|Year : 2016 | Volume
| Issue : 1 | Page : 143-146
Radiation therapy outcomes in muscle invasive urinary bladder cancer: A single institution experience
MS Tiwana1, LH Ni1, S Saini2, SK Verma3, D Doddamani4, N Jain2, M Biswas4, Meenu Gupta1, Madhur Gupta1, M Saini5, N Chauhan6
1 Department of Radiation Oncology, STM Cancer Research Institute, Himalayan Institute Hospital Trust, Swami Ram Nagar, Jolly Grant, Dehradun, India
2 Department of Surgical Oncology, STM Cancer Research Institute, Himalayan Institute Hospital Trust, Swami Ram Nagar, Jolly Grant, Dehradun, India
3 Department of Medical Oncology, STM Cancer Research Institute, Himalayan Institute Hospital Trust, Swami Ram Nagar, Jolly Grant, Dehradun, India
4 Department of Urology, Himalayan Institute of Medical Sciences, Swami Ram Nagar, Jolly Grant, Dehradun, India
5 Department of Radiodiagnosis, Himalayan Institute of Medical Sciences, Swami Ram Nagar, Jolly Grant, Dehradun, India
6 Department of Pathology, Himalayan Institute of Medical Sciences, Swami Ram Nagar, Jolly Grant, Dehradun, India
|Date of Web Publication||28-Apr-2016|
L H Ni
Department of Radiation Oncology, STM Cancer Research Institute, Himalayan Institute Hospital Trust, Swami Ram Nagar, Jolly Grant, Dehradun
Source of Support: None, Conflict of Interest: None
Introduction: To audit the survival outcomes and loco-regional control in muscle invasive urinary bladder cancer patients treated with external beam radiation therapy (RT). Materials and Methods: From November 2008 through December 2011, 50 consecutively diagnosed muscle invasive urinary bladder carcinoma (T2-4a N0-2, M0) patients were included in this retrospective study. All these patients received external beam RT to a median dose of 60 Gy (range 30-66 Gy), and were not suitable for radical surgery due to patients' preference or medical comorbidities. A stepwise procedure using proportional hazard regression was used to identify prognostic factors with respect to survival. Results: Completion trans-urethral resection of bladder tumor was done in 38 (76%) patients of the cohort and 47 (94%) had transitional cell carcinoma on histopathology. Clinical stage T2 was diagnosed in 40 (80%) patients. The median follow-up for the entire cohort was 14 ± 8.9 months (range 1-36 months). In conclusion, 24 patients (48%) were free of disease, 5 patients (10%) had residual disease, and 13 patients (26%) had died of disease. Two-year and 3 year overall survival of intact bladder for the entire cohort was 58% and 43.6%, respectively. Cox regression modeling strongly suggested clinical stage (P = 0.01) and RT dose (P = 0.001) as being predictors for overall survival. Conclusion: RT shows reliable outcomes and excellent compliance in this advanced disease. Prescribing a higher RT dose could potentially correlate to better intact bladder control rates while maintaining good quality of life in selected patients.
Keywords: Chemotherapy, muscle invasive urinary bladder cancer, overall survival, radiation therapy
|How to cite this article:|
Tiwana M S, Ni L H, Saini S, Verma S K, Doddamani D, Jain N, Biswas M, Gupta M, Gupta M, Saini M, Chauhan N. Radiation therapy outcomes in muscle invasive urinary bladder cancer: A single institution experience. Indian J Cancer 2016;53:143-6
|How to cite this URL:|
Tiwana M S, Ni L H, Saini S, Verma S K, Doddamani D, Jain N, Biswas M, Gupta M, Gupta M, Saini M, Chauhan N. Radiation therapy outcomes in muscle invasive urinary bladder cancer: A single institution experience. Indian J Cancer [serial online] 2016 [cited 2020 Jun 3];53:143-6. Available from: http://www.indianjcancer.com/text.asp?2016/53/1/143/180842
| » Introduction|| |
Urinary bladder cancer is one of the most common cancers of the urinary tract and accounts for 3.9% of total cancer cases diagnosed as per the Indian cancer registry. Men are three times more commonly affected than women, and histologically 90% of the bladder tumors are transitional cell carcinoma (TCC). On an alarming note, a total of 40-45% of newly diagnosed bladder cancers are pathologically high grade, more than half of which are muscle invasive at the time of diagnosis. Muscle invasive bladder cancer has a dismal prognosis with a poor overall survival rates ranging from 30% to 50%. A slight favorable survival figure is seen in patients undergoing an optimal bladder conserving multimodality approach employing surgery, radiation therapy (RT), or concurrent chemoradiation therapy. However, the optimal sequenced approach is still controversially debated for this notorious subgroup wherein radical cystectomy is still the preferred urological option. It seems even more pertinent in patient populations with restricted access to tertiary level healthcare. In such clinical settings, patients' preference for a single modality non-invasive approach (post-trans-urethral resection of bladder tumor [TURBT]) is paramount to his or her overall quality of life, despite a clear understanding of relatively inferior outcomes. We report patient-related outcomes in muscle invasive bladder cancer from this retrospective study, conducted in our rural cancer center located in mountainous region of north India.
