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Outcome of Postchemotherapy Surgery After Treatment With Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Patients With Unresectable or Metastatic Transitional Cell Carcinoma

From the Genitourinary Oncology Service, Division of Solid Tumor, Oncology, Department of Medicine; Division of Urology, Department of Surgery; Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center; Department of Medicine, Cornell University Medical College, New York, NY.

Address reprint requests to Dean F. Bajorin, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021

	ABSTRACT

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PURPOSE: The role of postchemotherapy surgery for patients with metastatic transitional cell carcinoma (TCC) is controversial. We retrospectively analyzed our experience with patients who underwent postchemotherapy surgery after methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy to assess an impact on long-term survival.

PATIENTS AND METHODS: This report is based on the retrospective analysis of 203 patients with unresectable primary tumors or metastatic TCC, previously reported in five trials of M-VAC chemotherapy. Fifty patients underwent postchemotherapy surgery for suspected or known residual disease. Characteristics of patients selected for surgery, results of surgery, and the impact of surgery on survival were assessed.

RESULTS: In 17 patients, no viable tumor was found at postchemotherapy surgery, pathologically confirming a complete response to chemotherapy. Three patients had unresectable residual TCC. In 30 patients, residual, viable TCC was completely resected, which resulted in a complete response to chemotherapy plus surgery. Ten (33%) of these 30 patients remained alive at 5 years, similar to results observed for patients who attained a complete response to chemotherapy alone (41%). Analysis by baseline extent of disease suggested that patients with unresectable primary tumors or with metastases restricted to lymph node sites were most likely to survive for 5 years.

CONCLUSION: Postchemotherapy surgical resection of residual cancer may result in 5-year disease-free survival in some patients who would otherwise succumb to disease. Optimal candidates include patients whose prechemotherapy sites of disease are restricted to the primary or lymph node sites and who have a major response to chemotherapy.

	INTRODUCTION

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CHEMOTHERAPY IS THE mainstay of treatment for metastatic or unresectable urothelial cancer. Transitional cell carcinoma (TCC) is the most common histology and is a chemotherapy-sensitive malignancy. The activity of the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) in unresectable or metastatic TCC is well documented. An initial trial in 121 patients treated with this chemotherapy regimen at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, NY, reported a 72% major response rate, including 36% of patients rendered disease-free by chemotherapy alone or chemotherapy in combination with postchemotherapy surgery.¹ A complete response (CR), after either chemotherapy alone or chemotherapy in combination with postchemotherapy surgery, is the best correlate of prolonged survival and a prerequisite for cure in patients treated with M-VAC.^1,2

Although the use of postchemotherapy surgery to resect viable residual cancer to achieve CR is well defined in other genitourinary tumors, it is not well defined in urothelial cancer. Several studies suggest that postchemotherapy surgery may have an impact on survival. In the original MSKCC M-VAC series, 13 patients who had complete resection of viable tumor at postchemotherapy surgery achieved a median survival time of 25 months. Several of these patients achieved long-term (greater than 5-year) survival. Using postchemotherapy surgery after cisplatin, methotrexate, and vinblastine chemotherapy, investigators at Stanford University reported 14 patients who attained a CR with chemotherapy plus surgery, five of whom were disease-free at 18 to 79 months.³ In a phase II trial of vinblastine, ifosfamide, and gallium nitrate, postchemotherapy surgery contributed to CR in six of 11 patients who achieved disease-free status, at least three of whom remained disease-free at the time of the report.⁴ One proposed rationale for the use of postchemotherapy surgery is the high incidence of relapse at prior sites of disease,⁵ and a recent report emphasized the value of combined-modality therapy in selected patients with initially unresectable bladder cancer, both in terms of improved survival and palliation of pelvic cancer.⁶ Despite these data, the impact of postchemotherapy surgery in patients with metastatic TCC is not well characterized and remains controversial. In particular, questions remain regarding long-term survival and case selection for postchemotherapy surgery.

This retrospective analysis of our experience with postchemotherapy surgery was conducted using the records of more than 200 patients treated on five consecutive M-VAC chemotherapy trials for patients with unresectable or metastatic TCC. Our aims were to gain further insight into the survival impact of postchemotherapy surgery on this disease and to guide selection of patients who might benefit most from this multimodality approach.

