Clinical validation of a prognostic tool in a population of outpatients treated for incurable cancer undergoing anticancer therapy: PRONOPALL study.

BACKGROUND: In 2008, a study of the characteristics of hospitalised patients led to the development of a prognostic tool that distinguished three populations with significantly different 2-month survival rates. The goal of our study aimed at validating prospectively this prognostic tool in outpatients treated for cancer in terminal stage, based on four factors: performance status (ECOG) (PS), number of metastatic sites, serum albumin and lactate dehydrogenase. PATIENTS AND METHODS: PRONOPALL is a multicentre study of current care. About 302 adult patients who met one or more of the following criteria: life expectancy under 6 months, performance status ≥ 2 and disease progression during the previous chemotherapy regimen were included across 16 institutions between October 2009 and October 2010. Afterwards, in order to validate the prognostic tool, the score was ciphered and correlated to patient survival. RESULTS: Totally 262 patients (87%) were evaluable (27 patients excluded and 13 unknown score). Median age was 66 years [37-88], and women accounted for 59%. ECOG PS 0-1 (46%), PS 2 (37%) and PS 3-4 (17%). The primary tumours were: breast (29%), colorectal (28%), lung (13%), pancreas (12%), ovary (11%) and other (8%). About 32% of patients presented one metastatic site, 35% had two and 31% had more than two. The median lactate dehydrogenase level was 398 IU/l [118-4314]; median serum albumin was 35 g/l [13-54]. According to the PRONOPALL prognostic tool, the 2-month survival rate was 92% and the median survival rate was 301 days [209-348] for the 130 patients in population C, 66% and 79 days [71-114] for the 111 patients in population B, and 24% and 35 days for [14-56] the 21 patients in population A. These three populations survival were statistically different (P <0.0001). CONCLUSION: PRONOPALL study confirms the three prognostic profiles defined by the combination of four factors. This PRONOPALL score is a useful decision-making tool in daily practice.

Maintaining professional activity during breast cancer treatment.

The question of returning to work and pursuing professional activity during cancer treatment is an increasingly important consideration. The present work focuses on factors affecting the feasibility of maintaining professional activity during treatment for breast cancer, for women who wished to do so. Written questionnaires were collected from 216 patients between March and November 2012. Since the onset of their treatment, 31.4% of the women (68/216) had not been on sick-leave. The main factors associated with the pursuit of professional activity were: considering the availability of their physician to answer questions as unimportant [OR = 18.83 (3.60-98.53); P ≤ 0.05]; considering the diagnosis of cancer as likely to have a weak impact on career perspectives [OR = 4.07 (2.49-6.64); P ≤ 0.05]; not having any children in the household [OR = 3.87 (2.38-6.28); P ≤ 0.05]; being in a managerial position [OR = 3.13 (1.88-5.21); P ≤ 0.05]. Negative predictive factors were: physician mentioning adverse effects of the treatment [OR = 0.31 (0.16-0.58); P ≤ 0.05], and patient rating workload as high [OR = 0.26 (0.15-0.46); P ≤ 0.05]. As a result of advances in therapeutic strategies, more patients will expect healthcare professionals, as well as employers and occupational health societies, to prioritise issues pertaining to the maintenance of professional activities during cancer treatment.

[Non-targeted effects (bystander, abscopal) of external beam radiation therapy: an overview for the clinician]. / Effets non ciblés (bystander, abscopal) de la radiothérapie externe : potentielles implications pour le clinicien ?

Radiotherapy is advocated in the treatment of cancer of over 50 % of patients. It has long been considered as a focal treatment only. However, the observation of effects, such as fatigue and lymphopenia, suggests that systemic effects may also occur. The description of bystander and abscopal effects suggests that irradiated cells may exert an action on nearby or distant unirradiated cells, respectively. A third type of effect that involves feedback interactions between irradiated cells was more recently described (cohort effect). This new field of radiation therapy is yet poorly understood and the definitions suffer from a lack of reproducibility in part due to the variety of experimental models. The bystander effect might induce genomic instability in non-irradiated cells and is thus extensively studied for a potential risk of radiation-induced cancer. From a therapeutic perspective, reproducing an abscopal effect by using a synergy between ionizing radiation and immunomodulatory agents to elicit or boost anticancer immune responses is an interesting area of research. Many applications are being developed in particular in the field of hypofractionated stereotactic irradiation of metastatic disease.

