Oliver Glidewell

Amputation and adriamycin in primary osteosarcoma.

Abstract Adriamycin has been found effective in metastatic osteogenic sarcoma. To determine its efficacy in osteosarcoma without detectable metastases, 21 patients were given adjuvant adriamycin th...

A randomized combined modality trial in small cell carcinoma of the lung comparison of combination chemotherapy-radiation therapy versus cyclophosphamide-radiation therapy effects of maintenance chemotherapy and prophylactic whole brain irradiation

A randomized trial of combined modality therapy employing combination chemotherapy (cyclophosphamide (CTX) and methotrexate (MTX), CTX, MTX and Vincristine (VCR) and CTX, VCR and high‐dose MTX with citrovorum rescue) and radiation therapy was compared to cyclophosphamide and radiation therapy in 258 patients with pulmonary small cell carcinoma. Patients were also randomized: 1) to determine the effects of prophylactic whole brain irradiation; and 2) to establish the effects of maintenance chemotherapy. Survival, frequency of response and site of relapse were different in patients with limited disease (LD) (disease confined to lung, mediastinum and supraclavicular lymph nodes) when compared with disease spread beyond these sites (extensive disease) (ED). No survival advantage was seen in LD when combination chemotherapy was employed, although the frequency of complete remission was greater with three drugs than with one or two drugs (48% vs. 32%). In ED frequency of response was greater for three drugs than for one and two drugs (60% vs. 40%), but there was no survival advantage. The median survival time for complete responders was similar for limited or extensive disease (12.1 months), but 23.8% were alive at 24 months with LD compared to none with ED. Maintenance chemotherapy significantly prolonged survival by 16.8 months with 33% alive at 24 months compared to 9% who were unmaintained. Prophylactic whole brain irradiation prevented brain metastases with only 4% developing this complication as compared to 18% of control subjects, but did not influence survival.

Adjuvant chemotherapy of breast cancer

One hundred women with primary breast cancer with 4 or more metastatic axillary nodes were treated for 9 months postoperatively with vincristine, prednisone, cyclophosphamide, methotrexate, and fluorouracil (VPCMF). Sixty‐five women have been observed for a minimum of 5 years or until failure and the rest for 3 years or more. For 73 women who received adjuvant chemotherapy only, observed for 5 1/2 years median, disease‐free status by life table analysis is 68% at 8 years. No significant difference was found between response of pre‐ and postmenopausal women in disease‐free interval or survival. Mortality compared to expectation was sharply reduced; only 9 of 73 have died. These findings demonstrate the long term effectiveness of relatively short‐term surgical adjuvant combination chemotherapy in pre‐ and postmenopausal patients with breast cancer at righ risk.

Chemotherapy of acute lymphocytic leukemia of childhood.

CUTE LYhfPHOCYTIC I~EL‘KEMIA IS A NEOA plastic disease predominantly of childhood which in its untreated state leads swiftly to death. The manifestations of the disease in its florid state result from the defects in normal Iiematopoiesis with deficient production of granulocytes, tlwombocytes, antl erythrocytes. Normal lymphocytic function is also impaired. Although turneraction itself can lead to fatal outcome, particularly in the central nervous system, ordinarily death comes from infection or bleeding, atteiidiiiit upon the compromise in normal marrow function because of leukemic invasion or the ravages of treatment of atlvancetl disease. Dramatic alteration of leukemic mortality rate began alter 1948 with tlie first report OE an effective antimetabolite which produced selective toxicity against the tumor cells leading to temporary remission of the disease.5 ‘The discovery of other antimetabolites active ;against experimental leukemias of mice allowed the demonstration of the potential advantages of combination chemotherapy.l7 Furthermore, the critical importance of dose scheduling and dose levels was c:lemonstrated.lo Small (young) tumors were found more responsive to drug treatment than large (old) tumors which contained more cells potentially resistant to the drug, and which liad destroyed more of the animal’s normal i:issues and impaired its functions, thus plating it closer to deatli.lo In the last 20 years, we have been involved in extrapolating these fundamental principles 1.0 clinical medicine and, from the design of similar experiments in man, have derived observations which themselves have become .___ Presented at the National Conference on Cancer

A comparison of intermittent vs. continuous and of adriamycin vs. methotrexate 5-drug chemotherapy for advanced breast cancer A Cancer and Leukemia Group B study

