Hypofractionated Intensity Modulated Radiation Therapy in Combined Modality Treatment for Bladder Preservation in Elderly Patients With Invasive Bladder Cancer

International Journal of

Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation: Genitourinary Cancer

Hypofractionated Intensity Modulated Radiation Therapy in Combined Modality Treatment for Bladder Preservation in Elderly Patients With Invasive Bladder Cancer Guy-Anne Turgeon, MD,* Luis Souhami, MD, FASTRO,* Fabio L. Cury, MD,* Sergio L. Faria, MD, PhD,* Marie Duclos, MD,* Jeremy Sturgeon, MD,y and Wassim Kassouf, MDz Departments of Oncology, *Division of Radiation Oncology, yMedical Oncology, and zUrology, McGill University Health Centre, Montreal, Quebec, Canada Received Oct 3, 2013, and in revised form Nov 1, 2013. Accepted for publication Nov 4, 2013.

Summary This study shows that the use of sensitized hypofractionated IMRT is an encouraging bladder-preservation treatment strategy in the elderly population with muscle-invasive bladder cancer.

Purpose/Objective(s): To review our experience with bladder-preserving trimodality treatment (TMT) using hypofractionated intensity modulated radiation therapy (IMRT) for the treatment of elderly patients with muscle-invasive bladder cancer. Methods and Materials: Retrospective study of elderly patients treated with TMT using hypofractionated IMRT (50 Gy in 20 fractions) with concomitant weekly radiosensitizing chemotherapy. Eligibility criteria were as follows: age 70 years, a proven diagnosis of muscle-invasive transitional cell bladder carcinoma, stage T2-T3N0M0 disease, and receipt of TMT with curative intent. Response rate was assessed by cystoscopic evaluation and bladder biopsy. Results: 24 patients with a median age of 79 years were eligible. A complete response was confirmed in 83% of the patients. Of the remaining patients, 1 of them underwent salvage cystectomy, and no disease was found in the bladder on histopathologic assessment. After a median follow-up time of 28 months, of the patients with a complete response, 2 patients had muscle-invasive recurrence, 1 experienced locoregional failure, and 3 experienced distant metastasis. The overall and cancer-specific survival rates at 3 years were 61% and 71%, respectively. Of the surviving patients, 75% have a disease-free and functioning bladder. All patients completed hypofractionated IMRT, and 19 patients tolerated all 4 cycles of chemotherapy. Acute grade 3 gastrointestinal or genitourinary toxicities occurred in only 4% of the patients, and acute grade 3 or 4 hematologic toxicities, liver toxicities, or both were experienced by 17% of the cohort. No patient experienced grade 4 gastrointestinal or genitourinary toxicity. Conclusions: Hypofractionated IMRT with concurrent radiosensitizing chemotherapy appears to be an effective and well-tolerated curative treatment strategy in the elderly population and should be considered for patients who are not candidates for cystectomy or who wish to avoid cystectomy. Ó 2014 Elsevier Inc.

Reprint requests to: Luis Souhami, MD, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H4X 2C5, Canada. Tel: (514) 9348040; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 88, No. 2, pp. 326e331, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.11.005

Conflict of interest: none.

