Mahir Maruf, MD Disclosures: Nothing to Disclose and Piyush K. Agarwal, MD Disclosures: Nothing to Disclose Urologic Oncology Branch National Cancer Institute — Chris M. Gonzalez, MD, MBA Disclosures: Nothing to Disclose Medical Oncology Branch Center for Cancer Research   National Institutes of Health Bethesda, Maryland * This AUA Update addresses the Core Curriculum topic of Oncology - Adult: Bladder Neoplasms and the American Board of Urology Module A: Oncology, Urinary Diversion and Adrenal

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Learning Objective: At the conclusion of this continuing medical education activity, the participant will be able to weigh the risks and benefits of perioperative chemotherapeutic regimens, describe the evolution of perioperative chemotherapy, and discuss the contemporary role of neoadjuvant and adjuvant systemic therapy for the management of muscle invasive bladder cancer.

Key Words:  urinary bladder neoplasms; neoadjuvant therapy; chemotherapy, adjuvant; drug therapy; perioperative care

INTRODUCTION

Bladder cancer is the fourth most common non-cutaneous malignancy in the United States and was the eighth leading cause of estimated cancer specific deaths in 2016.¹ Despite surgical management for muscle invasive bladder cancer, 5-year disease-free survival and overall survival rates are 68% and 66%, respectively, and significantly lower for patients with positive lymph nodes.² Following cystectomy, distant recurrences are noted more frequently than local recurrences (29% to 75% vs 9% to 25%, respectively), suggesting the presence of micrometastases at the time of diagnosis.^2,3,4,5 This finding suggests a potential role for systemic therapy in the initial management of MIBC.

Neoadjuvant chemotherapy and adjuvant perioperative chemotherapy have indications and obstacles. Historically, adjuvant chemotherapy has been used more frequently than neoadjuvant chemotherapy. According to the National Cancer Database, between 1998 and 2003 NAC was administered to 1.2% of patients with stage 3 bladder cancer, while AC was used in 10.4% of cases.⁶ Since then, Level 1 evidence for NAC has emerged from randomized clinical trials. From 2003 to 2007 the use of perioperative chemotherapy surpassed 30%, primarily due to an increase in NAC.⁷ Still, neoadjuvant cisplatin based chemotherapies remain underused.^8,9 MIBC is a curable disease, and the objective of systemic chemotherapy is to provide a survival benefit to those at high risk for disease recurrence while minimizing associated toxicities. In this Update we discuss evidence in support of the use of NAC and AC.

Urothelial carcinoma of the bladder is particularly chemosensitive. The chemotherapy regimen of methotrexate, vinblastine, doxorubicin and cisplatin has been used to treat advanced urothelial carcinoma since the 1980s.^10,11 Alternative regimens, such as gemcitabine and cisplatin and dose-dense MVAC, have demonstrated comparable efficacy to MVAC and an improved toxicity profile for patients with metastatic urothelial carcinoma, providing a rationale for the use of these cisplatin based combinations in the perioperative setting.^12,13,14 There is a growing body of evidence in support of perioperative chemotherapy, particularly NAC, and yet its use remains relatively uncommon in clinical practice. Clinical decision making is complex and individualized, and many reasons have been posited for clinician hesitancy to adopt this approach.^6,15 For example, toxicity and tolerability are major considerations in the use of systemic chemotherapy. MVAC toxicities include grade 4 neutropenia and grade 3 gastrointestinal toxicities, which may delay or disqualify the performance of cystectomy.¹⁶ Alternatives to MVAC, such as GC and ddMVAC, have demonstrated considerably lower toxicity profiles,^12,17 and clinical trials of NAC for MIBC have indicated no delays in cystectomy performance due to chemotherapy toxicity.¹⁸

NEOADJUVANT CHEMOTHERAPY

Randomized clinical trials. The effect of NAC of various agents and combinations has been assessed in numerous randomized trials, resulting in modest to no survival benefit. The Nordic I and Nordic II trials of multi-agent cisplatin based NAC in patients with MIBC showed no survival benefit compared to control patients treated with either low dose radiation before cystectomy or cystectomy alone.^19,20 However, a pooled analysis of both trials demonstrated a statistically significant 5-year survival benefit of 56% favoring NAC (95% CI 50.1%–61.3%) vs 48% (95% CI 42.3%–53.9%), corresponding to an 8% absolute risk reduction and a 20% reduction in the relative risk of death.²¹ Overall 145 of 306 deaths occurred in the experimental arm vs 173 of 314 in the control arm.

