Safety and Efficacy of Hypofractionated Radiotherapy With Capecitabine in Elderly Patients With Urothelial Carcinoma

Accepted Manuscript Safety and Efficacy of Hypofractionated Radiation Therapy with Capecitabine in Elderly Patients with Urothelial Carcinoma Jim Leng, Adil S. Akthar, Russell Szmulewitz, Peter H. O'Donnell, Randy F. Sweis, Sean P. Pitroda, Norm Smith, Gary D. Steinberg, Stanley L. Liauw PII:

S1558-7673(18)30479-8

DOI:

10.1016/j.clgc.2018.10.003

Reference:

CLGC 1144

To appear in:

Clinical Genitourinary Cancer

Received Date: 26 June 2018 Revised Date:

26 September 2018

Accepted Date: 4 October 2018

Please cite this article as: Leng J, Akthar AS, Szmulewitz R, O'Donnell PH, Sweis RF, Pitroda SP, Smith N, Steinberg GD, Liauw SL, Safety and Efficacy of Hypofractionated Radiation Therapy with Capecitabine in Elderly Patients with Urothelial Carcinoma, Clinical Genitourinary Cancer (2018), doi: https://doi.org/10.1016/j.clgc.2018.10.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT 1 Safety and Efficacy of Hypofractionated Radiation Therapy with Capecitabine in Elderly Patients with Urothelial Carcinoma

Pitroda2, Norm Smith4, Gary D. Steinberg4, and Stanley L. Liauw2

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University of Chicago Pritzker School of Medicine, 924 E 57th St Suite 104, Chicago, IL

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60637, USA 2

Department of Radiation & Cellular Oncology, University of Chicago, 5841 S Maryland Ave,

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Chicago, IL 60637, USA 3

Department of Medicine, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637,

USA 4

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Jim Leng1, Adil S. Akthar2, Russell Szmulewitz3, Peter H. O'Donnell3, Randy F. Sweis3, Sean P.

Department of Surgery, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637,

Correspondence:

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USA

Stanley Liauw

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5758 S Maryland Ave, MC 9006, Chicago, IL 60637 Phone: (773) 702-6870

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Fax: (773) 834-0039 E-mail: [email protected]

ACCEPTED MANUSCRIPT 2 Conflicts of interest None. MicroAbstract

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Chemoradiation with concurrent capecitabine is a potential treatment option for select elderly or infirm patients with bladder cancer. 11 patients with poor performance status and comorbidities with a median age of 80 years were treated with this regimen and experienced a favorable

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toxicity profile with high rates of local control, at a median follow-up of 16 months.

ACCEPTED MANUSCRIPT 3 Abstract Background: Bladder cancer is commonly diagnosed in patients ineligible for radical cystectomy

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or chemoradiation (chemoRT) with cisplatin or fluorouracil with mitomycin.

Methods: Patients with high-grade urothelial bladder cancer ineligible for radical cystectomy or high-intensity chemoRT underwent maximal transurethral resection of bladder tumor followed

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by capecitabine (median 825 mg/m2/d BID) and radiation (median 55 Gy in 2.2 Gy/fx). Patients underwent surveillance cystoscopy and imaging, and were evaluated for toxicity, freedom from

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local failure and distant metastasis (FFLF, FFDM), progression-free survival (PFS), and overall survival (OS).

Results: 11 patients (median age 80 y) with localized disease (n=7), locally advanced disease

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(n=3), or local-only recurrence after cystectomy (n=1) were treated. 4 patients (35%) had an ECOG performance status of 2; median Charlson Comorbidity Index was 5. There was 1 acute grade 3 genitourinary (GU) event (9%), 6 acute grade 3 hematologic events (55%) of

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lymphopenia, and no acute grade 4+ events or hospitalizations. 10 (91%) patients completed RT, while 4 patients (36%) had temporary capecitabine discontinuation. The complete response rate

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in the bladder was 64%. Two patients (18%) experienced late grade 1-2 GU toxicities, and one (9%) experienced a transient late grade 4 GU toxicity. With a median follow-up of 16.6 months, OS, PFS, FFLF, and FFDM at 1-yr were 82%, 55%, 100%, and 55% respectively, and at 2-yr were 61%, 41%, 80%, and 55%, respectively.

