Intensive combination chemotherapy, concurrent chest irradiation, and warfarin for the treatment of limited-disease small-cell lung cancer: a Cancer and Leukemia Group B pilot study.

PURPOSE: In prior Cancer and Leukemia Group B (CALGB) studies, combined chemotherapy and thoracic irradiation was superior to chemotherapy alone in limited-disease (LD) small-cell lung cancer (SCLC). A combined modality pilot study was performed to test the feasibility of adding warfarin to aggressive chemoradiotherapy for LD SCLC. PATIENTS AND METHODS: Combination chemotherapy with doxorubicin 45 mg/m2 intravenously (IV) on day 1, cyclophosphamide 800 mg/m2 IV on day 1, and etoposide (ACE) 80 mg/m2 on days 1 to 3 was given every 21 days for the first three courses. The fourth and fifth courses substituted cisplatin 33 mg/m2 IV on days 1 to 3 for the doxorubicin, with concurrent chest irradiation to a total of 4,000 cGy given in 20 fractions during a 4-week period followed by a boost of 1,000 cGy in five fractions during a 1-week period. Prophylactic cranial irradiation, 3,000 cGy was given concurrently in 10 fractions during a 2-week period. Courses 6 to 8 again used ACE chemotherapy, but courses 4 to 8 were given on a 28-day schedule with dose adjustment for hematologic or renal toxicity. Warfarin was given throughout the treatment period titrated to achieve a prothrombin time (PT) of 1.5 to 2 times the control. Patients with histologically proven limited-stage SCLC, good performance status, and normal renal, hematologic, and hepatic functions were eligible. RESULTS: Sixty-one of 66 patients entered onto the study were eligible and assessable. Fifty-four (89%) (95%) confidence interval [CI], 78% to 95%) experienced an objective response, 35 (57%) achieved a complete response (CR) (95% CI, 44% to 70%), and 17 (28%) achieved a partial response (95% CI, 16% to 39%). Median durations were CR, 26.3 months; failure-free survival, 11.8 months; and survival, 18 months. Forty-one percent of the patients were alive at 2 years, 33% were alive at 3 years, and 25% were alive at 4 or more years. Median follow-up for survivors is 5 years (range, 3.5 to 5.9 years). Severe or life-threatening myelosuppression occurred in 90%, infection occurred in 34%, fever without documented infection occurred in 26%, and pulmonary toxicity occurred in 6%. Another 6% of patients experienced severe or life-threatening hemorrhages. There were four treatment-related fatalities. The pulmonary toxicities have been associated with the resumption of ACE chemotherapy after chest irradiation. CONCLUSIONS: These highly encouraging response and survival results compare favorably with any prior CALGB group study. Although they are somewhat more toxic, they are comparable to the best published results. A randomized study that examines the role of warfarin is underway.

Immunotherapy with IL2 by constant infusion and weekly doxorubicin.

Twelve women and 7 men, median age 58 (range 17-74), with a diagnosis of non-small-cell lung cancer (11 patients), inflammatory breast cancer (5 patients), osteosarcoma (2 patients), and colon carcinoma (1 patient) were studied. Treatment consisted of four consecutive 6-day courses of infusional interleukin-2 (IL2); 9 patients were treated with 20 X 10(6) IU/m2/day and 10 patients received weekly dose increments of 50% until the maximally tolerated dose was reached. One day after each course was completed patients received doxorubicin, 30 mg/m2; infusional IL2 was resumed 24 h after receiving doxorubicin. Rebounds of lymphocytes with high spontaneous synthetic rates of DNA occurred one day after stopping the infusion, despite doxorubicin administration. The kinetics were not different from earlier trials using IL2 alone. Sequential lymphocyte analysis showed that helper (CD4) and suppressor (CD8) T-cell subsets increased after the first week of treatment and declined thereafter, whereas the proliferation of natural killer (NK) cells (CD16) progressed through the 4-week treatment unaffected by doxorubicin. Mean cytolytic ability induced by IL2 against NK-resistant tumors in vitro was higher in patients who had evidence of clinical tumor regression and therefore is prognostically valuable (p = .02). Three patients left the study prematurely. Five partial remissions and 2 minimal responses were seen in the remaining 16 patients, but they were short-lived. Of the responding patients, only one had failed prior doxorubicin-containing chemotherapy. Toxicities attributable to IL2 and doxorubicin were encountered, and were manageable at these doses. Our data suggest that doxorubicin did not have cytotoxic or suppressive effects on lymphokine-induced lymphocyte functions and that both treatment modalities in combination are worthy of further investigation since they exert distinct and compatible cytotoxic mechanisms and induced tumor regressions with acceptable toxicity in a group of patients with poorly responsive cancers.

Cardiac abnormalities in patients with diffuse malignant pleural mesothelioma.

Many patients with diffuse malignant pleural mesothelioma have dyspnea or chest pain. Cardiac symptomatology is frequently difficult to differentiate from symptoms of pleuropulmonary disease. To better define the clinical characteristics of cardiac involvement in patients with mesothelioma, the electrocardiographic (EKG) and echocardiographic findings in 64 patients with biopsy-proven malignant pleural mesothelioma were reviewed. A total of 19/64 (30%) patients had autopsy studies available for review. The EKG was abnormal in 55 patients (89%). Over half (60%) had an arrhythmia, including sinus tachycardia (42%), premature atrial and ventricular contractions (13%), atrial fibrillation (3%), and atrial flutter (1%). Over one third (37%) had a conduction abnormality, including bundle branch block (13%), hemiblock (8.5%), and incomplete right bundle branch block (13%). Echocardiography revealed a total of 13 patients with pericardial effusions, two with pericardial thickening, and one with an anterior sonolucent space. Of 19 autopsies, cardiac invasion was found in 14 (74%), with more than half to the pericardium and more than one quarter to the myocardium. It is concluded that: clinical cardiac abnormalities occur in the great majority of patients with malignant pleural mesothelioma, pathologic cardiac invasion occurs in the great majority of patients with pleural mesothelioma, and the EKG and echocardiogram are helpful in differentiating cardiac involvement from progressive pulmonary disease in patients with pleural mesothelioma.

