Prostate cancer as an environmental disease: an ecological study in the French Caribbean islands, Martinique and Guadeloupe.

Using a transdisciplinary methodological approach we have conducted a multifactorial analysis in Martinique and Guadeloupe in order to elucidate the aetiology of prostate cancer. In 2002, world age standardized rates of prostate cancer were 152 new cases per 100,000 person-years in the two islands; one of the highest worldwide rates and much higher than those reported for other Caribbean islands and metropolitan France. Using a linear regression analysis, we found that the growth curves of incidence rates for Martinique and metropolitan France have been significantly diverging since 1983. That these curves are not parallel suggests that although a Caribbean genetic susceptibility factor may be involved in carcinogenesis, this factor cannot per se account for the observed growing incidence. On the basis of mapping analysis of soil pollution, we further showed that water contamination by pesticides originates from banana plantations. Moreover, we have established retrospectively that general population subjects investigated in 1972 in Martinique for the presence of organochlorinated pesticides in their adipose tissue had been contaminated by extremely high levels of DDT, DDE, alpha, beta and gammaHCH, aldrin and dieldrin. Our study leads to the conclusion that the growing incidence of prostate cancer cannot be related either to a modification of ethnographic factors nor to a change in lifestyle and therefore suggests that environmental factors such as the intensive and prolonged exposure to carcinogenic, mutagenic and reproductive toxin pesticides may cause prostate cancer.

Ex vivo study of incorporation into adipocytes and lipolysis-inhibition effect of polycyclic aromatic hydrocarbons.

We have previously shown that benzo[a]pyrene (B[a]P) administrated at extremely low dose can cause weight gain in mice and that the increase in adipose tissue mass is due to inhibition of beta-adrenergic stimulation of lipolysis. Moreover we have suggested that in addition to its endocrine properties, adipose tissue act as a reservoir for many chemical carcinogens including Polycyclic Aromatic Hydrocarbons (PAHs). In this paper we show that B[a]P as well as the two C4 PAHs, pyrene and phenanthrene can bioaccumulate into adipocytes in a similar manner, but that at the difference of B[a]P, have no impact on epinephrine-induced lipolysis. On the basis of this ex vivo study, we therefore suggest that B[a]P may play a central role in carcinogenesis not only by inducing cancer through its mutagenic properties, but also by increasing the bioaccumulation capacity of the adipose tissue mass.

The growing incidence of cancer: role of lifestyle and screening detection (Review).

The increasing incidence of a variety of cancers after the Second World War confronts scientists with the question of their origin. In Western countries, expansion and ageing of the population, as well as progress in cancer detection using new diagnostic and screening tests cannot fully account for the observed growing incidence of cancer. Our hypothesis is that environmental factors play a more important role in cancer genesis than it is usually agreed: i) over the last 2-3 decades, alcohol consumption and tobacco smoking in men have significantly decreased; ii) obesity is increasing in many countries, but the growing incidence of cancer also concerns cancers not related to obesity nor to other lifestyle-related factors; iii) there is evidence that the environment has changed over the same time scale as the recent rise in cancer incidence, and that this change included the accumulation of many new carcinogenic factors in the environment; iv) genetic susceptibility to cancer due to genetic polymorphism cannot have changed over one generation and actually favours the role of exogenous factors through gene-environment interactions; v) age is not the unique factor to be considered since the rising incidence of cancers is seen across all age categories, including children; vi) the fetus is specifically vulnerable to exogenous factors. A fetal exposure during a critical window period may explain why current epidemiological studies may be negative in adults. We therefore propose that the involuntary exposure to many carcinogens in the environment contributes to the rising trend in cancer incidence.

Overweight/obesity and cancer genesis: more than a biological link.

The classical view according to which overweight/obesity is related to cancer considers adipose tissue as an active and metabolic "organ", acting through endocrine, autocrine and paracrine processes. Consequently, it has been hypothesized, that genesis and progression of cancer may be caused by different biological factors acting through diverse mechanisms including changes in the synthesis and bioavailability of sex hormones, insulin resistance, release of growth factors and/or proinflammatory cytokines and abnormal energetic disposal and expenditure. We have shown that overweight/obesity can be experimentally induced by benzo[a]pyrene, a universal well characterized chemical pollutant and that overweight/obesity may in fact be caused by several types of chemical pollutants. In this paper we propose that in addition to the above hypothetical biological mechanisms, adipose tissue acts as a reservoir for lipophilic, liposoluble environmental carcinogens, so that chemical pollution may in fact generate both overweight/obesity and cancer. More precisely, we propose that many carcinogens, be they mutagens or promotors can be stored in the adipose tissue, be released at convenient dose in the blood circulation and therefore target peripheral tissues to induce carcinogenesis. Such carcinogens mainly include organochlorine pesticides and PCBs. Their association with an increased risk of cancer seems to be demonstrated for breast and prostate carcinoma, as well as for lymphoma, not only in obese patients, but also in normal weight or even leaner patients suggesting that the adipose tissue may act as a reservoir for environmental carcinogens in obese as well as in non-obese patients.

