|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2002 American Society for Clinical Oncology Phase III Trial of Fluorouracil, Interferon Alfa-2b, and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Metastatic or Unresectable Urothelial CancerByFrom the Center for Genitourinary Oncology and Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, TX, and Cancer Center of Kansas/Wichita Community Clinical Oncology Program, Wichita, KS. Address reprints requests to Randall E. Millikan, MD, Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Box 427, 1515 Holcombe Blvd, Houston, TX 77030-4009; email: rmillika{at}notes.mdacc.tmc.edu
PURPOSE: Previously, we developed a novel biochemotherapy regimen combining interferon alfa-2b with fluorouracil and cisplatin (FAP). We now report the results of a prospective randomized trial comparing FAP with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), the standard chemotherapy regimen for locally advanced and metastatic urothelial cancer. The purpose of this study was to compare the response rates and overall survival of patients with metastatic or unresectable urothelial cancer treated with these two chemotherapy regimens. PATIENTS AND METHODS: Between October 1992 and September 1999, 172 previously untreated patients were registered and randomly assigned to treatment with either FAP or M-VAC. Patients were followed until their death. RESULTS: The pretreatment clinical characteristics of the groups were similar except for sex (P < .01). Sex did not affect prognosis or survival. The objective response rate for patients assigned to FAP was 42% (35 of 83 patients), with complete response observed in eight (10%) of 83 patients. Among the patients assigned to M-VAC, 51 (59%) of 86 had an objective response, with complete response observed in 21 (24%) of 86. The Kaplan-Meier estimate of median survival was 12.5 months for both groups. Both regimens were quite toxic, with more mucocutaneous toxicity in the FAP arm and more myelosuppression in the M-VAC arm. CONCLUSION: Although overall survival was not significantly different, patients assigned to M-VAC had a much better chance of responding to front-line therapy. Thus, FAP is very likely to be inferior to M-VAC and is certainly no less toxic. FAP cannot be recommended as part of the standard armamentarium for urothelial cancer.
NONLOCALIZED UROTHELIAL cancer is a chemosensitive disease. With the application of current multiagent chemotherapy regimens, short-term symptom palliation is reliably achieved. In addition, survival is more than doubled relative to symptomatic care alone. Nonetheless, the impact of chemotherapy in absolute terms is quite modest. For more than a decade, the median survival of patients with metastatic urothelial cancer treated with chemotherapy has been stranded on the rather modest plateau of approximately 13 months. There is growing conviction that new agents, and probably new paradigms, will have to be brought to bear in order to produce an incremental improvement from the methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) era.1-3 In 1994, Logothetis et al reported rather surprising activity for fluorouracil (5-FU) and interferon alfa-2b in patients who did not respond to first-line M-VAC.4 The overall response in this group of previously treated patients was 30%, with a median survival not yet reached at 14 months. Given the modest expectation of benefit from 5-FU as a single agent in this setting, this was a striking finding, and suggested that interferon alfa-2b might qualitatively change the impact of cytotoxic therapy. Another promising lead came from the parallel experience in non–small-cell lung cancer in which interferon potentiated the impact of cisplatin.5 In order to build on the observations with 5-FU and interferon alfa-2b, cisplatin was added,6 even though this required a reduction in the duration of exposure to interferon alfa-2b. This triplet of 5-FU, interferon alfa-2b, and cisplatin (FAP) was then formally compared with M-VAC in patients with metastatic or unresectable urothelial cancer. Herein we report the results of this phase III trial conducted at the University of Texas M.D. Anderson Cancer Center and the Community Clinical Oncology Program affiliates.
Patients One hundred seventy-two patients with either unresectable locally advanced cancer (ie, fixation to the pelvic sidewall, cT4b; or clinically node-positive disease) or distantly metastatic urothelial cancer were randomly assigned to receive chemotherapy with either M-VAC or FAP. Of those registered, 151 were enrolled at the University of Texas M.D. Anderson Cancer Center and 21 were enrolled by our Community Clinical Oncology Program affiliates. Patients were enrolled with any histologic finding that was diagnosed as being of urothelial origin. No prior systemic chemotherapy, including adjuvant or neoadjuvant therapy, was allowed. Any prior intravesical therapy was permitted. Patients had adequate physiologic reserve as demonstrated by a normal serum creatinine, or a creatinine clearance (as calculated by the method of Cockcroft-Gault)  40 mL/min; total bilirubin  2 mg/dL, and transaminases less than three times the upper limit of normal. All patients had at least bidimensionally measurable disease by either examination under anesthesia or by radiographic studies.
