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Year : 2018  |  Volume : 45  |  Issue : 2  |  Page : 84-89

Bladder preservation protocols in the management of muscle-invasive bladder cancer: A systematic review

1 Department of Urology, JN Medical College, KLE Academy of Higher Education and Research (Deemed-to-be-University), Belagavi, Karnataka, India
2 Department of Urology, JN Medical College, KLE Academy of Higher Education and Research (Deemed-to-be-University); KLES Kidney Foundation, KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Nehru Nagar, Belagavi, Karnataka, India
3 Department of Urology, KLES Kidney Foundation, KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belagavi, Karnataka, India
4 Department of Biotechnology and Microbiology, Karnatak University, Dharwad, Karnataka, India

Date of Web Publication10-Dec-2018

Correspondence Address:
Shridhar C Ghagane
Department of Urology, KLES Kidney Foundation, KLES Dr. Prabhakar Kore Hospital and M.R.C, Nehru Nagar, Belagavi - 590 010, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jss.JSS_28_18

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Bladder cancer is one of the most common cancers worldwide causing a significant burden on healthcare system and society. Muscle-invasive bladder cancer (MIBC) is highly fatal, and if untreated, >85% of patients die within 2 years of diagnosis. Although radical cystectomy (RC) is the preferred treatment of choice in patients with MIBC, bladder preservation can be considered in patients who are either not eligible for cystectomy or are not willing to undergo cystectomy. The goal of bladder preservation is to achieve cancer survival at least equivalent to RC and to maintain better quality of life including sexual function. Strategies for bladder preservation include partial cystectomy, radical transurethral resection, radiation therapy, and chemotherapy. It is widely accepted that combination of these approaches could result in better outcomes in patients with MIBC. In this review, we describe different approaches for bladder preservation and their outcomes.

Keywords: Bladder preservation therapy, muscle-invasive bladder cancer, partial cystectomy, trimodal therapy

How to cite this article:
Pentyala S, Nerli R B, Ghagane SC, Hiremath MB. Bladder preservation protocols in the management of muscle-invasive bladder cancer: A systematic review. J Sci Soc 2018;45:84-9

How to cite this URL:
Pentyala S, Nerli R B, Ghagane SC, Hiremath MB. Bladder preservation protocols in the management of muscle-invasive bladder cancer: A systematic review. J Sci Soc [serial online] 2018 [cited 2021 Sep 25];45:84-9. Available from: https://www.jscisociety.com/text.asp?2018/45/2/84/247151

  Introduction Top

Bladder cancer is the ninth most common cancer worldwide, with 430,000 newly diagnosed cases in 2012.[1] It significantly contributes to the burden on healthcare system and society and affects quality of life of the patient. More than half of patients with bladder cancer and more than half of all bladder cancer deaths are reported from less developed countries.[2] Overall, there is strong male predominance with three-fourth cases reported in males. Bladder cancer is the seventh most common cancer in men and the nineteenth most common cancer in women worldwide. The worldwide incidence of bladder cancer in men was around 4.5%, and the mortality rate is 2.6%; however, the incidence and mortality rate are 1.5% and 1.2%, respectively, in women. In India, bladder cancer is the twelfth most common cancer in men and the nineteenth most common cancer in women.[1]

Histologically, the majority (>90%) of bladder cancers are urothelial carcinomas and squamous cell carcinoma that contribute to 5% of cases and adenomatous carcinoma to 3% of the cases.[3] Around 70%–80% of de novo bladder cancers are diagnosed in early stages (Ta, Tis, and T1) with no muscular invasion; however, one-fifth of these cases will progress to muscle invasion.[4] Muscle-invasive bladder cancer (MIBC) is highly fatal, and if untreated, >85% of patients die within 2 years of diagnosis.[5] Under staging of bladder cancer is not uncommon and is one of the reasons contributing to increased mortality.

  Treatment Options Top

Treatment of bladder cancer depends on the stage of the lesion. In early-stage bladder cancer (Ta, T1, and carcinoma in situ), transurethral resection of bladder tumor (TURBT) is the most commonly used modality followed by adjuvant intravesical administration of Bacillus Calmette–Guérin in patients with high-grade disease. The extent of disease and the type of surgery have direct impact on the overall outcome of MIBC. Once cancer invades bladder wall (stage T2 onward), called as MIBC, TURBT is typically the first-line treatment primarily performed to determine the extent of invasion rather than to treat cancer. In patients with MIBC (stage T2–T4a, N0, and M0), radical cystectomy (RC) and pelvic lymph node dissection are the gold standard treatments. Several clinical studies and series have demonstrated the usefulness and long-term outcomes of RC. In some cases, neoadjuvant/adjuvant chemotherapy is given before surgery, particularly in cases with T4a and T4b.

