Digestive Toxicity Research Articles

Contrast analysis of oxaliplatin adverse reactions though different intravenous injection ways

Objective To compare the adverse reaction′s incidence of oxaliplatin with three different injection ways, to explore the most appropriate infusion. Methods A total of 90 patients were randomly divided into 3 groups averagely: peripheral vein (PV) group, central venous catheterization (CVC) group and peripherally inserted central catheter (PICC) group. The occurrence rate and degree of adverse reaction were compared among groups including peripheral neuritis, blood system, digestive system toxicity. Results The occurrence rates of peripheral neuritis were 37.50%, 21.43%, 10.00% in the PV group, CVC group and PICC group, and the difference was statistically significant (χ2=6.628, P 0.05). Conclusions The best method of oxaliplatin infusion among these three ways is PICC, followed by CVC, and PV is not recommended. Key words: Catheterization; CVC; Peripheralvein; Oxaliplatin; Toxic action

FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma.

To evaluate the efficacy and tolerance of FOLFIRI plus bevacizumab treatment outcome as second-line treatment for metastatic intrahepatic cholangiocarcinoma. Thirteen consecutive patients with metastatic intrahepatic cholangiocarcinoma who were refractory to first-line therapy consisting of gemcitabine plus oxaliplatin-based first-line chemotherapy given intravenously via intra-arterial infusion were treated with FOLFIRI [irinotecan (180 mg/m² i.v. over 90 min) concurrently with folinic acid (400 mg/m² i.v. over 120 min) followed by fluorouracil (400 mg/m² i.v. bolus) then fluorouracil 2400 mg/m² intravenous infusion over 46 h] and bevacizumab (5 mg/kg) every 2 wk. Tumor response was evaluated by computed tomography scan every 4 cycles. The best tumor responses using response evaluation criteria in solid tumor criteria were: complete response for 1 patient, partial response for 4 patients, and stable disease for 6 patients after 6 mo of follow-up. The response rate was 38.4% (95%CI: 12.5-89) and the disease control rate was 84.5% (95%CI: 42-100). Seven deaths occurred at the time of analysis, progression free survival was 8 mo (95%CI: 7-16), and median overall survival was 20 mo (95%CI: 8-48). No grade 4 toxic events were observed. Four grade 3 hematological toxicities and one grade 3 digestive toxicity occurred. An adaptive reduction in chemotherapy dosage was required in 2 patients due to hematological toxicity, and a delay in chemotherapy cycles was required for 3 patients. FOLFIRI plus bevacizumab combination treatment showed promising efficacy and safety as second-line treatment for metastatic intrahepatic cholangiocarcinoma after failure of the first-line treatment of gemcitabine plus oxaliplatin chemotherapy.

Tóxicos vegetales: un problema aún vigente

IntroductionA medical visit for plant ingestion is rare in the pediatric emergency services but may involve a high toxicity. The botanical toxicology training of health staff is often very limited, and it can be difficult to make a diagnosis or decide on the appropriate treatment. ObjectiveTo study the epidemiological and clinical characteristics of poisoning due to plant ingestion in order to increase the knowledge of the health professional. Material and methodsA descriptive retrospective study was conducted on patients seen in a pediatric emergency department after the ingestion of plant substances from January 2008 to December 2012. ResultsDuring the period of study, 18 patients had ingested possible toxic plants. In 14 cases, it was considered to be potentially toxic: broom, oleander, mistletoe, butcher's-broom, and vulgar bean (2), Jerusalem tomato, castor (2), Jimson weed, potus, marijuana, and mushrooms with digestive toxicity (2). Among the potentially toxic cases, the ingestion was accidental in 10 patients, 2 cases were classed as infantile mistreatment, 1 case had recreational intention, and another one suicidal intentions. The ingestion of oleander, castor and Jimson weed had major toxicity. ConclusionsThe potential gravity of the ingestion of plant substances and the variety of the exposure mechanism requires the pediatrician to bear in mind this possibility, and to be prepared for its diagnosis and management. Specific preventive information measures need to be designed for the families and for the regulation of toxic plants in playgrounds.