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Introduction

Treatment

In the past decades, numerous studies have shown that trimodality therapy (TMT) for muscle-invasive transitional cell carcinoma (TCC) of the bladder is an appealing alternative to radical cystectomy, resulting in overall survival (OS) rates (1-11) comparable with those in contemporary surgical series (12-14). The most effective TMT involves maximally feasible transurethral resection of the bladder tumor (TURBT) followed by concomitant chemotherapy and radiation therapy (RT), with or without adjuvant chemotherapy. Prospective studies using this approach have shown a complete response rate of 60% to 90% (1-11, 15-21). There is a general underutilization of curative bladder therapies in the elderly population. As many as 23% to 35% of patients aged between 70 and 80 years do not receive curative therapy, and in those over the age of 80 years this proportion increases to 35% to 55% (22-24). This population is often affected by multiple competing comorbidities that contraindicate major surgery. The tolerance to a curative course of radiation therapy can also be compromised because of changes in physiologic reserves and functional status, influencing physicians toward less aggressive and less effective palliative radiation therapy approaches, even in patients with stage T2 disease. Intensity modulated radiation therapy (IMRT) allows the delivery of high tumor dose with a higher degree of conformality to the target volume and greater sparing of normal tissue, in comparison with conventional 2-dimensional and traditional 3dimensional conformal RT techniques. On the basis of an encouraging previous report (15) of hypofractionated conventional RT plus weekly gemcitabine, which showed a complete tumor response rate of 88%, we began, in 2008, a multidisciplinary TMT program for elderly patients (age 70) who were not considered good surgical candidates because of medical comorbidities. After maximal TURBT, patients would receive hypofractionated IMRT given concomitantly with weekly radiosensitizing chemotherapy. This article reports our preliminary results.

Transurethral resection of bladder tumor

RT was delivered daily, 5 days a week, for a total of 50 Gy in 20 fractions (assuming an a/b of 10 for tumor control, the biological equivalent total dose in 2-Gy fractions is 52 Gy). All patients were treated by an inverse IMRT technique. Patients were requested to empty the bladder at simulation and before each treatment. IMRT was delivered with 6-MV photons using either Rapid Arc or 5 to 7 static IMRT fields. IMRT was delivered to the bladder volume (clinical target volume, CTVbladder) with or without the pelvic lymph nodes (CTVnode). When the lymph nodes were treated, the obturator and the internal and external iliac chains were included. The CTVbladder and the CTVnode were expanded 1.5 to 2.0 cm and 0.7 cm, respectively, to generate a planning target volume (PTV). The superior limit of the lymph nodes was described as the PTVnode covering up to the anterior aspect of the S1-S2 junction. Weekly portal imaging was performed for treatment setup verification. Field-in-field technique was used to deliver 40 Gy in 20 fractions to the lymph nodes and 50 Gy in the same 20 fractions to the bladder. The prescription dose was defined at the isodose line that encompassed at least 95% of the PTV. Doseevolume histograms were generated for all critical normal structures. Normal structures contoured were the femoral heads, the rectum (defined from the anus to the junction with the sigmoid colon), the small bowel, and the pelvic bones (bone marrow). Dose constraints for the organs at risk were as follows: femoral heads Dmax <40 Gy, rectum V40 50%, small bowel V30 50%, and pelvic bones V30 30%.

Methods and Materials

Chemotherapy

Patients All patients aged 70 years treated between January 2008 and August 2012 in our institution with a curative hypofractionated IMRT regimen of 50 Gy in 20 fractions and concomitant chemotherapy for invasive TCC bladder cancer, stage T2T3N0M0, were selected for our retrospective review. These patients were not candidates for surgery because of comorbid disease or personal preference. This review was approved by the ethics committee of the McGill University Health Center.

Clinical tumor staging Pretreatment assessment and staging included a complete history and full physical examination, routine hematologic and biochemical laboratory studies, cystoscopy with biopsy, chest radiography, and abdominopelvic computed tomography (CT). Positron emission tomography scans or isotope bone scans were obtained in selected patients with equivocal findings or if they were clinically indicated. All pathologic specimens were evaluated at our institution.

A maximally feasible TURBT was performed 4 to 12 weeks before the start of radiation treatment. Most patients underwent this procedure under spinal anesthesia. Two patients, at high risk for anesthesia, had limited diagnostic biopsies and were exempted from the TURBT.

Radiation therapy

All patients received concomitant weekly gemcitabine 100 mg/m2 or cisplatin 40 mg/m2. Chemotherapy was typically administered on days 1, 8, 15, and 22 of the radiation treatment. A subset of patients treated with gemcitabine also received neoadjuvant, concomitant, and adjuvant everolimus as part of a phase 1/2 inhouse trial. No adjuvant chemotherapy was administered to this population.

