Phase II Study of Concurrent Methotrexate and Bleomycin Chemotherapy1

[CANCER RESEARCH 34, 2240-2242, September 1974]

Jacob J. Lokich2 and Emil Frei, III Children's Cancer Research Foundation, and Harvard Medical School, Boston, Massachusetts 02115

SUMMARY MATERIALS AND METHODS

Methotrexate and bleomycin are both active in epidermoid Thirty patients with a histologically established diagnosis of tumors. They have different mechanisms of action and metastatic cancer were entered on the study. All patients had different host effects particularly with regard to myelosuppres- an expected survival of more than 4 weeks and fulfilled sion. The concurrent administration of methotrexate and serological and hematological parameters according to the bleomycin was used in 30 patients with metastatic tumors, following criteria for normal liver, renal, and marrow function: primarily epidermoid in type. Ten of 19 patients Ã©valuablefor blood urea nitrogen, <20 mg/100 ml; alkaline phosphatase, therapeutic response demonstrated objective tumor regression <80 lU/ml; bilirubin, <1.2 mg/100 ml; hemoglobin, >11 (2 complete and 8 partial) with a median duration of response g/100ml; white blood count, >4500/cu mm; platelet count, of 4 months. Bleomycin-induced pulmonary toxicity occurred >150,000/cu mm. Patients with chronic pulmonary disease in 14% with 1 mortality (25%). Marrow suppression developed were not excluded. Twenty-seven patients had had previous in 50% of Ã©valuablepatients (10 of 21 WBC <2500/cu mm antitumor therapy: radiotherapy, 18; chemotherapy, 2; and and 8 of 21 platelets <100,000/cu mm) but no complications both radiotherapy and chemotherapy, 7. were observed. Future modifications of the regimen may Twenty-three patients had squamous cell carcinomas. The substantially improve the therapeutic index over that observed primary site was head and neck, 6; lung, 6; esophagus, 5; here. female genitalia, 4; penis, 1; and bladder, 1. In addition, there were 3 patients with undifferentiated carcinomas (primary lung), 2 with soft tissue sarcomas, and 1 each with melanoma INTRODUCTION and lymphosarcoma. Bleomycin was administered by pulse i.v. injection at a dose Bleomycin is a mixture of glycopeptides derived from of 10 to 15 mg/sq m twice weekly to a maximum dose of 200 Streptomyces verticillus. This antibiotic has a qualitatively mg/sq m or less depending upon toxicity. Methotrexate was distinctive mechanism of action and produces unique host given i.v. at a dose of 15 or 25 mg/sq m depending on risk effects. Antitumor activity has been demonstrated in epider moid cancer, Hodgkin's disease, and non-Hodgkin's lymphoma status determined on the basis of age, debility, and previous therapy, with good-risk patients (10 patients) receiving the and, in combination with other agents, bleomycin has higher dose. Both drugs were given concurrently twice weekly provided a greater antitumor effect without increasing for a 6-week period. At 6 weeks bleomycin was eliminated myelosuppression (2, 3, 5, 9, 10). Dose-limiting toxicity for from the combination to avoid pulmonary complications bleomycin relates to the induction of interstitial pneumonitis (estimated dose at 6 weeks, 180 mg/sq m) and methotrexate at doses above 150 to 200 mg/sq m (6). was continued at the same dose and schedule. Therapy was Methotrexate is an antimetabolite that inhibits dihydro- interrupted or terminated upon the development of unaccept folate reducÃase,and dose-restricting toxicity includes myelo able toxicity or objective evidence of progressive increase in suppression and mucosal and gastrointestinal ulcÃ©ration. tumor size. Clinical antitumor activity occurs in a broad spectrum of Response was defined as complete if regression of all known tumors including leukemia, choriocarcinoma, epithelial disease was total. Partial response was defined as a greater than tumors, and sarcomas (11,14, 15). 50% reduction in the product of the greatest perpendicular The 2 agents therefore demonstrate an overlapping spec diameters persisting for a minimum of 8 weeks. Regression of trum of antitumor activity but are distinctive with regard to less than 50% or progression of disease while on therapy was dose-limiting host effects. Furthermore, both drugs affect considered to represent essentially a nonresponding category. epithelial tumors. On this basis the combined use of these 2 Patients were monitored by weekly physical examination, agents was evaluated in a Phase II study. complete blood counts, and platelet count. Liver function tests, blood urea nitrogen, and chest roentgenograms were 1This study carried out at Children's Cancer Research Foundation, performed monthly and specific tumor measurements were Boston, Mass. Supported by Research Grant C-6516 from the National made at biweekly intervals. Cancer Institute, NIH. 2To whom reprint requests should be addressed, at Children's Cancer RESULTS Research Foundation 35 Binney St., Boston, Mass. 02115 Received March 28, 1974;accepted May 15, 1974. Nineteen patients were Ã©valuablefor therapeutic response.

