Neoadjuvant Chemotherapy for Bladder Cancer

By Bernard Bochner, MD and Jonathan Rosenberg, MD
Tuesday, May 27, 2014

Memorial Sloan Kettering’s bladder cancer disease management team aims to optimize the treatment of all patients with bladder and other urothelial cancers. We offer a coordinated approach to invasive disease that individually evaluates each patient to provide the best therapy and maximize chances of a long-term cure.

While the majority of patients with urothelial carcinoma have non-muscle-invasive disease, 25 percent present with or develop muscle-invasive tumors. For invasive bladder tumors, radical cystectomy involving removal of the bladder and reconstruction of the urinary system remains the treatment of choice in the United States.

However, once invasive, bladder tumor cells can metastasize to lymph nodes around the bladder or to other organs. Once this occurs, cure is difficult to achieve.

Positive Results with Neoadjuvant Chemotherapy

Based on positive phase III trial results using preoperative drugs, the use of chemotherapy around the time of surgery has increased in recent years.

The INT-080 clinical trial, which compared three cycles of MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) followed by radical cystectomy to surgery alone, showed a 25 percent reduction in the risk of death and a 14 percent absolute improvement in five-year survival in the group that received combination treatment.(1) A pathologic complete response (pT0N0) after chemotherapy was more common in the chemotherapy arm (38 percent versus 15 percent), and 85 percent of these patients were alive at five years.(2)

Results from the EORTC-30894 trial, which tested definitive radiotherapy against three cycles of CMV (cisplatin, methotrexate, vinblastine) as neoadjuvant therapy prior to cystectomy, indicated a 16 percent reduction in the risk of death (p = 0.037). This translates to a six percent increase in ten-year survival.(3)

In both studies, the toxicities of chemotherapy did not make surgery more difficult or increase the risk of postoperative complication.

Trials in Adjuvant Chemotherapy

In contrast to the neoadjuvant approach, adjuvant chemotherapy has not been definitively proven to improve cure rates. Most studies have closed early due to either poor accrual or early recurrence-free improvements that did not translate into overall survival improvements.

Three modern adjuvant studies testing gemcitabine/cisplatin-based regimens and/or MVAC closed early due to poor accrual.

One of the studies, conducted in Italy, enrolled cT2-4a N0-2 bladder cancer patients who received four cycles of gemcitabine and cisplatin chemotherapy or observation after cystectomy.(4) Adjuvant chemotherapy demonstrated no benefit, and only 62 percent of patients were able to complete all the treatment cycles.

Another study (available only in abstract form) evaluating higher-risk patients (pT3-4 and/or node positive) treated with paclitaxel, gemcitabine, and cisplatin (PGC) or observation(5) also closed due to poor accrual, with only 142 of 340 subjects randomized. A marked improvement in survival favoring the chemotherapy arm was observed, leading to a 64 percent reduction in risk of death compared to observation. In this trial, 81 percent of patients received all four cycles of treatment. This small study is the only one to show an overall survival benefit with adjuvant chemotherapy.

Unfortunately, approximately 30 percent of patients who require postoperative chemotherapy experience complications related to surgery that prevent them from receiving treatment in a timely fashion.(6)

At Memorial Sloan Kettering

Based on the added challenges of completing chemotherapy after major surgery, as well as the known survival advantage of preoperative chemotherapy in bladder cancer, at Memorial Sloan Kettering we recommend neoadjuvant cisplatin-based chemotherapy for individuals who present with invasive disease and are cisplatin candidates.

Gemcitabine and cisplatin (GC) doublet chemotherapy has been demonstrated to have similar levels of antitumor activity in the metastatic setting as both MVAC and PGC — and with lower toxicity. Retrospective data from 154 patients treated with neoadjuvant GC chemotherapy at our institution show similar rates of pathologic complete response, down-staging to non-muscle invasive cancer, and survival as those treated with MVAC chemotherapy.(7) GC chemotherapy is therefore considered a standard of care in this context as well.

We are currently testing a dose-intensified version of GC that has been shown to be safe and effective in the metastatic setting in a single-arm phase II study. The goal of this trial is to determine whether the proportion of patients with pathologic complete responses is higher than historically seen with standard-intensity regimens.

In addition, we are testing whether the addition of panitumumab (which binds the epidermal growth factor receptor) to gemcitabine and carboplatin in non-cisplatin-eligible patients leads to pathologic responses at cystectomy. EGFR overexpression is very common in muscle-invasive bladder cancer, and targeting this pathway may yield additional clinical benefits.

Approach to Upper Tract Urothelial Carcinoma

Whether perioperative chemotherapy provides benefit to patients with upper tract (ureter and renal pelvis) urothelial carcinoma is unknown.

We are also testing GC neoadjuvant chemotherapy on a modified schedule for renal protection in patients with upper tract urothelial carcinoma to establish whether pathologic response rates to cisplatin-based chemotherapy observed in the bladder trials are also observed when upper tract tumors are treated.

This data will provide the basis for ongoing evaluation of neoadjuvant therapy for upper tract disease in the cooperative group setting.

  1. 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 Nov 6;349(19):1880.
  2. Sonpavde G, Goldman BH, Speights VO, et al. Quality of pathologic response and surgery correlate with survival for patients with completely resected bladder cancer after neoadjuvant chemotherapy. Cancer. 2009 Sep 15;115(18):4104-9.
  3. 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 Jun 1;29(16):2171-7.
  4. 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. Annals of Oncology. 2012 Mar;23:695-700.
  5. Paz-Ares LG, 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 (Meeting Abstracts) 2010;28:LBA4518. 
  6. 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 Jan;55(1):177-85.
  7. Tully CM, Bochner BH, Dalbagni G, et al. Gemcitabine-cisplatin (GC) plus radical cystectomy-pelvic lymph node dissection (RC-PLND) for patients (pts) with muscle-invasive bladder cancer (MIBC): Assessing impacts of neoadjuvant chemotherapy (NAC) and the PLND. ASCO Meeting Abstracts 2014;32:355.