Lifestyle-related factors and environmental agents causing cancer: an overview.

The increasing incidence of a variety of cancers after the Second World War confronts scientists with the question of their origin. In Western countries, expansion and ageing of the population as well as progress in cancer detection using new diagnostic and screening tests cannot fully account for the observed growing incidence of cancer. Our hypothesis is that environmental factors play a more important role in cancer genesis than it is usually agreed. (1) Over the last 2-3 decades, alcohol consumption and tobacco smoking in men have significantly decreased in Western Europe and North America. (2) Obesity is increasing in many countries, but the growing incidence of cancer also concerns cancers not related to obesity nor to other known lifestyle-related factors. (3) There is evidence that the environment has changed over the time period preceding the recent rise in cancer incidence, and that this change, still continuing, included the accumulation of many new carcinogenic factors in the environment. (4) Genetic susceptibility to cancer due to genetic polymorphism cannot have changed over one generation and actually favours the role of exogenous factors through gene-environment interactions. (5) Age is not the unique factor to be considered since the rising incidence of cancers is seen across all age categories, including children, and adolescents. (6) The fetus is specifically vulnerable to exogenous factors. A fetal exposure during a critical time window may explain why current epidemiological studies may still be negative in adults. We therefore propose that the involuntary exposure to many carcinogens in the environment, including microorganisms (viruses, bacteria and parasites), radiations (radioactivity, UV and pulsed electromagnetic fields) and many xenochemicals, may account for the recent growing incidence of cancer and therefore that the risk attributable to environmental carcinogen may be far higher than it is usually agreed. Of major concern are: outdoor air pollution by carbon particles associated with polycyclic aromatic hydrocarbons; indoor air pollution by environmental tobacco smoke, formaldehyde and volatile organic compounds such as benzene and 1,3 butadiene, which may particularly affect children and food contamination by food additives and by carcinogenic contaminants such as nitrates, pesticides, dioxins and other organochlorines. In addition, carcinogenic metals and metalloids, pharmaceutical medicines and some ingredients and contaminants in cosmetics may be involved. Although the risk fraction attributable to environmental factors is still unknown, this long list of carcinogenic and especially mutagenic factors supports our working hypothesis according to which numerous cancers may in fact be caused by the recent modification of our environment.

Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer.

PURPOSE: Serious cumulative toxicity is a well-recognized consequence of chemotherapy. Amifostine, an organic thiophosphate, has demonstrated the ability to protect selectively a broad range of normal, but not neoplastic, tissues from the cytotoxic effects of chemotherapy and radiotherapy. This study was designed to determine if amifostine could reduce the serious toxicities associated with cyclophosphamide and cisplatin (CP), without reducing antitumor efficacy in patients with ovarian cancer. PATIENTS AND METHODS: Two hundred forty-two patients with advanced ovarian cancer were randomized to receive six cycles of cyclophosphamide (1,000 mg/m2) and cisplatin (100 mg/m2) with or without amifostine (910 mg/m2) every 3 weeks for six cycles. The occurrence of hematologic, renal, neurologic, and ototoxicity was evaluated. Antitumor efficacy was assessed by pathologic tumor response and survival. RESULTS: Pretreatment with amifostine before each cycle of chemotherapy resulted in a reduction of cumulative toxicities. Hematologic toxicity consisted of grade 4 neutropenia associated with fever and/or infection that required antibiotic therapy (P = .005), days in hospital (P = .019), and days on antibiotics (P = .031). Platinum-specific toxicities consisted of protracted serum creatinine elevations (P = 0.004), > or = 40% reduction from baseline in creatinine clearance (P = .001), and severity of neurologic toxicity (P = .029). Twenty-four percent of CP patients compared with 9% of amifostine plus CP patients discontinued therapy because of protocol-specified toxicity (P = .002). Pathologic tumor response rates were 37% with amifostine and 28% in controls, with comparable median survival times of 31 months. Amifostine was generally well tolerated; the principal side effects were emesis and a transient decrease in blood pressure. CONCLUSION: Pretreatment with amifostine reduces the cumulative hematologic, renal, and neurologic toxicities associated with the CP regimen, with no reduction in antitumor efficacy.

Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16-year median follow-up duration.

PURPOSE: To determine the long-term impact on disease-free survival (DFS) and overall survival (OS) of adjuvant anthracycline-based chemotherapy, when prospectively compared by random allocation with standard cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-positive (N+) breast cancer patients. PATIENTS AND METHODS: Two hundred forty-nine patients with N+ breast cancer, recruited from eight French cancer centers, were randomized to receive 12 monthly cycles of adjuvant chemotherapy, either CMF (n = 112) or doxorubicin, vincristine, cyclophosphamide, and fluorouracil (AVCF) (n = 136). All had a negative metastatic work-up before inclusion, which was stratified by accrual center, tumor stage (International Union Against Cancer [UICC]), and menopausal status. RESULTS: No severe adverse effect related to grade 4 (World Health Organization [WHO]) toxicity was observed. There was no difference in second primary tumor incidence between the two arms. The treatment given was 88% of planned for AVCF and 75% for CMF in both premenopausal and menopausal patients. With a median follow-up time of 16 years (range, 13 to 17), the OS and DFS rates are significantly longer in the AVCF arm (56% v 41% [P = .01] for OS, and 53% v 36% [P = .006] for DFS). These differences are significant, irrespective of tumor stage (T1 to T2 v T3 to T4), and remain positive in patients with or without postoperative locoregional radiotherapy (55% of cohort). When analyzed according to menopausal status, the differences remain significant only for premenopausal patients. CONCLUSION: This set of mature controlled data confirms the added value of anthracycline-based combination adjuvant therapy for N+ breast cancer patients when compared with CMF, with both regimens given for 1 year.

mu-chain disease. Report of two new cases.

We report two cases of mu-heavy-chain disease. Both patients were affected with a lymphoproliferative disease that shared several suggestive features with the previously reported cases of mu-chain disease: the presence of vacuolated plasma cells in bone marrow, a small amount of alpha 2 moving abnormal mu-chain protein, and urinary kappa Bence Jones protein in one case.

[The contribution of the physico-chemical environment to the genesis of cancer: what extent and how to measure it?]. / La part de l'environnement physico-chimique dans la genèse des cancers: quelle amplitude et comment la mesurer?

The growing incidence of cancers for the last 20 years in France and in Europe confronts scientists with the problem of their origin. Apart from standard factors such as addiction to smoking, alcoholism and overweight due to inadequate diets, the hypothesis that other environmental causes have recently appeared, is formulated. The author aims at reinforcing this hypothesis based on epidemiological, biological and toxicological arguments. Addiction to smoking and alcoholism have significantly decreased for the last 20 to 30 years and the incidence rise concerns cancers that are not related to these factors. Endogenous factors of genetic susceptibility can hardly have changed over one generation and actually can favour interaction with exogenous factors involving either our life style or the environment. The role of biological factors associated with ageing to explain the increase in cancer rate according to age is worth discussing. Many factors (radiation and chemical molecules) present in the environment, factors that international organizations have proven to be certainly, probably or possibly cancer-inducing, are considered. Some acting as mutagenic, others as promoters can add their cancer-inducing effects to smoking or other factors associated with our lifestyle. However, with the exception of smoking, most of the factors associated with our lifestyle are not mutagenic, an observation which leads to consider mutagenic factors from the environment, because any cancer implies the occurrence of mutations at its initiation step. The magnitude of the risk related to environmental factors is not yet known, therefore implying the need for new research aiming at assessing them accurately. Although, as far as public health is concerned, fighting addiction to smoking, alcoholism and unhealthy eating habits needs to be pursued, evidence regarding these new environmental factors of physico-chemical nature poses the problem of their prevention.

300 mg/m2 carboplatin (Cb), adriamycin (A) cyclophosphamide (C) (CACb-300) combination in advanced ovarian carcinoma: a feasibility study.

