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The MSI phenotype in colon cancer is a good prognostic factor, with an impact probably more pronounced for stage II than stage III tumor. This survival advantage may be related to the tumor-infiltrating lymphocytes observed in MSI tumors, thus explaining the existence of a probably more effective anti-tumor immune response. In addition, the MSI status would also be a biomarker able to predict the lack of efficacy of adjuvant 5-fluorouracil (5FU) chemotherapy. In contrast, as observed in MSS colon cancer, the MSI tumors would have a survival benefit with the addition of oxaliplatin to adjuvant 5FU chemotherapy. Based on these data, the "French National Thesaurus of Digestive Oncology" suggests for patients with MSI colon cancer, an adjuvant chemotherapy combining fluoropyrimidine and oxaliplatin for stage III, and surgery alone without adjuvant chemotherapy for stage II (excepted for pT4b tumors in which the combination of fluoropyrimidine and oxaliplatin may be a therapeutic option). Beyond these recommendations, the discussion of adjuvant treatment in MSI tumors should also include other factors such as the patient's age and comorbidities. The duration of the adjuvant treatment (3 or 6 months) and the regimen used (FOLFOX or XELOX) should be based on the recommendations of the international IDEA consortium pending the results of the translational studies of this trial. Finally, the promising results of immunotherapy in metastatic MSI colorectal led to the development of clinical trials evaluating "immune checkpoint blockers" in combination with FOLFOX in the treatment of stage III MSI colon cancer.

The introduction of new regimens and targeted therapies has prolonged survival in metastatic colorectal cancer from 1 year during the fluoropyrimidines-only era to more than 30 months today. Avoiding the cumulative toxicity of oxaliplatin, but also the physical or psychological asthenia of prolonged chemotherapy, is currently a worthwhile management goal. Data from randomized controlled trials indicate that a formalized stop-and-go approach to the delivery of oxaliplatin does not compromise efficacy. This paper presents also a critical review of the randomized trials evaluating the place of bevacizumab and cetuximab as maintenance therapy. To conclude we recommend chemotherapy holidays only after 4 to 6 months of chemotherapy and only in the population of very good responders to the induction treatment.

External irradiation and brachytherapy still have a major place in the treatment of cervix and endometrial carcinoma. This review presents the French guidelines in terms of preparation and choice of irradiation techniques of these gynecological malignancies.

Retrospective analysis of clinical aspects and therapeutic results of nasopharynx cancer local failures.Forty patients with local failure with or without nodal involvement of nasopharyngeal carcinoma were treated between 1993 and 2013. Reirradiation of nasopharynx was delivered at the dose of 60Gy. Platinum-based chemotherapy was indicated in case of locally advanced disease and/or associated nodal failure.The mean age at diagnosis of primitive tumour was 41.9 years (26-67 years). The mean time of relapse occurrence was 31.7 months (6-104 months). Sixty five percent of failures were confined to the nasopharynx. Nodal failure was seen in 14 cases. Twenty-eight patients had chemotherapy. Twenty-five patients had reirradiation of nasopharynx. Mean follow-up was 98 months (12-191 months). Fourteen patients were still alive and in complete remission. Five-year survival was 40.7%. Xerostomia was the most frequent late toxicity. No haemorrhage was seen.Reirradiation is the mainstay treatment of nasopharyngeal local failure. Late toxicity seems to decrease with novel techniques of reirradiation.

The identification of RAS status (KRAS and NRAS) has changed the management of metastatic colorectal cancer (mCRC). The impact of the RAS mutation on cytotoxic chemotherapy efficacy has not yet been determined. Nevertheless, several retrospective studies suggest a greater efficacy of oxaliplatin in mCRC with KRAS mutation.We analyzed retrospectively the progression free survival (PFS) and overall survival (OS) in 216 patients with mCRC receiving first line treatment between 2008 and 2010 according to KRAS status and chemotherapy regimen used (oxaliplatin- or irinotecan-based, in association with fluoropyrimidine and bevacizumab).In KRAS mutated tumors, median OS was 23.4 months with oxaliplatin-based regimen, and 23.6 months with irinotecan-based regimen, with no significant difference (HR 1.30; 95 % CI 0.81-2.09; P=0.27). In KRAS wild-type tumors, median OS was 30.3 months with oxaliplatin-based regimen, and 25.4 months with irinotecan-based regimen, with no significant difference (HR 0.81; 95 % CI 0.52-1.24; P=0.33). Similarly, KRAS mutational status had no significant effect on efficacy of oxaliplatin or irinotecan regarding PFS.In this retrospective study, KRAS mutational status does not influence the efficacy of first line cytotoxic chemotherapy in association with bevacizumab.

