EXPERIENCE WITH WEEKLY DOXORUBICIN (ADRIAMYCIN) IN HORMONE-REFRACTORY STAGE D2 PROSTATE CANCER

CHRISTINA RANGEL, M.D. HAIM MATZKIN, M.D. MARK S. SOLOWAY, M.D.

From the Department of Urology, University of Tennessee, Memphis, Tennessee

ABSTRACT-One hundred eleven patients with endocrine-refractory Stage D prostate cancer were treated with weekly administration of 20 mg/m2 body surface area of doxorubicin hydrochloride (Adriamycin). Fifty-seven were part of a randomized study comparing doxorubicin and prednisone to prednisone alone. There were significantly more subjective responders in the doxorubicin group than in the prednisone group (p < 0.01). The number of patients with evidence of stable disease was also higher during the chemotherapy arm com- pared with prednisone alone (p = 0.02). Patients taking dororubicin had a slightly longer period of stable disease than did those taking prednisone (p = 0.08). Overall survival, however, was not prolonged (p = 0.26). Fifty-four patients took part in an open trial and 69 percent responded to treatment. All of these had clinical improvement. Side effects were minimal with cardiotoxicity noted in less than 15 percent among patients with side effects. Over 35 percent had no side effects. Thus single agent, weekly doxorubicin therapy as evaluated in our experience, while well tolerated and of subjective benefit, does not pro- vide the patient with a significant longer progression-free survival or improved overall survival.

Cancer of the prostate is the most common ma- lignancy in men. At the time of diagnosis, more than half of the patients have regional or meta- static disease. Me&static carcinoma of the pros- tate responds well to hormonal manipulation with 70 to 80 percent of patients experiencing symptomatic improvement. * After an initial re- sponse to endocrine manipulation, most pa- tients show evidence of relapse within two years. l Patients with hormonally resistant pros- tate cancer have a poor prognosis. Nearly 50 percent die within one year.2.”

The management of hormone-refractory prostate carcinoma continues to be a thera- peutic challenge. Although a variety of second- ary hormonal and chemotherapeutic regimens have been employed, none has provided satis- factory long-term results.3 Compounding the

execution of clinical trials is the difficulty in judging the quantitative response in elderly de- bilitated patients with bone only or bone-domi- nant disease. Nevertheless, the problem of pa- tients with poorly controlled bone pain refractory to any other treatment is compelling. Doxorubicin hydrochloride (Adriamycin) has been used in several trials either as a single drug or in combination with other chemotherapeutic agents. 4-7 Doxorubicin is well-tolerated and, in a few studies, was reported to have some effi- cacy in this group of patients.5.7

This report is a review of our experience in both a prospective randomized control study and an open trial of weekly administration of doxorubicin in patients with hormone-refrac- tory metastatic adenocarcinoma of the pros- tate.

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Material and Methods

One hundred eleven men with metastatic hormone-refractory prostate cancer received weekly doxorubicin. Fifty-seven patients were part of a randomized study comparing doxoru- bicin plus prednisone to prednisone alone, and 54 patients were treated in an open study.

Eligibility The inclusion criteria for both studies were

patients with Stage D2 prostate cancer at the time of diagnosis who had progressed on andro- gen deprivation. Progression was defined as new areas of metastatic disease on a bone scan or a decline in performance status and increase in pain due to prostate cancer. Patients were eli- gible if their performance status was less than 4, their white blood cell count >3,5OO/pL, plate- lets >lOO,OOO/~L, serum creatinine 52 mg/ dL, and liver function test results less than twice the upper limit of the normal, and a bili- rubin below 3 mg/dL. Patients with a history of myocardial infarction within six months prior to treatment, congestive heart failure, and/or second active malignancy were excluded.

Treatment protocol Patients received doxorubicin in a dose of 20

mg/m2 intravenously weekly. Doxorubicin was prepared in normal saline and delivered in- travenously over approximately ten minutes. The maximum cumulative dose of doxorubicin was 700 mg/m2 body surface area (BSA). The patient’s white blood cell count (WBC), and granulocytes and platelet count were monitored and dose of doxorubicin alternated by 2.5 mg/ m2 BSA depending on these values. At 400 mg/ m2 BSA and then after every subsequent 100 mg/m2 BSA the cardiac ejection fraction was calculated using a radionuclide (MUGA) scan. Serum prostatic acid phosphatase (PAP) and/or prostate-specific antigen (PSA) were monitored every three months. Pain was assessed at each weekly visit together with the need of analge- sia. Performance status was documented using the Karnofsky score of 0 to 4, and bone scan, graded from 0 to 4 according to the number of lesions as previously described by Soloway et aLa

Objective response was established if there was evidence of decreasing serum markers by 50 percent of the previous levels, and/or im- provement in the bone scan (decrease number of lesions and/or decreased intensity of previous evaluable lesions). Subjective response (clinical

TABLE I. Response to dororubicin plus prednkone vs. prednisone alone

Response ADRIPred. Pred. Alone

Subjective Responders 17 2 .g = 11.57 Non-responders 39 45 p < 0.01 - TOTALS 56 47

Stable disease Responders 28 13 X2 = 5.32 Non-responders 28 34 p = 0.021 - - TOTALS 56 47

improvement) was established by weight gain, increased appetite, and decreased use of analge- sics. For the purpose of the randomized study, patients were categorized into stable or progres- sive disease. Stable disease was interpreted as a stabilization of the serum markers and/or bone scan or clinical improvement, without evidence of progression for a minimum of three months.

