Benign breast disease: absence of genetic alterations at several loci implicated in breast cancer malignancy.

Benign breast disease (BBD) is a heterogeneous group of benign breast problems that has been associated with breast cancer risk by several investigators. Genetic alterations have been described in breast carcinomas under the headings of loss of heterozygosity (1p, 3p, 7q, 11p, 17p, 17 and 18q), mutations (p53, c-H-ras-1), and/or gene amplifications (c-myc, int-2/FGF3, and c-erbB-2/neu). In an attempt to determine whether these genetic alterations might also be involved in the development of BBD, we have analyzed such alterations in 50 BBD lesions. The histological types of samples studied were: 37 fibroadenomas; 8 benign phyllode tumors; and 5 fibrocytic diseases. Cellular DNA was extracted from tissues and from corresponding blood leukocytes according to standard techniques, digested with appropriate restriction endonucleases, and analyzed by Southern blot. The following are informative cases found in a total number of patients analyzed for each locus: 13 of 26 for L-myc (1p); 9 of 23 for THRB (3p); 11 of 29 for met (7q); 27 of 50 for c-H-ras-1 (11p); 3 of 13 for TP53 (17p); 14 of 50 for D17S30 (17p); 20 of 33 for D17S4 (17q); and 13 of 33 for D18S5 (18q). No loss of heterozygosity was detected at any of the examined loci. Alternatively, none of the 50 BBD cases displayed an amplification of the three genes tested (c-myc, int-2/FGF3, and c-erbB-2/neu). Our results show that molecular alterations, which are more frequently involved in malignant breast carcinomas, do not occur in BBD lesions. These results indicate that these molecular alterations could constitute late events in the pathogenesis of breast carcinomas.

Modification of Kiel and working formulation classifications for improved survival prediction in non-Hodgkin's lymphoma.

The total survival of 203 patients with non-Hodgkin's lymphoma (NHL) was analyzed according to the working formulation (WF) and "expanded" Kiel classifications. The original Kiel classification consisting of low grade (LG) and high grade (HG) forms corresponded well to the LG and HG forms of the WF. When an expanded Kiel containing an intermediate grade (IG) composed of the original LG diffuse group was devised, this gave a much better separation of survival of the three grades as compared with the WF where the survival of IG and HG forms were nonsignificantly different. The main reason for this difference was the inclusion of the so-called centroblastic diffuse form in the HG Kiel, but in the IG according to the WF. In a "modified" WF analysis where this histologic entity was placed in the HG subgroup, the three survival curves then gave excellent separation like the expanded Kiel classification. Since the centroblastic diffuse form (and its analogous forms according to other classifications) has a poor prognosis, it is important that it be so recognized and treated accordingly with aggressive therapy. We propose either our expanded Kiel or modified WF classification of the three grade forms as an excellent predictor of survival.

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.

p53 gene alterations are associated with a decreased responsiveness to neoadjuvant chemotherapy in human breast cancer.

Recent evidence indicates that alterations of the p53 tumor suppressor gene can modulate the response of tumor cells to DNA-damaging agents and increase drug resistance. To evaluate whether p53 alterations affect response to chemotherapy in breast cancer, we examined the p53 status before and after treatment of primary tumors from 44 patients who received neoadjuvant chemotherapy. p53 status was determined by gene mutations and by mRNA expression levels. Eleven patients (25%) showed alterations in the p53 gene. Comparison of the clinical response between subgroups with or without p53 alterations revealed that p53 alterations were strongly associated to clinical resistance to chemotherapy (p<0.001).

Urinary beta 2-microglobulin: early indicator of high dose cisdiamminedichloroplatinum nephrotoxicity? Influence of furosemide.

To evaluate the efficacy of beta 2-microglobulin as an indicator of cisplatinum nephrotoxicity, creatinine clearance and urinary beta 2-microglobulin were measured in 19 patients during 5 h after administration of a single dose of 80 mg/m2 cisplatinum. Eleven patients received furosemide as a concomitant therapy. Serum creatinine and beta 2-microglobulin remained unchanged. A decrease of creatinine clearance was observed. Urinary beta 2-microglobulin increased between 1 and 3 h after administration. This suggests transient tubular damage immediately after the treatment course. The concomitant administration of furosemide does not modify these results. However, patients who developed long-term nephrotoxicity had no early rise of urinary beta 2-microglobulin excretion; thus, it is not possible to predict cumulative nephrotoxicity by measuring beta 2-microglobulin immediately after the first course of high-dose cisplatinum.

