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Table of Contents
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 98-109

Systemic treatment options in bladder cancer

Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication17-May-2019

Correspondence Address:
Vanita Noronha
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_8_19

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Since the 1980's, with the advent of MVAC (methotrexate, cisplatin, vinblastine, adriamycin) the role of chemotherapy for bladder cancer was defined. Since then, multiple chemotherapy regimens have been used and the field of chemotherapy has reached a therapeutic plateau. In the last decade, there have been recent updates in the systemic options used in bladder cancer. Early stage disease is managed with cystectomy. The role of neoadjuvant chemotherapy is well established and the trimodality approach for bladder preservation is widely being practiced worldwide. With the advent of immunotherapy, the survival pattern has changed in patients with metastatic disease, and still, more research work needs to be done. Here we aim to review all the latest trends in the systemic treatment options of bladder cancer.

Keywords: Bladder cancer, chemotherapy, immunotherapy, muscle invasive, MIBC, transitional cell, urothelial

How to cite this article:
Ravind R, Prabhash K, Joshi A, Patil V, Noronha V. Systemic treatment options in bladder cancer. Cancer Res Stat Treat 2018;1:98-109

How to cite this URL:
Ravind R, Prabhash K, Joshi A, Patil V, Noronha V. Systemic treatment options in bladder cancer. Cancer Res Stat Treat [serial online] 2018 [cited 2022 May 29];1:98-109. Available from: https://www.crstonline.com/text.asp?2018/1/2/98/258546

  Introduction Top

Bladder cancer is the second most common genitourinary malignancy and the ninth most common malignancy worldwide.[1] From the year 1990 to 2016, there has been an increase of bladder cancers in the Indian subcontinent, with the age-standardized mean percentage change in incidence rate of 13.6%.[2] Bladder cancers are more commonly seen in men of the older age group, with a median age at diagnosis of 68 years. Recently there has been a rising trend in women.[3] The rising incidence could be attributed to the usage of tobacco (cigarette smoking), and other risk factors (chlorination by-products or arsenic, drug use such as cyclophosphamide/phenacetin-containing analgesics, and Schistosoma haematobium infestation contribute to the rising incidence).[4]

The major histological subtype is transitional cell carcinoma (92%); the rarer histologies include squamous (3%) and adenocarcinoma (2%). Unique to these histologies are the mixed variants, which are more common than the pure non - transitional types, and the management of these mixed variants differ.[5] Seventy percent of the tumors present at an early stage (non-muscle invasive); survival for the non-muscle invasive tumors reaches 90% at 5 years.[6] The challenge in treatment lies in the rest of the 30% of muscle-invasive (≥T2) tumors whose cumulative survival is below 65%.[7] Less than one-fourth of the muscle-invasive bladder cancers (MIBC) present with metastasis at presentation and nearly half of the non-metastatic MIBC recur within 2 years of treatment. MIBC has a high risk of distant metastasis.[8]

Even though the chemosensitivity of these MIBC has long been accepted, there has been little progress made in systemic chemotherapy in the last few decades with few systemic therapies, including immunotherapy being evaluated in the recent years.[9] To further tap into the intricacy of bladder cancer, molecular profiling of tumors has been used to develop novel therapies.

This review article will highlight some of the systemic treatments in bladder cancer in the adjuvant, and concurrent setting, along with systemic options in the metastatic setting and with a glimpse into future treatment options.

  Methodology Top

The resources for this article were generated using comprehensive search string in PubMed, including systemic treatment, MIBC, metastatic bladder cancer, chemotherapy, immunotherapy, trimodality treatment, neoadjuvant chemotherapy (NACT), and adjuvant treatment.

Neoadjuvant chemotherapy

MIBC is considered an aggressive disease, and NACT is an important tool in the management of MIBC with many cisplatin-based regimens. The three reasons to give NACT include the survival advantage conferred by eradicating micrometastatic disease, response evaluation in terms of chemosensitivity and for organ preservation.[10]

Until 2003, the definitive treatment for MIBC was radical cystectomy; however, the disease later recurred at distant sites. The need for management of the micrometastatic disease was then recognized, and trials were undertaken to evaluate the role of NACT in patients with MIBC.

Randomized trials done prior to 2003 (Wallace et al. 1991, Martinez Pinerio et al. 1995, Coppin et al. 1996, and Sherif et al. 2002) failed to show a survival advantage of NACT, as these trials had several limitations like small sample size, poor study design, and lack of standardized local therapy (radiotherapy). Trials with multiagent chemotherapy showed improvement in pathological response rate and overall survival. The evidence from NACT comes from two randomized controlled trials (RCTs) and two meta-analyses.[11]

One of the first proof for NACT came from Europe – European Organization for Research and Treatment of Cancer (EORTC) BA 06 Phase III trial (with 491 patients in each arm) with three cycles of methotrexate, cisplatin and vinblastine followed by surgery versus surgery/definitive local therapy alone. The NACT regimen led to a 16% reduction in the risk of death (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.72–0.99; P = 0.037) and 6% absolute increase in 10-years survival rate from 30% in the surgery alone arm to 36% in patients treated with NACT.[12]