ACCEPTED MANUSCRIPT 4 Conclusions: Hypofractionated chemoRT was well-tolerated and associated with a high rate of local control in this comorbid population, providing a treatment option for select bladder cancer patients.

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Keywords: bladder cancer; chemoradiation; capecitabine; bladder preservation; muscle invasive

ACCEPTED MANUSCRIPT 5 Introduction

Bladder cancer is the second most common genitourinary malignancy in the United States,

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leading to nearly 17,000 deaths in 20171. With a peak incidence at 85 years, bladder cancer is a disease of the elderly2. While radical cystectomy and selective bladder preserving therapy are both considered standard of care treatment options for non-metastatic, muscle-invasive bladder

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cancer (MIBC)3, comorbidities in elderly patients may significantly increase the risk of

postoperative complications and mortality from surgery4. Therefore while cystectomy remains

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the common treatment of choice in younger patients with good performance status5, the majority of elderly patients do not undergo cystectomy due to medical comorbidity, functional status, and social factors6.

Combined-modality bladder preserving therapy consists of maximal transurethral resection of

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bladder tumor followed by concurrent chemoradiation (chemoRT). Cisplatin-based doublet chemotherapy, and fluorouracil with mitomycin (5-FU/MMC) are two well-established

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radiosensitizing regimens3,7. However, not all patients are candidates to receive these chemotherapies due to pre-existing medical comorbidities or poor performance status. For such

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patients, single agent capecitabine with radiation therapy (RT) may provide a more suitable therapeutic ratio8. This potentially milder form of chemoRT has been given at our institution to patients ineligible for radical cystectomy or aggressive chemotherapy. The goal of this study is to describe our initial experience regarding tolerability, efficacy, and toxicity of hypofractionated radiotherapy with capecitabine in this challenging population given limited existing data for this regimen.

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Material and Methods Eligibility Criteria

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Patients with locally advanced, non-metastatic urothelial carcinoma who were unfit for surgery or high-intensity chemoRT with cisplatin or 5-FU/MMC based on multidisciplinary tumor board consensus (generally with KPS≤70, or major medical comorbidity) who received maximal

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TURBT followed by concurrent capecitabine and RT at a single academic institution were

eligible for this study. Electronic medical records were reviewed retrospectively for patient and

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tumor characteristics, Charlson Comorbidity Index9, treatment details, toxicities, and patient outcomes. This study received institutional review board approval from the University of Chicago (IRB#17-1436).

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Treatment

Maximal transurethral resection of bladder tumor (TURBT) was performed for all patients with an intact bladder prior to the start of chemoRT, and no patients received TURBTs after the

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initiation of chemoRT. Patients received capecitabine at a median dose of 1500 mg/m2/day (range 1050-1700 mg/m2) using twice-daily dosing on all days of RT (Monday through Friday),

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with the last dose administered at the end of RT. One of the daily doses was given approximately one hour before RT.

Computed tomography (CT) based simulation for radiation planning was performed after completion of TURBT, with patients in the supine position with upper and lower alpha cradles

ACCEPTED MANUSCRIPT 7 used for custom immobilization. Patients voided to completion for the simulation and for daily treatment to obtain an empty bladder volume.

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3D conformal RT (n=3, 27%) or IMRT (n=8, 73%) was delivered using 6-15 MV photons.

IMRT was mostly used for patients with suspected lymph node positive disease (n=5). The

planning target volume (PTV) was generally defined as the empty bladder plus a 1.5 cm margin

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(Figure 1). An initial PTV included pelvic lymph nodes based on clinician discretion in 6 (55%) patients with either radiographic suspicion of lymph node involvement (n=5) or high-risk for

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involvement (n=1), and was defined as internal and external iliac vessels plus a 1.5 cm margin modified around bone and muscle (Figure 2), with the superior border typically at the L5/S1 junction.

