Role of single-breath carbon monoxide-diffusing capacity in monitoring the pulmonary effects of bleomycin in germ cell tumor patients.

Serial pulmonary function tests including single-breath carbon monoxide-diffusing capacity (DLCO), forced vital capacity (FVC), and forced expiratory volume in 1 sec were performed in a relatively homogeneous group of male patients with germ cell tumors treated with vinblastine, bleomycin, and cis-diamminedichloroplatinum. Of the pulmonary function tests used, the DLCO was shown to be the most sensitive indicator of subclinical bleomycin pulmonary effects. Decreases in DLCO were both total dose and schedule dependent. Patients receiving their total dose of bleomycin at a rate of 25 +/- 2 (S.D.) units/week developed a linear decrease in DLCO with increasing total doses of bleomycin. Changes in FVC did not correlate with bleomycin total dose. Although both the mean DLCO and FVC decreased after completion of bleomycin therapy, the mean FVC returned to base-line levels rapidly, whereas the decrease in mean DLCO was persistent for several months. When routine volumetric tests (FVC and forced expiratory volume in 1 sec) and DLCO are used in a systematic manner, DLCO is the most sensitive indicator of the subclinical pulmonary effects of bleomycin in germ cell tumor patients treated with vinblastine, bleomycin, and cis-diamminedichloroplatinum.

A phase I and clinical pharmacology study of intravenously administered carminomycin in cancer patients in the United States.

Carminomycin (CMN) was administered i.v. to 44 patients with a variety of nonhematological cancers every 4 weeks at doses of 15, 20, 22.5, and 25 mg/sq m. Granulocytopenia was the dose-limiting toxicity. The median granulocyte count for previously untreated patients receiving 22.5 mg/sq m was 0.962 cells/microliters, and for previously treated patients receiving 20 mg/sq m it was 0.420 cell/microliters. Moderate to severe phlebitis was associated with drug administration in 50% of cases. Nausea, vomiting, and alopecia were mild. Three of nine patients who received a total CMN dose of greater than or equal to 100 mg/sq m (mean, 132 mg/sq m) developed unexplained decreases in radionuclide cardiac ejection fraction, with one patient developing decreased QRS amplitude and congestive heart failure at a total dose of 160 mg/sq m. CMN is rapidly metabolized to carminomycinol. The elimination half-lives of CMN and carminomycinol are 6 to 10 and 50 hr, respectively. CMN was found to be a more potent inhibitor of human granulocyte-macrophage colony-forming units than was carminomycinol. Objective partial responses were seen in two of seven previously untreated patients with non-small cell lung cancer and one of three patients with squamous cell carcinoma of the head and neck previously untreated with chemotherapy.

Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081.

In a prospective, randomized trial Cancer and Leukemia Group B (CALGB) evaluated CAF chemotherapy (cyclophosphamide + doxorubicin + 5-fluorouracil [5-FU]) v CAF plus tamoxifen (TCAF) in advanced breast cancer. Patients were stratified by estrogen receptor (ER) status, dominant site of metastatic disease, menopausal status, and prior adjuvant therapy. Regardless of ER status or menopausal status, the addition of tamoxifen conferred no significant advantage in response rate, response duration, time to treatment failure (TTF) or survival over CAF alone. A secondary objective was to compare the response to CAF of ER positive (ER+) and ER negative (ER-) patients to determine if there was a differential response to cytotoxic chemotherapy. Response rates of ER+ and ER- patients to CAF were identical (56%), but the response duration, time to treatment failure, and survival of ER+ patients were significantly longer than ER- patients. This lack of differential response implies that chemotherapy and hormonal therapy may compete for the same pool of ER+ cells. It also suggests that chemotherapy kills breast cancer cells indiscriminately, regardless of ER status.

Small cell anaplastic carcinoma of the lung with mesangial proliferative glomerulonephritis.

Mesangial proliferative glomerulonephritis is an uncommon manifestation of renal injury associated with neoplastic disease. A 50-year-old woman with small cell anaplastic cancer of the lung and nephrotic syndrome had renal biopsy findings that were consistent with diffuse mesangial cell proliferation. Electron microscopic evaluation of renal tissue demonstrated numerous intramesangial and paramesangial dense deposits. Resolution of the nephrotic syndrome with improvement in renal function was noted after a response of the patient's tumor to combination chemotherapy.

Selective surgical resection in small cell carcinoma of the lung.

