Ontario Clinical Oncology Group Research Articles

Lung SBRT credentialing in the Canadian OCOG-LUSTRE randomized trial

PurposeTo report on the Stereotactic Body Radiation Therapy (SBRT) credentialing experience during the Phase III Ontario Clinical Oncology Group (OCOG) LUSTRE trial for stage I non-small cell lung cancer. MethodsThree credentialing requirements were required in this process: (a) An institutional technical survey; (b) IROC (Imaging and Radiation Oncology Core) thoracic phantom end-to-end test; and (c) Contouring and completion of standardized test cases using SBRT for one central and one peripheral lung cancer, compared against the host institution as the standard. The main hypotheses were that unacceptable variation would exist particularly in OAR definition across all centres, and that institutions with limited experience in SBRT would be more likely to violate per-protocol guidelines. ResultsFifteen Canadian centres participated of which 8 were new, and 7 were previously established (≥2 years SBRT experience), and all successfully completed surveys and IROC phantom testing. Of 30 SBRT test plans, 10 required replanning due to major deviations, with no differences in violations between new and established centres (p = 0.61). Mean contouring errors were highest for brachial plexus in the central (C) case (12.55 ± 6.62 mm), and vessels in the peripheral (P) case (13.01 ± 12.55 mm), with the proximal bronchial tree (PBT) (2.82 ± 0.78 C, 3.27 ± 1.06 P) as another variable structure. Mean dice coefficients were lowest for plexus (0.37 ± 0.2 C, 0.37 ± 0.14 P), PBT (0.77 ± 0.06 C, 0.75 ± 0.09 P), vessels (0.69 ± 0.29 C, 0.64 ± 0.31 P), and esophagus (0.74 ± 0.04 C, 0.76 ± 0.04 P). All plans passed per-protocol planning target volume (PTV) coverage and maximum/volumetric organs-at-risk constraints, although variations existed in dose gradients within and outside the target. ConclusionsClear differences exist in both contouring and planning with lung SBRT, regardless of centre experience. Such an exercise is important for studies that rely on high precision radiotherapy, and to ensure that implications on trial quality and outcomes are as optimal as possible.

Metformin in Combination With Chemoradiotherapy in Locally Advanced Non–Small Cell Lung Cancer

Unresected locally advanced non-small cell lung cancer (LA-NSCLC) shows poor survival outcomes even after aggressive concurrent chemoradiotherapy. Whether metformin, a diabetes agent that inhibits the mitochondria oxidative phosphorylation chain, could improve radiotherapy and chemotherapy response in LA-NSCLC remains to be studied. To examine whether metformin, given concurrently with chemoradiotherapy and as consolidation treatment, could improve outcomes in patients with LA-NSCLC. The Ontario Clinical Oncology Group Advanced Lung Cancer Treatment With Metformin and Chemoradiotherapy (OCOG-ALMERA) study was a multicenter phase 2 randomized clinical trial. Patients were stratified for stage IIIA vs IIIB LA-NSCLC and use of consolidation chemotherapy. The trial was designed to enroll 96 patients with unresected LA-NSCLC who did not have diabetes. The trial was conducted from September 24, 2014, to March 8, 2019. Patients were randomized to platinum-based chemotherapy, concurrent with chest radiotherapy (60-63 Gy), with or without consolidation chemotherapy or the same treatment plus metformin, 2000 mg/d, during chemoradiotherapy and afterward for up to 12 months. The primary outcome was the proportion of patients who experienced a failure event (ie, locoregional disease progression, distant metastases, death, and discontinuation of trial treatment or planned evaluations for any reason within 12 months). Proportions were compared using a 2-sided Fisher exact test. Conventional progression-free and overall survival were estimated using the Kaplan-Meier method. Adverse events were graded with Common Terminology Criteria for Adverse Events, version 4.03. All randomized patients were included in an intention-to-treat analysis. The trial was stopped early due to slow accrual. Between 2014 and 2019, 54 patients were randomized (26 in experimental arm and 28 in control arm). Participants included 30 women (55.6%); mean (SD) age was 65.6 (7.6) years. Treatment failure was detected in 18 patients (69.2%) receiving metformin within 1 year vs 12 (42.9%) control patients (P = .05). The 1-year progression-free survival rate was 34.8% (95% CI, 16.6%-53.7%) in the metformin arm and 63.0% (95% CI, 42.1%-78.1%) in the control arm (hazard ratio, 2.42; 95% CI, 1.14-5.10) The overall survival rates were 47.4% (95% CI, 26.3%-65.9%) in the metformin arm and 85.2% (95% CI, 65.2%-94.2%) in the control arm (hazard ratio, 3.80; 95% CI, 1.49-9.73). More patients in the experimental arm vs control arm (53.8% vs 25.0%) reported at least 1 grade 3 or higher adverse event. In this randomized clinical trial, the addition of metformin to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects compared with combined modality therapy alone. Metformin is not recommended in patients with LA-NSCLC who are candidates for chemoradiotherapy. ClinicalTrials.gov Identifier: NCT02115464.

