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Resume Objectifs Environ 5 % des cancers du sein sont lies a une predisposition hereditaire, les genes de susceptibilite les plus connus etant BRCA1 et BRCA2. Recemment, de nouveaux genes de susceptibilite, dont PALB2, ont ete identifies. Les risques de cancer du sein lies a une mutation deletere de PALB2, l’âge de survenue de ces cancers, leur pronostic et les cancers associes faisaient jusqu’a present l’objet de controverses. L’objectif de notre mise au point etait de clarifier ces differentes interrogations a partir d’une revue actualisee de la litterature. Methodes Une recherche sur PUBMED a ete effectuee en combinant les mots cles « breast cancer » et « PALB2 ». Les etudes publiees entre janvier 2008 et decembre 2017 ont ete retenues. Resultats Les femmes porteuses d’une mutation PALB2 ont un risque superieur a la population generale de developper un cancer du sein. Le risque relatif est important, variant selon les differentes etudes entre 3,4 (IC 95 % : 2,4–5,9) et 9,47 (IC 95 % : 5,72–14,39). Ces resultats sont a nuancer en fonction des differentes mutations et des facteurs geographiques. A l’heure actuelle, il n’existe pas de lien etabli entre une mutation PALB2 et la survenue d’un cancer de l’ovaire ou du pancreas. Conclusion PALB2 doit etre considere comme un gene de susceptibilite elevee dans le developpement du cancer du sein. Il est associe a un risque plus eleve de cancer triple negatif et a un pronostic plus sombre.

Tumor characteristics are used today to evaluate the possibility of mutation and to target mutation screening in families with high risk of breast and/or ovarian cancer. We studied the breast tumor profile associated to the c.3481_3491del11 French founder effect mutation on the BRCA1 gene to an attempt to identify any particularity or difference when comparing it to that related to other BRCA1 mutations. Within the population who were referred to our oncogenetic clinic at the Lorraine Oncology Institute in France and who underwent genetic testing between 1994 and 2012, we identified 404 women carrying a BRCA1 mutation. Interestingly, 45% (180/404) women had the germline c.3481_3491del11 mutation. These included 91 patients affected by first breast cancer. Clinical and pathologic data were retrieved from medical files. Descriptive statistics were conducted using the SPSS software (version 20.0). For the entire cohort of 91 women, the mean age was 43.64 years (SD 10.04). Tumors were identified in 37.4% of cases aged < 40 years. Estrogen receptor status and progesterone receptor status were reported to 67 patients. Seventy-four percent were ER negative. Hormonal receptors status was negative in 68.6% of tumors. HER2 status was available for 32 tumors. The triple-negative subtype was found in 21 cases, which accounts for 65.6% of the patients. High tumor grade was found in 81% of triple negative breast cancer patients. Based on our results compared to those of previous international studies, we concluded that the breast cancer associated to the c.3481_3491del11 is not different from that associated to other BRCA1 mutations. A larger cohort with complete information on the breast cancer pathologic characteristics and including other BRCA1 mutations would allow us to statistically compare the breast tumor profile associated to the c.3481_3491del11 to that related to other BRCA1 mutations.

Summary Background In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events. Methods PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901. Findings 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3–8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93–1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group. Interpretation The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months. Funding The French National Cancer Institute.

The aim of the current analysis is to evaluate any differences of breast or ovarian cancer age at diagnosis between mothers and daughters carrying the c.3481_3491del11 mutation in the BRCA1 gene. A study cohort of 38 women carrying the c.3481_3491del11 mutation and affected by first breast or ovarian cancer who reported a first breast or ovarian cancer in their mother carrying the c.3481_3491del11 mutation, was identified in 37 different families including members with breast and/or ovarian cancer at the Oncology Institute of Lorraine. Twelve mothers underwent genetic testing. Twenty-five pairs of the 38 mothers-daughters pairs with c.3481_3491del11 mutation were affected by breast cancer and 13 pairs by ovarian cancer. Clinical and genetic data were collected from medical files and family pedigrees. Analyses were conducted for each cancer type. We investigated an early breast cancer detection effect due to early screening programs and also an increased breast tumor aggression. Since major improvements in breast cancer clinical management and imaging techniques appeared after 1980, we compared the age at breast cancer diagnosis and the age at death in mothers and daughters before and after 1980, first, in the group of women including mothers and daughters taken together and then in mothers and daughters separately. The mean age at breast cancer diagnosis was 45.28 ± 10.27 years in mothers and 39.80 ± 7.79 years in daughters (p = 0.026). The difference of age at ovarian cancer diagnosis in mother-daughter pairs was 8.62 ± 12.76 years (p = 0.032). When considering the group of women including mothers and daughters taken together, no significant difference of age at breast cancer diagnosis was found between women affected before 1980 and those affected after 1980 (p = 0.577). However, the age at death increased in these women after 1980 (p = 0.026). Comparison of age at breast cancer diagnosis in mothers and daughters separately, showed that daughters were affected at an earlier age after 1980 (p = 0.002). Daughters had a poor prognosis and died earlier than mothers after 1980. Our results may have reflected genetic anticipation in c.3481_3491del11 mutation breast and ovarian cancer families. In order to confirm our findings, a larger cohort would provide more precision to the difference of ages at breast or ovarian cancer diagnosis between mothers and daughters and more powerful statistical analyses. Increased aggression in daughters’ tumors compared to those of mothers could be also considered as a parameter of genetic anticipation. Complete information on tumor profile and proliferation would allow us to study genetic anticipation by comparing the tumor phenotypes between mothers and daughters in the future.

