GALLIUM NITRATE IN ADVANCED BLADDER CARCINOMA: SOUTHWEST ONCOLOGY GROUP STUDY E. DAVID CRAWFORD, M.D. J O S E P H H. SAIERS, M.D. L A U R E N C E H. BAKER, D.O. i JOHN H. COSTANZI, M.D. RONALD M. BUKOWSKI, M.D.

From the University of Colorado Health Sciences Center, Denver, Colorado; Veterans Affairs Medical Center, Albuquerque, New Mexico; Wayne State University Medical Center, Detroit, Michigan; Thompson Cancer Survival Center, Knoxville, Tennessee; and Cleveland Clinic Foundation, Cleveland, Ohio

ABSTRACT--Gallium nitrate is a heavy metal anticancer agent that has demonstrated widespread activity in a number of phase I studies. This phase II study employed a starting dose of 700 mg/m ~ I V every two weeks in patients with advanced bladder carcinoma. Significant nephrotoxicity observed in 4 of the first 10 patients required extending the time between cycles to three weeks in the remaining 24 patients. One complete response and six partial responses were achieved. Nephrotoxicity was the major dose-limiting toxicity. Gastrointestinal toxicity and myelosuppression were minimal. Gallium nitrate appears to be an active agent in advanced carcinoma of the bladder. Further clinical trials with this agent are warranted.

:, chemotherapy of Lding carcinoma of bind other areas of 9st active agents in 9latin.1 In part ber heavy metal, gald in a phase II trial Sited a wide spectudies 2-4 with antil in osteogenic sar•oid cancer, oat cell noma, neural crest ma, Hodgkin's dispart by the following PHS awarded by the National ~A-03096, CA-12213, CA36, CA-32734, CA-12644, k-37981, CA-27057, CA35, CA-21116, CA-13238,

ease, non-Hodgkin's lymphoma, and bladder carcinoma. The minimal degree of myelosuppression observed with gallium nitrate makes it an attractive drug for investigation. Material and Methods Patients with histologically proved advanced metastatic bladder cancer were eligible for the study. All patients had clearly measurable disease, a life expectancy of at least six weeks, and Karnofsky performance level of at least 50 percent. In addition, adequate bone marrow and liver and renal functions were entry requirements. These were defined as a white blood cell count of greater than 4,000/ram 3, platelets greater than 100,000/mm 3, blood urea nitrogen (BUN) less than 20 mg/dL, serum creatinine less than 1.2 mg/dL, a creatinine clearance of greater than 60 ec/minute, and a bilirubin of

VOLUME XXXVIII, NUMBER 4

355

TABLE I. Priortherapy Therapy

No. of Pts.

Doxorubiein + eisplatin Doxorubiein + eisplatin + eyclophosphamide Doxorubiein Cisplatin Doxorubicin + cisplatin + 5-FU Cyclophosphamide Methotrexate + 5-FU Methotrexate Methotrexate + 5-FU + vincristine Vindesine No prior chemotherapy Radiation therapy

2 2 2 2 1 1 1 1 1 1 17 24

less than 2 m g / d L . Patients receiving prior irradiation or c h e m o t h e r a p y were allowed. Informed consent in accordance with government and institutional policies was obtained from all patients.

Treatment plan All patients were hydrated with 2 L of fluid over usual intake the night before t r e a t m e n t and 200 ee per hour of a saline-containing fluid for six to eight hours the day of treatment. This was followed by administration of the study drug in a dose of 700 m g / m 2 as a thirty-minute infusion in 200 ee of n o r m a l saline. Courses were repeated at two-week intervals in the first 10 patients, provided renal and bone m a r r o w functions h a d returned to baseline levels. In the next 24 patients, the interval between courses was increased to three weeks with the provision of escalating the dose to 1,000 m g / m 2 if no toxicity occurred. The first 10 patients were allowed to have received prior eisplatin (7 patients), after w h i e h no prior p l a t i n u m was allowed in an attempt to reduce renal toxicity. An adequate trial consisted of two courses of therapy.

Criteria ]or response A complete remission was defined as the disappearance of all clinical evidence of active tum o r for a m i n i m u m of four weeks. A partial response was defined as a 50-percent or greater decrease in the sum of the products of the perpendicular diameters of all measured lesions. Stable disease was defined as an objective tum o r regression not qualifying for partial remission but lasting at least four weeks or a steady state not qualifying for increasing disease of at least eight weeks' duration. Increasing disease was defined as an unequivocal increase of at least 25 percent in the size of any measured lesions or the appearance of any n e w lesions.