Hypofractionated Postoperative Radiation Therapy for Breast Cancer – Do We Need More Evidence or Adapted Reimbursement Policies?

"More than 10 years ago, two pivotal trials, the Ontario Clinical Oncology Group trial and START B trial, firmly established that hypofractionated radiation therapy (RT) of 40–42.5 Gy in 15–16 fractions over 3 weeks after breast conserving surgery or mastectomy results in similar rates of local recurrence and normal tissue effects. This led to a new standard for postoperative whole breast and chest wall RT. Further trials confirmed these findings and show that hypofractionated RT can also be applied for other indications, including regional nodal RT and for ductal carcinoma in situ (DCIS). More recently, a so-called ultra-fractionation trial demonstrated that 26 Gy in 5 fractions over 1 week was non-inferior to 40 Gy, in 15 fractions in 3 weeks for local recurrence at 6 years and that late effects were similar between fractionation schedules being a treatment option for most patients with early breast cancer. Several countries and departments are now adopting hypofractionated schedules as a new standard for breast, chest wall or partial breast RT. In addition to the improvement in convenience and reduction in resources required, hypofractionated RT offers important benefits with respect to acute and late toxicity that can improve the quality of life of patients receiving breast RT."

A phase II trial of dovitinib in previously-treated advanced pleural mesothelioma: The Ontario Clinical Oncology Group

ObjectivesFollowing failure of a platinum-antifolate combination regimen, there is no standard therapy for advanced malignant pleural mesothelioma (MPM). The fibroblast growth factor receptor (FGFR) signaling pathways may be a relevant target in MPM. Dovitinib inhibits multiple tyrosine receptor kinases, predominantly the vascular endothelial growth factor receptors (VEGFR), but also FGFRs, and could be active in MPM. MethodsThis open-label multicentre phase II trial [NCT01769547] enrolled fit, consenting adult patients with advanced MPM who had previously received platinum-antifolate combination chemotherapy and up to one additional line of systemic therapy. Dovitinib was administered orally at 500mg/day for 5days on, 2days off, in 28-day cycles. Response was assessed every 2 cycles using RECIST 1.1 criteria modified for MPM. Correlative studies included FGFR-1 amplification on archival tumour and serum samples for circulating angiogenesis factors. The primary end-point was the proportion of patients progression-free at 3 months (PF3) using a two-stage design. Results12 patients (10 males, median age 67) were enrolled. The median number of cycles administered was 2.5 (range 1–8). One unconfirmed partial response was observed. PF3 was 50% (95% confidence interval 28.4% to 88.0%); although the criterion for proceeding to stage II accrual was met, the trial was halted due to a combination of minimal activity with several early progression events and poor tolerability in this patient population. One of 12 tumour specimens had low amplification of FGFR-1. ConclusionsDovitinib has minimal activity in previously-treated MPM. The role of the FGFR pathway in MPM remains unclear.

