Prolongation of overall treatment time as a cause of treatment failure in early breast cancer: an analysis of the UK START (Standardisation of Breast Radiotherapy) trials of radiotherapy fractionation

AbstractBackgroundTests of tumour treatment time effect in patients prescribed post-operative radiotherapy for early breast cancer have focussed on time to start of radiotherapy rather than overall treatment time. The START randomised trials of radiotherapy fractionation provide an opportunity to directly estimate the effect of treatment acceleration.MethodsBetween 1986 and 2002, a total of 5861 women with early breast cancer were recruited into the UK START pilot (START-P), START-A and START-B randomised trials. START-P and START-A tested 13 fractions of 3.0–3.3Gy against 25 fractions of 2.0Gy with a fixed treatment duration of 5weeks for all schedules; START-B tested 15 fractions of 2.67Gy in 3weeks against 25 fractions of 2.0Gy over 5weeks. Estimates of the effect of length of treatment for local–regional relapse and for a measure of late normal tissue effects (change in photographic breast appearance, for patients following breast conserving surgery) were obtained from Cox proportional hazards regression analyses stratified according to trial.ResultsAt a median follow-up of 10years, 444/5831 (7.6%) patients with data available had a local–regional relapse, and 1135/3185 (35.6%) had mild or marked change in photographic breast appearance by 5years. Adjusting for prognostic factors, the estimate of the overall treatment time effect for local–regional relapse was 0.60Gy/day (95%CI 0.10 to 1.18Gy/day, p=0.02), and 0.14Gy/day (95%CI −0.09 to 0.34Gy/day, p=0.29) for change in photographic breast appearance.ConclusionsCombined analysis of the START trials generates the hypothesis that overall treatment time is a significant determinant of local cancer control after adjuvant whole breast radiotherapy, with approximately 0.6Gy per day ‘wasted’ in compensating for tumour cell proliferation

Gene expression profiling of human dermal fibroblasts exposed to bleomycin sulphate does not differentiate between radiation sensitive and control patients

Background: Gene expression profiling of the transcriptional response of human dermal fibroblasts to in vitro radiation has shown promise as a predictive test of radiosensitivity. This study tested if treatment with the radiomimetic drug bleomycin sulphate could be used to differentiate radiation sensitive patients and controls in patients who had previously received radiotherapy for early breast cancer.Findings: Eight patients who developed marked late radiation change assessed by photographic breast appearance and 8 matched patients without any change were selected from women entered in a prospective randomised trial of breast radiotherapy fractionation. Gene expression profiling of primary skin fibroblasts exposed in vitro to bleomycin sulphate and mock treated fibroblast controls was performed. 973 genes were up-regulated and 923 down-reguated in bleomycin sulphate treated compared to mock treated control fibroblasts. Gene ontology analysis revealed enriched groups were cellular localisation, apoptosis, cell cycle and DNA damage response for the deregulated genes. No transcriptional differences were identified between fibroblasts from radiation sensitive cases and control patients; subgroup analysis using cases exhibiting severe radiation sensitivity or with high risk alleles present in TGF beta 1 also showed no difference.Conclusions: The transcriptional response of human dermal fibroblasts to bleomycin sulphate has been characterised. No differences between clinically radiation sensitive and control patients were detected using this approach

TP53 modulates radiotherapy fraction size sensitivity in normal and malignant cells

Recent clinical trials in breast and prostate cancer have established that fewer, larger daily doses (fractions) of radiotherapy are safe and effective, but these do not represent personalised dosing on a patient-by-patient basis. Understanding cell and molecular mechanisms determining fraction size sensitivity is essential to fully exploit this therapeutic variable for patient benefit. The hypothesis under test in this study is that fraction size sensitivity is dependent on the presence of wild-type (WT) p53 and intact non-homologous end-joining (NHEJ). Using single or split-doses of radiation in a range of normal and malignant cells, split-dose recovery was determined using colony-survival assays. Both normal and tumour cells with WT p53 demonstrated significant split-dose recovery, whereas Li-Fraumeni fibroblasts and tumour cells with defective G1/S checkpoint had a large S/G2 component and lost the sparing effect of smaller fractions. There was lack of split-dose recovery in NHEJ-deficient cells and DNA-PKcs inhibitor increased sensitivity to split-doses in glioma cells. Furthermore, siRNA knockdown of p53 in fibroblasts reduced split-dose recovery. In summary, cells defective in p53 are less sensitive to radiotherapy fraction size and lack of split-dose recovery in DNA ligase IV and DNA-PKcs mutant cells suggests the dependence of fraction size sensitivity on intact NHEJ

Caveat medicus:Clinician experiences in publishing reports of serious oncology-associated adverse drug reactions

Oncology-associated adverse drug/device reactions can be fatal. Some clinicians who treat single patients with severe oncology-associated toxicities have researched case series and published this information. We investigated motivations and experiences of select individuals leading such efforts. Clinicians treating individual patients who developed oncology-associated serious adverse drug events were asked to participate. Inclusion criteria included having index patient information, reporting case series, and being collaborative with investigators from two National Institutes of Health funded pharmacovigilance networks. Thirty-minute interviews addressed investigational motivation, feedback from pharmaceutical manufacturers, FDA personnel, and academic leadership, and recommendations for improving pharmacovigilance. Responses were analyzed using constant comparative methods of qualitative analysis. Overall, 18 clinicians met inclusion criteria and 14 interviewees are included. Primary motivations were scientific curiosity, expressed by six clinicians. A less common theme was public health related (three clinicians). Six clinicians received feedback characterized as supportive from academic leaders, while four clinicians received feedback characterized as negative. Three clinicians reported that following the case series publication they were invited to speak at academic institutions worldwide. Responses from pharmaceutical manufacturers were characterized as negative by 12 clinicians. One clinician's wife called the post-reporting time the "Maalox month," while another clinician reported that the manufacturer collaboratively offered to identify additional cases of the toxicity. Responses from FDA employees were characterized as collaborative for two clinicians, neutral for five clinicians, unresponsive for negative by six clinicians. Three clinicians endorsed developing improved reporting mechanisms for individual physicians, while 11 clinicians endorsed safety activities that should be undertaken by persons other than a motivated clinician who personally treats a patient with a severe adverse drug/device reaction. Our study provides some of the first reports of clinician motivations and experiences with reporting serious or potentially fatal oncology-associated adverse drug or device reactions. Overall, it appears that negative feedback from pharmaceutical manufacturers and mixed feedback from the academic community and/or the FDA were reported. Big data, registries, Data Safety Monitoring Boards, and pharmacogenetic studies may facilitate improved pharmacovigilance efforts for oncology-associated adverse drug reactions. These initiatives overcome concerns related to complacency, indifference, ignorance, and system-level problems as barriers to documenting and reporting adverse drug events- barriers that have been previously reported for clinician reporting of serious adverse drug reactions

Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.

BACKGROUND: We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial. METHODS: FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio [HR] of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132. FINDINGS: Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were -0·3% (-1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and -0·7% (-1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1-5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, p<0·0001) for 27 Gy in five fractions and 1·12 (0·94 to 1·34, p=0·20) for 26 Gy in five fractions. Patient and photographic assessments showed higher normal tissue effect risk for 27 Gy versus 40 Gy but not for 26 Gy versus 40 Gy. INTERPRETATION: 26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. FUNDING: National Institute for Health Research Health Technology Assessment Programme