Long-Term Outcomes of Selective Bladder Preservation by Combined-Modality Therapy for Invasive Bladder Cancer: The MGH Experience

EUROPEAN UROLOGY 61 (2012) 705–711

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Platinum Priority – Bladder Cancer Editorial by Giuseppe Simone and Michele Gallucci on pp. 712–713 of this issue

Long-Term Outcomes of Selective Bladder Preservation by Combined-Modality Therapy for Invasive Bladder Cancer: The MGH Experience Jason A. Efstathiou a,*, Daphna Y. Spiegel a, William U. Shipley a, Niall M. Heney b, Donald S. Kaufman c, Andrzej Niemierko a, John J. Coen a, Rafi Y. Skowronski a, Jonathan J. Paly a, Francis J. McGovern b, Anthony L. Zietman a a

Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA; b Department of Urology, Massachusetts General Hospital, Boston,

MA, USA; c Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA

Article info

Abstract

Article history: Accepted November 3, 2011 Published online ahead of print on November 12, 2011

Background: Whether organ-conserving treatment by combined-modality therapy (CMT) achieves comparable long-term survival to radical cystectomy (RC) for muscleinvasive bladder cancer (BCa) is largely unknown. Objective: Report long-term outcomes of patients with muscle-invasive BCa treated by CMT. Design, setting, and participants: We conducted an analysis of successive prospective protocols at the Massachusetts General Hospital (MGH) treating 348 patients with cT2–4a disease between 1986 and 2006. Median follow-up for surviving patients was 7.7 yr. Interventions: Patients underwent concurrent cisplatin-based chemotherapy and radiation therapy (RT) after maximal transurethral resection of bladder tumor (TURBT) plus neoadjuvant or adjuvant chemotherapy. Repeat biopsy was performed after 40 Gy, with initial tumor response guiding subsequent therapy. Those patients showing complete response (CR) received boost chemotherapy and RT. One hundred two patients (29%) underwent RC—60 for less than CR and 42 for recurrent invasive tumors. Measurements: Disease-specific survival (DSS) and overall survival (OS) were evaluated using the Kaplan-Meier method. Results and limitations: Seventy-two percent of patients (78% with stage T2) had CR to induction therapy. Five-, 10-, and 15-yr DSS rates were 64%, 59%, and 57% (T2 = 74%, 67%, and 63%; T3–4 = 53%, 49%, and 49%), respectively. Five-, 10-, and 15-yr OS rates were 52%, 35%, and 22% (T2: 61%, 43%, and 28%; T3–4 = 41%, 27%, and 16%), respectively. Among patients showing CR, 10-yr rates of noninvasive, invasive, pelvic, and distant recurrences were 29%, 16%, 11%, and 32%, respectively. Among patients undergoing visibly complete TURBT, only 22% required cystectomy (vs 42% with incomplete TURBT; log-rank p < 0.001). In multivariate analyses, clinical T-stage and CR were significantly associated with improved DSS and OS. Use of neoadjuvant chemotherapy did not improve outcomes. No patient required cystectomy for treatment-related toxicity. Conclusions: CMT achieves a CR and preserves the native bladder in >70% of patients while offering long-term survival rates comparable to contemporary cystectomy series. These results support modern bladder-sparing therapy as a proven alternative for selected patients. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Keywords: Bladder cancer Chemotherapy Combined-modality therapy Cystectomy Radiation therapy

* Corresponding author. Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street, Cox 3, Boston, MA 02114, USA. Tel. +1 617 726 5866; Fax: +1 617 726 3603. E-mail address: [email protected] (J.A. Efstathiou). 0302-2838/$ – see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.eururo.2011.11.010

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1.

EUROPEAN UROLOGY 61 (2012) 705–711

Introduction

2.

