Introduction 

The development of combination chemotherapy in the treatment of locally advanced or metastatic bladder cancer almost 20 years ago has prolonged the median survival for patients with this disease. The combination of methotrexate, vinblastine, doxorubicin and Platinol® (MVAC) had been considered the standard of care until the year 2000 when a large phase III randomized trial demonstrated the equivalence of Gemzar® and Platinol® (GC) when given in combination. ¹ Treatment related mortality and neutropenic sepsis were both lower in the GC arm suggesting that MVAC should no longer be considered the only treatment for this group of patients. At ASCO 2003 new combinations of Gemzar®-based therapy were explored for the treatment of patients with locally advanced or metastatic bladder cancer. 

First-line therapy with agents given as doublets

One of the two randomized Gemzar®-based doublets presented at this year’s meeting was a phase II trial comparing Gemzar® with either Platinol® or Paraplatin® in previously untreated patients. ² Interestingly, the main outcome measure was toxicity and tolerability with response rate, time to treatment failure, and median survival being secondary endpoints. Patients were treated with Gemzar® at 1250mg/m2 on day 1 and day 8 and randomized to receive either Platinol® (GP) 70mg/m2 or Paraplatin® (GC), AUC 5, on day 2 of each three week cycle. In the GP group 56 patients received a median of 4.7 cycles and in the GC group 57 patients received a median of 4.6 cycles. The hematologic toxicities were significant and are shown in Table 1. The non-hematologic toxicities were generally mild, including no grade 3/4 renal toxicity and grade 3/4 nausea and vomiting occurred in 9% of the GP group and 4% of the GC group. Growth factor support was required for almost one-third of the patients in both groups and transfusions were more common in the GC group (see Table 1). No statistical comparisons between the two groups were made for any of the measures reported in the study. The overall response rate was 66% in the GP group and 59% in the GC group (Table 2). Due to the limited follow-up and the phase II nature of the study, the outcome measures are preliminary and not subject to statistical analysis. The median overall survival is shown in Table 2. The authors concluded that both regimens were active in locally advanced or metastatic bladder cancer and no difference in efficacy or toxicity has been shown to date.

Garcia del Muro presented one of two Gemzar®-Taxotere® doublets tested in the first-line setting. ³ Knowing that Taxotere® and Gemzar® each have single agent activity against advanced or recurrent bladder cancer, these investigators tested the combination of Taxotere® given at 65mg/m2 on day 1 and Gemzar® 2000mg/m2 on day 1 given every 2 weeks for a maximum of eight cycles or until disease progression (GD). Forty-two patients were treated for a median of 6.5 cycles. The major toxicities were hematologic and are shown in Table 1. There was one episode of febrile neutropenia. The major non-hematologic toxicity was asthenia which occurred in 14% of the treated patients. The overall response rate for the 37 evaluable patients was 56% (Table 2). The authors conclude that the combination of GD appears to be effective and well tolerated in this group of patients.

Table 1. Hematologic toxicities, growth factor support and transfusion requirements for selected doublets.

# Treatment abbreviations: G-Gemzar®, P-Platinol®, C-Paraplatin®, D-Taxotere®

*N/A – not available

The other study that tested a Gemzar®-Taxotere® doublet was presented by Boyer et al. ⁴ Untreated patients were treated with either Gemzar® 1000mg/m on days 1 and 8 with Paraplatin® AUC 5 on day 1 (GC) or Gemzar ®1200mg/m on days 1 and 8 with Taxotere® 85mg/m on day 8 (GD) both regimens being repeated every 3 weeks. Of the 57 patients completing therapy, the overall response rates were 37% for the GC group and 47% for the GD group. Table 2 details the response rates and survival outcome. There was significant hematologic toxicity, but no treatment related deaths. Both treatments have activity with the GD arm being better tolerated.

Li et al treated 34 patients with weekly paclitaxel and Gemzar® (GT). ⁵ They were treated with two dose schedules, the lower one containing paclitaxel at 90mg/m2 and Gemzar® at 800mg/m2. There were no episodes of neutropenic fever, despite 36% of the patients experiencing grade 3/4 granulocytopenia. There were two treatment related deaths due to pulmonary toxicities even after lowering the dose to the levels described above. The overall response rate for 33 evaluable patients was 67%, Table 2. Despite the activity seen with this regimen, the associated toxicities are concerning.

In an effort to overcome some of the toxicities found in the well studied combination of Gemzar® and Platinol® reported by von der Maase in 2000, a group of British investigators studied the response and toxicity in a regimen using a fractionated dose of Platinol®. ^1,6 Patients were treated with Gemzar® given at 1000mg/m on day 1 and 8 and Platinol® given at 35mg/m on day 1 and 8 over a 3 week cycle (GP). Patients were treated for a maximum of six cycles or until disease progression. The regimen was well tolerated in the 32 enrolled patients with only 3 grade IV toxicities in total at the dosages described here. There was an overall response rate of 66%, Table 2. After a median follow-up of 14 months, the median survival was 14 months. This may prove to be a useful regimen for patients with impaired renal function as 50% (16/32) of the patients included in the study had a GFR between 40 and 60ml/min.

Table 2. Response rates and outcome of Gemzar®-based doublet therapy.