Purpose: This study assessed the relation between age, family history (breast and/or ovarian cancer) and BRCA1 and BRCA2 mutations prevalence in a cohort of patients with triple-negative breast cancer (BC). Methods: We identified in our database 218 patients (pts) with triple negative (TN) breast carcinoma (defined as We compared this cohort to 498 pts with a family history of breast cancer (non triple-negative tumors) and/or ovarian cancer that were also screened for BRCA1/2 mutations. Results: In the TN cohort, 146 tests were realized, 72 are still on going. We identified 31 deleterious mutations (21.2%) in BRCA1 and 3 (2.1%) in BRCA2. In 100 cases (68.5%), we found no BRCA mutations and in 13 cases, we found Variants of Unknown Signification (VUS) (8.9%) (5 (3.4%) in BRCA1 and 8 (5.5%) in BRCA2). Concerning family history, 74 pts belonged to families with a history of breast cancer only, 3 pts to families with ovarian cancer only and 10 pts to families with both breast and ovarian cancer. Fifty nine pts were screened on the basis of a TN tumor at age ≤ 50 years old with no other family history of breast or ovarian cancer. The mean age at first diagnosis for all the TN cohort tested is 45.4 ± 10.2 (min 26 - max 76). The mean age of patients for whom a mutation was identified is : 40.6 ± 8.7 for BRCA1 (min 29 - max 69), 45.7 ± 8.5 for BRCA2 (min 37 - max 54). The mean age of patients for whom no BRCA mutation was identified is 46.8 ±10.2 (min 26 - max 76). All patients studied were symptomatic. In the “control cohort”, we identified 26 deleterious mutations (5.2%) in BRCA1 and 28 (5.6%) in BRCA2. In 408 cases (81.9%), we found no BRCA mutations and in 36 cases, we found Variants of Unknown Signification (VUS) (7.2%) (8 (1.6%) in BRCA1 and 28 (5.6%) in BRCA2). We have in our region (Lorraine), a recurrent BRCA1 mutation with founder-effect (c.3481_3491del11 p.Glu1161Phe), the prevalence of which we evaluated in both cohorts. Conclusions: Among the TN cohort, mean age for BRCA1 mutation is lower than for BRCA2 (40.6 ± 8.7 vs 45.7 ± 8.5, non-significant results). By comparing BRCA mutation frequency between the 2 cohorts, we could conclude that: - BRCA mutations are more frequent in the TN cohort : 23.3% vs 10.8% (p = 0.035) - Among these, there are more BRCA1 mutations in the TN cohort : 21.2% vs 5.2% and less BRCA2 mutations : 2.1% vs 5.6% (p = 0.02) Moreover, according to our preliminary results, this particular mutation seems to be more represented among the mutations of the TN cohort (3.5 folds) but we still have to test its impact concerning TN tumors. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-12-02.

Background The upfront addition of trastuzumab (Herceptin, H) to anthracycline/taxane-based primary chemotherapy significantly increases pathological complete response (pCR) in HER2−positive breast cancer (BC) patients (pts). However, concerns about the cardiac toxicity of concurrent administration of H and standard anthracyclines limited its use (Seidman et al 2002, J Clin Oncol 20:1215–21). MYOCET® (M) has a better cardiac tolerance profile than standard doxorubicin (Adriamycine, A) and might allow to give anthracyclines safely in combination with H. We explored the added benefit of early and longitudinal exposure to the combination of M with H in early-stage HER2−positive BC in a phase II multicentric randomized trial. Methods: Women with stage II or IIIA HER2−positive BC were randomized to receive 4 cycles of either M + cyclophosphamide (C) + H (MCH) or AC every 3 weeks (q3w); then followed by 4 cycles of docetaxel + H (q3w). The primary endpoint was the pCR rate. Secondary endpoints included the overall and cardiac safety (using left ventricular ejection fraction [LVEF] and NYHA classification). Results: Since September 2008, 126 pts with a median age of 51 and stage II (85 pts) or III (39 pts) BC were randomized: 1 pt did not initiate treatment, 12 discontinued treatment prematurely, 21 were still receiving treatment, 91 had completed treatment and 90 underwent surgery, as of January 15th 2011. Pathological responses are under central review. In the MCH arm, 1 pt reported a NYHA class II cardiac event and 1 pt had asymptomatic LVEF decrease down to 42%. In the AC arm, 2 pts experienced NYHA class II events, 1 pt had LVEF value 17% below baseline, and 1 patient had LVEF value 6% below the lower normal limit. Mean (±SD) LVEF decrease from baseline to endpoint was 0.8% (±6.3) in the MCH arm and 3.8% (±5.8) in the AC arm. Patients tended to report more grade 3 gastrointestinal (GI) adverse event in the MCH arm (8.1% of pts) than in the AC arm (4.8% of pts), mainly diarrhea (6.5% of pts in the MCH arm vs 1.6% in the AC arm). Other grade 3 GI toxicities were infrequent. Hematological toxicity was similar in both arms: 56.4% and 61.9% of pts developed grade 3/4 neutropenia, and 16.1% and 14.3% of pts reported febrile neutropenia, in the MCH and AC arms respectively. No severe case of palmar-plantar erythrodysaestheia syndrome was reported. Conclusion: The concurrent administration of the non-pegylated liposomal doxorubicin MYOCET® and H has an acceptable early safety profile that should be confirmed with longer follow-up. Pathological response data are pending and will be presented at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-13.