Two large randomized landmark studies of cisplatin based chemotherapy combinations, conducted by the EORTC (European Organisation for Research and Treatment of Cancer) and the MRC (Medical Research Council), and SWOG (formerly the Southwest Oncology Group), demonstrated the benefit of NAC for the treatment of MIBC.^18,22

The EORTC and MRC trial randomized 976 patients with T2 grade 3, T3-T4N0M0 bladder cancer to 3 cycles of neoadjuvant cisplatin, methotrexate and vinblastine vs no chemotherapy before local radical therapy (physician choice) consisting of either radical cystectomy (50%), radiation therapy (43%) or radiation therapy plus cystectomy (8%).²² When initially published, the study showed a non-statistically significant overall 3-year survival benefit of 5.5% for patients in the neoadjuvant arm (HR 0.85, 95% CI 0.71–1.02, p=0.075). A follow-up study showed a statistically significant 10-year overall survival benefit of 6% (30% vs 36%) for neoadjuvant CMV (HR 0.84, 95% CI 0.72–0.99, p=0.037).23 Chemotherapy associated mortality was 1% and surgical mortality was 3.7%. Pathological complete response, defined as pT0 after cystectomy, was observed in 32.5% of patients treated with neoadjuvant CMV and radical cystectomy compared to a 12.3% pCR rate in patients undergoing cystectomy alone. The 2 important considerations of this trial are 1) CMV is no longer used and has not been compared to MVAC in a prospective trial, and 2) the efficacy of definitive therapy with radical cystectomy vs radiation therapy has not been compared in prospective randomized trials.

In SWOG 8710, another prospective trial, 317 patients with T2–T4aN0M0 bladder cancer accrued in 11 years were randomized to receive either cystectomy alone or 3 cycles of MVAC prior to cystectomy.¹⁸ Patients were stratified by age (younger or older than 65 years) as well as clinical stage (T2 disease and T3/T4a disease), and the rates of survival were compared between the 2 groups as well as the rates of pathological response after cystectomy. The trial was designed to identify a 1-sided significance, in other words the combination of neoadjuvant MVAC with cystectomy must demonstrate superior outcomes to cystectomy alone for the results to affect the standard of care. The median survival of patients receiving neoadjuvant MVAC was 77 months (95% CI 55–104) vs 46 months for patients treated with cystectomy alone (95% CI 25–60). Neoadjuvant chemotherapy trended towards conferring a 5-year overall survival benefit (57% vs 43%, 2-sided p=0.06). The neoadjuvant MVAC group had a higher pCR rate vs cystectomy group (38% vs 15%, p <0.001). There was a high rate of NAC related toxicities, with 33% of patients experiencing grade 4 granulocytopenia and 17% experiencing grade 3 gastrointestinal toxicities (nausea, vomiting, stomatitis, diarrhea or constipation). No deaths were attributable to NAC.

Meta-analysis of neoadjuvant trials. Since many trials have produced insufficient evidence for the use of NAC due to small sample sizes, early study termination or inconclusive survival outcomes, meta-analyses have been used to combine and interpret the data.²³ The Advanced Bladder Cancer Meta-analysis Collaboration reported an individual patient level meta-analysis conducted by the Medical Research Council Clinical Trials Unit. This study, originally published in 2003,²⁴ was updated to include the results of the SWOG 8710 study and included 3005 patients from 11 randomized trials.^{18,21,22,25,26,27,28} The overall survival benefit of NAC (HR 0.89, 95% CI 0.81–0.98, p=0.022) was primarily driven by the subset of patients receiving multi-agent cisplatin based therapy, which provided a 14% reduction in risk of death (HR 0.86, 95% CI 0.77–0.95, p=0.003). This therapy yielded a 5-year overall survival benefit of 5% (95% CI 2–9) as overall survival improved from 45% to 50%. No single chemotherapy regimen used in the multi-agent trials demonstrated superiority. Furthermore, neither radical cystectomy alone, radiation therapy alone nor a combination of radiation therapy and radical cystectomy had superior results. Single agent platinum based NAC did not provide a survival benefit.

