Perioperative chemotherapy for urothelial cancer

How have we made a “sow's ear” out of a chemotherapy-sensitive tumor?

In the beginning, the concept of adjuvant chemotherapy after surgery or other localized treatment modality was met with skepticism, especially among surgeons. Slowly, with earnest work from many—but notably the Milan Group in breast cancer; the National Surgical Adjuvant Breast and Bowel Project in colon cancer; and the International Adjuvant Lung Cancer Trial Collaborative Group, the Eastern Cooperative Oncology Group (ECOG), and others in lung cancer—a 4% to50% reduction in the risk of cancer recurrence was demonstrated with adjuvant, systemic therapy after surgery in patients who were stratified based on historic criteria and categorized as being at elevated risk of recurrence.1-3 Consequently, adjuvant therapy is now standard for patients with these cancers.

Progress in defining the role of neoadjuvant, adjuvant, or adjunctive systemic therapies in genitourinary cancer has been uneven. The use of adjuvant chemotherapy in the most chemosensitive tumor, testicular cancer, has been well studied to the point that success against the cancer is almost universal. The goal now is not to over treat patients and expose too many to chemotherapy-associated morbidity with the use of risk-adapted surveillance strategies based on pathologic and serum marker criteria. In prostate cancer, adjuvant androgen deprivation is a standard of care for patients who have lymph node metastases at radical prostatectomy, whereas adjuvant radiation has benefit for patients with extracapsular extension, and adjunctive androgen deprivation is a standard for patients with high-risk, localized disease who receive radiation therapy as their primary treatment. The potential role of perioperative chemotherapy in prostate cancer is unclear. Renal cell cancer has suffered from a lack of drugs that are suitable for use in the adjuvant setting until the recent advent of agents targeting the vascular endothelial growth factor pathways.

One of the great paradoxes of modern genitourinary cancer therapeutics is the relative lack of benefit for chemotherapy in the adjunctive setting for patients with bladder cancer who either undergo surgery or receive radiation. In advanced transitional-cell urothelial cancer, cisplatin-based chemotherapy has a response rate in excess of 45%, albeit with limited durability in many patients.4 Concurrent cisplatin chemotherapy is of incremental benefit for patients who receive definitive radiation therapy for muscle-invasive transitional cell cancer according to an adapted protocol from a series of Radiation Therapy Oncology Group trials.5 However, the use of neoadjuvant or adjuvant combination chemotherapy regimens has not improved outcome over and above concurrent chemoradiation therapy alone. For patients who undergo cystectomy for bladder cancer, neoadjuvant chemotherapy with combined methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) for patients who have transitional cell cancer or with cisplatin and etoposide for patients who have small cell cancer has net benefits as measured by overall or disease-specific survival.6, 7

The Southwest Oncology Group (SWOG)/Intergroup Trial 8710 demonstrated that patients who received neoadjuvant MVAC before they underwent cystectomy for transitional cell cancer had better survival than patients who proceeded directly to surgery.6 On an intention-to-treat basis, the statistical significance was marginal. In addition, further analysis of the data demonstrated that surgical technique used for the cystectomy was very important in determining outcome, so that the extent of lymph node dissection was a greater factor in predicting survival than randomization to chemotherapy or not.8 Nonetheless, these data, which built upon updated analyses of 2 Nordic trials and 2 sizeable meta-analyses that demonstrated a small but robust overall survival advantage of 5% total difference at 5 years for neoadjuvant, cisplatin-based combination therapy, influenced therapeutic decision-making with a large upswing in the use of neoadjuvant chemotherapy.9-11

In small cell bladder cancer, which accounts for <5% of cancers at this anatomic site, case series data from the M. D. Anderson Cancer Center describe an approximate doubling of cancer-specific survival at 5 years for patients with localized cancer who received neoadjuvant cisplatin-based chemotherapy compared with those who underwent cystectomy alone.7 Corroborative data from several large centers, including the University of Southern California, confirmed this finding, making neoadjuvant therapy the standard for this subset of patients with small cell bladder cancer.12

Given the data supporting neoadjuvant chemotherapy in bladder cancer, is there a role for adjuvant or postoperative therapy? Neoadjuvant chemotherapy and adjuvant chemotherapy both have their advantages and clinical proponents. Neoadjuvant therapy allows us to observe whether the cancer responds and allows the patient to experience chemotherapy in the absence of postoperative morbidity. Adjuvant therapy, in a postoperative context, allows us to give treatment based on a very accurate concept of the disease stage. The only trial to our knowledge that assessed preoperative versus postoperative chemotherapy in this setting suggested no difference in cancer control outcomes for MVAC given before or after cystectomy.13 An early phase 2 trial demonstrated the efficacy of adjuvant MVAC compared with untreated historic controls. Unfortunately, subsequent studies have been underpowered or otherwise flawed, often producing marginally better outcomes that were not statistically significant. Despite this, a meta-analysis (in itself flawed by omitting the largest trial undertaken to date) concluded that there was a survival advantage for cisplatin-combination chemotherapy that was of similar magnitude to the advantage observed with neoadjuvant chemotherapy.9, 10 It is noteworthy that data supporting the most commonly used perioperative chemotherapy regimen, cisplatin and gemcitabine, largely are empiric and are based on extrapolation from data in the advanced setting. The assumption that activity in the advanced setting translates to the adjuvant setting may not always be borne out as exemplified in colon rectal cancer, in which irinotecan/fluoropyrimidine combinations have major activity in patients with advanced disease but are relatively inefficacious in unselected populations who receive the same regimen as adjuvant therapy.14

