September

Clinical Drug Trials for...

The September issue of Cancer Treatment Reports contains a number of important clinical studies emphasizingboth negative and positive results.

Lung CancerBernath and co-workers (Veteran's Administration Hospital, Washington,D.C.) attempted a three-drug trial containing MeCCNU, 5-FU and vincristinein 19 patients with adenocarcinoma andlarge cell carcinoma of the lung. Therewere no responses in this Phase II study.Sorensen et al. (Renström's Hospital,Göteborg, Sweden) reported a 33 percent response rate (two complete) in 24patients with small cell carcinoma of thelung, treated with a vinblastine-adriamycin-procarbazine combination. Theyhave thus identified a relatively activeregimen that appears non-cross-resistantto more commonly used combinations.

Malignant MelanomaSamson and co-workers (Wayne StateUniversity, Detroit, Michigan) undertook a Phase II study in 16 evaluablepatients with metastatic malignant melanoma using a combination of DTIC andcyclocytidine. They observed one partial and two complete responses in thisgroup and concluded that the combination was not different from the resultsobtained from DTIC alone. In another

Phase II study in metastatic melanoma,Carmo-Pereira and co-workers (Institutu Portugues de Oncologia, Lisbon,

Portugal) treated 20 patients with avincristine-DTIC-BCNU combination.They observed seven responses (35 percent), five of which were complete. DeWasch et al. (InstitütJules Bordet, Brussels, Belgium) treated 42 patients withmetastatic melanoma with a vincristineDTIC-bleomycin combination, notingresponses in 17 (49 percent), of whichsix were complete. All authors point outthe variables that affect responses inmetastatic melanoma (sex of patients,disease-free interval, sites of tumor,prior chemotherapy); patient heterogeneity continues to frustrate the validation of various drug combinations forthis tumor.

Colorectal and Gastrointestinal CancerPerry and co-workers (University ofMissouri Medical Center, Columbia,Missouri) performed a Phase II trial ofgalactitol and VP- 16-213 in patientswith metastatic colorectal cancer. Theyobserved no responses out of 30 patientstreated with galactitol at a dose of 30mg./m.2/day x five. Further, they observed no responses in 28 patientstreated with VP-16-213 at a dose of 130mg./m.2 on days one, three and five. Itwas concluded that these agents are inactive in colorectal cancer. DeJager andco-workers (Memorial Sloan-Kettering

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Highlighting

Cancer Treatment ReportsCommentary on theSeptember 1976 (Volume 60,Number 9) issue

John L. Ziegler, M.D.Scientific Editor

Cancer Center, New York, New York)tested a combination drug regimen including mitomycin-C, 5-FU and Ara-C(MFC regimen) in patients with metastatic gastrointestinal cancer. They observed an overall response rate of 15 percent (31 percent in patients with gastriccancer) among 96 evaluable patients.There was no apparent difference in patients who had previously not respondedto 5-FU. Bellet and co-workers (TheFox Chase Cancer Center, Philadelphia,Pennsylvania) undertook a study ofICRF- 159 in 35 patients with metastaticcolorectal cancer at a .dose of 1g./m.2/day x three. Five responses inthis patient group suggest that ICRF-l59may be effective in combination with5-FU in future trials. Bullen et al. (St.James Hospital, Leeds, England) treated65 patients with advanced gastrointestinal cancer in a randomized trial comparing phenylalanine mustard (L-PAM)(32 patients) with 5-FU (33 patients).Objective responses were noted in fourand five patients respectively, indicatingthat L-PAM appears to have comparableactivity. Its ease of administration andexcellent patient tolerance warrant further trials in gastrointestinal cancer. In21 patients with metastatic cancer of theliver who had been treated previouslywith 5-FU, Buroker and colleagues(Wayne State University, Detroit,Michigan) observed a 35 percent re

sponse rate following the infusion of 5-FUdR into the hepatic artery. The authors conclude that this may be a usefulmodality in the management of liver metastasis in patients who have failed withparenteral 5-FU.

SarcomasCreagan and co-workers examined twodrug combinations versus a single agentin patients with advanced sarcomas. Of80 patients randomized in this study, response rates were as follow: 11 percentfor the combination of adriamycin,DTIC and vincristine; eight percent forthe combination cyclophosphamide, actinomycin D and vincristine and 0 percent for MeCCNU used as a singleagent. These response rates are considerably lower than those reported fromother cooperative group and single institution studies; the explanation for thepoor response is not apparent.

New Drugs: Piperazinedione andChromomycin A3

A number of new drugs have receivedboth preclinical and clinical evaluation.Wheeler et al. (Southern Research Institute, Birmingham, Alabama) have evaluated a drug, piperazinedione, using anL12l0 assay system. They observed theaccumulation of cells in G2 phase withcell enlargement following exposure tothis drug. They present evidence that themode of action is by alkylation, al

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though alkylating agent resistant linesappear to be susceptible to the action ofthis agent. It will be of considerable interest to observe whether piperazinedione is cross-resistant in human tumorswhich are refractory to alkylatingagents. Reynolds and co-workers(David Grant USAF Medical Center,Travis AFB, California) have conducteda Phase I study of chromomycin A3given in alternate day doses with escalation to 1.3 mg./m.2 They observed thatrenal toxicity was dose limiting, andnoted responses in 43 patients withHodgkin's disease, rhabdomyosarcoma, adenocarcinoma of the lung and malignant melanoma. The dose level of 1.3mg./m.2 given on alternate days for fivedoses appeared to be a tolerable level ofdrug administration; therefore, theyconclude that Phase II trials at this doselevel are indicated in some tumors.

Notes on Patients Receiving BCNU,5-Azacytidine and Adnamycin

Several interesting clinical observationsare also reported in this issue. The firstconcerns the observation by Cohen et al.(University of Maryland, Baltimore,Maryland) of acute non-lymphocyticleukemia in two patients with malignantgliomas treated previously with BCNUresulting in prolonged myelosuppression. The authors speculate as towhether leukemia was the result of mar

row hypoplasia or attributable to a carcinogenic effect of the nitrosourea therapy. Ho and co-workers (University ofToronto, Toronto, Canada) report a previously undescribed observation of severe symptomatic hypophosphatemia intwo patients with AML treated with 5-azacytidine. Both patients had profoundly low levels of phosphate, accompanied by severe muscle pain and tenderness. Ramos and colleagues (Children's Hospital Medical Center, Cincinnati, Ohio) monitored serial echocardiograms in 30 children receiving adriamycm. Using the “¿�shorteningfraction―derived from echo measurements, theydetected progressive abnormalities insome subjects, and feel that such monitoring may detect patients at risk of cardiomyopathy from this agent. Finally,Rao et al. (Downstate Medical Center,Brooklyn, New York) describe strikingpigmentation of the tongue in two blackpatients undergoing treatment withadriamycin. Since it is well known thatanticancer antibiotics and alkylatingagents affect pigmentation, it is not surprising that in blacks, where aberrantpigmentation occurs in the mucousmembranes and on the palms and thesoles, this may be accentuated followingtreatment with these agents. Black patients should be warned that pigmentarychanges may be anticipated in themucous membranes, nail beds, palmsand soles.

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