DOXORUBICIN

CHEMOTHERAPY

TRANSITIONAL

CELL CARCINOMA

STEPHEN JOSEPH

H. WEINSTEIN, D. SCHMIDT,

From the Department Hospitals and Clinics,

IN ADVANCED

M.D.

M.D.

of Urology, University Iowa City, Iowa

of Iowa

ABSTRACT -During the past year 25 patients with advanced transitional cell carcinoma were treated with intravenous doxorubicin hydrochloride (Adriamycin), 60 to 75 mg. per square meter of body surface area, every three weeks. Among the 19 evaluable patients, one partial objective remission lasting five months was observed. All 7 patients with bone pain had symptomatic relief and 12 patients had significant subjective improvement lasting an average of six-and-a-half months. Side effects were minimal and consisted of alopecia, mild leukopenia, and mild stomatitis; no signi$cant cardiotoxicity was observed. Doxorubicin hydrochloride appears to have important antitumor activity in advanced urothelial tumors. Controlled clinical trials with this agent alone and in combined drug regimens are needed.

The results of systemic chemotherapy in advanced transitional cell carcinoma are less than satisfactory. Until recently, the most extensively studied agent had been 5fluorouraci1, which showed some therapeutic efficacy when used alone or as an adjuvant to surgery. In a recent review of the literature Carter’ found fifteen clinical trials with an over-all response rate of 35 per cent. However, a variety of dose schedules was used, and the criteria of response were not clearly defined. Doxorubicin (Adriamycin) is a relatively new cytotoxic antibiotic isolated from a mutant strain of Streptomyces. It differs from an earlier clinically important agent, daunorubicin (Daunomytin) only by hydroxylation of the fourteenth carbon (Fig. 1). Both agents have shown significant antitumor activity against a wide variety of neoplasms including acute leukemias, breast carcinoma, sarcomas, bronchogenic carcinoma, and transitional cell tumors. However, the therapeutic index of doxorubicin is higher than that of daunorubicin in several experimental

tumor systems2 The proposed mechanism of action of doxorubicin is drug-binding to deoxyribonucleic acid and inhibition of ribonucleic acid synthesis. 3 Various administration schedules have been investigated. The currently recommended schedule, derived from clinical experience, is 60 to 75 mg. M2 (square meter of body surface area) given as a single rapid infusion and repeated every twenty-one days. The drug is metabolized predominantly by the liver and therefore dose reduction is required in patients with impaired hepatic function4 There

AORIAMYCIN

OAUNOMYCIN

Presented in part at Annual Meeting, North Central Section, American Urological Association, Inc., Phoenix, Arizona, October 5, 1975.

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FIGURE

1.

(Daunomycin)

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Chemical structure of daunorubicin and doxorubicin (Adriamycin).

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may also be reason to reduce the dose in patients with prior extensive irradiation therapy or with renal insufficiency, but documentation for this is lacking.5 Toxicity is generally tolerable and reversible and consists primarily of dose-related bone marMinor toxicities include row depression. nausea and vomiting, and alopecia, stomatitis, phlebitis. Cardiac toxicity can occur and consists of transient electrocardiographic changes or the more serious occurrence of cardiomyopathy refractory to therapy and occurring when the cumulative dose exceeds 550 mg. M2.6,7 This article reviews the experience at the University of Iowa Hospitals with the use of doxorubicin in therapy of advanced transitional cell carcinoma. Material

and Methods

From August, 1974, to September 1, 1975, 25 patients with advanced transitional cell carcinoma were treated with intravenous doxorubitin. This group included 13 patients with distant metastases from bladder carcinoma (Stage Dz), 8 with extensive bladder carcinoma and regional node involvement (Stage Dr), 2 with extensive localized bladder carcinomas (Stage C) in whom operative intervention was not advisable, 1 patient with metastatic transitional cell carcinoma of the prostate, and 1 with metastatic transitional cell carcinoma of the renal pelvis (Table I). There were 21 men and 4 women who ranged in age from forty-five to eighty with an average of 65 years. No patient had received prior chemotherapy with any agent and 10 patients had received prior extensive pelvic irradiation (greater than 3,000 rads). TABLE

I. Patients

treated with doxorubicin No.