We report a case of pericarditis supervening after 5-fluorouracil infusion in a 52-year-old patient suffering from metastatic rectal cancer. Besides its well-known side-effects (mucitis, diarrhea, nausea, hematotoxicity), this molecule sometimes induces cardio-toxicity, which can take different clinical forms, pericarditis being one of the most uncommon. Several risk factors have been described and have to be kept in mind when initiating this therapy. Prevention may consist of close monitoring of patients considered at risk. Treatment of 5-FU induced cardiotoxicity basically consists in stopping the use of this drug and replacing it with another chemotherapy agent.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in France. Recently, colorectal cancer subtyping consortium (CRCSC) identified 4 consensus molecular subtypes (CMS). CMS1 is enriched for CRC with deficient DNA mismatch repair system (dMMR) and tumors with mutated BRAF. Intriguingly, CMS1 is characterized by better relapse-free survival but worse survival after relapse, compared with the other subtypes. In this review, we provide a comprehensive overview of prognostic and predictive impacts of MMR and BRAF status. We highlight immune checkpoints inhibitors as potentially future therapeutics for CRC with deficient MMR. We also focus on the management of BRAF mutant metastatic CRC, with a particular interest on targeted therapies.

Over the last decade, there have been many technical advances in radiation therapy, such as the spread of intensity-modulated conformal radiotherapy, and the rise of stereotactic body radiation therapy. By allowing better dose-to-target conformation and thus better organs at risk-sparing, these techniques seem very promising, particularly in the field of head and neck tumors. The present work aims at analyzing the level of evidence and recommendation supporting the use of high-technology radiotherapy in head and neck neoplasms, by reviewing the available literature.

In recent decades, the management of rectal cancer has been significantly improved by optimizing the surgical treatment with the total mesorectal excision and the development of neoadjuvant radiotherapy with or without chemotherapy. In this study, we investigated the impact of changes in practice over a period of 15 years in an expert centre.A monocentric study was conducted retrospectively on cT3-resectable T4 patients who received chemoradiotherapy for a locally advanced rectal adenocarcinoma between 1993 and 2008. We studied sphincter preservation, pathological complete response (ypT0), survival, and toxicities by different concomitant chemotherapy and treatment period.Among the 179 patients who had a chemoradiotherapy, 56.4% were received concomitant 5-fluoro-uracil-leucovorin, 28.5% with concomitant capecitabine, and 15.1% with concomitant oxaliplatin and capecitabine. The average dose of radiotherapy was 45 Gy (25×1.8 Gy). Five-year disease-free survival was 74.3% and overall survival 68.8%. The rate of local recurrence and distant metastases were 6.1 and 23.6%. In multivariate analysis, concomitant chemotherapy oxaliplatin and capecitabine improved the pathological complete response rate (ypT0; capecitabine: 6%, 5-fluoro-uracil-leucovorin: 10.3%, capecitabine-oxaliplatin: 22.2%), but not significantly (P=0.12) and with more toxicities, and treatment interruptions. Sphincter preservation rate was not improved significantly during the study period (1993-2004 vs. 2005-2008), but disease-free survival improved from 72.2% up to 87.5% (P=0.03).Our results are consistent with those published in the literature. Concomitant chemotherapy with 5-fluoro-uracil or capecitabine remains the standard scheme. Upfront chemotherapy, before chemoradiotherapy, should be investigated with regard to the predominance of metastasis.

The majority of pleural and peritoneal mesotheliomas are linked to asbestos exposure but, in around 20% of cases, no history of such exposure is found. Periodic disease is associated with recurrent serositis, which could favor the development of mesothelioma.We report a case of pleural mesothelioma in a 50-year-old Lebanese woman, with no detectable exposure to asbestos but suffering from periodic disease (familial Mediterranean fever) with recurrent episodes of serositis.Many cases of peritoneal mesothelioma in patients with FMF are reported in the literature. This is the second reported case of pleural mesothelioma associated with periodic disease. Because of the low incidence of both diseases, further publications are required to support the hypothesis of a causal link. It is important, therefore, that all cases of an association of periodic disease and mesothelioma are reported.

Microsatellite instability (MSI) phenotype occurs in approximately 15 to 24% of colorectal cancer (CRC) patients and may be sporadic or hereditary. It reflects a mutator phenotype in the tumor due to a lack of mismatch repair system. MSI is indeed one of the characteristics of CRCs occurring in Lynch syndrome and some sporadic cases. CRCs with MSI have a better prognosis than CRCs with microsatellite stability (MSS). This is explained partly by a more important anti-tumor immune response and by apoptosis of tumor cells in which mutations accumulate. However, in some retrospective studies, microsatellite instability in stage II CRCs was associated with no benefit to or even a deleterious effect of 5-FU alone based adjuvant therapy. Nevertheless, results obtained in stage III CRCs with FOLFOX type adjuvant chemotherapy remain favorable in retrospective studies.