Notwithstanding the Level 1 evidence of survival benefit conferred by NAC, urologists rarely refer patients for NAC, primarily because of the low absolute benefit of a 5% increase in overall survival, toxicity and the delay in time to radical cystectomy.6 They are hesitant to recommend NAC because they believe the small survival benefit may not justify toxicities associated with systemic therapy.30 Patients who consult with a medical oncologist at initial diagnosis are more likely to accept NAC before cystectomy. In recent series from academic centers with established expertise in MIBC, approximately 60% of patients are currently receiving NAC. In the EORTC/MRC and SWOG 8710 trials eligibility included creatinine clearance >50 mL/minute, and the median ages of the patients included in these trials were 64 and 63 years, respectively. However, retrospective studies have revealed similar clinical benefits of NAC in elderly vs younger patients with MIBC.²⁹ Other retrospective data suggest that a lower cT stage (

Alternative neoadjuvant agents. To date, there have been no prospective outcome comparisons of the most commonly used neoadjuvant chemotherapy regimens in the U. S. today. ddMVAC has been studied in patients with advanced and metastatic disease, and has demonstrated improved efficacy with decreased toxicity compared to a standard MVAC regimen. 14 Two single-arm studies explored the feasibility of neoadjuvant ddMVAC in patients with MIBC. In the first study 39 patients with either T2–T4N0 (54%) or T2–T4N1 (43%) disease were enrolled in a phase II trial and received 4, 2-week cycles of ddMVAC before radical cystectomy.32 Overall, 37 patients (95%) completed all 4 cycles of NAC, and high grade chemotherapy related toxicities were relatively low (10%). A pCR was observed in 26% of patients. In the second phase II study 44 patients with either T2–T4a (93%) or T2–T4N1 (7%) disease were accrued to undergo 3 cycles of ddMVAC followed by radical cystectomy.33 Ultimately, 43 patients underwent cystectomy. Toxicities were primarily grade 1 to 2 (82%). A pCR was observed in 38% of patients.

The GC combination has been prospectively studied in patients with metastatic bladder cancer as an alternative to MVAC, and a lower toxicity profile was demonstrated in a noninferiority study.¹² In a large multicenter retrospective study GC was compared to MVAC in 935 patients with cT2–T4a MIBC. Patients were given ≥3 cycles of NAC (MVAC, GC or other regimens) prior to radical cystectomy.³⁰ The pCR rate was 23.9% for 602 patients receiving neoadjuvant GC and 24.5% for 183 patients receiving neoadjuvant MVAC, while the pCR of neoadjuvant agents other than MVAC or GC was significantly lower (15.3%).

Cisplatin based therapies have also been evaluated in combination with novel biological agents in phase II clinical trials. Bevacizumab, an antiangiogenic monoclonal antibody, has shown feasibility and pathological response in combination with ddMVAC.³¹Sunitinib has also been combined with cisplatin based therapies but trial accrual was incomplete and pCR was low.³²

Cisplatin ineligible patients. A major obstacle for oncologists administering NAC are patients who are ineligible for cisplatin based therapies due to poor renal function, hearing deficit or heart failure. In modern series approximately 40% of patients with MIBC are ineligible for cisplatin. There is a paucity of data regarding the use of chemotherapeutic agents in patients with MIBC and renal insufficiency. It is important to rule out a mechanical cause of the renal insufficiency, such as an obstructed ureteral orifice caused by tumor location. Such cases may be managed with a ureteral stent or percutaneous nephrostomy tubes to relieve the obstruction. Should renal function normalize, cisplatin based NAC may be reconsidered. However, renal insufficiency may be associated with age, as 12.6% of patients 60 to 69 years old and 47.3% of healthy adults 70 years old or older have a creatinine clearance <50 mL/minute.³³

Given its reduced renal toxicity, carboplatin may be an alternative to cisplatin, although outcome data are limited. In retrospective studies carboplatin has been shown to have similar pCR rates to cisplatin in combination therapy for patients with advanced bladder cancer.^34,35 A multicenter, phase II, 2-arm study of neoadjuvant paclitaxel, carboplatin and gemcitabine was performed.³⁶ In the first arm 31 patients with T2–T3 bladder cancer and hydronephrosis were administered 3 cycles before radical cystectomy. In the second arm 37 patients with T4 disease or any N1-3 disease were administered 3 cycles and evaluated for surgical eligibility. Of 22 patients in arm 1 who were available for pathological evaluation 7 (32%) had a pCR after cystectomy. Of the 29 patients in arm 2 who were available for evaluation after paclitaxel, carboplatin and gemcitabine therapy 21 underwent radical cystectomy and a pCR was observed in 5 (24%). Grade 3 to 4 myelosuppression was common, and 7 patients ultimately died on study. As carboplatin regimens have yet to provide an activity level comparable to other available regimens, its role in NAC currently remains unclear.

