eTable 1. Original Whole Breast Dose
eTable 2. Circulating Tumor Cell Analysis
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Arthur DW, Winter KA, Kuerer HM, et al. Effectiveness of Breast-Conserving Surgery and 3-Dimensional Conformal Partial Breast Reirradiation for Recurrence of Breast Cancer in the Ipsilateral Breast: The NRG Oncology/RTOG 1014 Phase 2 Clinical Trial. JAMA Oncol. 2020;6(1):75–82. doi:10.1001/jamaoncol.2019.4320
Is partial breast reirradiation after a second lumpectomy for recurrence of breast cancer in the ipsilateral breast after previous whole breast irradiation associated with long-term local control?
In this phase 2 clinical trial of 58 patients with recurrence of breast cancer, the 5-year estimate of re-recurrence of breast cancer in the ipsilateral breast was 5%. Late grade 3 treatment-related adverse events were reported in 7% of patients, with no grade 4 or higher adverse events reported, and the 5-year cumulative incidence of ipsilateral mastectomy was 10%.
The findings suggest that a second lumpectomy followed by partial breast reirradiation is an effective alternative to mastectomy in those experiencing recurrence of breast cancer in the ipsilateral breast after an initial lumpectomy and whole breast irradiation.
Mastectomy is standard for recurrence of breast cancer after breast conservation therapy with whole breast irradiation. The emergence of partial breast irradiation led to consideration of its application for reirradiation after a second lumpectomy for treatment of recurrence of breast cancer in the ipsilateral breast.
To assess the effectiveness and adverse effects of partial breast reirradiation after a second lumpectomy and whether the treatment is an acceptable alternative to mastectomy.
Design, Setting, and Participants
The NRG Oncology/Radiation Therapy Oncology Group 1014 trial is a phase 2, single-arm, prospective clinical trial of 3-dimensional, conformal, external beam partial breast reirradiation after a second lumpectomy for recurrence of breast cancer in the ipsilateral breast after previous whole breast irradiation. The study opened on June 4, 2010, and closed June 18, 2013. Median follow-up was 5.5 years. This analysis used all data received at NRG Oncology through November 18, 2018. Eligible patients experienced a recurrence of breast tumor that was less than 3 cm and unifocal in the ipsilateral breast more than 1 year after breast-conserving therapy with whole breast irradiation and who had undergone excision with negative margins.
Adjuvant partial breast reirradiation, 1.5 Gy twice daily for 30 treatments during 15 days (45 Gy), using a 3-dimensional conformal technique.
Main Outcomes and Measures
The main outcomes of the present study were the predefined secondary study objectives of recurrence of breast cancer in the ipsilateral breast, late adverse events (>1 year after treatment), mastectomy incidence, distant metastasis–free survival, overall survival, and circulating tumor cell incidence.
A total of 65 women were enrolled, with 58 evaluable for analysis (mean [SD] age, 65.12 [9.95] years; 48 [83%] white). Of the recurrences of breast cancer in the ipsilateral breast, 23 (40%) were noninvasive and 35 (60%) were invasive. In all 58 patients, 53 (91%) had tumors 2 cm or smaller. All tumors were clinically node negative. A total of 44 patients (76%) tested positive for estrogen receptor, 33 (57%) for progesterone receptor, and 10 (17%) for ERBB2 (formerly HER2 or HER2/neu) overexpression. Four patients had breast cancer recurrence, with a 5-year cumulative incidence of 5% (95% CI, 1%-13%). Seven patients underwent ipsilateral mastectomies for a 5-year cumulative incidence of 10% (95% CI, 4%-20%). Both distant metastasis–free survival and overall survival rates were 95% (95% CI, 85%-98%). Four patients (7%) had grade 3 and none had grade 4 or higher late treatment adverse events.
Conclusions and Relevance
For patients experiencing recurrence of breast cancer in the ipsilateral breast after lumpectomy and whole breast irradiation, a second breast conservation was achievable in 90%, with a low risk of re-recurrence of cancer in the ipsilateral breast using adjuvant partial breast reirradiation. This finding suggests that this treatment approach is an effective alternative to mastectomy.