Influence of hydration on ultrafilterable platinum kinetics and kidney function in patients treated with cis-diamminedichloroplatinum(II).

It has been reported that hypertonic saline provides protection against the renal toxicity of cisplatin (CDDP). We therefore evaluated its influence on the plasma and urinary pharmacokinetics of ultrafilterable platinum and kidney function as estimated by creatinine, inulin and PAH clearance. We undertook a randomized trial including two groups of ten patients receiving 100 mg/m2 CDDP in isotonic (group 1) or hypertonic saline (group 2) by a 20-min infusion. The hydration consisted of dextrose in group 1 and isotonic saline in group 2. Maximal concentration (Cmax), protein binding and cumulative urinary excretion were significantly higher in the dextrose group. Urinary flow decreased in this group but not in the other one. Inulin clearance was higher in the dextrose group than in the saline group and P-aminohippuric acid (PAH) clearance was not significantly different in these groups of patients. Hyponatremia was observed in the dextrose group. These results suggest that hypertonic saline infusion and saline hydration may enhance the diffusion of CDDP into tissues, lowering Cmax and renal excretion of platinum. The reduction of protein binding may indicate a diminution of aquation of CDDP in plasma. Our results suggest that the infusion of CDDP in hypertonic saline with salt hydration could exert a protective effect on the kidney. Moreover, there is a lessening of the risk of cellular hyperhydration. However, the better influence of dextrose hydration on glomerular filtration leads us to recommend a combination of the two methods of hydration for better tolerance and efficacy.

Evaluation of the effect of furosemide on ultrafilterable platinum kinetics in patients treated with cis-diamminedichloroplatinum.

It has been reported that furosemide can prevent platinum nephrotoxicity by dilution of the toxic drug in the tubule or by another unknown mechanism. To evaluate its influence on ultrafilterable platinum pharmacokinetics, we undertook a randomized prospective trial of cis-diamminedichloroplatinum (CDDP) (80 mg/m2 by a 20-min infusion) administered to 20 patients with hydration-induced diuresis. Ten patients received 20 mg/m2 furosemide 1 h before CDDP administration, and 10 patients received no diuretic drug. Plasma and urinary pharmacokinetics of platinum and creatinine were compared in both groups of patients. Plasma total and ultrafilterable platinum was always higher in the furosemide group. However, protein binding, urinary concentrations, cumulative urinary excretion, renal clearance and creatinine clearance/renal clearance ratio (fractional clearance) were not statistically different. Moreover, the fractional clearance was successively lower, equal and higher than one in both groups. These results suggest that: (1) furosemide probably causes water depletion leading to a rise in plasma concentrations; (2) its protection by a pharmacokinetic interaction is doubtful, since all other parameters (especially urinary parameters) are not significantly modified; (3) renal clearance and fractional clearance suggest a bidirectional transport of platinum in the tubule not influenced by the diuretic drug.

Cisplatinumdiamminodichloride (CPDD) in chemotherapy of cancers: a phase II therapeutic trial.

We have conducted a phase II trial of cisplatinumdiamminodichloride (CPDD) which not only demonstrated its remarkable activity in embryonic carcinoma of the testes, but also in ovarian carcinoma, in melanoma, and in epidermoid carcinoma, especially of the head and of the uterus cervix. Its toxicity, manifested mainly in the digestive and renal tracts, confines its administration to hospitalized patients only. This compound is now indicated in combination therapy for the above-mentioned tumors.

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.

[Role of chemotherapy in adjuvant treatment of breast cancer: modulation of the immune status]. / Place de la chimiothérapie dans les traitements adjuvants des cancers du sein: modulation de l'état immunitaire.

Adjuvant antimitotic chemotherapy increases the survival rates of patients suffering from breast cancer with nodes involvement, but its effects on the immune status are still unclear. The immune status of these patients was studied from the general point of view and particularly from the antitumoral immunity. The most studies which have been made, indicated a such immunity was present, and proved it was more important when the tumor's invasiveness is limited without node involvement. From a general point of view, when an immunologic impairment is present in patients with breast cancer, it seems to have a poor prognosis. Many modulations of this immune status are determined by the treatment's modalities: surgery and radiotherapy have more or less local or general immunologic effects and in certain conditions, antimitotic chemotherapy is immunosuppressive, but it may also interfere as an immunoregulator with a good effect on antibody secreting cells or on suppressive cells. Several situations may be considered according to the tumor immunogenicity and the host immunologic competence. In these different cases, immunotherapy is not always indicated and when this one is, its specificity is still not sufficient. The recent results of specific or non specific immunotherapy trials performed after locoregional treatment or antimitotic chemotherapy are generally not significant and do not lead us to propose a modulation of immune status without controlled trials.