Organ conservation by combined-modality therapy (CMT) is commonplace in contemporary oncology, with success in cancer of the breast, anus, larynx, limb, esophagus, and prostate. In primary muscle-invasive bladder cancer (BCa), however, radical cystectomy (RC) still remains the most commonly offered treatment, even though cystectomy can be associated with significant morbidity [1]. Modern bladder-sparing strategies combine maximal transurethral resection of bladder tumor (TURBT) followed by an induction course of concurrent radiation therapy (RT) and sensitizing chemotherapy. An early assessment of treatment response is performed by cystoscopy and rebiopsy. Patients achieving a clinical complete response (CR) continue with consolidation chemotherapy–RT followed by adjuvant chemotherapy. Incomplete responders are advised to undergo immediate cystectomy. Those with conserved bladders are followed by close cystoscopic surveillance, with prompt salvage cystectomy at the first sign of invasive recurrence. Although no randomized comparisons between cystectomy and CMT exist, a large body of experience has accumulated suggesting that bladder-sparing approaches may yield favorable results in appropriately selected patients [2–10]. General acceptance of bladder-sparing therapy awaits studies that address concerns about limited followup and the possibility of high rates of late failure. Here we report long-term overall survival (OS) and disease-specific survival (DSS) data for a large group of patients treated at our institution.

Patients and methods

This is an analysis of patients with muscle-invasive BCa enrolled in successive, prospective, institutional or Radiation Therapy Oncology Group (RTOG) bladder-sparing protocols at the Massachusetts General Hospital (MGH). Table 1 summarizes the protocols. These phase 1, 2, and 3 protocols reflect an evolution in the scheduling of chemotherapy–RT and the combination of drugs. Further details of the eligibility criteria, chemotherapy drugs, RT technique, response criteria, and follow-up have been described previously [6–12].

2.1.

Patient eligibility and selection

Eligible patients had clinical stage T2–T4aN0M0 transitional cell carcinoma of the bladder and were candidates for RC. After initial evaluation and staging radiology, as thorough a TURBT as possible was performed. Patients were then treated per protocol with induction chemotherapy and RT. Immediate RC was recommended for patients who had less than CR, as determined by cystoscopy, cytology, and tumorsite biopsy. Clinical complete responders received consolidation therapy. Patient exclusion criteria were as previously described [6–12]. All institutional, state, and federal guidelines were followed. All subjects were provided with written informed consent approved by the institutional review board (IRB) before enrollment.

2.2.

Protocol design and treatment

2.2.1.

MGH 180, MGH 880, and RTOG 8903

Between 1986 and 1993, 151 patients were entered onto phase 1 or 2 protocol MGH 180 and phase 3 protocols MGH 880 and RTOG 8903 [6]. These patients either received (MGH 180) or were randomized (MGH 880, RTOG 8903) to receive (or not) two cycles of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) before 39.6-Gy pelvic

Table 1 – Protocol design and treatment Protocol

Neoadjuvant chemotherapy

Induction or concurrent

Response

Consolidation or cystectomy

Adjuvant chemotherapy

MGH 180

MCV 2 cycles

CP + RT

CR

CP + RT

None

50 (14.4)

MGH 880, RTOG 89-03 Arm 1

MCV 2 cycles

CP + RT

IR CR

Cystectomy CP + RT

None

56 (55.4)

MGH 880, RTOG 89-03 Arm 2

None

CP + RT

45 (44.6)

None

CP + 5FU + BID RT

Cystectomy CP + RT Cystectomy CP + 5FU + BID RT

None

MGH 930A

IR CR IR CR

MCV 3 cycles

21 (6.0)

RTOG 95-06

None

CP + 5FU + BID RT

14 (4.0)

None

CP + BID RT

Cystectomy CP + 5FU + BID RT Cystectomy CP + BID RT

None

RTOG 97-06

IR CR IR CR

MCV 3 cycles

22 (6.3)

RTOG 99-06

None

CP + Taxol + BID RT

IR CR

Cystectomy CP + Taxol + BID RT

CP + Gem 4 cycles

45 (12.9)

Per protocol

Varied

Varied

IR CR IR

Cystectomy Varied Cystectomy

Varied

95 (27.3)

Total

Patients, no. (%)

348

MGH = Massachusetts General Hospital; MCV = methotrexate, cisplatin, vinblastine; CP = cisplatin; RT = radiation therapy; CR = complete response; IR = incomplete response; RTOG = Radiation Therapy Oncology Group; 5FU = 5-fluorouracil; BID = twice daily; Gem = gemcitabine.