Canadian Phase III Randomized Trial of Stereotactic Body Radiotherapy Versus Conventionally Hypofractionated Radiotherapy for Stage I, Medically Inoperable Non–Small-Cell Lung Cancer – Rationale and Protocol Design for the Ontario Clinical Oncology Group (OCOG)-LUSTRE Trial

We describe a Canadian phase III randomized controlled trial of stereotactic body radiotherapy (SBRT) versus conventionally hypofractionated radiotherapy (CRT) for the treatment of stage I medically inoperable non–small-cell lung cancer (OCOG-LUSTRE Trial).Eligible patients are randomized in a 2:1 fashion to either SBRT (48 Gy in 4 fractions for peripherally located lesions; 60 Gy in 8 fractions for centrally located lesions) or CRT (60 Gy in 15 fractions). The primary outcome of the study is 3-year local control, which we hypothesize will improve from 75% with CRT to 87.5% with SBRT. With 85% power to detect a difference of this magnitude (hazard ratio = 0.46), a 2-sided α = 0.05 and a 2:1 randomization, we require a sample size of 324 patients (216 SBRT, 108 CRT). Important secondary outcomes include overall survival, disease-free survival, toxicity, radiation-related treatment death, quality of life, and cost-effectiveness. A robust radiation therapy quality assurance program has been established to assure consistent and high quality SBRT and CRT delivery.Despite widespread interest and adoption of SBRT, there still remains a concern regarding long-term control and risks of toxicity (particularly in patients with centrally located lesions). The OCOG-LUSTRE study is the only randomized phase III trial testing SBRT in a medically inoperable population, and the results of this trial will attempt to prove that the benefits of SBRT outweigh the potential risks.

972P - Dovitinib in advanced adenoid cystic carcinoma of the salivary glands: Ontario Clinical Oncology Group DOVE trial

972P - Dovitinib in advanced adenoid cystic carcinoma of the salivary glands: Ontario Clinical Oncology Group DOVE trial

An integrative cross-tumors approach identifies FOSL1 as an oncogene dependency in KRAS-driven lung cancer

The Ontario Clinical Oncology Group (OCOG) – ALMERA trial (NCT02186847) is a Canadian multicenter randomized phase II trial funded by the Canadian Institute for Health Research, which is designed to examine whether metformin has chemo-radio-sensitization activity as well as activity as a single agent in advanced localized NSCLC. A total of 94 patients will be randomized in this screening trial to standard CRT with or without treatment with 2000mg of metformin, which is delivered during CRT (2 cycles of cisplatin based chemotherapy, concurrent with chest RT of 63 Gy in 30 fractions) but continues also as a single agent for a total of 12 months. ALMERA is designed to detect a 20% improvement in lung cancer progression free survival at 12 months. This trial is now open in several centers across Canada. The primary outcome is 12 month Progression Free Survival (PFS) and secondary outcomes include 1 and 2 y overall survival (OAS), time to loco-regional progression, distant progression free survival, adverse events and collection of biospecimens for biomarker studies. These will involve investigation of circulating serum and blood cell biomarkers of metformin activity and tumor biomarkers such as tumor histology, TP53, LKB1 and K-Rasmutation status. When completed ALMERAwill provide some of the first prospective evidence on the potential of metformin to improve the outcomes of standard cytotoxic therapy in locally advanced NSCLC. Biospecimen collect will allow us to investigate serum and tumors biomarkers ofmetformin response. Comparison of the results of ALMERA with other studies, like NRG-LU001, may be able to provide evidence on the value of metformin as maintenance therapy and assist in the design of future phase III trials with metformin in the setting of locally advanced NSCLC.

Data collection in cancer clinical trials: Too much of a good thing?

Substantial staff time and costs are incurred in the collection of data for cancer clinical trials. Anecdotal experience suggests that much of these data are never used in the analysis or reporting of a trial. To quantify data items collected in cancer clinical trials and calculate what percentage is used in subsequent published manuscripts. Cancer clinical trials completed by the Ontario Clinical Oncology Group (OCOG) between 2003 and 2012 and the corresponding primary outcome publication were identified. The number of data items collected on each trial's case report form (CRF) was counted and sorted into 18 categories including eligibility, baseline characteristics, medical history, toxicity, and recurrence. The data items were then counted within the corresponding published manuscripts to determine percent of data used overall and within each section. In all, 8 trials, with 9 corresponding publications, were evaluated. The CRF analysis revealed that the total collected items per subject ranged from 186 to 1035 per trial with a median of 599. Across all the publications, a median of 96 data items (18%) were reported in each manuscript, ranging from 11% to 27% per trial. In 8 of the 18 categories, 4% or less of collected data items were used. The number of trials reviewed is small and were conducted from a single clinical trial coordinating centre. The main outcome of the number of data items used in the published manuscript is a surrogate for trial information considered valuable by investigators. Some data may be deemed important by investigators but not included in manuscripts. In this analysis of publications from 8 clinical trials, a small amount of data collected was ultimately used in peer-reviewed journal manuscripts. A large amount of data collected in cancer trials appears to go unused and could be omitted from CRFs, thus simplifying data collection and improving trial efficiency.