In this month's issue of Cancer, Gallagher and colleagues15 from Memorial Sloan-Kettering Cancer Center report on their adjuvant pilot study of novel regimens incorporating 4-drug, rapid-replicating dosing of doxorubicin and gemcitabine followed by paclitaxel and either cisplatin or carboplatin, depending on the patient's postoperative renal function, with granulocyte-colony–stimulating factor (G-CSF) support, for patients with extravesical and/or lymph node metastatic disease at surgery for urothelial cancer. Patients were compared for disease-specific and overall survival with a contemporary control group from the same institution that did not receive adjuvant chemotherapy. Although efforts were made to control for variables among controls, such cohorts tend to be biased to better outcome based on less aggressive disease (do not warrant adjuvant therapy) or worse outcome based on a perceived lack of tolerance of adjuvant therapy (would not tolerate adjuvant therapy) as well as patient selection bias for a variety of reasons. In addition, patients on protocol always are followed more closely, especially for disease recurrence, compared with patients who receive standard therapy and are used as post-hoc controls. Within these caveats and the limitations of phase 2 design, the study was well conducted. Significantly, 80% of patients required dose delay or modification, and neutropenia was the most common cause for delay or change, suggesting that the regimens were overly ambitious in this population and despite G-CSF. The study did not provide evidence of improved disease-specific survival in either cohort compared with controls but did suggest a difference in overall survival in favor of chemotherapy versus controls. Although these results may seem divergent for methodological reasons, generally, an effect on overall survival is considered strong evidence for further pursuit in larger studies, because it is a “hard” endpoint. The net impact of the study is inconclusive, and the authors' statement that further focus on neoadjuvant therapy was reasonable but hardly definitive. The current “negative” result from Gallagher et al with a novel dose-dense strategy should not preclude further evaluation of dose-dense strategies like as high-dose-intensity MVAC in the adjuvant setting for patients with normal renal function and good performance status.16

Based in part on the data presented by Gallagher et al, the Cancer and Leukemia Group B (CALGB) initiated a randomized phase 3 trial comparing the rapid replicating regimen of doxorubicin, gemcitabine, paclitaxel, and cisplatin with cisplatin plus gemcitabine in patients with extravesical disease and/or lymph node involvement at cystectomy for transitional cell bladder cancer (CALGB 90104). Unfortunately, the trial was closed early because of poor accrual and before full Intergroup endorsement could be obtained. Concurrently, several other phase 3 trials assessed cisplatin-based chemotherapy in the adjuvant setting compared with initial observation and chemotherapy at first evidence of recurrence in Europe, including European Organization for Research and Treatment of Cancer (EORTC) Trial 30994 (recently closed because of poor accrual), and Italian Study Group (closed early with presented data showing no benefit to adjuvant chemotherapy) and Spanish Oncology Genitourinary Group (SOCOG) (ongoing accrual) trials. Each of these trials has had major challenges in accruing patients despite large numbers of patients undergoing cystectomy for bladder cancer within potential referral areas. This pattern of poor accrual to perioperative chemotherapy trials on both sides of the Atlantic continues a theme in such trials; even the SWOG/Intergroup 8710 neoadjuvant trial took 11 years to accrue 317 patients.

The sad fact is that, from the most recent round of phase 3 trials, it is likely that little conclusive will emerge until they are analyzed in composite rather than individually. In the interim, we are provided with little help in deciding whether or not to offer adjuvant chemotherapy and with which regimen, if we believe MVAC is not an option. Our current approach to patients is risk stratified based on disease stage.17 Biomarkers have the potential to guide our therapy. We await the results from 499 patients who were screened prospectively for the pathologic stage T2, p53, adjuvant MVAC trial along with the retrospective International Bladder Network Study of patients with T3 bladder cancer treated with or without perioperative chemotherapy.18, 19 These studies will provide data to power predictive and prognostic studies of p53 and cell cycle markers as well as markers potentially predictive of platin response or resistance, such as excision repair cross-complementing factor 1 or ERCC1.20, 21 The EORTC and SOCOG studies may provide biospecimens to help confirm the value of these markers.

The current best-practice perioperative chemotherapy regimen for patients with muscle-invasive urothelial cancer who elect to undergo cystectomy is neoadjuvant or postoperative MVAC. Such practice needs to incorporate individual counseling of patients related to the narrow window between benefit and risk that exists with such an approach. The use of any other regimens should be considered less proven, although non-MVAC, cisplatin-based combinations do have some supportive data; and cisplatin with gemcitabine is equivalent in the advanced setting. In contradistinction to this, noncisplatin-based regimens, including those that incorporate carboplatin, have no proven benefit in the perioperative setting, actually may be harmful by increasing perioperative risk, and should not be used routinely but, rather, should be reserved for use in clinical trials. There is a particular unmet need for patients with moderate-to-severe renal impairment. The way forward is to leverage promising new drugs in the perioperative setting while recognizing that surgical technique, particularly extensive lymph node dissection, may have a very significant effect on patient outcome. The sow's ear that is perioperative chemotherapy for urothelial cancer could not be construed as a silk purse but presents a challenge to all of us who are confronted by this disease. The best treatment for patients with muscle-invasive bladder cancer is the best available clinical trial. Such trials need to be powered and accrued not only to answer clinical questions but also to provide information about patient selection through biologic specimen acquisition and biomarker assessment. A renewed focus on collective buy-in and accrual to trials by urologists and oncologists who treat bladder cancer needs to move beyond generic motherhood statements and unfulfilled promissory notes; our patients deserve more than a sow's ear.

Conflict of Interest Disclosures

The authors made no disclosures.