Men, women and primary lung cancer--a Saskatchewan personal interview study.

In a previous study conducted by mail questionnaire and with a large proportion of surrogate responders, we found differences in smoking habits, age at diagnosis, tumour cell type distribution and occupational exposures between men and women who developed primary lung cancer. This study was designed to confirm those findings by conducting personal case interviews and extend them by examining the impact of certain biological factors. We have investigated demographic, smoking, occupational and medical history sex differences in cases with primary lung cancer by interviewing 273 male and 103 female cases diagnosed between November 1983 and July 1986. The females were significantly younger at diagnosis, a pattern consistent for all cell types. Squamous cell (40%), small cell anaplastic (20%) and adenocarcinomas (16%) were the most prevalent cell types in men. In women, similar frequencies of adenocarcinomas (32%) and squamous cell carcinomas (29%) occurred. Despite a higher prevalence of physician diagnosed allergy and asthma among women, minimal sex differences in the prevalence of atopy as measured by prick skin test were found. Female cases were more likely to be lifetime non-smokers (15% vs 3%), to have started smoking on average 3 years older and to smoke 6 fewer cigarettes per day. The mean pack years of female cases was significantly lower than males' for squamous, adenocarcinoma and small cell anaplastic tumours. The majority of these women had not been occupationally exposed to any substance known to be carcinogenic or to damage the lung. However, in a small subset of cases pulmonary function variables were as depressed in women as in men with significantly higher mean pack years.(ABSTRACT TRUNCATED AT 250 WORDS)

Determinants of cell type in patients with cancer of the lungs.

In order to evaluate the determinants of cell type in patients with primary lung cancer, we compared smoking characteristics in 1,939 patients (1,474 men and 465 women). Patients with squamous cell carcinomas, adenocarcinomas, or small-cell carcinomas were eligible. This study did not consider smoking as a risk factor for lung cancer, as all subjects had a confirmed diagnosis. We were interested in smoking history and the pattern of smoking among those whose risk was 100 percent. Among these patients, we confirmed that a larger subset of nonsmoking individuals developed adenocarcinomas than squamous cell or small-cell carcinomas; however, the duration and intensity of cigarette smoking, as measured by pack-years, were not determinants of tumor cell type in male patients. Small-cell carcinomas in women were more strongly associated with cigarette smoking than either squamous cell carcinomas or adenocarcinomas. More than 3,500 different substances have been measured in tobacco smoke, including tumor initiators, promoters, and those involved in tumor progression. These data confirm the hypothesis that factors other than cigarette smoking are more likely to be involved in the initiation of adenocarcinomas than other cell types. Endogenous and exogenous factors related to gender may be more important than the duration or intensity of cigarette smoking.

Is pesticide use related to the risk of primary lung cancer in Saskatchewan?

Ascertaining cases from a population-based tumor registry in which registration of primary lung cancer is virtually complete, we have consistently found that 40% to 50% of male lung cancer patients were farmers. We interviewed 273 newly diagnosed men and compared their occupational exposures, medical history and smoking characteristics to those of 187 male randomly selected community control subjects. We found that more of the control subjects were farmers (53.5% v 41.4%), that the control subjects tended to have larger farms (P less than .05), and that more control subjects spilled chemicals on their hands or clothing (47% v 28%, P less than .01) and had an accidental inhalation of a chemical directly into the lung (54% v 33%, P less than .005). We report an absence of correlation of lung cancer risk with occupational exposure to any specific pesticide or pesticides grouped by chemical composition. Adjusting for smoking pack-years or extent of pesticide use did not alter our preadjustment conclusions.

Characteristics of patients with primary lung cancer diagnosed at age of 50 years or younger.

We examined the extrinsic and intrinsic characteristics of patients with primary lung cancer diagnosed at early ages and compared them with those of older patients. Significant differences in gender distribution and histologic cell type were present. Cigarette smoking was an important etiologic factor in both groups.

The effects of continuing medical education on family doctor performance in office practice: a randomized control study.