	PATIENTS AND METHODS

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Patient Population
Two hundred twenty-nine patients have been reported in five trials of M-VAC chemotherapy conducted at our institution between 1983 and 1994 (Table 1). One hundred thirty-three patients were treated with standard-dose M-VAC in a phase II setting.¹ Twenty-seven patients were enrolled onto a trial of recombinant human granulocyte colony-stimulating factor (rh-G-CSF) with standard-dose M-VAC.⁷ Twenty-nine patients were treated in a trial of intermediate-dose methotrexate (1,000 mg/m² per cycle) and standard-dose VAC.⁸ Twenty-three patients were treated in a phase I trial testing the feasibility of dose-intense M-VAC with rh-G-CSF.⁹ Finally, 17 patients were randomized to receive M-VAC as initial therapy in a phase II randomized comparison of dose-intense M-VAC with rh-G-CSF and gallium nitrate plus fluorouracil.¹⁰ Of these 229 patients, 26 were excluded from the current analysis: three had urothelial tumors of non-TCC histology, four were treated in an adjuvant setting, and 19 had clinical tumor-node-metastasis stages T3bN0. The remaining 203 patients, treated with M-VAC chemotherapy for unresectable or metastatic TCC, were eligible for this analysis.

Inclusion criteria for the five studies were similar.^1,7-10 TCC was confirmed histologically at MSKCC in all cases. In the first study, a low Karnofsky performance status (KPS) was not an exclusion criterion, whereas patients who had KPS less than 60% were excluded from the other four trials. Patients with known brain metastasis were excluded from all studies. Adequate renal, hepatic, and cardiac function was required in all cases. All trials were approved by the institutional review board at MSKCC, and informed consent was given by all patients.

Patients received a median of four cycles of M-VAC chemotherapy (range, one to 12 cycles). Response to chemotherapy was evaluated after every two cycles of M-VAC, unless otherwise clinically indicated. After maximum response to chemotherapy was determined, suitable patients were referred for postchemotherapy surgery. Prospective criteria for consideration of postchemotherapy surgery were not defined; multidisciplinary evaluation of suitability was performed on a case-by-case basis. Ultimately, 50 (24%) of 203 patients underwent postchemotherapy surgery in an attempt to achieve or confirm CR status and form the basis of this report. Patients in whom postchemotherapy surgery was performed for palliation or at the time of relapse were excluded from the analysis of postchemotherapy surgery. Four patients in whom pathologic confirmation of CR was obtained by nonsurgical means (percutaneous biopsy or cystoscopy with biopsy) were also excluded.

Response Criteria
Response criteria for all trials of M-VAC chemotherapy were similar and have previously been defined.^1,8,10 CR was defined as the disappearance of all clinical or radiographic evidence of tumor for a minimum of 4 weeks. CR was determined by noninvasive means or confirmed pathologically at postchemotherapy surgery or by percutaneous biopsy. Whether determined by clinical or pathologic evaluation, the absence of detectable disease after M-VAC chemotherapy reflects the effect of chemotherapy alone (CR-chemotherapy). When residual, viable cancer was detected and completely resected at postchemotherapy surgery, CR was considered to result from the combined effects of chemotherapy plus postchemotherapy surgery (CR-chemotherapy-+-surgery). A partial response (PR) represented a greater than 50% decrease in the summed products of the longest perpendicular diameters of all measured lesions without simultaneous increase in size of any lesion or appearance of new lesions for more than 4 weeks. For unresectable primary tumors, PR was defined as downstaging of the primary tumor by two or more clinical stages as determined by examination under anesthesia and cystoscopy. A nonresponse (NR) was defined by failure to meet criteria for a response or for progression. Progression was defined as a greater than 25% increase in tumor size, the appearance of new lesions, or a mixed response to therapy. Before postchemotherapy surgery, CR-chemotherapy or CR-chemotherapy + surgery may have been categorized clinically as CR, PR, NR, or progression. The major response category included CR-chemotherapy and PR. CR-chemotherapy-+-surgery was not considered a major response unless CR or PR to M-VAC was documented before postchemotherapy surgery.

Survival duration was defined as the interval from the start of therapy to the date of last follow-up or death. Survival was estimated by the method of Kaplan and Meier.¹¹ Response proportions were estimated assuming binomial distribution. Nineteen patients remain alive with a median follow-up period of 113 months (range, 34 to 167).