Evaluation of treatment Acute toxic reactions were defined according to the criteria of the Common Terminology Criteria for Adverse Events, version 3.0 (25). Late toxicities were reported as per the RTOG Late Radiation Morbidity Scoring Schema. During the concomitant chemoradiation treatment, each patient was evaluated weekly. A weekly hematologic and biochemical blood count was monitored before each chemotherapy administration. Response to treatment was evaluated by cystoscopy at 1 to 3 months after the end of treatment. A complete response was defined as the absence of visible tumor on cystoscopy, with a negative cytology or negative biopsy result at the site of the previous lesion. Additional cystoscopy was performed every 3 months for the first 2 years and every 6 months thereafter. CT scan imaging was performed at 6 and 18 months after treatment

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Table 1

Patient and treatment characteristics Characteristic

n

Median age Sex Male Female Clinical stage T2 T3 Reason for no cystectomy Not surgical candidate Cystectomy refusal Comorbidities Cardiac Pulmonary Diabetes Vascular periphery Genitourinary Others ECOG 0 1 2 Hydronephrosis Visibly complete TURBT Lymph nodes irradiation Chemotherapy Cisplatin only Gemcitabine only Gemcitabine þ everolimus

79 (range 72-88) 20 4 22 2 15 9 9 4 7 11 9 6 15 7 2 4 19 17 3 15 6

Abbreviations: ECOG Z Eastern Cooperative Oncology Group; TURBT Z transurethral resection of bladder tumor.

and afterward as clinically indicated. Some patients residing in distant areas were followed up at the discretion of their urologist.

Table 2 Acute toxicities assessed by the Common Terminology Criteria for Adverse Events, version 3.0 Grade 1 2 3 4

GI

GU

12 (50%) 7 (29%) 1 (4%) 0

10 (42%) 7 (29%) 1 (4%) 0

Hematologic 14 4 2 1*

(58%) (17%) (8%) (4%)

Hepatic 0 0 2 (8%) 0

Abbreviations: GI Z gastrointestinal; GU Z genitourinary. Pretreatment abnormal complete blood count was present in 42% (10/ 24) of patients. * Patient hospitalized for febrile neutropenia.

and 1 received salvage radiation therapy. The characteristics of the 24 eligible patients are shown in Table 1. The median length of follow-up for all patients was 28 months (range, 7-60 months), whereas it was 30 months (range, 11-60 months) for patients at risk. The pretreatment TURBT was performed at a median time of 8 weeks (range, 3-13 weeks) before chemoradiation. Three patients had deep or bulky tumors considered by the urologist to have been incompletely resected. The 2 patients exempted from TURBT underwent their respective limited biopsies at 13 and 19 weeks. Including these 2 patients, a total of 5 pretreatment TURBT were considered incomplete. All patients received concomitant chemoradiation therapy. Twenty-one received gemcitabine 100 mg/m2 weekly, and 3 others received cisplatin 40 mg/m2 weekly. Six patients were included in an in-house trial combining the mammalian target of rapamycin inhibitor everolimus with weekly gemcitabine 100 mg/m2. The chemotherapy was interrupted in a total of 5 patients (21%) because of acute toxicities. Of these, 3 patients received 3 of the 4 cycles, and 2 other patients received 2 of the planned 4 cycles (both participating in the everolimus study). All 24 patients completed their RT course, with a median treatment time of 29 days (range, 26-32 days). A total of 17 patients (71%) received RT to the bladder and nodal areas.

Statistical analysis Treatment-related toxicities Survival was measured from the date of the pretreatment TURBT to the date of death or the most recent follow-up visit. The rates of OS and cancer-specific survival (CSS) were calculated by the actuarial method of Kaplan-Meier (26). Data collected are presented by descriptive statistics. Analyses were performed with GraphPad Prism, version 4 statistics software (GraphPad Software, San Diego, CA).