A randomized controlled study was conducted to determine if specifically designed continuing medical education in the fields of cardiovascular and cancer medicine could change doctor office behaviour significantly. Thirty-one volunteer family doctors from 25 offices participated. Six (three cardiovascular and three cancer) learning objectives were defined. Two educational formats were selected as the independent variables: (1) group interaction opportunities (face-to-face and teleconference); and (2) concisely written newsletters. Chart measures of doctor performance prior to and 6 and 12 months following education served as the dependent variables. The family doctors receiving education were found to perform the recommended behaviours significantly more than those who did not receive the education (P less than 0.05) at 6 months post-education. This difference was maintained at the 12-month post-educational period for one of the educational programmes offered. A carefully planned programme of continuing medical education will result in favourable changes in the office practice of volunteer doctors. These changes can persist for as long as 12 months. Adherence to several essential learning principles is required.

Lower prevalence of positive atopic skin tests in lung cancer patients.

Allergy prick skin testing was performed on 137 newly diagnosed patients with primary lung cancer and 137 age-(+/- 3 years) and sex-matched randomly selected control subjects. We also compared 38 patients with lung cancer and 38 of their closest in age, same-sex siblings. Demographic data, personal, medical, smoking and occupational histories were obtained by personal interview. We skin tested these individuals with a standard battery of seven common allergens and a diluent control. Fewer patients (35.8 percent) than control subjects (58.4 percent) responded with one or more positive skin reactions (p less than .005). There was no significant difference between patients (27.8 percent) and control subjects (37.2 percent) responding to more than one allergen. Fewer of the 38 sibling-matched patients had one or more positive skin tests (23.7 percent) than did their siblings (55.3 percent) (p less than .01). There were fewer patients with greater than one positive skin test (15.8 percent) than sibling control subjects (42.1 percent) (p less than .025). There were no differences in smoking pack-years between patients and siblings. Historic evidence of allergy was greater in both control groups compared to their matched cancer groups; p less than .05 for community controls, p less than .005 for sibling control subjects. These findings raise the possibility that atopy, by either immunologic or nonimmunologic means, protects against development of lung cancer, or alternately, that lung cancer affects immunologic status as gauged by (type 1) skin sensitivity.

Farming and exposure to chemicals in male lung cancer patients and their siblings.

We conducted a retrospective questionnaire study concerning farming and exposure to chemicals on 165 male lung cancer patients, mean age +/- SE, 64.2 +/- 1.0 years, and 165 closest in age male siblings, mean age 64.5 +/- 0.7 years. The patients were diagnosed as having primary lung cancer between January 1, 1979, and November 1, 1983. Among the lung cancer patients, 38.5% had a same-sex sibling eligible for inclusion and of these, 62.0% responded to the questionnaire. Mean pack-years of smoking for patients was 41.0 +/- 2.2 (n = 135) and among the siblings 36.9 +/- 2.4 (118) (P less than .002). The occupation of farming was present in 47.8% of 163 patients with known occupations as compared to 37.6% of 155 siblings with known occupations (not significant). Patients were consistently exposed more frequently to herbicides (P = .05), grains (P less than .015), and diesel fuels (P less than .005), and were consistently exposed to greater numbers of chemicals than were siblings (P less than .005). These findings raise the possibility that, in addition to smoking, farming and related exposures could be implicated in the etiology of lung cancer in men.

Female-male differences in patients with primary lung cancer.

This report is based on responses to a mailed questionnaire from 927 patients with lung cancer (730 men, 197 women), or their next of kin, and information obtained from the Saskatchewan Cancer Foundation Tumour Registry. Women were diagnosed at an earlier mean age than males (means +/- SE, 63.5 +/- 0.85 years versus 67.6 +/- 0.37 years, P less than 0.001), a finding which was consistent for each major histologic type. Women were more frequently diagnosed before age 60 years (42.0%) than were men (25.6%) (P less than 0.001). Female patients were significantly more likely to be lifetime nonsmokers of cigarettes than male patients (23% versus 3.7%, P less than 0.001). Among current smokers, women started smoking at an older age (19.3 +/- 0.69 versus 16.5 +/- 0.21 years, P less than 0.001), smoked for fewer years (41.0 +/- 1.2 years versus 47.4 +/- 0.57 years, P less than 0.001) and smoked slightly fewer cigarettes per day than male patients (23.6 +/- 1.0 versus 26.7 +/- 0.63, P less than 0.05). Similar results were found for the duration of the smoking habit and number of cigarettes smoked among exsmokers. When current smokers and exsmokers were combined, the distribution of pack years by gender was significantly different. A higher percentage than expected of women as compared to men, are clustered in the lower pack-year categories (P less than 0.0003). No occupational exposure or familial factors which might act in synergism with cigarette smoking were identified. Thus, women developed primary lung cancer at an earlier age while smoking for fewer years than men.