[Ovarian cancer: role of medical treatment]. / Cancers de l'ovaire: place des traitements médicaux.

The objective of medical treatment is to define the most active regimen and to combine them with optimal efficiency in the overall management of ovarian cancer patients, according to the results of surgical examination and the radiotherapeutic possibilities. The chemotherapy of common epithelial tumours is basically composed of alkylating agent, adriamycin, cis-platinum and hexamethylmelamine. The combination of these drugs leads to a high rate of surgically controlled tumor regressions and more complete responses, the only treatment which significantly increases survival. Results are less efficient for relapses or after failure of first line chemotherapy. The adjuvant chemotherapy of malignant germ cell tumours is used more and more often. The present indications of hormonotherapy are limited. Immunostimulant agents are being studied by several assays and preliminary results are interesting.

[Chemotherapy in cervical cancer. Assessment of 267 palliative treatments and current trends (author's transl)]. / La chimiothérapie des cancers du col utérin. Bilan de 267 traitements palliatifs et orientations actuelles.

Over the last 10 years 267 treatments with cervical cancer have been treated with chemotherapy in 4 anticancer centers. The analysis of these results shows: 1) 9 per cent of the treatments were discontinued because of clinical and hematological intolerance reactions; these intolerance reactions were responsible for 1 per cent of the therapeutic deaths; 2) an effect on the functional symptoms in 52 per cent of the patients with multiple drug regimens; 3) an objective global response in 18 per cent of the patients treated with single drug therapy (3 regressions greater than 50% out of 6 cases treated with cis-platinum) and in 22 per cent of the patients treated with various associations. Comparison of these results to recent data in the literature confirms: 1) the hope of improving objective results by developing more rational protocols of association, since, for the moment more active drugs are not available; 2) a much more marked chemotherapeutic action on lesions which have not been previously irradiated (statistically significant differences in response). Chemoresistance in cervical cancers may not be as frequent or as insurmountable as generally believed. The role of chemotherapy may be visualized from: 1) the palliative point of view, for efficacy while reducing toxicity); 2) induction sequence in curative treatment programs for advanced local forms with unfavorable prognosis (logical and attractive orientation of therapeutic studies); 3) the point of view of adjuvant treatment which remains to be defined. Rigorous studies are required to assess whether chemotherapy can give eventual long term improvement in high risk cervical cancers.

[Amplification of c-myc and c-erbbeta-2(HER-2/neu) in breast cancer without axillary lymph node metastasis: correlation with other prognostic parameters]. / Amplification des protooncogènes c-myc et c-erb beta-2 (HER-2/neu) dans les cancers du sein sans métastase ganglionnaire axillaire: corrélation avec les autres paramètres de pronostic.

Amplification of c-myc and c-erb beta-2 (HER-2/neu) proto-oncogenes were analyzed in breast cancer tissues obtained from 100 patients without lymph node involvement (N-). An amplification of the c-myc gene was detected in four cases and a c-erb beta-2 (HER-2/neu) amplification in eight cases. The frequency of these abnormalities were compared to classical prognostic parameters as well as to new biological prognostic markers (cellular cycle, cathepsin-D and pS2 protein). Most of altered tumors were associated to some classical poor prognostic factors such as: steroid receptor-negative tumors, poorly differentiated tumors, high histoprognostic grade and tumor cell density. In contrast, no relation was found with new biological parameters. The analyses of these data in relation to clinical evolution will be of interest to evaluate their prognostic value.

[Prognostic value of CA 125 initial half-life measured during first-line chemotherapy in 62 patients with epithelial ovarian cancer stage III or IV]. / Valeur pronostique de la demi-vie initiale du CA 125 mesurée au cours de la chimiothérapie d'induction chez 62 patientes porteuses de tumeur épithéliale ovarienne stade III ou IV.

