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  Table of Contents 
REVIEW ARTICLE
Year : 2021  |  Volume : 37  |  Issue : 3  |  Page : 226-233
 

Perioperative therapy in muscle invasive bladder cancer


Department of Uro-Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India

Date of Submission04-Oct-2020
Date of Decision17-May-2021
Date of Acceptance18-Jun-2021
Date of Web Publication1-Jul-2021

Correspondence Address:
Gagan Prakash
Department of Uro-Oncology, Tata Memorial Centre, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/iju.IJU_540_20

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   Abstract 

Radical cystectomy with bilateral pelvic lymph node dissection is the standard of care for muscle invasive bladder cancer (MIBC). The role of neoadjuvant and adjuvant therapy has evolved over the last 3–4 decades, and neoadjuvant chemotherapy (NACT) has now become the standard recommended treatment. However, there are many nuances to this and the utilization of chemotherapy has not been universal. The optimum chemotherapy regimen is still debated. Adjuvant radiation has a role in high-risk patients although not established and immunotherapy has shown promising results. We reviewed the evidence on NACT and adjuvant chemotherapy (ACT) regimens, NACT versus ACT, and the role of adjuvant radiotherapy and immunotherapy in MIBC.



How to cite this article:
Chatterjee A, Bakshi G, Pal M, Kapoor A, Joshi A, Prakash G. Perioperative therapy in muscle invasive bladder cancer. Indian J Urol 2021;37:226-33

How to cite this URL:
Chatterjee A, Bakshi G, Pal M, Kapoor A, Joshi A, Prakash G. Perioperative therapy in muscle invasive bladder cancer. Indian J Urol [serial online] 2021 [cited 2021 Jul 28];37:226-33. Available from: https://www.indianjurol.com/text.asp?2021/37/3/226/320412



   Introduction Top


Cancers of urothelial lining can arise anywhere from renal pelvicalyceal system to proximal urethra. Nearly all cases of urothelial carcinoma (UC) are urinary bladder cancers (BCs), whereas upper tract urothelial cancer accounts for 5%–10% of all urothelial malignancies. Worldwide, BC is the 10th most-common cancer, sixth most-common cancer in men, and ninth most-common cause of cancer-related deaths.[1] Radical cystectomy (RC) and bilateral pelvic lymph node dissection are the standard of care for muscle invasive BC (MIBC). While the surgical management of this cancer has remained the same for the last 3–4 decades, evidence exploring the role of perioperative therapy has been evolving. This article compiles the established and evolving evidence favoring neoadjuvant and adjuvant systemic (chemo and immuno) therapy, trends and hurdles in its utilization, and rationale and ongoing research exploring the role of adjuvant radiotherapy (RT) in urothelial cancer.


   Methodology Top


The literature search was performed for a narrative review. The electronic search included a PubMed database using MeSH terms: “bladder cancer,” “urothelial cancer,” “neoadjuvant chemotherapy,” “adjuvant chemotherapy,” “immunotherapy,” and “radiotherapy.” The inclusion criteria were randomized controlled trials, ongoing trials, systematic reviews and meta-analyses, and selected retrospective analyses related to the above terms. The exclusion criteria were articles that were not in English. From the articles retrieved in the first round of search, additional references were identified by a manual search among the cited references. Each article was critically evaluated for key results, limitations, quality of the results, interpretation of the results, and impact of the conclusions in the field.


   Drug Regimens for Neoadjuvant Chemotherapy Top


The choice of regimen differs across institutions and depends primarily on the patients' performance status and glomerular filtration rate (GFR) [Table 1]. For cisplatin-ineligible candidates, there are no data to support a recommendation for perioperative chemotherapy. Carboplatin should not be substituted for cisplatin in the perioperative setting.[2] Neoadjuvant chemotherapy (NACT) is preferred over adjuvant chemotherapy (ACT) with a higher level of evidence. Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) regimen is preferred over classic MVAC based on evidence from metastatic or advanced disease where it was better tolerated and more effective than classic MVAC.[3],[4] Gemcitabine-Cisplatin (GC) regimen is an alternative to dd-MVAC based on evidence from metastatic or locally advanced disease which showed equivalence to classic MVAC.[5],[6] The preliminary results of a recently conducted phase III trial (GETUG/AFU V05 VESPER trial) were presented in ASCO GU 2020.[7] The trial compared four cycles of GC with six cycles of dd-MVAC as perioperative chemotherapy for MIBC patients. The trial showed that pathological complete responses (pCRs) and organ-confined diseases were more frequently observed in the dd-MVAC arm (42% vs. 36% [P = 0.02]). However, it should be noted that the primary end point of this study is 3-year progression-free survival (PFS), which has not been reported yet. The toxicities were manageable in both the groups with more severe asthenia and gastrointestinal side effects in the dd-MVAC arm. The results are intriguing, but we need to wait for the final results before changing our practice.
Table 1: Chemotherapy regimens

