|Year : 2015 | Volume
| Issue : 4 | Page : 704-707
Radiotherapy concurrent with weekly gemcitabine after transurethral tumor resection in muscle ınvasive bladder cancer
Umut Demirci1, Omer Dızdar2, M Faik Cetindag3, Serkan Altınova4, Atiye Ozsavran3, Didem Sener Dede5, Nurgul Kızılırmak3, F Aysun Eraslan3, Bulent Yalcın5, Havva Yesil Cinkir1
1 Department of Medical Oncology, Dr. A.Y. Ankara Oncology Training and Research Hospital, Ankara, Turkey
2 Department of Medical Oncology, Faculty of Medicine, Baskent University, Ankara, Turkey
3 Department of Radiation Oncology, Faculty of Medicine, Baskent University, Ankara, Turkey
4 Department of Urology, Faculty of Medicine, Baskent University, Ankara, Turkey
5 Department of Medical Oncology, Atatürk Training and Research Hospital, Ankara, Turkey
|Date of Web Publication||15-Feb-2016|
Havva Yesil Cinkir
Department of Medical Oncology, Dr. A.Y. Ankara Oncology Training and Research Hospital, Demetevler, Ankara
Source of Support: None, Conflict of Interest: None
Objective: In this report, we determined the efficacy and the toxicity of low dose weekly gemcitabine with radiotherapy, in medically unfit or refused surgery muscle-invasive bladder cancer (BC) patients.
Materials and Methods: From 2008 to 2012, 15 patients were included into the retrospective analysis. Weekly gemcitabine was administered at a rate of 50 mg/m 2 with a median dose of 63 Gy radiotherapy.
Results: The median age was 69 (range, 55-86). Median follow-up was 15 months (range, 5-53 months). A complete response was achieved in 12 patients (80%). Median progression free survival and overall survival were 15 months (range, 7-23 months) and 18 months (range not calculated), respectively. Local recurrence was found in 3 patients (20%) and distant recurrence was found in 5 patients (33.3%) for the entire group. While salvage surgery was performed on 1 patient, salvage chemotherapy was delivered for 4 patients. Treatment was well tolerated, there was no treatment interruption or instances of toxic death. A serious toxicity (grade 3) cystitis was seen in only 1 patient.
Conclusions: Multimodality treatment of muscle invasive BC proved a feasible and effective treatment option. Gemcitabine based chemoradiation is an active treatment option with a low toxicity profile for patients with muscle invasive BC, who are not suitable medically or refused to surgery.
Keywords: Bladder cancer, gemcitabine, radiotherapy, transurethral tumor resection trimodality approach
|How to cite this article:|
Demirci U, Dızdar O, Cetindag M F, Altınova S, Ozsavran A, Dede DS, Kızılırmak N, Eraslan F A, Yalcın B, Cinkir HY. Radiotherapy concurrent with weekly gemcitabine after transurethral tumor resection in muscle ınvasive bladder cancer. J Can Res Ther 2015;11:704-7
|How to cite this URL:|
Demirci U, Dızdar O, Cetindag M F, Altınova S, Ozsavran A, Dede DS, Kızılırmak N, Eraslan F A, Yalcın B, Cinkir HY. Radiotherapy concurrent with weekly gemcitabine after transurethral tumor resection in muscle ınvasive bladder cancer. J Can Res Ther [serial online] 2015 [cited 2019 Sep 18];11:704-7. Available from: http://www.cancerjournal.net/text.asp?2015/11/4/704/147381
| > Introduction|| |
Bladder cancer (BC) is the most frequent urinary tract cancer, and the majority of BC are trantional cell carcinomas (TCCs). The standard treatment for the muscle invasive BC is radical cystectomy (RC) that achieves a 55-60% rate for 5 year overall survival (OS). 
Bladder-preserving approaches are alternatives to RC for patients, who are refused to surgery or are considered medically unfit. The trimodality treatment approach consists of transurethral maximal tumor resection (TUR-M) followed by radiotherapy (RT) with concurrent chemotherapy (CRT). Trimodality treatment has been tested in several studies as an organ-sparing treatment alternative to RC. Recently, trimodality treatment has achieved the advantage of 2 year locoregional disease free survival (LDFS); however, OS remained similar.  Salvage RC reserved for patients with incomplete response, or local recurrence yielded a similar outcome to primary RC.  Cisplatin is the most studied agent concurrent with RT, especially among fit patients with good renal function.  The use of cisplatin in patients with muscle invasive BC is limited, because remarkable patients have impaired renal function. Gemcitabine is an active agent in advanced BC, and single agent activity is 23-28%. , It has a synergistic effect with RT and can enhance the local tumor control.  RT, concurrent with a weekly gemcitabine treatment, has been tested in different doses as 27 mg/m 2 /twice weekly to 150 mg/m 2 /week. In these trials, complete response (CR) rates and bladder intact survival rates were 88-100% and 75-88% at 20 months, respectively. ,,
Herein, we analyzed the outcome of RT concurrent with weekly gemcitabine treatments in patients with muscle invasive BC, who were medically unfit or refused surgery.