| » Materials and Methods|| |
We retrospectively reviewed the records of patients diagnosed with muscle invasive urinary bladder cancer from November 2008 through December 2011. The included patients were evaluated initially by a multidisciplinary team of radiation, medical and surgical oncologist and/or urologist. Patients with histologically confirmed muscle invasive primary urinary bladder carcinoma (T2-4a N0-2, M0), Eastern Cooperative Oncology Group ( ECOG) performance status 0-2 were eligible for the study. Patients who had metastatic bladder cancer and/or received prior chemotherapy or RT were excluded from the analysis. Diagnosis was initially made through a routine cystoscopic-guided TURBT or a biopsy. Pre-treatment staging investigations included chest X-ray, abdominal and pelvic computed tomography (CT) scans, or an ultrasound. The requisition for a (18 F) 2-fluoro-2-deoxy-d glucose positron emission tomography scan was done only at the discretion of financially assisted patients. Staging was done as per the tumor, node, and metastasis (TNM) system.
The routine protocol of treatment after obtaining informed consent for muscle invasive bladder cancer at our institute is either radical cystectomy and/or RT. All of the retrieved patients underwent TURBT followed by radical RT with or without concurrent chemotherapy. Poor nutritional status and patient's reluctance to chemotherapy and surgery guided the treating oncologist to largely radical external beam RT alone protocol.
Pelvic RT in the latter half of 2008 was delivered through two-dimensional planning, whereas three-dimensional conformal RT with CT simulator-based planning in supine position was used with effective from 2010 onwards. Treatment planning was done with the ONCENTRA ® planning system (Nucleotron Medical Systems Incorporation, Veenendaal, Netherlands) and delivered through 6 or 15 MV linear accelerator. Radical RT prescription dose was 60-66 Gy with a conventional 2 Gy per fraction schedule delivered over a period of 6-6.5 weeks. RT was split into two phases: Phase I included whole pelvis, whereas phase II was planned as a bladder boost. Phase I RT treatment was planned with full bladder and field borders superiorly coincided at the level of L5-S1 junction, lower border at inferior margin of obturator foramen, and lateral borders 1.5-2 cm from bony pelvis to include the pelvic lymph nodes. Phase II RT planning was done with empty bladder as a pre-requisite. Phase I pelvic RT dose given was 40 Gy in 20 fractions by antero-posterior fields followed by 20-26 Gy/10-13#/2 weeks boost to bladder with 2 cm margins with three-field technique, one anterior and two posterior oblique. Radiation oncologists who prescribed concurrent chemotherapy usually preferred weekly cisplatin 40 mg/m 2 or a schedule of weekly Gemcitabine 200 mg for a total of 5-6 cycles. RT-induced genitor-urinary and gastrointestinal toxicity was scored as per the Radiation Therapy Oncology Group (RTOG) acute radiation morbidity scoring criteria.
Follow-up response was assessed at 6 weeks from the date of treatment completion with a check cystoscopy and CT scan or an ultrasound of abdomen and pelvis. Patients at our center are advised for a follow-up with the same set of investigations at 4 months interval for the first 2 years, and then every 6 months thereafter. However, due to a difficult albeit beautiful mountainous terrain in our region, a stringent follow-up is always lacking. Although we request for patients physical presence on every follow-up, we routinely utilize telephonic services to do the same if otherwise. The telecommunication mode has certainly its own limitations, primarily in the event of death, it becomes difficult to ascertain the preceding events from relatives of the deceased patient.
Overall survival was the primary endpoint of this study and time was calculated from the date of diagnosis to patients' death from any cause. We were not able to establish disease-free survival and disease progression descriptive data due to the mentioned follow-up limitations. The overall survival was compared to the grouped variables using the log-rank test. Cox's proportional hazards model was used for multivariate analysis (MVA) to estimate the simultaneous impact of covariate factors on survival. All P values were two-sided with P ≤ 0.05 considered significant. This study was statistically analyzed on Statistical Package for the Social Sciences (SPSS) software (version 19.0; SPSS, Inc., Chicago, IL, USA).
| » Results|| |
Clinical and pathological characteristics
The clinical and pathological characteristics are summarized in [Table 1]. From 2008 to 2011, 50 patients were eligible for analysis. Patient's age ranged from
40 to 84 years (median 63 years). Seventy-six percent of the patients had ECOG performance score of 1. Ten percent of the patient had prior history of recurrence from carcinoma urinary bladder before initiating first time radical treatment at our institution. 92% gave history of hematuria at presentation, whereas 83% of the patients were confirmed smokers. Eighty-four percent had a unifocal growth with 58% characterizing infiltrative growth on cystoscopy. Upfront hydronephrosis was seen in 28% of the patients. Completion TURBT was possible in 76% of the cohort and 94% had TCC on histopathology. Clinical stage T2 was established in 80% of the patients.
