Pemetrexed in Transitional Cell Carcinoma of the Urothelium

November 2, 2004

Currently, the four-drug combination of methotrexate, vinblastine,doxorubicin (Adriamycin), and cisplatin (MVAC) or the two-drug combinationof gemcitabine and cisplatin (GC) represents the standard ofcare for patients with locally advanced and metastatic transitional cellcarcinoma of the urothelium. Recently, there has been a plethora ofdata from other chemotherapeutic regimens. Promising new agents,such as the multitargeted antifolate pemetrexed (Alimta), and new drugcombinations have demonstrated increased efficacy and/or decreasedtoxicity compared with current regimens. Currently, data are availablefrom three phase II studies utilizing pemetrexed or the combination ofpemetrexed/gemcitabine (Gemzar) in patients with locally advanced andmetastatic transitional cell carcinoma of the urothelium. Further investigationof combinations of pemetrexed and other active drugs inthe treatment of patients with locally advanced and metastatic diseaseis warranted.

ABSTRACT: Currently, the four-drug combination of methotrexate, vinblastine,doxorubicin (Adriamycin), and cisplatin (MVAC) or the two-drug combinationof gemcitabine and cisplatin (GC) represents the standard ofcare for patients with locally advanced and metastatic transitional cellcarcinoma of the urothelium. Recently, there has been a plethora ofdata from other chemotherapeutic regimens. Promising new agents,such as the multitargeted antifolate pemetrexed (Alimta), and new drugcombinations have demonstrated increased efficacy and/or decreasedtoxicity compared with current regimens. Currently, data are availablefrom three phase II studies utilizing pemetrexed or the combination ofpemetrexed/gemcitabine (Gemzar) in patients with locally advanced andmetastatic transitional cell carcinoma of the urothelium. Further investigationof combinations of pemetrexed and other active drugs inthe treatment of patients with locally advanced and metastatic diseaseis warranted.

