Pemetrexed in Transitional Cell Carcinoma of the Urothelium

The four-drug combination of methotrexate(Drug information on methotrexate), vinblastine(Drug information on vinblastine), doxorubicin(Drug information on doxorubicin) (Adriamycin), and cisplatin(Drug information on cisplatin) (MVAC) has represented the standard care of treatment for patients with locally advanced and metastatic transitional cell carcinoma of the urothelium for the past 15 years.[1,2] In 2000, data from a randomized phase III trial of 405 patients comparing the combination of gemcitabine(Drug information on gemcitabine) (Gemzar) and cisplatin (GC) with the classic MVAC regimen were published.[ 3] Patients received either gemcitabine at 1,000 mg/m² days 1, 8, and 15 plus cisplatin at 70 mg/m² day 2 or MVAC every 28 days for a maximum of six cycles. This study demonstrated that the two regimens were associated with similar efficacy with respect to objective response, time to progression, and overall survival, whereas GC was associated with less toxicity than MVAC.[3] More patients in the MVAC arm had grade 4 neutropenia (65% vs 30%), neutropenic fever (14% vs 2%), neutropenic sepsis (12% vs 1%), and grade 3/4 mucositis (22% vs 1%) and alopecia (55% vs 11%) compared to those receiving GC. While qualityof- life parameters were similar for both arms, more patients in the GC arm fared better regarding weight, performance status (PS), and fatigue. Based on this superior risk-benefit ratio, GC is favored as a new standard treatment to patients with locally advanced and metastatic urothelial cancer. Other promising two- and three-drug combinations include combinations of gemcitabine with a taxane with or without cisplatin, and also the triple combination of ifosfamide(Drug information on ifosfamide), paclitaxel(Drug information on paclitaxel), and cisplatin.[2,4] Based on these results, the standard chemotherapeutic regimens for first-line chemotherapy are GC or MVAC, including intensified MVAC reported by Sternberg et al.[5] Patients with an initial major response upon first-line chemotherapy with a progression-free interval of at least 6 months should be offered reinduction chemotherapy; however, there is still no standard chemotherapeutic regimen for second-line treatment. An exception is the administration of gemcitabine following nongemcitabine- containing chemotherapy, because the efficacy of gemcitabine is achieved independently whether (or not) patients have received prior cisplatincontaining chemotherapy including MVAC.[4] Thus, many advances have been made in recent years in chemotherapy of patients with transitional cell carcinoma of the urothelium. In line with these advances, it is still important to explore new drugs, such as pemetrexed(Drug information on pemetrexed), as well as new combinations that might possess increased efficacy and/or decreased toxicity when compared with current regimens. Pemetrexed in Urothelial Cancer Pemetrexed is a novel, new generation multitargeted antifolate that has demonstrated broad antitumor activity in a variety of solid tumors.[6,7] (These are discussed in detail elsewhere in this supplement.) Preliminary data are currently available from three phase II studies in patients with locally advanced and metastatic transitional cell carcinoma of the urothelium. The final, mature data from these studies are eagerly awaited. Single-Agent Pemetrexed
Paz-Ares et al reported the first study of pemetrexed in urothelial cancer as part of a review article.[8] They administered pemetrexed as first-line chemotherapy in 31 evaluable patients with locally advanced and metastatic transitional cell carcinoma of the urothelium. All patients had bidimensionally measurable disease, no previous chemotherapy for metastatic disease, PS ≤ 2, creatinine clearance > 45 mL/min, and adequate organ function, and gave signed, informed consent. Patient characteristics included PS of 0 (n = 9), PS of 1 (n = 16), and PS of 2 (n = 6); the median age was 65 years. Nineteen patients (61%) had visceral metastases. The initial pemetrexed dose was 600 mg/m² administered intravenously (IV) as a 10-minute infusion every 21 days, but subsequent doses were 500 mg/m² after six patients reported significant toxicity. A possible explanation for the observed substantial toxicity is the lack of vitamin supple supplementation in the study design (now standard clinical practice).[9,10] The frequency of grade 3/4 hematologic toxicity was as follows: anemia, 23%; thrombocytopenia, 6%; neutropenia, 71%; and febrile neutropenia, 26%. Nonhematologic toxicity was primarily mild to moderate fatigue, mucositis, and diarrhea. There were three toxic deaths (10%). Nine patients achieved a partial response (PR). There were no complete responses (CRs) observed. Based on an intent-to-treat analysis, the overall response rate was 29%. The median duration of response was 8 months, and the overall median survival duration was reported to be 9.4 months. However, to our knowledge, patients with stable disease after two treatment cycles were taken off protocol and offered platinum-based chemotherapy. Thus, it is difficult to relate the overall median survival of 9.4 months to the effects of pemetrexed alone. This treatment change from the study design of Paz-Ares et al to a documented, effective platinum-based regimen after two treatment courses makes clinical sense. However, this strategy also demonstrates an inherent difficulty with the investigation of a new single-agent drug in first-line chemotherapy. Other notable parameters appear to be significant, independent prognostic factors (or features) for predicting survival in patients with metastatic transitional cell carcinoma. In trials with effective combination chemotherapy as MVAC or GC, patients with good prognostic factors (ie, Karnofsky PS ≥ 80, or Eastern Cooperative Group [ECOG] PS of 2 or better; absence of visceral metastases) achieved a long-term survival rate exceeding 15%, and up to 24% (4-year survival based on multivariate analysis of the impact of visceral metastases).