A Population-Based Study of the Fractionation of Postlumpectomy Breast Radiation Therapy

The optimal fractionation schedule of post lumpectomy radiation therapy remains controversial. The objective of this study was to describe the fractionation of post-lumpectomy radiation therapy (RT) in Ontario, before and after the seminal Ontario Clinical Oncology Group (OCOG) trial, which showed the equivalence of 16- and 25-fraction schedules. This was a retrospective cohort study conducted by linking electronic treatment records to a population-based cancer registry. The study population included all patients who underwent lumpectomy for invasive breast cancer in Ontario, Canada, between 1984 and 2008. Over the study period, 41,747 breast cancer patients received post lumpectomy radiation therapy to the breast only. Both 16- and 25-fraction schedules were commonly used throughout the study period. In the early 1980s, shorter fractionation schedules were used in >80% of cases. Between 1985 and 1995, the proportion of patients treated with shorter fractionation decreased to 48%. After completion of the OCOG trial, shorter fractionation schemes were once again widely adopted across Ontario, and are currently used in about 71% of cases; however, large intercenter variations in fractionation persisted. The use of shorter schedules of post lumpectomy RT in Ontario increased after completion of the OCOG trial, but the trial had a less normative effect on practice than expected.

Prospective Study of 2-[18F]Fluorodeoxyglucose Positron Emission Tomography in the Assessment of Regional Nodal Spread of Disease in Patients With Breast Cancer: An Ontario Clinical Oncology Group Study

2-[(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) is potentially useful in assessing lymph nodes and detecting distant metastases in women with primary breast cancer. Women diagnosed with operable breast cancer within 3 months underwent FDG-PET at one of five Ontario study centers followed by axillary lymph node assessment (ALNA) consisting of sentinel lymph node biopsy (SLNB) alone if sentinel lymph nodes (SLNs) were negative, SLNB with axillary lymph node dissection (ALND) if SLNB or PET was positive, or ALND alone if SLNs were not identified. Between January 2005 and March 2007, 325 analyzable women entered this study. Sentinel nodes were found for 312 (96%) of 325 women and were positive for tumor in 90 (29%) of 312. ALND was positive in seven additional women. Using ALNA as the gold standard, sensitivity for PET was 23.7% (95% CI, 15.9% to 33.6%), specificity was 99.6% (95% CI, 97.2% to 99.9%), positive predictive value was 95.8% (95% CI, 76.9% to 99.8%), negative predictive value was 75.4% (95% CI, 70.1% to 80.1%), and prevalence was 29.8% (95% CI, 25.0% to 35.2%). Using logistic regression, tumor size was predictive for prevalence of tumor in the axilla and for PET sensitivity. PET scan was suspicious for distant metastases in 13 patients; three (0.9%) were confirmed as metastatic disease and 10 (3.0%) were false positive. FDG-PET is not sufficiently sensitive to detect positive axillary lymph nodes, nor is it sufficiently specific to appropriately identify distant metastases. However, the very high positive predictive value (96%) suggests that PET when positive is indicative of disease in axillary nodes, which may influence surgical care.

P4-12-05: Impact of the Lifestyle Intervention Study in Adjuvant Treatment of Early Breast Cancer (LISA) Weight Loss Intervention upon Physical Activity.