Treatment and outcome characteristics
Treatment and outcome characteristics are summarized in [Table 2]. All the patients underwent RT, 88% received it with radical intent. Ten patients (20%) received concurrent chemotherapy; six of these patients were given weekly gemcitabine, whereas four patients received weekly cisplatin. Four patients (40%) completed the planned course of 5-6 cycles of weekly chemotherapy. Sixty-six percent were prescribed > Gy RT dose and 80% showed complete compliance to RT. At the completion of planned treatment, 54% had Grade II genitourinary toxicity, whereas 48% had Grade II gastrointestinal toxicity.
The median follow-up for the entire cohort was 14 ± 8.9 months (range 1-36 months). At the conclusion of the study, 24 patients (48%) were free of disease, 5 patients (10%) had residual disease, and 13 patients (26%) had died of disease. Eight patients (16%) were lost to follow-up. Two-year and 3 year overall survival of intact bladder for the entire cohort was 58% and 43.6%, respectively [Figure 1]. In the univariate analysis, clinical stage T2, and ≥60 Gy RT dose yielded superior overall survival [Table 3], [Figure 2] and [Figure 3]. In the subsequent Cox regression modeling for MVA, clinical stage (P = 0.01) and RT dose (P = 0.001) maintained their statistical significance as being strong predictors for survival [Table 3].
| » Discussion|| |
The ultimate aim of any oncological intervention is to achieve cure with organ preservation and minimal normal tissue side effects. This directly correlates to an optimal quality of life. The most favorable therapeutic strategy to combat muscle invasive bladder cancer is yet to be clearly defined. Surgery in the form of radical cystectomy is considered the standard of care for high-grade muscle invasive bladder cancer. Inspite of an aggressive removal of bladder, a significant number of patients may still develop local relapse., This adversely affects the overall quality of life of patients affected with this dismal disease. This is evidently seen in our restrained patient population as none of them opted for a radical surgery at any point of their disease. Nonetheless, this does not undermine the role of radical surgery as a definite option to achieve cure. In the majority of patients, current data favor neoadjuvant chemotherapy followed by radical cystectomy, including complete Pelvic Lymph Node Dissection (PLND), as the optimal curative strategy for muscle invasive bladder cancer.
Alternatively, definitive radiotherapy has been frequently indicated for preservation of bladder in muscle invasive bladder cancer but the results are far from assuming. Overall survival at 5 years and local control rate are 22-35% and 35-40%, respectively. Similar study comprising 75 patients with muscle invasive bladder cancer treated with external beam radiotherapy showed 65% complete response and 3 year actuarial overall survival of 56%. In our study, 48% of the patients were still disease free at the conclusion of analysis. Two-year and 3 year overall survival with intact bladder for the entire cohort were 58% and 43.6%, respectively. This may seem far from encouraging as compared to outcomes achieved after established current guidelines. But nonetheless, the same inferior figures would appear hopeful to regions with similar socio-economic factors and patients with somewhat different perspectives on quality of life as compared to patients from developed nations.
RT has a conclusive role in improving bladder preservation therapies with a good impact on quality of life and offering patients a choice of treatment, even in the absence of more effective systemic treatment. Chemoradiation therapy has shown promising results in bladder cancer as compared to RT alone. A study planned with induction chemotherapy followed by RT demonstrated a 67.3% complete response rate to induction therapy and an encouraging 60% 3-year survival with an intact bladder. But a poor nutritional status and synergistic toxicities observed in our patients inhibited oncologists and patients alike in our study to utilize an optimal chemoradiation therapy schedule. Early tumor stage, absence of hydronephrosis, and a complete response are the most important factors predicting bladder preservation rate and survival., A safe maximal TURBT is a strong prognostic marker for survival, and is a critical parameter for recurrence-free survival. In our retrospective study, we observed early stage T2 and high external beam radiation dose to be strong independent predictors for intact bladder overall survival. A retrospective study of 136 muscle invasive bladder cancer patients showed that the patients treated with an external beam RT dose below 57.5 Gy had a significant higher bladder relapse rate.
