Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: A prospective translational study in the BECOX (GEMCAD 09-01) trial.

Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study. Serum levels of vascular endothelial growth factor-A165, soluble vascular endothelial growth factor receptor 1, and hepatocyte growth factor were assessed by enzyme-linked immunosorbent assay method basally and every 3 cycles (at the time of computed tomography evaluation) in a preplanned translational study in the first-line BECOX trial in metastatic colorectal cancer patients treated with CAPOX plus bevacizumab. Response was evaluated by routine contrast-enhanced computed tomography by RECIST 1.1 by investigator assessment and by three blinded independent radiologists. Ratios between soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A and hepatocyte growth factor/vascular endothelial growth factor-A were established and variations through time were related to RECIST 1.1 by investigator assessment and independent radiologist. The BECOX trial included 68 patients, and 27 patients were analyzed in the translational trial. A total of 80 RECIST 1.1 evaluations were done by investigator assessment and 56 by independent radiologist. We found that a 3.22-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by investigator assessment and a 3.06-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by independent radiologist from previous determination were associated with responses compared with 1.38-fold increase by investigator assessment and 1.59 by independent radiologist in non-responders (p = 0.0009 and p = 0.03, respectively). Responders had a 3.36-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A from previous determination by investigator assessment and 3.66-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A by independent radiologist compared with 1.43-fold increase by investigator assessment and 1.53 by independent radiologist for non-responders (p = 0.002 and 0.003, respectively). In conclusion, a decrease in vascular endothelial growth factor-A and an increase in soluble vascular endothelial growth factor receptor 1 during chemotherapy and bevacizumab exposure can contribute to both chemotherapy (due to c-MET/b-catenin activation) and bevacizumab (due to low vascular endothelial growth factor requirements) resistance. Because hepatocyte growth factor levels decrease also during acquired resistance, alternative strategies to hepatocyte growth factor-ligand inhibition should be investigated.

Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial†.

BACKGROUND: The primary results of our phase II randomized trial suggested that compared with conventional preoperative chemoradiation (CRT), the addition of chemotherapy (CT) before CRT and surgery allows most patients receive their planned treatment with a better toxicity profile without compromising the pathological complete response and complete resection rates. We now report the 5-year outcomes. PATIENTS AND METHODS: Patients with distal or middle third, T3-T4 and/or N+ rectal adenocarcinoma selected by magnetic resonance imaging, were randomly assigned to arm A-preoperative CRT followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)-or arm B-four cycles of CAPOX followed by CRT and surgery. The following 5-year actuarial outcomes were assessed: the cumulative incidence of local relapse (LR) and distant metastases (DM), disease-free (DFS) and overall survival (OS). RESULTS: A total of 108 eligible patients were randomly assigned to arm A (n = 52) or arm B (n = 56). With a median follow-up of 69.5 months, 5-year DFS was 64% in arm A and 62% in arm B (P = 0.85) and 5-year OS was 78% in arm A and 75% in arm B (P = 0.64). The 5-year cumulative incidence of LR was 2% and 5% (P = 0.61) and 5-year cumulative incidence of DM was 21% and 23%; (P = 0.79) in arms A and B, respectively. CONCLUSION: Both treatment approaches yield similar outcomes. Given the lower acute toxicity and improved compliance with induction CT compared with adjuvant CT, integrating effective systemic therapy before CRT and surgery is a promising strategy and should be examined in phase III trials.

First-line bevacizumab and capecitabine-oxaliplatin in elderly patients with mCRC: GEMCAD phase II BECOX study.

BACKGROUND: Subgroup analyses of clinical studies suggest that bevacizumab plus XELOX is effective and tolerable in elderly patients with metastatic colorectal cancer (mCRC). The prospective BECOX study examined the efficacy and safety of bevacizumab plus XELOX, followed by bevacizumab plus capecitabine in elderly patients with mCRC. METHODS: Patients aged ⩾70 years with Eastern Cooperative Oncology Group performance status 0 out of 1 and confirmed mCRC were included. Patients received bevacizumab 7.5 mg kg(-1) and oxaliplatin 130 mg m(-2) on day 1, plus capecitabine 1000 mg m(-2) bid orally on days 1-14 every 21 days; oxaliplatin was discontinued after 6 cycles. The primary end point was time to progression (TTP). RESULTS: The intent-to-treat population comprised 68 patients (65% male, median age 76 years). Median TTP was 11.1 months; median overall survival was 20.4 months; overall response rate was 46%. Grade 3 or 4 adverse events included diarrhoea (18%) and asthenia (16%). Grade 3 or 4 adverse events of special interest for bevacizumab included deep-vein thrombosis (6%) and pulmonary embolism (4%). CONCLUSIONS: Bevacizumab plus XELOX was effective and well tolerated in elderly patients in the BECOX study. The adverse-event profile was similar to previous reports; no new safety concerns were identified. Fit elderly patients with mCRC should be considered for treatment with bevacizumab plus XELOX.

A signature of circulating microRNAs predicts the response to treatment with FOLFIRI plus aflibercept in metastatic colorectal cancer patients.