Grossman et al. in the RCT by Southwest Oncology Group (SWOG) randomized 317 node-negative MIBC patients to three cycles of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) administered 4-weekly followed by cystectomy versus cystectomy alone. There was an absolute survival advantage of 31 months, although this was not statistically significant; median survival increased from 46 months in the control group who underwent cystectomy alone, to 77 months in the patients who received NACT (P = 0.06).[13] The patients in the NACT group had a significantly higher chance of having no evidence of malignancy in the surgical specimen as compared to the patients in upfront surgery group (38% vs. 15%, P<0.001). Lack of detectable cancer in the surgical specimen correlated with an improvement in survival. At 5 years, 85% of patients with T0 tumors were alive. However, this study did not describe what further treatment options were offered to the patients with residual disease in their pathology specimens. It is quite interesting to note that not all patients were able to receive even one complete cycle of MVAC (87% patients received), and the addition of chemotherapy did not add to the postoperative complication rate.[14] Even though the results showed only a trend toward survival, the advantage conferred was quite impressive, and could not be ignored.

Kitamura et al. conducted a Phase III trial in Japanese population (n=130) with MIBC, in which two cycles of MVAC + cystectomy led to an overall survival (OS) of 102 months, compared to 82 months in patients treated with cystectomy alone, P = 0.07. The investigators had planned for a sample size of 360 patients, but the trial was terminated early after only 130 patients had been recruited, due to slow accrual. Therefore, the trial was underpowered to answer the question whether NACT prolongs survival in MIBC. 34% of patients who received MVAC neoadjuvantly had pathological CR in the surgical specimen compared to 9% in the patients who had upfront surgery, P<0.01. This rate of pathological CR was similar to that in the earlier described SWOG trial.[11] The 44% rate of grade 4 neutropenia limits its use, but with the advent of better granulocyte colony-stimulating factor (GCSF) agents and pegylated forms, the toxicity rates could be managed much better.[15]

Sternberg et al. have used the dose-dense (DD) MVAC every 15 days with GCSF support versus conventional MVAC, which showed statistically significant survival advantage (9.1 vs. 8.2 months, P = 0.037) in metastatic setting and the same regimen is now being extrapolated to neoadjuvant setting.[16],[17] Van de Putte et al. conducted a Phase II trial comparing neoadjuvant DD-MVAC every 2 weeks (n = 80), classical MVAC every 4 weeks (n = 35), and gemcitabine/ cisplatin (GC) every 3 weeks (n = 51). They reported similar pathological response rates in the three arms (DD-MVAC-29%, classical MVAC-20%, GC-32%) and significantly lower grade 3 or higher toxicity rate from DD-MVAC and GC (44%) compared to classical MVAC (55%). The authors concluded that because of the similar rate of pathological CR, the lower toxicity rate and the shorter cycle duration, DD-MVAC could be considered the preferred neoadjuvant regimen in MIBC.[18],[19]

The search for a less toxic regimen ended in the trial by von der Maase et al., in which 405 patients with locally advanced (T4b/ N2/ N3) or metastatic (M1) bladder cancer were randomized to GC or MVAC. GC led to similar efficacy and lower toxicity. Long-term survival data showed similar OS (HR, 1.09; 95% CI, 0.88–1.34; P = 0.66) with a median survival of 14 months for GC and 15.2 months for MVAC. The 5-year OS rates were 13.0% and 15.3%, respectively (P = 0.53). The similar efficacy and lower toxicity of GC led to it be preferentially used as the regimen of choice in locally advanced or metastatic bladder cancer. This preference of the GC regimen has crept into the neoadjuvant arena as well, without robust phase III trial data.[20]

A meta-analysis published in 2005, reviewed data of 3005 patients from 11 trials, which included patients who received NACT with a platinum-based multiagent chemotherapy regimen. Even though trials with negative outcome were added into this analysis, an OS benefit of 5% at 5 years (HR = 0.86, 95%CI 0.77–0.95, P = 0.003) and a disease-free survival (DFS) benefit of 9% at 5 years (HR = 0.78, 95% CI 0.71–0.86, P < 0.0001) were noted which were statistically significant.[21] Although several individual randomized trials were unable to definitively demonstrate an improvement in survival as a result of NACT, this was possibly due to insufficient patient numbers. The meta-analysis overcame this hurdle.

The equivalence of definitive treatment (cystectomy versus radiotherapy) has not been tested in any RCT. Herr et al. in their study evaluating the impact of surgical factors on bladder cancer outcomes, reported that negative margins (HR, 0.37; P = 0.0007) and dissection of > 10 lymph nodes (HR, 0.51; P = 0.0001) predicted for a longer post-cystectomy survival.[14]

Patients with operable T2 to T4a tumors are candidates for NACT. In spite of the high level of evidence, chemotherapy is underutilized. Concerns from the urosurgeons regarding delay in initiating the definitive treatment is one reason. Moreover, only 50% of the NACT candidates are eligible for cisplatin-based regimen, reason being advanced age with multiple comorbid illnesses and poor renal functions. NACT has shown survival advantage yet only 15%–20% of the patients receive it.[22] In patients who are unfit for cisplatin-based NACT, gemcitabine and carboplatin may be considered a reasonable alternative regimen, based on retrospective data,[23] however level 1 evidence is lacking in this situation.