[11,12] Thus, we recommend such factors be taken into consideration when new agents and drug combinations are under investigation as first-line chemotherapy in patients with good prognostic features, as well as those who might undergo a treatment change while on study. Sweeney et al conducted a phase II study of pemetrexed as second-line chemotherapy in patients with progressive disease following first-line chemotherapy for metastatic disease, or those who relapsed within 1 year after adjuvant or neoadjuvant chemotherapy.[ 13] All patients had bidimensionally measurable disease, PS ≤ 1, creatinine clearance > 45 mL/min, and adequate organ function, and gave signed, informed consent. The median age of the 46 patients was 64 years (range: 26 to 84 years). Other patient characteristics included PS of 0 (n = 28), PS of 1 (16), and PS of 2 (2); presence of visceral metastases in 40% of patients. The study dose was pemetrexed at 500 mg/m² IV as a 10-minute infusion every 21 days. In this study, patients received standard vitamin supplementation of folic acid(Drug information on folic acid) 400 μg orally daily and vitamin B₁₂ at 1,000 μg intramuscularly (IM) every 9 weeks starting 1 to 2 weeks before pemetrexed administration. Patients also received oral dexamethasone(Drug information on dexamethasone) at 4 mg twice daily for 3 days peritreatment to avoid cutaneous reactions. Toxicity was generally mild to moderate, with very few grade 4 toxicities. Grades 3 and 4 neutropenia occurred in two patients each. Based on the preliminary analysis, two patients achieved a complete response and five patients a partial response, giving an overall objective response rate of 15%. The overall median survival was 9.8 months. With respect to second-line chemotherapy, a potentially complicating factor in this study is that the accrual included patients relapsing within 1 year after adjuvant or neoadjuvant chemotherapy. However, in many trials of first-line chemotherapy, adjuvant or neoadjuvant chemotherapy is allowed within an interval exceeding 6 months following adjuvant chemotherapy. Thus, for some patients in this trial, pemetrexed may actually be considered first-line chemotherapy for metastatic disease in patients relapsing between 6 and 12 months after receiving adjuvant chemotherapy. A separate analysis of efficacy in the subgroup of patients receiving pemetrexed as true secondline therapy after first-line chemotherapy for locally advanced and metastatic disease is therefore pertinent. Nevertheless, the data by Sweeney et al demonstrate that pemetrexed is an active and well-tolerated drug in the treatment of transitional cell carcinoma of the urothelium. Pemetrexed Plus Gemcitabine Combination
Based on preclinical evidence of a synergistic effect between pemetrexed and gemcitabine,[14] (detailed elsewhere in this supplement) our group has initiated a European phase II study of pemetrexed plus gemcitabine as first-line chemotherapy in patients with locally advanced and metastatic transitional cell carcinoma of the urothelium. The patients should have bidimensionally measurable disease, no previous chemotherapy for metastatic disease, PS ≤ 2, creatinine clearance > 45 mL/min, and adequate organ function, and give signed, informed consent. Patients received gemcitabine at 1,250 mg/m² as a 30-minute infusion on days 1 and 8 plus pemetrexed at 500 mg/m² as a 10-minute infusion on day 8, every 3 weeks. This sequence of gemcitabine and pemetrexed was chosen to avoid reductions in the gemcitabine dose on day 8. Standard vitamin supplementation with folic acid and B₁₂ was started 1 to 2 weeks before pemetrexed, also with oral dexamethasone at 4 mg twice daily for 3 days peritreatment. The study has recently finalized recruitment of a total of 43 patients. Preliminary response data indicate an overall response rate about 26%, with a complete response rate of 6%; the final data analysis will update the response and survival results. Until the data are mature, it remains to be determined whether it will ultimately reflect the preliminary data. Note that the pooled response data for gemcitabine monotherapy from seven studies (totaling 192 evaluable patients) generated an overall response rate of 25%, with a 9% complete response rate.[4] The preliminary data with the gemcitabine/pemetrexed combination demonstrated a response rate of 26%, similar to that obtained by single-agent gemcitabine in urothelial cancer. Whether this trend in response rate is maintained and whether increased survival is associated with the gemcitabine/ pemetrexed combination remains to be seen. Conclusion Pemetrexed is an active agent in the treatment of patients with locally advanced and metastatic transitional cell carcinoma of the urothelium. The role of the drug in the management of urothelial cancer should be explored further. However, clinicians may choose to wait for the publication or presentation of the final results of the first three studies with a pemetrexed in urothelial cancer described herein. So far, the administration of combinations of pemetrexed with other active agents in patients with locally advanced and metastatic transitional cell cancer appears to be most appropriate as second-line chemotherapy, again pending further mature data in this setting.