Intra-Arterial Cisplatin for Bladder Cancer

0022-5347/87/1382-0302$02.00/0 Vol. 138, August

THE JOURNAL OF UROLOGY

Copyright© 1987 by The Williams & Wilkins Co.

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INTRA-ARTERIAL CISPLATIN FOR BLADDER CANCER DAVID J. STEWART,* LIBNI EAPEN, WOLFGANG E. HIRTE, NORMAN G. FUTTER, DAVID E. MOORS, PATRICK G. MURPHY, ALAN H. IRVINE, PAUL GENEST, DAVID E. McKAY, WILLIAM K. EVANS, PASTEUR RASULI, REBECCA A. PETERSON AND JEAN A. MAROUN From the Ontario Cancer Treatment and Research Foundation, Ottawa Regional Cancer Centre and The University of Ottawa Faculty of Health Sciences, Ottawa, Ontario, Canada

ABSTRACT

Cisplatin (25 to 120 mg. per m. was injected into the internal iliac arteries of 33 patients with locally advanced bladder cancer. Of the patients 9 were inevaluable for response to the cisplatin, since they began radiotherapy to the bladder before course 2 of cisplatin as part of a preplanned therapeutic approach. One patient received the treatment as postoperative adjuvant therapy, 1 did not return for followup and 1 with metastatic disease did not undergo repeat cystoscopy. Of 21 evaluable patients 3 (14 per cent) achieved complete remission, 12 (57 per cent) achieved partial remission, 2 (14 per cent) were stable and 4 (19 per Cf'nt) failed. The response rate was higher in patients receiving 100 to 120 mg. per m. 2 per course than in patients receiving lower doses (all except 1 of whom received 60 or less mg. per m. 2 per course) (86 versus 64 per cent) and it was higher in patients without prior radiotherapy or chemotherapy. The response rate in patients with previously untreated invasive transitional cell carcinoma was 88 per cent. Of the 33 patients 21 were alive at last followup, with a median duration of followup of 32 weeks. Toxicity was dose-related and local neurotoxicity was excessive at cisplatin doses of 100 to 120 mg. per m. 2• Diabetic patients were particularly prone to have neurotoxicity. Other toxicity generally was not severe and consisted of ototoxicity, nephrotoxicity, myelosuppression, nausea, vomiting and diarrhea. Even elderly patients and patients with cardiac disease tolerated the treatment well. We plan to proceed with further intra-arterial cisplatin studies in which all patients except those more than 80 years old will be treated with an intra-arterial cisplatin dose of 90 mg. per m. 2 per course combined with radiotherapy with or without cystectomy. J. Ural., 138: 302-305, 1987 2)

Intra-arterial administration of cisplatin previously has been effective in the treatment of a number of malignancies, including primary and metastatic brain tumors, 1- 3 liver metastases from various malignancies,4 •5 head and neck carcinoma,6 osteogenic sarcoma,4· 7 malignant melanoma4 and carcinoma of the cervix.8 In addition, we9 and others10• 11 have found the drug to be valuable in the treatment of localized invasive carcinoma of the bladder. In our original small series all 5 evaluable patients with invasive nonirradiated transitional carcinoma of the bladder experienced complete or partial remissions, while 1 patient with localized squamous cell carcinoma of the bladder had a minor response. 9 Wallace and associates previously reported a 60 per cent response rate in a series of patients that included many with extensive prior treatment. 10 While not all chemotherapeutic agents are of value when injected intra-arterially, 12• 13 the pharmacokinetic properties of cisplatin are such that an advantage would be expected for intra-arterial infusion. 12• 13 Moreover, augmentation of local tissue concentrations of platinum have been documented after intra-arterial administration of cisplatin in humans14- 16 and animals, 17 and we have seen responses to intra-arterial cisplatin alone or in combination with other drugs after tumor progression on higher doses of the drug given intravenously. 18•19 The pharmacokinetics of cisplatin in peripheral venous blood gen erally are the same after intra-arterial as after intravenous administration, 20 indicating that intra-arterial cisplatin could have an effect against systemic tumor comparable to that resulting from the same dose of drug being given intravenously, while the local effect would be augmented. Since our original report on intra-arterial cisplatin in the Accepted for publication February 12, 1987. *Requests for reprints: Ontario Cancer Foundation Clinic, 501 Smyth Rd., Ottawa, Ontario, Canada KlH 8L6.