No. Patients Treated

Patients* Evaluable

23

17

Transitional cell carcinoma bladder Stage Dzt Stage DI Stage C Metastatic transitional cell cancer of prostate Metastatic transitional cell cancer renal pelvis TOTALS

13 8 2

10 5 2

1 1

1 1

25

19

*Patients receiving two or more doses of chemotherapy. tTwo of these patients also had transitional cell cancer renal pelvis.

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The drug is supplied in lo-mg. vials and is prepared by dissolving the powder in 0.9 per cent saline. It was administered by direct intravenous injection or into the tubing of an intravenous infusion. The usual dose was 60 to 75 mg. M2 given every three weeks. Dose reductions were made in the face of bone marrow depression; dose reductions were made in patients with prior extensive irradiation therapy, especially if evidence of bone marrow depression developed during therapy. A total dose of 600 mg. M2 was not exceeded in any patient because of reports of cumulative cardiac toxicity with this agent. Six patients were excluded from evaluation of therapeutic response because they had received less than two doses of chemotherapy. Patients were generally managed in the outpatient department unless conditions warranted hospitalization. All patients were evaluated initially and at three-week intervals with the following studies prior to the administration of chemotherapy: complete blood count, routine chemical profile, electrocardiogram, and chest x-ray film. Bone x-ray films or scans, bone marrow examinations, liver scans, and other more sophisticated studies were performed when indicated. Body weight and tumor measurements were obtained at each evaluation. Subjective response was defined as the occurrence of two or more of the following criteria: weight gain of 3 per cent or more, pain relief, improvement in sense of well-being, improvement of functional status. Partial objective remission was defined as subjective improvement accompanied by 50 per cent reduction in measured tumor size and no new lesions. Complete objective remission was defined as complete disappearance of all signs of tumor activity. Results Nineteen patients with advanced transitional cell carcinoma received 60 to 75 mg. M2 of doxorubicin intravenously every three weeks. The total dose ranged from 76 to 581 mg. M2 (130 to 940 mg.) in evaluable patients. Responses

All 7 patients with bone pain from metastatic lesions had significant symptomatic relief early in their treatment course. Ten patients (53 per cent) experienced subjective remission during treatment (Table II). This was often short-lived

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TABLE II.

Response to doxorubicin chemotherapy No. Patients Evaluable

Transitional cell carcinoma bladder Stage Ds Stage Dr Stage C Metastatic transitional cell cancer prostate Metastatic transitional cell cancer renal pelvis TOTALS

Subjective Response

Partial Objective Remission*

Progression

10 5 2

5 3 1

. . 1 . .

5 1 1

1

1

. .

. .

_ 1 19

L

1

A 10

1

8

*There were no cases of complete objective remission.

but averaged sixand-a-half months before progression of disease became evident. There was no apparent correlation between subjective response and age, sex, histologic grade of tumor, or previous treatment. One patient (5 per cent) experienced a partial objective regression of his tumor. He is a sixtysix-year-old man who was treated for an infiltrative bladder carcinoma with invasion of the prostatic substance by prostatocystectomy and ureterosigmoid diversion in 1973. He returned in April, 1975, with local recurrence in the pelvis and invasion of pelvic skeletal muscle on biopsy. Treatment with doxorubicin, 65 mg. M2, every three weeks, for a total of 450 mg. M2 thus far, has resulted in subjective improvement and a reduction of tumor by greater than 50 per cent. Eight of the 19 evaluable patients (42 per cent) never showed signs of response to chemotherapy. The 6 patients excluded from evaluation were terminally ill at the time of initial treatment and died shortly thereafter. We have not used this agent long enough to determine if survival time is extended beyond that obtained with standard supportive measures. (range

four to nine months),

rectly into the tubing of an intravenous infusion. There were five instances of dose modification related to moderate, transient leukopenia. This occurred with equal frequency in patients who had received prior extensive irradiation therapy and those who had not been irradiated. Mild stomatitis developed in three patients after initial therapy with the drug; this resolved in all cases without difficulty and did not require dose modification. Alopecia occurred in all patients and was emotionally disturbing but medically benign; hair regrew after therapy was stopped. Nausea and vomiting occurred infrequently. There were two instances of transient electrocardiographic abnormalities (nonspecific ST and T-wave changes) and no cases of congestive heart failure in this small group of patients. A summary of side effects observed is presented in Table III.