Radiotherapy for invasive breast cancer: guidelines for clinical practice from the French expert review board of Nice/Saint-Paul de Vence.

PURPOSE: While new strategies for the treatment of invasive breast cancer (BC) are emerging, radiotherapy (RT) modalities are still under debate. The French expert review board of Nice-Saint-Paul de Vence was asked firstly to conduct a qualitative evidence-based systematic review and then to establish clinical practice guidelines for the use of post operative RT in invasive BC. METHODS AND MATERIALS: A search to identify eligible studies was undertaken using the Medline® database. All phase III randomized trials and systematic reviews evaluating the role and modalities of RT in invasive BC were included, together with some noncontrolled studies if no randomized trials were identified. The quality and clinical relevance of the studies were evaluated to determine the level of evidence. RESULTS: The maximum delay between surgery and RT should ≤8 weeks when chemotherapy (CT) is not indicated. This should not exceed 24 weeks when adjuvant CT is administered. Whole breast RT delivering 50 Gy in 25 fractions followed by a boost of 10-16 Gy remains the standard of care after conservative surgery (CS). In the elderly population, for certain cases presenting comorbidities associated with a limited life expectancy, RT indication (even hypofractioned) and boost delivery may be unnecessary in the light of an unfavourable risk/benefit ratio. RT technique and indications should not vary in case of neoadjuvant CT followed by CS. After total mastectomy, RT should be indicated in N+ and in N- patients with high risk of local recurrence. The experts recommend to initiate tamoxifen at the end of RT, while aromatase inhibitors could be administered either concomitantly or sequentially with RT. There is no consistent data to delay (or suspend) trastuzumab administration during RT. As for all patients, in case of concurrent RT-trastuzumab administration, reduction of cardiac tissues exposure is highly recommended. After breast reconstruction, RT should be delivered as after standard CS without boost. CONCLUSION: Due to significant variations in practice in the treatment of patients with BC, our group aimed to provide guidelines for clinical practice. The systematic review of the literature formed the basis of our evidence-based recommendations; however expert agreements were necessary on those subjects that are still under debate. Our group will update these guidelines every 4 years, taking in consideration new advances in technology, new drugs administration, biologic tools and innovative therapeutic options.

[Esophageal cancer]. / Cancer de l'œsophage.

Esophageal cancers are highly malignant tumours with often a poor prognostic, except for minimal lesions treated with surgery. Radiation therapy, or combined radiation and chemotherapy is the most used therapeutic modality, alone or before oesophagectomy. The delineation of target volumes is now more accurate owing the possibility to use routinely the new imaging techniques (mainly PET). The aim of this work is to precise the radio-anatomical particularities, the pattern of spread of esophageal cancer and the principles of 3D conformal radiotherapy illustrated with a clinical case.

[How to improve cancer patients' satisfaction with medical information]. / Comment améliorer la satisfaction des patients sur l'information médicale en cancérologie ?

The medical information becomes integrated into a communications strategy, the generally admitted model of which is centered on the patient; that is in the listening of these concerns and these values. The medical quality information is facilitated by the preliminary collection of the symptoms and the needs of the patients thanks to the questionnaires of quality of life, if they are used during the consultation to direct the discussion. Satisfactory medical information includes a discussion about the questions of the patients in terms of outcomes. Patient's individual factors can influence the need of medical information, as the age and the pathology. Patient's needs can also vary with time and according to the phase of the disease. Cultural factors are essential, in particular as regards the information about prognosis. Tools to help giving the medical information are now validated as the audio cassettes or video. Those tools can take the shape of a prompt list to help patients to ask questions. The majority preference of style of participation in the medical and therapeutic decisions and is the collaborative mode. Physician's attitude is determinant to leave the patients who wish it to have an active role, what allows them a very beneficial feeling psychologically of control over the disease. Decision-making helps are successfully sometimes elaborated to support the participation of the patients. In palliative phase, the need of medical information about prognosis associated with preservation of hope is not still understood by physicians who oscillate between saying the all or none. Honest information at the right time is the majority wish of the patients, although certain patients adopt clearly a strategy of avoidance. The medical communication requires a specific training on this subject. Talking time must be opened to the doctors to approach the relational problems which they meet. The clinical research has to continue to understand better the interactions in doctors/patients communication.

