Recruiting cancer patients to participate in motivating their relatives to quit smoking. A cancer control study of the Cancer and Leukemia Group B (CALGB 9072).

BACKGROUND: A diagnosis of cancer provides a teachable moment in which a physician can counsel or teach the patient. The Cancer and Leukemia Group B hypothesized that this teachable moment could also be used to encourage counseling of the patients' relatives who smoke. The authors' first study sought to determine the feasibility of such an intervention, the cooperation of the patients, and the compliance of relatives who were smokers. The long-range goal is to recruit by mail a large population of adult smokers into an intervention program and to assist them in quitting cigarette smoking. METHODS: Oncologists and their clinical research associates asked recently diagnosed cancer patients to identify their relatives who were smokers and assist in persuading them to quit. Consenting patients spoke to relatives and mailed them a personalized motivational leaflet along with a list of the benefits of quitting smoking. Intervention was continued only with relatives who were contacted in this manner. The participating physicians then wrote to the smokers, advising them to quit; enclosed with each physician's letter were the National Cancer Institute booklet "Clearing the Air," which is about quitting smoking, and a questionnaire determining "stage of change" (the stage of the smoker's inaction or action regarding quitting smoking). After 6 months, a postintervention questionnaire was mailed to the relatives. RESULTS: Written consent was obtained from 89% of 144 eligible patients solicited. Eighty percent of patients involved in the study contacted relatives. Sixty-three percent of contacted relatives returned the first questionnaire and 40% answered the second. Nine percent of all contacted relatives reported having quit smoking after the intervention. CONCLUSIONS: The intervention proved to be feasible and will lead to the next study, which will randomize relatives who smoke within a more intensive intervention over 12 months and compare the results with nonintervention controls.

A phase I trial of ifosfamide, mesna, and cisplatin in advanced non-small cell lung cancer. A cancer and leukemia group B study.

BACKGROUND: This Phase I study was designed to determine the maximum tolerated dose of ifosfamide-mesna with a fixed dose of cisplatin without growth factor or hematopoietic precursor support. METHODS: Twenty-five patients with previously untreated advanced non-small cell lung cancer were treated at four dose levels. Initially, the cisplatin dose was 100 mg/m2 given on day 1. Seven patients were treated with ifosfamide 2.0 g/m2 days 1 to 3, and six patients received ifosfamide 2.5 g/m2 days 1 to 3. Mesna was given at 20% of the ifosfamide dose at 0, 4, and 6 hours after ifosfamide. Cycles were repeated every 4 weeks. RESULTS: Dose-limiting toxicities (myelosuppression and renal toxicity) were seen at dose level 2 (ifosfamide 2.5 g/m2). Because 5 of the first 13 patients experienced Grade 3 renal toxicity, the study was amended to give cisplatin in divided doses. An additional six patients each were treated at dose level 3 (ifosfamide 2.0 g/m2 days 1-3) and dose level 4 (ifosfamide 2.5 g/m2 days 1-3) with cisplatin 33 mg/m2 days 1 to 3. Dose-limiting toxicity (myelosuppression) was reached at ifosfamide 2.5 g/m2. No further Grade 3 renal toxicity was seen. Grade 3 or worse toxicities were seen as follows: neutropenia 80%, thrombocytopenia 48%, nausea/vomiting 36%, anemia 32%, renal 20%, central nervous system 16%, and infection 16%. Two toxic deaths occurred, both with infection, renal failure, and neutropenia. Partial responses were seen in 8 of 25 eligible patients (32%). CONCLUSIONS: The maximum tolerated dose in this group of patients was defined as ifosfamide 2.0 g/m2 days 1 to 3 when given with cisplatin 33 mg/m2 days 1 to 3. When combining high-dose cisplatin with ifosfamide, it is advisable to give cisplatin in divided doses.

Phase I/II trial of etoposide and carboplatin in extensive small-cell lung cancer. A report from the Cancer and Leukemia Group B.

Previously untreated extensive small-cell lung cancer (SCLC) patients with performance status 0-2 were treated with etoposide 200 mg/m2/day on days 1-3 and carboplatin doses of 50, 100, or 125 mg/m2/day on days 1-3 in a Phase I format. Among the ten eligible patients treated with 125 mg/m2/day of carboplatin, grade 3 or 4 infection occurred in six patients, grade 4 thrombocytopenia in four patients, and there was one death with myelosuppression. Thus, this dose was considered the maximum tolerated dose (MTD), and a Phase II trial was then conducted utilizing this treatment program. In the Phase II trials, 81% of the 48 eligible patients had grade 3 or 4 leukopenia, 76% had grade 3 or 4 thrombocytopenia, and 55% had grade 3 or 4 anemia. There were three (6%) toxic deaths from myelosuppression. The objective response rate was 63% (17% complete responders) with a median response duration of 6.2 months for complete responders and 6.4 months for partial responders. Median survival was 12 months. The MTD defined by this Phase I trial represents a 67-100% increase in etoposide and a 25% increase in carboplatin compared to prior studies. Cancer and Leukemia Group B (CALGB) plans to study further dose intensification of this regimen with colony-stimulating factors.

