Author Correction: Sex-Related Differences in Impact on Safety of Pharmacogenetic Profile for Colon Cancer Patients Treated with FOLFOX-4 or XELOX Adjuvant Chemotherapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Sex-Related Differences in Impact on Safety of Pharmacogenetic Profile for Colon Cancer Patients Treated with FOLFOX-4 or XELOX Adjuvant Chemotherapy.

Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/-), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.

Genetic markers for toxicity of adjuvant oxaliplatin and fluoropyrimidines in the phase III TOSCA trial in high-risk colon cancer patients.

We investigated 17 polymorphisms in 11 genes (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT1, GSTP1, GSTM1, ABCC1, ABCC2) for their association with the toxicity of fluoropyrimidines and oxaliplatin in colorectal cancer patients enrolled in a prospective randomized trial of adjuvant chemotherapy. The TOSCA Italian adjuvant trial was conducted in high-risk stage II-III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In the concomitant ancillary pharmacogenetic study, the primary endpoint was the association of polymorphisms with grade 3-4 CTCAE toxicity events (grade 2-4 for neurotoxicity). In 517 analyzed patients, grade ≥ 3 neutropenia and grade ≥ 2 neurotoxicity events occurred in 150 (29%) and in 132 patients (24.8%), respectively. Diarrhea grade ≥ 3 events occurred in 34 (6.5%) patients. None of the studied polymorphisms showed clinically relevant association with toxicity. Hopefully, genome-wide association studies will identify new and more promising genetic variants to be tested in future studies.

Developing a decision-making model based on an interdisciplinary oncological care group for the management of colorectal cancer.

AIM: To report our experience on implementation and preliminary results of a decision-making model based on the recommendations of an Interdisciplinary Oncological Care Group developed for the management of colorectal cancer. PATIENTS AND METHODS: The multidisciplinary team identified a reference guideline using appraisal of guidelines for research and evaluation (AGREE) tool based on a sequential assessment of the guideline quality. Thereafter, internal guidelines with diagnostic and therapeutic management for early, locally advanced and metastatic colonic and rectal cancer were drafted; organizational aspects, responsibility matrices, protocol actions for each area of specialty involved and indicators for performing audits were also defined. RESULTS: The National Institute for Health and Care Excellence (NICE) UK guideline was the reference for drafting the internal guideline document; from February to November 2013, 125 patients with colorectal cancer were discussed by and taken under the care of the Interdisciplinary Oncological Care Group. The first audit performed in December 2013 revealed optimal adherence to the internal guideline, mainly in terms of uniformity and accuracy of perioperative staging, coordination and timing of multi-modal therapies. To date, all patients under observation are within the diagnostic and therapeutic course, no patient came out from the multidisciplinary "path" and only in 14% of cases have the first recommendations proposed been changed. The selected indicators appear effective and reliable, while at the moment, it is not yet possible to assess the impact of the multidisciplinary team on clinical outcome. CONCLUSION: Although having a short observation period, our model seems capable of determining optimal uniformity of diagnostic and therapeutic management, to a high degree of patient satisfaction. A longer observation period is necessary in order to confirm these observations and for assessing the impact on clinical outcome.

Paralytic ileus associated with capecitabine.

Paralytic ileus is a temporary arrest of intestinal peristalsis. We report on two patients with breast cancer who developed paralytic ileus following treatment with capecitabine. The pathophysiology of this disorder and its possible connection to capecitabine are described with the aim of promoting the early recognition of the clinical picture so that unnecessary surgery can be avoided.

Multicenter phase 2 study of interleukin-2 and 13-cis retinoic acid as maintenance therapy in advanced non-small-cell lung cancer.