Background Elderly metastatic cancer patients typically have short life expectancy and frequently suboptimal treatment. Goals of therapy should include preservation of functional status as well as clinical response. For elderly patients, oral chemotherapy could be a valuable strategy, avoiding the constraints and risks of intravenous drugs. Methods This study assessed effect of an all-oral combination of capecitabine and vinorelbine on functional status (measured by basic Activities of Daily Living [ADL]), toxicity, efficacy and compliance in patients ≥70 years with advanced breast, prostate or lung cancer. Results Eighty patients were enrolled. After three cycles, 81.8% of patients had stabilised or improved ADL, and 8.6% and 42.9% had a response or stabilised disease. Compliance was excellent (68.8%). The most common grade 3–4 toxicities were haematological (17.9%) and gastrointestinal (7.7%). Conclusion In elderly cancer patients, an all-oral combination of capecitabine and vinorelbine maintains functional status, is well tolerated, and provides good disease control.

Le champ des biomarqueurs est vaste, de la prevention au traitement en passant par la detection des populations cibles. Il est tres frequemment associe au concept de medecine personnalisee regroupant la theranostique et la recherche de test compagnon [1]. C’est actuellement un sujet qui suscite un interet majeur et une curiosite au sein de l’ensemble de la communaute medicale et de l’industrie pharmaceutique. Le concept de biomarqueur n’est pas nouveau, leur utilisation dans le domaine de la Recherche et Developpement du medicament et du diagnostic date de plusieurs dizaines d’annees. Ce sont l’apparition des nouvelles technologies permettant d’etendre les possibilites d’analyse comme la genomique, la proteomique et la metabolomique, combinees avec le developpement des automates et de systemes biologiques integres et l’amelioration de la sensibilite analytique, au cours des dix dernieres annees, qui ont conduit a une acceleration du taux de decouverte de biomarqueurs et une amelioration majeure de la qualite et de l’utilite de ces marqueurs.

Background Studies have found that reproductive factors might have a variable effect on the occurrence of breast cancer (BC) according to the existence or not of a family history of BC. The effect of a family history of BC on the risk of BC may also vary according to the age at diagnosis and the degree of kinship. This may confound the relation between familial risk and reproductive factors. A combined analysis was performed to study the interaction between familial risk and reproductive factors according to degree of familiality, age at interview and menopausal status. Methods The present analysis included 2948 cases and 4170 controls in seven case-control studies from four countries. The combined relative risks were estimated using a Bayesian random-effects logistic regression model. Results The main effects of reproductive life factors on the risk of BC are in agreement with previous studies. Two-way interactions between subject's age or menopausal status and a family history of BC were not significant. Although the three-way interaction between age, familial risk and parity was not significant, familial risk seemed to be increased slightly for women with high parity compared with women with low parity in the older age group, and seemed to be slightly decreased for women with high parity compared with women with low parity in younger women. The subject's age also appeared to have an effect on the interaction between familial risk and the age at first childbirth (P = 0.1). Conclusions A possible influence of reproductive and menstrual factors on familial risk of BC has been suggested previously and was also evident in the present study. Three-way interactions between age, family history and parity or age at first childbirth might exist and they merit further investigation.

In this paper, a combined analysis was performed to study the interaction between familial risk and reproductive life factors. In particular, the interaction between familial risk and breast cell mitotic activity (BCMA), as assessed by duration of ovarian activity, was investigated because of the potential importance of mitotic activity on genetically susceptible cells. The present analysis included 3152 cases and 4404 controls in seven case-control studies from four countries. The interaction effect was estimated in each study separately, then combined using two different methods: a multivariate weighted average and a Bayesian random-effects model. The main effects of reproductive life factors on the risk of breast cancer were in agreement with the previous findings. In particular, an increased duration of BCMA before the first childbirth and over life was found to increase the risk of breast cancer (P < 0.001). Slightly increasing but non-significant, familial risks were observed with increasing number of children (P = 0.17), increasing age at first childbirth (P > 0.2) and increasing duration of BCMA (P > 0.2). There was no modification in familial risk with age at menarche and no clear pattern with menopause characteristics. A weak influence of reproductive and menstrual factors on the familial risk emerged from the present study.

Our study focuses on a series of 1344 cases of carcinoma of the oral cavity and oropharynx treated between 1973 and 1992. Brachytherapy was always performed with iridium 192, either alone or in combination with external-beam irradiation or with surgery for the treatment of the primary tumor. For the oral cavity, we studied 565 cases of mobile tongue. The local control and overall survival rates, respectively, at 5 years are as follows: for T1, 92% and 70%; for T2, 62% and 42%; and for T3, 50% and 29%. For the subgroup T1T2NO, there was a better prognosis for treatment by brachytherapy of the primary lesion alone (p < 0.0001). Two hundred seven cases of floor-of-mouth carcinoma have been reported. The T3T4 patients were not considered surgical candidates. The local control and overall survival rates, respectively, at 5 years are as follows: for T1, 97% and 71%; for T2 72% and 42%; and for T3, 51% and 35%. Ninety-seven patients were treated by postoperative brachytherapy. These were patients for whom the margins after surgery were positive or narrow. A technique termed the modified bridge is described for lesions located in the mandible. Carcinomas of the buccal mucosa are rare in our country; only 42 cases were treated in this comparison of two techniques, and the overall survival rate was 48%. Epidermoid carcinomas of the oropharynx have nearly always been treated by a combination of external-beam irradiation and brachytherapy because of the bilateral node risk. Seventy-two patients with epidermoid cancers of the base of the tongue had an overall survival rate of 44%. The tonsil, soft palate, and pillars benefited from the use of the loop technique of brachytherapy combined with external-beam irradiation. Three hundred sixty-one patients were treated. Among these patients were two groups with different prognoses. Patients with tonsil, soft palate, and posterior pillar carcinomas had a local control rate of 84% and an overall survival rate of 57%. Conversely, the anterior pillar and the pharyngoglossal sulcus have a local control rate of only 65% and an overall survival rate of 38%. Statistical analysis revealed the prognostic factors for local control. The complications were classified into four grades: minor (20%), moderate (9%), major (4%), or inducing death (0.2%). The bone complications of grade 2 or 3 are more frequent for the floor of the mouth than for other locations.

