Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group.

PURPOSE: The trial was undertaken to determine (1) the relative efficacy/toxicity of two commonly used combination chemotherapy regimens in patients with extensive small-cell lung cancer (SCLC) and (2) whether the rapid alternation of these two regimens could provide superior therapeutic results compared with either regimen alone. PATIENTS AND METHODS: In this phase III trial, 437 eligible patients were stratified by performance status (PS) and sex and were randomly assigned to receive either 12 weeks of cisplatin and etoposide (EP); 18 weeks of cyclophosphamide, doxorubicin, and vincristine (CAV); or 18 weeks of alternation of these two regimens (CAV/EP). RESULTS: There were no significant differences in treatment outcome for EP, CAV, or CAV/EP in terms of response rate (61%, 51%, 59%, respectively), complete response rate (10%, 7%, 7%, respectively), or median survival (8.6 months, 8.3 months, 8.1 months, respectively), with a non-statistically significant trend toward a longer median time to progression with alternating therapy (4.3 months, 4.0 months, 5.2 months, respectively). Crossover second-line chemotherapy given at progression produced low response rates and short survival, regardless of the regimen used. Myelosuppression was the dose-limiting toxicity for all patients, although the pattern and severity differed among the treatment arms. CONCLUSIONS: The combination regimens EP and CAV can be considered equivalently effective induction therapies in extensive SCLC, and these two regimens are, to some degree, crossresistant. Alternating therapy provides no therapeutic advantage compared with the use of either of these regimens alone and should not be considered as standard treatment in this clinical setting.

Progressive neuropathologic lesions in vitamin E-deficient rhesus monkeys.

A consistent group of progressive central and peripheral nervous system lesions developed in seven rhesus monkeys maintained on a vitamin E-deficient diet for 30 to 33 months. These lesions were absent from vitamin E-supplemented monkeys. The principal neuropathologic alteration was loss of sensory axons in the posterior columns, sensory roots, and peripheral nerves. Morphologic and morphometric studies indicated that the distal segments of the axons were affected most severely and large-caliber myelinated fibers are selectively involved. Swollen, dystrophic axons (spheroids) occurred infrequently. Degeneration and phagocytosis of small numbers of neuronal perikarya were observed in the dorsal root ganglia and the anterior horns. The number of affected neurons was not proportional to the number of affected axons. Accumulation of lipopigment was evident in neuronal perikarya and CNS endothelial cells. The nervous system lesion were usually accompanied by a chronic necrotizing myopathy. The neuropathologic lesions in vitamin E-deficient monkeys are compared with those in vitamin E-deficient rats and in humans with low serum vitamin E concentrations. A similar type of sensory axonopathy is associated with chronic deficiency of vitamin E in these three species.

Factors involved in immunization program for swine influenza.

The decision to undertake a nationwide program of vaccination against swine influenza requires assessment of the status of immunity of those in various age groups in our population against this agent. Pools of serum were collected from persons born in the years from 1889 to 1943; they were tested for hemaggultinin inhibiting (HI) antibody against the HSW 1N1 influenza virus strains isolated in 1931 and 1976. The titers secured serve as an indication of the average level of immunity of those of different ages. Persons less than 43 years of age are found to be without antibody protection. The need for vaccination of people in different age groups based on mortality statistics of previous epidemics is evaluated. It is realized that no epidemic may occur and that a reduced virulence of the viral agent and use of antibiotics may reduce the death rate if the infection recurs. The extraordinary high mortality in 1918 in people between 15 and 44 years of age deserves recognition together with the fact that those in the same age group are now without protection. The fact that women of childbearing age fall into this group deserves special consideration in view of increased mortality in puerperal women observed in the pandemics of 1918 and 1957. The degree of protection afforded the newborn by transplacental transmission of maternal antibodies is discussed. The need of increasing the level of immunity in those who have varying titers of HI antibodies is considered in relation to the prevalence of cardiopulmonary complications and other chronic diseases in older subjects.

A phase II trial of vincristine in advanced or recurrent endometrial carcinoma. A Gynecologic Oncology Group Study.