High serum levels of vascular endothelial growth factor (VEGF) are a poor prognostic factor for patients with advanced non-small-cell lung cancer (NSCLC). We have previously shown that low-dose interleukin (IL)-2 and 13-cis retinoic acid (RA) decreased VEGF and improved the immune function of patients with advanced tumors treated with chemotherapy. The primary end point of this study was to verify whether IL-2 and RA decreased serum VEGF in NSCLC patients showing a clinical benefit from chemotherapy. The secondary end point was the evaluation of clinical outcome. We treated 38 patients with advanced NSCLC who had a complete or partial response or disease stability to chemotherapy and had a median serum VEGF level of 508 ng/mL; as maintenance therapy, they received subcutaneous IL-2 (1.8 x 10(6) IU) and oral RA. Matched controls (n = 87) were selected from a large cohort of patients with a similar disease status, including clinical benefit from chemotherapy. The most common adverse events were mild cutaneous skin rash and fever. Serum VEGF decreased to a mean level of 152 ng/mL (P = 0.0002). A statistically significant improvement in immune function was observed (lymphocyte and natural killer cell numbers and CD4+/CD8+ ratio) with respect to baseline values and controls. An improvement in the clinical outcome was also observed compared with controls. These data show that the administration of low-dose subcutaneous IL-2 and oral RA to patients with advanced NSCLC showing a clinical benefit from chemotherapy is feasible with a low-toxicity profile, decreases VEGF, and seems to improve progression-free and overall survival.

Oxaliplatin fractionated over two days with bimonthly leucovorin and 5-fluorouracil in metastatic colorectal cancer.

PURPOSE: To evaluate the efficacy and safety of oxaliplatin (L-OHP) fractionated over two days with bimonthly 5-fluorouracil (5-FU) and leucovorin (LV), as first-line treatment of metastatic colorectal cancer (MCC) patients. PATIENTS AND METHODS: Fifty-four patients with inoperable MCC (median age, 60 years) were entered into the study. Outpatient treatment consisted of L-OHP 50 mg/m2 and LV 200 mg/m2 administered in a 2-hour i.v. infusion, followed by 5-FU 400 mg/m2 bolus and 5-FU 600 mg/m2 in a 22-hour continuous infusion, on days 1 and 2 every 2 weeks. RESULTS: A total of 488 courses of chemotherapy were administered. Responses were as follows: 3 complete responses (5.6%) and 24 partial responses (44.4%) giving an overall response rate of 50% (95% CI: 36% to 64%). Median time to progression and overall survival were 10.3 and 19.2 months, respectively. Grade 3-4 neutropoenia, leucopoenia, thrombocythopoenia and anaemia occurred in 33%, 9%, 2% and 2% of patients, respectively, while peripheral neuropathy occurred in 10% of patients. CONCLUSION: The fractionated bimonthly schedule of L-OHP plus de Gramont gave a less than anticipated neurological toxicity profile, while maintaining expected efficacy.

Ultra-low-dose interleukin-2 in unresectable hepatocellular carcinoma.

At present, no effective therapy is available for hepatocellular carcinoma, when local treatments have failed. We reported the results obtained with prolonged, ultra-low-dose (1 MIU/d until progression), subcutaneous interleukin-2 (IL-2) in a series of 18 consecutive patients (14 men and 4 women, median age 66 years, range 49-82 years) with advanced, histologically proven HCC on liver cirrhosis. During a median follow-up time of 19.5 months, two complete responses (11.1%), lasting 35 and 46 months, respectively, and one partial response (5.5%) were recorded (overall response rate: 16.6%; 95% CI: 0-33.8%). Thirteen patients (72.3%; 95% CI: 61.6-82.7) had stable disease lasting at least 4 months; 1 of these patients obtained a complete response on lung metastases. Median time to progression was 15.3 months (95% CI: 10-33). Median overall survival was 24.5 months (95% CI: 12-43). Two patients (11.1%) progressed during therapy. Toxicity was only local (usually pain and pomphus in the site of injection). Low-dose IL-2 can be considered an active and well-tolerated treatment for unresectable hepatocellular carcinoma. Future studies on large numbers of patients are necessary to confirm these results.