In one of the largest series, 1054 patients with MIBC who underwent RC with bilateral pelvic iliac lymphadenectomy between July 1971 and December 1997 showed overall recurrence-free survival of 68% and 66% at 5 and 10 years, respectively, for the entire cohort.[6] In patients with organ-confined, lymph node-negative tumors (P0, Pis, Pa, and P1), the 5-year recurrence-free survival was 92%, 91%, 79%, and 83%, respectively, and 10-year recurrence-free survival was 86%, 89%, 74%, and 78%, respectively.[6] Patients with stage P2 and P3a with negative lymph node had 89% and 87% and 78% and 76% at 5- and 10-year recurrence-free survival, respectively. This rate was 62% and 61% for P3b tumors and 50% and 45% for P4 tumors, respectively.[6] Another study by Goodney et al. showed that RC has the second highest readmission rate compared to other urological or nonurological procedures.[7] In patients who are not eligible for cystectomy or patients who are not willing to undergo cystectomy, bladder preservation can be considered. It is important that patients and their relatives are made aware of the fact that cystectomy may impact sexual and bowel functions.

  Bladder Preservation Top

The goal of bladder preservation is to achieve cancer survival at least equivalent to RC and to maintain good quality of life including sexual life. According to the American Urological Association 2017 guideline (AUA/ASCO/ASTRO/SUO guideline) “for patients with newly diagnosed nonmetastatic MIBC who desire to retain their bladder and for those with significant comorbidities for whom RC is not a treatment option, clinicians should offer bladder-preserving therapy when clinically appropriate.”[8]

Strategies for bladder preservation include partial cystectomy, radical transurethral resection, radiation, and chemotherapy. It is widely accepted that combination of these approaches could result in the best outcomes in patients with MIBC. Hence, bladder preservation could include single modality treatment or trimodal therapy. Single modality bladder preservation techniques include radical transurethral resection (TUR), chemotherapy, or radiotherapy alone; however, trimodal therapy includes complete TUR, chemotherapy, and radiotherapy.

Several series have demonstrated that single modality bladder preservation has inferior outcomes compared to trimodal bladder preservation approach. Hence, it is important to carefully select the patient for bladder preservation evaluating risk and benefits, and patients who are medically fit to undergo cystectomy should be offered cystectomy. [Table 1] summarizes selection criteria for bladder preservation.[9]
Table 1: Patient selection for bladder preservation

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In contrast, some studies have demonstrated inferior outcomes among patients who underwent bladder preservation than those who had RC. In a recent study by Cohn et al., they evaluated 32,300 patients from the National Cancer Database who underwent bladder preservation (n = 9620) or RC (n = 22,680) for MIBC, and overall results showed that bladder preservation was associated with decreased overall survival (OS) compared with RC in patients with stage II–III urothelial carcinoma.[10]

  Radical Transurethral Resection Top

Transurethral resection is primarily used in patients with T2 bladder cancer. Although the usability of TUR is questioned considering the presence of local microfocus extensions and digital tumor spread in several cases, few studies have demonstrated benefits of TUR in small selected population.[11],[12],[13] In a study by Herr, 10-year outcome of patients with MIBC treated by TUR alone was evaluated, and the results showed that the disease-specific survival was 76% in patients who received TUR as definitive therapy compared with patients who immediate cystectomy (71%).[11] A total of 82% of patients who had T0 on restaging TUR survived versus 57% of the patients who had residual T1 tumor on restaging TUR.[11]

Another report of 133 patients with MIBC (grade 2/3) who underwent TUR from April 1981 to September 1992 and patients followed up for 15 years showed the OS at 5, 10, and 15 years was 81.9%, 79.5%, and 76.7% and progression-free survival with bladder preservation was 75.5%, 64.9%, and 57.8%, respectively.[13]

  Partial Cystectomy Top

The advantage of partial cystectomy is that it allows complete resection of the cancerous lesion with wide surgical margins and helps maintain bladder and sexual function. Partial cystectomy also allows full dissection of pelvic lymph node and removal of full thickness, which help a surgeon in complete staging. An ideal patient for partial cystectomy is one who has a solitary lesion (<5 cm) present in a region which can be removed with adequate margin. Patients who have multiple lesions, concomitant carcinoma in situ, or defunctionalized or acontractile bladders are not suitable for partial cystectomy.[14],[43]