Rates of breast cancer recurrence in the ipsilateral breast (hereafter referred to as in-breast recurrence) after breast conservation surgery followed by whole breast irradiation (WBI) have steadily decreased with modern treatment approaches and are less than 5% to 10% in the long term.1 For women who experience in-breast recurrence (or a new ipsilateral primary tumor), mastectomy has historically been the only treatment option offered. As screening has advanced to find small recurrences after initial breast-conserving therapy, there has been renewed interest in identifying a means of salvage treatment for those with a desire to preserve the breast. However, subsequent breast-conservation surgery has been associated with high rates of 20% to 30% for second in-breast recurrences.2-6 In the past, there was limited enthusiasm for additional breast conservation treatment that includes another course of WBI because of concerns about toxic effects and poor cosmetic outcome. Partial breast irradiation has emerged as a viable alternative to WBI in selected patients undergoing initial breast conservation, resulting in low rates of in-breast recurrence.7 It was therefore proposed that applying partial breast irradiation after a second breast-conserving surgery to those with in-breast recurrence would be associated with a reduced risk of a second in-breast recurrence while limiting the risk of toxic effects by reducing the volume of tissue receiving reirradiation.
The NRG Oncology/Radiation Therapy Oncology Group (RTOG) 1014 trial is a prospective phase 2 trial of 3-dimensional (3D), conformal, external beam partial breast reirradiation after a second lumpectomy for in-breast recurrence after initial breast conservation with WBI. The primary end point for this phase 2 protocol was treatment-related skin, fibrosis, and/or breast pain adverse events (AEs). In the first 55 patients who were evaluable, these specific AEs were recorded as grade 1 in 64%, grade 2 in 7%, and grade 3 in less than 2%, with no grade 4 or 5 AEs reported.8 Therefore, the results demonstrated that partial breast reirradiation delivered with 3D conformal radiotherapy (3D-CRT) was well tolerated and at the 1-year follow-up interval was safe and feasible with acceptable treatment quality achieved.8 This analysis from the NRG Oncology/RTOG 1014 phase 2 trial now focuses on secondary end points, which include effectiveness of treatment in terms of second in-breast recurrence, distant metastases, mastectomy rate, and AEs occurring more than 1 year from treatment completion. Patients undergoing breast conservation who experience an in-breast recurrence can have a significant risk of distant metastasis.9,10 It was hypothesized that circulating tumor cells (CTCs) may be a means of identifying which patients with an invasive in-breast recurrence would later develop distant metastases. Therefore, this trial also sought to study the frequency of CTCs in the context of a local recurrence and whether a change in CTCs after treatment could be identified in this relatively small cohort.
The study opened on June 4, 2010, and closed June 18, 2013. Median follow-up was 5.5 years. This analysis used all data received at NRG Oncology through November 18, 2018. Complete details of eligibility criteria, target definition and dose delivery, quality assurance, and rapid reviews have been previously described.8 Selected details are highlighted below. Protocol approval was received from the institutional review boards at each participating study site, and written informed consent was obtained from each patient before participation. All data were deidentified.
Eligibility criteria included in-breast recurrence of tumor 3 cm or smaller occurring 1 year or more after initial breast-conserving therapy that was confirmed to be unicentric by magnetic resonance imaging and was without evidence of skin involvement. Recurrent invasive and noninvasive histologic subtypes were included. If invasive, documentation of a negative metastatic workup was required. Breast-conserving surgery during which negative histologic margins (no tumor on ink) were obtained was followed by pretreatment computed tomography that confirmed that the target lumpectomy cavity was unmistakably demarcated and technically appropriate for partial breast irradiation as defined by the target lumpectomy cavity or whole breast reference volume less than 30%. Demarcation of the cavity relied on clear visualization of the excision cavity by computed tomography or, if placed, with the help of surgical clips. Patients with 0 to 3 positive axillary lymph nodes without extracapsular extension were eligible for enrollment. Methods of axillary evaluation in this cohort were tailored based on recurrent histologic findings and previous axillary surgery.