	RESULTS

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Patient Characteristics
The subset of 50 patients who underwent postchemotherapy surgery had less extensive disease than the overall population of 203 patients with unresectable or metastatic disease treated with M-VAC chemotherapy (Table 2). Most patients (72%) who underwent postchemotherapy surgery had baseline extent of disease restricted to the lymph nodes or to an unresectable tumor without definite lymph node metastasis. No patient with more than one anatomic site of visceral metastatic disease at baseline underwent postchemotherapy surgery. For the 50 patients who underwent postchemotherapy surgery, the clinical responses to chemotherapy were CR (n = 8), PR (n = 33), NR (n = 7), and not assessable (n = 2).

Thirty patients (60%) subjected to postchemotherapy surgery underwent complete resection of residual tumor at postchemotherapy surgery (CR-chemotherapy-+-surgery). Seventeen patients (34%) had no viable tumor at postchemotherapy surgery, thus providing pathologic confirmation of CR to chemotherapy (CR-chemotherapy). Three patients (6%) had unresectable residual tumor and therefore did not attain a CR.

Analysis by Baseline Extent of Disease
The 50 patients who underwent postchemotherapy surgery were further analyzed according to baseline extent of disease, which was divided into five categories: T4 tumor only; primary tumor plus regional lymph nodes; primary tumor plus distant lymph nodes; primary tumor plus visceral metastasis; and metastatic disease only (Tables 3 through 7). Forty patients had disease at the primary site at the initiation of M-VAC chemotherapy (primary site: bladder, 35 patients; renal pelvis, three patients; ureter, one patient; and urethra, one patient). Ten patients had metastatic disease without disease at the primary site at baseline, having undergone previous definitive therapy for the primary tumor.

Primary tumor plus regional lymph nodes.
Sixteen patients had baseline extent of disease consisting of a primary bladder tumor plus regional lymphadenopathy (Table 4). At postchemotherapy cystectomy, nine patients underwent complete resection of residual viable disease, six had no residual cancer, and one patient's tumor was unresectable. Among patients with residual disease, all had persistent disease in the bladder, but only two had persistent lymph node involvement. Six (38%) of the 16 patients in this group were alive at 5 years, three who had residual cancer at postchemotherapy surgery and three who were disease-free. Among the six patients who survived for 5 years, three patients died of disease at 6, 8, and 11 years, one died of uncertain causes at 10 years, one remains alive with disease at 14 years, and one is relapse-free 9 years after treatment.

Primary tumor plus distant lymph nodes.
The third group consists of 11 patients with baseline extent of disease consisting of a primary tumor plus extraregional lymph node or soft tissue disease (Table 5). The primary tumor site was the bladder in eight patients, renal pelvis in one, ureter in one, and urethra in one. Sites of metastatic disease included the retroperitoneal lymph nodes in eight patients, the inguinal lymph nodes in one, supraclavicular lymph nodes in one, and peritoneal carcinomatosis plus retroperitoneal lymph nodes in one. Postchemotherapy surgery in this group consisted of cystectomy in seven patients, exploratory laparotomy with ureterectomy, lymph node resection, and/or biopsy in three patients, and nephroureterectomy in one patient. Five patients underwent complete resection of residual disease, five were disease-free, and one had unresectable disease. For the five patients who underwent resection of residual cancer, tumor was located in the primary organ; in no case was persistent metastatic disease documented. Only two (18%) of 11 patients in this group were alive at 5 years, one patient who had residual disease at postchemotherapy cystectomy and one who was disease-free at exploratory laparotomy. These two patients remain disease-free 12 and 13 years after treatment.

Primary tumor plus visceral metastases.
The fourth group consists of nine patients with baseline extent of disease consisting of a primary tumor, variable lymph node involvement, and a solitary site of visceral metastasis (Table 6). The primary site was the bladder in seven patients and renal pelvis in two. Seven patients had pulmonary disease and two had bone disease at baseline. Postchemotherapy surgery was directed at the primary site of disease in all patients, and included cystectomy in six patients, nephroureterectomy in two, and palliative urinary diversion in one. Seven patients underwent complete resection of viable tumor, one patient had no residual disease, and one had unresectable disease. Persistent primary tumor site involvement was noted in all patients with residual disease, whereas only two had persistent lymph node involvement. One patient was alive at 5 years and remains relapse-free at 7 years.