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The most common dose prescription to the entire bladder was 55 Gy in 2.2 Gy/fx (n=8/11, 73%; range 45-64 Gy at 2.0-2.25 Gy/ per fraction). This slightly hypofractionated regimen was chosen due to its comparable biologically equivalent dose (BED) with BC2001’s 55 Gy/20 fx5,

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published tolerability with concurrent capecitabine for pelvic malignancies10,11, and ease of matching pelvic nodal RT dosing over the same 25 days of therapy. The most common dose

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given to the pelvic lymphatics was 45-50 Gy in 1.8-2 Gy/fx, using a simultaneous integrated boost technique to the bladder of 55 Gy in 25 fractions (n=5/6, 83%).

Initial treatment planning directives were adapted from previous prospective studies12,13. Greater than 99% of the PTV received at least 95% of the prescription dose (V95%>99%) with less than 10% of the PTV receiving 105% (V105%<10%) and no volume receiving greater than 115% of

ACCEPTED MANUSCRIPT 8 the prescription dose. Organs at risk and dose constraints included small bowel (V45<90cc, V40<130cc, V35<230cc), rectum (V30<50%, V55<10%, posterior one-half < 80% total dose), and femoral heads (V50<20%). Image guidance for setup verification was performed using daily

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kilovoltage (kV) and cone beam CT to verify that pelvic nodal volumes and the bladder were within the PTV.

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Toxicity and Treatment Response

Treatment-related toxicities were recorded prospectively at each clinical evaluation by the

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treating physician using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 toxicity grading criteria. Acute toxicities were defined as toxicities during treatment and within 90 days of treatment completion. Late toxicities were defined as toxicities occurring ≥90 days post-treatment. Laboratory-related toxicities were evaluated for the duration of treatment

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only. Clinical findings, imaging reports, and cystoscopy results were used to classify treatment response as complete or partial. A complete response was defined as an absence of tumor on cystoscopy, normal cytology, and no evidence of disease on CT, and a partial response was

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defined as any response on cystoscopy, normal cytology, or CT. Stable disease was defined as no interval response on first cystoscopy or CT, and no response was defined as disease progression

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on first cystoscopy or CT. Overall response was defined as complete responses plus partial responses.

Follow-Up and Statistical Analysis Patients were generally followed by a multidisciplinary group at 3-month intervals with physical examinations, cystoscopy, cytology, and surveillance CTs for the first 2 years after therapy,

ACCEPTED MANUSCRIPT 9 followed by 6 month intervals thereafter. Descriptive statistics were generated through retrospective review of electronic medical records. Overall survival (OS), progression free survival (PFS), freedom from local failure (FFLF) and freedom from distant metastasis (FFDM)

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were estimated using Kaplan-Meier survival analysis with GraphPad Prism (version 7.0a, GraphPad Software Inc). Results

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Patient and Tumor Characteristics

Between April 2012 and August 2016, 20 patients were referred to the radiation oncology

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department at a single academic institution for curative-intent chemoRT. Eleven (55%) patients with locally advanced, non-metastatic bladder cancer were felt to be unfit for standard chemoRT with cisplatin or 5-FU/MMC based on multidisciplinary discussion, and were treated with maximal TURBT followed by concurrent capecitabine and RT (Table 1). The median age was 80

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years (range 63-87), and 10/11 (91%) of the patients were greater than 78 years old. The majority of patients were male (n=8, 73%), Caucasian (n=6, 55%), and current or prior smokers (n=8, 73%). The median Charlson Comorbidity Index (CCI) in these patients (excluding points for

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solid tumor) was 5 (range 3-7), and 4/11 patients (35%) had an Eastern Cooperative Oncology

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Group (ECOG) performance status of 2.

Two patients received a prior nephroureterectomy, and one patient received a prior cystoprostatectomy with ileal conduit who was treated for a recurrence in the cystectomy bed. The median number of TURBTs prior to the start of treatment was 1 (range 1-5), and the median time between the last resection (either surgery or TURBT) and RT was 1.9 months. Three patients received prior intravesical therapy, either with mitomycin C (n=1), Bacillus-Calmette-

ACCEPTED MANUSCRIPT 10 Guerin (BCG) vaccine (n=1), or BCG followed by gemcitabine (n=1). No patients received neoadjuvant chemotherapy.

