12 years after treatment. 2
96. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-1684. Review/Other-Tx 394 reported events; 133 in the trastuzumab group; 261 controls 2 randomized trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER-2-positive breast cancer. The absolute difference in DFS between the trastuzumab group and the control group was 12% at 3 years. Trastuzumab therapy was associated with a 33% reduction in the risk of death (P=0.015). The 3-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1% in trial B-31 and 2.9% in trial N9831. Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER-2-positive breast cancer. 4
97. Schechter NR, Strom EA, Perkins GH, et al. Immediate breast reconstruction can impact postmastectomy irradiation. Am J Clin Oncol. 2005;28(5):485-494. Review/Other-Tx 152 patients 18 PMRT plans identified To qualitatively assess the effect of immediate reconstruction on the design of PMRT fields at our institution. 4 /18 plans resulted in optimal treatment of the chest wall breadth and internal mammary chain region while well avoiding the heart and lung. Of the remaining 14 plans, 12 compromised coverage of the chest wall breadth medially and/or laterally, and 9 provided no internal mammary chain coverage. Immediate breast reconstruction may impose limitations on the treatment planning of PMRT, particularly in regard to providing broad coverage of the chest wall and internal mammary chain region while avoiding excess exposure of the heart and lung. 4
98. The NCCN Clinical Practice Guidelines in Oncology™ Breast Cancer Version 3.2015.  Available at: http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf. Review/Other-Tx N/A To provide guidelines on breast cancer. No results stated in abstract. 4
99. Dincoglan F, Beyzadeoglu M, Sager O, et al. Dosimetric evaluation of critical organs at risk in mastectomized left-sided breast cancer radiotherapy using breath-hold technique. Tumori. 2013;99(1):76-82. Experimental-Tx 27 patients To evaluate the dosimetric impact of the active breathing control-moderate deep inspiration breath-hold (ABC-mDIBH) technique on normal tissue sparing in locally advanced left-sided breast cancer radiotherapy. Between June 2011 and February 2012, 27 consecutive patients with left-sided locally advanced breast cancer referred to our department for adjuvant radiotherapy were enrolled in the study. Dose-volume parameters of left anterior descending coronary artery, lungs, heart, contralateral breast, esophagus and spinal cord were significantly reduced with the use of ABC-mDIBH (P <0.001). 1
100. Pierce LJ. The use of radiotherapy after mastectomy: a review of the literature. J Clin Oncol. 2005;23(8):1706-1717. Review/Other-Tx N/A To emphasize the role of PMRT in the presence of adjuvant (or neoadjuvant) systemic therapy. No results stated in abstract. 4