Patient treatment planning and treatment delivery were acceptable with patients in a supine or prone position. Computed tomography visualization-guided lumpectomy cavity delineation and the clinical target volume were defined by uniform expansion by 15 mm with limitation to the posterior breast tissue extent (chest wall structures and pectoralis muscles were not included) and 5 mm from the skin surface. The planning target volume (PTV) was created with an additional 10 mm expansion of the clinical target volume. The PTV for evaluation was used for dose volume histogram analysis constraints and defined as the PTV limited to exclude the first 5 mm of tissue under the skin and any of the PTV expansion beyond the posterior extent of breast tissue. Guidelines for all target volume and normal tissue contouring have been previously published.8
Postlumpectomy adjuvant treatment consisted of the use of 3D-CRT partial breast reirradiation to deliver 1.5 Gy twice per day for a total dose of 45 Gy in 30 fractions to the defined partial breast target. The treatment course was to be delivered during 15 consecutive working days with each fraction separated by a minimum of 6 hours. The treatment plan used for each patient was based on analysis of the volumetric dose, including dose volume histogram analysis of the PTV for evaluation and critical normal tissues. Dose calculations with tissue inhomogeneity correction were used. Photon field combinations (with or without electrons) and field-within-a-field treatment approaches were accepted.
Treatment-related toxic effects were documented with use of the Common Terminology Criteria for Adverse Events, version 4.0 of the National Cancer Institute. Patients were to be seen weekly during treatment, every 3 months for year 1 of follow-up, every 4 months during years 2 and 3, every 6 months for years 4 and 5, and then yearly thereafter. During each follow-up visit, patients were evaluated for any AEs, and if identified, AEs were recorded.
Treatment outcome end points were evaluated using the following definitions. In-breast recurrence was defined as histologic evidence of recurrent carcinoma, invasive or noninvasive (excluding lobular carcinoma in situ), in the ipsilateral breast. Mastectomy failure was the cumulative incidence of mastectomy performed for any reason. Distant metastasis–free survival was the appearance of a distant metastasis confirmed radiographically and/or pathologically or death from any cause. A distant metastasis was only considered a treatment failure if preceded or accompanied by an in-breast recurrence. Overall survival was defined as death from any cause.
To assess the presence and correlation of CTCs with disease control outcomes, a translational objective was incorporated as a secondary end point. All patients enrolled were offered the opportunity to participate in the tissue or specimen sample submission portion of this protocol. The CTCs were assessed using the Cellsearch kit and assay before and within 3 weeks after completing radiotherapy. Nine samples were shipped after the recommended timeline and were analyzed after more than 72 hours. These data are included in the present analysis.
The primary end point of this study was previously reported, focusing only on the first 55 patients achieving 1-year follow-up.8 This article addresses secondary end points and includes all 58 patients eligible for analysis before treatment; tumor characteristics for all 58 eligible patients are given in Table 1.
All outcomes end points were measured from the date of registration to the date of failure or last follow-up for nonfailures. For the secondary end point of in-breast recurrence, assuming a 3-year cumulative incidence of 25% using a χ2 test, a sample size of 55 patients ensured at least 90% statistical power to detect a reduction to 9%, with a significance level of P < .05 (1-sided). The assumption of a 25% 3-year cumulative incidence of in-breast recurrence was determined after literature review of corresponding treatment experiences.8,11 The in-breast recurrence and mastectomy failure rates were estimated using the cumulative incidence method in which death was a competing risk.12 The distant metastasis–free survival and overall survival rates were estimated using the Kaplan-Meier method.13 The rate of CTCs present, the reduction of CTCs by treatment, and the correlation of CTCs with effectiveness were evaluated. All analyses regarding CTCs are descriptive. Statistical analyses were performed using SAS statistical software, version 9.4 (SAS Institute Inc).
Of 65 women enrolled in the NRG Oncology/RTOG 1014 trial, 7 patients were excluded from this evaluation: 3 did not receive protocol treatment, 2 axilla were not managed per protocol guidelines, 1 had a mammogram outside the 120-day window, and 1 had unsatisfactory breast for partial breast radiotherapy. Thus, 58 (mean [SD] age, 65.12 [9.95] years; 48 [82.8%] white) were determined to be evaluable for the present end points and received treatment per protocol. A total of 35 enrolled patients (60%) had invasive histologic subtypes, with the remaining 23 (40%) having ductal carcinoma in situ (DCIS). In-breast recurrences were discovered early; therefore, most were small, with an invasive median tumor size of 1.0 cm (range, 0.2-2.5 cm) and a DCIS median tumor size of 1.0 cm (range, 0.2-3.0 cm). Of these invasive tumors, 3 (7%) were ERBB2 (formerly HER2 or HER2/neu) (OMIM 164870) positive and 8 (23%) were triple negative. All cases were clinically node negative. Fourteen patients (24%) were assessed with sentinel lymph node biopsy or sentinel lymph node biopsy and axillary node dissection, and all tested pathologically negative. Systemic management decisions were at the discretion of the managing physicians. In this cohort of 58 patients, 4 (7%) received chemotherapy, 22 (38%) hormonal therapy, 2 (3%) both, and 30 (52%) neither.