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RT with concurrent cisplatin. Patients who achieved a CR received

hazard ratios (HR) were calculated for all covariates using Cox

consolidation therapy with 25.2 Gy of additional RT (total dose: 64.8 Gy)

proportional hazards regression analyses with associated 95% confi-

and one additional course of cisplatin. Small pelvic RT fields (similar for all

dence intervals (CI) and p values. Separate logistic regression analyses

protocols) using a four-field technique included the whole bladder, bladder

were performed to evaluate the effect of the above covariates on

tumor, prostate (in men), and adjacent regional pelvic lymph nodes.

achieving a CR to induction therapy. All statistical comparisons were two sided, and a p value <0.05 was considered statistically significant. Stata

2.2.2.

v.11 statistical software (StataCorp, College Station, TX, USA) was used.

MGH 930A, RTOG 9506, and RTOG 9706

Between 1993 and 1999, 57 patients were entered into phase 1 and 2 protocols MGH 930A, RTOG 9506, and RTOG 9706 [7–9,11]. Following

3.

Results

3.1.

Pretreatment characteristics

TURBT, patients were treated with induction chemotherapy–RT consisting of cisplatin with or without 5-fluorouracil (5FU) concurrent with twicedaily RT to the pelvis and tumor. Patients who achieved a CR received consolidation therapy with the same chemotherapy and additional RT to the pelvis, bladder, and tumor given in twice-daily fractions. Adjuvant MCV chemotherapy was also administered in MGH 930A and RTOG 9706.

2.2.3.

RTOG 9906

Between 1999 and 2002, 45 patients were entered into RTOG phase 1 and 2 protocol 9906 [10]. After TURBT, induction therapy involved 13 d of concomitant-boost RT with 1.6 Gy to the pelvis in the morning followed by 1.5 Gy to the bladder for the first five sessions (7.5 Gy), then

Between 1986 and 2006, 348 patients with clinical T2–T4aN0M0 invasive BCa underwent CMT at MGH. Median age was 66.3 yr of age (range: 27.3–88.6), body mass index was 26.3 kg/m2 (range: 17.4–47.1), and tumor size was 4 cm (range: 1–11). Pretreatment characteristics are shown in Table 2. One hundred twenty-three patients received neoadjuvant chemotherapy. Median follow-up for surviving patients was 7.7 yr (range: 0.12–21.3).

to the tumor for eight sessions (12.0 Gy) in the afternoon (20.8 Gy to the

3.2.

Outcomes

Patients who achieved a CR received consolidation chemoradiation

3.2.1.

Response to induction therapy, rates of failure, and need for

consisting of 1.5-Gy pelvic RT delivered twice daily to 24 Gy (total dose:

cystectomy

64.3 Gy to the tumor and 44.8 Gy to the pelvic lymph nodes) with the

Seventy-two percent of all patients (78% with T2 disease) achieved CR to induction chemoradiation. Among patients achieving CR, 10-yr rates of noninvasive, invasive, pelvic (nodal or sidewall), and distant recurrences were 29%, 16%, 11%, and 32%, respectively. One hundred two patients (29%) ultimately required a cystectomy—60 (17%) immediately for less than CR and 42 (12%) in a prompt salvage fashion for recurrent invasive tumors identified during follow-up with close cystoscopic surveillance. Median time to cystectomy in the salvage group was 1.1 yr (95% CI, 0.75–1.5). No patient required cystectomy resulting from treatmentrelated toxicity.

pelvis, 28.3 Gy to whole bladder, and 40.3 Gy to the bladder tumor). Weekly cisplatin and paclitaxel were included as radiation sensitizers.

same chemotherapy, followed by adjuvant gemcitabine and cisplatin. Ninety-five patients were treated as per the above protocols when active protocols had closed and successor protocols were pending IRB approval.

2.3.

Follow-up

Patients with conserved bladders were closely followed with cystoscopy, tumor-site rebiopsy, bimanual examination under anesthesia (EUA), urine cytology, and radiology [8]. Cystoscopic surveillance occurred every 3 mo in the first year, every 3 to 4 mo in the second year, every 6 mo for 3 yr, and then annually. After 1–2 yr, in patients with negative evaluations, the biopsy and EUA were usually omitted if no worrisome office endoscopic findings were present. Patients were promptly considered for intravesical therapy for noninvasive recurrences and salvage RC for an invasive recurrence.

2.4.

