Michele Deschamps

Carcinogenic and endocrine disrupting effects of cigarette smoke and risk of breast cancer

BACKGROUND Results of epidemiological studies, assessing the relation between smoking and breast cancer, have been inconclusive. Our aim was to assess the carcinogenic and possibly antioestrogenic effects of cigarette smoke on risk of breast cancer. METHODS We sent a questionnaire to 1431 women younger than age 75 years who had breast cancer and were listed on the population-based British Columbia cancer registry between June 1, 1988, and June 30, 1989. We also sent questionnaires to 1502 age-matched controls, randomly selected from the 1989 provincial voters list. We obtained information on all known and suspected risk factors for breast cancer, and on lifetime smoking, alcohol consumption, and occupational history. We assessed the effect of smoking separately for premenopausal and postmenopausal women, adjusting for confounding variables. FINDINGS 318 premenopausal women and 340 controls replied. Risk of breast cancer was significantly increased (adjusted odds ratio 1.69, 95% CI 1.13-2.51) in women who had been pregnant and who started to smoke within 5 years of menarche, and in nulliparous women who smoked 20 cigarettes daily or more (7.08, 1.63-30.8) and had smoked for 20 cumulative pack-years or more (7.48, 1.59-35.2). Postmenopausal women (700 breast cancer and 685 controls) whose body-mass index increased from age 18 to current and who started to smoke after a first fullterm pregnancy had a significantly reduced risk of breast cancer (0.49, 0.27-0.89). INTERPRETATION Our results suggest that cigarette smoke exerts a dual action on the breast, with different effects in premenopausal and postmenopausal women. Our observations reinforce the importance of smoking prevention, especially in early adolescence, and draw attention to the timing of exposure in relation to susceptibility and refractory windows in the design of studies to investigate associations between environmental carcinogens or putative endocrine disruptors and risk of breast cancer.

Identification of occupational Cancer risks in British Columbia : A population-based case-control study of 995 incident breast Cancer cases by menopausal status, controlling for confounding factors

Lifetime occupational histories as well as information on known and suspected breast cancer risk factors were collected by means of a self-administered questionnaire from 1018 women with incident breast cancer ascertained from the British Columbia Cancer Registry, and from 1020 population controls. A matched case-control study design was used. Conditional logistic regression for matched sets data and the likelihood ratio were used in a two-step procedure and were performed separately for pre-menopausal women, post-menopausal women, and for all cases combined. Excess risk was noted for several white-collar occupations. Significantly increased risk was observed: (1) among pre-menopausal women: in electronic data-processing operators; barbers and hairdressers; in sales and material processing occupations; and in the food, clothing, chemical and transportation industries; (2) among post-menopausal women: in schoolteaching; in medicine, health, and nursing occupations; in laundry and dry-cleaning occupations; and in the aircraft and automotive, including gasoline service station, industries. Several significant associations were also seen in the combined group of pre- and post-menopausal women, particularly in crop farmers and in the fruit and vegetable, publishing and printing, and motor vehicle repair industries. The results of this study suggest excess breast cancer risk in a number of occupations and industries, notably those that entail exposure to solvents and pesticides.

Assessment of adult cancer pain: shortcomings of current methods.

&NA; The evaluation of cancer pain remains a problematic clinical problem, not only due to the subjective and multidimensional nature of pain per se, but also because of its specific characteristics. Cancer pain has an insidious onset, often involves many sites, and is frequently multicausal. Tools have been developed to quantify pain, the most commonly used being the verbal rating scale (VRS), the visual analogue scale (VAS), and the McGill Pain Questionnaire (MPQ). The first 2 scales are short, easy to administer and to score, but only measure pain intensity. The VRS is assumed to be an ordinal scale although unequal differences between pain descriptors have been demonstrated; it offers a restrictive choice of words that may not represent pain experience with sufficient precision, and is not sensitive to change especially for mild pain. The VAS on the other hand, represents pain as a continuum and is sensitive to change. The MPQ has the advantage of evaluating the sensory, affective and evaluative dimensions of pain. However, it is lengthy to administer and some words are not readily understandable. In addition, the words within a given category are considered to be equidistant, the number of words in each category are unequal, and the number of categories evaluating a given dimension are not taken into account when calculating the total pain rating index. A further issue in assessing pain, other than the choice of a valid and reliable tool, is the frequency with which pain evaluations should be repeated. To date no studies have addressed this problem. The timing of pain assessment has been determined more by convenience than by data related to cancer pain fluctuations. In addition to discussing the difficulties specific to each instrument, suggestions for improving cancer pain evaluation are presented.

Pharmacokinetics of Lonidamine after Oral Administration in Cancer Patients

The pharmacokinetics of Lonidamine has been studied in cancer patients after single and chronic oral administrations. After single administration the plasma kinetics are highly variable, while the dose eliminated in the urine is over 70% in all subjects. This suggests an active but interindividually variable first-pass effect. After repeated administrations, both the residual plasma concentration before administration (C infinity min) and that obtained after drug intake (C infinity max) have been studied. The C infinity max values range from 4.5 to 25 micrograms/ml and C infinity min values from 0.4 to 7 micrograms/ml. In patients where a therapeutic response was noted, a mean value of 2.98 micrograms/ml for C infinity min was measured. In patients unresponsive to drug therapy the mean C infinity min was 1.5 micrograms/ml.