ADJUVANT CHEMOTHERAPY

As NAC has shown a benefit for patients with MIBC, adjuvant chemotherapy has also been investigated as a potential systemic option. Most of the trials evaluating AC have been underpowered and inconclusive.³⁷ In addition, clinicians have found that up to 30% of patients may be ineligible for AC due to postoperative complications or worsened renal function.³⁸ Six prospective trials, 4 of which were terminated early, accrued between 49 and 108 patients to evaluate the benefit of cisplatin based multi-agent AC in patients with MIBC.^{39,40,41,42,43,44}

In 2005 the Advanced Bladder Cancer Meta-analysis Collaboration conducted an individual patient level analysis of 491 patients in 6 clinical trials and determined a 25% reduction in relative risk of death for patients receiving AC after cystectomy compared to those undergoing cystectomy only (HR 0.75, 95% CI 0.60–0.96, p=0.019). The meta-analysis is still insufficiently powered by the number of patients and the number of deaths to make conclusive decisions.

Since then, 4 additional trials have reported results of cisplatin based multi-agent AC.^45,46,47,48 Between 58 and 284 patients were accrued and randomized to AC with cystectomy or cystectomy alone. Notably, a large proportion of patients in each trial did not complete all the cycles of AC, primarily due to chemotherapy related toxicities. The outcomes of administering 2 cycles of cisplatin based NAC have yet to be thoroughly investigated, as most studies demonstrating benefit administered at least 3 cycles of therapy. A more recent meta-analysis included the 6 trials from the 2005 advanced bladder cancer meta-analysis and 3 newer trials.⁴⁹ This analysis demonstrated an overall 23% reduction in relative risk of death (HR 0.77, 95% CI 0.59–0.99, p=0.049) and a benefit in disease-free survival (HR 0.66, 95% CI 0.45–0.91, p=0.14).

Recently, in the largest randomized phase III EORTC trial to date AC immediately after radical cystectomy in patients with pT3–T4 disease and/or node positive bladder cancer was compared to deferred chemotherapy at the time of clinical relapse of disease.⁴⁸ There was statistically significant improvement in median progression-free survival in the immediate AC group vs the deferred group (3.11 vs 0.99 years, p <0.0001). However, the results are tempered by the fact that the trial failed its accrual goal and closed early. Furthermore, there was no impact on overall survival.

Given the limited prospective data, retrospective studies have been performed to evaluate AC. In one of the larger studies data were pooled from 3947 patients, of whom 932 (23.6%) received AC following radical cystectomy.⁵⁰ On a multivariate Cox proportional hazards model AC conferred an improved overall survival (HR 0.83, 95% CI 0.72–0.97, p=0.017). The authors hypothesized that the benefit of AC may depend on disease risk, and thus determined the most significant disease specific survival benefit (HR 0.75, 95% CI 0.62–0.90, p=0.002) in patients within the highest risk quantile, defined by a predicted 33% 5-year disease-free survival.

The largest retrospective study included 5653 radical cystectomy cases from the National Cancer Database with T3–4 and/or node positive disease, of which 23% received AC.⁵¹ A 5-year overall survival benefit was noted in patients who received AC vs the observation group (37% vs 29%, HR 0.70, 95% CI 0.64–0.76), with a propensity score based analysis of patient, facility and tumor characteristics. Although propensity score based analysis may reduce the influence of observed confounders, it does not obviate the effect of unobserved confounders, such as patient selection. Retrospective studies, by their design, are subject to patient selection biases and, therefore, are not a replacement for randomized clinical trials.

COMPARISON OF ADJUVANT AND NEOADJUVANT THERAPY

Treating patients with MIBC remains a challenge, and choosing between NAC and AC is difficult. Both therapies have comparable efficacy but data on AC are limited, while there is Level 1 evidence for NAC. Hence, there are multiple treatment paradigms, each with its own considerations. The major phase III trials evaluating perioperative cisplatin based chemotherapy in patients with MIBC are summarized in the table.