302

treatment of localized bladder carcinoma,9 we have treated several additional patients. Some received intra-arterial cisplatin alone, while others received it in conjunction with bladder irradiation. These latter studies were done since cisplatin is a radiosensitizer, 21 and previous studies of intravenous cisplatin combined with radiation for localized bladder carcinoma22 • 23 and for tumors in other sitell24-27 had shown the combination to be tolerated well. In our original bladder cancer series the intra-arterial cisplatin was tolerated well, even by elderly patients with cardiac disease, diabetes and other chronic medical conditions. We update our experience with intra-arterial cisplatin for localized bladder carcinoma, with particular reference to toxicity encountered. MATERIALS AND METHODS

To date 33 patients with localized bladder carcinoma have been treated with intra-arterial cisplatin. Informed consent was obtained from all patients. To be eligible for treatment patients had to have stage T3 or T4 bladder carcinoma, although patients also were considered for study if they had had multiple recurrences of superficial bladder tumors refractory to intravesical treatment and did not want a cystectomy. For the purposes of this study the International Union Against Cancer staging system was used: stage T3-muscle invasion on biopsy and palpable tumor at the time of examination with the patient under anesthesia, and stage T4-fixation of the bladder as a result of tumor invasion. All patients had residual tumor in the bladder at initiation of chemotherapy. Bone marrow function had to be adequate (granulocytes greater than 2,000/µl. and platelets greater than 100,000/µl.). Estimated creatinine clearance had to be greater than 30 ml. per minute unless renal dysfunction was secondary to ureteral obstruction by tumor.