Table 2 – Pretreatment patient characteristics (n = 348) Characteristic

Outcomes and survival end points

Response of the primary tumor was considered complete if no tumor were visible on cystoscopy and tumor-site rebiopsy was negative. Cause of death was investigator defined and reported in follow-up case report forms, and then independently confirmed by a convened panel of investigators (JE, WS, DS, DK, NH). DSS was defined as surviving protocol treatment and having no evidence of distant metastasis, nodal recurrence, or recurrence within the RT field that could not be salvaged in a curative fashion. Bladder-intact DSS was defined as DSS and retaining one’s native bladder [8].

2.5.

Statistical analysis

DSS and OS were estimated according to the Kaplan-Meier method, and comparisons were performed using the log-rank test. Univariate Cox proportional hazard regression analyses using the x

2

test were

performed to evaluate the solitary effect of each variable on the various survival end points. Multivariate analyses were performed using a Cox proportional hazards regression model, and categoric variable cut points were selected before the data were examined. Unadjusted and adjusted

Gender Male Female Clinical stage T2 T3 T4 Grade High Intermediate Visibly complete TURBT Yes No Unknown Hydronephrosis No Yes CIS No Yes

No.

%

257 91

73.9 26.2

188 132 28

54.0 37.9 8.1

298 50

85.6 14.4

227 116 5

65.2 33.3 1.4

290 58

83.3 16.7

263 85

77.6 24.4

TURBT = transurethral resection of bladder tumor; CIS = carcinoma in situ.

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3.2.2.

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Disease-specific survival

Five-, 10-, and 15-yr cumulative DSS rates were 64%, 59%, and 57%, respectively (Fig. 1A). For clinical stage T2, rates were 74%, 67%, and 63% and for T3–4 disease 53%, 49%, and 49%, respectively (Fig. 1C). Even for clinical stage T3–4 disease, there was an approximate 50% long-term disease-specific cure rate. Five-, 10-, and 15-yr cumulative bladder-intact DSS rates were 60%, 45%, and 36%, respectively. The 10-yr DSS rate for the subset of 102 patients who underwent salvage

[(Fig._1)TD$IG]

cystectomy was 44%. Results were comparable among both younger and older patients when stratified around 75 yr of age (log-rank p = 0.6). Of note, six deaths occurred that were treatment related (five hematologic/infectious following chemotherapy and one cardiopulmonary arrest following cystectomy). 3.2.3.

Overall survival

Five-, 10-, and 15-yr cumulative OS rates were 52%, 35%, and 22%, respectively (Fig. 1B). For clinical stage T2, rates were

Fig. 1 – (A and B) Kaplan Meier plots for rates of disease-specific survival and overall survival, respectively, for all patients; (C and D) stratified by clinical T2 versus T3/4; and (E and F) stratified by induction response status.

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Table 3 – Treatment outcomes by extent of transurethral resection of bladder tumor* Outcomes

All patients

TURBT visibly complete

TURBT not visibly complete

All patients, no. CR rate OS: At 5 yr, % (range) At 10 yr, % (range) DSS At 5 yr, % (range) At 10 yr, % (range) % undergoing cystectomy TOTAL Immediate (non-CR), % Salvage, %

343* 72%

227 79%

116 57%

52 (46–57) 35 (30–41)

57 (50–63) 39 (32–46)

43 (33–51) 29 (21–38)

64 (58–70) 59 (53–65)

68 (61–75) 63 (55–70)

56 (46–66) 51 (40–61)

29% 17 12

22% 11 11

42% 29 13

p value – <0.001** 0.003***

0.03***

<0.001**

TURBT = transurethral resection of bladder tumor; CR = complete response; OS = overall survival; DSS = disease-specific survival. Includes only patients with known TURBT status; univariate analysis only; numbers in brackets represent 95% confidence limits. 2-sided Fisher exact test. *** Log-rank test for equality of survivor functions. *

**

Table 4 – Univariate Cox regression analyses for survival end points Covariates

Age, yr Gender Clinical stage Complete TURBT Hydronephrosis Induction response Neoadjuvant chemotherapy Radiation fractionation Cystectomy

Comparison

>65 vs. 65 Male vs female T2 vs T3/T4 Yes vs no Yes vs no Complete vs incomplete Yes vs no BID vs QD Delayed vs immediate Any vs none