The prognostic value of CA 125 initial half-life in serum (Tb) during the first cycles of first-line chemotherapy was studied in 62 patients with stage III or IV ovarian cancer. The half-life was strongly correlated; 1) with the rate of biological remission (P < 0.001). This one was respectively equal to 94.7% when Tb was lower than 20 days, 66.6% when Tb was between 20 and 40 days and 7.7% when Tb was higher than 40 days; 2) with the rate of histological remission (P < 0.001) which was equal to 66.6% when Tb was lower than 13 days; 3) with the speed of recurrence growth measured by the doubling time (dT) of CA 125. The median of dT was equal to 182 days when Tb was lower than 13 days, 63 days when Tb was between 13 and 20 days (P < 0.02) and 38 days when Tb was higher than 20 days (P < 0.001); 4) with the duration of disease-free survival (DFS) (P < 0.001): the medians were equal to 23.9 months, 18.0 months, 12.0 months, and 5.5 months, respectively, when Tb was lower than 13 days, between 13 and 20 days; 20 and 40 days, and higher than 40 days; and 5) with the duration of overall survival (OS). The probability of survival at five years was equal to 48% when Tb was lower than 13 days. This probability falled to 13%, 12%, and 8%, when Tb was respectively between 13 and 20 days, 20 and 40 days and higher than 40 days. Multiple regression analysis showed that CA 125 half-life was the most important prognostic factor for DFS and OS. Analysis of correlation allowed to identify a relation between: 1) dT and Tb [dT = Tb/[-0.305 + (0.0388)(Tb)]; P < 10(-4)]; 2) the slope of CA 125 initial regression (P) and DFS [DFS = 201.9e (-16.64*P); P < 10(-8)]; 3) P and OS [OS = 285.0e(-17.00*P); P < 10(-7)]. The initial CA 125 half-life measured during the first cycles of first time chemotherapy seemed to be a critical predictor of response to therapy.

[Neoadjuvant chemotherapy FEC-HD in locally advanced breast cancer]. / Chimiothérapie néoadjuvant FEC-HD dans le cancer du sein localement évolué.

The tolerance and the clinical and histological efficacy of a neoadjuvant chemotherapy FEC-HD including hematopoietic growth factors have been studied in 40 patients with stade II or III breast cancer between February 1991 and February 1997. Four courses were given, every 21 days, with 5-fluorouracil (750 mg/m2/day D1 to D4 by continuous infusion), epirubicin (35 mg/m2/day D2 to D4) and cyclophosphamide (400 mg/m2/day D2 to D4) with G-CSF (5 mug/kg/day D6 to D15). The surgery was performed 3 or 4 weeks after the end of the chemotherapy. All patients had radiotherapy. The neoadjuvant chemotherapy induced 37.5% CR, 45% PR, and 15% SD. In 40% of the patients, the surgery was conservative. An histological CR was obtained in 15% with no axillary involvement one time out of two. There was intraductal carcinoma without invasive carcinoma in 7.5%. There was no differences between the response of inflammatory and non inflammatory tumors. One hundred and fifty-eight courses have been delivered. A grade 3 or 4 leuconeutropenia, anemia and thrombopenia have been observed in respectively 34.6%, 6.3% and 8.8% of the courses. A grade 3 or 4 mucositis has been noticed in 2.5% of the courses. A febrile granulocytopenia has occurred in 3.8% of the courses. The median survival without metastatic progression was 48 months and the median overall survival was not achieved. In stade II and III breast cancer, neoadjuvant chemotherapy with FEC-HD obtains an important histological response with an acceptable toxicity. The role of the dose-intensity increase on survival remains to be determined.

[Randomized trial of vincristin-methotrexate-bleomycin and cis-platin or detorubicin for advanced head and neck cancer (author's transl)]. / Etude randomisée d'une association de vincristine-méthrotréxate-bléomycine et cis-plastine ou détorubicine dans les cancers avancés des voies aérodigestives supérierures et de l'oesophage.

In a randomized multicenter trial, 151 patients, with advanced epidermoid carcinoma of the head, neck and oesophagus, were treated with an association of vincristin, methotrexate, bleomycin and cis-platin (group I) or detorubicin (group II). Prognostic factors were equally distributed for the both groups. Partial or complete responses were obtained in 22 patients of group I (29 p. cent) and 9 in group II (12 p. cent, p less than 0.05). Objective response rates were higher in untreated patients or those in good condition but the difference was not statistically significant. Five probably treatment induced deaths (3 p. cent) were observed. Treatment was stopped in 2 patients (15 p. cent) for haematological, general or digestive toxicity. This trial confirms the efficacy of vincristin, methotrexate, bleomycin and cis-platin for advanced head and neck carcinomas.

[Cancer of the prostate. Epidemiologic evaluation, incidence, and trends, especially in France]. / Cancer de la prostate. Bilan épidémiologique, fréquence, tendance, en particulier en France.