303

INTRA-ARTERIAL CISPLATIN FOR BLADDER CANCER

Patients with metastatic disease were considered eligible if the local bladder tumor was the most symptomatic area of disease. Patient age ranged from 44 to 83 years (median age 69 years). Pre-treatment Zubrod performance status was O (asymptomatic) in 9 patients, 1 (symptoms that were not limiting) in 18, 2 (moderately severe symptoms but the patient bedridden less than 50 per cent of the day) in 5 and unspecified in 1. Of the patients 28 had transitional cell carcinoma, 1 had transitional cell carcinoma with foci of squamous cell carcinoma, 3 had squamous cell carcinoma and 1 had small cell undifferentiated carcinoma. Tumor stage was T3 in 13 patients, T4 in 16 and T3 to 4 in 3. One patient had multiple superficial papillomas that had recurred despite multiple different intravesical regimens. Seven patients were believed to have pelvic lymph node metastases (documented histopathologically in 4 and suspected radiologically in 3) and 2 had distant metastases. Tumor grade was II in 10 patients, II to III in 2, III in 11, IV in 5 and unspecified in 5. Treatment consisted of cisplatin delivered simultaneously into both internal iliac arteries using bilateral percutaneous catheters inserted temporarily under fluoroscopic guidance. Patients more than 70 years old, with an estimated creatinine clearance of less than 60 ml. per minute and with a history of congestive heart failure (1), moderate to severe coronary artery disease (4) or severe hypertension (3) received a cisplatin dose of 60 mg./m. 2 or less (30 mg./m. 2 or less to each side). Other patients initially received 100 to 120 mg./m. 2 (50 to 60 mg./m. 2 to each side). Doses administered were 120 mg./m. 2 in 8 patients, 100 mg./m. 2 in 3, 80 mg./m. 2 in 1, 60 mg./m. 2 in 18, 50 mg./m. 2 in 2 and 25 mg./m. 2 in 1. Most patients were hydrated with 1,000 ml. 5 per cent dextrose in 0.45 per cent saline intravenously during 2 to 3 hours before the cisplatin, and the cisplatin was administered in 500 ml. 0.45 per cent saline (250 ml. per side) during 2 hours. For patients with a history of congestive heart failure fluid volumes were cut in half and infusion times were doubled. Mannitol (50 gm.) was given intravenously to all patients beginning 15 minutes before the cisplatin and ending concurrently with the end of the cisplatin administration. No additional special intravenous hydration was administered, although if patients were unable to drink any fluids an intravenous line was left running at 100 to 125 ml. per hour until adequate oral intake resumed. Dexamethasone, metoclopramide and prochlorperazine were used as antiemetics. Nitroglycerin paste was applied to the chest wall of patients with coronary artery disease before initiation of treatment. The arterial catheters were removed upon completion of drug infusion and the patient was discharged from the hospital the following day. Treatment courses were repeated at 3 to 4week intervals upon recovery from toxicity. A complete blood count, differential and platelet count were done once per week while on treatment, and renal function tests were repeated before each course of treatment (and more frequently in many patients). Tumor response was evaluated by repeat cystoscopy performed after course 3 of treatment. In each case followup cystoscopy was performed by the same urologist who had performed the first cystoscopy. A complete remission was defined as complete disappearance of tumor and resolution of all symptoms, partial remission consisted of an estimated 50 per cent or greater decrease in tumor size, stable disease consisted of less than 50 per cent tumor shrinkage and less than 25 per cent tumor growth for more than 8 weeks, and failure consisted of greater than 25 per cent tumor growth or the appearance of new lesions. Urine cytology was not used in the evaluation of response. Patients who began local irradiation before repeat cystoscopy were not considered evaluable for response to cisplatin alone but they were considered evaluable for toxicity. RESULTS

Twelve patients were not evaluable for response to the intraarterial cisplatin. As part of a preplanned therapeutic approach

9 of these 12 inevaluable patients were started on radiotherapy at course 2 of cisplatin and before a repeat cystoscopy study was done: 6 achieved complete remission with the radiotherapy plus intra-arterial cisplatin, data are unavailable regarding the response status at the time of repeat cystoscopy in 1 and 2 had metastatic disease early after initiation of treatment. One of the 2 patients with metastatic disease did not undergo repeat cystoscopy and 1 had residual tumor at cystoscopy. The latter patient initially had transitional cell carcinoma but histopathological evaluation of the residual tumor revealed squamous cell carcinoma. Of the remaining 3 inevaluable patients 1 was treated after surgical removal of squamous cell carcinoma of the bladder with pelvic lymph node metastases, 1 was lost to followup and 1 with metastatic disease did not undergo repeat cystoscopy. Of the 21 patients evaluable for response to intra-arterial cisplatin alone 3 (14 per cent) achieved complete remission, 12 (57 per cent) achieved a partial response, 2 (14 per cent) were stable and 4 (19 per cent) failed. Of the patients with partial remission 2 underwent cystectomy while continuing to respond and 2 began radiotherapy while continuing to respond. It is possible that 1 or more of these 4 patients would have had complete remission with chemotherapy alone if given sufficient time. One of the 2 stable patients was referred for radiotherapy after 3 courses of treatment and he has not yet been reevaluated, while 1 had squamous cell carcinoma and achieved a minor response (tumor shrinkage but less than 50 per cent). Of the 4 patients who failed to respond 1 had multiple low grade superficial papillary tumors that had recurred and progressed despite 2 different intravesical chemotherapy regimens, 1 had had prior radiotherapy, 1 had had prior intravenous cisplatin and only 1 had had no prior therapy. If only previously untreated patients with invasive transitional cell carcinoma were considered the response rate was 14 of 16 (88 per cent), with 1 patient stable and 1 failing. Response is presented as a function of cisplatin dose per course and initial tumor stage in table 1. The response rate was 86 per cent in evaluable patients receiving 100 to 120 mg./m. 2 compared to 64 per cent in patients receiving less than 100 mg./m. 2 • The only patient at the higher dose level who did not achieve a partial response had squamous cell carcinoma of the bladder and achieved a minor response. All 4 treatment failures occurred among the 14 evaluable patients who received 60 or less mg./m. 2 • The response rate was 86 per cent in patients with stage T3, 70 per cent with stage T4 and 67 per cent with stage T3 to 4 disease. Median followup was 32 weeks (range 5 to 193 weeks), and 21 of the 33 patients were alive at the last followup. All 33 patients were considered to be evaluable for toxicity (table 2). Toxicity clearly was dose-related. Neurotoxicity generally consisted of numbness in 1 or more dermatome of the legs and buttocks. It usually but not always was bilateral and it sometimes was associated with painful dysesthesias. In 1 patient chronic burning pain in the end of the penis was believed to be a manifestation of a neuropathic condition, although it possibly could have been owing to chronic inflammation of the urothelium. The neuropathic condition was seTABLE 1.