THE THERAPEUTIC EFFECTIVENESS OF INTERMITTENT vs. continuous combination chemotherapy and of the substitution of adriamycin for methotrexate in a 5-drug regimen was evaluated in women with metastatic breast carcinoma. Patients were randomly allocated to receive continuous therapy with cyclophosphamide, methotrexate, 5-fluo-rouracil, vincristine, prednisone (CMFVP-C, 86 patients), intermittent CMFVP (CMFVP-I, 109 patients), or intermittent CAFVP (107 patients). The CR + PR rate with CAFVP (71%) was superior to CMFVP-C (50%, p = 0.003) and to CMFVP-I (50%, p = 0.002). The remission duration with CAFVP (14 months, median) was superior to CMFVP-I (7 months) (p < 0.01), and tended to be superior to CMFVP-C (9 months) (p = 0.07). There was a survival advantage of CAFVP (19 months, median) over CMFVP-I (13 months) (p = 0.01), but not over CMFVP-C (16 months) (p = 0.24). Among CR + PR patients, the survival with CAFVP (29 months, median) was superior (p = 0.02) to both CMFVP-I (18 months) and CMFVP-C (21 months). The CMFVP-C regimen was associated with the highest incidence of leukopenia and neurologic toxicity, but the lowest incidence of GI toxicity. The results indicate that the CAFVP regimen is well tolerated and is superior to the CMFVP regimens.

A randomized trial of five and three drug chemotherapy and chemoimmunotherapy in women with operable node positive breast cancer.

Women with breast carcinoma and four or more involved ipsilateral axillary lymph nodes were randomly assigned to receive an induction course and 2 yr of maintenance chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF, 150 patients), CMF plus vincristine and prednisone (CMFVP, 166 patients), or chemoimmunotherapy with CMF plus the methanol extraction residue of BCG (CMF-MER, 85 patients). After 5 yr of accrual and a median follow-up of 34 mo, CMFVP is superior to CMF (p less than 0.01) with disease-free survival estimates at 4 yr of 60% for CMFVP compared to 45% for CMF. The disease-free survival advantage of CMFVP over CMF was greater in postmenopausal (p = 0.02) than in premenopausal patients (p = 0.09). CMF-MER was similar to CMF alone. CMF related side effects were similar in each regimen (see text), except for a greater incidence of leukopenia during induction with CMF than with CMFVP (p less than 0.01).

Comparative study of cytosine arabinoside therapy alone and combined with thioguanine, mercaptopurine, or daunorubicin in acute myelocytic leukemia.

Three hundred twenty‐six patients with acute myelocytic leukemia were randomly and prospectively assigned to four therapeutic regimens: cytosine arabinoside either alone or in combination with daunorubicin, 6‐mercaptopurine, or 6‐thioguanine. The results in 231 qualified previously untreated patients were analyzed. The combination treatments produced a significantly greater frequency of complete or partial remission than single drug therapy. Treatment with cytosine arabinoside and thioguanine led to 48% ageadjusted complete and partial responses. The median survival from diagnosis of all 66 evaluable patients treated with these two drugs was 18 weeks, while the median survival for those who responded to this combination was 15 months.

Recombinant Interleukin-2 by Continuous Infusion and Adoptive Transfer of Recombinant Interleukin-2-Activated Cells in Patients With Advanced Cancer

