Towards a "Lyon molecular signature" to individualize the treatment of rectal cancer. Prognostic analysis of a prospective cohort of 94 rectal cancers T1-2-3 Nx MO to be the basis of a molecular signature.

PURPOSE: In 1998 a translational research was initiated in Lyon aiming at identifying a prognostic "biomolecular signature" in rectal cancer. This paper presents the clinical outcome of the patients included in this study. PATIENTS AND METHODS: A total of 94 patients were included between 1998 and 2001. A staging with rectoscopy and biopsies was performed before treatment. In case of surgery, the operative specimen was analysed to evaluate the pathological response. There were two types of treatment: neoadjuvant radiotherapy (with or without concurrent chemotherapy) followed by surgery (76 cases) and radiotherapy alone with 'contactherapy' often associated with external beam radiotherapy (18 patients). RESULTS: The patients had a mean age of 63years. Stage was T1: 4, T2: 24, T3: 65 and T4: 1. The overall survival of the 94 patients was 62% at 8years with a rate of distant metastases of 29%. Rate of local recurrence at 8years was 6% in the neoadjuvant group and 16% in the radiotherapy group with an overall 8years survival in both groups respectively: 64% and 53%. There was a trend towards more metastases in cT3, tumour diameter above 4cm, circumferential extension. There was a significant increase in the risk of metastases for ypT3, ypN1-2 and Dworak score 1-2-3. In multivariate analysis ypT3 was significantly associated with a high rate of metastases (55%; P=0.0003). CONCLUSION: The rate of distant metastases is a major prognostic factor. These clinical results will serve as the base line to identify a "biomolecular signature" which could complement the TN(M) classification.

[Economic assessment of pulsed dose-rate (PDR) brachytherapy with optimized dose distribution for cervix carcinoma]. / Evaluation économique de la curiethérapie de débit pulsé gynécologique (PDR) avec optimisation de la dose pour les cancers du col utérin.

PURPOSE: Our study aims at evaluating the cost of pulsed dose-rate (PDR) brachytherapy with optimized dose distribution versus traditional treatments (iridium wires, cesium, non-optimized PDR). Issues surrounding reimbursement were also explored. MATERIALS AND METHODS: This prospective, multicentre, non-randomised study conducted in the framework of a project entitled "Support Program for Costly Diagnostic and Therapeutic Innovations" involved 21 hospitals. Patients with cervix carcinoma received either classical brachytherapy or the innovation. The direct medical costs of staff and equipment, as well as the costs of radioactive sources, consumables and building renovation were evaluated from a hospital point of view using a microcosting approach. Subsequent costs per brachytherapy were compared between the four strategies. RESULTS: The economic study included 463 patients over two years. The main resources categories associated with PDR brachytherapy (whether optimized or not) were radioactive sources (1053euro) and source projectors (735euro). Optimized PDR induced higher cost of imagery and dosimetry (respectively 130euro and 367euro) than non-optimized PDR (47euro and 75euro). Extra costs of innovation over the less costly strategy (iridium wires) reached more than 2100euro per treatment, but could be reduced by half in the hypothesis of 40 patients treated per year (instead of 24 in the study). CONCLUSION: Aside from staff, imaging and dosimetry, the current hospital reimbursements largely underestimated the cost of innovation related to equipment and sources.

Male breast cancer. Evolution of treatment and prognostic factors. Analysis of 489 cases.

BACKGROUND: Infiltrating MBC represents less than 1% of all male cancers. Our study details clinico-pathological features, treatments and prognostic factors in a large French cohort. MATERIAL AND METHODS: Four hundred and eighty-nine patients were collected from 1990 to 2005. Median age was 66 years (34% over 70 years) and median follow-up 58 months. RESULTS: According to TN classification, we found T(1): 39%, T(2): 41%, T(3)T(4): 9%, T(x): 11% and N(1)N(2): 27%. Lumpectomy (L) and mastectomy (M) were performed in 8.6% and 91.4% of the cases. Axillary dissection (AD), sentinel node biopsy or both were performed in 90%, 2% and 5% of the cases, respectively. Ninety-five percent of tumours were ductal carcinomas; 47% were pT(1), 20% pT(2) and 33% pT(3)-T(4). Axillary nodal involvement was present in 52.8% cases. ER and PgR were positive in 92% and 89% cases. Radiotherapy (RT) was performed in 85% of the patients. Hormonal treatment (HT) was delivered in 72% of the cases. Tamoxifen and aromatase inhibitors were used in 85% and 12% of the cases; 34% of the patients received chemotherapy (CT). Local recurrence (LR), nodal recurrences (NR) and metastases occurred in 2%, 5% and 22% of the cases; 2% and 10% developed contralateral BC and second cancer. The 5- and 10-year overall survival (OS) rates were 81% and 59%; disease-specific survivals (DSS) were 89% and 72%. Death causes were BC 56%, second cancer 8%, complications 3%, intercurrent disease 15% and unknown 18%. In a univariate analysis, metastatic risk factors were T stage (T1: 19%, T(2): 26%, T(3)T(4): 40%; p=0.013), pN status (pN(0): 12% pN(1-3): 26% pN(>3): 44%; p<0.0001) and presence of locoregional recurrence (62% versus 18% p<0.0001). In a multivariate analysis, axillary nodal involvement and high SBR remain prognostic factors. CONCLUSION: Earlier diagnosis and wide use of adjuvant treatments (RT/HT/CT) widely decreased LR and increased survival rates in MBC, reaching female ones. Prognostic factors were also very similar to female ones.

