Omitting Radiotherapy after Breast-Conserving Surgery in Luminal A Breast Cancer.

BACKGROUND: Adjuvant radiotherapy is prescribed after breast-conserving surgery to reduce the risk of local recurrence. However, radiotherapy is inconvenient, costly, and associated with both short-term and long-term side effects. Clinicopathologic factors alone are of limited use in the identification of women at low risk for local recurrence in whom radiotherapy can be omitted. Molecularly defined intrinsic subtypes of breast cancer can provide additional prognostic information. METHODS: We performed a prospective cohort study involving women who were at least 55 years of age, had undergone breast-conserving surgery for T1N0 (tumor size <2 cm and node negative), grade 1 or 2, luminal A-subtype breast cancer (defined as estrogen receptor positivity of ≥1%, progesterone receptor positivity of >20%, negative human epidermal growth factor receptor 2, and Ki67 index of ≤13.25%), and had received adjuvant endocrine therapy. Patients who met the clinical eligibility criteria were registered, and Ki67 immunohistochemical analysis was performed centrally. Patients with a Ki67 index of 13.25% or less were enrolled and did not receive radiotherapy. The primary outcome was local recurrence in the ipsilateral breast. In consultation with radiation oncologists and patients with breast cancer, we determined that if the upper boundary of the two-sided 90% confidence interval for the cumulative incidence at 5 years was less than 5%, this would represent an acceptable risk of local recurrence at 5 years. RESULTS: Of 740 registered patients, 500 eligible patients were enrolled. At 5 years after enrollment, recurrence was reported in 2.3% of the patients (90% confidence interval [CI], 1.3 to 3.8; 95% CI, 1.2 to 4.1), a result that met the prespecified boundary. Breast cancer occurred in the contralateral breast in 1.9% of the patients (90% CI, 1.1 to 3.2), and recurrence of any type was observed in 2.7% (90% CI, 1.6 to 4.1). CONCLUSIONS: Among women who were at least 55 years of age and had T1N0, grade 1 or 2, luminal A breast cancer that were treated with breast-conserving surgery and endocrine therapy alone, the incidence of local recurrence at 5 years was low with the omission of radiotherapy. (Funded by the Canadian Cancer Society and the Canadian Breast Cancer Foundation; LUMINA ClinicalTrials.gov number, NCT01791829.).

The Feasibility of Quality Assurance in the TOPGEAR International Phase 3 Clinical Trial of Neoadjuvant Chemoradiation Therapy for Gastric Cancer (an Intergroup Trial of the AGITG/TROG/NHMRC CTC/EORTC/CCTG).

PURPOSE: The TOPGEAR phase 3 trial hypothesized that adding preoperative chemoradiation therapy (CRT) to perioperative chemotherapy will improve survival in patients with gastric cancer. Owing to the complexity of gastric irradiation, a comprehensive radiation therapy quality assurance (RTQA) program was implemented. Our objective is to describe the RTQA methods and outcomes. METHODS AND MATERIALS: RTQA was undertaken in real time before treatment for the first 5 patients randomized to CRT from each center. Once acceptable quality was achieved, RTQA was completed for one-third of subsequent cases. RTQA consisted of evaluating (1) clinical target volume and organ-at-risk contouring and (2) radiation therapy planning parameters. Protocol violations between high- (20+ patients enrolled) and low-volume centers were compared using the Fisher exact test. RESULTS: TOPGEAR enrolled 574 patients, of whom 286 were randomized to receive preoperative CRT and 203 (71%) were included for RTQA. Of these, 67 (33%) and 136 (67%) patients were from high- and low-volume centers, respectively. The initial RTQA pass rate was 72%. In total, 28% of cases required resubmission. In total, 200 of 203 cases (99%) passed RTQA before treatment. Cases from low-volume centers required resubmission more often (44/136 [33%] vs 13/67 [18%]; P = .078). There was no change in the proportion of cases requiring resubmission over time. Most cases requiring resubmission had multiple protocol violations. At least 1 aspect of the clinical target volume had to be adjusted in all cases. Inadequate coverage of the duodenum was most common (53% major violation, 25% minor violation). For the remaining cases, the resubmission process was triggered secondary to poor contour/plan quality. CONCLUSIONS: In a large multicenter trial, RTQA is feasible and effective in achieving high-quality treatment plans. Ongoing education should be performed to ensure consistent quality during the entire study period.

Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3-07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study.