[Initial management in oncology: results of CPRIM surveys on 2,583 patient's perceptions and expectations (outside Anticancer Centers)]. / Prise en charge initiale: résultats des enquêtes CPRIM sur le ressenti et les attentes de 2,583 patients (hors centres de lutte contre le cancer).

During the initial phase of management, the caregivers' role is particularly difficult. These two consecutive surveys have been conducted to cover three main aspects: 1) How the initial management took place; 2) What the perceived deficits were; 3) What improvements could be made. A self administered and anonymous questionnaire was given to the patients by physicians. Surveys were conducted in numerous institutions representative of all kinds of practice except for Anticancer Centres. Two thousand five hundred and eighty three adult patients have completed the questionnaire (1366 and 1217 respectively in the first and subsequent survey): women (55%), age under 70 years (76%), breast cancer (32%). Results were rather encouraging. About sixty per cent of the patients are entirely satisfied by the given information and 95% are confident with the department of care. The mean level of global aid is 8.2/10 in the first survey and 8.6/10 in the second one. However, improvements remain needed, particularly for the 8% dissatisfied patients. In spite of the classical bias for these studies, this work gives several concrete responses for improving initial management, particularly for the first consultation in the centre, which has a major impact on the patient satisfaction.

Urinary volatile molecules vary in males of the 2 European subspecies of the house mouse and their hybrids.

Mice recognize other mice by identifying chemicals that confer a molecular signature to urinary marks. Such molecules may be involved in species recognition, and previous behavioral studies have related divergence of sexual preference between 2 subspecies of the house mouse (Mus musculus musculus and Mus musculus domesticus) to urinary odors. To characterize the differences between odors of males of the 2 subspecies and their first-generation offspring, the urinary volatile molecules were examined via gas chromatography coupled to mass spectrometry. Seven molecules were present in the samples from mice of at least one group. Their quantity varied among groups: M. m. domesticus showed a quantitatively richer panel of odorants in their urine when compared with M. m. musculus. The hybrids showed a more complex picture that was not directly related to one or the other parental subspecies. These quantitative differences may contribute to the specificity of the odorant bouquet of the 2 subspecies.

[Setting up supportive care in oncology: reflexions and suggestions.]. / A propos de la mise en place des soins de support en cancérologie : pistes de réflexions et propositions.

A group of 19 health professionals implicated in supportive care wanted to suggest some reflexions for organization, setting and evaluation of the supportive care in institutions and health territories. The suggested organization must be applicable to any cancer patient and the place of the care whatever the age, the stage of the disease; in the future, must be applicable to any patient with serious chronic illness. This organization must allow to optimize the accompaniment and the care of the patients and their close relations by 1) precise and regular analysis of their needs; 2) the respect of the continuity of the health care; 3) the setting of collaborative practice and transversality in the care. It is not a new medical speciality but a coordination of competences for patients and their families.

Variation in mate preference across a house mouse hybrid zone.