La decision medicale, en particulier en cancerologie, est de plus en plus assistee par des referentiels s’appuyant sur des classifications, des thesaurus, des avis d’experts et des recommandations. Les informations qu’ils contiennent guident les RCP. Elles peuvent aussi etre vehiculees par des sites en ligne.

Un constat s’impose : il n’y a pas de standard en premiere ligne metastatique et il faut recourir a des accords d’experts. En deuxieme et troisieme lignes metastatiques, il n’est pas possible de faire des accords d’experts. Nos choix therapeutiques sont le plus souvent empiriques. Les resultats des essais existent mais sont souvent mal connus ou mal utilises.

L’analyse faite pour les facteurs UPA PA1 est exemplaire et doit faire partie d’un travail plus general de classification et d’evaluation standardisee de tous les facteurs biologiques proposes a ce jour. Ceci permettant de passer d’etudes retrospectives, qui ont un interet essentiel dans la connaissance et les publications de travaux, a une utilisation clinique prospective dans des essais cliniques randomises dont le marqueur biologique serait l’objectif principal. Cette demarche permettra de repondre aux questions cliniques de pronostic, de ciblage et de reponse therapeutique. Enfin, tout nouveau marqueur propose devra etre evalue de facon prospective par rapport a l’ensemble des parametres classes en LOE I et UC+++ pour evaluer la complementarite, la redondance ou la facilite d’utilisation.

Le travail de recommandations pour la pratique clinique de Saint-Paul-de-Vence 2007 presente deux volets: d’une part une mise a jour du texte de 2005 et d’autres part la redaction de textes sur de nouvelles questions cliniques.

Le pronostic du cancer du sein metastatique reste un probleme majeur pour l’oncologue ; depuis ces sept dernieres annees, les progres therapeutiques, du fait des nouveaux traitements mais aussi de l’evaluation de nouvelles strategies, montrent une amelioration significative de la survie. De plus, les soins de support et la prise en charge psychologique ont modifie considerablement le contexte de cette maladie. La meilleure connaissance des facteurs biologiques est une donnee capitale pour les donnees a venir et devrait permettre de selectionner les populations dans le cadre des essais cliniques.

After a dominant role for more than 30 years, tamoxifen has been progressively replaced by aromatase inhibitors as adjuvant treatment for breast cancer in the menopaused woman. We present here a recall of the mechanisms of action involved together with a review of clinical trials leading to the current situation. Giving trial results in detail, we discuss the current evidence as well as open questions. The populations concerned and trial methodologies are analyzed. Comparative tolerance is detailed. Several questions remain open, either due to the lack of evidence to be obtained from ongoing trials or sufficient follow-up. The evidence presented is commented in light of the American (ASCO) and European (Saint-Gallen) or French (Saint-Paul) guidelines.

La chimiotherapie postoperatoire adjuvante est le standard pour le traitement du cancer du sein a un stade precoce depuis plus de 10 ans. Commencer par un traitement neo–adjuvant en preoperatoire (chimiotherapie premiere ou chimiotherapie d’induction) est toujours le standard pour les tumeurs inflammatoires et les tumeurs localement avancees inoperables. Cette approche a ete etendue aux tumeurs du sein operable pour lesquelles la mammectomie etait la seule option therapeutique et ceci dans le but de conservation mammaire. Ce modele de chimiotherapie neo–adjuvante est devenu le modele in vivo le plus approprie pour evaluer la reponse therapeutique et cette approche therapeutique est d’autant plus interessante du fait des developpements actuels de la biologie moleculaire en particulier de la genomique et de la proteomique. Cette strategie therapeutique est interessante pour evaluer les nouveaux traitements, d’autant que la plupart des patientes ont une chimiotherapie en adjuvant. La reponse histologique est importante a evaluer mais egalement les futurs essais therapeutiques ou deja en cours devraient permettre de trouver de nouveaux marqueurs de reponse intermediaire permettant de predire la reponse therapeutique. Cette approche therapeutique est logique compte tenu que 4 essais avec un recul suffisant ont montre que realiser une chimiotherapie avant chirurgie ou apres chirurgie ne modifiait en rien ni la survie sans recidive ni la survie globale. Cet article fait le point sur les essais de chimiotherapie neo–adjuvante dans le cancer du sein operable d’emblee et aborde les problemes methodologiques, lies aux essais de phase II (comparaison non possible entre 2 traitements, difficultes de faire une mise en face a face d’etudes compte tenu des classifications anatomopathologiques differentes) et les difficultes de mener des essais de phase III en neo–adjuvant, du fait du nombre de protocoles associant des drogues qui ont fait la preuve d’une efficacite dans le cancer du sein.