Metastatic disease only.
The final group consists of 10 patients whose baseline extent of disease consisted of metastatic disease without disease at the primary tumor site (Table 7). Prior therapy in this group included radical cystectomy (n = 4), partial cystectomy (n = 2), definitive radiation (n = 2), transurethral resection (n = 1), and nephrourecterectomy (n = 1). Sites of disease included lymph node and soft tissue sites in five patients and visceral sites in five patients (Table 6). Surgery was directed at the metastatic site in this group of patients and included thoracotomy (n = 5), exploratory laparotomy (n = 4), and resection of an abdominal wall mass (n = 1). Residual tumor was detected in six patients, and four patients were disease-free at postchemotherapy surgery. Three patients were alive at 5 years after complete resection of residual tumor and one patient was disease-free. Three patients remain disease-free at 7, 10, and 14 years after treatment; one died of recurrent TCC at 8 years.

Correlates of Long-Term Survival
Among 30 patients who attained CR-chemotherapy-+-surgery, 24 had primary site tumors at baseline. In all 24, postchemotherapy surgery was directed at the primary tumor site. Residual viable cancer was found in the primary organ in all 24 patients and was invasive in 22. Specifically, five patients had p4a tumors, five had p3b tumors, 10 had p2 or p3a tumors, and two had p1 tumors. Two patients, one each with a renal pelvis and bladder primary tumor, had carcinoma-in-situ only at postchemotherapy surgery. Sites of clinically evident or pathologically proven lymph node disease before chemotherapy were frequently disease-free at postchemotherapy surgery.

Two patients (20%) among 10 who had p3b disease and five (36%) of 14 who had p3a disease survived for 5 years. In contrast, none of the four patients who had persistent tumor involvement of lymph nodes at postchemotherapy surgery survived for 5 years.

Response to chemotherapy also correlated with likelihood of 5-year survival after postchemotherapy surgery. No patient categorized as a nonresponder to chemotherapy was alive at 5 years.

Survival in Patients Who Underwent Postchemotherapy Surgery
Among the 203 patients in the M-VAC treatment population, 194 were assessable for response (Table 8). Seventy-six patients attained disease-free status, including 46 patients with CR-chemotherapy and 30 with CR-chemotherapy-+-surgery. Among the 46 patients with CR-chemotherapy, 25 were determined to be disease-free by noninvasive means, four had histologic confirmation by percutaneous biopsy or cystoscopy with biopsy, and 17 had confirmation at postchemotherapy surgery. The remaining 118 patients did not attain disease-free status. Survival curves are shown for patients who attained CR-chemotherapy, patients who had CR-chemotherapy-+-surgery, and patients who were not rendered free of disease (Fig 1).

View larger version (20K): [in this window] [in a new window]   Fig 1. Survival of complete responders. Tick mark (|) indicates last follow-up.

Among the 46 patients who attained CR-chemotherapy, the median survival time was 46 months (95% confidence interval [CI], 32 to 79 months), and 41% survived for 5 years. For 17 patients who underwent postchemotherapy surgery with pathologic proof of CR-chemotherapy, the median survival time was 42 months (95% CI, 26 to 120 months). Six (35%) of these 17 patients survived for 5 years. Four remain alive and continuously free of disease at the time of last follow-up 6, 9, 13, and 14 years after treatment. Two patients died at 8 and 10 years after treatment, one of recurrent metastatic TCC and the other of uncertain causes.

Among 30 patients who attained CR-chemotherapy-+-surgery, the median survival time was 37 months (95% CI, 18 to 73 months). Ten (33%) of 30 patients attained 5-year survival. Six patients remain disease-free at the time of last follow-up, and one is alive with TCC. Three patients died of recurrent TCC at 6, 8, and 11 years after treatment. Among patients who achieved less than disease-free status, none survived for 5 years.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This analysis demonstrates that postchemotherapy surgery provides a survival benefit to selected patients with metastatic TCC after maximum response to M-VAC chemotherapy, confirming previous observations. Although the benefit of postchemotherapy resection of persistent viable disease for patients with unresectable disease is well documented, this series specifically extends the recommendations of cystectomy to selected patients with metastatic TCC. One third of patients rendered disease-free in this manner attained 5-year survival, and the majority of them remain disease-free. It is apparent that a fraction of patients found to have residual viable tumor at postchemotherapy surgery are cured by complete resection of their disease. These patients would otherwise undoubtedly succumb to recurrent TCC.