Our results demonstrate that radiation dose above 60 Gy is associated with improved bladder preserved overall survival rates. Certainly, our study being retrospective in nature, relative smaller follow-up with limited number of patients, it has inherent flaws to deduce a definite conclusion. It is difficult to interpret the actual recurrences from our study, considering a short median follow-up period of only 14 months. The majority of recurrences in invasive bladder cancers are usually seen at a median time interval of 18 months after treatment. Nonetheless, randomized dose escalation studies with external beam RT alone in specific group of patients not suitable for cystectomy or chemotherapy may yield interesting results conducive to the developing world. Overall, external beam RT alone in muscle invasive bladder cancer has demonstrated reasonable efficacy in achieving a near desirable survival outcomes with an intact bladder.
| » Acknowledgment|| |
Presented at AROICON 2012 Kolkata under GC Pant Young Doctor award category.
Source of Support:
Conflict of Interest:
| » References|| |
Gupta P, Jain M, Kapoor R, Muruganandham K, Srivastava A, Mandhani A. Impact of age and gender on the clinicopathological characteristics of bladder cancer. Indian J Urol 2009;25:207-10.
Rabbani F, Cordon-Cardo C. Mutation of cell cycle regulators and their impact on superficial bladder cancer. Urol Clin North Am 2000;27:83-102.
Messing EM, Young TB, Hunt VB, Gilchrist KW, Newton MA, Bram LL, et al
. Comparison of bladder cancer outcome in men undergoing hematuria home screening versus those with standard clinical presentations. Urology 1995;45:387-96.
Shipley WU, Kaufman DS, Tester WJ, Pilepich MV, Sandler HM, Radiation Therapy Oncology Group. Overview of bladder cancer trials in the Radiation Therapy Oncology Group. Cancer 2003;97:2115-9.
Yadav BS, Ghoshal S, Sharma SC. Outcome following radical cystectomy and bladder-preservation therapy in patients with invasive carcinoma of urinary bladder. Indian J Urol 2008;24:48-53.
Hayter CR, Paszat LF, Groome PA, Schulze K, Math M, Mackillop WJ. A population-based study of the use and outcome of radical radiotherapy for invasive bladder cancer. Int J Radiat Oncol Biol Phys 1999;45:1239-45.
Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol 1998;22:1435-48.
Yildirim G, Ozsaran Z, Yalman D, Kamer S, Aras A. Evaluation of acute and late radiation morbidity in patients with gynaecologic malignancy using the RTOG criteria and Franco-Italian glossary. Eur J Gynaecol Oncol 2008;29:154-7.
Hussain SA, Stocken DD, Peake DR, Glaholm JG, Zarkar A, Wallace DM, et al
. Long-term results of a phase II study of synchronous chemoradiotherapy in advanced muscle invasive bladder cancer. Br J Cancer 2004;90:2106-11.
Smith JA Jr, Crawford ED, Paradelo JC, Blumenstein B, Herschman BR, Grossman HB, et al
. Treatment of advanced bladder cancer with combined preoperative irradiation and radical cystectomy versus radical cystectomy alone: A phase III intergroup study. J Urol 1997;157:805-7.
Hall CM, Dinney CP. Radical cystectomy for stage T3b bladder cancer. Semin Urol Oncol 1996;14:73-80.
Herr HW, Dotan Z, Donat SM, Bajorin DF. Defining optimal therapy for muscle invasive bladder cancer. J Urol 2007;177:437-43.12.
Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, et al
. Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 2001;19:666-75.
Langsenlehner T, Döller C, Quehenberger F, Stranzl-Lawatsch H, Langsenlehner U, Pummer K, et al
. Treatment results of radiation therapy for muscle-invasive bladder cancer. Strahlenther Onkol 2010;186:203-9.
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.
Moonen L, vd Voet H, de Nijs R, Hart AA, Horenblas S, Bartelink H. Muscle-invasive bladder cancer treated with external beam radiotherapy: Pretreatment prognostic factors and the predictive value of cystoscopic re-evaluation during treatment. Radiother Oncol 1998;49:149-55.
Gamal El-Deen HS. Initial results of retrospective study: Preoperative transurethral excision plus chemotherapy and radiation therapy and trial of bladder preservation. J Egypt Natl Canc Inst 2007;19:133-46.
Gakis G, Efstathiou J, Lerner SP, Cookson MS, Keegan KA, Guru KA, et al
. ICUD-EAU International Consultation on Bladder Cancer 2012: Radical Cystectomy and Bladder Preservation for Muscle-Invasive Urothelial Carcinoma of the Bladder. Eur Urol 2013;63:45-57.
Moonen L, vd Voet H, de Nijs R, Horenblas S, Hart AA, Bartelink H. Muscle-invasive bladder cancer treated with external beam radiation: Influence of total dose, overall treatment time, and treatment interruption on local control. Int J Radiat Oncol Biol Phys 1998;42:525-30.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]