When partial cystectomy is planned, it is important that patients are counseled before surgery for possible RC in cases where negative margin is not achieved. Furthermore, the surgeon must consider that during lymph node dissection, the borders must be similar to that of RC. Outcomes can be reasonable for carefully selected patient. In a population-based study, the 5-year OS was 57.2% and cause-specific survival was 76.4% in patients who were treated with partial cystectomy; however, these rates were 50.2% and 65.8%, respectively, among patients treated with RC (P < 0.001).[15] When cohorts were matched for age, race, pT stage, pN stage, tumor grade, and year of surgery, the OS and cause-specific survival were still significantly (P < 0.05) higher in patients treated with RC; however, when the number of removed lymph nodes was added to the matching criteria, the OS and cause-specific survival were similar in both the groups (P > 0.05). Overall, the authors concluded that partial cystectomy does not undermine cancer control in carefully selected patients.[15] Several other studies have also demonstrated the OS between 50% and 70% for patients undergoing partial cystectomy for MIBC.[16],[17],[18],[19],[20],[21]

  Radiotherapy Top

Radiotherapy is an alternative treatment which has reasonably decent results among patients who are very weak or unfit for other treatment options or for those who refuse operation. Conventional radiotherapy in combination with chemotherapy, or alone, may result in better outcomes in locally advanced bladder cancer patients. However, a limitation of radiotherapy is that dose cannot be reduced to critical organs which may cause unavoidable adverse effects. Radiotherapy is generally administered 1.8–2 Gy per day fractions and a total dose of 45–50 Gy is delivered to the pelvis and 55–70 Gy to the bladder tumor bed.[22]

A population-based study evaluated the outcome of radical radiotherapy. This study assessed 20,906 new cases of bladder cancer diagnosed between 1982 and 1994, of which 1372 patients received radical radiotherapy.[23] The results from this study showed 5-year survival rates as follows: bladder cancer cause-specific, 41%; overall, 28%; cystectomy-free, 25%; bladder cancer cause-specific following salvage cystectomy, 36%; overall following salvage cystectomy, 28%.[23] In a study by Chung et al., 340 patients (T1–T4) were treated, between 1986 and 1997, with radiotherapy alone, radiotherapy and concurrent cisplatin chemotherapy, or neoadjuvant chemotherapy followed by radiotherapy.[24] Complete response rate was 63.5% for the whole group. The 10-year OS, cause-specific survival, and local relapse-free rates were 19%, 35%, and 32%, respectively. Authors also reported that younger patients and patients with early stage and absence of carcinoma in situ were associated with significant improvement in survival and local control.[24] Kotwal et al. compared outcomes between patients receiving either RC or radiotherapy between 1996 and 2000 and found that there was no difference in OS and cause-specific and distant recurrence-free survival at 5 years between the two groups, despite the radiotherapy group being older.[25]

  Chemotherapy Top

Chemotherapy in patients with MIBC can be neoadjuvant or adjuvant primarily given before RC. There are a number of studies and meta-analyses that have demonstrated that neoadjuvant chemotherapy before RC improves survival.[26],[27],[28],[29],[30] In an initial study that was conducted over an 11-year period, a total of 317 patients with MIBC (stage T2 to T4a) who received neoadjuvant chemotherapy (three cycles of methotrexate, vinblastine, doxorubicin, and cisplatin) before the treatment of RC.[26] The results showed that the median survival was 46 months in patients who were treated with RC alone, as compared with 77 months in patients who received neoadjuvant before chemotherapy RC. In addition, significantly higher number of patients who received neoadjuvant chemotherapy before RC had no residual disease.

A recent meta-analysis of 15 randomized clinical trials compared neoadjuvant chemotherapy plus local treatment with the same local treatment alone in patients with MIBC and found that cisplatin-based neoadjuvant chemotherapy had better OS benefit (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79–0.96).[28] The meta-analysis also evaluated the benefits comparing methotrexate, vinblastine, doxorubicin, and cisplatin versus gemcitabine and cisplatin/carboplatin using 13 retrospective studies and found that there is no difference in pathological complete response in both the regimen; however, gemcitabine and cisplatin/carboplatin significantly reduced OS (HR, 1.26; 95% CI, 1.01–1.57), and when these data were analyzed excluding carboplatin data, gemcitabine and cisplatin were found to be inferior to patients who received methotrexate, vinblastine, doxorubicin, and cisplatin.[28] Another meta-analysis evaluated the role of cisplatin-based neoadjuvant chemotherapy on survival in patients with bladder cancer using data from 14 studies and found that patients in the neoadjuvant chemotherapy group had similar OS (pooled HR 0.92, 95% CI: 0.84–1.00, P = 0.056) and progression-free survival (P = 0.725) to that observed in radiation therapy or cystectomy.[31] Overall, authors concluded that the platinum-based neoadjuvant chemotherapy was associated with similar survival benefit as patients undergoing cystectomy and/or radiotherapy. Based on the available literature, it seems to be still debatable whether all patients with MIBC should be treated with chemotherapy.