Thirty-three evaluable patients who had not received prior chemotherapy were entered on a study of vincristine therapy for advanced or recurrent endometrial carcinoma. Vincristine 1.4 mg/m2 was given weekly as an i.v. bolus for 4 weeks and then every other week. There was one complete response (CR) lasting 5 months. Five patients had partial responses (PR) lasting 3-18 months. The CR+PR rate was 18% (95% confidence interval for CR+PR was 7-36%). Thirteen patients (38%) had stable disease from 2-28 months, and 14 had progressive disease. The major toxicity was neurological, with 11 patients having grade 2 or 3 peripheral neuropathy. Vincristine at this dose and schedule has modest activity, but troublesome toxicity in advanced or recurrent endometrial carcinoma.

Abnormalities of iron metabolism and erythropoiesis in vitamin E-deficient rabbits.

Rabbits fed a vitamin E-deficient diet developed severe muscular dystrophy in 3-4 wk, but they did not become anemic. Nevertheless, reticulocyte counts increased in deficient rabbits (3.2%) compared to control rabbits (0.9%), and erythroid hyperplasia was evident in the bone marrow. Comparing deficient rabbits to controls, the plasma iron concentration was lower (134.4 versus 206.6 microgram/dl); the TIBC was higher (335.9 versus 228.3 microgram/dl); the whole blood protoporphyrin concentration was higher (131.6 versus 81.7 microgram/dl); and the total iron content was lower in spleen (71 versus 153 microgram), higher in skeletal muscle (4956 versus 3054 microgram), and unchanged in bone marrow, liver, and heart. Studies of iron absorption and excretion using 59Fe showed no abnormalities in deficient rabbits. There were abnormalities of ferrokinetics, however. The half-time of disappearance of 59Fe was shorter (100.6 versus 169.4 min), the plasma iron turnover was greater (1.25 versus 0.95 mg/dl blood/day), and the reappearance of 59Fe in circulating erythrocytes at day 9 was greater (77.2% versus 57.2%) in deficient rabbits. Anemia induced by phlebotomy accentuated the abnormal iron metabolism of deficient rabbits, and the animals were unable to correct the anemia. These findings show that vitamin E deficiency in rabbits causes abnormal erythropoiesis associated with abnormal iron metabolism and sequestration of iron in skeletal muscle.

Phase I study of pyrazofurin and 5-azacytidine in refractory adult acute leukemia.

Twenty-eight patients with refractory adult acute leukemia were treated with pyrazofurin and 5-azacytidine. Seven patients showed a response. Dermatitis and mucositis were severe at doses of pyrazofurin greater than 50 mg/m2/day and precluded administration of multiple courses in most patients. As a result of this toxicity, 16 patients received only one course of chemotherapy. The response rates achieved with this combination were not superior to those achieved with 5-azacytidine alone.

Cisplatin, BCNU, cyclophosphamide, and prednisone in multiple myeloma.

Using the MOPC 104E murine plasmacytoma model, Ghanta et al have shown major synergism when cisplatin was added to a treatment program with BCNU and cyclophosphamide (CTX). To evaluate possible synergism in the treatment of human multiple myeloma (MM), 23 evaluable patients who had relapsed with standard treatment were treated with cisplatin, BCNU, CTX, and prednisone. There were five good and four fair responses in this group of heavily pretreated patients. These included responses in four patients who had failed to respond to or had relapsed with BCNU, CTX, and prednisone therapy at higher doses than those used in this protocol, indicating that there is synergism from the addition of cisplatin in the treatment of human MM. Gastrointestinal toxicity was significant but acceptable. Transient renal and hematologic toxicity was also seen. The number of responses and the apparent synergism seen suggest that this combination of drugs should be studied as therapy for untreated patients with MM, especially those with poor prognostic features.

Phase II study of hexamethylmelamine in refractory Hodgkin's disease, other lymphomas, and chronic lymphocytic leukemia.

