CMV front-line chemotherapy in transitional bladder carcinoma

Annals ofOncology 4: 147-150, 1993. O 1993 Kluwer Academic Publishers. Printed in the Netherlands

Original article CMV front-line chemotherapy in transitional bladder carcinoma L. Paz-Ares,1 P. Lianes,1 M. Diaz-Puente,1 F. Rivera,1 J. Passas,2 P. Costas,1 C. Mendiola1 & H. Cortes-Funes' 1

Medical Oncology Division;

2

Urology Division, '12 de Octubre' University Hospital, Madrid, Spain

8 and vinblastine 4 mg/m2 i.v. d 1, 8 every 3 weeks). Patients who yielded clinical complete responses (cCR) by cystosBackground: Despite standard treatment, surgery and/or copy, TUR biopsies and imaging techniques were given 3 radiotherapy, most patients with muscle invasive bladder car- additional courses. Cystectomy was performed in non-cCR cinoma die early of distant metastasis. CMV chemotherapy patients and as salvage treatment. has demonstrated a high response rate with moderate toxicity Results: Following 3 CMV cycles, 29 patients (81%) rein advanced bladder carcinoma. In an attempt to eradicate sponded (20 cCR and 9 cPR) and 7 (19%) did not (NR). undetectable metastatic disease and to avoid cystectomies, Currently, with a median follow-up of 23.5 months (13-59), 36 patients were given up-front CMV. 13 have died and 23 are alive, 12 of whom retain their bladMaterials and methods: The patients were 34 males and 2 ders. The projected overall survival is 51% at 4.5 years. females with a median age of 62 years (45-75); performance Grade 3-4 hematological toxicity was presented in 8% of the status 0-1 (WHO) in 34 patients; histology: 34 transitional cycles. No toxic deaths were observed. carcinomas and 2 anaplastic carcinomas (grade II: 8, grade Conclusion: The CMV regimen, after TUR, produces a III: 28). Clinical staging was T2_3n: 19 patients, T3b: 14 pa- high response rate with tolerable toxicity. Bladders could be tients and T4: 3 patients. Nineteen patients had complete preserved in half of the CR patients. trans-urethral resections (TUR) at diagnosis. The multimodal protocol started with 3 CMV courses Key words: bladder carcinoma, bladder preservation, neo(cisplatin 100 mg/m2 i.v. d 1, methotrexate 30 mg/m2 i.v. d 1, adjuvant chemotherapy, CMV regimen Summary

Introduction

Materials and methods

Cystectomy and/or radiotherapy remain the standard therapy for locally invasive bladder carcinoma [1, 2]. In selected cases trans-urethral resection (TUR) may have a role [3]. With these approaches, the 5-year survival rate ranges from 20% to 50%, with most of the patients dying of metastatic disease during the first 2 years after diagnosis [1, 2]. Therefore, it is reasonable to assume the presence of occult systemic disease present before local treatment. During the last few years some chemotherapy combinations with cisplatin, methotrexate ± vinblastine ± adriamycin have shown a response rate of 40% to 70% in patients with metastatic and/or recurrent disease [4, 5]. Tumor regression includes 20% complete responses, half of which will result in long-term survival. The response rate is directly related to tumor burden and also depends on the disease location [5]. It is higher in the bladder, nodal and lung sites than in bone or hepatic metastases. With these premises, we designed a multimodal protocol starting with up-front CMV chemotherapy effective against primary tumors and micrometastatic spread in an effort to avoid subsequent cystectomies and increase overall survival.

From March 1987 to May 1990, all patients with histologically proven transitional cell carcinoma of the bladder with clinical stages T2, T3 or T4 (NO, M0) were included in the study. Other eligibility criteria were age <75 years, performance status (WHO) <2, creatinine clearance >60 ml/min, normal blood counts, bilirubin <1.5 mg%, no major systemic disease and no prior irradiation or systemic chemotherapy. At diagnosis, clinical staging procedures included full blood counts, serum biochemistry profile, urinary cytology, bimanual palpation of the pelvis under anesthesia, cystoscopy with multiple selected and random biopsies and transurethral resection of the tumor, chest x-ray and CT scan of the abdomen and pelvis. Transrectal sonography and radionuclide bone scan were performed optionally or when clinically indicated. All relevant investigations including cytoscopy with TUR and CT scans were repeated after 3 and 6 courses of chemotherapy and subsequently every 3 months. The response criteria used were as follows: complete remission (CR): complete disappearance of all evidence of disease including no in situ carcinoma (Cis) for more than 1 month; partial remission (PR): >50% decrease in tumor size or downstaging of more than 1 category and no response (NR): <50% decrease in tumor size or downstaging of 1 category. The designation of pathological (p), clinical (c) or surgical (s) response was used depending on the methods of assessment employed. Initially, all patients were treated with 3 courses of cisplatin 100 mg/m2 i.v. day 1, methotrexate 30 mg/m2 i.v. days 1 and 8 and vinblastine 4 mg/m2 i.v. days 1 and 8. Cycles were repeated on day 21 or delayed until day 28 if the white blood counts were below 3,000/mL. Thereafter, a new complete evaluation was made and