Carboplatin (Cb) is an active drug in ovarian carcinoma that has fewer visceral side effects than cisplatin (CDDP) but higher myelotoxicity, which makes it difficult to combine at efficient doses with other myelotoxic drugs. In a preliminary study in advanced ovarian carcinoma, Rosso et al. showed the maximum tolerated dose of Cb given in combination with cyclophosphamide (C) and adriamycin (A) to be 200 mg/m2. Since the efficacy of Cb may be dose-dependent, as is that of CDDP, we started a feasibility study of a CACb-300 regimen, that is, using Cb at 300 mg/m2 with lower C and A doses. Our data shows that the CACb-300 combination can safely be given in previously untreated patients for at least six 28-day cycles.

Phase-II trial with vindesine for regression induction in patients with leukemias and hematosarcomas.

Vindesine (VDS) has been submitted to a phase-II trial, the results of which were assessed in terms of regression induction. VDS was given weekly IV in doses of 2 mg/m2 on two consecutive days to 59 patients, 55 of whom were evaluable. A high proportion of complete (36%) and over 50% partial regressions were obtained in acute lymphoid leukemias (ALL) (overall response 63%) whatever the perceptible phase, in blastic crisis of chronic myeloid luekemia (55%), and some responses were recorded in lymphosarcoma (40%). No effect has so far been seen in acute myeloid keukemia or in Hodgkin's disease. Malignant neoplasms of the immunoblastic type seem to be particularly sensitive to VDS. Continuous 48 h IV infusion can induce a remission where an IV push administration of the same dose has failed. One remarkable characteristic of VDS is the apparent absence of cross-resistance with VCR: in acute leukemic forms, 55% of patients who failed to obtain remission induction after three weekly injections of VCR (used in combination chemotherapy) achieved a complete or partial remission with VDS. The toxicity was mainly neurologic (paralytic ileus, constipation, paresthesias, loss of reflexes) and hematologic (leukopenia and thrombopenia), and was not more significant than with the other agents: four patients died of infection or hemorrhage.

Increase in "Null" cells in acute lymphocytic leukemia in remission on long-term immunotherapy.

In an attempt to elucidate a possible mode of action of immunotherapy in ALL, we studied the mononuclear subpopulation in a group of patients with all in remission on long-term immunotherapy, a similar group on chemotherapy, and a group of normal individuals. Comparison of the three groups demonstrated a significant increase in the number and percentage of "null" cells in the immunotherapy group relative to the two others. Although the nature of these cells is unknown, circulating stem cells, "K" cells, or modified T, B, or monocytic cells are raised.

Chemotherapy of carcinomas of the digestive tract.

Adjuvant chemotherapy trials in gastric and colorectal carcinomas are reviewed and no clear benefit from such treatment could be observed. To improve existing chemotherapy regimens, several pilot studies were performed in 95 gastric cancer and 85 colorectal carcinomas patients. Response rate for gastric carcinomas using the mitomycin C plus adriamycin plus 5-fluorouracil (5-FU) (FAM) regimen was 40% and was not improved by the addition of nitrosoureas. In colorectal carcinomas none of the combinations used gave better results than 5-FU alone. Fourteen patients with esophageal carcinoma were treated with combination CDDP and the response rate was as high as 50%.

Prognostic factors and treatment of multiple myeloma: interest of a cyclic sequential chemohormonotherapy combining cyclophosphamide, melphalan, and prednisone.

1. A type 2 therapeutic trial consisting of the administration of monthly cycles of chemohormonotherapy, each cycle combining weekly sequences of mephalan, prednisone, cyclophosphamide, and prednisone, has been achieved in 20 stage II or III myeloma patients. Tolerance of this regimen in treated out-patients was found to be excellent. Preliminary data indicate that the better survival rate in patients treated by this regimen is still not reached at a 30-month follow-up examination by three other nonrandomized control groups of patients receiving continuous therapy with prednisone alone, prednisone + cyclophosphamide, or prednisone + melphalan. 2. Analysis of the main prognostic factors of the four trials indicates that a) IgG-type myelomas are associated with a better prognosis than IgA type; nonexcreting myelomas are associated with the best prognosis, while Bence Jones myelomas are associated with a prognosis as poor as that of the IgA type; b) tumor volume as well as renal insufficiency, at the time of diagnosis, are also prognosis factors; this study confirms the prognostic value of the recently proposed clinical staging system based on these parameters but outlines that 10% of the patients died from a cause not directly related to myeloma plasmocyte proliferation. 3. In conclusion, these results point out: a) the possible advantage of using two alkylating agents instead of one at the beginning of the disease; b) the need to classify multiple myeloma according to prognosis before attempting therapeutic trials.