With 7,172 deaths in 1982, prostatic cancer is a frequent cancer in France observed among old men, coming just after the lungs cancers and representing 9.6% of male mortality from malignant disease. Its incidence in the French regional population based on departmental registries is about 25/100.000 (age adjusted to the world standard population). The geographical distribution throughout the world shows a high incidence rate among the black american, the Scandinavian countries and low rates in the south-east of Asia. As well as incidence as for mortality low trends of increase all over the world are observed. In the clinical data from the "Enquete Permanente Cancer" (E.P.C.) the high proportion of metastatic dissemination (48%) at initial time of diagnosis, and also the high proportion of epithelial cancer (92%) emerge from a series of 1,223 prostatic cancer registered between 1975 and 1982. The 9 year-survival relative rate (32%) for the whole group lets appear a level of cure observed after the 8 years of follow-up. Few risk factors have been yet recognized so that it is not easy to identify risk population and propose them any preventions.

[Feasability of the dose adjustment of continuous infusion administration over 120 hours of 5-fluorouracil associated with cisplatin]. / Faisabilité de l'adaptation de la posologie du 5-fluorouracile administré en perfusion continue de 120 heures associé au cisplatine.

Therapeutic monitoring of 120 hours continuous 5-fluorouracil associated with cisplatin. For 31 patients treated by continuous 5-fluorouracil with cisplatin, a therapeutic monitoring of 5-fluorouracil is performed, based on the 48 first hours area under the curve (AUC) and the total AUC. The 5-fluorouracile taylorization allows to reduce some toxicity's while preserving an efficiency (objective responses 42%). Many patients are considered with potentially low 5-fluorouracile clearance. Dose reductions of 5-fluorouracile are frequent, reach 50% during the third cure and allow the achievement of targeted AUC. The role of cisplatin in this necessary reduction of dose is unknown.

[Clinical value of the estimation of growth kinetics of primary ovarian cancer recurrences by CA125 doubling time]. / Intérêt clinique de l'estimation de la vitesse de croissance des récidives ovariennes premières par le temps de doublement du CA125.

The aim of this retrospective work was to study the clinical importance of growth rate determination for ovarian cancer primary recurrence in term of CA125 doubling time (dt). Fifty-one patients with epithelial ovarian carcinoma stage III or IV who developed a recurrence were included. Eighteen spontaneous dt values were calculated in non-treated patients during follow-up and 33 apparent dt values were estimated in patients undergoing treatment during CA125 increase before the clinical and/or radiological diagnosis of recurrence. No early treatment of the recurrence has permitted a drop in CA125 level. We applied exponential regression models to CA125 individual kinetics in order to calculate dt values. Individual dt values vary from 5 to 375 days. Spontaneous and apparent dt medianes (respectively 64 and 39 days) are not significantly different. Among all early clinical, histological, biological and therapeutic parameters, the initial CA125 half-life calculated during the third courses of the first-line chemotherapy is the unique predictive parameter of dt (relative risk (RR) = 78; p < 0.01). The prognostic impact was more important in spontaneous dt values than in apparent ones. Being spontaneous or apparent dt was the major predictive parameter of the delay between the initial CA125 increase and clinical and/or radiological signs of recurrence (RR = 0.3; p < 0.0001). Its prognostic impact is superior to the T1/2 one (RR = 2.9; p = 0.0010). For equivalent treatments, dt (RR = 0.4; p < 0.0001) and T1/2 (RR = 4.0; p < 0.0001) are the only predictive parameters of the survival after CA125 increase. This work shows that dt was an essential predictive parameter of ovarian epithelial tumor recurrences.

[Polychemotherapy of advanced breast cancer. Triple combination with doxorubicin. Analysis of 209 observation]. / Polychimiothérapie des cancers mammaires en phase avancée. Association ternaire avec doxorubicine. Analyse de 209 observations.

Two hundred and nine patients with breast cancer in an advanced stage were treated according to a chemotherapeutic regimen associating doxorubicin, vincristine and methotrexate, administered in courses of 5 days every three weeks. This analysis deals only with the short range results; they confirm those of a previous randomized study. A global objective response was obtained in 187 cases (89%) and a measurable regression of the lesions in 150 cases (71%); in these later cases 90 (43%) had a regression of more than 50 per cent. The most striking effects, often rapidly observed, involve sites which are not generally sensitive: liver (40%), pleura (24%) and bone (only 6%, but 8 times out of 10 a definite action on the pain syndrome). Side effects were, on the whole, acceptable (only one severe hematologic complication); however, the risk of myocardiac toxocity due to the accumulation of doxorubicin limits the utilization of this association. It thus needs to be relayed by other drug regimens which are included in a program of long term action, but has interesting characteristics as induction chemotherapy.