  Trimodal Therapy Top

Trimodal therapy includes TUR followed by concurrent chemoradiation. It is primarily reserved for two types of patients, one those who are medically unfit for RC and second for those who meet strict criteria for curative intent. An ideal patient for trimodal therapy presents with unifocal cT2N0M0 urothelial carcinoma of the bladder, good bladder function and capacity, no carcinoma in situ, no infiltration of prostatic stroma, and no hydronephrosis, which represents 15% of current RC patients.[32]

In general, a patient selected for trimodal therapy undergo a maximal, preferably visually complete TUR, ideally with bladder mapping, followed by the delivery of cisplatin-based chemoradiotherapy to a dose of approximately 40–45 Gy. After this, final consolidative phase of chemotherapy is initiated in patients with evidence of minimal residual disease or no disease, and in patients with progressive or unresponsive disease, RC is considered.[9] Although there are no randomized controlled trials comparing trimodal therapy versus RC, several retrospective and prospective studies have confirmed the effectiveness of trimodal therapy in patients with MIBC and an alternative to RC. [Table 2] summarizes outcomes among patients with MIBC treated with trimodal therapy.[33],[34],[35],[36],[37],[38],[39],[40]
Table 2: Summary of few recent studies reporting trimodal/combination therapy

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A recent systematic review and meta-analysis assessed trimodal therapy and RC for the treatment of MIBC with or without neoadjuvant chemotherapy and included a total of 57 studies including 30,293 patients. The results showed that the mean 10-year OS and disease-specific survival were 30.9% and 50.9%, respectively, for trimodal therapy and 35.1% and 57.8%, respectively, for RC (P > 0.05).[41]

Mak et al. pooled five phase II studies and one phase III study from prospective Radiation Therapy Oncology Group protocols in patients with MIBC (T2 = 61%, T3 = 35%, and T4a = 4%) and found that the OS at 5 years was 57% and at 10 years was 36%; disease-specific survival was 71% and 65% at 5 and 10 years, respectively. The muscle-invasive local failure and distant metastasis were 13% and 14% and 31% and 35%, respectively, at 5 and 10 years. Considering these results, authors concluded that combined modality can be considered as an alternative to RC, particularly in elderly patients who are not fit for surgery.[42]

The basic strategy of trimodal therapy is to combine an aggressive but safe transurethral resection of the tumor followed by concurrent chemotherapy and radiotherapy. Trimodal treatment is more an attempt at bladder preservation than definitive bladder preservation. In the continuous course, cystoscopic assessment with adequate biopsy of the previous tumor site and voided urine cytology is performed at completion of trimodal therapy or after induction in the split course. In case of incomplete response, patients are advised to undergo immediate RC. To date, no prospective study has compared both courses (continuous versus split). Induction therapy mainly consists of radiation to a dose of 40 Gy. Consolidation radiation is continued to a full dose of approximately 65 Gy in most trials. In the continuous course strategy, cystoscopic evaluation with biopsy is deferred up to 1–3 months after the end of TMT.[43],[44]

In a study by Kim et al., outcomes among 50 patients who received RC and 29 patients who received trimodal therapy were compared and found 58%, 56%, and 69% 5-year distant metastasis-free survival, OS, and cancer-specific survival, respectively, in RC group and 67%, 57% and 63%, respectively, in trimodal therapy group.[33]

  Conclusion Top

The goal of bladder preservation is to achieve cancer survival at least equivalent to RC and to maintain quality of life including sexual life. Based on the available literature, it is evident that carefully selected patients can benefit from bladder preservation. Hence, it is important to carefully select the patient for bladder preservation evaluating risk and benefits. Bladder preservation can be achieved using single modality treatment; however, patients undergoing trimodal therapy have better outcomes.

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  [Table 1], [Table 2]


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