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148 patients judged to have clinical complete remissions (cCR) received 3 additional CMV courses. At this point, patients who maintained cCR were closely followed and those who showed clinical progression underwent cystectomy. Non-cCR patients at evaluation after 3 courses of chemotherapy were also cystectomized (Fig. 1). Among the 38 patients entered, 36 are evaluable (Table 1>, 2 were excluded for protocol violation during the first cycle (one refused further chemotherapy and was immediately cystectomized, and the other had metastasic disease at diagnosis). There were 34 males and 2 females, with a median age of 62 years (45-75). Performance status was 0 or 1 (WHO) in 37 patients. Histology was transitional carcinoma in 34 cases and anaplastic carcinoma in 2 (including 3 patients with synchronous in-situ carcinoma). Most of the tumors (74%) were poorly differentiated (grade III). The initial clinical stage was T2 or T3a in 19 patients (53%), T3b in 14 patients (39%) and T4 in 3 patients (8%). Macroscopic complete TUR of primary tumor was performed in 19 patients before start of chemotherapy. Eleven patients had histories of prior superficial bladder carcinoma treated with TUR and/or intravesical therapy. Statistical analyses of factors predicting for response was done using the chi-square test and Fisher exact-test [6|. Survival was counted from the date of the first cycle to last control, and time to treatment progression (TTP) from the same date to progression not amenable to rescue by cystectomy. Actuarial curves of survival and TTP were plotted by the Kaplan-Meier method (7] and comparison between curves using the log-rank-test |8|.

Table I. Patient characteristics. Number of patients Median age (years)

36

62 (45-75)

Sex

FemaJe Male P. status

2 34

0-1 2

32 4

TURB at diagnosis Complete Incomplete Histology Transitional Anaplastic Histological grade

19 17 34 2 o

ii ii

o 28

III Stage

19 14 3

TV,.

T» T4

Table 2. Current status according to response to chemotherapy.

Results Response After the first 3 CMV courses, 29 patients (81%), including 20 patients with cCR (56%) and 9 with cPR (25%), showed tumor regression. Of 7 cNR patients (19%), two had progression (Table 2). None of the following analyzed prognostic factors had influence on the type of response: age, history of prior local therapy, degree of TUR at diagnosis, histological grade and clinical stage. Follow-up All of the 20 cCR patients received 3 further CMV courses. Three of these patients showed muscle invasive disease at the time of second evaluation. An additional 4 patients progressed locally at 9, 12, 15 and 35 months and 2 locally and distantly at 6 and 14 months after the end of chemotherapy. Five of these patients with local relapse were salvaged with cystectomy, although 2 patients had further locoregional recurrences at 14 and 35 months, and another had local and metastatic relapse at 6 months. Two patients judged unfit for

CMV x 3

E V A L U A T 1 O N

cCR -

CMV X 3

cPR cNR cPROQ

cCR

No evidence of disease Alive with tumor Dead Global

cNR

Total

7(2)

1

1° 1

— 6

9

7

20 3 13 36

(B.R)

cPR (B.R)

12(10) 2" 6 20

cCR

(B.E): Bladder preservation. " In each group 1 patient with only Cis.

surgery received pelvic radiation with poor results, because both showed new pelvic recurrences. Two patients showed Cis at 16 and 17 months of diagnosis. One of them was reinduced to cCR by intravesical BCG and the other one is still on treatment. The estimated probability of being free of disease with preserved bladder for cCR patients is 44% at 4.5 years (Fig- 2). Of the 9 cPR patients, one with only Cis after chemotherapy who refused surgery is still receiving local therapy (BCG + ADM). The other 8 patients * OF PATIENTS IN cCR

> Follow up

••• Cystectomy

Fig. 1. Therapeutic schema.

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12

24

36

MONTHS Fig. 2. Probability of preserving bladder after complete remission.

149

underwent cystectomy (2 partial and 6 radical). One patient progressed (pelvic and bone) 4 months after the radical procedure. All but 2 (surgically contraindicated) NR patients underwent cystectomies. Four patients had renewed progression of their diseases (2 metastatic and 4 local and systemic) a median of 6 months later (3-12). One patient has been free of recurrence since surgery. A total of 18 cystectomies (2 partial and 16 radical) were performed in the group as a whole. All the pathological specimens showed viable tumor. Comparing preoperative clinical stage versus pathological stage, we found that 75% of patients were correctly staged, 7% overstaged and 18%understaged. Survival

* too o F p A T E N T S S U R V I V I N O 24

36

MONTHS Fig. 3. Survival curves of the whole group (patients ( ) and NR patients ( •).