Abstract Observational evidence shows a relationship between obesity and poor prognosis in breast cancer (BC). Physical activity (PA) is an important component of weight loss and maintenance, but most large-scale interventions in BC patients have produced only modest improvements in activity. We sought to evaluate changes in PA in women participating in LISA, a randomized trial coordinated by the Ontario Clinical Oncology Group which was designed to examine the impact of a telephone-based weight loss intervention (WLI) upon disease free survival in BC patients. Methods: Participants were randomized 1:1 to the WLI or educational control (EC) group. Eligibility included diagnosis of Stage I-III BC, BMI ≥24 kg/m2, and treatment with letrozole. The WLI, based on the Diabetes Prevention Program, focused on weight reduction through calorie restriction and increased physical activity. Delivery involved 19 calls, mailings and a participant manual. The PA goal was 150 minutes/week. PA was measured using the International Physical Activity Questionnaire (Short Form) at baseline, 6, 12, and 18 months. Changes in time (minutes/week) spent sitting and engaging in moderate, vigorous, and walking activities were compared between groups. Results 338 women were randomized to WLI (n=171) or EC (n=167) from 20 centers in Canada and the USA. The study was discontinued due to loss of funding. The WLI arm lost significantly more weight than EC arm, with mean weight loss of 6.1% of body weight vs. 0.6% at 12 months (p<0.001). Activity data are presented in Table 1. At baseline, participants were inactive; median vigorous activity was zero minutes/week and median time spent sitting was more than 35 hours/week. WLI participants reported significantly higher participation in vigorous, moderate and walking activities, and lower levels of sedentary behavior, compared to controls at 6 and 12 months. Higher levels of PA were significantly associated with increased weight loss at all time periods. Factors associated with increases in activity included higher baseline BMI (p=0.014), lower baseline activity (p<0.001) and assignment to the WLI arm (p=0.02). Women assigned to WLI increased their PA during the intervention period (p=0.017) even after adjusting for other significant baseline factors. Conclusion Participants in the LISA WLI reported significantly higher levels of PA compared with controls. Activity increased most in women who were heavier and less active at baseline. Further study of this WLI as a potential means to improve BC outcomes is warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-12-05.

Randomized trial of a lifestyle intervention for women with early-stage breast cancer (BC) receiving adjuvant hormone therapy: Initial results.

512 Background: Obesity is an adverse prognostic factor in early BC. We conducted a randomized clinical trial (RCT) to evaluate a 2-year, centrally delivered, telephone-based weight loss intervention (WLI) compared to a mailed educational intervention (EI) on recurrence, weight loss and QOL in postmenopausal women receiving adjuvant Letrozole. The trial was terminated after 338 of a planned 2,150 women were enrolled due to loss of funding. Methods: 338 women with stage I-IIIa BC were randomized to WLI (n%171) or EI alone (n%167) at 20 centers in Canada and USA. Eligibility included BMI ≥24 kg/m2and <3 years of definitive surgery. WLI involved 19 calls, mailings and a participant manual. Weight loss goal was 10% of baseline via reduction of caloric and fat intake (500-1000 kcal/day, 20% calories fat) and increased physical activity (150-200 minutes/week). Results: Mean age and BMI were 61 years and 31.3 kg/m2. Baseline BMI, adjuvant chemotherapy, and tumor characteristics were balanced between arms. 87.5% of protocol mandated WLI calls took place. Mean weight change is shown in the table. Results were similar for baseline BMI ≥/<30 kg/m2 and adjuvant chemotherapy (yes/no). Mean SF 36 normalized physical component score was improved in WLI vs. EI at 6 (+ 4.1 WLI vs. + 2.1 C, p%0.046) and 12 months (+3.9 WLI vs. + 2.7 EI, p%0.33). Conclusions: A 2-year, telephone-based WLI resulted in significant weight loss at 6, 12, and 18 months in early BC. Results were similar with BMI <30 or 30+ and with or without adjuvant chemotherapy. Follow-up continues to evaluate longer term effects. Funded by Novartis Pharmaceuticals Inc. Sponsored by the Ontario Clinical Oncology Group. Weight (kg) Weight loss intervention Educational intervention P value N Mean (sd) N Mean (sd) Baseline 171 82.7 (15.3) 167 81.3 (14.5) 6 months % Change from baseline 147 -5.6 (4.9) 142 -0.8 (4.9) <.001 12 months % Change from baseline 113 -6.1 (6.2) 121 -0.6 (6.0) <.001 18 months % Change from baseline 68 -5.0 (7.6) 77 -1.2 (6.5) .003

An Ontario Clinical Oncology Group (OCOG) randomized trial (PET START) of FDG PET/CT in patients with stage III non-small cell lung cancer (NSCLC): Predictors of overall survival.