Reproductive character displacement is known to occur at the borders of a secondary contact zone between the two European subspecies of the house mouse (in Jutland, Denmark), where selection against hybridization occurs. This study assessed patterns of mate preference in naturally occurring hybrids of the two subspecies. Mate odour choice was investigated in male and female mice sampled across the hybrid zone. Odour samples comprised urine (from the opposite sex to the test animal) obtained from populations geographically distant from the hybrid zone. Urine is known to carry subspecies recognition signals. The behavioural results changed across the hybrid zone, and were analysed by a model of clinal variation. This behavioural cline was compared with the allozyme cline across the same hybrid zone. Males on both sides of the hybrid zone showed an assortative preference, which shifted significantly and abruptly approximately 10 km from the genetic centre of the hybrid zone on the Mus musculus musculus side. Directional preference was not detected in females, which could relate to variation in sexual receptivity. Our model indicates that the peculiar pattern of male preference could involve several genes and be characterized by mild to strong epistasis favouring the expression of M. m. domesticus-like preference over a large portion of the hybrid zone. This study may provide the first picture of the genetic determination of mate preference in a mammal.

Patterns of genic diversity and structure in a species undergoing rapid chromosomal radiation: an allozyme analysis of house mice from the Madeira archipelago.

The chromosomal radiation of the house mouse in the island of Madeira most likely involved a human-mediated colonization event followed by within-island geographical isolation and recurrent episodes of genetic drift. The genetic signature of such processes was assessed by an allozyme analysis of the chromosomal races from Madeira. No trace of a decrease in diversity was observed suggesting the possibility of large founder or bottleneck sizes, multiple introductions and/or a high post-colonization expansion rate. The Madeira populations were more closely related to those of Portugal than to other continental regions, in agreement with the documented human colonization of the island. Such a Portuguese origin contrasts with a study indicating a north European source of the mitochondrial haplotypes present in the Madeira mice. This apparent discrepancy may be resolved if not one but two colonization events took place, an initial north European introduction followed by a later one from Portugal. Asymmetrical reproduction between these mice would have resulted in a maternal north European signature with a nuclear Portuguese genome. The extensive chromosomal divergence of the races in Madeira is expected to contribute to their genic divergence. However, there was no significant correlation between chromosomal and allozyme distances. This low apparent chromosomal impact on genic differentiation may be related to the short time since the onset of karyotypic divergence, as the strength of the chromosomal barrier will become significant only at later stages.

Asymmetrical reproductive character displacement in the house mouse.

Our study addressed reproductive character displacement between two subspecies of the house mouse, Mus musculus musculus and Mus musculus domesticus that hybridize in Europe along a zone where selection against hybridization is known to occur. Based on a multi-population approach, we investigated spatial patterns of divergence of mate preference in the two taxa. Mate preference was significantly higher in the contact zone than in allopatry in both subspecies, suggesting that reproductive character displacement occurs. Moreover, patterns of preference were stronger in M. m. musculus than in M. m. domesticus, indicating an asymmetrical divergence between the two. In the context of selection against hybridization, our results may provide empirical support for the hypothesis of reinforcement in a parapatric hybrid zone. We discuss factors that could explain the asymmetrical pattern of divergence and the possible impact of a unimodal structure on the maintenance of premating divergence between the two subspecies.

Comprehensive geriatric assessment predicts tolerance to chemotherapy and survival in elderly patients with advanced ovarian carcinoma: a GINECO study.

BACKGROUND: Data from prospective clinical trials are needed to better define standards of care in elderly patients with advanced ovarian carcinoma and to demonstrate the interest of Comprehensive Geriatric Assessment (CGA) in this fragile and heterogeneous population. PATIENTS AND METHODS: From July 1998 to October 2000, 83 advanced ovarian carcinoma patients >70 years old received carboplatin AUC 5 and cyclophosphamide 600 mg/m2, on day 1 of six 28-day cycles. The clinical and biological geriatric covariates prospectively studied were: comorbidities, comedications, cognitive functions (Mini-Mental test), nutritional status and autonomy. RESULTS: Patient characteristics were: median age 76 years, serous histology (73%), FIGO stage III (75%), optimal initial surgery (21%) and performance status (PS) > or =2 (44%). Sixty patients (72%) received six chemotherapy cycles without severe toxicity (STox) or tumor progression. Multivariate analysis retained three factors as independent predictors of STox: symptoms of depression at baseline (P = 0.006), dependence (P = 0.048) and PS > or =2 (P = 0.026). Independent prognostic factors identified for overall survival (Cox model) were depression (P = 0.003), FIGO stage IV (P = 0.007) and more than six different comedications per day (P = 0.043). CONCLUSION: CGA could predict STox and overall survival of elderly advanced ovarian carcinoma patients.