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Six patients had localized muscle-invasive disease (T2-T4N0), 1 patient had non-muscle invasive disease (T1N0) and underwent chemoRT given 5 prior TURBT’s and multiple cycles of

intravesicular chemotherapy, 3 patient had locally advanced disease (T2-3N1-2), and 1 patient

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had recurrent disease in the cystectomy bed. All patients had high-grade urothelial carcinoma

Capecitabine and Radiation Treatment

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and were treated with curative intent.

Patients received concurrent capecitabine with RT for a median of 5 weeks, ranging from of 3.9 to 6.4 weeks. Seven patients (64%) completed the planned course of capecitabine, and 4 patients

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(36%) required discontinuation or interruptions due to diarrhea (n=2, for 2 and 7 days, respectively), hyperbilirubinemia (n=1, for 4 days), or hospitalization for pre-existing cardiac

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disease (n=1, for 17 days). Of these 4 patients, 3 completed radiation after stopping capecitabine.

Toxicities and Hospitalizations

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Acute and late toxicities are summarized in Table 2. During the course of treatment, there was one grade 3 non-hematological toxicity consisting of severe urinary urgency leading to catheter placement for one week and discontinuation of RT during the last week of treatment. No grade 4 non-hematological toxicity was observed. Furthermore, no clinically significant hematologic toxicities were observed; the only cases of grade 3 hematologic toxicity included lymphopenia and there were no grade 3+ neutropenia events.

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One patient was hospitalized during treatment for grade 2 atrial fibrillation secondary to underlying cardiac disease and went on to complete RT without capecitabine after medical

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management of the atrial fibrillation. Furthermore, three patients required hospitalizations in the 3 months immediately post-treatment. The reasons for hospitalization included concern for

bladder perforation after surveillance TURBT which was ultimately ruled out by CT (n=1),

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lower extremity edema and pain (n=1), and urinary tract infection in the setting of catheter

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placement with readmission two weeks later for aspiration pneumonia (n=1).

No late gastrointestinal toxicity was observed. Three patients (27%) experienced late genitourinary toxicities including one grade 4 radiation cystitis 18 months after the completion of treatment, which required a transfusion for 2 units of RBCs and fulguration of a vessel in a

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bladder diverticulum.

Treatment Response and Outcomes

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Responses to treatment and clinical outcomes are described in Table 3. No progression was observed during therapy. Median follow up was 16.6 months (range 1.6-44.9 months). The

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overall response rate in the bladder was 9/11 (82%) based on surveillance cystoscopy and imaging (n=8) or imaging alone (n=3) within 3 months of treatment completion. In the 8 patients with cystoscopy, 7 had a complete response. Five (45%) of these patients with complete response, including both suspected node-positive patients in this cohort, achieved long-term complete remissions for a median of 28 months, and are without disease at last follow-up. One delayed local failure was observed 21 months after treatment, in a patient who had complete

ACCEPTED MANUSCRIPT 12 clinical response by cystoscopy. This local relapse was salvaged with repeat TURBT and intravesical BCG. Five patients (45%) developed metastasis at a median of 3 months to the lung

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(n=3) or peritoneum (n=2).

The OS, PFS, FFLF and FFDM at 1 year were 82%, 55%, 100%, and 55% respectively, and at 2

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years were 61%, 41%, 80%, and 55%, respectively (Figure 3).

Discussion

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In this study, we adopted a bladder-sparing approach using maximal TURBT followed by concurrent chemoRT with capecitabine in an elderly patient population with a median age of 80 years. Treatment was well-tolerated with minimal acute or late severe toxicity, and high rates of local control were observed at 2 years post-treatment. Despite a limited sample size, these

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favorable results warrant further prospective investigation of concurrent capecitabine and radiation for select patients with MIBC who may not be candidates for other potentially curative

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therapies including radical cystectomy or more aggressive chemoradiotherapy regimens.