Results Demographic data Between January 2008 and August 2012, 55 patients with diagnoses of bladder cancer were treated with IMRT using 50 Gy in 20 fractions. Applying our eligibility criteria, our study included 24 patients with a median age of 79 years (range, 72-88 years). The patients not meeting the eligibility criteria were excluded for the following reasons: 15 were younger than 70 years, 13 had stage 4 disease or received palliative intent treatment, 1 had squamous cell carcinoma, 1 was followed up outside the country,

The TMT was relatively well tolerated. Table 2 shows the frequency of acute toxicities. No grade 4 gastrointestinal (GI) or genitourinary (GU) toxicity was seen. The single patient with acute grade 3 GI and GU toxicity also required hospitalization because of febrile neutropenia. At this limited follow-up, 2 patients have experienced late (more than 3 months after therapy) grade 2 hematuria, 1 experienced grade 2 urinary frequency, and 2 others required urethral dilatation. No patient experienced late grade 3 or 4 GU toxicity or required a cystectomy for treatment-related toxicity. In all surviving patients with intact bladders, late toxicities have mostly resolved. No late grade 2 GI toxicity has been seen.

Response to trimodality therapy Treatment response was assessed in 23 of our 24 patients. One noncompliant patient was not evaluated after treatment and could not be included in the response assessment. Followed up by his family physician, he presented with hematuria 40 months after his

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Fig. 1. Kaplan-Meier projection of overall and cancer-specific survival rates. treatment. A local superficial recurrence was diagnosed at that time. A complete response was confirmed in 19 of the 23 evaluable patients (83%). Response was assessed by cystoscopy with biopsy in 10 patients and with cystoscopy and cytology in 13 patients. Of the 4 patients not achieving a complete response, 1 underwent a salvage cystectomy 6 months treatment after a transurethral resection showed residual invasive disease, but the final pathologic designation of the cystectomy specimen was pT0N0. Two other patients had sparse focus of viable TCC on a background of nearly complete necrosis. In 1 of them, a follow-up cystoscopy 4 months later showed no residual disease, but unfortunately the patient died of metastatic disease.

Pattern of failure Muscle-invasive recurrence occurred at 20 and 24 months in 2 of the patients who had initially a complete response. Both patients underwent salvage cystectomy. Two additional patients experienced superficial recurrence at 17 and 41 months; both were treated with TURBT alone, and 1 of them has no evidence of disease at a follow-up time of 60 months. The other was scheduled for a repeat cystoscopic evaluation at the time of this review. One patient, who received pelvic irradiation, experienced regional failure at 30 months, and 3 others received diagnoses of distant metastasis at 5, 6, and 11 months.

Overall and cancer-specific survival The actuarial OS rates at 2 and 3 years were 69% and 61%, respectively, and the CSS rates at 2 and 3 years were 80% and 71%, respectively (Fig. 1). A total of 8 patients had died. Of those, 5 died of bladder cancer and 3 died of their associated comorbidities. Of the surviving patients, 75% have a disease-free and functioning bladder.

Discussion Not infrequently, elderly patients with invasive bladder cancer have competing comorbidities with an anticipated higher complication risk after therapy and are less likely to undergo curative treatment. Recently, Noon et al (27) reviewed their experience with cancer-specific mortality and competing other-