To retrospectively assess the impact of age on tolerance and oncologic outcomes treated by neoadjuvant treatment for patients of 70 years old or above with locally advanced rectal cancer.Ninety-one consecutive patients were divided into three groups: group 1 from 70 to 75 years (n=31); group 2: 76 to 79 years (n=31) and group 3, patients aged 80 years or above (n=29). Radiation therapy was delivered according two schemes: 25Gy in five fractions (short scheme) or 45 to 50Gy with a classical fractionation (long scheme). Long scheme patients received a concomitant chemotherapy with 5-fluoro-uracile alone or associated with oxaliplatin.The three groups were comparable for performance status, Charlson's score and T staging. Long scheme radiation therapy and chemotherapy were performed in 77.5, 74.5 and 48.3% of patients (P=0.03) and 77.4, 71 and 41.4% (P=0.006) in the groups 1, 2 and 3, respectively. All patients treated with the short scheme irradiation received the treatment without any acute toxicity. In the long scheme group, 65% of patients received the treatment on time and grade 3 or above toxicity was observed in 12% of patients who did not receive oxaliplatin and in 48% of patients who received oxaliplatin. The overall survival rate at 3 and 5 years was 66.9% and 60.8% in the group 1, 90.5% and 75.9% in the group 2 and 80.5% and 73.8% in the group 3 (P=0.15).Neoadjuvant treatment is feasible with encouraging survival rates for patients aged 70 years and older. Short scheme radiation therapy seems to be an interesting option in this population.

One hundred and ten consecutive patients suffering from a colorectal cancer received chronotherapy infused over two days every two weeks. Each course comported 5 FU 3g/m(2), folinic acid (600 mg/m(2) - l. form or 1200 mg/m(2)--racemic form) and oxaliplatin (85/mg/m(2)--adjuvant indication or 100mg/m(2)--palliative indication). According to chronobiological concepts, 5 FU and folinic acid were infused from 10 pm to 10 am with a peak at 4 am while oxaliplatin was delivered from 10 am to 10 pm with a peak at 4 pm. The overall tolerance was excellent with a maximum of 17% patients experiencing a grade 3 toxicity. The toxicity was higher in women, in older patients (=70) or in case of flat infusion. In adjuvant situation (60 cases), progression free and overall survivals established respectively at 76% (42+months) and 88% (45+months). Fifty-two percent response rate were recorded within the palliative group (50 cases) with an overall 68% disease control. Median progression free survival was seven months but median survival was not attained at 31+ months. Thirty percent patients could benefit from a curative surgery after chemotherapy. Older patients (=70) experienced worsened survival. In conclusion, we think that our chrono-FOLFOX 2-12 should be proposed as standard treatment for colorectal cancer patients.

KRAS status is now a mandatory prerequisite in order to treat metastatic colorectal patients with anti-Epidermal Growth Factor Receptor (EGFR) antibodies, such as cetuximab or panitumumab. KRAS mutations are unambiguously linked to a lack of response to these targeted therapies. Because of the major clinical impact of KRAS status, an observational study has been designed in France, focusing on the ability to perform KRAS testing between october 2008 and october 2009. The study was retro-prospective, national, multicentric, descriptive and non interventional, concerning public and private institutions and KRAS non mutated patients treated with panitumumab. The primary objective of this study was to evaluate delays between the genotyping KRAS request and the result. Secondary objectives were: type of genotyping requests (systematic/prospective or specific/retrospective), prevalence of the different genotyping techniques, delays between the genotyping KRAS request and therapy with panitumumab. Overall, 329 patients from 66 centres have been included. About half of them belonged to private institutions. The results were obtained with a mean delay of 33.4 ± 39.8 days (CI 95%: [28.8; 37.9] days; median: 24 days). Most of KRAS genotyping tests were performed on specific requests (65.3%), from a primary tumor (80.4%) and from a surgical specimen (73.9%). The more frequently used techniques for KRAS genotyping were: real time PCR (36.2%), sequencing (24.8%) and pyrosequencing (13.2%). This study emphasizes the functionality of cancer molecular genetic platforms dedicated to KRAS genotyping, which allow the use of molecular predictive biomarkers by different medical institutions. This study also underlines the broad spectrum of genotyping techniques (no consensus). The delays of response are still longer than expected but might be improved by optimizing the procedures.

The outcome for patients with metastatic pancreatic ductal adenocarcinoma is dismal. In this article, we will review current first-line treatments for metastatic pancreatic adenocarcinoma focusing on phase III randomized studies. Single-agent gemcitabine, the reference treatment since 1995, offers only slight benefit. Numerous trials using gemcitabine in combination with different cytotoxic agents have resulted in no major improvement compared to gemcitabine alone. Only the gemcitabine-erlotinib combination has shown a small, but statistically improvement in survival. In selected patients with good performance status ECOG 0-1, no cardiac ischemia and almost normal bilirubin level, the Folfirinox regimen, when compared to gemcitabine as single agent, was associated with more toxicities, but also with significant increased survival and delay in the degradation of quality of life. So, Folfirinox is a new more toxic and more efficient regimen that may be considered in patients with good performance status.