Gallium scanning in differentiating malignant from benign asbestos-related pleural disease.

In order to assess the utility of 67gallium citrate in delineating malignant pleural mesothelioma from benign asbestos-related pleural disease, 49 patients with malignant mesothelioma and 16 with benign asbestos-related pleural disease were studied. Seven patients with malignant mesothelioma had no history of asbestos exposure, while the remaining 58 patients were exposed. Forty-three of the 49 patients (88%) with malignant mesothelioma had a positive 67gallium scan including 36 of the 42 (86%) patients with asbestos exposure and all 7 patients without a history of asbestos exposure. Three of 16 patients (19%) with benign asbestos-related pleural disease had a positive scan. 67Gallium radionuclide imaging is nonspecific but may be valuable in noninvasive monitoring of asbestos-exposed populations, which have a high risk for the late development of benign and/or malignant pleural disease.

Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III cancer and Leukemia Group B Study.

Patients with limited-stage small-cell carcinoma of the lung (SCCL) were randomly assigned to a four-drug chemotherapy program consisting of methotrexate, doxorubicin, cyclophosphamide, and CCNU (MACC) or to a regimen consisting of cyclophosphamide, CCNU, and vincristine alternated with Adriamycin (Adria Laboratories, Columbus, Ohio) and vincristine (CCV/AV). All patients received 4,500 cGy, in a split course, to the primary tumor, mediastinum, and supraclavicular lymph node drainage areas and 3,000 cGy to the whole brain. After four cycles of chemotherapy, patients were randomly assigned to chemotherapy plus methanol extractable residue of BCG (MER-BCG) or no MER-BCG. The complete response frequencies were similar for the two regimens (54% and 48%) as were the median survivals (12.0 and 11.5 months) and the two-year survival rates (15% and 17%). Immunotherapy with MER-BCG did not prolong the time to disease progression or improve survival. Women had a greater chance of achieving a complete remission independent of performance status. There was a complex interaction between sex and the chemotherapy regimens that may have important implications for the design and stratification of future trials in SCCL.

Small cell anaplastic lung cancer presenting as an ovarian metastasis.

An unusual case of small cell anaplastic carcinoma of the lung, presenting as a pelvic mass, is presented. Histochemical and electron microscopic findings confirmed the diagnosis. The pathologic features and unique clinical characteristics are discussed with comments on the topic of metastatic ovarian tumors.

Chemotherapy for bronchogenic carcinoma. Methotrexate, doxorubicin, cyclophosphamide, and lomustine.

A combination chemotherapy (MACC) consisting of methotrexate, doxorubicin hydrochloride (Adriamycin), cyclophosphamide, and lomustine (CCNU) was given to 41 patients with stage III bronchogenic carcinoma, 34 of whom had disseminated disease. The objective response rate was 46% for all patients with a median actuarial survival of nine months. Response was seen in all cell types, including four of ten patients with squamous cell carcinoma, six of 17 with adenocarcinoma, and six of seven with small-cell anaplastic carcinoma. Prolongation of survival was apparent for patients of all cell types. Toxic reactions were moderate and allowed for easy outpatient use.

Ultrastructural immunoperoxidase demonstration of autologous albumin in the alveolar capillary membrane and in the alveolar lining material in normal rats.

The location of autologous serum albumin within the alveolar-capillary membrane was studied in the rat under physiological conditions using antialbumin antibodies labeled with peroxidase. Albumin was detected in the lung interstitium, and in numerous pinocytic vesicles within endothelial cells and type I alveolar epithelial cells. The immunoreaction was also positive at the level of plasmalemmal membranes of both cell types and in the alveolar lining material.

Response of 65 measurable epidermoid bronchogenic tumors of known spontaneous doubling time to four different chemotherapeutic regimens--strategic deductions.

Variations in the dimensions of 65 bronchogenic epidermoid tumors of known spontaneous doubling time were studied under the influence of four chemotherapeutic regimens: cyclophosphamide, 19 cases; Mitomycin C, 20 cases; CCNU, 9 cases; and a five-drug combination, 17 cases. Several parameters were measured, and escape was defined as the moment in time when the growth curve during treatment became parallel to the spontaneous growth curve. The parameters measured were nature and distribution of responses (unchanged progression, slowing-down, plateau, regression), duration of response, time required to achieve maximum response, and time lapse between maximum response and escape. Regarding application to lung cancer, we have concluded from out results that Mitomycin C should replace cyclophosphamide in combination chemotherapeutic regimens. With regard to general strategy, our results suggest that the drug regimen should be changed as soon as maximum response is reached or immediately following the first course if progression continues unchanged. Moreover, in all of the 27 patients whose tumors regressed, escape occurred within less than three months from the onset of the treatment. In view of this fact and insofar as chemotherapy is considered for adjuvant therapy aiming at complete eradication, sequential combinations would be preferable to prolonged administration of a single agent or combination.