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   Neoadjuvant Chemotherapy in Muscle Invasive Bladder Cancer Top


The risk of local recurrence and distant failures in BC is dependent on the grade and stage of the tumor. In case of MIBC, the predominant cause of distant failures is occult micrometastatic disease. NACT has advantages through treatment of occult micrometastatic disease, downstaging and making local therapy more effective, increase in pT0 rates which translates into survival benefit, assessing disease biology and response to chemotherapy, and assessing patient's tolerance to chemotherapy.

Randomized control trials

SWOG-8710 Study, JCOG-0209 Study, and International Collaboration of Trialists Study[8],[9],[10] were three multicenter phase III randomized control trials (RCTs) [Supplementary Table 1] [Additional file 1]that evaluated the role of NACT in MIBC. The SWOG-8710 Study showed that NACT was associated with overall survival (OS) and Disease-Specific Survival (DSS) benefit, and it reduced the risk of death by 33%. The JCOG-0209 Study[9] concluded that NACT is associated with OS and PFS benefit, significant pCR rates, and less lymphatic leaks and acceptable toxicity. However, the trial was terminated early due to slow accrual. The International Collaboration of Trialists Study[10] showed that NACT was associated with statistically nonsignificant improvement in 3-year OS. Patients with NACT had 15% and 13% decrease in risk of death and locoregional disease, respectively. There was statistical significant improvement in 3-year metastasis-free survival (21% decrease in risk of metastases). NACT arm had higher pCR rates with no increase postoperative complications.

Griffiths et al. published the long-term results of International Collaboration of Trialists Study[11] in 2011. The data had matured with a median follow-up of 8 years. The authors concluded that NACT was associated with 3-year and 10-year OS benefit (50% vs. 56% and 30% vs. 36%, respectively), with 16% reduction in risk of death (hazard ratio: 0.84; 95% confidence interval: 0.72–0.99; P = 0.037), 18% reduction in risk of disease (P = 0.008), 23% reduction in risk of metastases (P = 0.001), 13% reduction in local disease (P = 0.067) and 4% reduction in risk of locoregional relapse (P = 0.632), and median survival improvement of 7 months (37–44 months).

Meta-analysis

Advanced Bladder Cancer (ABC) meta-analysis collaboration group[12] analyzed 3005 individual patients' data (IPD) from 11 RCTs that compared NACT and local treatment versus local treatment alone. They found a statistically significant 5-year OS and DFS benefit with platinum-based combination NACT; 5% and 9% absolute improvement in OS (from 45% to 50%) and DFS, and 14% reduction in the risk of death with NACT. There was a statistically significant difference in the effect of chemotherapy between groups of single-agent (SA) and platinum-based combination NACT regimen favoring combination NACT (P = 0.024). The evidence was not sufficiently reliable to determine the effect of SA cisplatin on survival.

Winquist et al.[13] identified 3315 patients from 16 RCTs, and four review articles (which included three meta-analyses) on NACT for locally advanced BC. The stage of the disease varied from T1G3 to T4b (majority had T2–T4a), Nx to N2. The NACT regimens used were SA cisplatin, cisplatin-methotrexate (CM), cisplatin-doxorubicin, CMV, or MVAC, and the number of planned cycles ranged from 2 to 4. The local therapy included cystectomy, definitive RT, RT + cystectomy, or chemoradiation (CTRT). The largest among the 16 RCTs was the one published by the International Collaboration of Trialists.[10] The authors concluded that NACT was associated with statistical significant improvement in OS (P = 0.02) and PFS with 5% absolute improvement in OS (50%–55%) and 10% decrease in risk of death. Combination NACT had significant OS benefit (P = 0.006) with 13% decrease in the risk of death and 6.5% absolute improvement in OS (50%–56.5%). SA chemotherapy did not show significant survival benefit (P = 0.41). The pCR rates with combination NACT was 14%–38% while pathological “major response” (pT0, pTis, pTa/pT1) was seen in 33.9% (SA chemo) to 43.1% (MVAC) patients.


   Adjuvant Chemotherapy Top


The data on ACT are less robust; trials have been either inadequately powered, closed prematurely due to slow accrual or remained unpublished. The theoretical advantages of ACT over NACT include early definitive treatment, availability of accurate pathological staging and prognostic factors, and avoiding overtreatment to clinically over-staged patients.