A long-term daily dose of hexamethylmelamine was tested in patients with Hodgkin's disease, nodular and diffuse lymphomas, and chronic lymphocytic leukemia who had failed conventional treatment. There were no responses among 20 patients with chronic lymphocytic leukemia, 12 with nodular lymphomas, and 11 with diffuse well-differentiated lymphocytic lymphomas. However, five of 24 patients with Hodgkin's disease (21%) responded and seven of 36 (19%) with diffuse lymphomas other than diffuse well-differentiated lymphocytic lymphomas responded. This new agent is active in selected histologic types of lymphoma.

Phase II trial of piroxantrone in patients with recurrent and metastatic squamous cell carcinoma of the head and neck. A Southwest Oncology Group trial.

Twenty-two patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with piroxantrone 150 mg/m2 intravenously every 21 days. There were no objective responses. The 95% upper confidence bound for response is 15%. Primary toxicity was hematologic.

A randomized prospective study of vindesine versus doxorubicin and cyclophosphamide in the treatment of epidermoid lung cancer.

A randomized prospective study was conducted comparing vindesine (VDS) with doxorubicin and cyclophosphamide (D/C) in the treatment of advanced squamous cell carcinoma of the lung. No patient had a complete response. Seven of 28 (25%) patients had partial response (PR) to VDS while one of 19 (5%) had a PR to D/C (P less than 0.08). Adding PR plus minor response (MR), ten of 28 (36%) patients responded to VDS while two of 19 (11%) responded to D/C (P less than 0.05). Median survival was improved among patients showing PR and MR over those not responding (P less than 0.05). This study concludes, VDS is an active agent in the treatment of squamous cell carcinoma of the lung and should be considered for combination chemotherapy and adjuvant trials. VDS toxicity appears acceptable with six weekly doses of 3 mg/m2. The benefit of a maintenance schedule could not be demonstrated.

T-cell prolymphocytic leukemia with helper-cell phenotype and a review of the literature.

The majority of published cases of prolymphocytic leukemia (PLL) have been of B-cell origin. Nineteen cases of PLL of T-cell type have been described, as has a single case of PLL having a surface phenotype with features of both B-cells and T-cells. This report presents a review of these cases and comparison with one case of T-cell PLL. By using specific monoclonal antibody technique, this case was subcategorized into helper-cell phenotype: E-rosette(+), SIG(-), Anti-T(+), Anti-B(-), Anti-monocyte(-), OKT3(+), OKT4(+), OKT6(-), OKT8(-), Ia(+), and Tdt(-). Cytochemical studies showed paranuclear acid phosphatase granules. Postmortem examination revealed a predominant T-cell zone infiltration by the leukemic cells in the spleen and lymph nodes, with involvement of multiple organs. The application of the monoclonal antibody technique, which can be standardized among different laboratories to subclassify lymphoproliferative disorders into functional subtypes, should lead to a better understanding and more effective treatment of this disease.

Small cell undifferentiated carcinoma of the esophagus. Case report with hormonal studies.

This report details clinical and pathologic aspects of a case of small cell undifferentiated carcinoma of the esophagus. Transmission electron microscopic examination demonstrated neurosecretory granules, and indirect immunoperoxidase stain for adrenocorticotropic hormone (ACTH) was positive. However, the authors detected no abnormal hormone levels in urine or blood. The calculated tumor doubling time was approximately 2 days. The fulminant nature of this carcinoma was also evident from the rapid clinical progression in spite of surgical excision, radiotherapy, and chemotherapy.

Vindesine (VDS) monochemotherapy for non-small cell lung cancer: a report of 45 cases.

Fifty-three patients with non-small cell lung cancer were treated with vindesine. Of the 45 evaluable patients, 11 (24%) had a partial response. Responses were all evident within 6 weeks. Median duration of response was 8 weeks from documentation. Median survival was not improved significantly among responders (P less than 0.10, two-tailed test of significance). The most frequent toxic effect was leukopenia. The most troublesome toxic effect was peripheral neuropathy, with patients greater than 60 years old experiencing this more frequently.