Adjuvant chemotherapy

Adjuvant chemotherapy may be considered for selected patients who have not received NACT. Reduction in local recurrence and survival advantage are the rationale behind using adjuvant chemotherapy.

There is no RCT to prove the benefit of adjuvant chemotherapy as these studies are limited by poor accrual and conflicting results. A meta-analysis done in the year 2005 of 491 patients (data from six trials), representing 90% of all patients randomized in cisplatin-based combination chemotherapy trials, showed an overall HR for survival of 0.75 (95% CI 0.60–0.96, P = 0.019), which suggests a 25% relative reduction in the risk of death as a result of adjuvant chemotherapy compared to control.[24] In 2014, another review of 945 patients from 9 RCTs found similar results (HR, 0.77; 95% CI, 0.59–0.99). A DFS-pooled HR across seven trials was 0.66 (95% CI, 0.45–0.91; P = 0.014), and this was apparent in node-positive subsets.[25]

The largest trial was the Phase III EORTC 30994 intergroup study with 284 patients (planned 660 patients) from Europe and Canada with pT3/pT4, N+ non-metastatic disease who had undergone cystectomy and bilateral lymphadenectomy and were randomized 1:1 to receive either 4 cycles of high dose MVAC immediately or 6 cycles of deferred chemotherapy at the time of relapse. At 7 years, early treatment significantly prolonged progression-free survival (PFS) (HR, 0.54; 95% CI, 0.4–0.73; P < 0.0001), with 5-year PFS of 47.6% versus 31.8% (deferred treatment group). The trial concluded that adjuvant chemotherapy did not significantly prolong the 5-year OS (HR, 0.78, 95% CI, 0.56–1.08). A post hoc exploratory analysis revealed OS significantly improved in node positive patients (79.5% vs. 59%).[26]

The Spanish Oncology Genitourinary Group carried out a phase III RCT evaluating the role of adjuvant chemotherapy in bladder cancer. The trial accrued slowly and was prematurely terminated after enrolling 142 patients. Patients were randomized to receive four cycles of paclitaxel, gemcitabine, and cisplatin post-cystectomy or to observation. The results showed improved 5-year survival (60% vs. 31%, P < 0.0009) in the chemotherapy arm. However, because of the limited sample size, the trial was underpowered and the trial has only been reported in abstract form.[27]

An observational study from the National Cancer Database to compare the effectiveness of adjuvant chemotherapy versus observation in post-cystectomy pT3/pT4 N+ patients noted that, out of the total 5653 patients, there were 1293 patients who received adjuvant chemotherapy (for node-positive/margin-positive disease) and the rest were in the observation group. The comparison was done with a propensity score-matched control group which showed that adjuvant chemotherapy improved survival (HR, 0.70; 95% CI, 0.64–0.76).[28]

Forty percent of the patients are not eligible for cisplatin-based adjuvant chemotherapy, and hence alternative platinum with safer renal profiles have been tried. Carboplatin as an alternative to Cisplatin was used and this did not seem to affect the DFS however, the data are limited.[29] Gemcitabine was tried in Phase III trial in cisplatin-ineligible patients, but it showed insignificant increase in the of PFS and OS at 3 years.

There are many unanswered questions including what the optimal schedule of chemotherapy should be, how extensive the nodal dissection should be and how many cycles of chemotherapy are required.

The few randomized trials were limited by poor accrual and reviews of these trials showed methodological flaws in terms of small sample size, ineffective chemotherapy regimens, and inadequate statistical methodology.

With the current available data, systemic platinum-based chemotherapy should be offered to patients with pT3–T4 or pN+ disease. The 5-year survival rate in patients with N+ disease is 30% and nearly 50% for T3 disease.[30]

Trimodality approach for bladder preservation

Systemic chemotherapy with radiotherapy is a critical component of a trimodality bladder-preserving approach. Radiotherapy alone or transurethral resection of bladder cancer (TURBT) leads to 20%–40% success at local control.[31] A fair number of patients with MIBC would be unwilling or unfit for cystectomy. These patients could be treated with a bladder preservation protocol; trimodality approach of maximum TURBT followed by combined chemoradiotherapy (CRT).

Studies using cisplatin alone or in combination with 5 FU and radiotherapy (RT) showed average response rate of 75% with 5-year survival of 50%–60%, similar historically to that achieved with cystectomy.[32] Other agents used along with cisplatin were paclitaxel and gemcitabine which led to a 5-year OS of 50%. Results from the Radiation Therapy Oncology Group trial NCT00777491 comparing cisplatin and 5-FU to gemcitabine in combination with radiation are awaited, and the trial is closed to recruitment.[33]

James et al. did a Phase III RCT BC2001 which assigned 360 patients with MIBC to receive RT versus concurrent CRT. The chemotherapy used was 5FU and mitomycin. Two-year locoregional DFS was 67% in CRT arm versus 54% in RT alone arm (HR, 0.68; 95% CI 0.48–0.96). The 5-year OS was 48% in CRT group versus 35% in RT group (P = 0.16). Thus, CRT improved locoregional control rates with no significant adverse events.[34]