Phase II trial combining docetaxel and doxorubicin as neoadjuvant chemotherapy in patients with operable breast cancer.

BACKGROUND: This study was conducted to assess the antitumour activity of docetaxel in combination with doxorubicin for neoadjuvant therapy of patients with breast cancer. PATIENTS AND METHODS: Forty-eight women were treated with intravenous doxorubicin 50 mg/m(2) over 15 min followed by a 1-h infusion of docetaxel 75 mg/m(2) every 3 weeks for six cycles. Dexamethasone or prednisolone premedication was allowed. Granulocyte colony-stimulating factor was not allowed as primary prophylaxis. The primary end point was the pathologically documented complete response rate (pathological response). RESULTS: The mean relative dose intensity calculated for four or more cycles was 0.99 for doxorubicin and 0.99 for docetaxel. Overall, the pathological response rate was 13%. There were 11 complete and 29 partial clinical responses for an overall response rate of 85% [95% confidence interval (CI) 75% to 95%] in the evaluable population (n = 47). Disease-free and overall survival rates were 85% (95% CI 71% to 94%) and 96% (95% CI 85% to 99%), respectively, after a median follow-up of 36.6 months. Grade 3/4 neutropenia was observed in 65% of patients and 17% reported grade 4 febrile neutropenia. CONCLUSIONS: Docetaxel and doxorubicin is an effective and well-tolerated combination in the neoadjuvant therapy of breast cancer. Future controlled trials are warranted to investigate the best schedules and to correlate response with biological factors.

Multimodal therapy with intravenous biweekly leucovorin, 5-fluorouracil and irinotecan combined with hepatic arterial infusion pirarubicin in non-resectable hepatic metastases from colorectal cancer (a European Association for Research in Oncology trial).

BACKGROUND: The purpose of this study was to evaluate the tolerance and efficacy of combining i.v. irinotecan, 5-fluorouracil (5-FU) and leucovorin (LV) with hepatic arterial infusion (HAI) of pirarubicin in non-resectable liver metastases from colorectal cancer. PATIENTS AND METHODS: Thirty-one patients were included in a phase II trial with i.v. irinotecan/5-FU/LV administered every 2 weeks, combined with HAI pirarubicin 60 mg/m(2) on day 1 every 4 weeks. In most cases HAI was administered via a percutaneous catheter. RESULTS: The main grade 3/4 toxicity was neutropenia, encountered in 78% of the patients. When all patients were considered in the analysis, tumour response rate was 15 out of 31 [48%; 95% confidence interval (CI) 32% to 65%]. Liver resection was made possible in 11 patients (35%; 95% CI 21% to 53%). There were no toxic death. Median overall survival was 20.5 months, and median progression-free survival was 9.1 months. In patients with completely resected metastases, median overall survival was not reached and median progression-free survival was 20.2 months. CONCLUSION: The multimodality approach used in the present study was well-tolerated and yielded dramatic responses. An aggressive approach combining i.v. and HAI chemotherapy deserves further investigation.

Molecular studies on the colonization of the Madeiran archipelago by house mice.

To study the colonization history of the house mouse (Mus musculus domesticus) on the Madeiran archipelago, complete mitochondrial D-loop sequences were obtained for 44 individuals from Madeira, Porto Santo and Ilhas Desertas. Altogether, 19 D-loop haplotypes were identified which formed part of a single clade in a phylogeny incorporating haplotypes from elsewhere in the range of M. m. domesticus, indicating that the Madeiras were colonized from a single source. Similarities between the sequences found in the Madeiras and those in Scandinavia and northern Germany suggest that northern Europe was the source area, and there is the intriguing possibility that the Vikings may have accidentally brought house mice to the archipelago. However, there is no record of Vikings visiting the Madeiras; on historical grounds, Portugal is the most likely source area for Madeiran mice and further molecular data from Portugal are needed to rule out that possibility.