Treatment In the experimental arm, patients were treated with FAP on a 6-week cycle. In weeks 1 and 4, 5-FU was administered at 500 mg/m2/d as a continuous infusion for 5 days. Interferon alfa-2b (recombinant interferon alfa-2b; Schering, Kenilworth, NJ) was administered at 5 MIU/m2/d for 5 consecutive days in week 1 and week 4, and was given on Monday, Wednesday, and Friday in week 2 and week 3. Cisplatin was given at 25 mg/m2 on days 1, 8, 15, and 22. Thus, in each 6-week cycle patients were on active treatment for 4 weeks, and had 2 weeks of "rest." Patients were routinely premedicated with acetaminophen before interferon alfa-2b, and also treated prophylactically for nausea before each dose of cisplatin, with either metoclopramide or ondansetron, usually in combination with dexamethasone.
Response Criteria
Statistical Considerations
Patients Between October 1992 and September 1999, 172 patients were registered, with 86 assigned to receive FAP initially and 86 to receive standard therapy with M-VAC. Three patients (all assigned to FAP) were registered but never treated. In all three cases, either the patient or their physician refused to participate after learning their treatment assignment. Because consent to participate was immediately withdrawn, no follow-up data were collected for these patients. Baseline characteristics for the 169 patients reported are listed in Table 1. The pretreatment clinical characteristics of the groups were similar except for sex (P < .01). Sex has not been identified as a prognostic factor, and did not appear to influence survival in this study. Undoubtedly reflecting our tertiary referral practice, 37 patients (22%) had primary cancers of the upper urothelial tracts. Median age at registration was 65.5 years in the FAP arm, and 67.0 years in the M-VAC group. Overall, 56 patients (33%) were 70 years of age or older.
Toxicity and Deliverability Both of these regimens were associated with significant morbidity (Table 2). Adverse events are reported according to common toxicity criteria version 2.0, which became available in 1998, during the period of this study. To facilitate comparison with comtemporary series, toxicity data obtained before this date were retrospectively updated to common toxicity criteria version 2.0. Events are listed by treatment arm as the number of patients experiencing that adverse event.
Among patients treated with FAP, 59 (71%) of 83 experienced some nonhematologic toxicity of at least grade 3, and 45 (54%) of 83 required hospitalization for management of side effects. The most commonly encountered grade 3 nonhematologic toxicity with the FAP regimen was the expected mucocutaneous toxicity typical of 5-FU/interferon alfa-2b combinations. The median number of cycles delivered was two (range, one to five). Of the 62 patients receiving more than one cycle of FAP, 22 (35%) required a dose reduction because of toxicity. There were eight deaths within 30 days of last exposure to study drug (defined as on-study death): seven were thought to reflect toxicity of therapy, and one was thought to be from rapid disease progression. M-VAC was also associated with substantial toxicity, with 41 (48%) of 86 patients experiencing a nonhematologic toxicity of at least grade 3; 36 (42%) of 86 required hospitalization for management of side effects. The most commonly encountered toxicity of the M-VAC regimen was myelosuppression. The median number of cycles delivered was four (range, one to eight). There were eight on-study deaths: six were thought to reflect toxicity of therapy, one was secondary to rapid disease progression, and one was because of an accident apparently unrelated to the underlying cancer or treatment.
Response and Survival Among responders, the median time to progression (from registration) was 9.9 months in both arms. Response status by extent of disease at registration is shown in Table 3. Extent of disease was characterized according to three groups: locally advanced disease (including lymph nodes below the diaphragm), distant nodal and/or lung metastases, and distant extrapulmonary metastases (including intracranial and subcutaneous metastases). As expected, patients with a lower burden of disease were more likely to show an objective response.