The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of french cancer centers (FNCLCC), the 20 french cancer centers, and specialists from french public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery.To develop clinical practice guidelines for non metastatic breast cancer patients according to the definitions of the Standards, Options and Recommendations project.Data were identified by searching Medline, web sites, and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 148 independent reviewers.This article presents the chapter radiotherapy resulting from the 2001 update of the version first published in 1996. The modified 2001 version of the standards, options and recommendations takes into account new information published. The main recommendations are: (1) Breast irradiation after conservative surgery significantly decrease the risk of local recurrence (level of evidence A) and the decrease in the risk of local recidive after chest wall irradiation is greater as the number of risk factors for local recurrence increases (level of evidence A). (2) After conservative surgery, a whole breast irradiation should be performed at a minimum dose of 50 Gy in 25 fractions (standard, level of evidence A). (3) A boost in the tumour bed should be performed in women under 50 years, even if the surgical margins are free (standard, level of evidence B). (4) Internal mammary chain irradiation is indicated for internal or central tumours in the absence of axillary lymph node involvement (expert agreement) and in the presence of lymph node involvement (standard, level of evidence B1). (5) Sub- and supra-claviculr lymph node irradiation is indicated in patients with axillary node involvement (standard, level of evidence B1).

To study the safety of conformal radiotherapy dose escalation up to 80 Gy for curative treatment of prostate cancer.A multicentre trial sponsored by the PHRC include 164 patients under the age of 75 years with stage T1b-T3 N0 M0 prostatic adenocarcinoma, between 1995 and 1998. The prostate was treated at 5 dose levels: 18 patients at 66 Gy, 28 at 70 Gy, 49 at 74 Gy, 48 at 78 Gy, 21 at 80 Gy. The acute and delayed toxicity was graded according to a multidisciplinary glossary. Quality of life was evaluated before and one year after treatment using the EORTC QLQ-C30 questionnaire and additional questions.89% and 55% of mild or moderate gastrointestinal and urinary adverse effects were observed during treatment, respectively. At long-term follow-up, of the 162 evaluable patients, 12.3% presented grade 2 adverse effects and 2.5% presented grade 3 adverse effects (1 case of haematuria, 2 urethral strictures, 1 bladder neck lesion) with no significant difference between the various dose levels. Two successive quality of life questionnaires were available for 119 patients: tiredness, pain and dyspnoea increased in parallel, but non-significantly in the groups receiving conventional doses or high doses. The proportion of patients reporting sexual activity without endocrine therapy decreased from 48% before treatment to 35% one year later. The proportion of patients with no clinical or laboratory signs of progression was higher in the high-dose group.No significant difference was observed between conventional dose levels and high dose levels in terms of toxicity or quality of life. As the adverse effects were acceptable, a randomized trial comparing 70 Gy and 80 Gy has been initiated.

The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature systematic review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery.To develop clinical practice guidelines according to the definitions of Standards, Options and Recommendations for endocrine therapy in patients with non metastatic breast cancer.Data have been identified by literature search using Medline, Embase, Cancerlit and Cochrane databases - until july 1999 - and the personal reference lists of the expert group. Once the guidelines were defined, the document was submitted for review to 125 independent reviewers.The main recommendations for the endocrine therapy of patients with non metastatic breast cancer are: 1) Endocrine therapy modalities depend on menopausal status or age of women: ovarian suppression for premenopausal women, antiestrogen drug therapy for postmenopausal women (standard). 2) Tamoxifen (20 mg/d - 5 years) is beneficial to women with positive estrogen receptor tumor (standard, level of evidence A). There is no indication of tamoxifen treatment for women with negative estrogen receptor tumor (standard, level of evidence A). 3) For postmenopausal women with positive estrogen receptor tumor, tamoxifen is the standard adjuvant treatment (level of evidence A). For postmenopausal women with negative estrogen receptor, adjuvant chemotherapy has to be considered (option, level of evidence A). No adjuvant treatment has to be considered for women with poor health condition (option). 4) For premenopausal women with estrogen receptor tumor, results of clinical trials of chemotherapy versus endocrine therapy, suggest a benefit for endocrine therapy. However, there is no sufficient evidence to consider endocrine therapy alone as a standard adjuvant treatment. 5) For premenopausal women, chemotherapy + ovarian suppression or chemotherapy + tamoxifen are not better than chemotherapy alone (level of evidence A). 6) For postmenopausal women, administration of chemotherapy plus adjuvant tamoxifen versus the same tamoxifen alone, is of additional benefit in reducing recurrences but not in prolonging overall survival (standard, level of evidence A). 7) Balance of known benefits (delay to recurrence and death) and risks (side-effects of therapy) for adjuvant chemoendocrine therapy has to be taken into consideration before decision making. Chemoendocrine therapy can be indicated for women at high risk of developing metastatic disease (recommendation, experts agreement).

Medical decision making, especially in oncology, is more and more assisted by pre-established therapeutic protocols. But applying these protocols for particular cases is sometimes difficult; then, local expertise intervenes. For solving these difficult cases, Alexis-Vautrin like other centers, organizes committees for therapeutic decisions. This paper aims to describe, from a field study, the tools for medical decision making and the difficulties of using them. These result of the analysis of decision committee for breast cancers in a center using of protocols, which the first were established twenty years ago. This analysis was carried out by a team of oncologists and ergonomists; it stresses on collective decision making as a mean for adapting rules and exchanging knowledge. Furthermore, these findings lead to discuss using of decision committee for advancement and particularization of protocols themselves.

