Pre-Surgical Gemcitabine Plus Cisplatin Benefits Bladder Cancer

When used as a neoadjuvant therapy for patients with muscle-invasive bladder cancer (MIBC), split-dose of gemcitabine and cisplatin has a beneficial response and a high safety profile, according to a study presented at the 2017 American Urological Association Annual Meeting.

“Our aim was to evaluate our experience with respect to gemcitabine and split-dose cisplatin in terms of safety and efficacy, as well as pathologic downstaging and survival,” said Michael Williams, M.D., a practicing urologist at Urology of Virginia and assistant professor in the Department of Urology at Eastern Virginia Medical School. This is especially significant for patients who are unable to tolerate standard treatment with a combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).

A previous randomized phase 3 study investigated the combination of gemcitabine and cisplatin compared to treatment with MVAC in advanced or metastatic bladder cancer. This trial found that gemcitabine and cisplatin provided a similar survival advantage to MVAC, with a better safety profile and tolerability. The investigators even concluded that the standard of care should change for patient in this population from MVAC to gemcitabine and cisplatin.

In the large, randomized, multicenter trial, 405 patients were randomized to either receive gemcitabine and cisplatin (203 patients) or MVAC (202 patients). OS was similar in both arms, as were time to disease progression, time to treatment failure, and response rate. More patients completed six cycles of gemcitabine and cisplatin therapy, with fewer dose adjustments. The toxic death rate was 1 percent on the gemcitabine and cisplatin arm and 3 percent on the MVAC arm.

In terms of adverse events, more patients in the gemcitabine and cisplatin arm experienced grade 3/4 anemia (27 percent vs 18 percent in the MVAC arm) and thrombocytopenia (57 percent vs 21 percent). More patients in the MVAC arm had grade 3/4 neutropenia (82 percent vs 71 percent in the gemcitabine and cisplatin arm), neutropenic fever (14 percent vs 2 percent), neutropenic sepsis (12 percent vs 1 percent), grade 3/4 mucositis (22 percent vs 1 percent) and alopecia (55 percent vs 11 percent). Patients in the gemcitabine and cisplatin arm also had better improvement in terms of their weight, performance status, and fatigue.

A retrospective study investigating the role for neoadjuvant gemcitabine and cisplatin in MIBC similarly concluded that neoadjuvant gemcitabine and cisplatin is feasible and allows for timely drug delivery. Further, the proportion of patients who were treated with the combination of gemcitabine and cisplatin whose primary tumors were downstaged and who had prolonged disease-free survival with minimal or no residual disease, was similar to patients treated with MVAC.

With four cycles planned in the study, 39 of 42 patients received all four cycles, with complete responses achieved in 28 percent. Notably, all 15 patients receiving gemcitabine and cisplatin who achieved downstaging of their tumors below pathological stage T2 remained disease-free at a median follow-up of 30 months.

Williams presented a study that included patients who received gemcitabine and cisplatin split-doses followed by treatment with open radical cystectomy for T2 to T4 bladder cancer between 2004 and 2015 . The median age was 67.2 years, and the majority of patients had ECOG performance statuses of 1 or 2, according to Williams. The study included 82 patients, 47 (57.3 percent) of whom were clinical stage T2, 20 (24.3 percent) were T3, and 14 (17.1 percent) were T4. Of the patients with clinical stage T3 and T4 disease, 6 had hydronephrosis and 18 had a 3-D mass.

Patients were given 1000 mg/m2 of gemcitabine and 35 mg/m2 of cisplatin administered on days 1 and 8 of a 21-day cycle for a total of 4 cycles. Twenty-six of the patients were deceased at the time of the final evaluation, and 10 patients (12 percent) were unable to complete 4 cycles of treatment due to complications. Patients with unavailable follow-up data were excluded from the study.

The majority of patients were able to receive more than two cycles of therapy on this split-dose regimen.

“If you look at the number of cycles, 78 percent of patients received four cycles,” Williams commented. Twelve patients (14.6 percent) were treated with three cycles, and two patients (2.4 percent) received two cycles or fewer. The median time for the chemotherapy was a total of 12 weeks, “which is what you would expect for four cycles at three weeks apiece,” Williams said. The median time from the end of chemotherapy to the patient progressing to surgery was seven weeks.

In terms of pathologic response, the pathologic T0 downstaging rate was 31.7 percent, and when incorporating T1, Ta, and carcinoma in situ, the downstaging rate increases to 46.3 percent. At the end of the study, 72 percent of the patients achieved pathologic N stage 0, 14.6 percent had N1, and 11 percent had N2. “There is a rare cohort of patients who are pathologic T0 remaining node-positive, and of those patients, the vast majority have a very small number of lymph nodes that are actually positive,” Williams said.

The way the dosing regimen affects overall survival (OS) is based on factors that are “expected” to influence patient outcomes, said Williams, such as BMI, smoking history, and age. However, univariate analyses showed no significant effect on pathologic response due to gender, race, age, body mass index, T stage, N stage, presence of carcinoma in situ, squamous differentiation or presence of lymphovascular invasion. Notably, 38 patients (46.3 percent) were downstaged and 32 achieved complete response.

Ultimately, gemcitabine and split-dose cisplatin was demonstrated to be a well-tolerated regimen in the outpatient setting, and allows for a greater number of patients with MIBC to receive four cycles of chemotherapy prior to surgical consolidation, “which is what they really need,” Williams commented.

However, clinical staging of T3 or T4 secondary to a 3-D mass resulted in worse outcomes overall, and this was not mitigated by the split-dose approach. “For those who are in clinical stage T3 or T4 with the 3D mass, you need to do an in-between cycle of [transurethral resection of the bladder tumor], which, at our institution, is in between the second and third cycle,” he said. -