-), responding

cured only with complete TUR. Taking into account the inaccuracy of TUR biopsy in detecting muscle invasive cancer after chemotherapy, with 32% of false negatives [14], it is not surprising that 7 cCR patients (6 during the first 15 months) relapsed in the form of locally advanced disease. Therefore, the need for close follow-up with repeated cystoscopies and TUR should be stressed in such patients, some of whom can be reinduced to CR with suitable surgery. Two cCR patients also had distant recurrences during the first two years, which suggests the presence of undetected metastases at diagnosis. Although the policy of not performing immediate cystectomy in cCR patients could jeopardize some of these patients who have unresectable recurToxicity rences, this approach is also supported by the prelimiThe toxicity analysis of the administered 183 cycles nary report of the Memorial Sloan-Kettering neoadjushowed grade 3-4 nausea and vomiting in 78% and vant experience in which the outcome of cTo patients grade 3-4 neutropenia in 8%. Grade 1 mucositis, was similar whether they underwent cystectomy or not neuropathy and renal dysfunction were recorded in [12]. 22%, 8% and 7% of the patients, respectively. There As in other series using chemotherapy [15], radiotherapy [16] or both treatment modalities [9], respondwere no toxic deaths occurred. ing patients seem to do better than non-responders. The outcome of patients achieving PR was similar to those in CR, and in 2 cases partial cystectomy was feaDiscussion sible. The next step in the conservative management of Our study shows that the CMV regimen induces a high this cPR subset may be pelvic radiotherapy instead of remission rate in locally invasive bladder carcinoma surgery or even effective non-cross-resistant chemoafter TUR. The overall response rate (81%) is within therapy when available. the range previously reported by several other authors Patients without response to chemotherapy have a [9, 10] when TUR was performed at diagnosis, and very poor prognosis. The inherent biological determislightly higher than in other studies [11] in which only nants of these tumors could be responsible, but also the biopsy was initially performed. Its antitumor activity is 3-month delay in local therapy. Indeed, 2 of 7 patients not apparently significantly different from that of neo- had pathological progression in their cystectomy speciadjuvant M-VAC [12, 13]. Conversely, its toxic profile, mens. In an attempt to reduce the risk of progression as in metastatic patients [4, 5], seems to be milder during chemotherapy we would recommend a clinical (there were no toxic deaths in our study) when adria- evaluation after 2 courses (six weeks) instead of three. Also, efforts should be made to identify which submycin is not added to the CMV combination. group of the NR patients could benefit from surgery, The innovative feature of our protocol was the intenbecause in our experience most of them died early intional substitution of cystectomy by 3 consolidation dependently of the treatment applied. courses when cCR was achieved, which affords bladder preservation without relapse in almost half of our paOverall, the results in terms of survival are not tients. Indeed, a few of these patients could have been overwhelming and the study is non-randomized; thereWith a median follow-up of 23.5 months (13-59), 23 patients are alive, including 20 who are free of disease, one with locoregional relapse and two with Cis. Thirteen patients have died. The current status according to initial response is presented in Table 2. The expected overall survival at 4.5 years is 51% for the group as a whole, 62% at 4.5 years for responding patients (cCR + cPR) and 15% at 15 months for those without response to chemotherapy (Fig. 3). Using a univariate analysis none of the afore-mentioned factors have shown influence on survival. Similar results were obtained regarding TTP.

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150

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procedures.JRStatSoc|A| 1972; 135: 185. 9. Fung CY, Shipley WU, Young RH et al. Prognostic factors in invasive bladder carcinoma in a prospective trial of preoperative adjuvant chemotherapy and radiotherapy. J Clin Oncol 1991; 9: 1533-42. 10. Marino R, Wajsman Z. Bladder sparing approach to muscle invasive carcinoma of the bladder. In Splinter TAW, Scher HI (eds): Neoadjuvant chemotherapy in invasive bladder cancer. New York, NY: Wiley-Liss 1990; pp. 175-8. 11. Maffezzini M, Torelli T, Villa E et al. Systemic preoperative chemotherapy with cisplatin, methotrexate and vinblastine for locally advanced bladder cancer: Local tumor response and early follow-up results. J Urol 1991; 145:741-3. 12. Scher HI, Herr H, Sternberg C et al. M-VAC (methotrexate, vinblastine, adriamycin and cisplatin) and bladder preservation. In Splinter TAW, Scher HI (eds): Neoadjuvant chemotherapy in invasive bladder cancer. New York, NY: Wiley-Liss 1990; pp. 179-86. 13. Scher HI. Chemotherapy for invasive bladder tumors. In Splinter TAW, Scher HI (eds): Neoadjuvant chemotherapy in invasive bladder cancer. New York, NY: Wiley-Liss 1990; pp. 1-22. 14. Herr HW, Whitmore WF, Morse MJ et al. Neoadjuvant chemotherapy in invasive bladder cancer The evolving role of surgery.JUrol 1990; 144: 1083-8. 15. Splinter TAW, Jaquin D, Roberts JT et al. EORTC-GU group study of up front chemotherapy in patients with invasive bladder cancer. Proc Am Soc Clin Oncol 1990; 8:139 (544). 16. Blandy JT, England HR, Evans SJW et al. T, bladder cancer the case for salvage cystectomy. Brit J Urol 1980; 52:506-10. Received 24 August 1992; accepted 21 October 1992. Correspondence to: L. Paz-Ares, M.D. Servicio de Oncologia Medica Hospital Universitario' 12 de Octubre' Madrid 28041, Spain