International audience; Protracted preoperative radiochemotherapy with a 5-FU-based scheme, or a short course of preoperative radiotherapy without chemotherapy, are the standard neoadjuvant treatments for resectable stage II-III rectal cancer. Local failure rates are low and reproducible, between 6 and 15% when followed with a "Total Mesorectal Excision". Nevertheless, the therapeutic strategy needs to be improved: distant metastatic recurrence rates remain stable around 30 to 35%, while both sphincter and sexual sequels are still significant. The aim of the present paper was to analyse the ongoing trials listed on the following search engines: the Institut National du Cancer in France, the National Cancer Institute and the National Institute of Health in the United States, and the major cooperative groups. Keywords for the search were: "rectal cancer", "preoperative radiotherapy", "phase II-III", "preoperative chemotherapy", "adjuvant chemotherapy" and "surgery". Twenty-three trials were selected and classified in different groups, each of them addressing a question of strategy: (1) place of adjuvant chemotherapy; (2) optimization of preoperative radiotherapy; (3) evaluation of new radiosensitization protocols and/or neoadjuvant chemotherapy; (4) optimization of techniques and timing of surgery; (5) place of radiotherapy for non resectable or metastatic tumors.

Chemotherapy does not increase the survival time of patients treated for rectal cancer. Chemotherapy given concomitantly to radiotherapy and combined before or after radiation significantly reduces the risk of local recurrence. The sterilization of the tumour (complete pathological response) by chemotherapy is a favourable prognostic factor. New trials on optimisation of pathological complete response rates are based on using drugs effective on metastatic colorectal cancer, given prior to chemoradiotherapy and followed by a resection at least 8 weeks after the end of the radiotherapy. The level of evidence for postoperative chemotherapy is low due to lack of specific study. The indication of postoperative chemotherapy depends on the disease extent after preoperative treatment.

Being the second cancer for men and the third cancer for women in France, colorectal cancer represents a serious public health issue. Its incidence has increased these last years and despite new therapeutics being developed, it still has a bad prognostic. Thanks in part to Hemoccult national mass screening program, its diagnosis is made possible at an earlier stage, which makes a surgical curative resection and the carrying out of adjuvant chemotherapy possible. For stage III colic cancer that has been surgically removed, adjuvant chemotherapy by FOLFOX 4 has to be offered. Nevertheless, because of its toxicities, the patient's high age, important comorbidities or post-surgical complications, this chemotherapy occasionally cannot be done. What are the colorectal cancer prognostic factors which would guide the chemotherapy? TNM classification, number of examined lymph nodes, MSI status, and presence or not of a perforation or a perinervous, lymphatic or venous invasion is recognized prognostic factors. Also, what are the alternatives of FOLFOX 4 regimen as colorectal cancer adjuvant treatment?

To study the risks of haemodynamic instability, and the possible occurrence of spinal haematoma, meningitis and epidural abscess when epidural analgesia is performed for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).We retrospectively analyzed the data of 35 patients treated by HIPEC with oxaliplatin or cisplatin. An epidural catheter was inserted before induction of general anaesthesia. Postoperatively, a continuous epidural infusion of ropivacain, then a patient-controlled epidural analgesia were started.The epidural catheter was used peroperatively before HIPEC in 12 subjects (34%), and after HIPEC in 23 subjects (66%). The median dose of ropivacain given peroperatively in the epidural catheter was 40 mg (30-75). Norepinephrin was used in two subjects (6%) peroperatively (median infusion rate 0.325 μg/kg per minute [0.32-0.33]), and in four subjects (11%) in the postoperative 24 hours. No spinal haematoma, meningitis or epidural abscess were noted. Five subjects (14%) had a thrombopenia or a prothrombin time less than 60% before catheter removal. Two subjects (6%) had a leukopenia before catheter removal. No thrombopenia or blood coagulation disorders were recorded the day of catheter removal.In this series of 35 patients, the use of epidural analgesia for HIPEC does not seem to be associated with a worse risk of haemodynamic instability, spinal haematoma, meningitis or epidural abscess. HIPEC with platinum salt is not incompatible with the safety of epidural analgesia, with an optimized fluid management peroperatively and the following of perimedullary anesthesia practice guidelines.

Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is now the reference technique for limited peritoneal carcinomatosis (PC). Operative mortality is actually at 3 or 4%, and decrease as morbidity. Together, they did not limit acceptation of HIPEC. However, one of the major limitation of this aggressive treatment is that patient can be afraid to impair overall quality of life (QoL). The aim of this article was to assess QoL in patients at least 12 months after HIPEC using Oxaliplatin.Patients completed a questionnaire before and after surgery at 1, 3, 6 and 12 months. QoL was assessed with the EORTC QLQ-C30 questionnaire. RESULTATS: Between September 2006 and October 2008, 32 of 35 patients who had undergone HIPEC were interviewed. PC originated in primary lesions of the colon/rectum (N = 17), ovary (N = 3), stomach (N = 3), appendix (N = 2), mesothelium (N = 2), pseudomyxoma peritonei (N = 3) and primary carcinoma of peritoneum (N = 2). The percentage of patients completing the questionnaire at each time point was: baseline = 87% (N = 28); 1 and 3 months = 46% (N = 15); 6 months = 62% (N = 20); and 12 months = 59% (N = 19). Morbidity and mortality were respectively 35 and 5%. Median hospital stay was 19 days. QoL score had decreased considerably in 60% of patients in the early postoperative assessment period after HIPEC (1 month), as compared with baseline score. Forty five per cent had reported significant pain and limitations on physical functioning. QoL score had returned to baseline at 3 months in 53,3% of patients: 20% reported lack of energy and fatigue. Fifty-five and 73% of patients had recovered their overall QoL at 6 and 12 months, respectively. Also, psychosocial problems, diarrhea and constipation, and peripheral neuropathy of oxaliplatin were reported in 20% of survivors over the course of the first year after HIPEC.Short-term QoL with physical and functional well-being are impaired in the first few months after surgery plus HIPEC using oxaliplatin. Long-term QoL returns to baseline at 3 months; however 20% of patients still report psychosocial problems, gastrointestinal symptoms and oxaliplatin-induced neuropathy. It is useful and important for patients to see this HIPEC QoL data at the time of consultation before treatment.

Fundamental research identified new therapy targets implicated in tumor proliferation and angiogenesis which lead to the development of several targeted therapies. Currently, three drugs are used in the treatment of advanced colorectal cancer, cetuximab and panitumumab, two anti epidermal growth factor receptor, and bevacizumab, an anti vascular endothelial growth factor.We evaluated a treatment with oxaliplatin-based chemotherapy (Folfox7 regimen) and bevacizumab in patients with locally advanced and/or metastatic colorectal cancer. Objectives of the study are the evaluation of the efficacy, toxicity, progression free survival, overall survival and tumor cell expression of the vascular endothelial growth factor by immunochemistry.47 patients are included in the study during the period between April 2005 and June 2007; 28 men and 19 women. After six cycles of treatment, we achieved 67.3% of objectives responses and 76% of tumor control. The median progression free survival evaluated was 12 months (9.3-14.6 months) and median overall survival 18 months (9-26.9 months). The immunochemistry study of 46 tumours of the study achieved the following results: 13% (0), 17.4% (1+), 23.9% (2+) and 45.7% (3+). A correlation between the vascular endothelial growth factor expression, therapeutic responses and survival has been demonstrated but the difference was not significant in term of survival. Both chemotherapy toxicity and bevacizumab related toxicity are acceptable in our study.The fact that vascular endothelial growth factor expression is common in more than 80% of colorectal cancers, lead to recommend the systematic use of bevacizumab with chemotherapy in the treatment of advanced colorectal cancer.

Pure testicular seminoma is a rare disease with an excellent prognosis. Its management is controversial. In stage I disease, several treatment options are considered. Those are radiation therapy alone, chemotherapy alone or active surveillance, which is becoming increasingly popular. For more advanced stages, treatment is based on chemotherapy with or without radiation therapy. In this article, we review thoroughly the existing literature and recent recommendations the various treatment options, their advantages and disadvantages in different stages of the disease.

Colorectal cancer (CCR), which is one of the most common causes of cancer, has benefited from the major advances in the understanding of the intracellular signaling pathways implicated in the initiation, growing and local and metastasis dissemination of tumor, which have occurred during the 20 past years. The pharmacogenomics approach, especially the determination of the genetic polymorphisms, tries to find prognosis and predictive biomarkers permitting to identify patients who could benefit from a particular treatment or those exhibiting higher risks of toxicity. Among the numerous biomarkers, which have been studied, few are currently in use in clinical practice. The phenotyping of DPD and UGT1A1 activities, and to a lesser extent, its genotyping, appears as the most useful tool in terms of prediction of toxicities induced by two major drugs: 5-FU and irinotecan. For oxaliplatin, the determination of the polymorphisms of reparases and detoxification systems such as GSTpi seems interesting, but its exact place should be more defined. It is in the field of targeted therapies that the pharmacogenomics approach seems to be the more relevant. KRAS mutation is a dramatic example of single nucleotide polymorphism, which is able to identify a priori patients that could receive or not an anti-EGFR monoclonal antibody such as cetuximab or panitumumab. It is obvious that pre-clinical identification of molecular biomarkers predictive of the sensitivity of the drug targets, which subsequently implicate the selection of patients and the rational evaluation of responses, will be the cornerstone of any clinical trials concerning targeted therapies. Besides the determination of drug target polymorphisms, it is also important to consider those related to the distribution and metabolism. In this area, the determination of enzymatic activities should recover its place besides the genomic profiling.