Trials done by Shipley et al. at the Massachusetts General Hospital (n = 190) and Rodley et al. at the University of Erlangen (n = 415) in patients with bladder cancer (T2-T4) evaluated the role of TURBT + CRT. They reported 10-year disease specific survivals of 45% and 42% respectively.[32],[35]

RTOG (Radiotherapy and Oncology Group) did a pooled analysis of five phase II studies (RTOG 8802, 9506, 9706, 9906, and 0233) and one phase III study (RTOG 8903) of trials which evaluated bladder-preserving combined-modality therapy for MIBC, reserving cystectomy for salvage treatment. Majority of the patients enrolled in this analysis had T2/ T3 tumors and 69% had CR to the combined modality treatment. The 10-year OS rate was 36%, and the 10-year disease specific survival (DSS) rate was 65%. The long term DSS rate was comparable to that reported in immediate cystectomy series.[36]

A recent metaanalysis reported in 2018 examined the outcomes for trimodality therapy as compared to radical cystectomy. A total of 57 studies which included 30,293 patients were included in the analysis. The 10-year mean OS and DSS were 30.9% and 50.9% respectively for the trimodality approach and 35.1% and 57.8% respectively in patients treated with radical cystectomy (P = 0.32 and P = 0.26 for OS and DSS respectively). Of note, 75.3% patients treated with trimodality therapy had CR; in these patients, the 5 year OS was 66.9% and DSS was 78.3%. 29.1% patients had down-staging of the disease (≤pT1) after TURBT. Hence the survival outcome of patients with the trimodality approach was comparable to that of cystectomy group.[37] Similarly, reports from a metaanalysis of cohort studies found bladder preservation to be a superior modality especially for older patients and for selected subgroup T1 G3 or low-grade tumors.[38]

The risk of recurrence in patients after trimodality treatment appears greatest in the initial few years following treatment and the risk decreases after 5 years. Hence guidelines have been set for surveillance of these tumors. Apart from the routine history and physical examination, blood investigations and imaging studies, urine cytology and cystoscopy have a definite role. For organ confined/extra-vesical disease, urine cytology is done at three-monthly intervals for a period of 5 years. Patients should undergo a restaging transurethral resection at 3 months after the definitive treatment. Surveillance cystoscopy should then be performed at 3-monthly intervals for the first year, then every 6 months until 5 years, and annually thereafter.[39]

Newer chemotherapy regimens have been tried with taxanes, gemcitbine and platinums (other than cisplatin) and some have showed increased response rates as compared to platinum monotherapy. Radiation is delivered using conventional fractionation with a whole pelvic field treated to a dose of 40-45Gy followed by reassessment and boost to the bladder/ tumor margin to a dose of 20-24Gy. Recently, image-guided and adaptive radiotherapy is being tried with a hope to decrease radiation induced morbidity.

Patients who undergo organ preservation with almost retained bladder function have a better quality of life than patients with neo-bladder. One must keep in mind that the quality of life should also be considered along with the other efficacy endpoints, like survival. Few prognostic factors are identified for bladder preservation and these are T-stage of tumor, complete TURBT, a complete response rate to CRT, solitary tumor, absence of carcinoma insitu, absence of hydronephrosis and absence of nodal disease. Trimodality approach can be used for patients with early stage and unifocal tumors in whom a microscopically complete TURBT has been accomplished. The role of NACT prior to TURBT needs to be tested in this setting. Patient selection is paramount. The lack of RCT, therefore the lack of level 1 evidence precludes the use of this approach as the standard of care in all patients. Studies suggest that this regimen can be tried safely in elderly patients.[34]

Locally advanced/metastatic bladder cancer

Around 20% of the bladder cancers are muscle invasive and around 5% of bladder cancers are metastatic at presentation. These tumors are chemosensitive, and literature reports a response rate of nearly 75% to chemotherapy in the definitive setting and up to 35% complete remission in the metastatic setting.[40] The mainstay of treatment is cisplatin and methotrexate for metastatic bladder cancer and it has a proven benefit in the first-line setting.

A number of prognostic factors have been correlated with survival and for determining which specific patients will benefit from treatment. The poor prognostic factors include poor performance status at presentation and the presence of visceral metastasis (hepatic/ skeletal/ pulmonary). The presence of hepatic or skeletal metastasis and a poor performance status are predictive of poor survival.[41]

Several chemotherapeutic agents have shown single agent activity in metastatic bladder cancer. The most effective drugs are methotrexate and cisplatin; other agents like doxorubicin, 5-flurouracil, vinblastine, ifosfamide and mitomycin-c have been used with varying results.[42]

Studies conducted in late 1980's to 90's have proved that a multidrug regimen is better than single agent chemotherapy. This was initially proved by the Intergroup study which randomized 269 patients with advanced urothelial carcinoma to receive cisplatin alone versus MVAC. MVAC led to a superior response rate compared to single agent cisplatin, but increased toxicity (39% v 12%; P < 0.0001). The combination therapy prolonged the PFS (10.0 v 4.3 months) and OS (12.5 v 8.2 months).[41]