All patients with MIBC who are eligible for cisplatin based chemotherapy should be considered for NAC.⁵² Cumulative experience indicates that chemotherapy is better tolerated before, rather than after, surgery, and so patients are more likely to complete NAC than AC. A prospective trial comparing 5 rounds of adjuvant MVAC to 2 cycles of neoadjuvant MVAC with 3 cycles of adjuvant MVAC demonstrated no difference in survival between the groups of patients.⁵³ Of the 70 patients in the NAC group 68 (97%) completed at least 2 cycles of MVAC, whereas 54 of 70 (77%) patients in the AC group received ≥2 MVAC cycles, suggesting that NAC may be more viable than AC. At MD Anderson Cancer Center only patients with high risk features are selected for NAC, thus sparing patients with low risk disease the morbidities associated with systemic therapy.⁵⁴ Patients with hydronephrosis, a palpable mass found on examination under anesthesia (cT3b), invasion to local viscera (cT4a), evidence of lymphovascular invasion or micropapillary and/or small cell variant histology are given NAC, while those without these features undergo surgery. Although the high risk cases did exhibit lower overall survival, 50% of those without these features were up staged to high risk disease on final pathology. Thus, identifying patients with high risk disease is particularly challenging, as evident by the frequent pathological up staging of low risk disease after surgery.

Histological variants of urothelial carcinoma present with distinctly aggressive behaviors and varying responses to systemic therapy. Prospective evidence for the use of NAC for variant histologies, such as sarcomatoid and micropapillary urothelial carcinoma, is sparse and controversial. However, small cell bladder cancer is exceptionally chemosensitive, with response rates to cisplatin based chemotherapy >90% for metastatic disease and >75% for muscle invasive disease.⁵⁵ These outcomes make NAC the standard of care.

FUTURE DIRECTIONS

Future perioperative chemotherapy regimens will likely benefit from developments in personalized and precision medicine. NAC may be particularly suitable in this paradigm since pCR rates correlate with survival outcomes. Profiling cancer subtypes may provide information on chemotherapeutic sensitivity, thus allowing for better patient selection. For example, mutations in p53, a tumor suppressor gene, have been evaluated as a potential marker for responsiveness.^45,56,57 Yet the prognostic value of p53 mutations in perioperative chemotherapy is inconsistent, and further research will be required to elucidate the usefulness of p53 status in this setting.

Open/Close Table

Molecular subtypes of bladder cancer, as determined from The Cancer Genome Atlas data, have been explored as potential markers of response to NAC. In a phase II study neoadjuvant ddMVAC with bevacizumab was administered to 60 patients.⁵⁹ Gene expression profiling was done with transurethral resection of the bladder tumor or cystectomy specimens. Patients with a basal subtype of tumors had improved 5-year overall survival compared to those with a p53 or luminal subtype (91% vs 73% vs 36%, respectively, p=0.015).

In a retrospective study mutations in DNA repair genes (ATM, RB1 and FANCC) were predictive of pathological response in patients receiving neoadjuvant cisplatin based therapy.⁶⁰ Other gene mutations, such as in ERBB2 and ERCC2, have also shown an association with pathological response to cisplatin based NAC.^61,62 Similarly, deleterious alterations in DNA damage response genes have been reported to show a correlation with pathological response in patients treated with neoadjuvant dose-dense GC before cystectomy.⁶³

Co-eXpression ExtrapolatioN (COXEN) is a gene expression algorithm that uses in vivo and in vitro molecular profiles of drug responsiveness in 60 different human cancer cell lines from the National Cancer Institute to evaluate the sensitivity of those cell lines to chemotherapeutic drugs.⁶⁴ The gene expression biomarkers developed by the COXEN model have retrospectively been shown to predict the response of patients treated with neoadjuvant MVAC.⁶⁵ SWOG is currently conducting a prospective trial testing the ability of COXEN to predict the efficacy of cisplatin based NAC in patients with MIBC randomized to receive GC vs MVAC. When completed, this will be the first prospective randomized trial testing these 2 regimens in this setting. Positive results from this study would allow physicians to selectively treat patients deemed chemotherapy sensitive with GC or MVAC.

In the future immunotherapy may play a role in perioperative therapy. Checkpoint inhibitors, such as atezolizumab,⁶⁶ pembrolizumab,⁶⁷ durvalumab,⁶⁸ nivolumab⁶⁹ and avelumab,⁷⁰ have demonstrated activity in patients with advanced urothelial carcinoma. Atezolizumab⁷¹ and pembrolizumab⁷² have shown activity in first line treatment of cisplatin ineligible patients with urothelial carcinoma. Several large randomized clinical trials are ongoing (atezolizumab and nivolizumab) and in development (pembrolizumab) using checkpoint inhibitors in the adjuvant setting and in combination with chemotherapy in the neoadjuvant setting. A recently reported randomized trial of pembrolizumab vs chemotherapy as second line treatment in patients with metastatic urothelial carcinoma showed an overall survival benefit for pembrolizumab, supporting the concept of moving immunotherapy forward to earlier stages of bladder cancer, either as monotherapy or in combination with cisplatin based chemotherapy.⁷³ As with any novel agents, Level 1 evidence from phase III trials will be required to alter existing treatment strategies for MIBC.