The four-drug combination ofmethotrexate, vinblastine,doxorubicin (Adriamycin), andcisplatin (MVAC) has represented thestandard care of treatment for patientswith locally advanced and metastatictransitional cell carcinoma of theurothelium for the past 15 years.[1,2]In 2000, data from a randomizedphase III trial of 405 patients comparingthe combination of gemcitabine(Gemzar) and cisplatin (GC) with theclassic MVAC regimen were published.[3] Patients received eithergemcitabine at 1,000 mg/m2 days 1,8, and 15 plus cisplatin at 70 mg/m2day 2 or MVAC every 28 days for amaximum of six cycles. This studydemonstrated that the two regimenswere associated with similar efficacywith respect to objective response,time to progression, and overall survival,whereas GC was associated withless toxicity than MVAC.[3]More patients in the MVAC armhad grade 4 neutropenia (65% vs30%), neutropenic fever (14% vs 2%),neutropenic sepsis (12% vs 1%), andgrade 3/4 mucositis (22% vs 1%) andalopecia (55% vs 11%) compared tothose receiving GC. While qualityof-life parameters were similar forboth arms, more patients in the GCarm fared better regarding weight,performance status (PS), and fatigue.Based on this superior risk-benefitratio, GC is favored as a new standardtreatment to patients with locally advancedand metastatic urothelial cancer.Other promising two- andthree-drug combinations include combinationsof gemcitabine with a taxanewith or without cisplatin, and alsothe triple combination of ifosfamide,paclitaxel, and cisplatin.[2,4]Based on these results, the standardchemotherapeutic regimens forfirst-line chemotherapy are GC orMVAC, including intensified MVACreported by Sternberg et al.[5] Patientswith an initial major responseupon first-line chemotherapy with aprogression-free interval of at least 6months should be offered reinductionchemotherapy; however, there is stillno standard chemotherapeutic regimenfor second-line treatment. Anexception is the administration ofgemcitabine following nongemcitabine-containing chemotherapy, becausethe efficacy of gemcitabine is achievedindependently whether (or not) patientshave received prior cisplatincontainingchemotherapy includingMVAC.[4]Thus, many advances have beenmade in recent years in chemotherapyof patients with transitional cellcarcinoma of the urothelium. In linewith these advances, it is still importantto explore new drugs, such aspemetrexed, as well as new combinationsthat might possess increased efficacyand/or decreased toxicity whencompared with current regimens.Pemetrexed in UrothelialCancerPemetrexed is a novel, new generationmultitargeted antifolate that hasdemonstrated broad antitumor activityin a variety of solid tumors.[6,7](These are discussed in detail elsewherein this supplement.) Preliminarydata are currently available fromthree phase II studies in patients withlocally advanced and metastatic transitionalcell carcinoma of the urothelium.The final, mature data from thesestudies are eagerly awaited.Single-Agent Pemetrexed
Paz-Ares et al reported the firststudy of pemetrexed in urothelial canceras part of a review article.[8] Theyadministered pemetrexed as first-linechemotherapy in 31 evaluable patientswith locally advanced and metastatictransitional cell carcinoma of theurothelium. All patients had bidimensionallymeasurable disease, no previouschemotherapy for metastaticdisease, PS ≤ 2, creatinine clearance> 45 mL/min, and adequate organfunction, and gave signed, informedconsent. Patient characteristics includedPS of 0 (n = 9), PS of 1 (n = 16),and PS of 2 (n = 6); the median agewas 65 years. Nineteen patients (61%)had visceral metastases.The initial pemetrexed dose was600 mg/m2 administered intravenously(IV) as a 10-minute infusion every21 days, but subsequent doses were500 mg/m2 after six patients reportedsignificant toxicity. A possible explanationfor the observed substantial toxicityis the lack of vitamin supple supplementationin the study design (nowstandard clinical practice).[9,10] Thefrequency of grade 3/4 hematologictoxicity was as follows: anemia, 23%;thrombocytopenia, 6%; neutropenia,71%; and febrile neutropenia, 26%.Nonhematologic toxicity was primarilymild to moderate fatigue, mucositis,and diarrhea. There were threetoxic deaths (10%).Nine patients achieved a partial response(PR). There were no completeresponses (CRs) observed. Based onan intent-to-treat analysis, the overallresponse rate was 29%. The medianduration of response was 8 months,and the overall median survival durationwas reported to be 9.4 months.However, to our knowledge, patientswith stable disease after two treatmentcycles were taken off protocoland offered platinum-based chemotherapy.Thus, it is difficult to relatethe overall median survival of 9.4months to the effects of pemetrexedalone. This treatment change from thestudy design of Paz-Ares et al to adocumented, effective platinum-basedregimen after two treatment coursesmakes clinical sense. However, thisstrategy also demonstrates an inherentdifficulty with the investigation ofa new single-agent drug in first-linechemotherapy.Other notable parameters appearto be significant, independent prognosticfactors (or features) for predictingsurvival in patients withmetastatic transitional cell carcinoma.In trials with effective combinationchemotherapy as MVAC or GC, patientswith good prognostic factors(ie, Karnofsky PS ≥ 80, or EasternCooperative Group [ECOG] PS of 2or better; absence of visceral metastases)achieved a long-term survival rateexceeding 15%, and up to 24%(4-year survival based on multivariateanalysis of the impact of visceralmetastases).