BACKGROUND: Whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence. We investigated whether a tumour bed boost after WBI improved outcomes, and examined radiation dose fractionation sensitivity for non-low-risk DCIS. METHODS: The study was an international, randomised, unmasked, phase 3 trial involving 136 participating centres of six clinical trials organisations in 11 countries (Australia, New Zealand, Singapore, Canada, the Netherlands, Belgium, France, Switzerland, Italy, Ireland, and the UK). Eligible patients were women aged 18 years or older with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins. They were assigned to one of four groups (1:1:1:1) of no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each centre prespecified conventional or hypofractionated WBI. The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42·5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. Patients and clinicians were not masked to treatment allocation. The primary endpoint was time to local recurrence. This trial is registered with ClinicalTrials.gov (NCT00470236). FINDINGS: Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to have no boost (805 patients) or boost (803 patients). Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients. Median follow-up was 6·6 years. The 5-year free-from-local-recurrence rates were 92·7% (95% CI 90·6-94·4%) in the no-boost group and 97·1% (95·6-98·1%) in the boost group (hazard ratio 0·47; 0·31-0·72; p<0·001). The boost group had higher rates of grade 2 or higher breast pain (10% [8-12%] vs 14% [12-17%], p=0·003) and induration (6% [5-8%] vs 14% [11-16%], p<0·001). INTERPRETATION: In patients with resected non-low-risk DCIS, a tumour bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity. The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control. The international scale of the study supports the generalisability of the results. FUNDING: National Health and Medical Research Council of Australia, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, Canadian Cancer Trials Group.

International comparison of cosmetic outcomes of breast conserving surgery and radiation therapy for women with ductal carcinoma in situ of the breast.

PURPOSE: To assess the cosmetic impact of breast conserving surgery (BCS), whole breast irradiation (WBI) fractionation and tumour bed boost (TBB) use in a phase III trial for women with ductal carcinoma in situ (DCIS) of the breast. MATERIALS AND METHODS: Baseline and 3-year cosmesis were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Cosmetic Rating System and digital images in a randomised trial of non-low risk DCIS treated with postoperative WBI +/- TBB. Baseline cosmesis was assessed for four geographic clusters of treating centres. Cosmetic failure was a global score of fair or poor. Cosmetic deterioration was a score change from excellent or good at baseline to fair or poor at three years. Odds ratios for cosmetic deterioration by WBI dose-fractionation and TBB use were calculated for both scoring systems. RESULTS: 1608 women were enrolled from 11 countries between 2007 and 2014. 85-90% had excellent or good baseline cosmesis independent of geography or assessment method. TBB (16 Gy in 8 fractions) was associated with a >2-fold risk of cosmetic deterioration (p < 0.001). Hypofractionated WBI (42.5 Gy in 16 fractions) achieved statistically similar 3-year cosmesis compared to conventional WBI (50 Gy in 25 fractions) (p ≥ 0.18). The adverse impact of a TBB was not significantly associated with WBI fractionation (interaction p ≥ 0.30). CONCLUSIONS: Cosmetic failure from BCS was similar across international jurisdictions. A TBB of 16 Gy increased the rate of cosmetic deterioration. Hypofractionated WBI achieved similar 3-year cosmesis as conventional WBI in women treated with BCS for DCIS.

External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.

BACKGROUND: Whole breast irradiation delivered once per day over 3-5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. METHODS: We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5-8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035. FINDINGS: Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3-9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9-4·0) in the APBI group and 2·8% (1·8-3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84-1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5-15·0), 5 years (16·5%, 12·5-20·4), and 7 years (17·7%, 12·9-22·3). INTERPRETATION: External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. FUNDING: Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

Patient Reported Outcomes Following Lower Extremity Soft Tissue Sarcoma Resection with Microsurgical Preservation of Ambulation.

BACKGROUND: Lower extremity soft tissue sarcoma treatment has evolved from primarily amputation procedures toward limb salvage. This series assesses whether soft tissue sarcoma tissue defects, extensive enough to require microsurgical reconstruction, can reliably result in preservation of ambulation, as well as objectively evaluate functional outcomes utilizing a patient-reported validated scale. It will also look at whether immediate functional muscle reconstructions and tendon transfers can be successful at restoring ambulation, potentially expanding the indications for limb salvage procedures. METHODS: A retrospective review of all microsurgical reconstructions for limb salvage in lower extremity sarcoma patients was completed at our institution (2009-2013). Patients were additionally asked to complete the Toronto Extremity Salvage Score(TESS) quality of life survey. RESULTS: Over a 5-year period, 23 patients (mean age: 53 years) underwent free flap reconstructions for 23 sarcomas (mean follow-up: 14 months). Seventy-eight percent of patients received neoadjuvant radiation. The thigh was the most common tumor site (61%) and three muscles were resected on average. Perforator flaps were most frequently used (61%), and functional muscle transfers or immediate tendon transfers were used in four patients. There were no flap take-backs or failures, and 22 patients achieved independent ambulation. Three patients in the series died, two from metastatic disease found postoperatively and one from local recurrence. A 74% response rate was achieved for the TESS survey, with a mean score of 83. CONCLUSION: Microsurgical reconstruction of lower extremity sarcoma defects enables preservation of independent ambulation. Restoration of function utilizing immediate functional microsurgical reconstructions and tendon transfers should be considered.