Disadvantage of adjuvant chemotherapy

Only 50% of patients who are proposed to receive ACT actually receive it due to low GFR, older age, poor ECOG status, comorbidities, and refusals.

Randomized controlled trials

EORTC-30994 Intergroup Trial, Italian Trial, and Spanish (SOGUG-99/01) Trial[14],[15],[16] were three phase III RCTs evaluating the role of cisplatin-based combination chemotherapy (CCC) ACT [Supplementary Table 2][Additional file 2]. The EORTC-30994 trial showed that ACT benefits patients who have not received NACT with nonsignificant improvement in OS and significant improvement in PFS. Combining the analysis of this trial with two other trials (Italian[15] and Spanish[16] Cooperative Groups) and with the updated results of Leow et al.,[17] there was an overall benefit with ACT (P = 0.002).

Meta-analysis

Advanced BC meta-analysis[18] analyzed IPD from six trials (491 patients) which represented 90% of all patients randomized in CCC trials. All the patients were administered CCC and the choice of local treatment was cystectomy. The meta-analysis concluded that ACT was associated with 25% decrease in the risk of death (29% for CCC) (P = 0.019), 9% absolute improvement in 3-year OS (11% for CCC), 32% decrease in risk of recurrence (38% for CCC) (P = 0.004), and 12% absolute improvement in 3-year DFS. This meta-analysis had analyzed IPD and was hence able to answer some criticism of the individual trials, as all the individual trials were underpowered with major criticism against their design, analysis, and reporting.

Ruggeri et al.[19] analyzed five phase III RCTs and extracted data to analyze OS (350 patients) and DFS (273 patients). The authors found a significant OS and DFS benefit with ACT. The absolute benefit in 5-year OS and DFS was 11% and 16%, respectively. For OS and DFS benefit of one patient, the number needed to treat (NNT) was nine and six, respectively. The limitations of this meta-analysis were that trials analyzed were old, with problems in their design, accrual, and when analyzed individually, all trials had questionable conclusions. The numbers were too small to sustain ACT as a standard practice (required data of >1000 patients to be reliable). Chemotherapy given in few trials was not standard and was inferior in terms of response rates and survival. There was clinical heterogeneity among trials with respect to surgical technique, chemotherapy regimen, and patient selection (i.e., lymph node status).

The 2013 Updated Systemic Review and Meta-analysis of Randomized Trials[17] was built on the 2005 Cochrane meta-analysis,[20] which previous published as ABC meta-analysis[18] and incorporated additional RCTs published after 2005 (ACT arm: 475 patients, control arm: 470 patients). The inclusion criteria were ≥pT2, N0/N+ M0, except the RCT by Stadler et al.[21] and Studer et al.[22] which included pT1 patients also. The primary and secondary outcomes were OS and DFS, respectively. The meta-analysis concluded that ACT was associated with 23% decrease in risk of death (P = 0.049), 34% decrease in risk of recurrence (P = 0.014), and greater absolute DFS benefit in pN+ (hazard ratio HR =0.39). This updated meta-analysis had greater statistical power due to inclusion of additional trials and improved statistical methods. The flaws of this meta-analysis were small sample size across nine trials with heterogeneity among them (n = 945), methodological flaws in their trials, difference in chemotherapy regimens, eligibility criteria, DFS definitions and time to randomization across trials, and lack of information on the T stage across trials.[21],[22]

The 2017 Systematic Review and Network Meta-analysis of Randomized Clinical Trials[23] assessed the optimal ACT regimen for improving survival outcomes with data obtained from 1546 patients from 11 RCTs (1995–2015). The primary and secondary end points were PFS and OS, respectively. The authors found that ACT improved PFS and OS by 36% and 21%, respectively. Among ACT regimens, CMV and Paclitaxel-Gemcitabine-Cisplatin (PGC) had significant PFS benefit and PGC had significant better OS as compared to controls. The positive aspects of these trials were that it included only prospectively designed RCTs with consistent number and dose-specific regimens. However, it was limited by enrolling studies across several decades (1990s–2010s), resulting in different ACT regimens, different baseline characteristics (pT1-pT2/N0 to pT3-pT4/N+), and hence different survival outcomes. Some trials were underpowered (small sample size, difficult patient accrual, early termination, and statistical flaws).