Toxicity related to doxorubicin Side effects chemotherapy were generally mild in this series (including the 6 patients receiving only one dose of medication). The most troublesome problem was full-thickness skin loss in 2 patients secondary to extravasation of the drug into the subcutaneous tissues (Fig. 2). These mishaps occurred early in our experience and were subsequently prevented by injection of the drug di-

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FIGURE 2. Chemical cellulitis and skin loss related to subcutaneous extravasation of doxorubicin. This lesion healed without problem.

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TABLE III. Doxorubicin toxicity (25 patients evaluable) -Patients Number

Problem Chemical cellulitis Leukopenia, moderate, transient Stomatitis, mild Alopecia Transient electrocardiographic changes Congestive heart failure

AffectedPer Cent

2

8

5 3 2.5

20 I2 100

2 0

8 0

Comment Five-year survival rates in patients with advanced transitional ceil carcinoma treated by operation and/or radiotherapy are dismal. In large part these poor results are due to failure to control lymph node metastases. Only a systemic mode of therapy, such as chemotherapy, could possibly have an effect on these metastases. Unfortunately, the chemotherapy of advanced transitional cell carcinoma has not been studied extensively. 5Fluorouracil does appear to have some impact on this neoplasm but objective response rates are not well documented.’ Doxorubicin is a relatively new drug that has shown significant activity against transitional cell carcinoma. Most of the available data are from large drug-oriented series involving a broad range of tumors and generally including only a small number of cases of bladder canoer. A summary of results from the larger studies is presented in Table IV. The over-all objective remission rate of 24 per cent indicates significant antitumor activity. This article adds an additional 25 cases including one of transitional cell carcinoma of the prostate and one of transitional cell carcinoma of the renal pelvis. McGuire, Lytton, and Mitchell12 have reported a patient with metastatic transitional cell carcinoma of the renal pelvis who experienced a dramatic remission of his disease for sixteen months after therapy with doxorubicin. The toxic effects of doxorubicin are easily controlled and are well tolerated by patients. The major short-term toxicity is reversible myelosuppression. Leukopenia and thrombocytopenia are most often seen with the nadir occurring from thirteen to twenty-one days after the dose, and recovery generally occurring within three to four weeks. I3 A dose schedule of every 60 to 75 mg. M2 given intravenously three weeks is currently recommended. It may

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be wise to reduce the dose in patients with reduced bone marrow reserves due to previous radiotherapy and also in patients with hepatic insufhciency in view of the biliary excretion of the drug. Middleman, Lute, and Frei5 found “marked myelosuppression in azotemic patients” and recommend dose reduction in the face of renal insufficiency. Their patients, however, received 75 to 90 mg. M2 of the drug and this factor might explain the degree of myelosuppression -observed. Alopecia involving the scalp, axillary and pubic hair occurs in almost all patients; hair regrowth usually resumes on cessation of therapy. Vomiting occurs in a significant percentage of patients but generally resolves within twenty-four to forty-eight hours. Extravasation of drug during intravenous administration can produce local tissue necrosis; this complication is preventable by injection into the tubing of an established infusion line. Dose-related stomatitis and occasionally esophageal mucositis have been reported in as many as two thirds of patients in some studies.13 The data presented in this article indicate that adherence to the recommended dose schedule may minimize the incidence of this problem. Cardiac toxicity, which may involve transient electrocardiographic changes and/or cardiomyopathy, is a very important consideration in the use of doxorubicin. In one study of 399 patients, isolated transient electrocardiographic abnormalities occurred in 11 per cent.6 These changes occurred most frequently in the first TABLE IV.