Although the prognosis of patients with colorectal liver metastases (CLM) has improved dramatically with oxaliplatin and irinotecan, the enthusiasm for the preoperative use of these cytotoxic agents is being tempered by concerns about their impact on the nontumoral liver parenchyma. Bevacizumab, an anti-angiogenic agent that specifically targets the vascular endothelial growth factor, exerts an antitumor effect by inhibiting the development of the vascular network that is promoted by the tumor and mandatory for its growth. Yet angiogenesis is also a physiologic event contributing to wound healing and tissue regeneration. To date, it is well documented that the use of bevacizumab in combination with cytotoxic agents greatly improves pathologic response. Also well described is the protective effect of bevacizumab against sinusoidal injuries induced by oxaliplatin-based chemotherapy. Up to now, no side effects related to the perioperative use of bevacizumab have been reported in the setting of liver resection for CLM, and bevacizumab was shown not to impair liver regeneration following portal vein embolization. The clinical consequences of the protective effect of bevacizumab against sinusoidal injuries are hard to evaluate as patient selection and preparation have improved and these improvements contribute greatly to the favorable outcomes following liver resection for CLM. Indeed, patient safety in the setting of hepatic resection for CLM mainly depends on a careful preoperative evaluation of liver volumes and a limited use of cytotoxic agents followed by a delay of at least 5 weeks before the surgery.

To develop a treatment strategy for peritoneal carcinomatosis using a combination of extended peritoneal resections, local destructive procedures and hyperthermic intraperitoneal chemotherapy creates great concern between healthcare workers involved in these procedures. New professional risks exist: risk of exposure to cytotoxic drugs, environmental risks (inhalation of smoke, aerosolization of chemotherapy agents). Information, education and training of healthcare workers is mandatory in order to ensure proper evaluation, prevention, and management of professional exposure risks in coordination with the occupational health office.

FOLFOX 4 chemotherapy (5-fluorouracil, leucovorin and oxaliplatin) is the standard adjuvant treatment for stage III colon cancer. The principal secondary effects described are haematological, gastro-intestinal or neurological. A single case of obliterative bronchiolitis with organising pneumonia has been described recently.We report the case of a female patient aged 74 years who, after 12 courses of FOLFOX 4 chemotherapy, developed acute onset of severe shortness of breath and a dry cough but remained afebrile. A thoracic CT-scan showed symmetrical bilateral interstitial infiltration that was reticular in appearance, and predominantly basal and peripheral in distribution. Broncho-alveolar lavage revealed an alveolitis with 9% eosinophils and 4% neutrophils. Transbronchial biopsies showed the appearances of obliterative bronchiolitis with organising pneumonia. Systemic corticosteroid treatment led to a remarkable clinical and functional improvement.To our knowledge, this is the second case of obliterative bronchiolitis with organising pneumonia that has been described following adjuvant treatment based on FOLFOX 4.

Several drugs have been developed and demonstrated similar efficacy in colorectal cancer treatment therefore with choice, time comes for decision. The biologist will have to provide the tools allowing to clarify this choice. Among the tools available, those of pharmacogenetics and pharmacogenomics appear most promising and recent examples allow to illustrate their clinical interest. The pharmacogenetics of anti-cancer agents presents a clinical characteristic, which requires to hold into account the genetic variations not only of host cells but also of those of the tumor cells. Among the most conclusive examples one is that of the prediction of severe neutropenia induced by the irinotecan among patients homozygous for * 28 allele of UGT1A1 enzyme which conjugates SN38 active compound of irinotecan, the other one is the presence of a KRAS mutated allele in tumor cell to predict resistance to anti EGFR antibodies in the treatment of colorectal metastatic cancer.

Regarding the evolution of the treatments of colorectal cancer during the last five years, it appears that numerous questions have to be considered with a strategic point of view. In order to avoid inclusion of a lot of patients in clinical patients, we urgently need the help of biology to give us arguments to choose one treatment or another. The fact that ten years after their approval, we are not able to select responders to oxaliplatin or irinotecan, confirm that this is difficult problem to solve. The contribution of biology to the prescription of drugs commonly used in colorectal cancer is discussed in this paper. There are already situations where the contribution of biology to clinical practice and prescription is not debatable : this is the case for the use of UGT1A1 status determination when using irinotecan and the determination of KRAS status for the prescription of panitumumab (and cetuximab in a few months). This individual adaptation is a dream that becomes reasonable when we look on the recent results concerning EGFR inhibitors, but a lot of work has to be done and it is not sure that biological assessment of the tumour will be able to solve all the problems. For instance, to determine predictive factors of response to angiogenesis inhibitors, it is likely that solutions will come from new techniques of imaging rather than from biology. However, new tools such as proteomics or metabolomics, as well as a better dialogue between clinician and biologist, will allow fast improvements. It must be emphasised that, for the first time in 2008, it is possible to prescribe targeted therapies to a specific "targeted" group of patients with metastatic colorectal cancer.