7018 Background: Patients with stage 3 NSCLC are potentially curable using combined modality therapy (CMT) with chemotherapy and radical radiation therapy (RT). PET/CT imaging is commonly used to stage patients with NSCLC. In addition, PET/CT for planning of RT may improve the definition of RT treatment volumes compared with conventional CT planning and thus improve outcomes. Methods: Patients with stage 3 NSCLC, who were considered candidates for CMT, were randomized to either PET/CT or CT alone for RT treatment planning. The proportion of patients who did not receive CMT because their tumor was upstaged to stage 4 or their intra-thoracic tumor was too extensive for radical RT was presented at the ASCO 2009 meeting. The secondary outcomes of overall survival (OS) and relationship of the standard uptake value (SUV) and OS are reported now. Results: Overall 310 patients were randomized, 152 to the PET/CT and 158 to standard CT planning. 118 (78%) of the 152 patients randomized to the PET/CT arm received radical RT compared with 146 (92%) of the 158 CT patients. The median follow-up was 17 months. The 2-year OS of the PET/CT group was 47% compared with 39% for the CT arm (hazard ratio [HR] = 0.8; 95% confidence interval [CI]: 0.6 - 1.0). A multivariable analysis (MVA) for OS indicated that in addition to the intervention, stage (3B vs 3A; HR = 1.4, 95% CI: 1.1 - 1.9) and ECOG status (HR = 1.7 per unit increase, 95% CI: 1.3 - 2.6) were predictive of OS. In the 142 PET/CT patients with complete PET scans, a MVA showed that SUV (HR = 1.03 per unit increase, 95% CI: 1.01 - 1.05) and stage (3B vs 3A; HR = 1.9, 95% CI: 1.2 - 3.0) were strong predictors of OS. Conclusions: The PET START trial is the first randomized trial comparing PET/CT planning with standard CT planning in patients with NSCLC. As expected, the use of PET/CT resulted in fewer patients receiving radical RT. The OS trend favoring PET/CT may be primarily due to more accurate staging. The SUV and stage were strong predictors of OS in patients with stage 3 NSCLC.

An Ontario Clinical Oncology Group (OCOG) randomized controlled trial (RCT) assessing FDG PET/CT in resectable liver colorectal adenocarcinoma metastases (CAM).

3520 Background: Advances in chemotherapy and surgery have increased the number of colorectal cancer patients eligible for hepatic resection. Detection of extrahepatic metastases is important to av...

Results of an Ontario Clinical Oncology Group (OCOG) prospective cohort study on the use of FDG PET/CT to predict the need for neck dissection following radiation therapy of head and neck cancer (HNC).

5504 Background: A significant proportion of node-positive HNC patients will have residual nodes visible on CT following curative radiation therapy +/- concurrent chemotherapy (RT+/-Chemo). A third of these will harbor residual cancer and can be cured by neck dissection (ND). This study examines the ability of PET/CT to detect residual nodal cancer following RT+/-Chemo in HNC patients. Methods: This prospective multi-center study was conducted at 4 regional cancer centers in Ontario. Eligible patients had squamous cell carcinomas with N2 or N3 neck disease. They were treated curatively with RT+/-Chemo to include full radiation dose to nodes deemed involved by tumor. Contrast enhanced CT scans and PET/CT were performed prior to and 8-10 weeks following RT+/-Chemo. Patients with residual nodes >1cm axial dimension on CT were mandated to undergo ND within 4 weeks of imaging. The pathologic results of ND were correlated with post treatment imaging. Patients were followed for neck recurrence for 2 years. Resul...