| > Materials and methods|| |
The aim of the present study was to determine the clinical outcome of a bladder-sparing approach using CRT for T2-4N0-1 high grade (G3) TCC of the bladder. Between October 2008 and November 2012, 15 patients with muscle invasive BC, who were negative for macroscopic residual tumors, were treated by CRT after TUR-M. Patients either were unfit for surgery due to comorbidities or refused to RC. A metastatic disease was evaluated with computerized tomography (CT) and/or magnetic resonance imaging (MRI) for all patients before CRT. All the patients, except one received conformal pelvic RT with box technique using 18-MVphoton energy. The planning CT was obtained in the supine position with an empty bladder. After the irradiation of the pelvic lymph nodes, and the whole bladder to 45 Gy by daily 1.8 Gy fractions, the bladder was boosted by daily 2 Gy fractions to median 63 Gy (range, 54-65 Gy). Port film verification was done twice a week for all patients. Concurrent CRT was given through weekly gemcitabine treatments for all patients. Gemcitabine was given within 30 min of the IV infusion with 50 mg/m 2 /week started on 1 day with the treatment planned to continue weekly, until the last week of RT. A physical examination and labaratory tests were done weekly, and side effects were recorded once a week according to the common toxicity criteria v2.0. 
Three months after CRT, responses were evaluated by restaging cystoscopy; If persistent tumor detects, patient treated with gemcitabine and cisplatin as consolidation chemotherapy. Cystoscopy and radiological evaluation were performed every 3-6 months in the first 2 years and thereafter every 6 months for an additional 3 years, if needed.
Data were expressed with median values and in a range. Statistical analyses of progression-free survival (PFS) were measured from the date of CRT initiation to the date of progression. The OS was measured from the date of CRT initiation to the date of death from any cause or lost to follow-up. Kaplan Meier survival estimations were calculated. The survival curve was compared with the log-rank test. Statistical analyses were performed using the SPSS version 16. P <0.05 were accepted as statistically significant.
| > Results|| |
The median age was 69 (range, 55-86) in 15 patients (14 male, 1 female). Initial symptoms were hematuria (n = 8, 53.3%) and prostatism (n = 7, 46.7%). Performance status (PS) was 1, 2 and 3 in 12 patients, 2 patients, and only 1 patient, respectively. The stage 2 disease was in 1 patient (6.7%), stage 3 in 9 patients (60%) and stage 4 (lymph node positive disease) in 4 patients (33.3%). Intravesical Bacillus Calmette-Guerin (BCG) was performed on 2 patients before their tumors progressed to muscle invasive BC. Three cycles of neoadjuvant CRT (gemcitabine-cisplatin) were delivered to 3 patients before CRT. All patients either unfit for surgery due to comorbidities (n = 8, 53.3%) or refused RC (n = 7, 46.7%). Patient characteristics are shown in [Table 1].
Median follow-up was 15 months (range, 5-53 months). Over 6 weeks, RT was performed concurrent with low dose gemcitabine (50 mg/m 2 /w) in all patients, while week 6 indicated the median for gemcitabine treatment (range, 6-7). The median RT dose was 63 Gy (range, 54-66.4 Gy). Only 1 patient received 12 Gy boost dose to pelvic lymph nodes in stage 4 disease. A CR was achieved in 12 patients (80%). Consolidation gemcitabine and cisplatin was administered to three non-CR patients. Local recurrence occurred in 3 patients (20%), distant recurrence occurred in 5 patients (33.3%), and for the entire group in a median 15 months follow-up. Median PFS and OS were 15 months (range, 7-23 months) and 18 months (range not calculated), respectively [Figure 1] and [Figure 2], in all study groups [Table 2]. While salvage surgery was performed on 1 patient, salvage CRT was delivered to 4 patients. PS, age (< or > 60 years), stage, BCG, and CRT agent that was delivered with RT were not statistically significant to survival rates (PFS and OS) in the multivariate analysis. There was no treatment interruption or toxic death observed.While most common non-serious toxicities (grade 1/2) were cystitis (n = 10), emesis (n = 4), tenesm (n = 4), thrombocytopenia (n = 2), diarrhea (n = 2), neutropenia and fatique were monitored on a singular basis. Cystitis was seen as a serious toxicity (grade 3) for only 1 patient [Table 3].