Phase II trial of PALA in combination with 5-fluorouracil in advanced pancreatic cancer.

Phosphonacetyl-L-aspartate (PALA), in inhibitor of aspartate transcarbamylase that depletes uridine nucleotide pools, selectively potentiates the antitumor activity of 5-fluorouracil (5-FU) in preclinical models. Due to the promising results we obtained using PALA/5-FU in colorectal cancer, we performed a phase II trial in patients presenting with advanced pancreatic cancer. PALA was given intravenously at 250 mg/m2 on day 1, followed 24 h later by 2,600 mg/m2 5-FU given by 24-h infusion. Treatments were repeated weekly. A total of 41 patients who had not previously undergone chemotherapy were entered in the trial; of these, 35 were evaluable for response. Toxicity was generally mild to moderate; neurotoxicity (13/35) and diarrhea (8/35) predominated. Among the 35 patients, 1 achieved a complete response and 4, a partial remission, for an overall response rate of 14%. The median survival was 5.1 months. Pretreatment with PALA alone was not sufficient to enhance the activity of 5-FU in pancreatic cancer.

Continuous infusion 5-fluorouracil plus weekly cisplatin for pancreatic carcinoma. A Mid-Atlantic Oncology Program study.

Fifty-six previously untreated patients with biopsy-proven, locally advanced or metastatic and measurable adenocarcinoma of the pancreas were treated with the combination of a protracted intravenous infusion of 5-fluorouracil (5-FU) and low dose weekly bolus cisplatin administered continuously for 10 weeks followed by a 2-week rest period. The objective response rate was 16% with two patients (4%) achieving a complete response (confidence intervals, 8% to 29%). The median survival time for all treated patients was 5.8 months; however, 26% of all patients were alive at 1 year. Both median survival time and the proportion alive at 1 year exceed that of prior reports involving large patient groups, possibly due to better patient selection.

The use of neuroendocrine immunoperoxidase markers to predict chemotherapy response in patients with non-small-cell lung cancer.

Small-cell lung cancer (SCLC), a chemotherapy-responsive disease, is characterized by neuroendocrine properties. In contrast, non-small-cell lung cancer (NSCLC) is at best moderately responsive to chemotherapy, and only 10% to 20% of cases demonstrate neuroendocrine properties. The present study is a retrospective analysis of the use of immunoperoxidase markers for neuron-specific enolase (NSE), Leu-7, and chromogranin A in NSCLC patients treated with chemotherapy. It was designed to determine if the presence of neuroendocrine markers predict for response to chemotherapy. The diagnostic slides and blocks were obtained on 52 NSCLC patients who were treated with chemotherapy (26 responders and 26 nonresponders). Immunoperoxidase studies were performed, and slides were scored without knowledge of the patient's response. Markers were positive in responders and nonresponders, respectively, as follows: NSE, 14 of 26 (54%) versus seven of 26 (27%), P = .04; Leu-7, 11 of 25 (44%) versus five of 26 (19%), P = .08; and chromogranin A, three of 26 (12%) versus 0 of 26 (0%), P = .71. Two markers were positive in 10 of 26 responders (38%) and 0 of 26 nonresponders (0%), P less than .01. Responders with two or more positive markers showed superior survival (median, 79 weeks) compared with responders with fewer than two positive markers (median, 51 weeks) and nonresponders (median, 27 weeks). These data suggest that the presence of neuroendocrine markers in NSCLC is associated with an increased likelihood of response to chemotherapy and may add to the standard parameters (performance status, weight loss) used to select patients for chemotherapy.

Phase I--preliminary phase II trial of iproplatin, a cisplatin analogue.

Iproplatin was administered intravenously over 30 min daily for 5 consecutive days every 3 weeks to 80 evaluable patients with a variety of refractory solid tumor malignancies. Thrombocytopenia was the dose-limiting toxicity. Reversible drug-induced renal dysfunction was observed in 3 patients. One patient sustained mild ototoxicity but neurotoxicity was not encountered. Transient neutropenia, anemia, nausea, vomiting, diarrhea, elevations of liver enzymes, alopecia, and skin rash also occurred. The spectrum and severity of toxicity of iproplatin were found to differ from those of cisplatin. The maximally tolerated dose (MTD) was 45 mg/m2/day in patients who received prior chemotherapy and 65 mg/m2/day in those who did not. No complete responses occurred. Partial responses were obtained in 2/15 patients with colon cancer, 3/18 with breast cancer, 2/4 with carcinoma of unknown primary site and 1/2 with pancreatic cancer. Thirteen patients with lung (5), breast (4), colon (2), head and neck (1) and cervical (1) cancers had stable disease. Based on the different toxicity profiles between iproplatin and cisplatin and the possible antitumor efficacy of the former, phase II investigation of iproplatin has been initiated.