Surgery is the primary treatment for endometrial carcinoma. Methods of complementary treatment are still debated, with the potential association of external radiotherapy and/or brachytherapy before or after surgery. This study was aimed at evaluating local control and complications rates in a series of patients treated by hysterectomy followed by postoperative vaginal low-dose rate brachytherapy (BT) combined with pelvic irradiation in case of poor prognosis factors.From 1978 to 1993, 101 patients were treated at the Centre Alexis-Vautrin, France according to this scheme. Forty five had deep myometrial invasion, and thirteen cervical involvement. Fifty patients received pelvic irradiation (median dose 46 Gy) combined with BT (dose 14 Gy, median volume 127 cm3); 51 patients had BT alone (dose 60 Gy, median volume 71 cm3).The 5-year overall survival rate was 83% and the local control rate 97% with a median follow-up of 7 years. Multivariate analysis showed two factors of bad prognosis, i.e., deep myometrial invasion and cervical involvement. Three severe complications occurred in two patients for whom the treated volume was larger than the theoretical target volume. Eleven patients developed metastases.Results obtained from this series are comparable with those of previous studies, particularly in regard to pre-operative BT. The complication rate is also satisfactory and depends on the irradiation precision and the definition of the target volume.

From 1975 to 1996, 98 patients with infiltrative vesical carcinomas were treated at the Centre Alexis Vautrin by conservative surgery and interstitial brachytherapy (192lr). The mean follow-up was about eight years. From this retrospective non randomized study, we tried to determine the tolerance to this treatment.There were 86 men and 12 women. The mean age was 63 years. We found three pTis tumors, 28 stage pT1 tumors, 38 stage pT2 tumors, 24 stage pT3A tumors, four stage pT3B tumors and one stage Tx tumors. The therapeutic scheme consisted of pelvic radiation therapy (3 fractions of 3,5 Gy) immediately followed by lymphadenectomy (for stage pT3 tumors) and by cystotomy or partial cystectomy during which we inserted brachytherapy plastic tubes. The delivered dose was 50 Gy for superficially infiltrative tumors and 30 Gy for deeply infiltrative tumors; at the lowest dose, the treatment ended with external beam irradiation.At 5 years the control rate was 72%, the specific survival 80% and the global survival 71%. Twenty-nine patients had a local recurrence. Of these, seven underwent total cystectomy. Thirty-seven patients developed 43 complications; 35 were intravesical, 10 (28%) were estimated to be higher than grade 2 because of technical problems that led us to modify the technique.It is essential to develop close collaboration between surgeons and brachytherapists, to select patients and to use a rigorous technique. Interstitial brachytherapy for infiltrative vesical carcinomas thus yields both high local control and satisfying results in regard to patient's well-being.

Since tamoxifen is widely used in breast cancer treatment and has been proposed for the prevention of breast cancer, its endometrial iatrogenic effects must be carefully examined. We have investigated the association between endometrial cancer and tamoxifen use or other treatments in women treated for breast cancer in a case-control study. Cases of endometrial cancer diagnosed after breast cancer (n = 135) and 467 controls matched for age, year of diagnosis of breast cancer and hospital and survival time with an intact uterus were included. Women who had received tamoxifen were significantly more likely to have endometrial cancer diagnosed than those who had not (crude relative risk = 4.9, p = 0.0001). Univariate and adjusted analyses showed that the risk increased with the length of treatment (p = 0.0001) or the cumulative dose of tamoxifen received (p = 0.0001), irrespective of the daily dose. Women who had undergone pelvic radiotherapy also had a higher risk (crude relative risk = 7.8, p = 0.0001). After adjusting for confounding factors, the risk was higher for tamoxifen users (p = 0.0012), treatment for more than 3 years (all p0.03) and pelvic radiotherapy (p = 0.012). Women who had endometrial cancer and had received tamoxifen had more advanced disease and poorer prognosis than those with endometrial cancer who had not received this treatment. Our results suggest a causal role of tamoxifen in endometrial cancer, particularly when used as currently proposed for breast cancer prevention. Pelvic radiotherapy may be an additional iatrogenic factor for women with breast cancer. Endometrial cancers diagnosed in women treated with tamoxifen have poorer prognosis. Women who receive tamoxifen for breast cancer should be offered gynaecological surveillance during and after treatment. A long-term evaluation of the risk-benefit ratio of tamoxifen as a preventive treatment for breast cancer is clearly warranted.

