Vinblastine* in Neoplastic Diseaset MIDWEST COOPERATIVE CHEMOTHERAPY GROUPS COMMITTEE FOR THIS STUDY: THOMAS L. WRIGHT, JOHN IIURLEY, DONALD R. KORST, RAYMOND W. Mo@ro, ROBERT J. RORN, JOHN J. WILL, AND JOHN Loms SUMMARY In a cooperative study by members of the Midwest Cancer Chemotherapy Group, @65patients with neoplastic disease were treated with vinblastine to determine its spectrum of activity as an antineoplastic drug. The best and most frequent responses were obtained in patients with Hodgkin's disease, often after they were refractory to currently available modes of therapy. Patients with other types of neoplastic disease occasionally obtained worth-while objective responses with this agent, but these occurred infrequently. VLB is a relatively safe oncolytic agent when used with proper precautions. The dose is variable, and it is suggested that the optimum therapeutic dose is that quantity which will produce mild leukopenia without severely depressing the bone marrow or inducing other side effects. Recovery from leukopenia is usually prompt except with the severest toxicity. In a cooperative study by the members of the Vinblastine is an alkaloid of the common pen Midwest Cancer Chemotherapy Group a series of winkle, Vinca rosea Linn, and represents a new @65patients was treated with vinbiastine (VLB, class of oncolytic agents. During pharmacologic Vincaleukoblastine, and Velban) to determine its investigation (14, 15) it was noted that granulo spectrum of activity as an antineoplastic drug TABLE 1 (Table 1). iNSTITUTIONS CONTRIBUTING CASES TO VLB STUDY * Vinblastine is the generic name assigned to Vincaleuko blastine. t A preliminary report of this study was presented at the casesCleveland InstitutionNo. American Association for Cancer Research, April, 1961. Ohio4Cook Clinic, Cleveland, @ Supported by the following research grants from the Can illinois7HenryCounty Hospital, Chicago, cer Chemotherapy National Service Center, National Cancer Michigan82IndianaFord Hospital, Detroit, Institute, Public Health Service, U.S. Department of Health, University, Indianapolis, indiana Education, and Welfare: CYP 4919—Cleveland Clinic (Battle, Marquette University, Milwaukee, Wisconsin 82 8Presbyterian—St.Ohio State University, Columbus, Ohio96* J., Hewlett, J.); CYP 4913—HektoenInstitute (Schwartz, Luke's Hospital, Chicago, S.); CYP 4915—Henry Ford Hospital (Monto, R., Rebuck, illinoisIUniversity J.); CYP 4921—MarquetteUniversity (Pisciotta, A.); CYP Ohio19Universityof Cincinnati, Cincinnati, 4920—Ohio State University (Doan, C., Wall, R., Wilson, H., Illinois9Universityof Illinois, Chicago, Bouroncle,B.); CYP 5429—Presbyterian—St.Luke'sHospital Iowa15V.A. of Iowa, Iowa City, (Trobaugh, F.); CYP 4914—UniversityofCincinnati (Will,J., Wisconsin12V.A.Center, Wood, Vilter, R.); CYP 4912—University of illinois (Louis, J., Chair Michigan28V.A.Hospital, Ann Arbor, man, Best, W., Limarzi, L); CYP 4916—IndianaUniversity Research Hospital, Chicago, Illinois2Total: (Rohn, R., Bond, W.); CYP 4917—University of Iowa 265 (Fowler,W.); CYP4938—UmversityofMichigan(Bishop,R., Zarafonitis, C.); CYP 4918—Wayne State University (Clif ford, G.); V. A. Center, Wood, Wisconsin (Dessel, B.); V.A. *27 of these cases have been reported previously (10). Hospital, Ann Arbor, Michigan (Korst, D., Frenkel, E.); V.A. Hospital, Minneapolis,Minnesota (Hagen, P.); Veterans Ad cytopenia was produced in experimental animals ministration, Washington, D.C. (Lee, L); V.A.R. Hospital, and that the material possessed definite cytostatic Chicago, Illinois (Unman, J.). activity against transplantable mammary adeno Received for publication May 28, 1962. carcinoma in DBA/Jax mice and against a trans 169 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1963 American Association for Cancer Research. 170 Cancer Research Vol. @23,February 1963 plantable sarcoma in the rat. The alkaloid respon considered to have received an inadequate trial on sible for these effects was crystallized and named the drug. Of the 77 patients excluded from study, Vincaleukoblastine (14). 63 did not survive for 14 days and were considered Preliminary clinical trials (9) indicated that to have had terminal disease. The remaining four VLB possessed some degree of antineoplastic ac teen patients in this group were not evaluated for a tivity, and this study was accomplished to define variety of reasons, including loss to follow-up, con better the response of a wide variety of neoplastic comitant therapy with another antineoplastic diseases to this agent. agent, and refusal of further therapy by the pa tient. MATERIALS AND METHODS All patients had advanced neoplastic disease RESULTS confirmed by tissue biopsy. The types of neoplastic Toxicity.