Randomized study. Individuals received doxorubicin 20 mg/m2 BSA intravenously weekly plus prednisone 5 mg p.o. b.i.d. or prednisone alone. Patients were monitored for objective and subjective responses and stable disease (12 or more weeks). The parameters evaluated from this trial were the overall sur- vival per arm, the duration of response (time from initiation of treatment to progression), duration of stable disease, and duration of sub- jective response.

Open study. The patients received doxoru- bicin 20 mg/m2 BSA intravenously weekly and were followed to death. The evaluated parame- ters were duration of previous hormonal depri- vation, duration of doxorubicin therapy, total dose received, percentage of dose received from calculated one, duration of response to doxoru- bicin therapy, survival (from the beginning of chemotherapy to death), side effects, and type of response (objective and/or subjective).

Results

Randomized study Doxorubicin plus prednisone arm. Fifty-

nine patients were entered. Two were lost to follow-up. Two patients are still alive. The mean age at diagnosis was 64.7 years (range, 49 to 85 years).

The mean duration of response to doxorubi- tin plus prednisone (time to progression) for the 57 evaluable patients was 19.8 weeks (Fig. 1). Twenty-seven patients were thought to have

578 UROLOGY / JUNE1992 / VOLUMEXXXIX,NUMBER6

FIGURE 1. Duration of response (time to progression).

: --I_. _.. 0.0 *

,,,_ .,....... l., I I I I I I I I ‘_r- 1--y

0 10 20 30 40 50 60 70 80 90 100 110 120

Time to Progression (in weeks)

-Doxo&Pred (N=56) ----PredAlone (N=47) Symbols Represent Censored Observations

Median: Doxo & Pred = 15 weeks Pred Alone = 9 weeks Logrank p -value = 0.08 Wilcox011 p -value = 0.07

FIGURE 2. Overall survival.

1.0

0.8

2 .- 13 4 0.6

& ______-___-

1 0.4

cz

0.2

0 10 20 30 40 50 60 70 80

Duration of Survival (in weeks)

-Doxo&Pred (N= 56) ----PredAlone Symbols Represent Censored Observations

Median: Doxo & Pred = 47 weeks Rred Alone = 4t

90 loo 110 120

N=47)

weeks Logrank p- value = 0.70 Wikoxon p-value = 0.26

stable disease for a duration of 32.1 weeks. Prednisone alone arm. Fifty-one patients Seventeen patients had a subjective response were allocated to receive supportive prednisone with mean duration of 27.5 weeks (Table I). treatment only. Four patients were lost to fol- Survival from the beginning of treatment was a low-up. The mean age at the time of diagnosis mean of thirty-eight weeks (Fig. 2). was sixty-nine years (range 53 to 90 years).

UROLOGY / JUNE1992 / VOLUMEXXXIX,NUMBER6 579

TABLE II. Doxorubicin dose and percentage of calculated dose administered in the open study

Doxorubicin No. of Pts. Mean Dose Received Mean Calculated of (mg/m2 BSA) (%) (mg/m’) Max. Safe Dose (%)

O-100 11 (20) 58 8.3 101-200 12 (22) 155 22.2 201-300 9 (17) 236 33.6 301-400 13 (24) 355 50.8 401-500 3 (6) 475 67.7 Sol-600 4 (7) 526 75.3 601-700 2 (4) 672 94.5

The mean duration of response for the 47 evaluable patients was 15.2 weeks (Fig. 1). Thirteen patients were stable for a duration of 31.7 weeks. Only 2 patients had a subjective re- sponse (Table I). The mean survival from initia- tion of prednisone was 35.6 weeks (Fig. 2).

When both treatment arms were compared, there were significantly more subjective respon- ders in the chemotherapy arm compared with prednisone only (p < 0.01). The number of pa- tients with evidence of stable disease was again higher in doxorubicin arm versus supportive treatment only (p = 0.02). The patients on dox- orubicin had a longer period of stable disease before progression than did those on prednisone alone. This was only marginally significant (Wilcoxon’s test, p = 0.07) (Fig. 1). There was no difference in survival (Wilcoxon’s test, p = 0.26).