By today, systemic therapy for pancreatic cancer remains a huge challenge considering the last 10 years existing data. In 1997, gemcitabine emerged as a new reference treatment in advanced disease stage displaying a valuable clinical benefit rate but an overall survival limited to 6 months. In 2007, around 20 large phase III trials enrolling 7000 patients have evaluated a lot of new cytotoxic and biological compounds, but only a modest and poorly clinically relevant benefit in survival of 0.5 month was obtained, a result in sharp contrast to what it is observed in other types of cancer, where some substantial progress was noted over the last ten years. Considering the aggressive and multiresistant phenotype of this cancer, a different and more selective approach for development of new therapies has to be envisaged, starting with the deciphering of the biomolecular mechanism, first step towards the discovery of new therapeutic targets. By this way only, we could anticipate relevant advances and better exploitation and exploration of future targeted therapies.

Gemcitabine is one of the key products actually used in metastatic breast cancer. Thanks to its favourable toxicity profile, gemcitabine can be used in combination with a number of drugs. Recently published and presented results from different trials may modify our perception and strategies regarding metastatic breast cancer. In this overview we will focus on the results of these trials and particularly those recent concerning the combination of gemcitabine with taxanes, vinorelbine, platinum salts and trastuzumab.

Gemcitabine is a well-tolerated anti-tumour drug with broad-spectrum activity. It is now recommended for treatment in an increasing number of tumours. Locally advanced or metastatic pancreatic cancer is the only digestive cancer for which it has yet been approved. Numerous phase III trials have addressed gemcitabine's dosage, infusion modalities, and its potential association with other anti-tumour drugs in pancreatic cancer. Standard recommended treatment for this disease in 2006 is gemcitabine monotherapy following Burris'protocol, that is 1000 mg per square meter in a 30 minute-infusion weekly for seven weeks, one week off and then weekly for three weeks, repeated every 4 weeks. Many phase I or II trials have been carried out in all other digestive cancers. They show gemcitabine's potential activity, especially in esophageal cancer, biliary tract adenocarcinoma and hepatocellular carcinoma. Nevertheless, larger studies are required to confirm this efficacy. The aim of this review is to describe the trials that have contributed to determine gemcitabine's infusion modalities in pancreatic cancer. We will then present the studies that have been carried out in other digestive cancers.

Although the number of men presenting with metastatic prostate cancer has decreased significantly over the last several years, the death rate for those men is essentially unchanged. Effective treatments have not existed for prostate cancer progressing after androgen deprivation therapy until recently. Docetaxel based chemotherapy has demonstrated to extend patient survival in two large randomized studies. These studies have provided the impetus to combine docetaxel with novel biologic drugs to further consolidate the gains in long-term outcome. With the arrival of new therapies such as epothilone analogues, small molecule receptor tyrosine kinase inhibitors, monoclonal antibodies, bone-targeted drugs, antisense oligonucleotides, antiangiogenics drugs and endothelin receptor antagonists, the future of prostate cancer therapy appears promising.

Antineoplastic drugs used in the treatment of cancers present with variable renal tolerance profiles. Among drugs with a potential for renal toxicity, platinum salts, methotrexate, and gemcitabine are well-known. The mechanisms of their renal toxicity and the means of its prevention are presented in this article. Anti-angiogenic drugs, recently marketed or still under clinical development, may also interact with the kidneys. In general, optimising the renal tolerance of anticancer drugs requires an appropriate evaluation of patients'renal function, before and during treatment, at each course. Serum creatinine alone is not a reliable index of renal function. Its evaluation must be performed with the use of Cockcroft-Gault or aMDRD formulae. In patients with abnormal renal function, dosage adjustment is often required to improve the renal tolerance, and also to limit the risk of extra-renal toxicities (such as haematological toxicities) induced by a drug overdosage, in those patients with reduced drug-elimination.

Clinical implications associated with polymorphisms in drug-metabolizing genes involved in the chemotherapy of colorectal cancers (5-flurorouracil, oxaliplatin and irinotecan) are reviewed.Treatments of colorectal cancers have been greatly improved last years but patients respond differently to identical medication. Genetic polymorphisms are one of the major causes of these individual responses to drugs associated with sometimes severe adverse effects. Pharmacogenetics is based on all polymorphisms that determine genetic human diversity associated with variable response to anticancer drugs.Morbidity and mortality related to toxicity or inefficacy of these drugs could be reduced by analyzing the pharmacogenetic profile of patients before treatment. Results should be integrated in protocols for monitoring and assessment the dosage of drugs.

We report a case of laparoscopic ovarian transposition and ovarian cryopreservation in a nulliparous 25-year-old woman with rectal cancer. The authors focus on the surgical technique and the importance of preserving ovarian function.