—The types and incidence of toxicity disease studied are shown in Table @. are tabulated in Table 3. An incidence of 35 per The VLB was supplied as a dry, sterile powder cent leukopenia of less than @,000WBC/cu mm in ampules containing 10 mg. The drug was dis reflects the fact that some degree of leukopenia solved in sterile water, 5 per cent dextrose in Wa was sought in every case as an indication of ade ter, or physiologic saline, and given, except where quate dosage of the drug. Thrombocytopenia of specifically noted, into the rubber tubing of an in less than 100,000 platelets/cu mm was associated travenous infusion of physiologic saline. In out with the leukopenia in only two instances. Pa patients VLB was injected directly into veins in a tients with leukopenia usually recovered within concentration of 1 mg VLB/@ ml saline. 1-@ weeks. Nine patients had agranulocytosis, Drug administration.—Initially most of the pa which was considered a contributing cause of tients were treated with 0.10—0.15 mg/kg of body death. Three of these had had prior therapy with weight for 1, @,or3 days. In this report the total alkylating agents, two with 5-fluorouracil, and one dose given in the first 3 days of therapy has been with local radiation therapy. The total dose associ defined as the priming dose. Subsequent doses ated with agranulocytosis varied from 0.30 to 1.1 were increased or decreased to induce mild leuko mg/kg (mean, 0.54). Eight of these deaths oc penia, and in general were not administered until curred within 14 days of the onset of therapy. there had been some reversal of leukopenia in Gastrointestinal toxicity was prominent, and 11 duced by a previous dose. per cent of the patients reported nausea and 5 per An alternate schedule was to begin at a dose of cent vomited after the injection of VLB. Stomati 0.10 mg/kg and then to increase in increments of tis was the toxic manifestation of next greatest 0.05 mg/kg every 4—7days until toxicity or benefit frequency. Changes in gastrointestinal tract mo appeared. Maintenance therapy was then given, tility occurred in 6 per cent of the patients, and in usually weekly or biweekly at a level that just six patients a paralytic ileus developed which in avoided the production of toxicity. one case lasted for 7 days. Hemorrhagic enterocoli Criteria of evaluation.—The criteria for the tis was found at post-mortem examination in one evaluation of therapeutic response were defined as patient after treatment with VLB without con follows: comitant antibiotic therapy. 1. Complete remission. No evidence of disease Some degree of epilation occurred in 54 per in all parameters of measurement. cent. Phlebitis in five patients and necrosis in two @.Objective improvement. Improvement in a patients occurred at the injection site in spite of measurable parameter, either physical or labora the precautions taken in giving the medication. tory, which could not be attributed to the natural Transient pain at the site of the primary tumor im history of the disease, supportive therapy or prior mediately after the injection of VLB occurred in treatment. four patients, all of whom had carcinomas of the 3. Subjective improvement. Improvement in head and neck. symptomatology or performance status, without Neurological manifestations occurred in 9 per any improvement in physical or laboratory param cent of the patients. The commonest was some de eters capable of objective measurement. gree of lethargy and depression, and in two pa 4. No response. Patient remained unchanged or tients confusion lasting for approximately 48 hours demonstrated progression of the disease while un appeared to be related to VLB. In other patients der therapy. absence of deep tendon reflexes and paresthesias of Patients who for any reason could not be stud the hands and feet were noted, and two patients ied for a minimum of 14 days after the onset of experienced more severe transient peripheral therapy were not evaluated, because they were neuritis. Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1963 American Association for Cancer Research. TABLE 2 TUMOR RESPONSE TO VLB tive im dose dose of therapy TumorObjective improve evalu prove responseNot (mg/@cg)*Maintenance mentSubjec aPriming (mg/kg)Duration (days) mentNo Hodgkin'sDisease 12 3 6 6 0.80 1.0 74 (0 . 12—0.60) (0 08—3.40) (4—250) Lymphosarcoma 1 0 7 2 0 .27 0 .48 19 (0.13—0.45) (0.0—0.82) (2—55) Reticulum-cell Sarcoma S 0 2 2 0 .31 0 .64 46 (0.27—036) (0.18—1.39) (15—75) MycosisFungoides 0 0 1 0 0.20 0.66 70 Leukemia, Acute: Monoblastic 2 1 12 9 0.26 0.76 23 (0.10—0.47) (0.0—3.2) (2—72) Lymphoblastic 1 0 3 2 0.31 1.18 25 (0.10—0.50) (0-16—3.25) (10—58) Myeloblastic 1 0 2 1 0.32 0.42 15 (0 .20—0.46) (0 .33—0.48)