Details of previous WBI were available and submitted for 51 of the patients enrolled (eTable 1 in the Supplement). There was a wide range of time from initial radiation treatment to in-breast failure (median, 13.4 years; range, 1.6-27.7 years). Prior WBI was within expected standards, although a degree of variation was documented. Previously received WBI was delivered with a median dose of 50.4 Gy (range, 45.0-61.2 Gy) and delivered with a median fraction size of 1.8 Gy (range, 1.5-2.2 Gy). After WBI, 41 patients (80%) received a boost to the surgical bed.
With a median follow-up of 5.5 years (range, 0.1-7.2 years), there were 4 total second in-breast recurrences reported, representing a 3-year cumulative incidence of 3.4% (95% CI, 0.6%-10.7%) and a 5-year cumulative incidence of 5.2% (95% CI, 1.4%-13.2%). Characteristics of the 4 patients who reported a second in-breast recurrence are given in Table 2. Two of these second in-breast recurrences were inside the partial breast treatment volume, and 2 were outside and elsewhere within the ipsilateral breast. On the basis of the 3-year in-breast recurrence estimate, it can be concluded with 90% power that the trial’s hypothesized reduction from 25% to at least 9% was met (P < .001). Among the first 55 patients, the 3-year cumulative incidence was 3.6% (95% CI, 0.7%-11.2%; P < .001). A total of 7 patients underwent mastectomy of the treated breast. All 4 second in-breast recurrences resulted in a mastectomy, and 2 additional mastectomies were performed for treatment of nonhealing wounds. A seventh mastectomy was part of a bilateral mastectomy performed for the occurrence of a contralateral breast cancer. Therefore, the 5-year cumulative incidence for mastectomy was 10% (95% CI, 4%-20%). Both the distant metastasis–free survival and overall survival at 5 years were 95% (95% CI, 85%-98%) (Table 3).
The highest-grade AEs, identified as related to treatment and occurring more than 1 year from completion of partial breast reirradiation, were grade 1 in 14 patients (25%), grade 2 in 15 patients (26%), and grade 3 in 4 patients (7%) 3. There was no grade 4 or 5 AE reported. Breast skin and fibrosis changes were the most common AEs. Details are given in Table 4.
A total of 47 patients (81%) consented to participate in CTC collection (eTable 2 in the Supplement). Samples for 9 cases were shipped after the recommended timeline and were analyzed after more than 72 hours. These data are included in the analysis. Of 40 patients with pretreatment assessments, 8 (20%) had CTCs present; 5 patients had only 1 CTC identified, 2 patients had 2 CTCs identified, and 1 patient had 4 CTCs identified. Of the 8 patients with detectable CTCs, 4 had invasive in-breast recurrence and 4 had DCIS in-breast recurrence. Six of the 8 patients had estrogen receptor–positive disease. A total of 31 paired samples were obtained (from 66% of consented patients) for the purpose of evaluating the presence of pretreatment and posttreatment CTCs, but the event rate was low. Of the paired samples, 8 patients had a change in CTCs. Three patients had detectable CTCs before treatment and undetectable CTCs after treatment, and 5 patients had undetectable CTCs before treatment and detectable CTCs after treatment. There were 3 in-breast recurrences, 2 of which were in patients who had undetectable pretreatment and posttreatment CTCs and 1 of which was in a patient with undetectable CTCs before treatment and detectable CTCs after treatment.
