Chemotherapy Retains Vital Role in Bladder Cancer Care

Andrea Necchi, MD

Although immunotherapy shows great promise in meeting the need for effective treatment of muscle invasive bladder cancer (MIBC), chemotherapy continues to be an important tool in treating patients with this disease and other forms of bladder and urothelial cancer.

The current standard of care for eligible patients with ECOG performance status 0 to 1 is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy,¹ according to Andrea Necchi, MD, medical oncologist at the Fondazione Irccs Istituto Nazionale Dei Tumori in Milan, Italy. However, ECOG performance status ≥2 or glomerular filtration rate <60 mL/minute precludes chemotherapy and the recommendations call for upfront radical cystectomy (RC) or radiotherapy.

Necchi discussed whether chemotherapy retained a role in bladder cancer during the era of immunotherapy during the 2017 Global Congress on Bladder Cancer.

“There are multiple aspects to be accounted for across the clinical stages of bladder cancer. In patients with localized, muscle-invasive tumors, eligibility to cisplatin-based neoadjuvant chemotherapy is an important factor to drive multimodal decisions. Another important factor is the patient preference with regards to the decision to undergo radical cystectomy versus bladder-sparing chemoradiation approaches,” he said. Necchi added that other factors also drive treatment decisions: “Among these are the ECOG performance status, age, cisplatin eligibility, and comorbidities which usually are accounted for to decide towards standard therapy.”

While a small survival benefit of approximately 6% has been observed with neoadjuvant cisplatin, methotrexate, vinblastine (CMV) prior to RC in some trials, no significant improvement in 5-year survival rates over surgery alone has been demonstrated in several phase III trials, according to Necchi.

However, 2 phase III trials showed a survival advantage with neoadjuvant chemotherapy; the BA06 30894 trial showed 10-year overall survival rates (OS) of 36% versus 30% with CMV plus surgery over surgery alone (P = .037) and the SWOG-8710 trial demonstrated 5-year OS of 57% versus 43% with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) plus surgery over surgery alone (P = .06). In addition, phase II single arm trials with dose dense MVAC conducted by Choueiri et al and Plimack et al showed a 2 year-OS rate of 79% and a 1.8-year OS rate of 83%, respectively, (all trials⁴). These findings support the use of neoadjuvant chemotherapy plus surgery in MIBC.

Currently, this neoadjuvant chemotherapy approach is underutilized, with just 20% of patients in western Europe2 and approximately 41.1% of eligible patients in the United States receiving neoadjuvant chemotherapy. In the United States, a recent review showed that neoadjuvant chemotherapy is used in between 18% to 57% of high-risk patients and in 41% to 79% of all eligible patients, Necchi explained. Regarding the optimal time of delivering adjuvant chemotherapy in MIBC, results regarding immediate chemotherapy versus deferred chemotherapy following RC showed that patients with urothelial carcinoma had 5-year progression free survival (PFS) rates of 47.6% versus 31.8%, respectively (HR, 0.54; P <.001).⁵

In locally advanced bladder cancer, there is evidence that patient outcomes are improved by adjuvant chemotherapy over observation, where the probability of achieving OS of 108 months from time of diagnosis was improved two-fold with adjuvant chemotherapy.⁶ “Barriers to improving patient outcomes in the area of managing aggressive bladder cancer include inaccurate clinical staging and the lack of an effective non-cisplatin—based neoadjuvant regimen,” said Necchi, who cited several examples of patients being both up- and downstaged upon RC; the most recent of these studies found 41% of patients were upstaged at RC while 5.9% were downstaged.⁷ “The high metastatic relapse rates observed after radical cystectomy indicate muscle invasive bladder cancer is a systemic disease at diagnosis in many patients that requires a multidisciplinary approach,” Necchi commented, “ “Improving patient outcome in MIBC is a matter of improving systemic disease control.”

He cited one study where MVAC plus cystectomy improved median OS to 77 months over the 46 months seen with cystectomy alone.8 However, another study showed no advantage in chemoradiotherapy over radiotherapy in OS (HR, 0.82; P = .16).⁹

“Identification of genomic predictors of response to chemotherapy might lead to a more personalized approach,” Necchi said. His group has shown an association between response to gemcitabine/cisplatin/sorafenib combination therapy and patients with tumors mutated in DNA repair genes, RAS/RAF, and chromatin-remodeling genes.⁹ Another study showed that posttreatment tumor heterogeneity was associated with OS with each additional subclone associating with a 60% increase in mortality rates and each 10% increase in the subclone population associated with a 6% increase in the mortality rate (log rank P = .036).¹¹

“Treating patients according to the characteristics of their tumor, for example, according to the cluster of gene expression, or the presence of specific somatic gene alterations is becoming a possibility for immunotherapy or targeted therapy in clinical practice,” he said.

“Immunotherapy will probably reshape the MIBC treatment landscape,” commented Necchi, who noted that PD-1/PD-L1 inhibitors are being investigated in non-muscle invasive bladder cancer, MIBC, and metastatic urothelial cancer, both in the first line and second-line setttings and beyond.

He posited the “Milano Model” for treatment of MIBC, which his group is currently enrolling patients with confirmed TCC (T2-T4) bladder cancer for the PURE01 trial. The paradigm proposes 3 X 3 weekly cycles of pembrolizumab followed by cystectomy and post cystectomy management according to current guidelines, with survival data collected at 2 years post cystectomy. Exome sequencing will also be done and the primary endpoint is pathologic CR rate. Patients will be monitored by multiparametric MRI, which he suggests may improve staging (NCT02736266). He pointed out that the ABACUS trial is testing a similar treatment model using atezolizumab (NCT02662309).

While immunotherapy may be the way forward, Necchi noted that both the KeyNote-045 study of pembrolizumab12 and IMvigor 211 trials of atezolizumab¹³ versus chemotherapy showed a notable effect with chemotherapy. An OS advantage was demonstrated between 2 and 5 months for chemotherapy prior to the onset of the immunotherapeutic response. He advised that the importance of this early chemotherapy response should not be overlooked and may indicate a role for chemotherapy in combination regimens.

Several large trials of immunotherapies in the postoperative setting in high-risk patients with bladder cancer or upper tract urothelial carcinoma are ongoing, and Necchi again mentioned the IMvigor 010 trial, as well as the Checkmate 274 trial (NCT02632409) of nivolumab versus placebo, and the Ambassador trial (NCT03244384) of pembrolizumab versus placebo, all of which are being conducted in patients that are unselected according to PD-L1 expression. He noted that a recent review of several small studies revealed that up to 13% CR and 40% PR have already been demonstrated with chemotherapy in the perioperative setting in patients with upper tract urothelial carcinoma, and that several neoadjuvant chemotherapy trials for patients with upper tract urothelial carcinoma are underway in the European Union, suggesting that chemotherapy still has a role in treating this disease.¹⁴

According to Necchi, conflicting results have been observed with the use of chemotherapy after recurrence following radical nephroureterectomy between Seisen et al,¹⁵ who found OS was improved with adjuvant chemotherapy (P <.001), and Necchi’s own group which found no significant difference in survival probability between adjuvant chemotherapy over chemotherapy alone.¹⁶ Necchi suggested that this may possibly be explained by the difference in tumor mutational load and other factors.

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