Sternberg et al. in 1985 presented their initial findings of MVAC regimen in 92 patients with advanced bladder cancers. The use of this regimen resulted in a response rate of over 50% with a 3-year survival of 20-25% and a median survival of over 12 months. Long term survival was low with only 10-15% of the patients surviving up to five years. This regimen was toxic and caused neutropenia in 20% patients with 3-4% treatment related mortality.[43],[44]

A less toxic regimen was gemcitabine with cisplatin. It was tested in two phase II trials. These studies showed 42%-50% response rates and median survival of 12-14 months. Thrombocytopenia and neutropenia of grade 3 to 4 were reported in these studies but there was no treatment-related mortality.[45],[46]

In a large randomized phase III trial in 405 patients with stage IV transitional cell carcinoma, patients was randomized to receive either MVAC or GC. Both arms demonstrated almost similar efficacy, with a median survival of 13.8 versus 14.8 months for GC and MVAC regimens respectively; median PFS was 7.4 months for both groups, and response rates around 47% for both regimens. GC scored over MVAC in terms of its toxicity profile, especially for rates of neutropenic sepsis (1% versus 12%), grade 3 and 4 mucositis (1% versus 22%) and drug-related death (1% versus 3%), which were all more common in the MVAC-treated group.[47]

In the first-line setting for metastatic bladder cancer, the best palliation can be offered by the use of gemcitabine cisplatin(GC) or MVAC chemotherapy. Even though the OS and PFS are similar in both regimens, the better toxicity profile of GC has led to its preferential use in the first-line palliative setting.[34]

Galsky et al. with their DD-MVAC showed an objective response rate of 72% versus 58%; there was a decrease in the relative risk of death by 24% as compared to classic MVAC.[28] Even though direct comparison of GC versus DD-MVAC is unavailable, DD-MVAC regimen can be a good treatment option in patients with good performance status and high disease burden.

As most of these patients have suboptimal renal functions, the question of trying a non-cisplatin regimen is always pondered upon. In patients with impaired renal function, carboplatin may be used as an alternative for cisplatin, but the efficacy needs to be proved in a clinical setting.

One of the RCT's for cisplatin-unfit patients is the EORTC study 30986 which assessed the combination of gemcitabine/ carboplatin (GC) versus methotrexate/carboplatin/vinblastine (MCAVI) in patients with advanced urothelial cancers. In this multi-institutional study, 238 patients were randomized. The ORR was 41.2% for patients receiving GC versus 30.3% for patients treated with MCAVI. Even though there was no significant difference in PFS, the GC arm led to a median OS of 9.3 months vs 8.1 months in the MCAVI arm; MCAVI had higher toxicity rates (21.2% vs 9.3%).[48]

Data from the Veterans Administration patients in stage IV cancers (2000-2010) (n=196) showed similar median survival for patients treated with Gemcitabine+Cisplatin (median OS 10.35 months) versus Gemcitabine +Carboplatin (median OS 11.4 months).[49]

Galsky et al. published a metaanalysis where he compared the effectiveness of gemcitabine - carboplatin versus gemcitabine- cisplatin. Four trials were included and had 286 patients with metastatic bladder cancer. Cisplatin-based chemotherapy was associated with a significantly higher likelihood of achieving a CR [pooled risk ratio [RR] = 3.54; CI 1.48-8.49; P = 0.005] and overall response (RR = 1.34; 95% CI 1.04-1.71; P = 0.02). Individual patient data was not available, and survival outcomes could not be evaluated. Very low quality evidence from two studies showed no difference in survival rate at 12 months (RR 0.76, 95% CI 0.56 to 1.07).[50]

Dogliotti et al in a phase II randomized trial compared gemcitabine with carboplatin vs cisplatin. There was no statistically significant difference in overall toxicity between the two regimens. Gemcitabine – carboplatin arm had more of hematological and less of nephrological toxicity. The overall response rate was 49.1% (CR-14.5%, PR-34.5%) in the gemcitabine-cisplatin arm and 40% (CR-1.8%, PR-38.2%) in the gemcitabine-carboplatin arm. The median time to progression was 8.3 and 7.7 months in the gem-cis and gem-carbo arms respectively. Median overall survival was 12.8 and 9.8 months in the gem-cis and gem-carbo arms respectively.[51]

Platinum-intolerant patients can be treated with single agent gemcitabine or paclitaxel /docetaxel and gemcitabine.[52],[53] Results from phase I/ II studies suggested that a three-drug regimen including paclitaxel had greater antitumor activity. This was tested in the phase III EORTC Intergroup Study 30987, which randomly assigned 626 patients to receive either paclitaxel/ cisplatin/ gemcitabine (PCG) or gemcitabine/ cisplatin (GC). The median OS was 15.8 months in the PCG arm versus 12.7 months in the GC arm (HR, 0.85; P = 0.075). PFS was not significantly longer in the PCG group (HR, 0.87; P = 0.11). Overall response rate was 55.5% in PCG and 43.6% in GC (P = 0.0031). Both the regimens were well-tolerated, with more thrombocytopenia and bleeding noted in patients receiving GC and more febrile neutropenia in patients receiving PCG. This study proved that the addition of a taxane resulted in a better response rate but did not prolong PFS or OS.[54]