Colorectal cancer is a real national healthy problem because of high frequency and high rate of mortality. Folfox4 is the new standard treatment since publication of Mosaic' results. Irinotecan associated with 5 fluorouracil (5FU) and leucovorin (LV) failed to demonstrate superiority over LV modulated 5FU. Oral fluoropyrimidines (capecitabine or UFT + LV) are an effective alternative to intravenous 5FU and LV. In stage II colon cancer, treatment strategies are more debated. Some data suggest that chemotherapy is not mandatory for stage II tumors low risk (T3N0 without risk factors). For stage II tumors with high risk factors (T4 or bowel obstruction, perforation, poorly differenciated tumor or,10 examined lymphs nodes), Folfox4 and fluoropyrimidine (oral and LV5FU2) should be candidate as adjuvant treatment. Now studies evaluate the role of bevacizumab (Avant, NSABP C08) and cetuximab (Petacc 8 and NCCTG-N0147) in combination with Folfox4 in stage III tumors.

Oxaliplatin is a reference drug in the treatment of digestive-tract tumors, especially colorectal cancer. Its toxicity profile is dominated by a peripheral sensitive neuropathy, with neuromuscular manifestations. This neurotoxicity has 2 components: an acute toxicity characterized by a rapid onset of cold-induced distal dysesthesia and/or paresthesia, muscular contractions, numbness, stiffness, usually transient but able to evolve into a chronic, persistent sensory peripheral neuropathy that eventually causes functional impairment. A persistent sensory peripheral neuropathy may develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia and functional impairment. This neurotoxicity is frequent, 80%of the patients and becomes chronic in 15 to 20%of the patients, sometimes irreversible. The mechanism of this neurotoxicity has been elucidated: an increased neuronal excitability is due to the action of oxaliplatin on voltage-gated sodium channels through chelation of calcium by the oxaliplatin metabolite. The prevention of this neurotoxicity is a major goal, taking in account the wide indications of this drug. Different approaches have been or are evaluated, based on pathogenic or practical concepts: 1) modifications of the administration schedule; 2) substances acting upon sodium channels : calcium-magnesium, carbamazepine, gabapentine, venlafaxin; 3) detoxifying agents and antioxydants: glutathion, amifostine, alphalipoic acid, tocopherol ; 4) substances used in other kinds of neuropathy: glutamine, alphalipoic acid; 5) neurotrophic factors: NGF, LIF; 6) oxaliplatin analogs, with a DACH platin, without oxalate. Calcium-magnesium infusion seem to be an efficient and safe approach. Further studies are necessary for a better understanding and prevention of this neurotoxicity, potentially severe.

Up to date, standard treatment of locally advanced rectal cancer is preoperative radiotherapy with concurrent chemotherapy. Results of FFCD and EORTC French randomised trials showed that preoperative radiochemotherapy with 5-fluorouracil (5FU) compared with radiotherapy increases operative specimen sterilisation and local control, without any benefit on overall survival. One of the greatest challenges in rectal cancer is to improve schedules of pre operative chemoradiotherapy. Oxaliplatin is proved to be a radiosentitizer and to be effective on advanced colorectal cancer. Consequently it is an adequate drug to associate with 5FU and radiation. Several phases I and II studied the association between 5FU infusion-oxaliplatin-radiation therapy or capecitabine-oxaliplatin-radiation therapy with a moderate toxicity (essentially diarrhoea) and a promising tumoral activity. All the studied schedules seem to have a similar efficiency with a questionable increased toxicity with continuous administration of 5FU or capecitabine. Only randomized trials comparing 5FU to 5FU or capecitabine plus oxaliplatin will attest the benefit of oxaliplatin on local control, sphincter preservation and overall survival, and will estimate its toxicity compared with monochemotherapy.

Surgery is the only curative treatment for patients with colorectal liver metastases with recent reports documenting 5-year survival results of 40-50%. In unresectable patients, the use of more effective regimens of chemotherapy has contributed to improve the results of survival at short term and new onco-surgical strategies have emerged. By allowing resection of previously unresectable liver metastases, these onco-surgical strategies now offer 15-20% of patients a real potential of long-term remission (5-year survival 30-40%). Chemotherapy is also used in the adjuvant setting, to prevent post-operative recurrence. In resectable metastases, it may also be used as neo-adjuvant treatment to control tumor progression before surgery and to select the patients likely to really benefit from liver resection. The objective of this article is to describe this multidisciplinary approach of liver metastases and to report the results of these new strategies.

Oxaliplatin was brought into clinical evaluation in ovarian cancer because of the in vitro and in vivo antitumor activity observed in experimental models resistant to cisplatin. As single agent at 130 mg/m2 every 3 weeks, the objective response rates rage from 16% to 29% in patients treated after failure of one or two regimens. As first line, in a randomized trial cyclophosphamide-cisplatin versus cyclophosphamide-oxaliplatine, no significant statistical differences were observed in efficacy parameters (response rate, progression free survival and overall survival). The toxicity profile seemed to favor the oxaliplatin arm. Many associations with other available active drugs as taxanes, gemcitabine and liposomal doxorubicin were performed with promising results.