Despite substantial toxicity associated with FAP and M-VAC, most patients went on to have a second regimen of systemic therapy. Among the 83 patients initially treated with FAP, 49 subsequently received an alternate systemic therapy at a median of 4.5 months from registration. Of these 49, 25 received M-VAC as their second regimen. Among the 86 initially assigned to M-VAC, 45 patients went on to have a second regimen, at a median of 6.5 months from registration. FAP was the second regimen in 14 M-VAC–treated patients. Patients were not followed up for response to second-line regimens because this was not mandated by the protocol. The Kaplan-Meier estimate of median all-cause survival was 12.5 months in both arms (Fig 1). As expected, overall survival was also related to extent of disease at entry (Fig 2). Patients with locally advanced disease and pulmonary or distal nodal involvement (n = 114) had a better outcome than those with nonnodal, extrapulmonary sites of metastasis (n = 55). Survival according to the categories identified in the prognostic model of Bajorin et al8 is shown in Fig 3. This model assigns a score from 0 to 2 for the presence or absence of zero, one, or two of the adverse prognostic factors identified in an analysis of the Memorial Sloan-Kettering Cancer Center (MSKCC) experience with M-VAC. These factors are as follows: presence of visceral disease (including pulmonary metastasis[es]), or a Karnofsky performance status less than 80%. For those with zero adverse factors, we observed an estimated median survival of 19.7 months, with an estimated 25% overall survival at 42 months. As shown in Fig 3, we did not observe a significant difference in outcome between the groups with one or two adverse prognostic factors (median survival, 10.1 and 8.6 months, respectively).
Among patients assigned to FAP, five are alive and free of disease, with a median follow-up of 61 months. Of these five patients, three received second-line therapy with M-VAC and four underwent surgical resection of residual disease. None obtained a durable complete remission with first-line FAP alone. Among patients assigned M-VAC, a total of 11 patients are alive and free of disease, with a median follow-up of 60 months. Of these 11 patients, four had a durable complete response to initial chemotherapy. The remaining seven were rendered free of disease with further chemotherapy and surgical resection. Of the 79 initially presenting with disease limited to the primary site and nodes below the renal hila, only three (all treated with M-VAC) are alive and free of disease from chemotherapy alone. Twenty went on to have consolidative surgery with curative intent (11 from the M-VAC arm and nine from the FAP group). The median survival in this group was 63.8 months from initiation of chemotherapy and 55.2 months from resection. Of these 20 patients, 11 remain disease free with a median follow-up of 51.8 months from surgery. Of the 35 patients with distant nodal or pulmonary disease, only one (treated with M-VAC) is alive and free of disease from chemotherapy alone. Ten went on to have consolidative surgery (nine from the M-VAC group and one from the FAP group). The median survival in this group was 19.0 months from initiation of chemotherapy and 11.2 months from resection. Only one of these 10 patients remains disease free, now surviving 31 months from surgery.
The FAP regimen represents our first attempt to incorporate noncytotoxic "response modifiers" into the treatment of urothelial cancer. We chose a regimen using an intermittent interferon alfa-2b schedule in which patients received interferon alfa-2b on only 16 days out of each 42-day cycle. It is likely that this is not the optimal schedule for interferon alfa-2b. Recent model studies in nude mice indicate that, with respect to suppression of angiogenic phenotype, low-dose, continuous exposure schedules are more biologically active than high-dose or intermittent interferon alfa-2b schedules.9 Thus, although this trial failed to establish FAP as a more active regimen than M-VAC, we may not have used the optimal interferon alfa-2b schedule. A low-dose, continuous exposure schedule of interferon alfa-2b might be a more appropriate test of the hypothesis that interferon alfa-2b can qualitatively improve outcome when combined with chemotherapy for metastatic urothelial cancer. Both regimens were associated with significant morbidity and mortality. The most commonly encountered toxicity for FAP was mucocutaneous toxicity. Myelosuppression was the most common toxicity in patients receiving M-VAC. The number of patients requiring hospitalization to manage toxicity emphasizes both the economic impact and the effect on quality of life of these treatment regimens. Treatment-related mortality was similar in both arms, at 9%. For comparison, the Eastern Cooperative Oncology Group phase III trial of M-VAC versus cisplatin alone encountered drug-related mortality in five (4%) of 126 M-VAC–treated patients.10 An additional two patients who were subsequently crossed over to M-VAC (after cisplatin failed) experienced treatment-related mortality. A recently published phase II study by Kosmidis et al used FAP as first-line treatment in a small group of patients with advanced urothelial cancer.11 They observed an objective response in 22 (65%) of 34 patients, with a complete response in six (18%) of 34 patients. The median survival was 15.3 months. Despite these encouraging results from Kosmidis et al,11 this large phase III