Building a shared patient record for breast cancer management: a French Delphi study.

Before electronic records become operational, patient-held records provide an opportunity to improve communication between patients and healthcare professionals. Our aim was to design the appropriate organization, layout and content for such a shared record for breast cancer management, based on a consensus between the various stakeholders. We therefore conducted a Delphi study within a working group of 48 members, including patients, oncologists, general practitioners, nurses and other professionals. The procedure featured three rounds during which participants' judgements were collected via mailed questionnaires and quantitative and qualitative feedback was provided on a regular basis. These three rounds were followed by an evaluation phase. Forty members (83%) participated in the three rounds. According to the agreement reached, the shared record was expected to include a front summary card, four sections for groups of users authorized to write down or insert information in the record (patient, physicians, medical auxiliaries and other healthcare professionals), and one section for medical imaging files. In addition, the record was to include specific categories of information as subsections within each of the various user sections. The participant satisfaction rate was over 90% for all aspects of the procedure, with the exception of interaction within the working group (79%).

Celecoxib and exemestane versus placebo and exemestane in postmenopausal metastatic breast cancer patients: a double-blind phase III GINECO study.

The aim of this study was to evaluate antitumor effects of cyclooxygenase-2 inhibitors in breast carcinoma and their ability to act synergistically with aromatase inhibitors (AIs). Postmenopausal metastatic breast cancer patients without previous adjuvant AI treatment received exemestane 25 mg/days plus either celecoxib 400 mg twice daily or placebo. The primary endpoint was progression-free survival (PFS). This trial was prematurely terminated (N = 157 of 342 planned) after cardiovascular toxicity was reported in other celecoxib trials. Although no PFS difference was observed between the two arms (9.8 months for both, P = 0.72), a trend favoring celecoxib was observed in 60 tamoxifen-resistant patients (9.6 vs. 5.1 months; P = 0.14) and in 126 patients treated >or=3 months before study termination (12.2 vs. 9.8 months; P = 0.09). No severe adverse events were reported. Cyclooxygenase-2 inhibitors seemingly contribute to reverse endocrine resistance in breast cancer patients, although further study is necessary to allow development of a new therapeutic strategy.

[Irradiation of lymph nodes areas in breast cancer]. / Irradiation des aires ganglionnaires dans le cancer du sein.

Postoperative radiotherapy after breast surgery increases overall survival by decreasing the local relapse rate. The main site of relapse is the breast or the chest wall. The value of irradiation of the nodal basins is still discussed. It must be emphasized that nodal areas were systematically irradiated in the postmastectomy randomized trials demonstrating a benefit in survival for adjuvant radiotherapy. Axillary relapses are infrequent in case of complete axillary dissection; complementary irradiation could be proposed if the axillary dissection is incomplete or if there is a massive pathologic involvement of the axilla. Its main complication is lymphoedema, which remains the most frequent sequellae of the treatment of breast cancer. Supraclavicular irradiation is logical in case of axillary involvement. Internal mammary nodes are involved in 20 to 40% of the patients, depending of the axillary involvement and location of the tumor inside the breast. Irradiation of the internal mammary basin is difficult: optimal dosimetry required a CT-based simulation. Its benefit remains to be proved. Internal mammary nodes irradiation probably increased cardiovascular mortality. Sophisticated techniques are needed to spare the heart from irradiation. Two large randomized trials (French group, European Organization for Research and Treatment of Cancer [EORTC]) are currently evaluating the possible benefit of internal mammary irradiation.

[Ductal carcinoma in situ: role of the boost]. / Radiothérapie des carcinomes canalaires in situ: impact du complément d'irradiation du lit tumoral.