942TiP - Encourage: the Use in Routine Practice of Bevacizumab in First-Line Therapy for Patients with Ovarian Cancer– a Gineco Prospective Cohort Study

ABSTRACT Background: The two phase III first-line trials GOG 218 and ICON 7 met their primary progression free survival endpoint, leading to an European Union approval in december 2011 of bevacizumab in combination with carboplatin and paclitaxel during 6 cycles, followed by a maintenance period for a total time of 15 months for the treatment of patients with FIGO IIIb-IV stage ovarian cancer. The ENCOURAGE prospective, multicenter cohort study has been developped to describe bevacizumab administration in ovarian cancer, in the daily practice, outside of trials with their usual patient selections and specific follow-up methods Trial design: A total number of 500 patients with ovarian cancer, treated with bevacizumab in first-line, in 100 French centers, will be included. Investigators will record the reasons why they indicate or exclude bevacizumab administration in the first-line treatment strategy of each of their patients with ovarian cancer. The primary endpoint is to report the cardio-vascular, renal and digestive toxicity of bevacizumab delivered in a wide scape of French centers (academic or not hospitals, private clinics, anticancer centers). The secondary endpoints include evaluation in real life of bevacizumab use in ovarian cancer treatment in first-line (the characteristics of the treated population, the reason of non administration of bevacizumab in first line), the modalities of use and the monitoring pratices. At last, the efficacy of the bevacizumab treatment strategy will be also evaluated by analysing the progression free survival in both first line and relapse with or without bevacizumab. From April 2013, to April 2014, more than 200/500 patients have been registered. Disclosure: I.L. Ray-Coquard: Roche, Pharmamar, Amgen, AstraZeneca board and lecture; A. Floquet: Investigator fees and congress participation support in Roche Clinical Studies; J. Alexandre: I am a member of an advisory board concerning bevacizumab. All other authors have declared no conflicts of interest.

Intérêt du génotypage de l’UGT1A1 dans le cadre du traitement des cancers digestifs par irinotécan

Irinotecan is a cytotoxic agent administered by IV infusion in the treatment of advanced colorectal cancer. Its anticancer activity results from its bioactivation into SN-38 metabolite, which is cleared through glucuronidation by the hepatic enzyme uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1). In the general population, there is wide inter-subject variability in UGT1A1 enzyme activity related to UGT1A1 gene polymorphisms. The French joint workgroup coming from the National Pharmacogenetic Network (RNPGx) and the Group of Clinical Oncologic Pharmacology (GPCO) herein presents an updated review dealing with efficacy and toxicity clinical studies related to UGT1A1 genetic variants. From a critical analysis of this review it clearly emerges that, for doses higher than 180mg/m2, hematologic and digestive irinotecan-induced toxicities could be prevented in daily clinical practice by generalizing the use of a simple pharmacogenetic test before starting treatment. The clinical relevance of this test is also discussed in terms of treatment efficacy improvement, with the possibility of increasing the irinotecan dose in patients not bearing the deleterious allele. This test involves using a blood sample to analyze the promoter region of the UGT1A1 gene (UGT1A1*28 allele). Best execution practices, laboratory costs, as well as results interpretation are described with the aim of facilitating the implementation of this analysis in clinical routine. The existence of a French laboratories network performing this test in clinical routine makes it possible to generalize UGT1A1 deficiency screening, so as to guarantee equal access to safe treatment and optimized irinorecan-based therapy for the many patients receiving irinotecan-based therapy in advanced colorectal cancer.

Digestive capacity and toxicity cause mixed diets in red knots that maximize energy intake rate.