[11,12] Thus, we recommendsuch factors be taken into considerationwhen new agents and drugcombinations are under investigationas first-line chemotherapy in patientswith good prognostic features, as wellas those who might undergo a treatmentchange while on study.Sweeney et al conducted a phase IIstudy of pemetrexed as second-linechemotherapy in patients with progressivedisease following first-linechemotherapy for metastatic disease,or those who relapsed within 1 yearafter adjuvant or neoadjuvant chemotherapy.[13] All patients had bidimensionallymeasurable disease, PS ≤ 1,creatinine clearance> 45 mL/min, and adequate organfunction, and gave signed, informedconsent. The median age of the 46patients was 64 years (range: 26 to 84years). Other patient characteristicsincluded PS of 0 (n = 28), PS of 1(16), and PS of 2 (2); presence ofvisceral metastases in 40% of patients.The study dose was pemetrexed at500 mg/m2 IV as a 10-minute infusionevery 21 days. In this study, patientsreceived standard vitaminsupplementation of folic acid 400 μgorally daily and vitamin B12 at 1,000μg intramuscularly (IM) every 9 weeksstarting 1 to 2 weeks before pemetrexedadministration. Patients also receivedoral dexamethasone at 4 mgtwice daily for 3 days peritreatmentto avoid cutaneous reactions. Toxicitywas generally mild to moderate,with very few grade 4 toxicities.Grades 3 and 4 neutropenia occurredin two patients each.Based on the preliminary analysis,two patients achieved a complete responseand five patients a partial response,giving an overall objectiveresponse rate of 15%. The overallmedian survival was 9.8 months.With respect to second-line chemotherapy,a potentially complicatingfactor in this study is that theaccrual included patients relapsingwithin 1 year after adjuvant or neoadjuvantchemotherapy. However, inmany trials of first-line chemotherapy,adjuvant or neoadjuvant chemotherapyis allowed within an intervalexceeding 6 months following adjuvantchemotherapy. Thus, for somepatients in this trial, pemetrexed mayactually be considered first-line chemotherapyfor metastatic disease in patients relapsing between 6 and 12months after receiving adjuvant chemotherapy.A separate analysis of efficacyin the subgroup of patientsreceiving pemetrexed as true secondlinetherapy after first-line chemotherapyfor locally advanced andmetastatic disease is therefore pertinent.Nevertheless, the data bySweeney et al demonstrate that pemetrexedis an active and well-tolerateddrug in the treatment of transitionalcell carcinoma of the urothelium.Pemetrexed Plus GemcitabineCombination
Based on preclinical evidence of asynergistic effect between pemetrexedand gemcitabine,[14] (detailed elsewherein this supplement) our grouphas initiated a European phase II studyof pemetrexed plus gemcitabine asfirst-line chemotherapy in patientswith locally advanced and metastatictransitional cell carcinoma of theurothelium. The patients should havebidimensionally measurable disease,no previous chemotherapy for metastaticdisease, PS ≤ 2, creatinine clearance> 45 mL/min, and adequate organfunction, and give signed, informedconsent. Patients received gemcitabineat 1,250 mg/m2 as a 30-minuteinfusion on days 1 and 8 plus pemetrexedat 500 mg/m2 as a 10-minuteinfusion on day 8, every 3 weeks.This sequence of gemcitabine andpemetrexed was chosen to avoid reductionsin the gemcitabine dose onday 8. Standard vitamin supplementationwith folic acid and B12 was started1 to 2 weeks before pemetrexed,also with oral dexamethasone at 4 mgtwice daily for 3 days peritreatment.The study has recently finalized recruitmentof a total of 43 patients.Preliminary response data indicatean overall response rate about 26%,with a complete response rate of 6%;the final data analysis will update theresponse and survival results. Untilthe data are mature, it remains to bedetermined whether it will ultimatelyreflect the preliminary data. Note thatthe pooled response data for gemcitabinemonotherapy from seven studies(totaling 192 evaluable patients)generated an overall response rate of25%, with a 9% complete responserate.[4] The preliminary data with thegemcitabine/pemetrexed combinationdemonstrated a response rate of 26%,similar to that obtained by single-agentgemcitabine in urothelial cancer.Whether this trend in response rate ismaintained and whether increased survivalis associated with the gemcitabine/pemetrexed combination remainsto be seen.ConclusionPemetrexed is an active agent inthe treatment of patients with locallyadvanced and metastatic transitionalcell carcinoma of the urothelium. Therole of the drug in the management ofurothelial cancer should be exploredfurther. However, clinicians maychoose to wait for the publication orpresentation of the final results of thefirst three studies with a pemetrexedin urothelial cancer described herein.So far, the administration of combinationsof pemetrexed with other activeagents in patients with locallyadvanced and metastatic transitionalcell cancer appears to be most appropriateas second-line chemotherapy,again pending further mature data inthis setting.