CONCLUSIONS

neoadjuvant MVAC and CMV demonstrate Level 1 evidence of overall survival benefit, GC is the most widely used NAC regimen. AC is administered predominantly to high risk patients but its actual benefit is open to question. Improvements in perioperative chemotherapy may hinge on genetic predictive biomarkers and the combination of immunotherapy with checkpoint inhibitors, which have shown promise in advanced urothelial carcinoma.

REFERENCES

AUA Reference

1. Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin 2016; 66: 7.
2. Stein JP, Lieskovsky G, Cote R et al: Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001; 19: 666.
3. Apolo AB, Vogelzang NJ and Theodorescu D: New and promising strategies in the management of bladder cancer. Am Soc Clin Oncol Educ Book 2015: 105.
4. Quek ML, Stein JP, Clark PE et al: Natural history of surgically treated bladder carcinoma with extravesical tumor extension. Cancer 2003; 98: 955.
5. Raza SJ, Wilson T, Peabody JO et al: Long-term oncologic outcomes following robot-assisted radical cystectomy: results from the International Robotic Cystectomy Consortium. Eur Urol 2015; 68: 721.
6.   David KA, Milowsky MI, Ritchey J et al: Low incidence of perioperative chemotherapy for stage III bladder cancer 1998 to 2003: a report from the National Cancer Data Base. J Urol 2007; 178: 451.
7.   Fedeli U, Fedewa SA and Ward EM: Treatment of muscle invasive bladder cancer: evidence from the National Cancer Database, 2003 to 2007. J Urol 2011; 185: 72.
8. Raj GV, Karavadia S, Schlomer B et al: Contemporary use of perioperative cisplatin-based chemotherapy in patients with muscle-invasive bladder cancer. Cancer 2011; 117: 276.
9. Apolo AB, Kim JW, Bochner BH et al: Examining the management of muscle-invasive bladder cancer by medical oncologists in the United States. Urol Oncol 2014; 32: 637.
10. Sternberg CN, Yagoda A, Scher HI et al: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer 1989; 64: 2448.
11.   Sternberg CN, Yagoda A, Scher HI et al: M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol 1988; 139: 461.
12. von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18:3068-77, 2000
13. Schultz PK, Herr HW, Zhang ZF et al: Neoadjuvant chemotherapy for invasive bladder cancer: prognostic factors for survival of patients treated with M-VAC with 5-year follow-up. J Clin Oncol 1994; 12: 1394.
14. Sternberg CN, de Mulder PH, Schornagel JH et al: Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 2001; 19: 2638.
15. Donat SM: Integrating perioperative chemotherapy into the treatment of muscle-invasive bladder cancer: strategy versus reality. J Natl Compr Canc Netw 2009; 7: 40.
16. Sonpavde G and Sternberg CN: Neoadjuvant systemic therapy for urological malignancies. BJU Int 2010; 106: 6.
17. Sternberg CN, de Mulder P, Schornagel JH et al: Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 2006; 42: 50.
18. Grossman HB, Natale RB, Tangen CM et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349: 859.
19.   Malmstrom PU, Rintala E, Wahlqvist R et al: Five-year followup of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. J Urol 1996; 155: 1903.
20. Sherif A, Rintala E, Mestad O et al: Neoadjuvant cisplatinmethotrexate chemotherapy for invasive bladder cancer—Nordic cystectomy trial 2. Scand J Urol Nephrol 2002; 36: 419.
21. Sherif A, Holmberg L, Rintala E et al: Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies. Eur Urol 2004; 45: 297.
22. International Collaboration of Trialists: Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. International collaboration of trialists. Lancet 1999; 354: 533.
23. Sylvester R and Sternberg C: The role of adjuvant combination chemotherapy after cystectomy in locally advanced bladder cancer: what we do not know and why. Ann Oncol 2000; 11: 851.
24. Advanced Bladder Cancer Meta-analysis Collaboration: Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 2003; 361: 1927.
25. Wallace DM, Raghavan D, Kelly KA et al: Neo-adjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder. Br J Urol 1991; 67: 608.