# Treatment abbreviations: G-Gemzar®, P-Platinol®, C-Paraplatin®, D-Taxotere®, T-paclitaxel
*N/A – not available

First-line therapy with agents given as triplets

von der Maase et al. reported on triplet therapy using Gemzar®, Platinol® and paclitaxel (GPT). ⁷ The regimen was given as follows: Gemzar® 1000mg/m2 on days 1 and 8, Platinol® 70mg/m2 on day 1, and paclitaxel 175mg/m2 on day 1 given over 3 hours all repeated every 3 weeks for a maximum of 6 cycles or until disease progression. Forty-seven patients received a median of 6 cycles of therapy. The major toxicities were hematologic with 30% of patients having grade 3/4 neutropenia and 4 episodes of neutropenic fever. The overall response rate was 60% and is detailed in Table 3. The authors conclude that this triplet combination shows encouraging activity with acceptable toxicity and is now the subject of a phase III EORTC trial to compare it to a standard Gemzar based regimen.

The Minnie Pearl Cancer Research Network reported their experience with paclitaxel, Paraplatin® and Gemzar® (GCT). ⁸ Patients were treated with paclitaxel at 200mg/m2 over 1 hour on day 1, Paraplatin® AUC 5 on day 1, and Gemzar® 1000mg/m2 on days 1 and 8 with the entire regimen repeated every 3 weeks. Almost all the doses were given on schedule with the exception of the second Gemzar dose which was delayed in 32% of the patients. The overall response rate was 50%, Table 3. The overall median survival was 11 months and the progression-free survival was 8 months. While this regimen proved to be feasible and well tolerated the addition of Paraplatin® to the previously studied regimen of paclitaxel and Gemzar® does not seem to improve response rates or overall survival.

Hussain et al. reported their results in patients who were HER2-positive and treated with the combination of Herceptin®, paclitaxel, Paraplatin® and Gemzar® on a 3 week schedule (GCTH). ⁹ Of the 73 patients tested, 37 (51%) overexpressed HER2 based on IHC or ELISA. Of these patients, the major toxicities were hematologic with 35% of patients experiencing grade 3/4 neutropenia, 30% with grade 3/4 thrombocytopenia and 2 episodes of neutropenic fever. The overall response rate in 28 evaluable patients to date was 54%, Table 3. It appears that the majority of tumors overexpressed HER2 and this regimen it tolerable and active in patients with advanced, metastatic or recurrent bladder cancer.

Table 3. Response rates and outcome of Gemzar®-based triplet therapy.

# Treatment abbreviations: G-Gemzar®, P-Platinol®, C-Paraplatin®, T-paclitaxel, H-Herceptin®

*N/A – not available

Conclusion

These trials all offer alternatives to treatment with Gemzar® and Platinol® given in combination for patients with locally advanced or metastatic bladder cancer. Based on the data presented, all regimens seem to have some activity and, except for the weekly Gemzar®-paclitaxel combination, most are well tolerated. To date, none have clearly been proven to be superior to Gemzar® and Platinol® when given in combination. If a well-designed phase III trial can accrue an adequate number of patients it may be possible to determine if one of these regimens is more favorable and should be considered as a new standard of care. Until that time the standard of care for patients who can tolerate combination chemotherapy remains either Gemzar® and Platinol® or MVAC with growth factor support.

References :

1. von der Maase H, Hansen SW, Roberts JT, et al. Gemzar and Platinol versus methotrexate, vinblastine, doxorubicin, and Platinol in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18:3068-77.

2. Carteni G, Dogliotti L, Crucitta E et al. Phase II randomised trial of Gemzar plus Platinol (GP) and Gemzar plus Paraplatin (GC) in patients (pts) with advanced or metastatic transitional cell carcinoma of the urothelium (TCCU). Proc Amer Soc Clin Oncol 2003;22 abstract # 1543.

3. Garcia Del Muro X, Marcuello E, Mellado B et al. Phase II multicenter study of Taxotere plus Gemzar as first-line treatment in advanced urothelial cancer. Proc Amer Soc Clin Oncol 2003;22 abstract # 1643.

4. Boyer MJ, Gurney H, Rosenthal MA, et al. Randomised phase II study of Gemzar (G) with either Paraplatin (C) or Taxotere (D) in patients with locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium: Preliminary results. Proc Amer Soc Clin Oncol 2003;22 abstract # 1568.

5. Li J, Juliar B, Ansari R, et al. A Hoosier Oncology Group phase II study of weekly paclitaxel (P) and Gemzar (G) in advanced transitional cell carcinoma (TCC) of the urothelium. Proc Amer Soc Clin Oncol 2003;22 abstract # 1639.

6. Hussain SA, Stocken D, Riley P, et al. A phase I/II outpatient study of Gemzar (G) and fractionated Platinol (C) in advanced, relapsed and metastatic bladder cancer in a 21-day schedule. Proc Amer Soc Clin Oncol 2003;22 abstract # 1570.

7. von der Maase H, Geertsen PF, Baekke J, et al. Gemzar, Platinol, and paclitaxel (GCP) as first-line treatment of locally advanced and metastatic transitional cell carcinoma (TCC) of the urothelium. Proc Amer Soc Clin Oncol 2003;22 abstract # 1646.

8. Thompson DS, Hainsworth JD, Greco FA, et al. Paclitaxel, Paraplatin, Gemzar in advanced transitional cell carcinoma (TCC) of the urothelial tract: A phase II Minnie Pearl Cancer Research Network trial. Proc Amer Soc Clin Oncol 2003;22 abstract # 1650.

9. Hussain M, Smith DC, Vaishampayan U, et al. Trastuzumab (T), paclitaxel (P), Paraplatin (C) and Gemzar (G) in patients with advanced urothelial cancer and overexpression of HER-2. (NCI study#198). Proc Amer Soc Clin Oncol 2003;22 abstract # 1569.