Clinical studies of biochemical modulation of 5-fluorouracil by leucovorin in patients with advanced colorectal cancer by the North Central Cancer Treatment Group and Mayo Clinic.

The North Central Cancer Treatment Group (NCCTG) and Mayo Clinic are collaborating in an ongoing, prospective, randomized clinical trial of new approaches to the chemotherapy of advanced metastatic colorectal cancer. Single agent 5-fluorouracil (FUra) given by intensive-course rapid intravenous administration serves as a control. Included among the experimental treatments are two regimens consisting of FUra plus leucovorin (folinic acid). One of these regimens uses folinic acid at a dose level of 200 mg/m2 daily for 5 days based on earlier studies by Machover et al. (4). The second regimen uses folinic acid at 1/10 the dose level (20 mg/m2 daily for 5 days), since this lower dose of folinic acid has been shown to produce peak serum levels equivalent to the concentration of folinic acid required in culture medium to produce optimal inhibition of L1210 cells by FUra in vitro, and because of the great expense of folinic acid when given at the higher dose levels. As of January 1986, 78 patients had been randomized to receive treatment with FUra alone or one of the FUra-folinic acid regimens. The toxicity of the folinic acid regimens has been clinically tolerable, with stomatitis and, to a lesser extent, diarrhea being dose-limiting. Hematologic toxicity has been very mild. There is suggestive evidence that folinic acid given at the higher dose level in combination with FUra at a constant dose produces more severe effects on the oropharyngeal mucosa. Preliminary tumor response and survival data remain blinded in accordance with NCCTG policy. Further patient accrual and follow-up are required to assess the therapeutic effect of these folinic acid regimens compared to FUra given alone.

A controlled evaluation of recent approaches to biochemical modulation or enhancement of 5-fluorouracil therapy in colorectal carcinoma.

Three hundred thirty-five previously untreated patients with advanced colorectal carcinoma were randomly assigned to treatment with 5-fluorouracil (5-FU) alone, 5-FU plus N-(phosphonacetyl)-L-aspartic acid (PALA), 5-FU plus high-dose thymidine, 5-FU plus levamisole, or 5-FU plus methyl CCNU, vincristine, and streptozotocin (MOF-Strept). Dosages were designed to produce definite toxicity in the majority of patients, although the nature of dose-limiting reactions varied considerably among regimens. 5-FU alone and 5-FU plus levamisole produced mucocutaneous reactions, diarrhea, and leukopenia; 5-FU plus PALA produced primarily mucocutaneous reactions and diarrhea; 5-FU plus thymidine produced leukopenia with occasional neurotoxicity and hypotension; and MOF-Strept produced substantial nausea and vomiting with both thrombocytopenia and leukopenia. Objective response rates among patients with measurable disease varied from 12% (5-FU plus PALA) to 34% (MOF-Strept), but none of the regimens were significantly superior to 5-FU alone. Both interval to progression and survival were comparable among the five regimens with no reasonable chance that any combination regimen could produce as much as a 50% improvement when compared with 5-FU alone. Whereas we observed definite modulation of 5-FU dose--toxicity relationships, particularly with the thymidine and PALA combinations, this did not result in a detectable improvement in therapeutic effect. None of the combination regimens, administered in the dosages and schedules we used, can be recommended as standard therapy of advanced colorectal carcinoma.

Combination chemo-radiotherapy for residual, recurrent or inoperable carcinoma of the rectum: E.C.O.G. study (EST 3276).