The 2019 Systematic Review and Meta-Analysis of Randomized Trials[24] evaluated the role of ACT in locally advanced MIBC (pT3/pT4 and/or pN+) from four RCTs.[14],[25],[26],[27] The meta-analysis concluded that ACT was associated with significant PFS and OS benefit.There was 17% and 10% absolute increase in PFS (NNT = 5.9; P < 0.00001) and OS (NNT = 10; P = 0.0009), respectively, and 52% and 48% relative risk reduction in progression and death, respectively. However, when pT2 was included, ACT had marginal OS benefit (4% increase; NNT = 25). The strength of this meta-analysis was that it focused only on locally advanced disease, whereas it was limited by flaws in methodology and design of the trials (definitions of PFS and OS, early termination).


   Trends in Utilization of Perioperative Chemotherapy Top


Despite statistical significant survival benefit, the utilization of perioperative chemotherapy has historically been poor due to the following commonly cited reasons:[28],[29],[30]

  1. Lack of knowledge and motivation physicians and surgeons
  2. Treatment in low-volume centers and nonacademic facilities
  3. Lack of multidisciplinary tumor (MDT) clinics
  4. Patients' ineligibility for cisplatin, poor performance status (PS), advanced age.
  5. Patients declining chemotherapy
  6. Geographical location, accessibility, and socioeconomic status.


Booth et al.[28] studied the uptake of perioperative chemotherapy (NACT and ACT) and medical oncology (MO) referral patterns among 5582 MIBC patients who had undergone cystectomy. The use of NACT increased significantly from 4% (1994–2008) to 27% (2013). The use of ACT has remained constant between 19% (1994–2008) and 20% (2009–2013). There was increase in referral rates to MO during 2009–2013 as compared to 1994–2008 (32% vs. 11%) and continued to increase in recent years (44% in 2013). The proportion of referred patients treated with NACT increased significantly, from 32% (1994–1998) to 54% (2009–2013) (P < 0.001).

Duplisea et al.[29] examined the trends of utilization of NACT among 18,188 patients who underwent cystectomy from the National Cancer Database from 2006 to 14. 21.7% of patients received NACT and its use increased from 9.7% (2006) to 32.2% (2014). Reardon et al.[30] studied the temporal changes in utilization of perioperative chemotherapy from 5692 MIBC patients' data who underwent RC for ≥ cT2N0M0 between 2006 and 2010. The use of perioperative chemotherapy increased from 29.5% (2006) to 39.8% (2010) and the use of NACT significantly increased from 10.1% (2006) to 20.8% (2010). The use of ACT remained stable between 18.1% and 21.3% (P = 0.68).

Martini et al.[31] prospectively analyzed 235 patients' data from the PROMETRICS 2011 database.Only 2.2% of patients received NACT; in 69% of cases the decision was made by individual clinicians, and only 29% of cases were discussed in MDT. Sixty-nine percent of urologists declared that tumor stage cT3-T4/N1M0 was the best indication for NACT.

Data from Tata Memorial Hospital[32] showed that the utilization of NACT has increased from 27.7% (2014) to 60% (2019) (P < 0.01). These figures show that the utilization of NACT has increased than that in Western literature.


   Neoadjuvant Chemotherapy Versus Adjuvant Chemotherapy Top


Retrospective data comparing the outcomes of NACT and ACT[33] of 687 patients from single institution (1988–2009) showed that the utilization of perioperative chemotherapy was 21%. Out of 146 patients who received chemotherapy (50% NACT/ACT each) for locally advanced MIBC, CCC was given to 83.6% of patients, while remaining received carboplatin-based chemotherapy. Majority of patients on CCC received MVAC (64.8%), while remaining received GC (35.2%). The median follow-up was 12.8 months for NACT and 14 months for ACT. The primary end points analyzed were DSS and OS. The study concluded that there was no significant difference in DSS (P = 0.46) and OS (P = 0.76). In CCC group, there were no significant differences in DSS and OS. There was no significant difference in DSS (P = 0.555) and OS (P = 0.573) between NACT-MVAC and ACT-MVAC (median survival: 16 months vs. 22 months). There was significant difference in DSS between NACT-GC and ACT-GC (P = 0.049), with no significant difference in OS (median survival 11 months vs. 16 months) (P = 0.607). In carboplatin-based group, there was no significant difference between NACT and ACT with respect to DSS and OS and CCC was a significant predictor of improved OS and DSS (P ≤ 0.001). The drawbacks of this study were retrospective nature, single-center data, heterogeneous population, different chemotherapy regimen, no record of comorbidity, performance status, complication rates, recurrence, and the follow-up period being short. There are some data to suggest that ACT post-NACT and RC might lead to OS benefit in patients with pT3/T4 and/or pN+.[34] However, such strategy is not suggested to be a routine clinical practice as there are no randomized data to support the same.