Other less nephrotoxic platinum compounds like oxaliplatin have been tested in the metastatic setting.[55] Gemcitabine and oxaliplatin (GEMOX) was tested in phase II trials and in the study by Theodore et al.; the regimen resulted in a response rate of 47% and a median survival of 15 months. Grade 3 and 4 toxicities included neutropenia, anemia, thrombocytopenia, peripheral neuropathy and fatigue. Even though the GEMOX regimen showed activity in bladder cancer, it has not been tested in larger population and oxaliplatin is not used routinely.[56],[57]

More recent trials have clarified that oxaliplatin is not an active agent in patients with bladdder cancer. One such trial is the French trial (GETUG V01) published in 2011 which was a randomized phase II trial (two stage Fleming Design) comparing the GEMOX regimen to gemcitabine alone. A total of 44 patients were randomly assigned into the study. The trial was closed after the first stage as the GEMOX arm did not reach the targeted response rate. The authors concluded that in terms of response rate, the addition of oxaliplatin did not add any significant activity, as compared with gemcitabine alone.[58]

The other combinations used in first line regimen were, gemcitabine - pemetrexed, gemcitabine – epirubicin, gemcitabine - vinorelbine and they showed a favourable response when compared to single agent chemotherapy.[59]

Trials with non-cisplatin based regimens have been evaluated and phase II data of gemcitabine with paclitaxel administered every 2 weeks in metastatic bladder cancer showed 37% overall response rate with a median time to progression of 5.8 months and a median overall survival of 13.2 months. The authors concluded that this regimen can be considered in patients who are unfit for cisplatin.[60]

Patients who progress after first-line systemic therapy unfortunately have limited treatment options. Vinflunine is the only chemotherapeutic agent which has been proven superior to best supportive care in the relapsed setting. The phase III trial was conducted in 370 patients who had failed first-line platinum-based chemotherapy and were then randomized to receive vinflunine versus best supportive care. Patients in the vinflunine arm had a 23% reduced risk of death (HR = 0.77; 95% CI, 0.61 to 0.98). The median OS was significantly longer in patients treated with vinflunine than supportive care (6.9 v 4.3 months, respectively (P = 0.0227). The overall response rate (P = 0.006), disease control rate (P = 0.002), and progression-free survival (P = 0.001) were all statistically significantly better in the chemotherapy arm.[61] The lack of availability of the drug unfortunately limits its use.

Other single agent chemotherapy drugs have been tried in the second line setting. Paclitaxel (weekly regimen) is well-tolerated and the overall response rate, disease control rate and median PFS have been reported to be 9.5%, 45.2% and 6.4 months respectively.[52] A randomized Phase II/III trial (SECAVIN) evaluated the role of cabazitaxel in comparison to vinflunine in patients with relapsed metastatic or locally advanced urothelial carcinoma. Seventy patients were included in the phase II part of the study. Three patients (13%; 95% CI, 2.7-32.4) had partial response (PR) with cabazitaxel while six patients (30%; 95% CI, 11.9-54.3) had a PR from vinflunine. The median PFS in the cabazitaxel arm was 1.9 months vs. 2.9 months for the vinflunine arm, (P = 0.039). There was a trend towards OS benefit for the patients treated with vinflunine (median OS 7.6 versus 5.5 months). The trial was stopped after the phase II portion, as there was no evidence of efficacy of cabazitaxel.[60],[82]

Many phase II studies have been conducted seeking alternative agents. In patients with poor performance status and extensive distant metastasis, best supportive care is the standard of care.

Before choosing a regimen for metastatic bladder cancer, one has to consider the patient as a whole, including the comorbid illnesses, performance status, age and the renal function, which is often compromised. Usually patients with T4a tumors and M1 metastatic disease are treated with the aforesaid chemotherapy.

Targeted therapy/immunotherapy/experimental therapy

The survival in a chemotherapy-naive metastatic bladder cancer patient treated with any platinum-based regimen is between 9 and 15 months. Considering the limited success of the treatment options in metastatic/locally advanced bladder cancer, the need for newer targets for tackling tumor growth was tested and the role of targeted therapy was evaluated.

Mutations in the PI3K/AKT/mTOR pathway are seen in 40% of urothelial cancers, and studies have shown that activation of PI3K/AKT can result in chemotherapy resistance and poor prognosis. Preclinical data on drugs targeting this pathway have not met their endpoints. Phase II study of pan-PI3K-inhibitor buparlisib, is ongoing for patients with metastatic, chemotherapy-refractory bladder cancer (ClinicalTrials.gov identifier: NCT01551030).[62],[63]

mTor inhibitors have been tried but have not shown effectiveness. Trials using mTor inhibitors (everolimus) and vascular endothelial growth factor (VEGF) inhibitors, like pazopanib, in combination, have not shown any benefit, but have shown response in a certain subset of patients. Whole-exome sequencing of a patient who experienced a 14-month CR on this trial revealed two concurrent mutations in mTOR, the target of everolimus, which may have caused this exceptional response.[64] Phase II trials in cisplatin-ineligible patients with everolimus and paclitaxel are underway (ClinicalTrials.gov identifier: NCT01215136).[63]