| > Discussion|| |
Radical cystectomy results in 90% local control and 40-60% over 5 years OS for muscle invasive BC. However, RC may cause urinary, sexual, and social dysfunctions.  A recent SEER analysis in patients with BC showed a decrease of radical treatment, especially among older patients.  Bladder-preserving approaches are an option to RC patients with a T2a-T3a tumor without lymph node involvement, for patients with muscle invasive BC, who are unfit for surgery or refused surgery. Only TUR-M, CT, or CRT after TUR-M are bladder-preserving approaches. ,
In present study, although the majority of the patients have comorbidities and 33.3% of the patients have lymph node involvement, CRT was well tolerated, and CR was achieved in 80% of the patients. Median PFS and OS were 15 months (range, 7-23 months) and 18 months (range not calculated), respectively. Local recurrence was found in 20% and distant recurrence was found in 33.3% of the patients. CRT is the only bladder-preserving approach that has prospective randomized data. , Additionally, CRT was found more effective than RT in several studies. , Cisplatin and its combination were widely used in CRT approaches, and CR rates were 56-81%. ,, Recently, the phase III study compared RT alone with CRT with concurrent 5-fluorouracil and mitomycin. The median follow-up period was 69.9 months and the 2 years LDFS was significantly improved for CRT when compared with RT alone (67% vs 54%). However, while the OS at 5 years improved by 13% for the CRT this was not statistically significant (P = 0.16). Although the median age of the study population was 71.9 years, concurrent CRT was well tolerated. Serious toxicities were more common for patients treated with CRT than RT alone. After 2 years, salvage RS for local recurrence was performed on higher numbers of patients in RT alone than CRT (16.8% vs 11%). This study confirms that the CRT significantly improves the local control and preserves the bladder and its function. 
Gemcitabine is a nucleoside analog that can inhibit DNA polymerases. Gemcitabine induces accumulation of cells in S phase that appears to be needed for radiosensitization. And the radiosensitizing effect of gemcitabine has been demonstrated in vivo and in vitro.  Gemcitabine was administered in different doses (27 mg/m 2 /twice weekly to 150 mg/m 2 /weekly) for the concurrent with RT and resulted in 76% of 5 years OS and 82% DFS rates. ,,, A recent trial from our country evaluated low dose weekly gemcitabine with RT in same patient group. In 51 months median follow-up, the CR rate was 62.5% and the 5 years LDFS rate, disease-specific survival rate, and OS rate were 40.6%, 59.5% and 58.5%, respectively.  Three patients of the present study were treated with gemcitabine and cisplatin before the CRT. The induction of CT before CRT was assessed in a study; however, CR rates, and OS rates were similar to without induction CT.  Local and distant recurrence occurred in 20% and approximately 35% of the patients in a median 15 months follow-up, respectively. BC is prone to develop late recurrences beyond 2 years thus long-term follow-up is needed for high salvage rates of these patients.
The quality of life for patients experiences of trimodality therapy is good, and it resulted in 22% of the reduced bladder compliance and only one third of these patients had reflected distressing symptoms in median 6.3 years follow-up.  In the present study, treatment was well tolerated, and there was no serious toxicity, treatment interruption, or toxic death. However, CRT was interrupted for five of 26 patients (19.3%) due to toxicities in a recent study that applied higher gemcitabine dose (75 mg/m 2 ).  We prefer 50 mg/m 2 doses of gemcitabine for the CRT as used in the present study.
Consequently, in the present study, while survival and response rates were similar, toxicities are less serious than in the previous studies. ,,, The conformal RT technique achieved an enhanced RT dose and reduced toxicity. Drawbacks of the present study include insufficient toxicity records due to the retrospective nature, its relatively small number patients and short follow-up time.
The multimodality treatment of muscle invasive BC proved a feasible and effective treatment option. Gemcitabine based CRT is an active treatment option with a low toxicity profile for patients with muscle invasive BC who are not suitable for or refused surgery.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]