Continued follow-up of patients enrolled in the NRG/RTOG 1014 trial demonstrated that a second breast conservation approach using lumpectomy and partial breast reirradiation for management of in-breast recurrence was associated with continued high breast preservation (5-year freedom from mastectomy rate of 90%), with good cancer control and low risk of toxic effects. Previous publications2-6,14-23 reporting outcomes of lumpectomy only for in-breast recurrences after breast conservation treatment have documented rates of second local recurrences of up to 20% to 30%. For this reason, mastectomy became the standard treatment for in-breast recurrence after prior breast conservation with WBI. Several small, retrospective reports24-28 have described promising results after a second lumpectomy and partial breast reirradiation. All but the Groupe Européen de Curiethérapie and the European Society for Radiotherapy and Oncology (GEC-ESTRO) multi-institution retrospective study29 had limited patient numbers and follow-up. The GEC-ESTRO29 is the largest study to date, with 217 cases reported from 8 European radiation therapy departments that retrospectively provided patient, treatment, and outcome information from partial breast reirradiation using brachytherapy. With a median follow-up of 3.9 years, a second in-breast recurrence occurred in 4.1%, distant metastasis in 10.6%, and grade 3 to 4 complications in 11.0%. The target was not defined but rather described as the tumor bed volume reirradiated with low-dose-rate brachytherapy in 102 patients (47%), pulsed-dose-rate brachytherapy in 88 patients (40.6%), and high-dose-rate brachytherapy in 27 patients (12.4%). Median clinical target volumes reported were 52 mL (range, 23-86 mL) for low-dose-rate brachytherapy, 68 mL (range, 18-165 mL) for pulsed-dose-rate brachytherapy, and 62 mL (range, 23–157 mL) for high-dose-rate brachytherapy. The median total doses delivered were 46 Gy (range, 30-55 Gy) for low-dose-rate brachytherapy, 50.4 Gy (range, 49-50 Gy) for pulsed-dose rate brachytherapy, and 32 Gy (range, 22-36 Gy) in 5 to 10 (median, 8) fractions (twice daily) for high-dose-rate brachytherapy. The GEC-ESTRO study, along with others, developed the foundation needed to support the continued study of this treatment approach, allowing women the option of continued preservation of the breast despite experiencing an in-breast recurrence after WBI.
The NRG Oncology/RTOG 1014 trial, with median follow-up of 5.5 years, provides prospective evidence that a second breast-conserving treatment is feasible and effective using 3D-CRT partial breast reirradiation. This finding was demonstrated by a 5% rate of in-breast recurrence and a 90% breast conservation rate at a median follow-up of 5 years. This prospective trial validates the hypothesis generated by the retrospective findings of the prior published literature24-29 and supports the use of a second lumpectomy followed by partial breast reirradiation as an alternative treatment approach to mastectomy for the local management of select in-breast recurrences after breast conservation surgery and WBI. The NRG/RTOG 1014 trial was not intended for all patients with an in-breast recurrence after first breast conservation but for the population of women with small recurrent disease amenable to a second lumpectomy who were motivated to avoid mastectomy. Because all patients had prior WBI, this multi-institutional, prospective clinical trial of partial breast reirradiation after second lumpectomy selected a hyperfractionated radiation regimen (1.5 Gy twice daily) for salvage of in-breast recurrence to spare normal tissue.30-32 This approach is in contrast to radiation delivered for first breast conservation, which currently uses mostly hypofractionated regimens for WBI (2.6 Gy each day) and accelerated partial breast irradiation (3.85 Gy twice daily or 5-6 Gy daily). Additional treatment in any location is associated with a potential risk of increased normal tissue toxic effects, and attention to normal structures included within the treatment area, volume, total dose, and fractionation scheme is always given due attention. Of note, this trial applied more restrictive eligibility criteria compared with earlier studies, as noted in the meta-analysis by Kuerer et al,11 and should be considered when evaluating patients for lumpectomy and partial breast reirradiation. In addition, patients enrolled in the NRG Oncology/RTOG 1014 trial were treated according to strict dosimetric guidelines that covered a defined target with a 3D-CRT external beam technique that delivered 1.5 Gy twice daily for 30 treatments for a total of 45 Gy. This fractionation scheme was chosen in this context of additional treatment based on basic radiobiologic principles to ensure the highest level of disease control and low risk of toxic effects with optimal cosmetic outcome.8 This method of external beam partial breast reirradiation is widely available in every radiation oncology department and may provide access to this alternative to mastectomy.
Chemotherapy improves outcomes from estrogen receptor–negative isolated local recurrences.33 Although systemic therapy was not protocol specified, its use was consistent with standard clinical practice given the mostly estrogen receptor–positive population accrued with DCIS and the small invasive recurrences, which likely did not significantly affect the results seen from partial breast reirradiation.
The incidence of detectable pretreatment CTCs of 20% in this cohort of patients with in-breast recurrence was similar to what was reported in early breast cancer in the German SUCCESS-A trial (Simultaneous Study of Gemcitabine-Docetaxel Combination Adjuvant Treatment, as Well as Extended Bisphosphonate and Surveillance Trial) and lower than the 35% to 60% in cohorts with distant metastases.34,35 No distinct pattern for reduced CTC after treatment was seen, and the low event rate precludes further conclusions regarding association with outcome.