Ductal carcinoma in situ is defined as breast cancer confined to the ducts of the breast without evidence of penetration of the basement membrane. Local treatment quality represents one of the most prognostic factors as half of recurrences are invasive diseases. The main goal of adjuvant radiotherapy after conservative surgery is to decrease local recurrences and to permit breast conservation with low treatment-induced sequelae. Several randomized trials have established the impact of 50 Gy to the whole breast in terms of local control. Nevertheless, no randomized trial is still available concerning the role of the boost in this disease. In this review, we present updated results of the literature and we detail the French multicentric randomized trial evaluating the impact of a 16 Gy boost after 50 Gy delivered to the whole breast in 25 fractions and 33 days. This protocol will start inclusions in October 2008.

[Patient-held health records: impact on breast cancer follow-up in the Rhône-Alpes region. Project Archimed]. / Le dossier de santé détenu par le patient : impact sur le suivi du cancer du sein dans la région Rhône-Alpes. Projet Archimed.

BACKGROUND: The conditions of use and access to medical records have become an important source of interest in the last decade. In this context, our main objective was to assess the impact of a paper patient-held records, shared with healthcare professionals. METHODS: In the particular case of breast cancer management, we identified the expectations of practitioners and patients. Secondly and according to a Delphi method, we defined the content and size of a medical record, which could be held by the patient. Following these preliminary studies, we conducted a randomized controlled trial, comparing patients with usual follow-up to others holding the new record containing essential information for coordination of care. RESULTS: The patient-held record favoured membership and satisfaction of both patients and health professionals. It was used as a communication tool between physicians and patients, but could also cause anxiety to some patients. Patient quality of life, data confidentiality and costs of care remained identical in the two arms. With its benefits for both patients and healthcare professionals, a new concept of medical records was revealed by this study. CONCLUSION: New models for healthcare organization deeply modify the roles and relationships of all the actors in the healthcare system. Further research on patient-held records is needed to evaluate the full range of its benefits and limits.

Capecitabine, irinotecan, oxaliplatin (CAPIRINOX) and concomitant irradiation in advanced rectal cancer: the Lyon R-02-01 phase I trial.

AIMS: To determine the feasibility of radiotherapy-associated capecitabine, irinotecan and oxaliplatin administration at five dose levels for the treatment of locally advanced rectal cancer, with or without metastasis. PATIENTS AND METHODS: This was a bicentric phase I trial, including patients with locally advanced rectal cancer, with or without metastasis. Chemotherapy comprised capecitabine (1100, 1300 or 1500 mg/m2/day, every day), irinotecan (30, 40 or 50mg/m2, once per week for 6 weeks) with the addition of oxaliplatin (40 mg/m2 at level 4 or 50 mg/m2 at level 5, once per week for 6 weeks). Radiotherapy at 46 Gy plus a boost of 4 Gy was administered concomitantly. RESULTS: Twelve patients received four levels of dose. As a supplement to radiotherapy, the combination of capecitabine and irinotecan at the respective doses of 1500 mg/m2/day and 50 mg/m2/week was feasible and well tolerated. The addition of oxaliplatin to this combination provoked toxicity (grade 3/4 vomiting, diarrhoea) for two-thirds of the patients. CONCLUSION: A treatment associating radiotherapy (46 Gy+4 Gy) with concomitant chemotherapy comprising capecitabine (1500 mg/m2/day, every day) and irinotecan (50 mg/m2/week, for 5 weeks) was feasible and well tolerated. The addition of oxaliplatin to these doses was prohibitory to the continuation of treatment due to unacceptable toxicity.

French experience with contact X-ray endocavitary radiation for early rectal cancer.

This paper is an overview of the French experience with contact X-ray radiation for rectal cancer. The analysis was mainly carried out on 50 years of experience in Lyon or since 1980 in the Centre Hospitalier Universitaire Lyon Sud. The results obtained in Dijon and Nancy are also reported. In early rectal cancer, contact X-ray radiation can play an important role in three different situations: (1) small T1 less than 2 cm: adjuvant contact X-ray radiotherapy after local excision; (2) T2 N0 or large T1: first-line contact X-ray radiotherapy combined with external beam radiotherapy (+/- chemotherapy) followed by surgery (anterior resection or local excision); (3) early T3 N0 in frail patients: the same approach as for T2 N0 with, in case of clinical complete response, local excision or follow-up.

Improved disease-free survival with epirubicin-based chemoendocrine adjuvant therapy compared with tamoxifen alone in one to three node-positive, estrogen-receptor-positive, postmenopausal breast cancer patients: results of French Adjuvant Study Group 02 and 07 trials.