Twenty-five patients with disseminated cancer (nine with renal cell carcinoma, five with melanoma, three with Hodgkins lymphoma and chronic myelocytic leukemia [CML], two with soft tissue sarcoma, one each with large-cell lymphoma, breast cancer, and colon cancer), 13 males and 12 females, aged 25 to 68, were treated with recombinant human interleukin-2 (rIL2) by continuous infusion and adoptive transfer of autologous lymphocytes activated in vitro with IL2. Patients underwent leukapheresis on days 1, 8, 15, and 22 of the treatment. Cells, bulk activated for 20 hours in serum-free culture medium with 1,000 U IL2/mL in transfusion transfer packs as culture vessels, were transfused the following day. The infusion of IL2 by continuous infusion for six days started immediately after each adoptive transfer for 4 weekly courses. The dose of IL2 was escalated weekly in each patient; starting doses of IL2 were also escalated in subsequent cohorts of patients until maximally tolerated doses were reached. Nine patients had objective tumor regressions (three with renal cell cancer, two with Hodgkins lymphoma, and one each with melanoma, sarcoma, breast, and colon cancer). Six responses were partial, two were minor, and one was mixed. Responding patients were maintained with IL2 by continuous infusion for six days every 6 to 8 weeks, without adoptive cell transfer. The median duration of responses was 16 weeks (3 to 60 + weeks). Tumor regression was related to the dose of IL2 (greater than or equal to 3.4 x 10(6) U/m2/d for six days) and to the in vivo lymphoproliferative effects of the lymphokine, but not to the total number of cells adoptively transferred. Side effects of treatment were transient and quickly reversible. Renal, hepatic dysfunction, and dyspnea were directly related to the dose of IL2 and to lymphocytosis. Other toxicities were mild hypotension with mild fluid retention, oral mucositis, anemia, thrombocytopenia, fever, and fatigue.

Combination chemotherapy and radiotherapy for acute lymphocytic leukemia in adults: results of CALGB protocol 7113.

Abstract One hundred and forty-nine adult patients with acute lymphocytic leukemia (ALL) were treated with protocol defined combination chemotherapy-radiotherapy by 25 member institutions of the Cancer and Leukemia Group B. Induction of remission was attempted with vincristine (V), prednisone (P), L-asparaginase (A), with or without intrathecal methotrexate (IT-MTX) and followed by daunorubicin (D) in those patients not in complete remission after 4 weeks. The overall complete remission (CR) rate was 72%; daunorubicin was needed to achieve CR in 20 of the 107 remitting patients. The administration of IT-MTX during remission induction, especially when given simultaneously with A, was found to increase toxicity without therapeutic benefit. Remissions were maintained with either parenteral courses of 6-mercaptopurine (6-MP), and methotrexate (MTX), plus intermittent doses of V, P, and bis-β-chloroethylnitrosourea(BCNU) or with daily oral 6-MP, weekly oral MTX, and periodic VP reinforcements. All patients remaining in remission for 3 months or longer received CNS chemoradiotherapy. Median remission duration was 15 months. Continuous oral maintenance proved at least equivalent to intermittent parenteral remission therapy. Median survival was 17 months for all patients and 29 months for qualified patients achieving CR. Frequency and duration of response, and duration of survival were independent of age between ages 30 and 60. Above age 60 the prognosis is significantly less good. Thirty-two percent of the responders (life table estimate) remain in continuous first remission at 5 y. Toxicity was acceptable, except for an excessive frequency and severity of infections: (1) when V, P. A, and IT-MTX were given simultaneously; and (2) early in remission when full doses of maintenance chemotherapy were employed prior to complete recovery of normal bone marrow function. Results of treatment of ALL in adults have improved markedly during the last decade but lag behind those observed in children for reasons as yet unexplained.

A new effective four-drug combination of CCNU (1-[2-chloroethyl]-3-cyclohexyl-1-nitrosourea) (NSC-79038), vinblastine, prednisone, and procarbazine for the treatment of advanced Hodgkin's disease

Five hundred and sixty‐six patients with either Stage III or IV Hodgkins disease were prospectively randomized to test whether CCNU and/or vinblastine are more effective than mechlorethamine and/or vincristine with procarbarine and prednisone. The combination of CCNU, vinblastine, procarbazine, and prednisone (CVPP) was shown to be a highly effective program with a complete response frequency of 69%. The use of CCNU as part of the induction program was also shown to be the most significant determinant of prolonged remissions (P = .025). Reduced vomiting and neurotoxicity, as well as the oral administration, were the chief advantages of the CVPP as compared with MOPP. These factors resulted in improved patient and physician compliance. The MVPP regimen was also shown to be a highly effective regimen with a complete response frequency of 73% in patients without prior exposure to chemotherapy. However, the induction regimens containing vinblastine were associated with a significantly higher frequency of fatal hematopoietic toxicities than the induction regimens containing vincristine (P = .05). This higher frequency was almost exclusively seen in the elderly or in patients previously treated with both chemotherapy and radiotherapy. At this time, the remission durations maintained by vinblastine with periodic reinforcement are longer when compared with vinblastine maintenance alone (P = .06), but there is no corresponding increase in survival.