Open study

Fifty-four patients were entered. The mean age at diagnosis was 65.2 years (range 50 to 87 years). All patients received at least one form of androgen deprivation prior to doxorubicin. Fifty- five percent received only one endocrine therapy. The mean duration of hormonal therapy until initiation of chemotherapy, whether one or multi- ple, was 93.2 f 59.6 weeks.

Prior to chemotherapy, performance status could be evaluated in 53 patients; 64 percent had a score of O-l, and 34 percent were 2-3. The bone scan was graded in 49 patients as fol- lows: grade O-l, 16 percent; grade 2, 22 per- cent; grade 3, 33 percent; and grade 4, 29 per- cent. Forty-eight patients (89%) received at least 10 percent of the calculated dose of dox- orubicin, and 49 (91%) were treated at least four weeks (Table II). All patients have died.

Seventeen patients did not respond to dox- orubicin. All patients who responded (69%),

had clinical improvement: weight gain, in- creased appetite, and a decrease in their analge- sic requirement. Six patients had improved per- formance status. Twelve of 29 patients (41%) showed improvement (3) or stabilization (9) on the bone scan. Changes in PSA and/or PAP were evaluable in 32 patients. Fifty percent had a decrease in one of their serum markers during therapy, and 3 patients had no change for a minimum of twelve years. Two patients had an improved bone scan grade and a reduction in serum markers, and 3 patients had stabiliza- tion/improvement in at least one of those pa- rameters.

The mean duration of doxorubicin therapy was 17.2 + 14.4 weeks. Responding patients received doxorubicin for 22 + 14.4 weeks. The mean overall ADR dose was 261.5 k 168.8 mgl m2 BSA (37.2 + 24 % of the total expected cal- culated dose) (Table II). The responders re- ceived 336.0 f 147.4 mg/m2 BSA (47.9 f 20.8 % of the total expected calculated dose). The overall mean response to doxorubicin was 15.2 + 21.2 weeks compared with 22.4 f 22.4 weeks for the responders; the overall mean sur- vival from initiation of doxorubicin was 38.8 f 34.8 weeks and 45.2 k 31.6 weeks for the re- sponders.

Nineteen patients (35.2 % ) did report side ef- fects. Thirty-five patients (64.8%) had some toxicity. The major toxicity was leukopenia. A reduction in dose at some point was required in all but 2 patients (94.3%). In no patient did sepsis related to myelosuppression develop. Alo- pecia occurred in 15 patients (43 %), and muco- sitis in 22 (63%); 5 patients (14.3%) had car- diotoxicity, which did not require intervention other than discontinuation of doxorubicin. Car- diac toxicity was not dose-dependent in 4 pa- tients. In 1 patient cardiotoxicity developed when he reached the maximum dose.

580 UROLOGY i JUNE1992 i VOLUMEXXXIX,NUMBER6

Comment Symptomatic disseminated carcinoma of the

prostate presents a therapeutic challenge to clinicians. Chemotherapy is not routinely of- fered to men with metastatic prostate cancer when they relapse from androgen deprivation. Patients with metastatic prostate carcinoma are not ideal candidates for chemotherapy. They are usually elderly, generally have a poor per- formance status, and their bone marrow is of- ten compromised by extensive metastases and/ or prior irradiation. Doxorubicin has been reported to be beneficial in 13 to 25 percent of cases.” 7~g *’ Treatment with doxorubicin is usually limited by dose-related cardiotoxicity. The administration of doxorubicin once a week appears to be less cardiotoxic than administra- tion every three weeks.12.13 The total dose usually delivered every three weeks, 60-70 mg/ m2 BSA, is split into weekly intervals. Over 1,000 patients have been treated with weekly doxorubicin for different tumors. The efficacy of this weekly program is entirely comparable with doxorubicin every three weeks.12 Our ex- perience in 111 patients indicates that weekly doxorubicin is well tolerated in the majority of patients, although less than half the population actually received more than 50 percent of the maximal calculated safe dose. Over one third of the patients had no side effects. Cardiotoxicity was a clinical problem in less than 15 percent of the patients.

Metastatic carcinoma of the prostate presents a problem in the evaluation of tumor response since few patients have measurable disease. Moreover, patients who do have measurable soft tissue disease do not reflect the vast major- ity of prostate cancer patients who have bone metastases. Objective regression in bone metas- tasis may not become obvious on bone scan for three to four months following effective treat- ment. Scher et ~1.‘~ stated that biochemical markers do not uniformly reflect disease activ- ity in hormone-refractory disease, and changes in biochemical markers must be interpreted cautiously when used as the sole end point to assess efficacy. In this specific subgroup of pa- tients, survival as an end point for therapeutic efficacy may be misleading unless a concurrent control group with similar prognostic features is included for comparison. Any benefit of che- motherapy to palliate patients with prostatic cancer can be judged only in relationship to their prognosis without such treatment. Pa- tients should probably be randomized to che-

motherapy or supportive treatment alone with assessment of quality of life and survival.