Fibroblast growth factor receptor (FGFR) leads to the downstream activation of multiple signaling molecules and its targets include angiogenesis, cell metabolism, and proliferation. Mutations in FGF/FGFR-related signaling have been shown to contribute to carcinogenesis, tumor cell invasion, and metastasis. Hence, it would be prudent to tackle the upstream activator, and various preclinical and clinical studies have been done.[65] Data from Phase II trial of dovitinib (FGFR III inhibitor), 500 mg daily as a 5 days on/2 days off regimen, was unimpressive in terms of response as out of the 44 patients only one patient in the non-mutated group showed partial response.[66] Erdafitinib, a pan fibroblast growth factor inhibitor (pan-FGFR) demonstrated promising phase 1 activity. Recently, the Food and Drug Administration (FDA) approved erdafitinib for use in metastatic bladder cancer, along with a companion diagnostic kit for FGFR RGQ RT-PCR. The recommended initial dose of erdafitinib is 8 mg orally once daily (with or without food). In the BLC2001 multicenter open-label Phase II trial, erdafitinib was tested in patients whose tumors had FGFR alterations. The outcome was measured in terms of objective response rate (ORR) which was 32.2% (95% CI, 22.4 to 42.0), with complete responses in 2.3% and partial responses in 29.9%. The median response duration was 5.4 months. FDA gave approval to this drug based on the response rate noted in this phase II trial.[67]

EGFR family pathways were tested and the very first anti-EGFR agent used was cetuximab. In a Phase II trial by Hussain et al., 88 previously untreated patients with metastatic bladder cancer were randomized to gemcitabine and cisplatin with or without cetuximab. Addition of cetuximab showed worse PFS and OS.[9] The addition of cetuximab resulted in similar overall response rates, 57.1% (95% CI, 37%-76%) and 61.4% (95% CI, 48%-74%), for GC and GC+cetuximab respectively. The median PFS was 8.5 months for GC (95% CI, 5.7-10.4 months) and 7.6 months for GC and cetuximab (95% CI, 6.1-8.7 months). The median OS was 17.4 months for GC (95% CI, 12.8 months to not reached) and 14.3 months for GC+ cetuximab (95% CI = 11.6-22.2 months).[44] The Cancer and Leukemia Group B conducted a phase II trial evaluating the addition of gefitinib to cisplatin/ gemcitabine for the first-line therapy of advanced urothelial cancer. The combination regimen was well-tolerated and resulted in an overall response rate of 42.6% (95% CI, 29.2-56.8), median time to progression of 7.4 months (95% Ci, 5.6-9.2) and median OS of 15.1 months (95% CI, 11.1-21.7). The authors concluded that the response rate and survival outcomes were not better than what was historically reported in cohorts treated with cisplatin and gemcitabine alone.[68] Phase II trial using trastuzumab in 44 patients with HER2/neu-positive tumors showed overall response rates (ORR) of 70%, median PFS of 9.3 months and median OS of 14.1 months.[69]

Even though these agents have shown some clinical benefit in selected patients, these trials have failed to show any survival advantage or meaningful clinical benefit for EGFR and Her 2 blockade in the treatment of bladder cancer.

Bladder cancer is noted to have significant angiogenesis activity and vascular endothelial growth factor (VEGF) overexpression is associated with more invasive tumors and worse prognosis. The anti-VEGF monoclonal antibody (bevacizumab) has been used in many Phase II trials. Bevacizumab in combination with cisplatin-gemcitabine was tested as first-line therapy in the metastatic setting, but the study failed to meet its primary endpoint, PFS. The regimen led to a response rate of 73%.[70] Currently, Phase III trials using gemcitabine, cisplatin and bevacizumab are awaiting final results.[71] (ClinicalTrials.gov identifier: NCT00942331).

Physicians have used various drugs from BCG to interferon therapy as immunotherapy agents for many decades together. The recent introduction of immunotherapy in almost all tumor types has led to changes in the treatment paradigm in bladder cancer as well. Tumor cells use the normal checkpoints in this process to evade immune destruction. Immunotherapy agents target this pathway. Immunotherapy in the form of checkpoint inhibitors is a promising new option for the treatment of bladder cancer. Smith and Zaharoff reported that expression of PDL1 and PD-1 was associated with more advanced pathologic stages. Its role is more evident in cisplatin-unfit patients.[72] In May 2016, the FDA approved atezolizumab, a monoclonal antibody targeting programmed death ligand 1 (PDL1) for localized or metastatic urothelial bladder cancers that have progressed during or after platinum-based chemotherapy.