Development of a dosimetry inter-comparison for IMRT as part of site credentialing for a TROG multi-centre clinical trial for prostate cancer

A methodology has been developed for a dosimetry inter-comparison of intensity modulated radiation therapy (IMRT) delivery in Australasia. The inter-comparison is part of site credentialing for those sites participating in the prostate fractionated irradiation trial (PROFIT) for intermediate-risk prostate patients developed by the Ontario Clinical Oncology Group and coordinated in Australasia by the Trans Tasman Radiation Oncology Group. Features of the dosimetry inter-comparison design included the use of a dedicated pelvic anthropomorphic phantom, the use of a single CT data set of the phantom including contours and the use of radiochromic film as a dosimeter. Action levels for agreement between measured dose and treatment planning system dose have been proposed based on measurement uncertainty and international experience. A trial run of the dosimetry procedure at the reference centre gave results within the predefined action levels.

Shorter fractionation schedules in breast cancer radiotherapy: Clinical and economic implications

An accumulating body of level I evidence from randomised trials of adjuvant radiotherapy in early breast cancer supports the safety and efficacy of giving a lower total dose in fewer larger fractions (hypofractionation) than the historical standard of 50 Gy in 25 fractions of 2.0 Gy over 5 weeks. 1 Bentzen S.M. Agrawal R.K. Aird E.G. et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet. 2008; 371: 1098-1107 Abstract Full Text Full Text PDF PubMed Scopus (861) Google Scholar , 2 Bentzen S.M. Agrawal R.K. Aird E.G. et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol. 2008; 9: 331-341 Abstract Full Text Full Text PDF PubMed Scopus (809) Google Scholar , 3 Owen J.R. Ashton A. Bliss J.M. et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol. 2006; 7: 467-471 Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar , 4 Whelan T. MacKenzie R. Julian J. et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst. 2002; 94: 1143-1150 Crossref PubMed Scopus (554) Google Scholar The published phase 3 trials relate to patients prescribed whole breast radiotherapy, but the principle is being extended to trials evaluating partial breast irradiation restricted to the tumour bed. 5 Orecchia R. Ciocca M. Lazzari R. et al. Intraoperative radiation therapy with electrons (ELIOT) in early-stage breast cancer. Breast. 2003; 12: 483-490 Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar , 6 Vaidya JS, Baum M, Tobias JS, Houghton J. Lancet. Targeted intraoperative radiotherapy; 1999. <http://www.thelancet.com/journals/lancet/misc/protocol/99PRT-47>. Google Scholar , 7 Strnad V, Polgar C. On behalf of the European Brachytherapy Breast Cancer GEC-ESTRO Working Group. GEC-ESTRO APBI Trial: interstitial brachytherapy alone versus external beam radiation therapy after breast conserving surgery for low risk invasive carcinoma and low risk duct carcinoma in-situ (DCIS) of the female breast; 2006. <http://www.apbi.uni-erlangen.de/outline/outline.html>. Google Scholar , 8 Wolmark N, Curran WJ. Trial protocol March 13, 2007. On behalf of NSABP and RTOG of the American College of Radiology (ACR). NSABP Protocol B-39. RTOG Protocol 0413. A randomized phase III study of conventional whole breast irradiation versus partial breast irradiation for women with stage 0, I, or II breast cancer. National surgical adjuvant breast and bowel project (NSABP); 2007. p. 1–132. Google Scholar , 9 OCOG. Ontario Clinical Oncology Group (OCOG), Canadian Institutes of Health Research (CIHR), Canadian Breast Cancer Research Alliance. RAPID: Randomized Trial of Accelerated Partial Breast Irradiation; 2008. <http://clinicaltrials.gov/ct2/show/NCT00282035>. Google Scholar , 10 Yarnold J, Coles C. Trial Protocol, version 4, 19.02.2008. On behalf of the IMPORT LOW Trial Management Group: Intesity Modulated and Partial Organ Radiotherapy. Randomised trial testing intensity modulated and partial organ radiotherapy following breast conservation surgery for early breast cancer. Sutton, Surrey, UK: The Institute of Cancer Research: Royal Cancer Hospital; 2008. p. 1–74. Google Scholar , 11 http://www.irmatrial.it/. Google Scholar Interest in hypofractionation is based not only on the practical advantages to patients and health services of fewer hospital visits, but also on two postulated clinical benefits. The first is that breast cancer is more sensitive to fraction size than formerly thought, so that fewer larger fractions maintain current levels of anti-tumour effect without increasing late adverse effects. The second is that shorter overall treatment times (accelerated hypofractionation) may be more effective in patients with rapidly proliferating tumours.