26.   Martinez-Pineiro JA, Gonzalez Martin M, Arocena F et al: Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. J Urol 1995; 153: 964.
27.   Bassi P, Pappagallo G, Sperandio P et al: Neoadjuvant M-VAC chemotherapy of invasive bladder cancer: results of a multicenter phase III trial. J Urol, suppl., 1999; 161: 264A, abstract 1021.
28. Sengelov L, von der Maase H, Lundbeck F et al: Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours. Acta Oncol 2002; 41: 447.
29. Chau C, Wheater M, Geldart T et al: Clinical outcomes following neoadjuvant cisplatin-based chemotherapy for bladder cancer in elderly compared with younger patients. Eur J Cancer Care (Engl) 2015; 24: 155.
30. Zargar H, Espiritu PN, Fairey AS et al: Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol 2015; 67: 241.
31. Mitra N, Monk J, Pohar K et al: Early outcomes with neoadjuvant high-dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin (HD-MVAC) or gemcitabine and cisplatin (GC) in muscle-invasive urothelial carcinoma of the bladder: a single-institution experience. J Clin Oncol, suppl., 2011; 29: abstract e15163.
32. Balar A, Iyer G, Apolo A et al: Phase II trial of neoadjuvant gemcitabine (G) and cisplatin (C) with sunitinib in patients (pts) with muscle-invasive bladder cancer (MIBC). J Clin Oncol, suppl., 2012; 30: abstract 4581.
33. Duncan L, Heathcote, J, Djurdjev O et al: Screening for renal disease using serum creatinine: who are we missing? Nephrol Dial Transplant 2001; 16: 1042.
34.   Mertens LS, Meijer RP, Kerst JM et al: Carboplatin based induction chemotherapy for nonorgan confined bladder cancer—a reasonable alternative for cisplatin unfit patients? J Urol 2012; 188: 1108.
35. Hussain M, Vaishampayan U, Du W et al: Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. J Clin Oncol 2001; 19: 2527.
36.   Smith DC, Mackler NJ, Dunn RL et al: Phase II trial of paclitaxel, carboplatin and gemcitabine in patients with locally advanced carcinoma of the bladder. J Urol 2008; 180: 2384.
37. Sternberg CN, Bellmunt J, Sonpavde G et al: ICUD-EAU International Consultation on Bladder Cancer 2012: chemotherapy for urothelial carcinoma-neoadjuvant and adjuvant settings. Eur Urol 2013; 63: 58.
38. Donat SM, Shabsigh A, Savage C et al: Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience. Eur Urol 2009; 55: 177.
39. Bono AV, Benvenuti C, Reali L et al: Adjuvant chemotherapy in advanced bladder cancer. Italian Uro-Oncologic Cooperative Group. Prog Clin Biol Res 1989; 303: 533.
40.   Freiha F, Reese J and Torti FM: A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol 1996; 155: 495.
41. Otto T, Goebell PJ and Rubben H: Perioperative chemotherapy in advanced bladder cancer—part II: adjuvant treatment. Onkologie 2003; 26: 484.
42.   Skinner DG, Daniels JR, Russell CA et al: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 1991; 145: 459.
43. Lehmann J, Franzaring L, Thuroff J et al: Complete longterm survival data from a trial of adjuvant chemotherapy vs control after radical cystectomy for locally advanced bladder cancer. BJU Int 2006; 97: 42.
44.   Studer UE, Bacchi M, Biedermann C et al: Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: results of a prospective randomized trial. J Urol 1994; 152: 81.
45. Stadler WM, Lerner SP, Groshen S et al: Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. J Clin Oncol 2011; 29: 3443.
46. Cognetti F, Ruggeri EM, Felici A et al: Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Ann Oncol 2012; 23: 695.
47. Paz-Ares L, Solsona E, Esteban E et al: Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. J Clin Oncol, suppl., 2010; 28: 18s, abstract LBA4518.
48. Sternberg CN, Skoneczna I, Kerst JM et al: Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol 2015; 16: 76.
49. Leow JJ, Martin-Doyle W, Rajagopal PS et al: Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol 2014; 66: 42.
50. Svatek RS, Shariat SF, Lasky RE et al: The effectiveness of off-protocol adjuvant chemotherapy for patients with urothelial carcinoma of the urinary bladder. Clin Cancer Res 2010; 16: 4461.
51. Galsky MD, Stensland KD, Moshier E et al: Effectiveness of adjuvant chemotherapy for locally advanced bladder cancer. J Clin Oncol 2016; 34: 825.
