Cisplatin, Etoposide, and Mitomycin in the Treatment of Non-Small Cell Carcinoma of the Lung

A Pilot Study

STEPHEN DAVIS, MD,*.t MAURlZlO TONATO, MD,+ LUClO CRINO, MD,+ MAR1 ANTONETTA COLOZZA, MD,* KENNETH LUBANSKY, MD,§ AND FAUSTO GRIGNANI, MD'

A total of 39 patients with non-small cell carcinoma of the lung (NSCL) were treated with cisplatin, etoposide, and mitomycin. A major response rate (complete response + partial response) was seen in 15 patients (39%). Median survival for all patients was 340 days; median survival of the responding group was 514 days. Toxic effects included moderate hematologic toxicity, nausea, and vomiting. There were no treatment-related deaths. This regimen clearly is effective in treating NSCL.

Cancer 58:1018-1019, 1986.

OMBINATION CHEMOTHERAPY for patients with n0n- C small carcinoma of the lung (NSCL) has had limited success.' It has not been conclusively proven in random- ized controlled trials that four-drug regimens are superior to one-, two- or three-drug regimens or, for that matter, no treatment, in increasing median survival. Recently, several publications have demonstrated that the combi- nation of cisplatin and etoposide yielded response rates of 24% to 52%, with significant prolongation in median survival.2 Because our experience with chemotherapy in NSCL has been di~appointing,~ our group instituted an in-house pilot study of cisplatin and etosopide (PE) and found a response rate of 25% (results not published). Ad- ditionally, mitomycin is believed to be effective as a single agent in NSCL,4 and published results further extend this belief to combination chemotherapy regimen^.^ We, therefore, instituted an investigation to evaluate the effi- cacy of cisplatin, etoposide, and mitomycin (PEM) in NSCL.

Patients and Methods

A standard Phase I1 design was employed.6 Forty-three consecutive eligible patients with biopsy-proven NSCL incurable by surgery or irradiation were accrued. Patients were younger than 70 years of age. had measurable or

* Istituto di Clinica Medica Universita di Perugia, Italy. $ Divisione Oncologia, Policlinica Perugia, Italy. 0 Chilton Memorial Hospital, Pompton Plains, New Jersey, U.S.A. t Professor? a contratto, Universit2 di Perugia, Italy. Address for correspondence: Stephen Davis, MD, 1777 Hamburg

Accepted for publication December 14, 1985. Turnpike, Wayne, NJ 07470.

evaluable disease, and a Karnofsky status of greater than 60. Previous chemotherapy rendered a patient ineligible for the protocol. Adequate hepatic (bilirubin level < 2.0 mg "/.) and renal function (creatinine clearance > 50 ml/ min) had to be documented. All patients were staged and response determined by computerized tomography (CT) and bone scans when indicated.

The PEM regimen consisted of 70 mg/m2 of cisplatin (day 1, 29, 57), etoposide 120 mg/m2 (day 1,29, 57) and mitomycin 10 mg/m2 (day 1,29,86). Cisplatin was given with intravenous (IV) hydration, mannitol and furose- mide-induced diuresis. No dosage modifications were made for changes in leukocyte (WBC) or platelets counts; these counts were allowed to normalize before the insti- tution of additional therapy. Because this was a pilot study, a patient was removed from protocol if a partial response (PR) or complete response (CR) had not been achieved (i.e. treatment failure within 85 days from initiation of treatment, or the creatinine clearance decreased to below 35 ml/min; these patients were not removed from eval- uation if 85 days on the protocol elapsed).

Results

Of the 43 patients who entered the study, 39 were eval- uable. Four patients withdrew after the first cycle due to intolerance to the chemotherapy (these patient's were ex- cluded from evaluation). There were 22 patients with squamous cell, 12 with adenocarcinoma, and 5 with large cell carcinoma. Patient characteristics are shown in Table 1. It can be seen that responding patients tended to be those with limited disease, good performance status, and no weight loss; although the small numbers of patients

1018

No. 5 PEN AND NON-SMALL CELL LUNG C A - Davis et a/. 1019

TABLE 1. Patient Characteristics

Response No. of

patients CR PR

Age (yr) Mean 56 Range 46-70

Evaluable patients 39 2 13 Histologic diagnosis

Squamous cell 1 I* 10 1 1 12 7 3 13 5 1

Adenocarcinoma 31 5 1 3 32 3 1 33 4 2

Large cell 40 5 2

Surgery 3 1 Radiotherapy? 1 1 3

Prior therapy

Limited 4 Disseminated 7

Performance status 60-80 26 8 80- 100 13 2 5

Yes 13 5 No 26 2 8

Limited 15 2 5 Disseminated 24 7

Weight loss$

Extent of disease

$ > 10% of body weight. t Delivered prior to chemotherapy; no irradiated site used in evaluating

* Histologic subtype (World Health Organization classification). CR: complete response; PR: partial response, i.e., <50% red~ct ion.~

response.

preclude definitive analysis. Three to eight courses of therapy (mean, 4.1) were given in the evaluable patients. Response rate (CR + PR), was 38% (15 patients). There were two CR in the responding group. Median survival for all patients was 340 days (225-420 days with a 95% confidence interval).’ The median survival for responders was 504+ days. Disease “stabilization” was not used in the evaluation as therapy was discontinued within 3 months if a PR was not obtained.

Hematologic toxicity was moderate, five patients having WBC count nadirs less than 1000/mm3 and seven platelet count nadirs less than 25,000/mm2 documented between days 9 to 19 of each cycle. Six patients who received pre- vious radiotherapy to the chest developed leukopenia and/ or thrombocytopenia. Two of the five leukopenic patients developed nadir sepsis; no deaths occurred. Anemia

(< 10.0 g/dl hemoglobin) occurred in 75% (29/39 patients) entered into the study. Nausea and vomiting were mild to moderate with the prophylactic use of antiemetics (IV compazine). In the group of 15 responding patients (PR + CR), the mean creatinine clearance decreased 36% from pretreatment values.

Discussion

Recent trials using cisplatin and etoposide (PE) in NSCL have shown response rates as high as 52%.2 Our group has confirmed the fact that this drug combination is active in an unpublished in-house study. Our previously published studies in NSCL had failed to show any survival advantage to chemotherapy in NSCL3 so these results with PE encouraged us to evaluate the present three-drug reg- imen, i.e., PEM.

Our results clearly show the PEM regimen highly ef- fective in treating NSCL. Our findings are similar to the preliminary results published by Martinelli et aL8 Also supporting the fact that PEM may be active in NSCL is the data of Chahanian et aL9 who found a 16% response rate of PEM plus hexamethylmelamine in patients pre- viously treated by chemotherapy. We believe that the next study must evaluate, in a controlled fashion, a comparison of PEM versus PE.

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