Split-Dose Gemcitabine and Cisplatin Well-Tolerated in Muscle-Invasive Bladder Cancer

Michael Williams, MD

Michael Williams, MD

A study presented at the 2017 American Urological Association Annual Meeting demonstrated that a split-dose of gemcitabine and cisplatin as a neoadjuvant chemotherapy regimen for treating muscle-invasive bladder cancer (MIBC) has a good pathologic response with a high safety profile.¹

“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, MD, 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 III 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.²

In the large, randomized, multicenter trial, 405 patients were randomized to either receive gemcitabine and cisplatin (n = 203) or MVAC (n = 202). OS was similar in both arms, as were time to disease progression, time to treatment failure, and response rate. More patients completed 6 cycles of gemcitabine and cisplatin therapy, with fewer dose adjustments. The toxic death rate was 1% on the gemcitabine and cisplatin arm and 3% on the MVAC arm.

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

With 4 cycles planned in the study, 39 of 42 patients received all 4 cycles, with complete responses achieved in 28%. 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%) of whom were clinical stage T2, 20 (24.3%) were T3, and 14 (17.1%) 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/m²of gemcitabine and 35 mg/m²of 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%) 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 2 cycles of therapy on this split-dose regimen. “If you look at the number of cycles, 78% of patients received 4 cycles,” Williams commented. Twelve patients (14.6%) were treated with 3 cycles, and 2 patients (2.4%) received 2 cycles or fewer. The median time for the chemotherapy was a total of 12 weeks, “which is what you would expect for 4 cycles at 3 weeks apiece,” Williams said. The median time from the end of chemotherapy to the patient progressing to surgery was 7 weeks.

In terms of pathologic response, the pathologic T0 downstaging rate was 31.7%, and when incorporating T1, Ta, and carcinoma in situ, the downstaging rate increases to 46.3%. At the end of the study, 72% of the patients achieved pathologic N stage 0, 14.6% had N1, and 11% 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 (P= .742), race (P= .783), age (P= .377), body mass index (P= .821), T stage (P= .982), N stage (P= .615), presence of carcinoma in situ (P= .096), squamous differentiation (P= .229) or presence of lymphovascular invasion (P= .749). Notably, 38 patients (46.3%) were downstaged (T≤1) and 32 achieved complete response (T0).¹

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 4 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 (P<.001). &ldquo;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,&rdquo; he said.

References:

1. Abdelhafez M, Williams M. Safety and efficacy gemcitabine-cisplatin split dose as a neoadjuvant chemotherapy for muscle invasive bladder cancer. Presented at: 2017 American Urological Association Annual Meeting; May 12-16, 2017; Boston, MA. Abstract PD62-04.
2. von der Masse 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. 2000;18(17):3068-3077.
3. Dash A, Pettus JA 4th, Herr HW, et al. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience.Cancer. 2008;113(9):2471-2477. doi: 10.1002/cncr.23848.