BACKGROUND: The purpose was to compare disease-free survival (DFS) between epirubicin-based chemoendocrine therapy and tamoxifen alone in one to three node-positive (N1-3), estrogen-receptor-positive (ER+), postmenopausal early breast cancer (EBC) patients. PATIENTS AND METHODS: We analyzed, retrospectively, 457 patients randomized in FASG 02 and 07 trials who received: tamoxifen alone (30 mg/day, 3 years); or FEC50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2, cyclophosphamide 500 mg/m2, six cycles every 21 days) plus tamoxifen started concurrently. Radiotherapy was delivered after the third cycle in FASG 02 trial, and after the sixth in FASG 07 trial. RESULTS: The 9-year DFS rates were 72% with tamoxifen and 84% with FEC50-tamoxifen (P = 0.008). The multivariate analysis showed that pathological tumor size >2 cm was an independent prognostic factor (P = 0.002), and treatment effects remained significantly in favor of chemoendocrine therapy (P = 0.0008). The 9-year overall survival rates were 78% and 86%, respectively (P = 0.11). In the multivariate model, there was a trend in favor of chemoendocrine therapy (P = 0.07). CONCLUSION: The addition of FEC50 adjuvant chemotherapy to tamoxifen significantly improves long-term DFS in N1-3, ER+ and postmenopausal women. Chemoendocrine therapy seems to be more effective than tamoxifen in terms of long-term survival.

Long-term cardiac toxicity after adjuvant epirubicin-based chemotherapy in early breast cancer: French Adjuvant Study Group results.

BACKGROUND: The aim of the study was to evaluate and compare incidence and risk factors of left ventricular dysfunction (LVD) in early breast cancer patients receiving (E+) or not (E-) epirubicin-based adjuvant chemotherapy. PATIENTS AND METHODS: Among eight FASG trials, 3577 assessable patients were analyzed retrospectively: 2553 received epirubicin, 662 received hormonotherapy alone and 362 had no systemic treatment. Chemotherapy was FEC regimen in 86% of cases (fluorouracil, epirubicin, cyclophosphamide). Epirubicin cumulative dose was < 300 mg/m2 in 1040 patients, 300-600 in 1155, > or = 600 in 279, followed by radiotherapy in 96% of cases. RESULTS: Twenty delayed LVD occurred: two in E- patients and 18 in E+ patients. In E+ patients, 14 patients normalized their cardiac function or did not require further investigations, one patient was stabilized with specific treatment, two patients worsened their functions and one died of congestive heart failure. The 7-year risk of LVD was 1.36% (95% CI 0.85-1.87) in E+ patients and 0.21% (95%CI: 0.00-0.52) in E- patients (P = 0.004). Two significant risk factors were identified: age > or = 65 years and body mass index > 27 kg/m2. CONCLUSION: After a long-term follow-up, epirubicin-related LVD risk was acceptable (1.36%) with one toxic death (0.04%). In 78% of cases, LVD were transient or well controlled.

[Radiotherapy optimization in breast cancer: filtration, electronic compensation, intensity modulation]. / Optimisation de la radiothérapie du cancer du sein: filtration, compensation électronique, modulation d'intensité

Purpose of radiation treatment after conservative surgery for breast cancer is improvement of long-term local control rate and reduction of heart and pulmonary toxic events for women with long life expectancy. Breast irradiation with intensity modulation might be promising, as results of treatment planning (dose-volume histogram and normal tissue complication probability) showed. Project of our study is to evaluate the advantage of each following techniques: wedged plans, electronic compensation and intensity modulation.

Effect of radiotherapy on pelvic lymph node metastasis in cervical cancer stages IB2-IVA: a retrospective analysis of two comparative series.

Efficiency of radiotherapy in controlling lymph node metastasis is a controversial issue. A continuous series of 87 patients affected by cervical cancer stages IB2-IVA and treated using pelvic radiotherapy is presented. A retrospective comparison is made between two populations. In the two populations, a staging lymphadenectomy was carried out before the onset of the therapeutic program. In the first population (53 patients), the pelvic nodes only were dissected and in the second one (34 patients), the pelvic lymph nodes were left in place and the paraaortic nodes only were dissected. In both series, a completion surgery was performed after finalization of the radiotherapy. It was carried out at open abdomen in both series. It included a systematic pelvic dissection for the patients whose pelvic nodes had been intentionally left in place at the time of the initial staging lymphadenectomy. Both series were identical as far as classic risk factors were concerned (FIGO stage, maximal tumor diameter, lymphovascular space involvement). The radiotherapy administered to the pelvis was the same in both populations. The number of patients with pelvic lymph node metastasis was 21 (39.6%) in the first population versus 6 (17.6%) in the second one (P = 0.03). The percentage of positive lymph nodes among the retrieved lymph nodes was 18.94 in the first population versus 2.8 in the second one (P = 0.0001). Pelvic radiotherapy is likely to control most of the pelvic lymph node metastasis, but not all of them. Practical deductions and further developments are discussed.

