Cancer Immunol Immunother (1987) 24: 178-179

Short communication

ancer mmunology mmunotherapy

© Springer-Verlag 1987

Combined treatment of advanced malignant melanoma with coumarin and cimetidine

A phase II study

Lise Pedersen, Carsten Rose, and Eyvind Langvad

Department of Oncology ONA The Finsen Institute, Rigshospitalet, Copenhagen, Denmark

Summary. Immunostimulant therapy with coumarin and cimetidine was evaluated in 17 patients with advanced malignant melanoma. Induction therapy with coumarin 100 mg daily was given for 8 weeks, whereupon cimetidine 1000 mg daily was added. No patients had been previously treated with cytotoxic drugs, and all patients had a good performance status. In 16 patients progressive disease was observed, and only 1 patient experienced no change in condition, lasting 30 weeks. We conclude that treatment with this schedule of coumarin and cimetidine is without effect in advanced malignant melanoma.

Introduction

Patients with recurrence of malignant melanoma often die rapidly with progressive disease refractory to systemic therapy. Several cytotoxic drugs have been tried with an average response af 20% as the best result. Responses are generally of short duration and survival has remained short [2]. Endocrine therapies have not proved effective [3], and immunotherapy of malignant melanoma has shown contradictory results [4]. After several months treatment with coumarin 100 mg (chemical name: 5,6-benzo-a-pyr- on) daily, Thornes and Lynch [6] recently obtained a par- tial remission in 3 patients with progressive disease when cimetidine was added. These remissions were maintained for more than 6 months. The disease was still progressing in 3 patients who received cimetidine and coumarin simul- taneously, and cimetidine alone had no effect in 2 patients. Flodgren et al. [1] have reported some activity of combined treatment with interferon and cimetidine in patients with disseminated malignant melanoma. However, other stud- ies have not been able to confirm this observation [5].

The present study was conducted to evaluate the effi- cacy of combined coumarin and cimetidine treatment in patients with metastatic malignant melanoma.

Materials and methods

The criteria of eligibility were as follows: (a) advanced progressive malignant melanoma with measurable and/or evaluable lesions according to the WHO criteria, (b) no

Offprint requests to: Lise Pedersen MD, Dept. of Oncology ONA, The Finsen Institute, 49, Strandboulevarden, DK- 2100 Copen- hagen 0. Denmark

prior cytotoxic therapy and no prior immunotherapy (pri- or endocrine therapy was allowed), (c) performance status _< 2, (d) no previous or concomitant malignancy, (e) no possibility of curative local treatment (surgical treatment and/or radiotherapy) and (f) the patients had to give their oral informed consent.

The patients were treated with coumarin (Schaper & Brfimmer, Salzgitter, FRG) 100 mg daily for 2 months, whereafter cimetidine 1000 mg daily (200 mg x 3 plus 400 mg nocte) was added.

Pre-treatment examinations included: history, physical examination, chest X-rays, laboratory tests (blood cell counts, serum calcium, liver enzymes and serum creati- nine) and estimation of performance status. All visible and palpable lesions were measured to provide a basis for sub- sequent examinations. Patients were assessed 8 and 12 weeks after initiation of therapy and thereafter at 2-month intervals. Response to treatment was defined according to the WHO criteria.

The treatment was meant to be given for 5 months in order to allow 3 months of combined treatment with cou- marin and cimetidine. The treatment was stopped if pro- hibitive side effects occured; otherwise it continued until progression of the disease. The time to treatment failure and the duration of a response or no change was measured from the initiation of therapy until disease progression. Survival was defined as the time from start of therapy till death.

Results

From January 1984 to December 1984, 17 patients with advanced malignant melanoma (admitted to Department of Oncology ONA at the Finsen Institute) were included consecutively in this phase II study. All 17 patients were eligible and evaluable. Only 1 of the patients had received prior systemic endocrine therapy for disseminated malig- nant melanoma (Clinovir). Patient characteristics are shown in Table 1. After 20 weeks of treatment 16 patients (94%) had shown disease progression, and only 1 patient had shown no change. The median time to treatment fai- lure was 8 weeks with a range from 3 to 30 weeks, and the median survival was 16 weeks with a range from 5 to 88 weeks (Table 2). Only 3 patients received the combined treatment for 12 weeks as originally planned; 7 patients (41%) did not receive cimetidine because of rapid disease progression and death.

Table I. Patient characteristics before treatment

Age (years) Median: 57 Range: 39- 84

Sex Female: 11 Male: 6

Disease-free interval (months) Median : 5.5 Range: 0-79

Prior therapy Cytotoxic therapy: 0/17 Endocrine therapy: 1/17 Immunotherapy: 0/17

Dominant site of disease Soft tissue: 3/17

cutaneous (3) lymph nodes (3)

Lung: 8/17 Liver: 5/17 Bone: 1/17

Recurrence number 1. Recurrence: 5/17

2.-3. Recurrence: 4/17 > 3. Recurrence: 8/17

Few side effects were recorded. Of the 4 patients who suffered from severe nausea /vomi t ing , 3 had liver involve- ment from the beginning. In 1 pat ient a lopecia developed, 1 pat ient suffered from polyneuropa thy and 1 pat ient de- ve loped bleeding tendency caused by increased act ivat ion

Table 2. Response data

Duration (weeks)

Time to treatment failure Median 8 Range 3 -- 30

Survival Median 16 Range 5 - 88

Treatment period Median 12 Range 3 - 32

179

o f the f ibr inolyt ic system. Thus the bleeding tendency was not caused by coumarin, but was related to the progressive mal ignant melanoma.

Discussion

The results from the present trial show that recurrent ma- l ignant me lanoma is non-sensit ive to combined t reatment with coumarin and cimetidine. We have not been able to confi rm the promis ing results repor ted by Thornes and Lynch [6]. However, their patients developed progressive disease on therapy with coumarin , but obta ined remission after addi t ion of cimetidine. All our patients had progres- sive disease at the ini t iat ion of coumarin therapy, and ci- met idine was arbi t rar i ly a d d e d after 8 weeks. Therefore, we can only conclude that coumar in 100 mg dai ly has no effect on progressive mal ignant me lanoma and that the combina t ion of coumarin and cimetidine after 2 months of induct ion t reatment with coumar in has no effect either.

References

1. Flodgren P, Borgstr6m S, J6nsson PE, Lindstr6m C, Sj6gren HO (1983) Metastatic malignant melanoma: regression in- duced by combined treatment with interferon (HuIFN-~ (Le)) and cimetidine. Int J Cancer 32:657

2. Lucas VS Jr, Huang AT (1982) Chemotherapy of melanoma. In: Clinical management of melanoma. Martinus Nijhoff Pu- blishers, The Hague, Boston, London, p 381

3. Rose C, Pedersen L, Mouridsen HT (1985) Endocrine treat- ment with anti-estrogen, anti-androgen, or progestagen of advanced malignant melanoma: three consecutive trials. Eur J Cancer Clin Oncol 2l : 1171

4. Seigler HF (1982) Immunotherapy of melanoma. In: Clinical Management of Melanoma. Martinus Nijhoff Publishers, The Hague/Boston/London, P 503

5. Slater DE, Krown SE, Pinsky CM, Livingston PO, Oettgen HF (1984) Human leukocyte (alpha) interferon (HuIFN-a (Le)) and cimetidine in malignant melanoma. Proc Annu Meet Am Soc Clin Oncol 3:54

6. Tbornes RD, Lynch G (1983) Combination ofcimetidine with other drugs for treatment of cancer, ew Engl J Med 308:591

Received May 8, 1986/Accepted October 20, 1986