Several biologic considerations provide the rationale for use of capecitabine as a radiosensitizing

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agent in the treatment of MIBC. Capecitabine is preferentially converted to 5-FU in urothelial carcinoma, providing selectivity for tumor cells14. Furthermore, radiation offers synergistic effects on the intracellular activation of capecitabine through the upregulation of thymidine phosphorylase, which may provide greater efficacy at lower and less toxic doses15. In regards to clinical data, only one other study has reported on the use of concurrent capecitabine and radiation in MIBC to our knowledge. Patel et al. also included a small cohort of patients (n=14)

ACCEPTED MANUSCRIPT 13 ineligible for platinum-based chemotherapies and demonstrated results consistent with our study in terms of tolerability and efficacy including no grade 4-5 toxicities, a 20% hospitalization rate, complete clinical response in 77% of patients, and only 3 of 11 responders with relapse at a

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median follow up of 10.5 months8. We undertook our study to verify the efficacy and safety of this regimen, and sought to expand on their report by including detail regarding radiation

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treatment planning, disease outcome, and toxicity.

Another recent effort to identify a concurrent chemotherapy regimen in patients not suitable for

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cisplatin-based chemotherapy includes RTOG 0524 which was a phase I/II trial of either combination paclitaxel and trastuzumab or paclitaxel alone after TURBT for 68 MIBC patients16. Acute grade 2 or higher treatment-related adverse events were observed in 7 of 20 (35%) patients in the paclitaxel+trastuzumab arm (group 1) and 14 of 46 (30.4%) patients in the paclitaxel alone

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arm (group 2). The majority of adverse events were gastrointestinal, including 1 grade 5 adverse event in group 1. Furthermore, the complete response rate at 1 year was 72% for group 1 and 68% for group 2, suggesting this regimen is an effective treatment strategy. Concurrent

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gemcitabine has also been studied as a radiosensitizing agent. A phase II trial tested either 5flourouracil/cisplatin or gemcitabine with radiation in 66 patients with MIBC13. Acute grade 3 or

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4 events were observed in 21 of 33 patients (64%) in the 5-flourouracil/cisplatin arm, and in 18 of 33 patients (55%) in the gemcitabine arm. Both regimens in this study demonstrated high rates of metastasis-free survival at 3 years of 67% and 72%, respectively. A Phase I study of 24 patients treated with 60 Gy and twice weekly gemcitabine reported a 91% rate of CR, disease specific survival of 82% at 5 years with 30% local and 22% distant failure17. While it is not possible to make valid comparisons of our results to these prospective studies, the response rates

ACCEPTED MANUSCRIPT 14 and disease outcomes of capecitabine with RT in our study do not appear to be strikingly less effective or more toxic, in what was likely to be a much less favorable patient population.

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The encouraging findings of the current and aforementioned studies are of particular importance given the availability of a more tolerable, curative-intent chemoRT treatment option may lessen the underutilization of definitive treatment and overutilization of suboptimal therapies such as

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radiation alone for MIBC due to concerns of toxicity18, particularly across older age groups. The superiority of chemoRT over RT alone in this setting is well established in the literature

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including results of the phase III BC2001 trial which randomized patients with MIBC who completed TURBT to either RT alone or chemoRT with 5FU/MMC and demonstrated improved two-year locoregional DFS of 67% in the chemoRT group vs. 54% in the RT alone group. A second study performed by the National Cancer Institute of Canada (NCIC) randomized patients

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with MIBC to RT alone versus with concurrent cisplatin and reported fewer recurrences in the pelvis in the chemoRT group (15 of 51 patients) versus the RT alone group (25 of 48 patients). Notably, elderly and medically infirm patients with bladder cancer were under-represented in

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both clinical trials with only 11% over the age of 80 and 3% with ECOG performance status 2 in BC20017, and a maximum eligibility age of 76 years in the study performed by NCIC19. Thus,

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further exploration of an alternate concurrent chemotherapy regimen in this population is needed to optimize the therapeutic ratio.