Response as a function of tumor stage and cisp/,atin dose per course

Stage Stage: Tl T3 T3-4 T4 Cisplatin (mg.fm.2 ): 100-120 <100*

No. No. Responding Stable Treated Evaluable No.(%) No.(%)

Failing No.(%)

1 13 3 16

1 7 3 10

1 6 (86) 2 (67) 7 (70)

0 0 0 2 (20)

1 1 1 1

11

6 15

5 (86) 10 (64)

1 (14) 1 (7)

0 4 (24)

22

* All except 1 patient in this group received 60 mg./m. 2 or less.

(100) (14) (33) (10)

304 TABLE

STEWART AND ASSOCIATES 2. Proportion of patients with toxicity as a function of cisplatin

dose per course Cisplatin (mg./m. 2 )

Neurotoxicity: Diabetic pts. Nondiabetic pts. Over-all pts. Ototoxicity Nephrotoxicity Myelosuppression

TABLE 3.

100-120 (% pts.)

<100 (% pts.)

100 56 63 20 60 33

25 11 18 5

19

13

Toxicity as a function of age

Dose Cisplatin (mg./ No. With Toxicity(%) m.2) Age No. (yrs.) Pts. 100-120 <100 Neurotoxicity Ototoxicity Nephrotoxicity (No.pts.) (No. pts.) 40-49 50-59 60-69 70-79 80-83

3

1

6

6

10 12 2

5

2 0 5 12 2

4 (67) 4 (40) 2 (17)

1 (33) 2 (33)

3 (50) 3 (30) 1 (8) 2 (100)

vere enough to interfere with walking in 2 patients. This complication was reversible slowly in at least some of the patients, although many have not yet had a long enough followup to be certain whether improvement will occur. The only patient to have a neuropathic condition involving the hands as well as the legs previously had received high dose intravenous cisplatin and was receiving 120 mg./m. 2 per course as part of this regimen. Peripheral neuropathic conditions were more likely to occur in patients with diabetes than in others. Ototoxicity generally was mild, although 1 patient had severe sensorineural hearing loss 3 days after course 2 of treatment at a dose of 60 mg./m. 2 per course. Severe ototoxicity is unusual after such a low cumulative dose. The onset of the hearing loss occurred a few hours after emotional trauma (a death in the family) but audiometric testing suggested that it was genuine. Nephrotoxicity generally was mild and at least partially reversible. No patient required dialysis and in all cases renal function recovered to the point that the serum creatinine was less than 1.5 times the upper limit of normal. Of the 33 patients treated 9 had an elevated serum creatinine level before initiation of treatment, usually related to ureteral obstruction by tumor. Of these 9 patients 3 (33 per cent) had a further increase in the serum creatinine, while 6 actually had improvement in renal function, since ureteral obstruction was relieved by the treatment. Of the 24 patients with normal pre-treatment renal function 6 (25 per cent) suffered nephrotoxicity. No episodes of infection or bleeding occurred secondary to myelosuppression, which was defined as a granulocyte count of less than 1,000/µl. or a platelet count of less than 100,000/µl. Nausea and vomiting were mild or nonexistent in 18 per cent of the patients, moderate in 58 per cent and severe in 24 per cent. Six patients had diarrhea secondary to the chemotherapy. One patient with coronary artery disease suffered angina half-way through the treatment. Angina responded rapidly to nitroglycerin and the treatment was completed uneventfully. Three patients who received radiotherapy concurrently with or after the cisplatin had severe bladder irritation that resolved with time in 2. Intra-arterial cisplatin alone did not cause bladder irritation in any patient. Toxicity is presented as a function of patient age in table 3. The data indicate that even elderly patients tolerated the treatment regimen well at the doses administered. DISCUSSION