2240 CANCER RESEARCH VOL. 34

The remaining 11 patients received inadequate therapy either of a progressive pulmonary tumor that developed concurrent because of early death (less than 4 weeks) in 9 patients or with the bleomycin toxicity. because of toxicity at low doses necessitating withdrawal from Oral ulcÃ©ration is a known side effect of both agents. the study (2 patients). Complete regression was achieved in 2 However, withdrawal of methotrexate and continuation of patients, 1 with epidermoid lung cancer and 1 with tonsillar bleomycin generally resulted in resolution of mucositis. cancer with pulmonary metastasis. The duration of response Nonetheless, 13 of 30 patients developed moderate to severe was 4 months and 5+ months, respectively, with 1 patient oral ulcÃ©rationrequiring interruption of therapy. Myelosup- presently surviving. pression is similarly attributed primarily to methotrexate, and Partial response was observed in 8 patients: squamous cell developed in 10 patients (Table 3). Leukopenia and thrombo- carcinomas of the lung, 2; tongue, 2; tonsil, 1; and penis, 1, cytopenia to a median nadir of 2,300/cu mm and 46,000/cu and in 2 patients with sarcomatous lesions. These incomplete mm, respectively, was rapidly reversible and unassociated with responses were sustained for a median duration of 4 months sepis or bleeding. (range: 2+ to 6 months.) A unique and paradoxical hematological effect was observed Response by category of tumor is presented in Table 1. The in 4 patients who developed thrombocythemia (platelets over patients designated as nonevaluable had a median survival of 3 106/cu mm). This effect was generally transient and was not weeks. The median survival was 20 weeks for complete associated with complications. regression, 20 weeks for partial regression, and 12 weeks for no response. DISCUSSION Toxicity was separated into those related to bleomycin and those secondary to methotrexate (Table 2). Bleomycin- Bleomycin and methotrexate are active antitumor agents associated fever occurred in 12 of 30 patients (41%). Fever particularly in epidermoid carcinomas as well as in tumors of developed approximately 4 to 6 hr following bleomycin mesenchymal origin. The 2 drugs have been used sequentially administration and was occasionally associated with shaking by Mosher et al. (9) and 6 of 7 patients demonstrated chills and profound weakness. Gradual defervescence occurred objective tumor responses, but severe skin and mucosal over a 24- to 36-hr period. Two patients developed a transient toxicity precluded continuation of the regimen. Concurrent desquamating dermatitis attributed to bleomycin. Pulmonary administration of methotrexate and bleomycin has been toxicity secondary to bleomycin therapy was observed in 4 of previously reported in a clinical trial in head and neck tumors 20 Ã©valuablepatients. The clinical syndrome was similar to by Broquet et al. (4) with 9 of 15 (60%) objective remissions. previous reports including the sudden onset of cough In an experimental tumor system (Sarcoma 180) simultaneous associated with sputum production and focal or generalized administration of bleomycin and methotrexate resulted in a pulmonary infiltrates by chest roentgenogram. The total dose synergistic antitumor effect (12). of bleomycin was 95, 150, 135, and 250 mg in each of the 4 Combined bleomycin and methotrexate in the regimen patients, respectively. Three of the 4 patients recovered reported here resulted in responses in a variety of tumors following discontinuation of bleomycin. The 4th patient died including epidermoid tumors of the head and neck, lung, and

Table 2 Table 1 Incidence of drug-related toxicity in 21 Ã©valuablepatients Primary tumor category related to response, duration of response, Fever, dermatitis, and pulmonary toxicity were related primarily to and survival bleomycin. Stomatitis and myelosuppression developed in 50% of the Median survival for nonevaluable patients was 3 weeks, and the patients, possibly because of the interaction of bleomycin with nonresponders survived to 12 weeks, in comparison to 20 weeks for methotrexate. respondÃ©is. %StomatitisFeverMyelo No. of patients

PathologicalcategoryEpidermoidHead patients656411231130NotÃ©valuable141211111<1CRÂ°1125+5PR321283

suppressionPulmonaryDermatitis13121042625747189 andneckEsophagusLungFemale genitaliaPenisBladderOtherSarcomaUndifferentiatedMelanomaLymphomaTotalsResponse Table 3 Incidence and nadir level ofleukopenia and thrombocytopenia Fifty % of Ã©valuablepatients developed leukopenia with (8 patients) or without (2 patients) thrombocytopenia that was rapidly reversible and unassociated with sepsis or bleeding.

Median No. No. nadir/cu duration0 Ã©valuable decreased mm Range Survival6Total 5NR11222193 WBC 21 10 47 2,300 1-3,000 " CR, complete regression; PR, partial regression; NR, no response, Platelets 21 8 38 46,000 5-123,000 k Median in months.

SEPTEMBER 1974 2241

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Jacob J. Lokich and Emil Frei III

Cancer Res 1974;34:2240-2242.

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