Among energy-maximizing animals, preferences for different prey can be explained by ranking the prey according to their energetic content. However, diet choice also depends on characteristics of the predator, such as the need to ingest necessary nutrients and the constraints imposed by digestion and toxins in food. In combination, these factors can lead to mixed diets in which the energetically most profitable food is not eaten exclusively even when it is abundant. We studied diet choice in red knots (Calidris canutus canutus) feeding on mollusks at a West African wintering site. At this site, the birds fed primarily on two species of bivalves, a thick-shelled one (Dosinia isocardia) that imposed a digestive constraint and a thin-shelled one (Loripes lucinalis) that imposed a toxin constraint. The latter species is toxic due to its symbiotic association with sulfide-oxidizing bacteria. We estimated experimentally the parameters of a linear programming model that includes both digestive and toxin constraints, leading to the prediction that red knots should eat a mixture of both mollusk species to maximize energy intake. The model correctly predicted the preferences of the captive birds, which depended on the digestive quality and toxicity of their previous diet. At our study site, energy-maximizing red knots appear to select a mixed diet as a result of the simultaneous effects of digestive and toxin constraints.

Circadian variation of mycophenolate mofetil pharmacokinetics in rats

The present work aims to investigate whether the pharmacokinetics of the active metabolite mycophenolic acid (MPA) varies according to the circadian dosing-time of mycophenolate mofetil (MMF). A total of 180 male Wistar rats aged 8 weeks and synchronized for 3weeks to 12h light and 12h dark were used. A single dose of 200mg/kg of MMF was administrated in rats by i.p route at either of the four different circadian stages (1, 7, 13, and 19 Hours After Light Onset, HALO) (45 rats/circadian time). At each circadian stage, blood samples were collected at 5, 10, 15, 20, 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 12h and 24h following drug injection. Plasma MPA concentrations were analyzed for each sample using a validated high-performance liquid chromatography (RP-HPLC) method.Tmax of MPA remained similar whatever the circadian time of injection mean Tmax=30min). However, the peak of plasma concentration Cmax varied significantly according to the circadian dosing-time. Maximum and minimum Cmax were obtained when MMF was injected at 7 HALO (69.1μg/ml) and at 19 HALO (22.7±1.74μg/ml) respectively. AUC0–24 varied significantly according to the circadian-time of injection (166.33±10.54mgh/L at 7 HALO vs 80.27±2.33mgh/L at 19 HALO) (p<0.05). The highest and lowest mean values of plasma clearance (CL calculated as Dos/AUC) were observed at 19 HALO (2.45±0.07L/h/kg) and at 7 HALO (1.08±0.06L/h/kg) respectively (p<0.05). Cosinor showed a circadian rhythm in the pharmacokinetic parameters Cmax, AUC0–24 and plasma clearance.The mechanism of circadian rhythm in MMF tolerance might be partly explained by the circadian variation of pharmacokinetics since the time (7 HALO) of maximum hematological and digestive toxicity corresponds to that of the lowest plasma clearance on the highest Cmax and AUC0–24 of MMF.

Toxicity of Oxaliplatin Plus Fluorouracil/Leucovorin Adjuvant Chemotherapy in Elderly Patients with Stage III Colon Cancer: A Population-Based Study

Results concerning the side effects of oxaliplatin associated with fluorouracil and leucovorin (FOLFOX) in older patients are controversial. The objective of this study was to assess the use and the toxicity of FOLFOX in patients aged 70years and older as administered in current practice. Among 305 stage III colon cancers registered in a well-defined population in Burgundy between 2004 and 2009, 210 had adjuvant chemotherapy, including 156 with FOLFOX. The cumulated rates of toxicity were calculated by using the Kaplan-Meier method. The risks of overall toxicity and of severe toxicity (grade 3 or 4) in patients less than 70years and in older patients were compared by using a Cox model. There was no difference between the group of the patients less than 70years and the older age group for the cumulative incidence of hematologic, neurologic, digestive, and general toxicity. There was also no difference between the two groups for the severity of side effects (grade 3 or 4, 31.4 vs. 39.0%; p=0.576). The multivariate analysis indicated after adjustment on sex and the Charlson comorbidity score that there was no difference between the two age groups for toxicity (hazard ratio=1.28; 95% CI 0.68-2.41; p=0.439). Cancer registries can be used to evaluate the toxicity of chemotherapy at the population level. Tolerance to the FOLFOX regimen among elderly patients did not significantly differ from that in younger patients. This treatment should be considered regardless of patients' age alone, but consideration should be given to the capacity of patients to tolerate adverse events.