The sample size required for this single-arm phase 2 trial does not allow for analyses to discern whether there are subgroups who would be at higher risk for re-recurrence with this partial breast reirradiation technique.
The NRG Oncology/RTOG 1014 trial outcomes demonstrated that a second lumpectomy with partial breast reirradiation was associated with high rates of breast preservation, low rates of second local regional recurrence, and acceptable toxic effects. This treatment approach was associated with high rates of in-breast recurrence control. Despite previous lumpectomy and WBI for an initial presentation of breast cancer, there were minimal late (>1 year) grade 3 treatment-related AEs and no grade 4 events after a second lumpectomy and partial breast reirradiation with 3D-CRT for patients experiencing in-breast failures. Looking forward, it is likely not feasible to complete a phase 3 trial randomizing patients to mastectomy or second breast conservation with partial breast reirradiation in the modern era because decisions for extent of local regional management of breast cancer reflect patient preferences and concerns. Further investigation into improving technical aspects of radiation delivery as well as refinement of patient selection criteria could prove to be important. The NRG Oncology/RTOG 1014 trial findings suggest that, for women experiencing in-breast recurrence after an initial lumpectomy and WBI and with desire to continue to preserve their breast, a second lumpectomy followed by partial breast reirradiation is a viable alternative to mastectomy.
Accepted for Publication: July 29, 2019.
Corresponding Author: Douglas W. Arthur, MD, Massey Cancer Center, Virginia Commonwealth University, PO Box 980058, Richmond, VA 23298-0058 (firstname.lastname@example.org).
Published Online: November 21, 2019. doi:10.1001/jamaoncol.2019.4320
Author Contributions: Dr Arthur had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis
Concept and design: Arthur, Winter, Kuerer, Haffty, Cuttino, Woodward, McCormick, White.
Acquisition, analysis, or interpretation of data: Arthur, Winter, Kuerer, Cuttino, Todor, Anne, Anderson, Woodward, Cheston, Sahijdak, Canaday, Brown, Currey, Fisher, Jagsi, Moughan, White.
Drafting of the manuscript: Arthur, Winter, Kuerer, Currey, Moughan, White.
Critical revision of the manuscript for important intellectual content: Arthur, Winter, Kuerer, Haffty, Cuttino, Todor, Anne, Anderson, Woodward, McCormick, Cheston, Sahijdak, Canaday, Brown, Fisher, Jagsi, Moughan, White.
Statistical analysis: Arthur, Winter, Moughan.
Obtained funding: Woodward, White.
Administrative, technical, or material support: Arthur, Cuttino, Todor, Cheston, Canaday, Fisher, White.
Supervision: Arthur, Winter, Kuerer, Haffty, McCormick, Sahijdak, White.
Conflict of Interest Disclosures: Dr Kuerer reported receiving grants from the National Cancer Institute and personal fees from Cardinal Health Inc, Targeted Medical Education Inc, Physicians Education Resource LLC, Genomic Health Inc, NEJM Group Inc, and UpToDate Inc outside the submitted work. Dr Woodward reported receiving personal fees from Merck and Genomic Health Inc outside the submitted work. Dr Jagsi reported receiving grants from the National Institutes of Health, Doris Duke Charitable Foundation, and Blue Cross Blue Shield of Michigan, Komen Foundation; receiving personal fees from Amgen and Vizient; receiving grants and personal fees from Greenwall Foundation; and receiving stock options from Equity Quotient outside the submitted work. No other disclosures were reported.
Funding/Support: This trial was supported by National Cancer Institute Community Oncology Research Program grant UG1CA189867, NRG Ops grant U10CA180868, NRG Statistics and Data Management Center grant U10CA180822, NRG Specimen Bank grant U24CA196067, and Imaging and Radiation Oncology Core grant U24CA180803.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Meeting Presentation: This paper was presented at the Annual Meeting of the American Society for Radiation Oncology; September 27, 2016; Boston, Massachusetts, and as a poster at the Annual Meeting of the American Association for Cancer Research; April 1-5, 2017; Washington, DC.
Additional Contributions: We thank all the patients and institutions participating in this trial.