Several investigators have reported their ex- perience with low-dose doxorubicin in the management of advanced carcinoma of the prostate. Robinson et al.‘” reported on 16 pa- tients who received weekly 10 mg/m2 BSA dox-’ orubicin. Eleven (68 % ) attained a reduction of pain and improvement in performance status. Objective remission was not observed. Torti et al7 reported on 25 patients with endocrine-re- fractory prostatic carcinoma. Patients were treated with 20 mg/m2 BSA. All had prior hor- monal treatment; 68 percent had 2 or more prior hormonal therapies. The overall response rate, including stabilization, was 84 percent. Gastrointestinal toxicity and alopecia were minimal, and myelosuppression was not life- threatening in any patient.

Fossa, Urnes, and Kaalhus’” reported on their experience with weekly doxorubicin 20 mg therapy per patient. The median duration of treatment was eight weeks with a range of three to sixty weeks. Six of 21 evaluable patients had subjective response with a median duration of four weeks. They concluded that weekly low- dose doxorubicin has marginal efficacy in pro- gressing hormone-resistant prostatic car- cinoma. Based on our experience, we can confirm the low toxicity of this weekly regimen. In a limited number of cases, objective im- provement was documented. The mean time to progression was only four weeks longer in the doxorubicin plus prednisone arm compared with prednisone only (p = 0.08), and the dif- ference i,n overall survival was even smaller (less than 3 weeks) (p > 0.5).

Chemotherapy, as evaluated in our expe- rience, i.e., single agent doxorubicin, given weekly although of subjective benefit, does not provide the patient with androgen-refractory disease, a significant longer progression-free survival, or improved overall survival.

Department of Urology University of Miami School of Medicine

p.0. Box 016960 (M814) Miami. Florida 33101

(DR. SOLOWAY) References

1. Resnick MI, and Grayhack JT: Treatment of stage IV car- cinoma of the prostate, Ural Clin North Am 2: 141 (1978).

2. Whitmore WF: The natural history of prostate carcinoma. Cancer 23: 1104 (1973).

3. Johnson DE, et al: National randomized study of chemo- therapeutic agents in advanced prostatic carcinoma: a progress report, Cancer Treat Rep 61: 317 (1977).

UROLOGY JUNE 1992 : VOLUME XXXIX, NUMBER 6 581

4. Murphy GP, Priore RL, and Scardino PT: Hormone-refrac- tory metastatic prostatic cancer treated with methotrexate, cy- clophosphamide plus Adriamycin, cis-platinum plus 5-fluoroura- cil pluscyclophosphamide, Urology 32: 33 (1988).

5. DeWvs WD. et al: A comnarative clinical trial of Adriamy- , tin and 5-florouracil in advanced prostatic cancer: prognostic fac- tors and response, Prostate 4: 1 (1983).

6. Smith MF, Lawson HH, Kirk D, and Kaye SB: Low dose methotrexate and doxorubicin in hormone resistant prostatic can- cer, Br J Urol 65: 513 (1990).

7. Torti FM, et al: Weekly doxorubicin in endocrine refractory carcinoma of the prostate, J Clin Oncol 1: 477 (1983).

8. Soloway MS, et al: Stratification of patients with metastatic prostate cancer based upon extent of disease on initial bone scan, Cancer 61: 195 (1988).

9. Scher H, et al: Phase II trial of doxorubicin in bidimen- sionally measurable prostatic adenocarcinoma, J Urol 131: 1099 (1984).

10. Fossa SD, Urnes T, and Kaalhus 0: Weekly low-dose Adriamycin in hormone-resistant metastatic cancer of the pros- tate. Stand I Urol Neuhrol 21: 13 (1987).

11. Eagen RT, Hahn RG, and Myers RP: Adriamycin versus 5- fluorouracil and cyclophosphamide in the treatment of metastatic prostate cancer, Cancer Treat Rep 60: 115 (1976).

12. Torti FM, et al: Reduced cardiotoxicity of doxorubicin de- livered on a weekly schedule, Ann Intern Med 99: 745 (1983).

13. Wein AJ, et al: Studies on Adriamycin using a weekly regi- men demonstrating its clinical effectiveness and lack of cardiac toxicity, Cancer Treat Rep 60: 813 (1976).

14. Scher HI, et al: Trimetrexate in prostatic cancer: pre- liminary observations on the use of prostate-specific antigen and acid phosphatase as a marker in measurable hormone-refractory disease, J Clin Oncol 8: 1830 (1990).

15. Robinson MRG, et al: Low-dose doxorubicin in the management of advanced carcinoma of the prostate, Br J Urol55: 747 (1983).

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