Phase II clinical trial of whole-brain irradiation plus three-dimensional conformal boost with concurrent topotecan for brain metastases from lung cancer

BackgroundPatients with brain metastases from lung cancer have poor prognoses and short survival time, and they are often excluded from clinical trials. Whole-cranial irradiation is considered to be the standard treatment, but its efficacy is not satisfactory. The purpose of this phase II clinical trial was to evaluate the preliminary efficacy and safety of the treatment of whole-brain irradiation plus three-dimensional conformal boost combined with concurrent topotecan for the patients with brain metastases from lung cancer.MethodsPatients with brain metastasis from lung cancer received concurrent chemotherapy and radiotherapy: conventional fractionated whole-brain irradiation, 2 fields/time, 1 fraction/day, 2 Gy/fraction, 5 times/week, and DT 40 Gy/20 fractions; for the patients with ≤ 3 lesions with diameter ≥ 2 cm, a three-dimensional (3-D) conformal localised boost was given to increase the dosage to 56–60 Gy; and during radiotherapy, concurrent chemotherapy with topotecan was given (the chemoradiotherapy group, CRT). The patients with brain metastasis from lung cancer during the same period who received radiotherapy only were selected as the controls (the radiotherapy-alone group, RT).ResultsFrom March 2009 to March 2012, both 38 patients were enrolled into two groups. The median progression-free survival(PFS) time , the 1- and 2-year PFS rates of CRT group and RT group were 6 months, 42.8%, 21.6% and 3 months, 11.6%, 8.7% (χ2 = 6.02, p = 0.014), respectively. The 1- and 2-year intracranial lesion control rates of CRT and RT were 75.9% , 65.2% and 41.6% , 31.2% (χ2 = 3.892, p = 0.049), respectively. The 1- and 2-year overall survival rates (OS) of CRT and RT were 50.8% , 37.9% and 40.4% , 16.5% (χ2 = 1.811, p = 0.178), respectively. The major side effects were myelosuppression and digestive toxicities, but no differences were observed between the two groups.ConclusionCompared with radiotherapy alone, whole-brain irradiation plus 3-D conformal boost irradiation and concurrent topotecan chemotherapy significantly improved the PFS rate and the intracranial lesion control rate of patients with brain metastases from lung cancer, and no significant increases in side effects were observed. Based on these results, this treatment method is recommended for phase III clinical trial.

Predictive Factors for Early and Late Local Toxicities in Anal Cancer Treated by Radiotherapy in Combination With or Without Chemotherapy

The treatment of anal cancer is based on concomitant radiotherapy and chemotherapy and is associated with a nonnegligible rate of local severe toxicities that can strongly impair the quality of life. A retrospective analysis was performed to screen the following factors as potential predictive factors for local skin and digestive toxicities, and as potential prognostic factors for cumulative colostomy incidence: sex, age, tumor size, clinical T and N stage, circumferential extension, invasion of anal margin, HIV status, type of chemotherapy, and type of radiotherapy and dose delivered. One hundred five patients in our database treated between January 2000 and February 2010 met the eligibility criteria. Median follow-up was 54.1 months (range, 1-133). Early and late severe local toxicities occurred in 33 patients (31.4%) and 18 patients (17.1%). The 5-year cumulative rate of colostomy was 26.6%. Predictive factors for local severe early toxicities were as follows: clinical stage III/IV (p = 0.01), no brachytherapy boost (p = 0.003), and use of chemotherapy (p = 0.01). Only brachytherapy retained its independence in multivariate analysis (OR = 4.8 (1.4-16.3), p = 0.01). Human immunodeficiency virus positivity (p = 0.04) was the only predictive factor for late toxicities in univariate analysis; it was linked independently to the occurrence of ulcer (OR = 0.1 (0.01-0.66), p = 0.01). Tumor size ≥4 cm (p < 0.001) and occurrence of grade 2 to 3 ulcers (p < 0.001) were correlated with greater cumulative colostomy incidence. In this cohort, nonuse of brachytherapy was an independent predictive factor for local acute toxicity. Human immunodeficiency virus positivity was the only predictive factor for local late toxicities and strongly influenced the onset of ulcer.