Because of its high incidence and the high number of deaths induced, breast cancers in elderly women is a major health problem. The diagnosis is often clinical and the tumors are often at advanced stage with many initial metastases due to some neglect. Breast cancer in elderly women has no specific radiological form and is more often infiltrating ductal carcinoma of SBR grade I. Hormonal receptors are generally higher in elderly than in young women. Surgery of breast cancers with equal anesthetic risks factors does not induce more complications in elderly women than in the general population. In 12% of cases, an associated pathology influences the decision (degradation of the respiratory or cardiovascular function or reduction of the renal function). Between 70 and 80 years, provided that life expectancy is compatible with radiotherapy, corollary to conservative treatments in the present state of our knowledge for tumors under 3 to 4 cm, there is an alternative between radiosurgical conservative treatment and modified mastectomy associated with axillary dissection. In case of bulky tumors (3 to 4 cm) and failure of the hormonal treatment or impossibility to perform a complementary radiotherapy treatment (for instance, senile dementia), of axillary node involvement, a fortiori if the tumor has no hormonal receptors, the modified mastectomy with axillary dissection remains the therapeutic standard. In case of bulky tumor, the hormonal status can be used to induce the patient to accept an operation and, if necessary, to perform a conservative surgery. However, despite hormonosensitivity of breast cancer, a tumoral progression after a mean duration of hormonosensitivity of 25 months is to be expected in 93% of the cases, included 25% in whom a complete response to hormonotherapy was observed. A fractionated irradiation delivering 2 Gy per fraction and 5 fractions per week with a total number of sessions of 25 gives better esthetical results. This optimal treatment lasts 5 weeks and the patients often get tired since they are old and their radiotherapy centre is far from their house. Therefore hypofractionated treatment (once a week) should be proposed. The adjuvant medical treatment of reference for menopausal women is hormonotherapy by tamoxifen. Breast cancer in elderly women reduces life expectancy at 5 years by 50%; the theoretical therapeutic indications are the same as for young women, but their application is adapted to the patient. It would be dangerous and illusive to undertreat such a disease when the life expectancy is longer than 3 years.

From 1977 to 1991, we treated 361 carcinomas of the velotonsillar region, either by brachytherapy alone (18 cases), or by an association of external radiotherapy and brachytherapy (343 patients). The latter was performed using a special technique with iridium wires in plastic tubes with afterloading. The primary was the tonsil in 128 patients, the soft palate in 134 patients. We numbered also 9 posterior pillars, 63 anterior pillars and 27 velotonsillar sulcus. According to the UICC staging system (28), we classified the patients in 90 T1, 141 T2, 119 T3, 2 T4, 9 Tx with 230 N0, 93 N1, 9 N2, 20 N3 and 9 Nx. The results at 5 and 10 years show respectively: local control (LC) 80% and 75%, locoregional control 75% and 70%, global survival 53% and 28%, specific survival 63% and 52%. The univariate study shows at 5 years a better local control for T1-T2 (87%) than for T3 (67%) with p = 0.00004. The locoregional control is better for N0 (80%) than for N+ (66%) with p = 0.002, this is the same for global survival (59% versus 42%, p = 0.002). The two groups were individualised according to the primary. Inside each of these groups, the prognosis is identical for different localisations, which allows to put them together. We can therefore distinguish a group A which includes the tonsil, the soft palate and posterior pillar. This group has a better prognosis (controls and survivals) than group B (anterior pillar and velotonsillar sulcus) (p0.002). The tumours extended to the mobile tongue, the base of the tongue or the velotonsillar sulcus have a poorer prognosis than those without propagation or with an upwards propagation (p0.002). The statistical study of radiobiological factors that can influence the tissular repair shows that there are less recurrences if the duration of treatment is inferior to 55 days and if the interval between external irradiation and brachytherapy is inferior to 20 days. A sufficient safety margin seems also necessary for a good local control. The dose rate within the limits used does not seem to influence the local control and the total dose delivered to the tumour, but this is not surprising since the highest doses are given to the tumours with the smallest regression during external irradiation. The multivariate study for local control shows that the most significant factors are the T, the tumoral localisation and the total duration of treatment. For complications (classified in 4 stages), the dose rate is the most significant factor.

Out of 332 epidermoid carcinomas of the base of the tongue treated in Centre Alexis Vautrin from 1978 to 1992, 136 received. a treatment with a curative intent. The median age was 58 years, the median follow-up was 57 months. We numbered 55 T1-T2 and 81 N0 or N1. From the therapeutic point of view, the patients were classified into three groups: in group 1 (45 cases), they were treated by external irradiation only (median dose: 71 Gy); in group 2 (72 cases), they were treated by external irradiation and brachytherapy (the mean dose delivered by external irradiation was 50 Gy, and by brachytherapy, the mean dose was 30 Gy with a mean dose rate of 55 cGy/h); in group 3 (19 cases), they were treated by a radiosurgical association, the surgical resection was always mutilating and completed by an external irradiation (55 Gy), 8 patients received an associated barrier brachytherapy. Thirty-nine patients presented a local failure, 50 a locoregional evolution. The rate of local control at 5 years was 19% for group 1, 39% for group 2 and 32% for group 3. The calculation of the equivalent biologic dose in group 1 allows to separate this population into two subgroups whose survival rates are significantly different (at 3 years: 26% and 6%, P = 0.02) and shows the influence of fractionation and treatment time. The actuarial survival at 3 years is 19% for group 1, 55% for group 2 and 45% for group 3, the survival without evolution is 33% for group 1, 66% for group 2 and 72% for group 3. For the whole series, we numbered 18 complications of grade equal or superior to 2 (healing in more than 3 months, or sequelae or death) out of which four bone complication and 14 tissular complications that occurred in a mean delay of 9 months. Because of technical modifications, there have been no grade complications for implantations performed from 1989. The prognosis remains poor for cancers of the base of the tongue. The rates of survival are still low when they are treated by external irradiation only. There seems to exist a slight advantage in favour of the radio-brachytherapy association compared to the radiosurgical association with a lower rate of sequelae and mutilations.