OS

DSS

HR

p

95% CI

HR

p

95% CI

1.41 1.06 0.59 0.67 1.79 0.49 1.03 0.86 0.76 1.41

0.013 0.72 <0.001 0.003 <0.001 <0.001 0.22 0.30 0.23 0.014

1.07–1.85 0.79–1.42 0.45–0.77 0.51–0.88 1.29–2.47 0.37–0.65 0.78–1.35 0.64–1.15 0.48–1.20 1.07–1.87

0.92 1.12 0.53 0.67 2.08 0.37 0.99 0.94 0.60 1.69

0.66 0.59 0.001 0.029 0.001 <0.001 0.94 0.78 0.096 0.005

0.64–1.32 0.75–1.66 0.37–0.76 0.46–0.96 1.37–3.17 0.25–0.53 0.68–1.43 0.65–1.38 0.33–1.09 1.71–2.43

OS = overall survival; DSS = disease-specific survival; HR = hazard ratio; CI = confidence interval; TURBT = transurethral resection of bladder tumor; BID = twice daily; QD = once daily.

61%, 43%, and 28% and for T3–4 disease 41%, 27%, and 16%, respectively (Fig. 1D). Eighty percent of those alive at 5 yr retained their native bladder.

CR to induction therapy (vs 57% with incomplete TURBT; p < 0.001), and only 22% required cystectomy (vs 42%; p < 0.001).

3.3.

3.4.

Extent of transurethral resection of bladder tumor

In subgroup analysis, there appears to be value in achieving a visibly complete TURBT in terms of CR and survival (Table 3). Among patients with a complete TURBT, 79% achieved

Univariate and multivariate analyses

In univariate Cox regression analyses, clinical T stage, visibly complete TURBT, lack of hydronephrosis, and CR to induction therapy were significantly associated with

Table 5 – Multivariate Cox regression analyses for survival end points Covariates

Age Gender Clinical stage Complete TURBT Hydronephrosis Induction response Neoadjuvant chemotherapy Radiation fractionation Cystectomy

Comparison

>65 vs 65 Male vs female T2 vs T3/T4 Yes vs no Yes vs no Complete vs incomplete Yes vs no BID vs QD Delayed vs immediate Any vs none

OS

DSS

HR

p

95% CI

HR

p

95% CI

1.39 1.09 0.66 0.88 1.30 0.56 0.88 1.13 1.20 0.95

0.032 0.54 0.014 0.45 0.18 0.008 0.72 0.60 0.91 0.18

1.03–1.87 0.79–1.52 0.47–0.92 0.63–1.23 0.89–1.90 0.36–0.86 0.62–1.25 0.75–1.70 0.74–2.31 0.57–1.58

0.90 1.15 0.55 1.00 1.31 0.37 0.91 1.42 1.30 0.92

0.60 0.51 0.008 0.99 0.27 <0.001 0.70 0.20 0.48 0.78

0.61–1.32 0.75–1.77 0.35–0.86 0.64–1.56 0.81–2.14 0.22–0.64 0.55–1.48 0.83–2.43 0.63–2.69 0.50–1.68

OS = overall survival; DSS = disease-specific survival; HR = hazard ratio; CI = confidence interval; TURBT = transurethral resection of bladder tumor; BID = twice daily; QD = once daily.

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improved DSS and OS (Table 4). In multivariate analyses, clinical T stage and CR to induction therapy remained significantly associated with these end points (Table 5; Fig. 1C–F). Use of neoadjuvant chemotherapy (two cycles of MCV) did not improve outcomes ( p = 0.7 for survival and incidence of distant metastases), while salvage cystectomy for recurrent invasive disease identified during follow-up with close cystoscopic surveillance did not confer worse outcomes when compared to immediate cystectomy for a non-CR ( p = 0.48 for DSS). In separate univariate logistic regression analyses, factors associated with CR to induction therapy included low clinical T stage, complete TURBT, and lack of hydronephrosis (all p < 0.01; data not shown). 4.