Disclosures:

The author has no significantfinancial interest or other relationshipwith the manufacturers of any productsor providers of any service mentioned in thisarticle.

References:

1.

Sternberg CN, Yagoda A, Scher HI, et al:Methotrexate, vinblastine, doxorubicin, andcisplatin for advanced transitional cell carcinomaof the urothelium: Efficacy and patternsof response and relapse. Cancer 64:2448-2458,1989.

2.

von der Maase H: Current and future perspectivesin advanced bladder cancer: Is therea new standard? Semin Oncol 29(1 suppl 3):3-14, 2002.

3.

von der Maase H, Hansen SW, RobertsJT, et al: Gemcitabine and cisplatin versusmethotrexate, vinblastine, doxorubicin, andcisplatin (MVAC) in advanced or metastaticbladder cancer: Results of a large randomized,multinational, multicenter, phase III study. JClin Oncol 18:3068-3077, 2000; comment inJ Clin Oncol 19:1229-1231, 2001.

4.

von der Maase H: Gemcitabine in transitionalcell carcinoma of the urothelium. ExpertRev Anticancer Ther 3:11-19, 2003.

5.

Sternberg CN, de Mulder PH, SchonagelJH, et al: Randomized phase III trial of highdose-intensity methotrexate, vinblastine, doxorubicin,and cisplatin (MVAC) chemotherapyand recombinant human granulocyte colonystimulatingfactor versus classic MVAC in advancedurothelial tract tumors: European Organizationfor Research and Treatment of CancerProtocol no. 30924. J Clin Oncol 19:2638-2646, 2001.

6.

Goldman ID, Zhao R: Molecular, biochemical,and cellular pharmacology ofpemetrexed. Semin Oncol 29(6 suppl 18):3-17,2002.

7.

Adjei AA: Pemetrexed (Alimta): A novelmultitargeted antifolate agent. Expert Rev AnticancerTher 3:145-156, 2003.

8.

Paz-Ares L, Ciruelos E, Garcia-CarboneroR, et al: Pemetrexed in bladder, head and neck,and cervical cancers. Semin Oncol 29(6 suppl18):69-75, 2002.

9.

Scagliotti GV, Shin DM, Kindler HL, etal: Phase II study of pemetrexed with and withoutfolic acid and vitamin B12 as front-linetherapy in malignant pleural mesothelioma. JClin Oncol 21:1556-1561, 2003.

10.

Bajetta E, Celio L, Buzzoni R, et al:Phase II study of pemetrexed disodium(Alimta) administered with oral folic acid inpatients with advanced gastric cancer. AnnOncol 14:1543-1548, 2003.

11.

Bajorin DF, Dodd PM, Maunder M, etal: Long-term survival in metastatic transitionalcell carcinoma and prognostic factors predictingoutcome of therapy. J Clin Oncol 17:3173-3181, 1999.

12.

Stadler WM, Hayden A, von der MaaseH, et al: Long-term survival in phase II trialsof gemcitabine plus cisplatin for advanced transitionalcell cancer. Urol Oncol 7:153-157,2002.

13.

Sweeney C, Roth BJ, Kaufman DS, etal: Phase II study of pemetrexed (PEM) for second-line treatment of transitional cell cancer(TCC) of the bladder (abstract 1653). Proc AmSoc Clin Oncol 22:411, 2003.

14.

Adjei AA: Preclinical and clinical studieswith combinations of pemetrexed andgemcitabine. Semin Oncol 29(6 suppl 18):30-34, 2002.