A high and sustained response rate in refractory or relapsing low-grade lymphoma masses after low-dose radiation: analysis of predictive parameters of response to treatment.

PURPOSE: To determine the efficacy of small doses of radiation in patients with recurrent or refractory low-grade lymphoma masses. METHODS AND MATERIALS: Patients with refractory or relapsing low-grade lymphoma masses. The two largest diameters of the tumor mass were measured, whenever possible, before and after treatment. A dose of 4 Gy of radiotherapy was delivered to tumor sites in 2 fractions. Patients were evaluated for response 1-4 months later and at regular follow-up visits. RESULTS: Forty-eight patients with low-grade lymphomas according to the working formulation received low-dose radiotherapy between March 1987 and November 1998. Most patients had advanced disease at the time of radiation treatment, and 80% had received at least two chemotherapy regimens before treatment. The median interval between the initial diagnosis and radiotherapy was 2.7 years (range 0-22 years). Low-dose radiation was delivered to 135 tumor sites. Nodal and extranodal tumor sites represented 80% and 20% of masses, respectively. An objective response was obtained in 81% of the sites, with 57% attaining a complete remission. The 2-year actuarial freedom from local progression (FFLP) rate was 56% (95% CI, 46-66%). Tumor masses 5 cm), the number of chemotherapy regimens (0-1 vs. more), and age at time of radiation treatment (< or =65 years or > 65 years) were significant predictive parameters of response to treatment. CONCLUSIONS: In this retrospective study, low-dose radiation proved efficient, with long-lasting effects in the majority of patients with recurrent or refractory low-grade lymphomas. This simple and nontoxic treatment should be investigated prospectively in patients with advanced disease and a low tumor burden not immediately warranting chemotherapy.

Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer.

This comparative phase III trial of mitoxantrone+vinorelbine (MV) versus 5-fluorouracil+cyclophosphamide+either doxorubicin or epirubicin (FAC/FEC) in the treatment of metastatic breast cancer was conducted to determine whether MV would produce equivalent efficacy, while resulting in an improved tolerance in relation to alopecia and nausea/vomiting. This multicentre study recruited and randomised 281 patients with metastatic breast cancer; 280 were evaluable for response survival and toxicity (138 received FAC/FEC, 142 received MV). Patient characteristics were matched in each arm and stratification for prior exposure to adjuvant therapy was made prospectively. The overall response rate (ORR) was equivalent in the two arms (33.3% for FAC/FEC versus 34.5% for MV), but MV was more effective in patients who had received prior adjuvant therapy (13% (95% confidence interval (CI) 3-23) for FAC/FEC versus 33% (95% CI 20-47) for MV P=0.025) with a better progression-free survival (PFS) (5 months (range 1-18 months) versus 8 months (range 1-27 months); P=0.0007 for FAC/FEC versus MV, respectively) while FAC/FEC was more effective in previously untreated patients (ORR 43% (95% CI 33-53) versus 35% (95% CI 25-45), P=0.26; PFS 9 months (range 0-29 months) versus 6 months (range 0-26 months) P=0.014). Toxicity was monitored through the initial six cycles of therapy; febrile neutropenia and delayed haematological recovery was more frequent for MV (P=0.001), while nausea/vomiting of grades 3-4 was greater for FAC/FEC (P=0.031), as was alopecia (P=0.0001), cardiotoxicity was the same for the two regimens. MV represents a chemotherapy combination with equivalent efficacy to standard FAC/FEC and improved results for patients who have previously received adjuvant chemotherapy. Toxicity must be balanced to allow for increased haematological suppression and risk of febrile neutropenia with MV compared with a higher risk of subjectively unpleasant side-effects such as nausea/vomiting and alopecia with FAC/FEC.