Radiothérapie préopératoire des cancers du rectum : volumes cibles

Preoperative radiochemotherapy followed by total mesorectal excision is the standard of care for T3-T4-N0 or TxN1 rectal cancer. Defining target volumes relies on the patterns of nodal and locoregional failures. The lower limit of the clinical target volume depends also on the type of surgery. Conformational radiotherapy with or without intensity-modulated radiotherapy implies an accurate definition of volumes and inherent margins in the context of mobile organs such as the upper rectum. Tumoral staging recently improved with newer imaging techniques such as MRI with or without USPIO and FDG-PET-CT. The role of PET-CT remains unclear despite encouraging results and MRI is a helpful tool for a reliable delineation of the gross tumour volume. Co-registration of such modalities with the planning CT may particularly guide radiation oncologists through the gross tumour volume delineation. Acute digestive toxicity can be reduced with intensity modulation radiation therapy. Different guidelines and CT-based atlas regarding the target volumes in rectal cancer give the radiation oncologist a lot of ground for reproducible contours.

A prospective phase II study of L-asparaginase- CHOP plus radiation in newly diagnosed extranodal NK/T-cell lymphoma, nasal type

PurposeTo explore the efficacy and safety of L-asparaginase in newly-diagnosed extranodal nature killer (NK)/T –cell lymphoma (ENKTL), we conducted a prospective phase II study of L-asparaginase, cyclophosphamide, vincristine, doxorubicin and dexamethasone (CHOP-L) regimen in combination with radiotherapy.Patients and methodsPatients with newly diagnosed ENKTL and an ECOG performance status of 0 to 2 were eligible for enrollment. Treatment included 6–8 cycles of CHOP-L (cyclophosphamide, 750 mg/m2 day 1; vincristine, 1.4 mg/m2 day 1 (maximal dose 2 mg), doxorubicin 50 mg/m2 day 1; dexamethasone 10 mg days 1–8; L-asparaginase 6000 u/m2 days 2–8). Radiotherapy was scheduled after 4–6 cycles of CHOP-L regimen, depending on stage and primary anatomic site. The primary endpoint was complete response (CR) rate.ResultsA total of 38 eligible patients were enrolled. The median age was 40.5 years (range, 15 to 71 years). Their clinical characteristics were male to female ratio, 24:14; Ann Arbor stage I, 20; II, 11; III, 3; IV, 4. CR and overall response rates were 81.6% (95% CI, 69.3% to 93.9%) and 84.2%, respectively. With a median follow-up of 25 months, the 2-year overall survival, progression-free survival and disease-free survival rates were 80.1% (95%CI, 73.3% to 86.9%), 81% (95%CI, 74.5% to 87.5%) and 93.6% (95%CI, 89.3% to 97.9%), respectively. The major adverse events were myelosuppression, liver dysfunction, and digestive tract toxicities. Grade 3 to 4 leukopenia and neutropenia were 76.3% and 84.2%, respectively. No treatment-related death was observed.ConclusionCHOP-L chemotherapy in combination with radiotherapy is a safe and highly effective treatment for newly diagnosed ENKTL.