Adriamycin, vincristine, cyclophosphamide and 5-fluorouracil (AVCF) compared with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in premenopausal breast carcinoma. Personal results.

Adjuvant treatment of breast cancer with AVCF gave significantly longer disease-free survival than CMF in the group of patients taken as a whole, in the subgroup with lymph node involvement and in the premenopausal subgroup. No significant difference was found regarding overall survival.

[Assessment of the quality of life of cancer patients. The preliminary applications to advanced bronchial cancers]. / Evaluation de la qualité de vie chez les malades atteints de cancer. Premières applications aux cancers bronchiques évolués.

So far there is no good evidence that chemotherapy improves survival in non small cell lung cancer. Reports of randomized trials testing chemotherapy versus supportive treatment alone are very few. In recent years, more and more emphasis has been put on the quality of life for cancer patients. Subjective tests such as Anamnestic comparative self Assessment (A.C.S.A. test, Dr. Bernheim) were designed as well as objective ones, using different types of self evaluation. However very few studies have been focused on this aspect in patients with non small cell lung cancer. Therefore the G.E.T.C.B. (Groupe d'Etude et de Traitement des Cancers Bronchiques) decided to initiate a cooperative randomized trial (02 CB 84) in metastatic epidermoid and large cell bronchus carcinoma, in order to test the potential benefit from chemotherapy in these tumors and how it affects the quality of live. In this trial, C.O.P.A.C. combination (Cyclophosphamide, Vincristine, Cis-Platinum, Adriamycin and CCNU) is randomized versus no chemotherapy. The quality of life is assessed monthly on the one hand by a modified A.C.S.A. test performed by a physician and on the other hand by a question list given to the patient. This question list attempts to evaluate the impact of disease as a reference point. Finally protocol 02 CB 84 (activated in 05/84) may give information about the effect of chemotherapy on both survival and quality of life.

[Response of bone metastases to medical treatment: definition of evaluation criteria and classification trials]. / Réponse des métastases osseuses aux thérapeutiques médicales: définition des critères d'évaluation et essai de classification.

Bone metastases are very frequent. Some are sensitive to the action of anticancer drugs. However, there is as yet an unsolved methodological problem in the evaluation of response to these drugs. The uniquely radiological UICC criteria are quite insufficient, in as much as they appear with a long delay and sometimes give erroneous results. In this work we give a brief review of biological and clinical knowledge about bone metastases, and we attempt to give an array of the possible evaluation criteria and their respective value. We propose as a working hypothesis a classification of responses taking into account the criteria: the urinary hydroxyproline to urinary creatinine ratio, the serum dosage of bone isoenzyme of alkaline phosphatase and propeptide of type III procollagen (P III NP), and as an essential element, an analysis of all available imaging techniques. A visual study of bone scintillation scans must precede that of radiographs and, when possible, it must be associated to computerized scintillation scanning. When metastasis are located to the pelvis, the vertebral column, or the sternum, a CT scan or better, a nuclear magnetic resonance study (IRM), is indispensable in order to have a direct measure of the tumor extension to soft tissues. Furthermore, in the case of isolated metastases, one of these imaging techniques allows a diagnostic biopsy. Finally an analysis of response at the bone level will always be associated with a measure of their duration and an evaluation of metastases to other sites.

[Inoperable primary bronchial cancers: treatment by chemotherapy combinations including cis-platinum]. / Cancers bronchiques primitifs inopérables: traitement par combinaisons chimiothérapiques incluant le cis-platinum.

Sixty-seven assessable patients with advanced primary bronchial carcinoma of the epidermoid or large cell undifferentiated type (37 with non-resectable stage III Mo and 30 with stage III M1) were included in two prospective non-randomized phase 2 chemotherapeutic trials. Thirty-five received a COPAC-type regimen and 32 were treated with a COPAB-RT protocol combining a COPAC-type chemotherapy with local radiotherapy. Both combination therapies contained cis-platinum. With either of these treatments the major response rate averaged 45% and the median survival rate was about 9 months. However, a significant (p = 0.03) difference in survival rate was elicited between the population of treated patients and a control group of 30 untreated patients of similar age, stage and histology (mean survival in controls: 5 months). Both chemotherapeutic regimens were regarded as reasonably well tolerated. These results suggest that platinum-based combination chemotherapy is effective in these carcinomas.