Thirty evaluated patients were randomized to either continuous radiation + 5-FU (16 patients), or split-course radiation + 5-FU (14 patients) for the treatment of residual, recurrent, or inoperable carcinoma of the rectum or recto-sigmoid. Twenty-one of these patients received maintenance MeCCNU + 5-FU chemotherapy following radiation. Entry was terminated when late treatment reactions were seen in the precursor pilot study. Twenty-four of the patients have died; the estimated median survival is 17 months in each of the treatment arms. Performance status was the only significant prognostic factor for survival. The rate of severe, acute reactions during the radiation treatment period was higher for the continuous-course than for the split-course regimen (69 vs. 21%, p = .01). The rates of severe late treatment reactions, 23% (7 of 30), and severe chemotherapy toxicity, 48%, were similar for the two treatment programs. Late treatment reactions, primarily bowel complications, were seen from 3 to 23 months after radiation in 3 patients treated with continuous course, and 4 patients treated with split course. Ten of 21 patients (48%) who received maintenance chemotherapy had severe or worse toxicity. Toxicity was seen for 6 of 12 continuous-course, and 4 of 9 split-course patients. Twenty-seven patients have had disease progression, and the median length of disease control is 11 months.

Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil--an Eastern Cooperative Oncology Group study.

One hundred ninety-one patients with pathologically confirmed, locally unresectable adenocarcinoma of the stomach (57 patients) and pancreas (91 patients), were randomly allocated to therapy with 5-fluorouracil (5-FU) alone, 600 mg/m2 intravenously (IV) once weekly, or radiation therapy, 4,000 rad, plus adjuvant 5-FU, 600 mg/m2 IV, the first three days of radiotherapy, then follow-up maintenance 5-FU, 600 mg/m2, weekly. Forty-three patients (22%) could not be analyzed because of ineligibility or cancellation, thus 148 patients were evaluable. The median survival time was similar for both treatment programs and for both types of primary carcinoma, and was as follows: gastric primary carcinoma, 5-FU, 9.3 months; 5-FU plus radiotherapy, 8.2 months; pancreatic primary carcinoma, 5-FU, 8.2 months; 5-FU plus radiotherapy, 8.3 months. Substantially more toxicity was experienced by patients treated with the combined modality arm than by those patients receiving 5-FU alone. Severe or worse toxicity experienced by patients with gastric primary carcinoma treated by 5-FU was 19%, and the combined modality arm was 31%. The toxicity experienced by patients with pancreatic primary carcinoma treated with 5-FU was 27%, and the combined modality arm was 51%. Significant prognostic variables included: weight loss in stomach-cancer patients; and performance status, degree of anaplasia, and reduced appetite in pancreas-cancer patients.

An Eastern Cooperative Oncology Group evaluation of combinations of methyl-CCNU, mitomycin C, Adriamycin, and 5-fluorouracil in advanced measurable gastric cancer (EST 2277).

In a prospectively randomized trial, patients with advanced locally recurrent or metastatic gastric adenocarcinoma were randomized to receive 5-fluorouracil (5-FU) and methyl-CCNU; 5-FU, Adriamycin (Adria Laboratories, Columbus, Ohio), and methyl-CCNU; 5-FU, Adriamycin, and mitomycin C; or Adriamycin and mitomycin C alone. One hundred eighty-three previously untreated evaluable patients were randomized among the four arms. An additional 39 patients previously treated with 5-FU, were assigned to treatment directly to Adriamycin and mitomycin C. Response rates were 14%, 29%, 39%, and 29%, respectively, among previously untreated patients and 21% for Adriamycin and mitomycin C among previously treated patients. 5-Fluorouracil, Adriamycin, and mitomycin C, the arm containing the largest number of responders (18), was the combination associated with the longest median survival. A larger proportion of patients in this arm survived one year or more. In addition, the 5-FU, Adriamycin, and mitomycin C program had the lowest rate of severe or worse toxicity of any of the treatments and was effective in patients who were less than fully ambulatory and in those who had lost weight. 5-Fluorouracil, Adriamycin, and mitomycin C appear to be a likely combination to be considered in a surgical adjuvant program.

Designing education interventions to improve physician performance in office practice.

Family doctors play a very important role in determining the health of the populace; however, surveys and expert opinions indicate that there is considerable room for improvement in the knowledge and skills of family physicians concerning the prevention, early detection and management of the major causes of death and disability. Effective Continuing Medical Education (CME) could help greatly to resolve this problem. THere is, however, little evidence that presently available systems of CME, though costly, are effective in improving either physician competence or patient health. Attractive and cost-effective CME methods are greatly needed. This study develops, field tests and evaluates more efficient office-based CME programs for family doctors. Prevention, early detection and improved management of cardiovascular disease and cancer are the primary goals. A pretest posttest control group and time series approach was chosen for the experimental design. Thirty-one family physicians are participating. Physician performance and patient outcome prior to and after education are being assessed largely through office record review.