Digestive stability and acute toxicity studies of exogenous protein in transgenic rice expressing lysine-rich fusion proteins

Evaluating exogenous protein expressed in transgenic crops is one of the most effective methods of assessing the safety of transgenic plants. The objective of this study was to assess the food safety of genetically modified (GM) rice containing a lysine-rich fusion protein gene (transgenic GL gene rice) by in vitro digestion and acute toxicity testing of exogenous protein, according to the national standard of the People’s Republic of China. The exogenous protein was rapidly degraded in the simulated gastric and intestinal fluids. In the acute experiment, the exogenous protein was injected into Institute of Cancer Research (ICR) mice via the tail vein at a dose of 438 mg kg−1 body weight. No adverse effects on animal behavior or mortality were observed during the following 15-day period and there were no significant biological changes in body weight, serum biochemistry parameters, relative organ weights or histopathological examinations, compared with the control group. Therefore, exogenous protein in transgenic GL gene rice has a low potential allergenicity or toxicity risk.

O-0022 - Comparison of Docetaxel, Fluorouracil and Oxaliplatin or Cisplatin with Other Modified Schedules: a New Therapeutic Index in Advanced Gastric Cancer

Background: The objective of chemotherapy of advanced gastric adenocarcinoma is quality of life and survival time, but the benefits are of limited duration and tolerability varies according to the protocol. Particularly, febrile neutropenia and digestive toxicity are often limiting effects. To date there is no universal standard. There is a need to compare schedules not only with efficacy criteria, but also in integrating safety data. We used results from a randomised phase 2 trial, the GATE study (NCT00382720), to build a new criteria based on the ratio of the most relevant toxicity rates and efficacy, to compare several regimens.

Ipilimumab-induced acute severe colitis treated by infliximab

Ipilimumab (anti-CTLA-4 antibody) is a new tool for the treatment of metastatic melanoma patients that has led to an improvement in survival rates worldwide. New types of toxicities have been described with ipilimumab called 'immune-related adverse events' or irAEs. Here, we report an acute and steroid resistant case of ipilimumab-induced colitis treated with infliximab in a melanoma stage IV AJCC patient. The patient presented with acute grade 3 diarrhea after the second perfusion of ipilimumab. After the administration of intravenous steroids, the patient continued to have grade 2 diarrhea with erythematous mucous with several ulceration sites on rectosigmoidoscopy. Infliximab perfusion (5 mg/kg) was performed and resulted in resolution of symptoms within 2 days with complete healing was observed by rectal sigmoidoscopy on day 7. After failure of two further lines of chemotherapy, the patient died 10 months after the diagnosis of stage IVM1C melanoma. Treatment algorithms exist for the management of these digestive adverse events; however, some points remain unclear. No predictive marker for the occurrence of this digestive toxicity has been validated to date. Modes of administration of steroids and dosage are not clearly defined, except in cases of acute abdomen; surgery is difficult to propose for patients with a poor prognosis. Infliximab is another option for the treatment of steroid-resistant ipilimumab-induced colitis but its use in metastatic melanoma raises questions of its possible impact on the evolution of cancer. We reviewed at least 19 cases published of infliximab administration for ipilimumab-mediated colitis. Unfortunately, tolerance and cancer evolution have scarcely been reported. Thus, because more patients are being treated with CTLA-4 blockade, management of ipilimumab-induced colitis requires further studies.