study found the objective and complete response rates of FAP were inferior to those of M-VAC (Table 3). There is a potential for bias in these results because responses for these two regimens were evaluated at different intervals: 8 weeks for M-VAC and 12 weeks for FAP. It is possible that more responses were captured on the M-VAC arm because radiologic evaluations were performed at more frequent intervals. In the initial design of this study, survival was to be analyzed by intention to treat. Three patients, all assigned to FAP, refused to participate after learning the treatment assignment. As study consent was immediately withdrawn, follow-up data were not collected for these patients. In an effort to evaluate the potential impact of these patients on our survival results, the data were analyzed on the basis of two different assumptions: that patients were alive at the time of analysis and that they died immediately. There was no difference in the Kaplan-Meier estimate of median survival using the best- and worst-case scenarios for these three patients (data not shown). Therefore, the exclusion of these patients did not affect our conclusions. The observed influence of established prognostic factors on survival was generally in keeping with the results reported by Bajorin et al.8 In these benchmark data, patients with no risk factors had a median survival of 33 months. Those with one or two risk factors had a median survival of 13.4 and 9.3 months, respectively. In the present trial, patients with no adverse factors had a median survival of 19.7 months. Those with one or two risk factors had a median survival of 10.1 and 8.6 months, respectively, which was not statistically significant in our series. Despite the significant objective and complete response rates observed, only four patients, all treated with M-VAC, are alive and free of disease from chemotherapy alone. Through further consolidative surgery, an additional 12 patients are alive and free of disease. Of the 20 patients who underwent resection for disease initially limited to the primary site with nodes below the renal hila, 11 remain alive and disease free at a median follow-up of 51.8 months from surgery. A similar group of patients who underwent resection at the MSKCC found nine of 20 patients alive at 5 years.12 Of the 10 patients who underwent consolidative surgery for initial distant nodal or pulmonary disease, only one remains disease free, now surviving 31 months from surgery. A comparable group from MSKCC had seven of 30 patients alive at 5 years.12 The results obtained in the standard arm of this trial were within historical expectation for M-VAC.1,2,10 Sadly, even combining "consolidative surgery" in selected patients, only 11 (13%) of 86 patients remain without evidence of disease for more than 3 years from registration. Eight of these were from the 37 with locally advanced disease, two were from the 23 patients with distant nodal or pulmonary disease, and only one was from the 26 with extrapulmonary involvement. Similarly, 13 (10%) of 121 MSKCC patients and five (4%) of 126 from the Eastern Cooperative Oncology Group trial remained continuously disease free. In view of such a limited expectation from standard care, it is clear that we must continue to explore new agents and new paradigms. Previous attempts to improve therapy with M-VAC have included escalating doses13,14 and adding G-CSF.15 Recently Sternberg et al and the European Organization for Research and Treatment of Cancer16 demonstrated that twice the dose density of cisplatin and doxorubicin can be achieved by the addition of G-CSF. In this phase III trial versus "classic" M-VAC, there was no improvement in overall survival. However, this dose-dense regimen showed a significant benefit in both rate of response and progression-free survival, and it was less toxic. In addition, M-VAC has been compared with single-agent cisplatin,10 with an analogous regimen substituting carboplatin for cisplatin,17,18 and with the doublet gemcitabine/cisplatin.19 Despite evidence that the latter is less toxic and of comparable activity, it is remarkable that in more than 15 years, no combination has yet outperformed the original regimen of Sternberg et al.7 More recently, other combinations based on either ifosfamide or gemcitabine have shown encouraging results; it is likely that several available regimens are at least as good as M-VAC.20,21 Of particular interest is the possibility of building new therapies not out of individual drugs, but from combinations of optimized doublets or triplets as the building blocks. This is reflected in ongoing work at MSKCC.21 Recently, we have described methodology for explicitly accounting for second-line responses in the setting of multiple courses of therapy in which treatment is altered in the face of inadequate response.22 Although these refinements may help us to get the most benefit out of available therapy, the need for qualitatively better treatments is clear. In conclusion, the FAP regimen produced an inferior rate of complete response and overall response compared with M-VAC. Although overall survival was not significantly different, most patients went on to have second-line therapy, and we do not believe that FAP should be considered to be comparably active. FAP was associated with unacceptable levels of grade 3/4 mucositis (35%), nonhematologic toxicity (71%), and constitutional toxicity (17%). FAP cannot be considered part of the established armamentarium for urothelial cancer.