Activity of doxorubicin in bladder cancer

Number Of

Investigator Middleman, Lute, Frei5 Tan et al. 8 O’Bryan et al. g Bonadonna et al. lo

Patients

Number of Responses*

Response Rate (%I

7 5

4 0

57 0

39

14

36

4

1

25

SWOG”t

50

8

COG” WOG” Weinstein and Schmidt (this series)

10 17

5 3

16 50 18

19

--I36

TOTALS

151

5 24

*Partial plus complete objective remissions. f Reference” involves studies by Southwestern, Central, and Western Oncology groups.

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few days after drug infusion, caused no significant morbidity, and were not dosedependent. They consisted of sinus tachycardia, S-T segment depression, T wave flattening, and occasional premature ventricular contractions. A return to the original electrocardiographic pattern usually occurred shortly after discontinuation of the chemotherapy. In this same study there were 10 cases, among the 33 patients (30 per cent) receiving more than 550 mg. Mz of this drug, in whom congestive heart failure developed. This occurred only once in the 366 patients (0.27 per cent) who received a cumulative dose of less clinical feathan 550 mg. M2. The outstanding tures of the syndrome of doxorubicin-induced cardiomyopathy include insidious onset of congestive heart failure and refractoriness to cardiotoxic drugs. Death occurred rapidly in 8 of the 10 patients affected. Postmortem examination showed a striking decrease in the number of cardiac muscle cells present, degeneration of the remaining myocardial cells, loss of contractile substance, mitochondrial swelling, and intramitochondrial dense inclusion bodies. Therefore, to permit safer use of this efficacious agent, the cumulative dose of doxorubicin should be limited to less than 550 mg. MP. Doxorubicin appears to have significant effectiveness against transitional cell carcinoma. Randomized controlled clinical trials are necessary for comparison of this agent with other single agents and with standard supportive measures. In addition clinical trials using doxorubicin in combination with other agents might be rewarding. Combination chemotherapy has several theoretical advantages over single drug treatment: (1) true therapeutic synergism, (2) a delay in the emergence of resistance to individual agents, and (3) the minimizing of individual drug toxicity. In combination regimens the reduced dose of doxorubicin may postpone the risk of cardiotoxicity associated with cumulative doses greater than 550 mg. M2. In a recent study by Corbett et al. l4 the antitumor activity of the combination of cyclophosphamide plus doxorubicin was found to be superior to the optimum effective dose of each agent alone against a variety of experimental tumor models. This combination given every three weeks at 50 per cent of their individually tolerable doses has proved to be highly effective and well tolerated in previously untreated patients with advanced breast cancer. The combination of doxorubicin with cyclophosphamide or

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5-fluorouracil or both would be of particular interest in advanced transitional cell carcinoma. There are several other areas of investigation which might prove rewarding. The use of doxorubicin chemotherapy as an adjunct to surgical procedures and/or radiotherapy warrants a clinical trial. In a study by DiPietro et al. l5 doxorubicin was given by intra-arterial infusion to 32 patients with different types of advanced cancer. This group included 2 patients with advanced transitional cell carcinoma of the bladder. In comparison with conventional drugs doxorubicin by prolonged arterial infusion produces a higher percentage of side effects and not a higher percentage of therapeutic responses. In another study by Pavone-MacalusolG 9 patients with superficial bladder carcinomas were treated with intravesical instillation of doxorubitin. This was well tolerated by the bladder mucosa and no systemic side effects were observed. Some partial regressions were observed but the drug appears to be less effective than thiotepa when administered intravesically. These two routes of administration may be deserving of further study. Cardiac toxicity is the main factor limiting long-term maintenance chemotherapy with doxorubicin. The early detection of doxorubicin cardiotoxicity would provide a means for more rational administration of the drug, allowing maximum cumulative dosage without excessive risk of cardiac toxicity. Serum cardiac enzyme elevations occur late in the course of doxorubicin-induced heart failure and are, therefore, not helpful in early detection.6 Rinehart, Lewis, and Balcerzak’ measured systolic time intervals by the simultaneous recording of electrocardiogram, phonocardiogram, and carotid pulse tracing in patients receiving doxorubicin. The ratio of the pre-ejection period to left ventricular ejection time, which is an estimation of left ventricular function, increases with left ventricular dysfunction, and provides a noninvasive means of detecting early cardiotoxicity associated with doxorubicin. This may represent a significant advance in the use of for long-term maintenance doxorubicin chemotherapy. Iowa City, Iowa 52242 (DR.