Phase II Trial of Loubo®(Lobaplatin) and Pemetrexed for Patients with Metastatic Breast Cancer not Responding to Anthracycline or Taxanes

This phase II study was undertaken to determine the efficacy and safety of Loubo® (Lobaplatin) in combination with pemetrexed in treating patients with metastatic breast cancer who failed to respond to anthracycline or taxanes. Metastatic breast cancer cases who had previously received an anthracycline and a taxane in either adjuvant or metastatic settings, were enrolled. All patients were recruited from Jiangsu Cancer Hospital and Research Institute, and were treated with Loubo® (Lobaplatin) 35 mg/m2 (intravenous; on day 1) and pemetrexed 500 mg/m2 (intravenous; on day 1) every 21 days. Efficacy and side effects were evaluated after at least two cycles of chemotherapy. All eligible 19 patients completed at least 2 cycles of chemotherapy with pemetrexed and lobaplatin, and were evaluable. Overall, 3 (15.8%) patients achieved partial response, 11 (57.9%) stable disease, 5 (26.3%) progression of disease, with no complete remission. Response rate was 15.8%, disease control rate was 42.1%. The median survival time was 10.3 months. Neutrophil suppression occurred in 36.8% of patients who had grade 2 toxicity, and 26.3% had grade 3, 26.4% had grade 4. Thrombocytopenia was encountered as follows: 21.1% grade 2, 15.8% grade 3 and 5.5% grade 4. Incidences of anemia were 10.5% in grade 2, 5.3% grade 3 and 0% grade 4. Only 5.3% of patients required packed red blood cell transfusion. Grade 3 digestive tract toxicity occurred in 5.5% of patients. Other toxicities included elevated transaminase, oral mucositis and skin rashes. The regimen of lobaplatin and pemetrexed is modestly active in metastatic breast cancer patients who failed anthracycline or taxanes, and the toxicity profile suggesting that the doses of chemotherapy should be further modified.

O2-059 - Phase II Study of Combination Therapy with S-1 and Cetuximab in Patients with Kras Wild-Type Unresectable Colorectal Cancer, who Had Previously Received Irinotecan, Oxaliplatin, and Fluoropyrimidines (KSCC0901)

ABSTRACT Background Anti-epidermal growth factor receptor (anti-EGFR) antibodies alone or in combination with irinotecan (Iri) can be considered standard third-line therapy for KRAS wild-type (wKRAS) unresectable colorectal cancer (UNCC). However, some UNCC patients cannot tolerate Iri-containing therapy. S-1, an oral fluorouracil (FU) derivative, enhances the anti-tumor effect by inhibiting dihydropyrimidine dehydrogenase activity and reducing digestive toxicity. Combination therapy with cetuximab (C-mab) may restore 5-FU resistance in 5-FU resistant CCs. Therefore, we examined the efficacy of S-1 + C-mab therapy in wKRAS UNCC patients, who had previously received Iri, oxaliplatin (OX), and FUs. Methods The study design was multicenter, single-arm, open-label phase II study. The major inclusion criteria were written informed consent; histologically proven CC and clinically proven UNCC; presence of measurable lesions; previous therapy with Iri, OX, and 5-FU; documented progressive disease after 5-FU-based chemotherapy; wKRAS tumors; age over 20 years; performance status (PS) 0-1; and adequate organ function. The treatment protocol was as follows: weekly durable intravenous (DIV) C-mab administration at 400 mg/m2 (day 1) and 250 mg/m2/week (except day 1) and oral administration of 80 mg/m2/day S-1 on days 1–28 of each 42-day cycle. The primary end point was progression-free survival (PFS). A sample size of 39 was planned for a threshold PFS of 3.5 months and expected value of 6.0 months, with one-sided alpha of 0.05 and beta of approximately 0.2. Results One patient was ineligible; 38 patients (PS 0/1, 32/6; 1/2/over 3 prior chemotherapy regimens, 4/23/11) were enrolled. The median PFS was 5.5 months; median overall survival (OS), 13.1 months; and the best ORR, 36.8%. The most common grade 3–4 adverse events were neutrophils, hypokalemia, rash, and dry skin. Conclusion S-1 + C-mab therapy may be a promising and well-tolerated treatment choice for wKRAS UNCC patients, who have previously received extensive treatment with Iri, OX, and FUs.