Results from IMvigor210 trial cohort 1 showed atezolizumab to be an effective first-line therapy option for cisplatin-ineligible patients with locally advanced and metastatic disease; irrespective of PDL1 receptor status, responses occurred in all groups. A total of 220 patients were enrolled and the median post-progression overall survival was 8.6 months in patients receiving atezolizumab, compared to 6.6 months in those receiving other treatments (chemotherapy) and 1.2 months in those receiving no treatment.[73],[74] These promising results have led to FDA approval of atezolizumab as a first-line treatment option in cisplatin ineligible patients. The results of the single arm phase II IMvigor210 trial paved the way for the Phase III trial, IMvigor 130 which is designed to test the efficacy and safety of atezolizumab given alone or in combination with platinum-based chemotherapy (gemcitabine+cisplatin/ carboplatin) or a placebo and chemotherapy. The trial plans to enroll 1200 patients 1200 patients, who will be randomized in will be randomized in 1:1:1 ratio. The coprimary endpoints of the trial are PFS and OS. The results of the trial are awaited.[75],[76]

Pembrolizumab has also produced meaningful and durable responses in a similar patient population in the KEYNOTE-052 Phase II trial; 370 patients were assessed for response and toxicity, at a median follow-up of 5 months. In patients who had a PDL1 expression of >10%, the response rate was 38% (95%CI, 29-48). Grade 3 and higher toxicities included fatigue in 2%, rise in alkaline phosphatase in 1% and colitis and muscle weakness in 1%. 10% of patients experienced a treatment-related serious adverse event. These results led to the FDA approval of pembrolizumab as a first-line treatment option in the cisplatin-ineligible population.[77],[78]

In a Phase III KEYNOTE-045 trial, pembrolizumab was compared to investigator's choice of second-line chemotherapy (paclitaxel/docetaxel/vinflunine). Significant prolongation of OS was recorded in both unselected (10.3 vs. 7.4 months) and PDL1 selected population (8 vs. 5.2 months). There was no significant between-group difference in the duration of PFS in the total population (HR for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P = 0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (HR, 0.89; 95% CI, 0.61 to 1.28; P = 0.24). The two-year follow up of the KEYNOTE-045 trial of pembrolizumab reported that the median OS was significantly longer with pembrolizumab vs. chemotherapy (10.3 v 7.3 mo; HR, 0.70; P < 0.0002). OS benefit with pembrolizumab vs. chemotherapy was seen in all PD-L1 expression subgroups (HR: combined positive score [CPS] < 1, 0.82; CPS ≥1, 0.58; CPS < 10, 0.75; CPS ≥10, 0.56).[79]

The Keynote 361 is a Phase III trial in approximately 990 patients and is evaluating the role of pembrolizumab alone versus pembrolizumab along with chemotherapy (gemcitabine+cisplatin) versus chemotherapy alone in advanced urothelial carcinoma. The primary end points are PFS and OS and the secondary end points are response rate, safety and tolerability. Results of this trial are awaited.[80]

Nivolumab in the Checkmate 275 trial was used for the treatment of metastatic or locally advanced inoperable urothelial carcinoma. In this multicentric phase II trial which evaluated 265 patients, the median OS was 7 months (IQR, 2.96–8.77). The confirmed objective response was 19.6%, 95% CI 15.0–24.9. Nivolumab provided a meaningful clinical benefit irrespective of the PDL1 expression status. This trial led to FDA's approval of nivolumab in metastatic urothelial carcinoma after platinum therapy.[81]

The anti PD-L1 antibodies, avelumab and durvalumab found their role in the second-line treatment of metastatic urothelial cancer. Avelumab received accelerated approval in May 2017 following the results of the phase Ib JAVELIN study that included a cohort of 249 metastatic bladder cancer patients who had progressed after platinum-based therapy or were platinum in-eligible. In the >6 months follow up - updated analysis of 161 patients, the ORR was 17%, including 6% patients with CR. The median PFS was 6.6 weeks and median OS was 6.5 months.[82]

The other anti-PD-L1 monoclonal antibody, durvalumab, also received accelerated approval in May 2017 in the platinum-refractory setting based on the results of a single-arm phase I/II trial in 191 patients, of whom 103 were eligible for efficacy analysis. The ORR was 17.8% in the entire population with 7 in CR and with an ORR of 27.6% in PD-L1 high and 5.1% in PD-L1 low/negative patients. Median PFS and OS were 1.5 months and 18.2 months, respectively.[83]

These results from various immunotherapy trials and the fact that the FDA has approved five immunotherapy drugs in various settings has expanded the role of immunotherapy to the first-line setting and in non-metastatic tumors, especially in cisplatin-ineligible patients. The results from the two ongoing immunotherapy phase III trials namely IMvigor130 (atezolizumab) and the KEYNOTE 361 (pembrolizumab) will help us to better define the role of immunotherapy in patients with bladder cancer.[80],[84]

  Conclusion Top

Bladder cancer is a chemosensitive disease with cisplatin-based treatment being the backbone of treatment. For over 15 years, not much progress was made in terms of prolonging survival in patients with bladder cancer. The advent of immunotherapy offers promising results in advanced bladder cancers. NACT followed by cystectomy should be the cornerstone of early disease management as its benefit has been tested in various Phase III trials. The future lies in finding predictive biomarkers, gene profiling, and PDL-1 expression in urothelial cancer cells, which could help us to give personalized treatment options for these patients.

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Conflicts of interest

There are no conflicts of interest.

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