Supported in part by grant nos. CA45809-13 from the National Cancer Institute, Bethesda, MD. Interferon alfa-2b was provided by grant no. U01 CA70172 from the Cancer Therapy Evaluation Program, within the Division of Cancer Treatment of the National Cancer Institute.
1. Sternberg CN, Yagoda A, Scher HI, et al: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium: Efficacy and patterns of response and relapse. Cancer 64: 2448-2458, 1989[CrossRef][Medline] 2. Logothetis CJ, Dexeus FH, Finn L, et al: A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 8: 1050-1055, 1990[Abstract] 3. Sternberg CN, Calabro F: Chemotherapy and management of bladder tumours. BJU Int 85: 599-610, 2000[CrossRef][Medline] 4. Logothetis CJ, Hossan E, Recondo G, et al: 5-Fluorouracil and interferon-alpha in chemotherapy refractory bladder carcinoma: An effective regimen. Anticancer Res 14: 1265-1269, 1994[Medline]
5.
Bowman A, Fergusson RJ, Allan SG, et al: Potentiation of cisplatin by alpha-interferon in advanced non-small cell lung cancer (NSCLC): A phase II study. Ann Oncol 1: 351-353, 1990 6. Logothetis CJ, Dieringer P, Ellerhorst J, et al: A 61% response rate with 5-fluorouracil, interferon-2alpha and cisplatin in metastatic chemotherapy refractory transitional cell carcinoma. Proc Am Assoc Cancer Res 33: 221, 1992 (abstr 1323) 7. Sternberg CN, Yagoda A, Scher HI, et al: M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol 139: 461-469, 1988[Medline]
8.
Bajorin DF, Dodd PM, Mazumdar 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
9.
Slaton JW, Perrotte P, Inoue K, et al: Interferon-alpha-mediated down-regulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule. Clin Cancer Res 5: 2726-2734, 1999 10. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: A cooperative group study. J Clin Oncol 10: 1066-1073, 1992 (published erratum appears in J Clin Oncol 11:384, 1993)[Abstract]
11.
Kosmidis PA, Bacoyiannis C, Fountzilas G, et al: 5-Fluorouracil, interferon-alpha-2b and cisplatin (FAP) for advanced urothelial cancer: A phase II study—Hellenic Co-operative Oncology Group. Ann Oncol 8: 373-378, 1997
12.
Dodd PM, McCaffrey JA, Herr H, et al: Outcome of postchemotherapy surgery after treatment with methotrexate, vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma. J Clin Oncol 17: 2546-2552, 1999
13.
Logothetis CJ, Finn LD, Smith T, et al: Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: Results of a randomized trial. J Clin Oncol 13: 2272-2277, 1995 14. Dodd PM, McCaffrey JA, Mazumdar M, et al: Phase II trial of intermediate dose methotrexate in combination with vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma. Cancer 85: 1145-1150, 1999[CrossRef][Medline] 15. Loehrer PJ, Elson P, Dreicer R, et al: Escalated dosages of methotrexate, vinblastine, doxorubicin, and cisplatin plus recombinant human granulocyte colony-stimulating factor in advanced urothelial carcinoma: An Eastern Cooperative Oncology Group trial. J Clin Oncol 12: 483-488, 1994[Abstract]
16.
Sternberg CN, de Mulder PHM, Schornagel JH, et al: Randomized phase III trial of high–dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating 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 17. Petrioli R, Frediani B, Manganelli A, et al: Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients: A randomized phase II study. Cancer 77: 344-351, 1996[CrossRef][Medline] 18. Bellmunt J, Ribas A, Eres N, et al: Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer 80: 1966-1972, 1997[CrossRef][Medline]
19.
von der Maase 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 18: 3068-3077, 2000
20.
Bellmunt J, Guillem V, Paz-Ares L, et al: Phase I-II study of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma of the urothelium: Spanish Oncology Genitourinary Group. J Clin Oncol 18: 3247-3255, 2000
21.
Dodd PM, McCaffrey JA, Hilton S, et al: Phase I evaluation of sequential doxorubicin gemcitabine then ifosfamide paclitaxel cisplatin for patients with unresectable or metastatic transitional-cell carcinoma of the urothelial tract. J Clin Oncol 18: 840-846, 2000 22. Thall PF, Millikan RE, Sung HG: Evaluating multiple treatment courses in clinical trials. Stat Med 19: 1011-1028, 2000[CrossRef][Medline] Submitted June 21, 2001; accepted November 5, 2001.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