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cause mortality in patients with bladder cancer and reported that fewer elderly patients received radical treatment for invasive cancer and that a higher cancer-specific mortality was seen in this group than in a younger cohort. Previous reports have shown a relatively high incidence of perioperative morbidity and mortality in elderly patients undergoing radical cystectomy for bladder cancer (28, 29). Similarly, acute grade 3 or higher hematologic or GI toxicity after TMT ranges from 11% to 25% and from 5% to 10%, respectively (10). Thus, particularly in this frail population, potentially serious acute and late toxicity after TMT is a valid concern. In our elderly cohort with invasive bladder cancer, whose members were medically unfit for radical cystectomy, TMT with the use of hypofractionated IMRT resulted in a complete response rate of 83%, with an acceptable toxicity rate. These preliminary results appear comparable with those in surgical series (12-14) and in other reports using TMT with conventionally fractionated RT (1-3, 10, 21, 30) in well-selected populations with invasive bladder cancer. Notwithstanding some differences in treatment parameters and patient selection, and also in the recognition that comparison of results across different studies has inherent limitations and cannot be considered definitive, when comparing our current results with those in our formerly treated elderly cohort (31), we observe a clear improvement in outcomes. Previously, the 3-year OS and CSS rates were 39% and 48%, respectively, whereas the current treatment regimen yielded a 3-year OS rate of 61% and a 3-year CSS of 71%. Most importantly, the number and grade of acute toxicities have declined considerably. In our 2009 elderly cohort, only 33% of the patients received full-dose concurrent radiosensitizing chemotherapy, and their acute grade 3 or 4 overall and GI toxicities were 23% and 15%, respectively. In this current cohort, 79% completed their concurrent chemotherapy with only 1 grade 4 toxicity (hematologic), and acute grade 3 GI and GU toxicities occurred in only 4% of the patients. The choice of weekly gemcitabine in this study was based on the compromised renal function for most patients at presentation. Recently, a randomized trial of synchronous chemotherapy with fluorouracil and mitomycin C with radiation therapy for invasive bladder cancer reported good tolerance to the regimen, and this combination could be another suitable option for patients with impaired renal function (30). Despite the hypofractionated approach with daily doses of 2.5 Gy, it is conceivable that the use of IMRT provided a better sparing of normal organs at risk, leading to a lower toxicity rate, in comparison with other trials using conventionally fractionated RT (1-3, 10, 30, 32) or twice-a-day fractionation (5, 6, 32). In a dosimetric study of patients undergoing radiation therapy for bladder cancer, van Rooijen et al (33) demonstrated a significant dose decrease in small intestines and rectum when using IMRT, while covering the PTV adequately. Hsieh et al (34) have treated 19 patients with invasive bladder cancer and were also able to demonstrate a superior sparing capability with the use of IMRT without a detrimental effect on local control of the disease. Limiting the side effects of treatment would certainly be a desirable goal, particularly for the elderly population, such as the population of patients in this study. Because we did not use imageguided IMRT, in the current study our PTV margin for the bladder volume ranged from 1.5 to 2 cm, which is the typical margin in patients undergoing conventional 3-dimensional RT. It is thus possible that further reduction of the PTV margin, by using accurate daily image guided radiation therapy, could lead to further

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sparing of the normal pelvic structures, with a subsequent decrease in toxicity and an improvement in patients’ tolerance to TMT. Our encouraging results should be interpreted in the context of several limitations, including the retrospective nature of data collection, the small sample size of our patient population, the limited follow-up time, and the unavoidable possibility of selection bias. Furthermore, it is always possible that a less detailed recording of toxicity occurred, although the more serious grade 3 or 4 toxicity, which often alters management, are more likely to have been accurately described. Despite these shortcomings, given these stimulating results we believe that this approach deserves to be tested further. Furthermore, fewer treatments are more convenient for patients, allow more patients to be treated with the same number of radiation therapy machines in departments with limited resources, and may have a positive impact on health costs, all of these aspects having important societal implications. In conclusion, our preliminary results show that the use of sensitized hypofractionated IMRT for elderly patients with invasive bladder cancer, multiple comorbidities, and a high risk for a radical surgical procedure is feasible, is well tolerated, and potentially leads to outcomes similar to those of other treatment strategies. We show that elderly patients with invasive bladder cancer and serious comorbid diseases can be safely treated with curative intent by the use of TMT. Sensitized hypofractionated IMRT, after maximum TURBT, is an attractive and well-tolerated therapeutic option that can be offered to frail patients with invasive bladder cancer.

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