52. Bajorin DF and Herr HW: Kuhn’s paradigms: are those closest to treating bladder cancer the last to appreciate the paradigm shift? J Clin Oncol 2011; 29: 2135.
53. Millikan R, Dinney C, Swanson D et al: Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. J Clin Oncol 2001; 19: 4005.
54.   Culp SH, Dickstein RJ, Grossman HB et al: Refining patient selection for neoadjuvant chemotherapy before radical cystectomy. J Urol 2014; 191: 40.
55. Siefker-Radtke AO, Kamat AM, Grossman HB et al: Phase II clinical trial of neoadjuvant alternating doublet chemotherapy with ifosfamide/doxorubicin and etoposide/cisplatin in small-cell urothelial cancer. J Clin Oncol 2009; 27: 2592.
56.   Herr HW, Bajorin DF, Scher, HI et al: Can p53 help select patients with invasive bladder cancer for bladder preservation? J Urol 1999; 161: 20.
57. Tsuji M, Kojima K, Murakami Y et al: Prognostic value of Ki-67 antigen and p53 protein in urinary bladder cancer: immunohistochemical analysis of radical cystectomy specimens. Br J Urol 1997; 79: 367.
58. Griffiths G, Hall R, Sylvester R et al: International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2011; 29: 2171.
59. McConkey DJ, Choi W, Shen Y et al: A prognostic gene expression signature in the molecular classification of chemotherapy-naive urothelial cancer is predictive of clinical outcomes from neoadjuvant chemotherapy: a phase 2 trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with bevacizumab in urothelial cancer. Eur Urol 2016; 69: 855.
60. Plimack ER, Dunbrack RL, Brennan TA et al: Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Eur Urol 2015; 68: 959.
61. Groenendijk FH, de Jong J, Fransen van de Putte EE et al: ERBB2 mutations characterize a subgroup of muscleinvasive bladder cancers with excellent response to neoadjuvant chemotherapy. Eur Urol 2016; 69: 384.
62. Van Allen EM, Mouw KW, Kim P et al: Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscleinvasive urothelial carcinoma. Cancer Discov 2014; 4: 1140.
63. Iyer G, Balar AV, Milowsky MI et al: Correlation of DNA damage response (DDR) gene alterations with response to neoadjuvant (neo) dose-dense gemcitabine and cisplatin (ddGC) in urothelial carcinoma (UC). J Clin Oncol, suppl., 2016; 34: abstract 5011.
64. Lee JK, Havaleshko DM, Cho H et al: A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery. Proc Natl Acad Sci USA 2007; 104: 13086.
65. Williams PD, Cheon S, Havaleshko DM et al: Concordant gene expression signatures predict clinical outcomes of cancer patients undergoing systemic therapy. Cancer Res 2009; 69: 8302.
66. Rosenberg JE, Hoffman-Censits J, Powles T et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387: 1909.
67. Plimack ER, Bellmunt J, Gupta S et al: Pembrolizumab (MK-3475) for advanced urothelial cancer: updated results and biomarker analysis from KEYNOTE-012. J Clin Oncol, suppl., 2015; 33: abstract 4502.
68. Massard C, Gordon MS, Sharma S et al: Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol 2016; 34: 3119.
69. Sharma P, Callahan MK, Bono P et al: Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol 2016; 17: 1590.
70. Apolo AB, Infante JR, Hamid O et al: Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: analysis of safety, clinical activity, and PD-L1 expression. J Clin Oncol, suppl., 2016; 34: abstract 4514.
71. Balar AV, Galsky MD, Loriot Y et al: Atezolizumab (atezo) as first-line (1L) therapy in cisplatin-ineligible locally advanced/metastatic urothelial carcinoma (mUC): primary analysis of IMvigor210 cohort 1. J Clin Oncol, suppl., 2016; 34: abstract LBA4500.
72. Balar A, Bellmunt J, O’Donnell PH et al: Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: preliminary results from the phase 2 KEYNOTE-052 study. Ann Oncol, suppl., 2016; 27: abstract LBA32_PR.
73. Bellmunt J, de Wit R and Vaughn DJ: Keynote-045: openlabel, phase III study of pembrolizumab versus investigator’s choice of paclitaxel, docetaxel, or vinflunine for previously treated advanced urothelial cancer. Presented at Society for Immunotherapy of Cancer annual meeting, National Harbor, Maryland, November 9-13, 2016.