Retrospective data from large databases reaffirm the value of pursuing potentially curative chemoRT over either modality alone or neither modality. In a National Cancer Data Base (NCDB) analysis of 1,783 patients with clinically node positive bladder cancer, median overall

ACCEPTED MANUSCRIPT 15 survival with chemoRT was 19 months compared to 13.8 months with chemotherapy alone. Another recent NCDB analysis including 1,369 patients ≥ 80 years of age with MIBC reported the 2-year OS for chemoRT to be 56% compared to 42% with radiotherapy (60-70 Gy) alone20,21.

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Furthermore, in a NCDB analysis of patients aged ≥75 treated for MIBC with either radical cystectomy (21%), chemoRT (13%), or neither (66%)22, median survival was significantly shorter in patients receiving neither therapy (12 months, compared to 26.5 months for

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cystectomy and 22.1 months for chemoRT). In the subset of patients with Charlson comorbidity >1, median survival was longer for those receiving chemoRT (15.9 months) compared to

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cystectomy (12.5 months) or neither (6.4 months), though this finding is subject to patient selection bias. Collectively these large datasets further support the use of chemoRT within a bladder conserving treatment paradigm for MIBC patients, even for elderly patients who may be

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subject to greater comorbidities and poor performance status than younger patients.

While this study provides encouraging results on initial toxicity and efficacy with the use of concurrent capecitabine and radiation following TURBT, there are several limitations of our

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including its small sample size, retrospective design, and the potential for patient selection bias to influence outcomes. As a retrospective study, it was not possible to describe exact criteria

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which classified patients as unfit for more standard therapy. Furthermore, competing risks of mortality have limited the length of follow-up time, making it difficult to estimate longer term control rates. Ideally, future prospective comparative studies will be conducted to validate our findings, and better understand which patients are likely to benefit most from this reducedintensity chemoRT regimen. Future studies may focus on molecular subtyping to offer additional

ACCEPTED MANUSCRIPT 16 guidance on proper patient selection and prediction of treatment response of MIBC to various chemoRT regimens23.

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Conclusion For well-selected elderly patients, chemoRT with capecitabine is a tolerable regimen with

effective local control that may increase the utilization of definitive treatment for MIBC. Patient

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characteristics such as poor performance status, renal failure, and other comorbidities are essential to guide clinical decision-making regarding eligibility for therapy.

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Clinical Practice Points

Elderly patients are less likely to receive definitive treatment for MIBC with radical cystectomy or chemoradiation (chemoRT) with concurrent cisplatin or mitomycin.

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Hypofractionated chemoRT with concurrent capecitabine may offer a more appropriate

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therapeutic ratio for this population, while preserving bladder function. We conducted this study to evaluate the tolerability and outcomes of this combination in 11 elderly patients with poor performance status or medical comorbidity. In this study, chemoRT resulted in low numbers of high-grade toxicities in the acute and

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late setting with high rates of local control. The encouraging results in this series support the need for larger prospective studies of

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hypofractionated chemoRT with capecitabine in select elderly patients who are unfit for more aggressive therapies.

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19. Coppin CM, Gospodarowicz MK, James K, et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1996;14(11):29012907. doi:10.1200/JCO.1996.14.11.2901 20. Haque W, Verma V, Butler EB, Teh BS. Chemotherapy Versus Chemoradiation for NodePositive Bladder Cancer: Practice Patterns and Outcomes from the National Cancer Data Base. Bladder Cancer Amst Neth. 2017;3(4):283-291. doi:10.3233/BLC-170137 21. Korpics MC, Block AM, Martin B, et al. Concurrent chemotherapy is associated with improved survival in elderly patients with bladder cancer undergoing radiotherapy. Cancer. 2017;123(18):3524-3531. doi:10.1002/cncr.30719 22. Bream MJ, Maurice MJ, Altschuler J, Zhu H, Abouassaly R. Increased Use of Cystectomy in Patients 75 and Older: A Contemporary Analysis of Survival and Perioperative