Secondary leukemia after epirubicin-based adjuvant chemotherapy in operable breast cancer patients: 16 years experience of the French Adjuvant Study Group.

BACKGROUND: The purpose of this study was to evaluate incidence and risk factors of secondary leukemia after adjuvant epirubicin-based chemotherapy in breast cancer patients. PATIENTS AND METHODS: Among eight French Adjuvant Study Group trials, 3653 patients were assessable: 2603 received epirubicin; 682 received hormonotherapy; and 368 had no systemic treatment. Chemotherapy was FEC regimen in 85% of cases (fluorouracil 500 mg/m2, epirubicin 50, 75 or 100 mg/m2, cyclophosphamide 500 mg/m2, three or six cycles). Epirubicin cumulative dose was <300 mg/m2 in 1045 patients; 300-600 mg/m2 in 1187; and > or =600 mg/m2 in 286, followed by radiotherapy in 96% of cases. The median follow-up was 104 months. RESULTS: Eight cases of leukemia occurred in epirubicin-exposed patients and one in non-exposed patients. After 9 years, the risk of developing a leukemia was 0.34% (95% confidence interval 0.11-0.57) in epirubicin-exposed patients. In patients receiving chemotherapy, leukemia subtypes were: AML2 (two), AML3 (one), AML4 (three) and ALL (two). None of the classically recognized risk factors was significantly correlated with the occurrence of a leukemia. CONCLUSION: Irrespective of the dose, the incidence of secondary leukemia after adjuvant epirubicin-based chemotherapy was low. After a long follow-up, the benefit/risk ratio for early breast cancer patients remained in favor of epirubicin-based adjuvant chemotherapy: eight cases (0.31%) occurred, and in some of them, treatment causality could be debatable.

'Parcours de Femme 2001': a French opinion survey on overall disease and everyday life management in 1870 women presenting with gynecological or breast cancer and their caregivers.

PURPOSE: The aim of the survey 'Parcours de Femmes 2001' was to evaluate the overall management and care of women with female cancers and to determine their needs. METHODS: Women with breast or gynecological cancer who had either received at least 3 months of treatment or had completed treatment <1 year before the study were enrolled in this cross-sectional, observational study. RESULTS: From February to November 2001, 2839 questionnaires were distributed; 1870 were returned (66% response rate), mainly by breast cancer patients (87%). While 92% of women reported having received information at diagnosis, 34% of relapsed patients complained of lack of information concerning their disease and treatment. Only 18% of patients were included in the treatment decision process and 66% of women obtained complementary information from the media, patients and care professionals. Fatigue was the most severe problem quoted (78% of cases) and was poorly managed by caregivers due to diagnostic and treatment difficulties. Problems relating to family and to affective and socio-professional life were poorly identified and remained largely unmanaged. CONCLUSIONS: Information given to female cancer patients must be improved in relapsed patients, particularly regarding the adverse effects of treatment. Psychosocial management requires a more holistic approach through new channels, together with the coordination of existing structures.

[To boost the tumor bed: the age of reason]. / Complément d'irradiation du lit tumoral: l'âge de raison.

It is well known that the conservative reference treatment of infiltrative carcinoma of the breast, after en bloc complete excision, should be completed by irradiation of the whole breast delivering 50 Gy in 25 fractions. The discussion related to the validity and the procedures of delivery of the boost of the tumor bed has to be adjusted with our knowledge of specific prognostic factors of local recurrence. Through the two phase III randomized trials published in the literature, the young age of the patient, palpable tumor and negative receptor to progesterone may be recognized as statistically linked to a higher risk of local recurrence. Tumor size and palpable tumor remain unquestionable factors of bad prognosis. The true level of significativeness of age remains controversial as well as peri-tumoral characteristics such as ductal carcinoma in situ. Treatment technique should be rigorous either in terms of prescription of external radiation therapy or for the boost. They have a major impact on the cosmetic result and the fibrosis rate. Improvement of the results is expected through careful analysis of genic and molecularly prognostic factors of the tumor in order to select patients amenable to this type of technique.