Predictors of adverse cosmetic outcome in the RAPID trial: an exploratory analysis.

PURPOSE: To evaluate factors associated with adverse cosmesis outcome in breast cancer patients randomized to accelerated partial breast irradiation (APBI) using 3-dimensional conformal radiation therapy or whole-breast irradiation in the RAPID (Randomized Trial of Accelerated Partial Breast Irradiation) trial. METHODS AND MATERIALS: Subjects were trial participants with nurse-assessed global cosmetic scores at baseline and at 3 years. Adverse cosmesis was defined as a score of fair or poor. Cosmetic deterioration was defined as any adverse change in score from baseline to 3 years. The analysis is based on data from the previously reported interim analysis. Logistic regression models were used to assess the association of risk factors for these outcomes among all patients and those treated with APBI only. RESULTS: Clinicopathologic characteristics were similar between subjects randomized to APBI (n=569) or whole-breast irradiation (n=539). For all subjects, factors associated with adverse cosmesis at 3 years were older age, central/inner tumor location, breast infection, smoking, seroma volume, breast volume, and use of APBI; factors associated with cosmetic deterioration were smoking, seroma volume, and use of APBI (P<.05). For APBI subjects, tumor location, smoking, age, and seroma volume were associated with adverse cosmesis (P<.05), and smoking was associated with cosmetic deterioration (P=.02). An independent association between the V95/whole-breast volume ratio and adverse cosmesis (P=.28) or cosmetic deterioration (P=.07) was not detected. On further exploration a V95/whole-breast volume ratio <0.15 was associated with a lower risk of cosmetic deterioration (p=.04), but this accounted for only 11% of patients. CONCLUSION: In the RAPID trial, a number of patient tumor and treatment-related factors, including the use of APBI, were associated with adverse cosmesis and cosmetic deterioration. For patients treated with APBI alone, the high-dose treatment volume was not independently associated with an adverse cosmetic outcome, and a useful clinical threshold could not be identified.

Interim cosmetic and toxicity results from RAPID: a randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy.

PURPOSE: To report interim cosmetic and toxicity results of a multicenter randomized trial comparing accelerated partial-breast irradiation (APBI) using three-dimensional conformal external beam radiation therapy (3D-CRT) with whole-breast irradiation (WBI). PATIENTS AND METHODS: Women age > 40 years with invasive or in situ breast cancer ≤ 3 cm were randomly assigned after breast-conserving surgery to 3D-CRT APBI (38.5 Gy in 10 fractions twice daily) or WBI (42.5 Gy in 16 or 50 Gy in 25 daily fractions ± boost irradiation). The primary outcome was ipsilateral breast tumor recurrence (IBTR). Secondary outcomes were cosmesis and toxicity. Adverse cosmesis was defined as a fair or poor global cosmetic score. After a planned interim cosmetic analysis, the data, safety, and monitoring committee recommended release of results. There have been too few IBTR events to trigger an efficacy analysis. RESULTS: Between 2006 and 2011, 2,135 women were randomly assigned to 3D-CRT APBI or WBI. Median follow-up was 36 months. Adverse cosmesis at 3 years was increased among those treated with APBI compared with WBI as assessed by trained nurses (29% v 17%; P < .001), by patients (26% v 18%; P = .0022), and by physicians reviewing digital photographs (35% v 17%; P < .001). Grade 3 toxicities were rare in both treatment arms (1.4% v 0%), but grade 1 and 2 toxicities were increased among those who received APBI compared with WBI (P < .001). CONCLUSION: 3D-CRT APBI increased rates of adverse cosmesis and late radiation toxicity compared with standard WBI. Clinicians and patients are cautioned against the use of 3D-CRT APBI outside the context of a controlled trial.