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Tables

Male Male

87 63 84 80 86 84 78 79

No. of Mo. from TURBTs last Resection 5 2.3 1 12.8

1

3

T4a(R1)*

0

13.3

1 2

4 7

T2N0 T2N0

1 3

1.8 1.4

2 0 1

6 5 4

T2N1 T2N0 T2N0

1 1 2

2.7 2.5 2.0

2 0

4 6

T4aN0 T2N2

3 1

0.5 1.3

6

T2N0

2

1.5

EP

78

White African American Male African American Male White Female African American Male White Male White Female African American Male White Female African American Male White

ECOG Charlson Tumor Comorbidity Stage Score 0 6 T1N0 1 5 T3N2

M AN U

79 83

Race

TE D

Sex

SC

Table 1: Baseline patient characteristics Age (yr)

2

AC C

* patient had prior cystectomy, treated for recurrence in the cystectomy bed

Table 2: Toxicities Acute toxicity Genitourinary Gastrointestinal Hematological Chemistry Late toxicity Genitourinary Gastrointestinal

Any (%)

Grade 3 (%)

Grade 4 (%)

9 (82%) 9 (82%) 11 (100%) 4 (36%)

1 (9%) 0 (0%) 6 (55%) 0 (0%)

0 (0%) 0 (0%) 0 (0%) 0 (0%)

3 (27%) 0 (0%)

0 (0%) 0 (0%)

1 (9%) 0 (0%)

ACCEPTED MANUSCRIPT 20 Table 3: Clinical outcome and response rates Tumor Response Local Distant Stage relapse relapse

Time to Relapse (mo) 2.8

Partial

No

Yes

T3N2 T4a(R1) T2N0 T2N0 T2N1 T2N0 T2N0

Complete Partial None Complete Complete Complete Complete

No No No No No Yes No

No Yes Yes No No No Yes

T4aN0 T2N2 T2N0

Stable Disease No Complete No Complete No

Yes No No

1.6

CR (%)

SD (%)

NR (%)

Follow-Up (mo)

Abdominal wall and umbilicus

Yes

12.1

No No No No No No Yes

44.9 4.1 1.6 28.8 27.6 28.3 16.6

No No No

22.2 15.6 12.8

SC

Lung Lung

M AN U

Peritoneal carcinomatosis Lung

ORR (%)

TE D

Local Distant Relapse Relapse 7 (64%) 2 (18%) 1 (9%) 1 (9%) 9 (82%) 1 (9%) 5 (45%) CR = Complete Response, PR = Partial Response, SD = Stable Disease, NR = No Response, and ORR = Overall Response Rate. Figures

PR (%)

3.0 0.6

21.4 6.2

Death

RI PT

T1N0

Distant Relapse Site

Figure 1A-C: Representative RT plan for a patient receiving 55 Gy in 2.2 Gy/fx to the bladder.

EP

Volumes of interest include bladder PTV (red colorwash), and organs at risk including small bowel (yellow), rectum (brown), and femoral heads (blue). Isodose lines shown for reference

AC C

include 100% (teal), 90% (green), 80% (orange) and 50% (magenta).

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

21

ACCEPTED MANUSCRIPT 22 Figure 2A-C: Representative RT plan for a patient receiving 45 Gy in 1.8 Gy/fx to the pelvic lymphatics and 55 Gy in 2.2 Gy/fx to the bladder utilizing a simultaneous integrated boost with 25 fractions. Volumes of interest include bladder PTV (yellow colorwash) and pelvis PTV (red

RI PT

colorwash). Isodose lines shown for reference include 100% (teal), 90% (green), 80% (orange)

AC C

EP

TE D

M AN U

SC

and 50% (magenta).

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

23

ACCEPTED MANUSCRIPT 24 Figure 3: Overall survival (OS), progression free survival (PFS), freedom from local failure (FFLF), and freedom from distant metastasis (FFDM) for patients receiving concurrent

AC C

EP

TE D

M AN U

SC

RI PT

capecitabine with RT.