Pemetrexed in Transitional Cell Carcinoma of the Urothelium
Pemetrexed in Transitional Cell Carcinoma of the Urothelium
The four-drug combination of
doxorubicin (Adriamycin), and
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
(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.
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,
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. 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
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, as well as new combinations
that might possess increased efficacy
and/or decreased toxicity when
compared with current regimens.
Pemetrexed in Urothelial
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.
Paz-Ares et al reported the first study of pemetrexed in urothelial cancer as part of a review article. 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 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 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, (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. 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.
2. von der Maase H: Current and future perspectives in advanced bladder cancer: Is there a new standard? Semin Oncol 29(1 suppl 3):3- 14, 2002.
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5. Sternberg CN, de Mulder PH, Schonagel JH, et al: Randomized phase III trial of highdose- intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colonystimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 19:2638- 2646, 2001.
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8. Paz-Ares L, Ciruelos E, Garcia-Carbonero R, et al: Pemetrexed in bladder, head and neck, and cervical cancers. Semin Oncol 29(6 suppl 18):69-75, 2002.
9. Scagliotti GV, Shin DM, Kindler HL, et al: Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin 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 in patients with advanced gastric cancer. Ann Oncol 14:1543-1548, 2003.
11. Bajorin DF, Dodd PM, Maunder M, et al: Long-term survival in metastatic transitional cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 17:3173- 3181, 1999.
12. Stadler WM, Hayden A, von der Maase H, et al: Long-term survival in phase II trials of gemcitabine plus cisplatin for advanced transitional cell cancer. Urol Oncol 7:153-157, 2002.
13. Sweeney C, Roth BJ, Kaufman DS, et al: Phase II study of pemetrexed (PEM) for second- line treatment of transitional cell cancer (TCC) of the bladder (abstract 1653). Proc Am Soc Clin Oncol 22:411, 2003.
14. Adjei AA: Preclinical and clinical studies with combinations of pemetrexed and gemcitabine. Semin Oncol 29(6 suppl 18):30- 34, 2002.