SCHMIDT)

ACKNOWLEDGMENT. To members of the Department of Urology for allowing review of their patients and to Mrs. Barbara Ziegler for manuscript preparation.

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References The chemotherapy of bladder 1. CARTER, S. K.: cancer, in Murphy, G. P., and Mittehnan, A., Eds.: Chemotherapy of Urogenital Tumors, Springfield, Charles C Thomas Company, 1975, p. 105. 2. BONADONNA, G., MONFARDINI, S., DELENA, M., and FOSSATI-BELLANI, F. : Clinical evaluation of Adriamycin, a new antitumour antibiotic, Br. Med. J. 3: 503 (1969). 3. BONADONNA, G., et al.: Phase I and preliminary Phase II evaluation of Adriamycin, Cancer Res. 30: 2572 (1970). 4. BLUM, R. H., and CARTER, S. K.: A new anticancer drug with significant clinical activity. Ann. Intern. Med. 80: 249 (1974). 5. MIDDLEMAN, E., LUCE, J. and FREI, E.: Clinical trials with Adriamycin, Cancer 28: 844 (1971). 6. LEFRAK, E. A., PITHA, J., ROSENHEIM, S., and analysis of AdGOTTLIEB, J. A.: A clinicopathologic riamycin cardiotoxicity, ibid. 32: 302 (1973). 7. RINEHART, J. J., LEWIS, R. P., and BALCERZAK, S. P.: Adriamycin cardiotoxicity in man, Ann. Intern. Med. 81: 475 (1974). 8. TAN, C., et al. : Adriamycin - an antitumor antibiotic in the treatment of neoplastic diseases, Cancer 32: 9 (1973).

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9. O’BRYAN, R. M., et al. : Phase II evaluation of Adriamycin in human neoplasia, ibid. 32: 1 (1973). 10. BONADONNA, G., et al. : Clinical trials with Adriamytin. Results of three-years study, in Carter, S. K., DiMarco, A., Ghione, M., K&off, I. H., and Mathe, G., Eds. : International Symposium on Adriamycin, New York, Springer-Verlag, 1972, p. 139. 11. SLAVIK, M.: Adriamycin activity in genitourinary and gynecologic malignancy. Presented at Fifth New Drug Seminar, Investigational Drug Branch, National Cancer Institute, December 17, 1974. 12. MCGUIRE, E. J., LYTTON, B., and MITCHELL, M. S.: Treatment of metastatic transitional cell carcinoma with Adriamycin: a case report, J. Urol. 110: 384 (1973). 13. WANG, J. J., CORTES, E., SINKS, L. F., and HOLLAND, J. F.: Therapeutic effect and toxicity of Adriamycin in patients with neoplastic disease, Cancer 28: 837 (1971). 14. CORBETT, T. H., et al. : CyclophosphamideAdriamycin combination chemotherapy of transplantable murine tumors, Cancer Res. 35: 1568 (1975). 15. DIPIETRO, S., et al.: Cancer chemotherapy by intra-arterial infusion with Adriamycin, J. Surg. Oncol. 5: 421 (1973). 16. PAVONE-MACALUSO, M. : Chemotherapy of vesical and prostatic tumours, Br. J. Urol. 43: 701 (1971).

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Doxorubicin chemotherapy in advanced transitional cell carcinoma.

DOXORUBICIN CHEMOTHERAPY TRANSITIONAL CELL CARCINOMA STEPHEN JOSEPH H. WEINSTEIN, D. SCHMIDT, From the Department Hospitals and Clinics, IN ADV...
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