   Radiotherapy Top


The 5-year survival rates post-RC + PLND for pT2 and pT3 diseases are 60% and 10%–50%, respectively.[35] Pelvic recurrences in locally advanced MIBC range from 32% to 58%.[8],[11] Locoregional recurrence (LRR) is associated with metastasis and locoregional control improves oncologic end points.[36],[37] Salvage treatment is rarely successful with a median survival of only 9 months.[36],[38] Perioperative chemotherapy does not reduce LRR.[39] Factors affecting LRR are pT3, N+, PLND, number of nodes dissected, positive surgical margin, hospital volume, and risk groups.[39],[40] The University of Pennsylvania developed a risk stratification model to predict LRR[39] and subsequently has been validated in several studies.[41],[42],[43],[44] These facts suggest a potential role of adjuvant RT in high-risk MIBC patients. The data on adjuvant RT are not yet robust and await the results from ongoing trials (NRG, GETUG-AFU, Tata Memorial Hospital, NCRI, University of Ghent, and NCI Cairo). At present, the NCCN guidelines recommends adjuvant RT for ≥pT3 and N+ disease.[2]

Number of RCTs conducted by Zaghloul et al.[45],[46],[47],[48],[49] has evaluated the role of postoperative RT (PORT) for MIBC or locally advanced disease [Supplementary Table 3][Additional file 3]. Studies have concluded that in high-risk patients, PORT or adjuvant CTRT reduces LR and DFS without significant improvement in OS. However, these studies included majority of squamous carcinoma patients and their applicability to UC (the most common type worldwide) needs further study. A retrospective multicenter study for adjuvant RT in MIBC was conducted by Orré et al.[50] [Supplementary Table 3]F. The study concluded that PORT is feasible in high-risk MIBC with oncological benefits and acceptable toxicities, and neobladders can tolerate moderate doses of RT without significant morbidity.

In a systematic review and meta-analysis on RT with RC, McAlpine et al.[51] evaluated the efficacy and safety of RT as neoadjuvant and adjuvant modality in MIBC patients undergoing RC. The study concluded that there was statistically nonsignificant improvement in OS with NART and there was improved OS with PORT in locally-advanced disease. This article had numerous limitations at individual study level and review level which is beyond the scope of our discussion.

Adjuvant RT to bladder bed and nodal basins renders the bowel at risk of radiation-induced injury, a condition called pelvic radiation disease (PRD) which encompasses radiation enteritis and radiation proctitis. PRD can present in three clinical phases: acute, chronic, and delayed (latent). PRD increases the risk of bowel wall strictures, adhesions, fissures, bleeding, and perforation. PRD may also cause acute or subacute small bowel obstruction. Concurrent chemotherapy can delay the reparative process, thus aggravating the condition.[52]


   Immunotherapy in Bladder Cancer Top


Programmed cell death-1 protein (PD-1)/PD-1 ligand checkpoint inhibitors have promising role in treating locally advanced and metastatic UC as the first-line therapy and also have potential in for neoadjuvant setting.[53],[54],[55],[56] Further clinical trials with longer follow-up are required to define their role as first-line therapy in cisplatin-eligible patients. Based on level 1 evidence, atezolizumab and pembrolizumab have been approved by the US Food and Drug Administration for locally advanced and metastatic UC patients who are cisplatin ineligible.[57]

Neoadjuvant immunotherapy

Two phase II studies, PURE-01[58] and ABACUS,[59] [Table 2] evaluated the role immunotherapy in neoadjuvant setting. ABACUS study[59] is yet to complete with final results; however, the clinical efficacy and biomarker analysis have been published.[60]
Table 2: ABACUS and PURE-01 studies

Click here to view


Adjuvant immunotherapy

Adjuvant immunotherapy is experimental and is not indicated outside of a clinical trial setting. Based on the results in patients with advanced disease, three phase III trials are in progress; Atezolizumab versus observation (NCT02450331), Nivolumab versus placebo (NCT02632409), and Pembrolizumab versus observation (NCT03244384).

The current international guidelines recommendations are summarized in [Table 3].
Table 3: International Guideline Recommendations

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   Conclusions Top


NACT is strongly recommended for cT2-T4aN0M0 disease with cisplatin-based combination chemotherapy regimens. ACT is advisable to pT3/T4 and/or pN+ disease if NACT has not been given. Adjuvant RT can be considered in pT3/T4 and/or pN+ and/or positive margin patients. Immunotherapy should only be used under trial setting and awaits further results.

Financial support and sponsorship: Nil.

Conflicts of interest: There are no conflicts of interest.



[62]

 
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    Abstract
   Introduction
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    Neoadjuvant Chem...
    Adjuvant Chemoth...
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    Neoadjuvant Chem...
   Radiotherapy
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