We report a retrospective series of 126 patients seen in 1992 for conservative surgery (group T) or Patey procedure (group P) for breast cancer. We looked for factors predictive of axillary lymphocele and their prevention. Axillary lymphadenectomy performed in patients undergoing surgery for breast cancer leads to a certain degree of morbidity including the development of lymphoceles. The mean number of lymph nodes removed was 16 in group T and 19 in group P. Mean lymphorrhea was 741 cm3. Two factors were significantly implicated in the pathogenesis of postoperative lymphorrhea : the number of nodes resected (p0.005) and obesity (p0.001). Prevention of lymphoceles requires meticulous lymphostasis and reduction of the surgical detachment spaces.

The study bears on 672 infiltrating carcinomas of the cervix treated from 1977 until the end of 1991, by a radiosurgical combination (311 patients) or by exclusive irradiation (361 patients). The radiosurgical series includes mostly stages IB and II and patients under 50 years because of the therapeutic protocol. Most of the patients aged over 50 years and all stages III were treated by exclusive irradiation. External beam irradiation was most often performed in 4 fields by linear accelerator of 12 and 25 MeV. Uterovaginal brachytherapy used the technique of molds. In 55 cases, a complementary interstitial brachytherapy was applied on residual node. A computer dosimetry was made for each patient with calculation of the doses delivered to organs at risk and to node areas (points of calculation ICRU n degrees 38). The results at 5 years are as follows for the total series: locoregional control (LRC) 79%, specific survival (SS) 73%, overall survival 70%. For stage I, the LRC of the radiosurgical series is 92%, that of the series of exclusive irradiation 87% (no significant difference, neither for SS if we consider the tumoral size); For stage II, the LRC is 70% in the radiosurgical series and 79% in the series of exclusive irradiation. There is no difference if proximal stage II is compared. Conversely, for distal stage II, the difference is very significant in favour of exclusive irradiation (LRC 31%/77%, SS 26%/70%, p0.006). If we consider the results according to age, the difference for distal stage II comes mostly from patients under 50 years and especially those aged 40 years or under. For stage III, the LRC is 61% for patients over 50 years and 34% for those aged 50 years or under (p = 0.006). As the nodes, the results of surgical pieces and lymphadenectomy are studied. The patients under 40 years in stages II and III present more metastases than others (p = 0.003). Among the therapeutic factors, the dose rate and the treatment duration were particularly studied. A detailed study of the complications is made for the radiosurgical series as for the series of exclusive irradiation according to the French Italian glossary of complications as well as a study of the factors inducing them.

Surgery is the golden standard of treatment of endometrial carcinoma. The risk of central or vaginal recurrences justifies adjuvant treatment.Brachytherapy for endometrial adenocarcinoma is given commonly as pre- or post-operative treatment. In case of medical contra-indications for surgery brachytherapy can be applied as the only treatment. Experience of the anticancer center Alexis Vautrin in Nancy of the years 1975 to 1988 is evaluated. Iridium-192 low-dose-rate (LDR) wires were used.Pre-operative brachytherapy was given with a vaginal mould applicator to 580 patients. The dose was 50 Gy at 0.5 cm below the surface of the vagina. The locoregional control rate was 93% after 5 years and the 5-year survival 82%. 139 patients received radiotherapy alone and no surgery. LDR-brachytherapy was given the upper third of the vagina and endometrium with an "umbrella" applicator. The locoregional control rate was 83% after 5 years and the survival rate 55%. 117 patients received a post-operative brachytherapy of the vagina. The locoregional control rate was 93% after 10 years and the survival rate 65%.A pre- and post-operative radiotherapy results in a reduction of the vaginal relapse rate. The LDR afterloading technique with primary radiotherapy of endometrial adenocarcinoma leads to a locoregional control slightly interior. The treatment results compare favourably with the best of the literature.

Seventy-seven pre-treated patients with advanced breast cancer were administered a combination chemotherapy with cisplatin 50 mg/sqm d1, 5-fluorouracil 300 mg/sqm/d protracted continuous infusion d1-d28, allopurinol 600 mg/d po d1-d28, q29d. Overall response rate was 26%, median survival time 46 weeks, survival rate 43.3% at 1 year, 20.2% at 2 years, 10.6% at 3 years. Response rate was rather high in CNS and meningeal involvement (6/10).

Mixed Mullerian Tumours (MMT) of the endometrium have a bad reputation as far as prognosis is concerned. We have studied 34 cases of MMT treated between 1976 and 1988 and have compared their outcome with a matched series of 68 cases of adenocarcinoma (ADC). These were taken out of 880 cases of ADC treated during this period of time after matching them for the stage, the type of treatment, the year of treatment and the age of the patient. The curves of survival and the totals of survival were determined using Kaplan-Meier's method and also compared using Logrank's test. The 5-years overall survival was 18% for MMT as against 55% for ADC (p less than 0.001). The difference was equally significant statistically in terms of specific survival without recurrences. The 16 patients in stages I and II who were treated with the same protocol as used for ADC were matched against 32 cases of ADC taken out of the 680 cases ADC in stages I and II and treated by the same protocol (84%). After five years MMT had a higher number of survivors (35% overall, 45% with specific survival and 35% without recurrences), but the difference with survival of ADC was as significant (respectively 75, 85, 85%). Recurrences of MMT were frequent (62%), with metastases in 9 out of 10 and early (50%), in every respect opposed with recurrences of ADC (16%) which were in three out of five cases localized and late (after 10 months). These figures make one have to think of modifying the way MMT is treated. External pelvic radiotherapy should be carried out before any other treatment. The place for other methods of therapy is to be discussed.