Cisplatin-Docetaxel Induction plus Concurrent 3-D Conformal Radiotherapy and Weekly Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer Patients: A Phase II Trial

Concurrent chemoradiotherapy (CHRT) is the standard of care for unresectable locally advanced stage III non-small cell lung cancer. However, the optimal combination remains unclear. The aim of this study was to evaluate the efficacy of 2 induction chemotherapy cycles (days 1 and 22) with docetaxel 75 mg/m² and cisplatin 75 mg/m² followed by concurrent chemotherapy (weekly docetaxel-cisplatin, 20 mg/m²) and 3-D conformal radiotherapy for 6 weeks (66 Gy/5 fractions per week/2 Gy per fraction). The primary endpoint was the response rate. Secondary objectives were toxicity, time to progression, and overall survival. Forty-four patients were included and 40 were eligible. The mean age was 60.5 years (range 40.7–72.1), and 75% had stage IIIB disease. Six patients underwent complete R0 resection including 2 pathologic complete responses after a planned intermediate evaluation. Thirty-three patients completed CHRT. The objective response rate was 65% (95% CI 50.2–79.8). Grade 3–4 hematologic and digestive toxicities were observed mainly during the induction phase. Grade 3 esophagitis (5%) was experienced during CHRT. With a median follow-up of 38.7 months, the median progression-free survival was 28.3 months (95% CI 11.0–35.0) and the median survival rate was 31.4 months. Cisplatin-docetaxel induction followed by concurrent 3-D conformal radiotherapy and weekly chemotherapy is a feasible protocol associated with a promising response rate and acceptable toxicity.

Radiothérapie guidée par l’image des cancers prostatiques : concepts et implications

Intensity modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) are technological developments, which when applied in a model of prostate cancer, led to a significant reduction in the toxicity and digestive and urinary sequelae of 3D conformational radiotherapy. The major clinical benefits of these techniques with regard to reduced digestive and urinary toxicity are unequivocal since very few sequelae have been reported at 10 years (2% of grade 2 and 1% of grade 3 digestive toxicity; 11% of grade 2 and 5% of grade 3 urinary toxicity). Even when these two techniques are combined, IG–IMRT significantly diminishes late genitourinary toxicity. In the absence of adaptive radiotherapy, there are many IGRT protocols and repositioning techniques, and every step in the IGRT process must be carried out with extreme rigor: installing the patient and contention system, repositioning technique with or without fiduciary markers, type of repositioning imaging, definition of margins inherent in each technique (prostate, seminal vesicles and/or pelvic lymph nodes), frequency of repositioning during treatment, dietary constraints with or without rectal lavage. For these reasons, every centre that performs IGRT must carefully and rigorously assess the uncertainties of repositioning linked to the IGRT technique. In this review, we analyzed data from the literature based on dosimetric studies and the proven clinical impact in order to answer the different questions asked by radiation oncologists at every step of the IGRT process for cancer of the prostate. Recommendations are made for the repositioning protocols according to the most widely used repositioning techniques: fiduciary markers or soft tissues, kV-CBCT or MV-CBCT, 3D ultrasonography.

Identification of novel phytotoxins from Australian range plants linked to severe mammalian digestive toxicity

We have used a digestive developmental in vivo zebrafish model to examine Australian rangeland plants for their involvement in specific digestive disorders in livestock. The model allows us to discover causative phytotoxins linked to a syndrome. Here, we report the isolation and structural elucidation of five isoflavonoid compounds 1-5 with specific biological activity. From the active fraction, we identified the causative phytotoxins as two novel isoflavonoids (1, 4), both with an unusual skeleton. In addition, we isolated an additional novel isoflavonoid (3), a novel pterocarpan derivative (5), and a known isoflavone, betavulgarin (2). Compound 4 contributed to the specific biological damage in the zebrafish. The compound is highly reactive and conjugates spontaneously with common nucleophilic biological molecules, indicating a strong electrophilic nature, suggesting a possible mechanism of action that explains death in the animals. The isolation and structural elucidation of 1- 5 , together with their biological data, will be presented.