In our earlier small series we found that intra-arterial cisplatin is highly active against localized bladder carcinoma, and it

is tolerated well even by elderly patients and those with medical contraindications to cystectomy. 9 This enlarged series confirms our earlier observations and the observations of other investigators.10· 11 Only 2 evaluable, previously untreated patients with transitional cell carcinoma failed to experience tumor shrinkage on treatment and 1 of these 2 patients was at least stable. Treatment failures primarily involved previously treated patients and those who received low dose intra-arterial cisplatin. Nevertheless, some extremely good responses (including complete remissions) also were seen in patients who received the lower doses of cisplatin. In our study patients with good renal function and those who were less than 70 years old received 100 to 120 mg./m. 2 cisplatin, while others received 60 mg./m. 2 (or occasionally less). The cisplatin dose of 120 mg./m. 2 caused an unacceptably high rate of local neurotoxicity. Other investigators also have noted neurotoxicity with intra-arterial infusions of high doses of cisplatin. 4 •10 In most cases the neurotoxicity was not severe but in some patients it was debilitating. For that reason we recently have lowered the dose of cisplatin in this patient population to 90 mg./m. 2 • On the other hand, dose-limiting toxicity was far less common in patients who received lower doses of cisplatin despite the fact that they were elderly or had pre-treatment renal dysfunction. Because of this finding and the fact that response rate was dose-related, we plan to increase the treatment dose in this patient group to 90 mg./m. 2 except for the most elderly (age greater than 80 years) or debilitated patients. Despite the high response rate most patients did not achieve complete remission. The complete remission rate with chemotherapy alone might have been higher if other local treatment had not been initiated in some patients when they were continuing to show response to the intra-arterial cisplatin after only 1 to 3 courses of treatment. In any event, 2 of the 3 patients who did achieve complete remission with intra-arterial cisplatin alone eventually had relapse. Therefore, this modality definitely is not sufficient treatment on its own to provide a substantial long-term survival rate free of disease. For this reason we initiated studies of intra-arterial cisplatin combined with local radiotherapy for localized bladder cancer. Operable patients undergo cystectomy after completion of intra-arterial chemotherapy and radiotherapy. It is hoped that this combination of modalities may increase our ability to control local tumor and that the systemic levels of cisplatin achieved after intra-arterial administration of the drug 20 may be adequate to have some impact on the development of distant metastases. The results of this study will be reported in detail at a later date. Our preliminary experience suggests that this approach is feasible. In summary, intra-arterial cisplatin is highly effective palliative treatment for locally advanced bladder cancer. While high doses cause an unacceptably high incidence of local neurotox icity, lower doses are tolerated well even by elderly patients with concurrent chronic diseases and by patients with renal dysfunction owing to ureteral obstruction by tumor. This treatment modality is not sufficient by itself to result in long-term control of tumor in most patients but it could contribute potentially to a combination of treatment modalities that would do so. REFERENCES 1. Stewart, D. J., Wallace, S., Feun, L., Leavens, M., Young, S. E.,

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