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.
Volume 88 Number 2 2014
Hypofractionated IMRT for bladder preservation
327
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
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.
Volume 88 Number 2 2014
Hypofractionated IMRT for bladder preservation
327
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