Increased Heinz body formation and impaired erythrocyte pentose phosphate shunt function during pregnancy.

The erythrocytes of 90 pregnant women were evaluated for the presence of in vivo or in vitro oxidant damage. The reduced glutathione (P less than 0.005) and the membrane reduced sulfhydryl (P less than 0.001) concentrations were decreased in fresh erythrocytes. Following incubation with acetylphenylhydrazine, Heinz body formation was significantly increased (P less than 0.001). Both the increase in Heinz body formation and the reduction in membrane reduced sulfhydryl content correlated strongly with duration of pregnancy. Glucose consumption was significantly decreased before, but not after, new methylene blue stimulation. Pentose phosphate shunt activity was impaired both before (P less than 0.05) and after (P less than 0.001) stimulation. No changes were observed in pentose phosphate recycling. The only alteration observed in the activity of the enzymes of the pentose shunt was an elevation of 6-phosphogluconate dehydrogenase activity. Although the clinical significance of these findings remains to be determined, medications with an oxidant potential should be used judiciously during gestation.

Adverse prognostic effect of N2 disease in treated small cell carcinoma of the lung.

We reviewed survival of patients with clinically localized small cell carcinoma of the lung treated by surgical resection, combination chemotherapy, and prophylactic cranial irradiation. Long-term survival was defined as continuing complete remission 30 months after the start of treatment. Initial TNM staging determined the course of treatment. Ten patients with disease in Stages I and II were treated over 30 months ago by initial resection followed by the full course of chemotherapy. Only one has had a relapse, whereas 80% remained disease-free at 30 months. Five of these patients have passed 5 years. Four patients with T3 N1 disease were treated by two cycles of chemotherapy, surgical resection, and cranial irradiation plus resumption of chemotherapy thereafter; two remained in remission at 30 months. Sixteen patients initially with N2 disease were treated according to the same schedule; 10 of the 16 underwent successful resection. All 16 patients have had a relapse, but the relapse occurred very late in three--at 27, 30, and 37 months. The reasons for the apparently poor prognosis of N2 disease are not clear. Considerations of tumor response kinetics and somatic mutation suggest that these biologic factors are fundamentally responsible. Other studies may find disease control achieved in a very few patients with N2 disease.

Histologic alterations in small cell carcinoma of the lung after two cycles of intensive chemotherapy.

In patients treated nonsurgically for "limited" small cell carcinoma of the lung, the most frequent site of relapse is within the chest. We have treated patients with clinical Stage III M0 disease (T3 and/or N2, M0) by two cycles of chemotherapy, surgical resection of the primary site and mediastinal nodes, and continued chemotherapy thereafter. Since May, 1979, the regimen has consisted of cyclophosphamide, doxorubicin, vincristine, and etoposide on a 3 week cycle. The first 12 patients so treated had partial or complete remission after two cycles. Resection was technically not possible in two. Residual small cell carcinoma was not identifiable in the specimens from two of the 10 patients undergoing resection. Microscopic tumor extended to a resection line in two of the eight with residual tumor. Malignant tissue appearing to have the structure of papillary adenocarcinoma was found in hilar and paratracheal nodes in one patient, but nowhere in the resected lung; some residual small cell carcinoma remained in the lung. Nuclear ballooning and eosinophilic inclusions were noted in cells still identifiable as small cell carcinoma in one case. Marked fibrotic scarring was noted in eight cases, acute and organizing bronchopneumonia in three, and multiple small parenchymal abscesses in one case. Long disease-free survival occurred in one patient, in whom residual tumor could not be found in the specimen; in at least one more in whom residual tumor was present; and even in one patient in whom tumor was present at the bronchial resection line.

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.

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.

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.

Acute leukemia with unusual cytoplasmic inclusions: a cytochemical and ultrastructural study.

A 76-year-old woman with acute leukemia responded incompletely to prednisone and vincristine. Cytochemistry of the blast cells demonstrated only focal alpha-naphthyl acetate and alpha-naphthyl butyrate esterase activity and focal coarse granular beta-glucuronidase activity, a pattern usually associated with acute lymphocytic leukemia. Electron microscopy demonstrated primitive cells with features usually associated with promonocyte differentiation including prominent parallel arrays of microfilaments and nucleoli of the nucleolonema type. In Wright-stained films, blasts contained oval, pale-blue, yellow tinged cytoplasmic inclusions about 2 to 4 micrometers in diameter which did not stain with any of the cytochemical methods employed. With electron microscopy, these inclusions were nonmembrane bound structures, varying from amorphous electron dense stippling to irregularly arranged short segments of filaments to prominent parallel arrays of filaments. We propose that the inclusions may have arisen from the parallel arrays of microfilaments and are nonspecific.