Surgical resection has failed notably as definitive treatment for small cell carcinoma of the lung. Newer treatment programs combining intensive chemotherapy with radiation therapy achieve a significant response in about 85 percent of cases, with about 50 percent of patients showing clinically complete remission. Long-term survival without recurrence has been the outcome in a small minority of cases. A frequent mode of failure after treatment of limited disease is recurrence within the chest. The course of one patient treated early in this series suggests that exclusion of initial surgical resection from programs of combined treatment may be a serious omission. Since that time, four patients have undergone initial resection, apparently with uniformly favorable courses to date. Selection criteria based on staging factors are proposed. Admittedly, only a minority of patients will be suitable for this treatment at the time of first diagnosis. Much opportunity exists for improvement in survival rates of patients, even those with limited disease.

Phase II trial of extended indications for resection is small cell carcinoma of the lung.

Surgical resection offers distinct theoretical advantages as the "local" modality in treatment of Stage I and II small cell carcinoma of the lung. We have treated 10 such patients by initial resection since 1975; all survivors but one received adjuvant chemotherapy for the full course thereafter. One patient died of a pulmonary embolus; the other nine remain without evidence of disease from 7 to 69 months after resection. A trial was undertaken of extended indications for resection in selected patients with Stage III-M0 disease. Criteria for patient selection have been developed gradually; these exclude patients for reasons of refusal, physiological inadequacy, disease unsuited to gross total eradication, or lack of adequate initial response to chemotherapy. Of six patients who survived the exclusion criteria and underwent resection, one has had a relapse at 26 months. All others remain without evidence of disease, 5 to 25 months after the start of treatment. We believe that systematic patient selection on the basis of defined criteria will identify a subset of patients having markedly improved chances for disease control. This group may represent as many as half of the patients first presenting with localized or MO disease. Patients excluded as candidates for resection have continued to receive standard nonsurgical combined-modality therapy.

Cardiac arrest after autologous marrow infusion.

A 27-year-old woman undergoing autologous bone marrow transplantation for relapsed, refractory Hodgkin's disease developed acute non-cardiogenic pulmonary edema immediately after transfusion of autologous bone marrow. A few similar cases in the literature are identified. Although the precise mechanisms for these rare reactions are not clear, several possibilities including anaphylaxis due to dimethylsulfoxide, leukoagglutination, complement activation, and transient left ventricular dysfunction are proposed and discussed. Features which might allow patients at risk for similar events to be identified include the presence of active pulmonary tumor, and a history of dyspnea and pulmonary infiltrates following transfusion of homologous blood products.

Immunoreactive hormones in human breast tissues.

Samples of breast tissue obtained at biopsy or mastectomy from women with benign breast disease and infiltrating duct or anaplastic carcinoma were maintained for 2 weeks in organ culture synthetic medium 199 without additional serum or hormones. Media were changed every 48 hours. Media withdrawn from the tissues were assayed for insulin, prolactin (Prl), and parathyroid hormone (PTH). In addition, tissue explants were extracted in acid-alcohol and assayed for insulin by standard radioimmunoassay (RIA) procedures. At day 0 portions of breast tissue from patients with malignant or benign disease were fixed in Bouin solution; they were then embedded in paraffin; and serial sections were obtained for histologic and immunocytochemical examination. The dissection media assayed for insulin and PTH by RIA showed that the hormones were present in media from patients with benign as well as malignant disease. However, there was no significant difference between the two groups of women. Only traces of Prl were detected in media. The amount of insulin present in certain tissue explants appeared to increase with time in culture. Immunocytochemical studies showed that insulin-like or PTH-like immunostaining appeared most often in malignant tumor tissue and was observed infrequently or not at all in patients with benign disease. Prl-positive cells were rare. These data suggest that breast tissues contain and may synthesize significant amounts of certain hormones that may influence the growth and proliferation of breast cells.

The prospect of disease control by surgery combined with chemotherapy in stage I and stage II small cell carcinoma of the lung.

Ten patients with localized small cell carcinoma of the lung (clinical stages I and II) were treated by surgical resection more than 2 years ago; operation was followed by a course of intensive combination chemotherapy. Relapse of the disease has occurred in the central nervous system in 1 patient. One patient died of a surgical complication, and another died more than 4 years later of an unrelated malignancy. All others remain well, and 3 patients have survived longer than 5 years following resection.

Phase II trial of iproplatin (CHIP) in previously untreated patients with colorectal cancer.

Nineteen previously untreated patients with colorectal cancer and measurable disease were treated with iproplatin (CHIP), 75 mg/m2 daily, for 5 days every 4 weeks for at least 2 courses. Toxicities included myelosuppression, mild nausea and vomiting, and rare mild nephrotoxicity. The dose-limiting toxicity was thrombocytopenia, which appeared to be cumulative. Dose reduction was frequently necessary. There were no toxic deaths. One partial response was observed, and four patients had stable disease for a median of 2 months. Iproplatin does not appear to have significant activity against colorectal cancer.