Postchemotherapy surgery had a sizeable impact on the response and survival of our overall study population. Almost 40% (30 of 76) of all CRs attained in this patient population occurred through the use of postchemotherapy surgery. Patients whose CR required chemotherapy plus postchemotherapy surgery had similar median (36 months v 46 months) and 5-year (33% v 41%) survival compared with patients whose CR was a result of chemotherapy alone. Postchemotherapy surgery also affected long-term survival of the TCC population. The 5-year survival rate in our collective M-VAC experience is 17%; one third of these patients underwent surgical resection of residual viable disease and two thirds attained CRs to chemotherapy alone.

Appropriate selection of patients for postchemotherapy surgery is essential if this approach is to be considered for general use. Although our study is limited by the size of our patient population and the retrospective nature of our series, several generalizations can be made. First, patients who had a major response to M-VAC chemotherapy were most likely to attain long-term survival after postchemotherapy surgery. No patient who achieved less than a major response to M-VAC chemotherapy survived for 5 years, which suggests that responsiveness to chemotherapy corresponds with curability from subsequent surgery. Second, for patients who had both primary site and metastatic disease at baseline, evidence of visceral metastasis portended a poorer outcome. Only one of nine patients who had primary site and visceral metastatic disease survived for 5 years. In contrast, eight of 27 patients with pretreatment metastases limited to the lymph nodes or soft tissue sites survived for 5 years. In particular, patients whose metastatic disease was limited to regional lymph nodes fared best, as six of 16 remained free of disease at 5 years. Third, long-term survival was greatest when the disease encountered at postchemotherapy was restricted to the primary site. All patients with persistent disease in both the lymph nodes and the primary site experienced rapid recurrence and death.

It is notable that even the late deaths in our series were a result of recurrent TCC. Recurrent TCC resulted in three deaths occurring more than 5 years after therapy. Two relapses occurred between 3 and 4 years after therapy in patients who survived for 73 and 94 months before succumbing to TCC. Only one relapse occurred more than 4 years after postchemotherapy surgery. This individual relapsed at 55 months after treatment and remains alive with TCC 13 years after treatment.

There are several potential criticisms of this analysis. First, no prospective criteria were used to select patients for postchemotherapy surgery. The activity of chemotherapy in this disease and early reported benefit raised enthusiasm that postchemotherapy surgery may play a more prominent role in the treatment of TCC. Patient selection was clearly an evolving process, and this series now provides both long-term data and general guidelines. Second, two patients with long-term survival had carcinoma-in-situ as residual disease, which is less likely to result in death. We chose to include these patients on the basis of our original intent to include any patient with viable disease in the series. However, if such patients are excluded, then eight (29%) of 28 patients were alive at 5 years. These percentages are comparable and would not change our treatment recommendations.

In conclusion, this analysis affirms the value of postchemotherapy surgery in a subset of patients presenting with metastatic TCC. We conclude that multimodality therapy, ie, chemotherapy plus surgical resection of residual cancer, is critical for long-term survival in selected patients who would otherwise succumb to recurrent disease.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Sternberg CN, Yagoda A, Scher HI, et al: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Cancer64:2448-2458, 1989[Medline]

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3. Miller RS, Freiha FS, Torti FM: Surgical resection of residual tumor mass following chemotherapy for advanced transitional cell carcinoma. Oncology Munchen Sympomed3:370-381, 1994

4. Einhorn LH, Roth BJ, Ansari R, et al: Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma. J Clin Oncol12:2271-2276, 1994[Abstract/Free Full Text]

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6. Donat SM, Herr HW, Bajorin DF, et al: Methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy and cystectomy for unresectable bladder cancer. J Urol156:368-371, 1996[Medline]

7. Gabrilove JL, Jakubowski A, Scher H, et al: Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med318:1414-1422, 1988[Abstract]

8. 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. Cancer85:1145-1150, 1999[Medline]

9. Seidman AD, Scher HI, Gabrilove JL, et al: Dose-intensification of M-VAC with recombinant granulocyte colony-stimulating factor as initial therapy in advanced urothelial cancer. J Clin Oncol11:408-414, 1993[Abstract/Free Full Text]

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Submitted February 12, 1999; accepted March 19, 1999.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dodd, P. M. Articles by Bajorin, D. F. Search for Related Content PubMed PubMed Citation Articles by Dodd, P. M. Articles by Bajorin, D. F. Social Bookmarking                            What's this?