Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 11  |  Issue : 4  |  Page : 704-707

Radiotherapy concurrent with weekly gemcitabine after transurethral tumor resection in muscle ınvasive bladder cancer


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 Publication15-Feb-2016

Correspondence Address:
Havva Yesil Cinkir
Department of Medical Oncology, Dr. A.Y. Ankara Oncology Training and Research Hospital, Demetevler, Ankara
Turkey
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.147381

Rights and Permissions
 > Abstract 

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 Top


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). [1]

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. [2] Salvage RC reserved for patients with incomplete response, or local recurrence yielded a similar outcome to primary RC. [3] Cisplatin is the most studied agent concurrent with RT, especially among fit patients with good renal function. [4] 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%. [3],[5] It has a synergistic effect with RT and can enhance the local tumor control. [6] 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. [7],[8],[9]

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 Top


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. [10]

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 Top


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].
Table 1: Patient characteristics


Click here to view


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].
Figure 1: Progression free survival by Kaplan-Meier

Click here to view
Figure 2: Overall survival by Kaplan-Meier

Click here to view
Table 2: Treatment outcome


Click here to view
Table 3: Toxicities


Click here to view



 > Discussion Top


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. [3] A recent SEER analysis in patients with BC showed a decrease of radical treatment, especially among older patients. [11] 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. [3],[4]

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. [3],[12] Additionally, CRT was found more effective than RT in several studies. [3],[12] Cisplatin and its combination were widely used in CRT approaches, and CR rates were 56-81%. [3],[4],[12] 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. [3]

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. [13] 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. [7],[8],[9],[14] 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. [14] 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. [15] 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. [16] 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 ). [14] 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. [7],[8],[9],[14] 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.

 
 > References Top

1.
Hautmann RE, de Petriconi RC, Pfeiffer C, Volkmer BG. Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: Long-term results in 1100 patients. Eur Urol 2012;61:1039-47.  Back to cited text no. 1
    
2.
James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477-88.  Back to cited text no. 2
    
3.
Kaufman DS. Challenges in the treatment of bladder cancer. Ann Oncol 2006;17 Suppl 5:v106-12.  Back to cited text no. 3
    
4.
Choueiri TK, Raghavan D. Chemotherapy for muscle-invasive bladder cancer treated with definitive radiotherapy: Persisting uncertainties. Nat Clin Pract Oncol 2008;5:444-54.  Back to cited text no. 4
    
5.
von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000;18:3068-77.  Back to cited text no. 5
    
6.
Shewach DS, Lawrence TS. Radiosensitization of human solid tumor cell lines with gemcitabine. Semin Oncol 1996;23:65-71.  Back to cited text no. 6
    
7.
Borut K, Lijana ZK. Phase I study of radiochemotherapy with gemcitabine in invasive bladder cancer. Radiother Oncol 2012;102:412-5.  Back to cited text no. 7
    
8.
Oh KS, Soto DE, Smith DC, Montie JE, Lee CT, Sandler HM. Combined-modality therapy with gemcitabine and radiation therapy as a bladder preservation strategy: Long-term results of a phase I trial. Int J Radiat Oncol Biol Phys 2009;74:511-7.  Back to cited text no. 8
    
9.
Kent E, Sandler H, Montie J, Lee C, Herman J, Esper P, et al. Combined-modality therapy with gemcitabine and radiotherapy as a bladder preservation strategy: Results of a phase I trial. J Clin Oncol 2004;22:2540-5.  Back to cited text no. 9
    
10.
Cancer Therapy Evaluation Program, 1999. Common Toxicity Criteria, Version 2.0. Avilable from: http://www.eortc.be/services/doc/ctc/ctcv20_4-30-992.pdf. [Last accessed on 2011 Jan 20].  Back to cited text no. 10
    
11.
Gore JL, Litwin MS, Lai J, Yano EM, Madison R, Setodji C, et al. Use of radical cystectomy for patients with invasive bladder cancer. J Natl Cancer Inst 2010;102:802-11.  Back to cited text no. 11
    
12.
Coppin CM, Gospodarowicz MK, James K, Tannock IF, Zee B, Carson J, 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;14:2901-7.  Back to cited text no. 12
    
13.
Shewach DS, Lawrence TS. Antimetabolite radiosensitizers. J Clin Oncol 2007;25:4043-50.  Back to cited text no. 13
    
14.
Atasoy BM, Dane F, Alsan Cetin I, Ozgen Z, Ucuncu Kefeli A, Ibrahimov R, et al. Concurrent chemoradiotherapy with low dose weekly gemcitabine in medically inoperable muscle-invasive bladder cancer patients. Clin Transl Oncol 2014;16:91-5.  Back to cited text no. 14
    
15.
Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: Initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 1998;16:3576-83.  Back to cited text no. 15
    
16.
Zietman AL, Sacco D, Skowronski U, Gomery P, Kaufman DS, Clark JA, et al. Organ conservation in invasive bladder cancer by transurethral resection, chemotherapy and radiation: Results of a urodynamic and quality of life study on long-term survivors. J Urol 2003;170:1772-6.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Materials and me...>Results>Discussion>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed3029    
    Printed58    
    Emailed1    
    PDF Downloaded158    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]