Author reply

We thank Dr. Evans for his interest in our report.1 Dr. Evans suggests that randomized prospective trials have shown definitively that development of ipsilateral breast tumor recurrence (IBTR) is a marker of risk for (and not a cause for) distant metastasis. We believe that, based on the results of existing trials, the question remains unanswered. Randomized trials have shown that radiotherapy significantly decreases IBTR after breast-conserving surgery;2-5 however, most of those studies were designed to evaluate the effect of radiation on the rate of IBTR as the primary endpoint and, thus, were not statistically powered to address the survival question. Although, in the Swedish trial, the decrease in IBTR did not translate into a decrease in distant metastases in the radiation therapy arm, in the Scottish trial, there was a trend toward fewer distant metastases in the irradiated group.4, 5 Furthermore, in the Ontario Clinical Oncology Group trial, a statistically significant increase in the relative risk for distant recurrence among patients who did not receive radiotherapy was observed (relative risk, 1.4; 95% confidence interval, 1.07–1.8; P = 0.01).3 However, the Ontario study also was not designed specifically to determine the effect of radiotherapy on distant metastases. Therefore, we cannot exclude the possibility that this result is biased due to the precipitation of screening for distant metastases by IBTRs. Finally, the Milan trial noted a poorer 10-year overall survival in patients with positive lymph nodes who were randomized to undergo quadrantectomy alone compared with quadrantectomy plus breast irradiation (34.1% vs. 19.3%, respectively; P = 0.038).6 The increase in deaths likely was due to the higher rate of locoregional recurrence in the group that did not receive radiation. Biologically, it would be difficult to argue that malignant cells in the primary tumor can metastasize and that malignant cells in the recurrent tumor cannot. Metastases arise from the spread of malignant cells from the primary tumor site and the formation of new tumors in distant sites. The metastatic process consists of series of steps that need to be completed successfully. First, the malignant cells at the primary site need to develop access to the circulation, either through the circulatory blood system or through the lymphatic system. Then, the malignant cells need to survive in the circulation. Next, the circulating cells need to arrest in a new organ and extravasate into the new tissue. Finally, the cells need to initiate growth in the new tissue and eventually establish vascularization to sustain the new tumor. Although the metastatic process overall is quite complex, none of the individual steps appear to be unique for primary tumors, and it appears that a locally recurrent tumor also should be vulnerable to these steps. We agree that IBTR, by definition, is local persistence of a tumor. In patients who have received radiation, it is possible to speculate that, through clonal selection, these tumor cells may have accumulated further genetic alterations conferring radiation-resistance. Many oncogenes that confer a survival advantage also facilitate one or more steps in the metastatic process. Although the theory that the host can defend against circulating cells until a certain primary tumor burden is reached is interesting, it may be argued that the tumor already has escaped host defense mechanisms by recurring. Further study is needed to define the molecular alterations in primary tumors and local recurrences. However, based on our current understanding of biologic principles, it is predictable that an IBTR would have a more aggressive phenotype with a metastatic advantage. Most studies to date have reported that IBTR after breast conservation is associated with an increased risk of distant metastases and poorer survival.7-11 Although it is very likely that patients at higher risk of systemic recurrence also are at risk for IBTR, the data are not sufficient to exclude the possibility that a portion of patients who initially are rendered free of distant disease subsequently develop an IBTR and develop a subsequent distant metastasis from the IBTR. The importance of negative surgical margins for local tumor control and survival has been documented repeatedly for several other tumor types, including sarcoma, pancreatic cancer, and rectal cancer.12-16 Because that is the case, we strongly believe that the ‘conservative’ strategy is to be aggressive about local control in breast cancer therapy. Funda Meric-Bernstam M.D.*, Kelly K. Hunt M.D.*, Thomas A. Buchholz M.D. , * Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas.

A multi-center phase I trial of chemotherapy in operable breast cancer: M. Levine, K. Pritchard for the Ontario Clinical Oncology Group McMaster University, Hamilton, Ontario, Canada(23)

A multi-center phase I trial of chemotherapy in operable breast cancer: M. Levine, K. Pritchard for the Ontario Clinical Oncology Group McMaster University, Hamilton, Ontario, Canada(23)