356

UROLOGY

Results Of the first lO patie~ tional cell and 1 h a d s~ All had advanced di~ prior c h e m o t h e r a p y ( adequate trial defined nitrate. Of the two w quate trial, one had ii (ereatinine 4.0 m g / d L spite objective evident ter the first course. The tion of his serum ereat in his second course. I tient and his family further therapy; and h his tumor. Of the 8 patients there were one eomple sions. The complete : one weeks, the partia and fifteen weeks, r w h o experienced t h e , with a partial response o r u b i e i n , eisplatin, p h a m i d e or 5-fluorou with a partial respon. elophosphamide. All had transitional cell e Gallium nitrate wa: sponding patients 1 nephrotoxieity, ereatil dL, or ereatinine elea than 50 percent of pr other 5 patients with toxicity was not obser Because of the deg: served in the initial 10 tween cycles was len Twenty-four patients, week schedule. Eight¢ sponse, two were in, early deaths, and two because of toxicity. chemotherapy (Table Of the 18 evaluable partial responses lastii one weeks. In additior qualified as a partial received his second e not return for his t quently, died of progn sidered an early death again, renal. Both 1~ h a d to be diseontinue~ toxicity as the cause.

/

OCTOBER

1991

/

TABLE II.

Toxicity No. of Pts. 12 11 5 4 3 1 1 1 1 1

Lxicity ing

,enid

renal toxicity (creatinine greater lg/dL or creatinine clearance less cent of pretreatment). In 2 patients tial response, a creatinine greater g/dL developed between courses of dch returned to normal, and the )ntinued at a reduced rate. :ieities in this study were relatively II). Significantly, no granuloeytototed in any of the patients. l~en the two groups are combined, there ie!;ie[ patients evaluable for response with l and 6 partial remissions for an overall e rate of 27 percent (95% confidence i l to 48 %). The median response dura~ sixteen weeks. The responses were seen l,~ents with lung (2), abdominal mass (2), ~Nass, skin, and lymph nodes.

cant activity with a 27-percent response rate in patients with varying amounts of prior therapy. Two other patients qualified as partial responses after one and two courses but then did not receive further treatment at their requests for unknown reasons. It should be noted that 3 of the responders had received prior cisplatin. However, renal toxicity was significant in 3 of the 7 responders; the drug was discontinued because of renal toxicity. All three were treated at twoweek intervals. The nephrotoxicity was lessened when the drug was given at three-week intervals as opposed to two-week intervals, but the problem may lie in the rapid infusion utilized in this protocol. There is evidence that gallium nitrate is better tolerated when given as a prolonged infusion6 and that perhaps the activity of the drug could be maintained and toxicity lessened if the drug were given by continuous infusion. Early results of phase II studies from our institution suggest that the activity of the agent is substantial when administered by continuous infusion. Four of 5 treated patients have responded. 7 Division of Urology University of Colorado Health Sciences Center Campus Box C-319 4200 East Ninth Avenue Denver, Colorado 80262 (DR. CRAWFORD)

~;N

References

'

Comment 021 ~ansiti°nal cell carcinoma of the bladder is iSi~e to a number of chemotherapeutic ,'These include doxorubiein, cisplatin, i~rexate, and cyclophosphamide with ree:rates of 5 to 30 percent, 33 to 57 percent, i'~50percent, and 15 to 0 percent, respec-

~

~

~guse of the responsiveness of transitional ~ e i n o m a of the bladder to cisplatin, gal~ nitrate, a heavy metal compound, was [:in ihe current study. Results show signifi-

/ :i

OCTOBER 1991

/

1. Yagoda A: Chemotherapy of metastatic bladder cancer, Cancer 45:1879 (1980). 2. Samson M, et ah Phase I-II clinical trial of gallium nitrate (NSC 15200), Cancer Clin Trials 3:131 (1980). 3. Brown J, et ah Phase I study of gallium nitrate in patients with advanced cancer, Proc Am Assoe Cancer Res 19:198 (1978). 4. Bedikian A, et ah Phase I clinical studies with gallium nitrate, Cancer Treat Rep 62:1449 (1978). 5. Stephens R: Chemotherapy of bladder carcinoma, in Crawford ED, and Borden TA (Eds): Genitourinary Cancer Surgery, Philadelphia, Lea & Febiger~ 1982, pp 371-374. 6. Warrell RP, Coonley CJ, Straus DJ, and Young CW: Treatment of patients with advanced malignant lymphoma using gallium nitrate administered as a seven-day continuous infusion, Cancer 51:1982 (1983). 7. Seligman P: Personal communication, 1990.

VOLUME XXXVIII, NUMBER 4

357

Gallium nitrate in advanced bladder carcinoma: Southwest Oncology Group study.

Gallium nitrate is a heavy metal anticancer agent that has demonstrated widespread activity in a number of phase I studies. This phase II study employ...
383KB Sizes 0 Downloads 0 Views