A phase II study of methotrexate, doxorubicin, cyclophosphamide, and lomustine chemotherapy and lonidamine in advanced non-small cell lung cancer.
BACKGROUND
Combination chemotherapy with conventional antiproliferative drugs is becoming the treatment of choice for patients with advanced non-small cell lung cancer (NSCLC), a good performance status, and no major clinical contraindications. Lonidamine (LND), a new drug with an innovative mechanism of action, might potentiate anticancer activity, without increasing toxicity.


METHODS
In a Phase II study, 46 patients with advanced NSCLC were assigned to receive chemotherapy with the methotrexate, doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), cyclophosphamide, and lomustine (MACC) regimen, as originally described, plus LND, 150 mg orally, three times per day. Treatment was continued until progression of disease, occurrence of unacceptable toxic effects, or refusal by the patient (the median duration of MACC treatment was 6 weeks; 7 weeks for LND).


RESULTS
For the whole group of patients, actual dose intensities (DI) of MACC and LND were 95% and 67% of those projected (median values), respectively. There was a negative correlation between duration of chemotherapy and the DI of MACC reached in each patient. On the contrary, there was no correlation between the duration of treatment with LND and its DI. The DI of LND and MACC were not correlated with each other. In all, seven objective responses (only partial responses) were observed. The overall median survival time was 42 weeks (confidence limits [CL], 20-52). The median survival length of patients receiving the full dose of LND (450 mg daily for at least 1 week) was 46 weeks (CL, 28-67), as compared with the median survival of 19 weeks (lower CL, 9 weeks) for the remaining patients; this difference was statistically significant (P < 0.05, Breslow test). Toxic effects were as expected with the use of MACC. They were mainly gastrointestinal (any grade of toxicity occurring in 64% of the patients), hematologic (anemia, 44%; leukopenia, 36%; thrombocytopenia, 8%), oral (25%), renal (14%), and cardiac (11%). There was only one treatment-related death, from myocardial infarction and neutropenic sepsis. Uncommon side effects, which were attributed to LND, were mild to moderate and reversible; they included myalgia (26%), asthenia (15%), testicle pain (11%), visual problems (7%), and gastric intolerance (7%).


CONCLUSIONS
MACC plus LND is a moderately active regimen in advanced NSCLC, with foreseeable and reversible toxic effects of low-medium grade. Potential enhancements of antitumor activity and possible host survival benefits may be expected by the addition of LND to MACC, but a Phase III study must be performed to identify them.
First Pulmonary Unit, A. Carle Hospital, Cuneo, Italy.
G
G
Buccheri
D
D
Ferrigno
A
A
Rosso
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage* / Q000009:adverse effects; D008130:Lomustine / Q000008:administration & dosage / Q000009:adverse effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009367:Neoplasm Staging; D010865:Pilot Projects; D012074:Remission Induction; D015996:Survival Rate
D007191:Indazoles; D008130:Lomustine; D004317:Doxorubicin; D003520:Cyclophosphamide; C016371:lonidamine; D008727:Methotrexate