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.

A randomized comparison of methotrexate dose and the addition of bleomycin to CHOP therapy for diffuse large cell lymphoma and other non-Hodgkin's lymphomas. Cancer and Leukemia Group B study 7851.

In 1978, Cancer and Leukemia Group B initiated a randomized study to determine the usefulness of the addition of bleomycin and/or high-dose methotrexate to standard therapy for the treatment of certain adult non-Hodgkin's lymphomas. Between 1978 and 1985, 177 patients with diffuse large cell lymphoma (DLCL) and 97 patients with other intermediate-grade non-Hodgkin's lymphoma were randomized to receive therapy with three courses of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) every 3 weeks with or without low-dose bleomycin by continuous IV infusion. Responders after three courses were further randomized to 3 weeks of therapy with either high-dose methotrexate (3 gm/m2/week intravenously with leucovorin rescue) or standard-dose methotrexate (30 mg/m2/week orally without rescue). Therapy was concluded with three additional courses of CHOP. Neither the addition of low-dose infusion bleomycin nor the use of high-dose rather than low-dose methotrexate had significant effects on response for patients with DLCL; complete response rates for the four treatment programs ranged from 47% to 51%. Median failure-free survival (FFS) for the entire group of DLCL patients was 12 months; 5-year FFS was 27%. There was no significant effect on FFS from the addition of either low-dose bleomycin to CHOP (5-year FFS: CHOP, 28%; CHOP-B, 26%, P = 0.81), or from the use of different doses of methotrexate (5-year FFS: high-dose, 34%; standard-dose, 33%, P = 0.51). Patients with follicular large cell lymphoma, with or without diffuse areas, had a better FFS (5-year FFS, 47%) than patients with DLCL (5-year FFS, 27%), while the patients with the other histopathologic subtypes of diffuse lymphomas had the poorest FFS (5-year FFS, 16%).

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.

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.

Treatment of refractory lymphoma with methotrexate, VM-26 (teniposide), procarbazine, and dexamethasone: Cancer and Leukemia Group B study 7902.

Seventy-eight individuals previously treated with chemotherapy for non-Hodgkin's lymphoma were enrolled in a phase II pilot study employing methotrexate 100 mg/M2 iv (day 1), calcium leucovorin 10 mg/M2 iv and/or po q6h (days 2-4), VM-26 (teniposide) 100 mg/M2 iv (days 2 and 9), procarbazine 100 mg/M2 po (days 2-15), and dexamethasone 15 mg/M2po (days 2-8) (MV26PD). Thirty percent of the 78 patients treated had a response to therapy (8% complete, 22% partial). Twenty-four percent of patients with diffuse histiocytic (large cell) lymphoma had a response (12% complete, 12% partial). The estimated failure-free survival was 41% at 3 months and the median survival (death from any cause) was 4.5 months for the entire cohort. Two individuals, including one individual with diffuse histiocytic lymphoma, remain in a complete response for over 900 days. Significant hematologic toxicity and infectious complications were seen in this heavily pretreated group of patients. MV26PD represents an active combination of agents for the treatment of non-Hodgkin's lymphoma. The optimal dosing for MV26PD remains to be determined.

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.

A randomized trial of high-dose methotrexate versus standard-dose methotrexate following cyclophosphamide, doxorubicin (adriamycin), vincristine, and prednisone with or without bleomycin in the therapy of diffuse large cell lymphoma: preliminary report of Cancer and Leukemia Group B Study 7851.

Between 1979 and 1985, 166 patients with diffuse large cell (histiocytic) lymphoma were randomized to receive therapy with 3 courses of cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisone (CAVP), with or without low-dose bleomycin, by continuous iv infusion. Responders were further randomized to 3 weeks of therapy with either high-dose methotrexate (3 g/m2 iv weekly with leukovorin rescue) or low-dose methotrexate (30 mg/m2 orally weekly without rescue). Therapy was concluded with 3 additional courses of CAVP. No significant differences among the 4 treatment programs were observed in complete response rates (ranging from 46% to 51%) or in failure-free survival. Of the 38 relapses that have occurred in patients treated with low-dose methotrexate, 5 included relapse in the central nervous system in conjunction with systemic relapse. However, none of 31 relapses observed in patients receiving high-dose methotrexate have occurred with involvement of the central nervous system. Patients entering this study with "B" symptoms had significantly poorer treatment results than those patients entering study without "B" symptoms.

Chemotherapy with cyclophosphamide, adriamycin, and 5-fluorouracil compared to chemotherapy plus hormonal therapy with tamoxifen in the treatment of advanced breast cancer: an interim analysis.

Between February 1980 and August 1982, the Cancer and Leukemia Group B (CALGB) performed a randomized study aimed to compare chemotherapy with CAF (Cyclophosphamide, Adriamycin, 5-Fluorouracil) versus the same chemotherapeutic regimen plus tamoxifen (T-CAF) in stage IV breast cancer patients. Patients were stratified on the basis of menopausal status, estrogen receptors (ER) status, dominant site of metastasis and prior adjuvant treatment. Overall 474 patients were entered into the study of whom 433 were assessable for response. 314 patients were postmenopausal, 85 premenopausal and 34 patients were unknown as far menopausal status was concerned. No difference was evident among postmenopausal patients in overall response rate and duration of responses between T-CAF and CAF (52% vs 50% respectively). Similarly no difference was shown among premenopausal patients, response rates being 63% with T-CAF and 60% with CAF. Lack of benefit from adding T to chemotherapy was seen also according to the different strata, including patients with ER positive tumors. The failure for this combination to be synergistic might reflect an effect of T on tumor kinetics interfering with the activity of chemotherapy.

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.

Acute nonlymphocytic leukemia complicated by severe cytophagocytosis of formed blood elements by nonmalignant histiocytes: cause of significant clinical morbidity.

A 52-year-old female presented with Philadelphia chromosome-positive acute nonlymphocytic leukemia and a morphologically benign-appearing histiocytosis with intramedullary cytophagocytosis of formed blood elements. No cause of the reactive histiocytosis could be found. Despite initial successful therapy of the acute nonlymphocytic leukemia with induction of a cytological remission, pancytopenia with marked cytophagocytosis persisted. Therapy aimed at reducing the degree of cytophagocytosis by the histiocytes, in the form of vinblastine-treated platelets and, subsequently, prednisone, was instituted. There was no significant clinical response to either therapeutic maneuver. Cytophagocytosis persisted until leukemic relapse and death ensued.

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.

Cyclophosphamide, doxorubicin, vincristine, and low-dose continuous infusion bleomycin in non-Hodgkin's lymphoma: Cancer and Leukemia Group B Study No. 7804.

Fifty-eight evaluable patients with non-Hodgkin's lymphoma were treated with a low dose, 120-hour continuous intravenous infusion of bleomycin in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone. Pharmacokinetic data, obtained in six patients, confirm that steady-state plasma concentrations of bleomycin can be attained even with the administration of 2 units/day of the drug. Neither clinical pulmonary toxicity nor subclinical pulmonary changes, as determined by serial measurement of the single breath carbon monoxide-diffusing capacity, were observed. Compared to similar chemotherapeutic programs utilizing bolus administration of bleomycin, pulmonary toxicity may be reduced. Response frequencies among 37 previously untreated patients were similar to those obtained using the same chemotherapeutic agents but with intravenous bolus administration of bleomycin. In addition, 18 of 21 patients who had received prior chemotherapy responded. Low dose, continuous intravenous infusion of bleomycin may improve the therapeutic index of combination chemotherapy programs for non-Hodgkin's lymphoma.

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.

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.

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.

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.