Chemotherapy of advanced colorectal carcinoma: fluorouracil alone vs. two drug combinations using fluorouracil, hydroxyurea, semustine, dacarbazine, razoxane, and mitomycin. A phase III trial by the Eastern Cooperative Oncology Group (EST: 1278).

Patients with advanced colorectal cancer and no prior chemotherapy were randomized to six treatment regimens: A) fluorouracil (FU) alone; B) FU + hydroxyurea (HU); C) semustine (SE) + dacarbazine (DA); D) FU + HU alternating with SE + DA; E) SE + razoxane (RA); F) mitomycin (MI) + DA. There were no significant treatment differences with respect to response, which ranged from 9-23% (overall 32/207 or 15%) or median survival duration, which ranged from 17 weeks to 32 weeks. Patients treated with FU or FU + HU experienced substantially less toxicity than those on the other treatment arms.

Cations and calmodulin in normal and neoplastic cell growth regulation.

The purpose of this presentation is to review pertinent literature pertaining to the role of divalent cations and calmodulin in regulating growth of nonneoplastic and neoplastic cells and to examine the anticancer efficacy of some calmodulin inhibitors. Although normal eukaryotic cell replication and proliferation is closely controlled by a complex system of endogenous substances, it is likely that the coordination of purposeful interactions between these substances is the ultimate responsibility of two groups of cellular components, namely the divalent cations Ca2+ and Mg2+ and the versatile intracellular Ca2+-binding protein calmodulin (CaM). When free Ca2+ enters normal cells, it acts as a positive signal for proliferation; this action appears to be specifically associated with the late G1 phase, just prior to DNA synthesis. This period is designated G1/S and is considered to contain Pardee's "restriction point." Reduction of extracellular Ca2+ concentrations between physiological levels (1-0.1 mM) results in gradually reduced rates of cell proliferation; at Ca2+ concentrations of 0.1 mM or less, normal cell proliferation is reversibly inhibited. Since an extracellular concentration of about 0.7 mM Mg2+ is required for Ca2+ to initiate cell replication, it has been proposed that Ca2+ and Mg2+ act in concert via a common mechanism, however, in contrast to Ca2+, Mg2+ appears to be required throughout the entire cell cycle. Intracellular Ca2+ can activate CaM which, in turn, can modulate various cellular processes that affect cell proliferation, including cyclic nucleotide metabolism, protein phosphorylation, polyamine metabolism, prostaglandin metabolism, Ca2+ transport, DNA synthesis, and microtubular function including mitosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of human breast cancer colony formation by anticalmodulin agents: trifluoperazine, W-7, and W-13.

The effects of anticalmodulin agents, namely trifluoperazine (TFP) and two naphthalene sulfonamide derivatives (W-7 and W-13), were tested on the growth of a human breast cancer cell line (MDA-MB-231) using a soft agar clonogenic assay. The results of this in vitro study reveal that TFP, W-7, and W-13 had the ability to inhibit the colony formation from this cell line. The inhibitory effect was greater when the cancer cells were exposed to these agents continuously than when the cells were exposed to the drugs for 1 h. The IC50 values for TFP, W-7, and W-13 in continuous exposure were about 18, 30, and 38 microM, respectively, whereas the corresponding values for 1-h exposure were 50, 53, and 70 microM, respectively. These findings suggest that anticalmodulin agents can inhibit the growth of human cancer cells at relatively low concentrations in vitro. Whether effective antitumor concentrations of these drugs can be achieved in vivo remains a subject for further study.

A phase II study of m-AMSA in patients with primary liver cancer.

Thirty-five evaluable patients with histologically confirmed primary liver cancer (PLC) were treated with m-AMSA. All patients had measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 1, 2, or 3. m-AMSA 120 mg/M2 IV was given every 21 days. Hemopoietic suppression was the major side-effect. In 26 of 35 patients (25 with leukopenia and five with thrombocytopenia), this toxic effect was documented. There was only one patient who had a partial remission (PR) of 51 weeks' duration, but a no change (NC) status was maintained in 28 patients for at least 6 weeks. The median survival time of all patients on this study was 13 weeks, which compares favorably with most previous studies.