Phase II study of iproplatin (CHIP) in previously treated small-cell lung cancer.

Eighteen patients with previously treated extensive small-cell carcinoma of the lung were entered into a Phase II study employing iproplatin (CHIP), a cis-platin analog. Patients had received a mean of two prior chemotherapeutic regimens. Fifty-five percent had received prior cis-platinum and 33% had received prior radiation therapy. CHIP (225 mg/m2) was administered by intermittent intravenous infusion over 30 min for 5 days of a 28-day cycle without prehydration. Sixteen patients with Zubrod performance scores of less than or equal to 3 received 27 courses of therapy (mean 1.7, range 1-6). One partial response of 167 days duration was observed, with complete regression of involved lymph nodes and stabilization of nonevaluable disease in the chest. Six patients had stable disease following one cycle of CHIP, but all progressed following a second cycle of drug. The main toxicity was myelosuppression with prominent thrombocytopenia. Median survival was 75 days from initiation of therapy. In this group of heavily pretreated patients with advanced disease, iproplatin has only minimal activity as a single agent and does not show non-cross-resistance with cis-platinum.

The development of hyponatremia following combination chemotherapy for metastatic germ cell tumors.

The combination of high dose vinblastine, cisplatin, and bleomycin is an extremely effective, but potentially quite toxic, program for the treatment of metastatic germ cell tumors. In addition to the well-described toxicities, we have noted moderate to severe hyponatremia associated with these drugs. Twelve patients who were receiving this combination chemotherapy program had serum electrolyte levels, plasma osmolality, and creatinine clearance performed prior to and again 5 to 9 days after chemotherapy. Nine of the patients had standard water load tests prior to and again 6 to 15 days after chemotherapy. All 12 patients developed a fall in serum sodium concentrations following chemotherapy, and four patients had severe symptoms attributable to the hyponatremia. Eight patients also developed hypoosmolality suggesting that the hyponatremia was secondary to impaired water handling. In five patients further evidence of impaired water handling was documented by the development of an abnormal standard water load test following chemotherapy. The hyponatremia and impaired water handling may be due primarily to the high doses of vinblastine in the chemotherapeutic program. Patients who are receiving this combination chemotherapy program should be observed for the development of hyponatremia. The presence of severe, symptomatic hyponatremia and impaired water handling may require appropriate treatment including water restriction and hypertonic saline administration.

Zinostatin and doxorubicin. A combination phase I study.

Because of encouraging single-agent activity for both zinostatin and doxorubicin in hepatocellular cancer, a phase I tolerance study with these drugs in combination was undertaken. The dose of zinostatin given daily for 5 consecutive days and repeated every 6 weeks was fixed at 2250 units/M2. The starting dose of doxorubicin was 45 mg/m2 on days 1 and 22 of every 6-week cycle, but this was escalated or deescalated by increments of 33% as tolerated. The occurrence of unpredictable severe and prolonged cumulative myelosuppressive toxicity in most patients resulted in considerable management difficulties. In addition, three patients developed congestive heart failure at cumulative doxorubicin doses ranging from 195 to 270 mg/m2 and two patients developed possible drug-related nephrotoxicity. Until reasons for the pharmacogenetic variability observed with zinostatin are defined, combination studies employing this drug are not recommended.

Abnormalities in water homeostasis in small cell anaplastic lung cancer.

Forty-one patients with newly diagnosed small cell anaplastic lung cancer were evaluated for abnormalities in water homeostasis. Each patient underwent a standard water load (SWL) test. Overall, 68% had abnormalities in the SWL test. Abnormalities were found in 47% of the patients with carcinoma clinically limited to one hemithorax and in 86% of the patients with more extensive carcinoma. The determination of urinary antidiuretic hormone levels was available for 27 patients. Abnormally elevated levels were found in 44% of those patients. Forty-six patients had clinically detectable syndrome of the inappropriate secretion of antidiuretic hormone (SIADH); in 12% of patients water restriction was necessary. The incidence of detectable abnormalities in water homeostasis in this study was higher than has been previously recognized. The SWL test is a sensitive and useful means of determining the presence of impaired water handling in patients with small cell carcinoma of the lung.

Unusual cause of increased intracranial pressure from metastatic germ cell cancer.

Metastatic lesions within the brain parenchyma are usually responsible for the development of increased intracranial pressure in patients with metastatic cancer. The lesions can usually be easily documented by computerized axial tomography (CT) of the head. Other causes must be sought in patients with metastatic cancer who present with signs of increased intracranial pressure and whose CT scan of the head fails to reveal any parenchymal lesions. Cranial metastases obstructing venous outflow from the brain may present in this manner.