Human Pharmacokinetic Study of Immediate‐Release (Codeine Phosphate) and Sustained‐Release (Codeine Contin) Codeine

The authors compared, in a double‐blind, randomized, crossover study in 13 healthy adult volunteers, the single‐ and multiple‐dose pharmacokinetics, relative bioavailability, and side effects of a new oral sustained‐release formulation of codeine (SRC) containing 150 mg codeine base, with oral immediate‐release codeine phosphate (IRC). Sustained‐release codeine was given at a dose of 150 mg every 12 hours for 5 doses; IRC was given at a dose of 60 mg (2 × 30 mg) every 4 hours for the first 3 doses, and 30 mg every 4 hours thereafter for 12 doses. Plasma codeine levels were determined using a sensitive and specific high‐performance liquid chromatography method and corrected for dose administered and codeine base equivalent. Mean values for single‐dose pharmacokinetic parameters for SRC and IRC, respectively, were: Cmax of 217.8 and 138.8 ng/mL; Tmax of 2.3 and 1.1 hours; AUC0‐inf of 1202.3 and 1262.4 ng • mL−1 • hour−1; and t1/2el of 2.6 hours for both formulations. Their respective mean steady‐state pharmacokinetic parameters were: Cmax of 263.8 and 222.9 ng/mL; Tmax of 3.2 and 1.1 hours; AUC0–12h of 1576.4 and 1379.1 ng • mL−1 • hour−1; and t1/2el of 2.8 and 2.3 hours. These results indicate comparable bioavailability between both formulations with SRC providing delayed peak plasma levels. The sustained‐release character of SRC can be explained by a delayed absorption, which is not limiting to drug elimination. Sustained‐release codeine provides higher plasma codeine levels over a broader time interval and is expected to improve pain management.

Treatment of benign breast disease with vitamin A

Twelve patients with benign breast disease (BBD) were treated with 150,000 IU of vitamin A daily taken orally. All patients were symptomatic and had measurable or evaluable breast masses. At 3 months of treatment, complete or partial responses were observed in five patients, and marked pain reduction in nine was observed. Side effects were generally mild in nature, consisting mostly of skin and mucosal changes, and were rapidly reversible upon discontinuation of the drug. Treatment was interrupted or discontinued in only two patients, and the dosage of vitamin A was reduced in one on account of toxicity. No hepatotoxicity was observed. Investigation of the chemopreventive role of either vitamin A or retinoids in patients with BBD who are at high risk of developing breast cancer is suggested.

Phase I Toxicologic Study of Lonidamine in Cancer Patients

15 patients with metastatic cancer were treated with Lonidamine, a substituted indazole carboxylic acid active against the Lewis lung and Sarcoma 180 tumors. Single doses of 600 mg (350-400 mg/m2) mostly induced somnolence and gastro-intestinal side effects. Toxicity occurring during chronic administration of Lonidamine at doses ranging between 45 and 275 mg/m2 twice daily, mainly consisted of somnolence, myalgias, hyperesthesia and mild hair loss. Myalgias and hyperesthesias were markedly relieved with prednisone 5 mg twice daily. No laboratory abnormalities were seen. In 1 patient with breast cancer resistant to standard chemotherapeutic agents, a 30% reduction of measurable tumor masses was seen. In view of the lack of overlapping toxicity between Lonidamine and other chemotherapeutic drugs, and of its potential activity, it is suggested that phase II studies of Lonidamine be initiated at a dose of 135 mg/m2 twice daily.

Health Care Services and Pap Testing Behavior for Chinese Women in British Columbia

The health care services and sociodemographic profiles of Chinese women residing in each of five neighborhoods of Vancouver and Richmond, British Columbia, were examined and compared to Pap testing rates. Information was collected from the provincial medical directory, the cervical cancer screening program, and a community-based survey. A total of 159 Chinese primary care physicians, 3 Chinese gynecologists, and 9 health clinics were identified within these neighborhoods and 769 Chinese women responded to the survey. Significant differences were found between neighborhoods in Pap testing rates, with Chinatown having the lowest rates. Differences between neighborhoods were also found in the availability of Chinese language health care services, sociodemographic profiles of the Chinese population, individual preferences and experiences with health care services, which were also related to Pap testing rates. The implications of these findings upon the planning of effective health care services within local neighborhoods are discussed.

Phase II Study of Lonidamine in Cancer Patients

12 patients with metastatic cancer were treated with the substituted indazole carboxylic acid Lonidamine at oral daily doses of 270 mg/m2. Toxicity, consisting mainly of myalgias, somnolence, hyperesthesia, anorexia and vomiting, generally decreased or disappeared over time despite continuing drug administration at unmodified dosage. Myalgias and hyperesthesias were markedly relieved with prednisone 5 mg twice daily. No laboratory abnormalities were seen. Partial responses were observed in a patient with hypernephroma and in a patient with breast cancer. Disease-oriented phase II studies with this new anticancer agent are warranted.

Retinoid Chemoprevention Timing and Dose Intensity

The concept of chemoprevention is generating increasing attention among oncologists. This article discusses the issue of dose of chemopreventive agents in relation to the stages of tumor development. Vitamin A-deficient animals have an increased susceptibility to cancer development, and epidemiologic studies have shown an inverse relationship between intake of food rich in vitamin A and/or beta-carotene and cancer risk. These data suggest that physiologic levels of these natural substances exert a protective effect against cancer development. In the presence of precursor lesions, however, this protective effect has been overwhelmed and pharmacologic doses of chemopreventive agents are required to induce regression or to arrest the progression of these lesions. Phase I pharmacologic and toxicologic studies, and Phase II dose-intensity investigation of chemopreventive agents in patients having precancerous lesions need to be carried out. Such studies would enable to select the least toxic effective chemopreventive dose for intervention trials in high-risk populations, which could then be undertaken based on evidence of activity.