Discussion

We present long-term results from a large series of patients treated according to prospective protocols with CMT for invasive BCa. Modern selective bladder-sparing therapy allows preservation of the native bladder in approximately 70% of patients, with long-term survival rates comparable to contemporary RC series [13–20]. Short of a randomized trial, any direct comparison to cystectomy is difficult and must account for selection bias and confounding resulting from discordance between clinical and pathologic staging. The 10-yr OS and DSS rates for all patients (35% and 59%, respectively) and those with clinical T2 tumors (43% and 67%, respectively) in bladderpreserving protocols compare favorably to results reported by primary RC (with or without adjuvant therapy) for patients with clinically staged muscle-invading BCa [6,17,19,20]. Similar to cystectomy series, there are few deaths from BCa beyond 5 yr with bladder-sparing therapy (Fig. 1A). Close cystoscopic surveillance with prompt salvage cystectomy for tumor persistence or an invasive recurrence is fundamental to the success of a bladderpreservation strategy, and any comparison to cystectomy series must include these nonresponders. Our study identified T stage and CR to induction therapy as significant predictors of survival. Although complete TURBT did not retain significance in multivariate analyses—likely because of confounding by T stage and CR—the value of a complete TURBT is highlighted by the 20% improvement in CR and the chance of avoiding eventual cystectomy. Although we, therefore, advocate for an aggressive maximally safe and visibly complete TURBT with success about two-thirds of the time, the inability to perform a complete TURBT does not necessarily preclude successful selective bladder preservation. It cannot be concluded that patients with incomplete resections would have gained a survival benefit from immediate cystectomy. Similar to prior findings by the RTOG [6], we saw no survival benefit from the use of neoadjuvant chemotherapy in the form of two cycles of MCV. In contrast, the value of concurrent sensitizing chemotherapy in addition to RT (compared to RT alone) is strongly supported by recent phase 3 evidence [21]. Although our study has substantial strengths, potential limitations need to be considered. First, our results reflect the experience of a single institution and a number of protocols

limiting generalizability. Yet the majority of prospective protocols on which we report were open through the RTOG at 62 other participating institutions within North America. Our results are also similar to those reported by other singleinstitution European series [3]. Second, although accelerated twice-daily radiation regimens might be difficult to adopt within the community setting, a randomized trial has suggested equivalent efficacy with conventional oncedaily fractions [22]. An RTOG protocol is currently assessing such a regimen that would be more convenient for both patients and providers. Third, we used investigator-defined cause of death as one study outcome. Our ascertainment of DSS and OS seems reliable given the close follow-up of our patients and the fact that cause of death was independently confirmed by a convened panel of investigators. Finally, although our study comprehensively addresses long-term cancer control, successful bladder preservation only has merit if the preserved bladder functions at a level acceptable to the patient. Concerns of late toxicity resulting from chemoradiation have limited the acceptance of bladder-sparing therapy. In separate companion quality of life studies at MGH, we have demonstrated that the retained native bladder functions well and sexual function may be maintained at rates higher than after cystectomy [23]. In a separate study looking at four RTOG trials, low rates of significant late pelvic (genitourinary or gastrointestinal) toxicity were seen for patients completing CMT and retaining their native bladder [24]. These results are consistent with other reports [25–28]. 5.

Conclusions

Bladder-sparing therapy offers a unique opportunity for urologic surgeons, radiation oncologists, and medical oncologists to work hand-in-hand in a truly multidisciplinary effort for the benefit of patients with invasive BCa. The optimal regimen and delivery of combined radiation and chemotherapy as well as the addition of rational molecular targeted therapy and use of predictive biomarkers continues to be actively investigated within the RTOG and other groups [29,30]. Author contributions: Jason A. Efstathiou 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. Study concept and design: Shipley, Kaufman, Heney, McGovern, Zietman, Efstathiou. Acquisition of data: Efstathiou, Shipley, Zietman, Skowronski, Spiegel, Paly, Coen, Heney, Kaufman, McGovern. Analysis and interpretation of data: Efstathiou, Shipley, Niemierko, Spiegel, Skowronski, Paly, Coen, Heney, Kaufman, Zietman. Drafting of the manuscript: Efstathiou, Zietman, Shipley. Critical revision of the manuscript for important intellectual content: Efstathiou, Zietman, Shipley, Niemierko, Spiegel, Paly, Coen, Heney, Kaufman. Statistical analysis: Niemierko, Coen, Spiegel, Paly, Shipley, Efstathiou. Obtaining funding: None. Administrative, technical, or material support: Skowronski, Spiegel, Paly, Coen, Niemierko, Efstathiou, Zietman.

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Supervision: Efstathiou, Shipley, Zietman. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.

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