The benefit of adding the antiangiogenic drug aflibercept to FOLFIRI regime in metastatic colorectal cancer (CRC) patients resistant to or progressive on an oxaliplatin-based therapy has been previously demonstrated. However, the absence of validated biomarkers to predict greater outcomes is a major challenge encountered when using antiangiogenic therapies. In this study we investigated profiles of circulating microRNAs (miRNAs) to build predictive models of response to treatment and survival. Plasma was obtained from 98 metastatic CRC patients enrolled in a clinical phase II trial before receiving FOLFIRI plus aflibercept treatment, and the circulating levels of 754 individual miRNAs were quantified using real-time PCR. A distinct signature of circulating miRNAs differentiated responder from non-responder patients. Remarkably, most of these miRNAs were found to target genes that are involved in angiogenic processes. Accordingly, some of these miRNAs had predictive value and entered in predictive models of response to therapy, progression of disease, and survival of patients treated with FOLFIRI plus aflibercept. Among these miRNAs, circulating levels of hsa-miR-33b-5p efficiently discriminated between responder and non-responder patients and predicted the risk of disease progression. Moreover, the combination of circulating VEGF-A and miR-33b-5p levels improved clinical stratification of metastatic CRC patients who were to receive FOLFIRI plus aflibercept treatment. In conclusion, our study supports circulating miRNAs as valuable biomarkers for predicting better outcomes in metastatic CRC patients treated with FOLFIRI plus aflibercept.

Association of Circulating Tumor Cells and Tumor Molecular Profile With Clinical Outcomes in Patients With Previously Untreated Metastatic Colorectal Cancer: A Pooled Analysis of the Phase III VISNÚ-1 and Phase II VISNÚ-2 Randomized Trials.

BACKGROUND: The bCTC count is a well-established prognostic biomarker in mCRC, as well as in other tumor types. The aim of this analysis was to evaluate the prognostic/predictive role of the bCTC count (≥3 vs. <3) in previously untreated mCRC. PATIENTS AND METHODS: The study involved 589 untreated mCRC patients included in the intention-to-treat population of 2 randomized clinical trials (phase III VISNU-1 [NCT01640405] and phase II VISNU-2 [NCT01640444] studies). RESULTS: Of the 589 patients, 349 (59.2%) had bCTC≥3 and 240 (40.7%) had bCTC<3. Multivariate analysis showed that the bCTC count is an independent prognostic factor for overall survival (OS) (HR 0.59, 95% CI 0.48-0.72; P = 0.000) and potential for progression-free survival (PFS) (P = 0.0549). Median OS was 32.9 and 19.5 months in patients with bCTC<3 and bCTC≥3 (P <0.001), respectively. This effect was also observed comparing OS in RASwt patients from both studies. Other prognostic factors were: ECOG-PS, primary tumor site, number of metastatic sites and surgery of the primary tumor. Median OS was lower for patients treated with anti-VEGF versus anti-EGFR (22.3 vs. 33.3 months, P <0.0001) while there were no significant differences in PFS according to the targeted treatment received. CONCLUSION: This post-hoc analysis of 2 randomized studies confirms the poor prognosis of patients with bCTC≥3 but this is not associated with other adverse independent prognostic factors such as RAS/BRAF mutations.

Phase II open-label study of erlotinib in combination with gemcitabine in unresectable and/or metastatic adenocarcinoma of the pancreas: relationship between skin rash and survival (Pantar study).

BACKGROUND: Skin rash is an adverse event which might be associated with longer survival in patients treated with epidermal growth factor receptor tyrosine kinase inhibitors. The aim of this nonrandomised phase II clinical trial is to prospectively evaluate the relationship between skin rash and overall survival (OS) in advanced/metastatic pancreatic cancer treated with erlotinib plus gemcitabine. PATIENTS AND METHODS: Patients were given gemcitabine (1000 mg/m2/week, 3 weeks every 4 weeks) plus erlotinib (100 mg/day orally continuously) until disease progression/unacceptable toxicity. The primary end point was OS. RESULTS: A total of 153 eligible patients were enrolled (grade≥2 rash, 25%; grade<2 rash, 75%). OS was longer in patients with grade≥2 rash versus grade<2 (11 versus 5 months; P<0.001). Progression-free survival was longer in patients with grade≥2 rash versus grade<2 (6 versus 3 months; P<0.001) and shorter in those without rash versus grade 1 (2 versus 4 months; P=0.005) or grade≥2 (2 versus 6 months; P<0.001). Patients with grade≥2 rash showed higher rates of overall response (21% versus 7%; P<0.05) and disease control (84% versus 43%; P<0.05) versus grade<2. CONCLUSIONS: This study prospectively confirms the relationship between rash and longer OS in unresectable locally advanced/metastatic pancreatic cancer treated with erlotinib plus gemcitabine.

Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines.

5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.

MUC4 is overexpressed in idiopathic pulmonary fibrosis and collaborates with transforming growth factor ß inducing fibrotic responses.

Several mucins are implicated in idiopathic pulmonary fibrosis (IPF); however, there is no evidence regarding the role of MUC4 in the development of IPF. Here we demonstrated that MUC4 was overexpressed in IPF patients (n = 22) compared with healthy subjects (n = 21) and located in pulmonary arteries, bronchial epithelial cells, fibroblasts, and hyperplastic alveolar type II cells. Decreased expression of MUC4 using siRNA-MUC4 inhibited the mesenchymal/myofibroblast transformations of alveolar type II A549 cells and lung fibroblasts, as well as cell senescence and fibroblast proliferation induced by TGF-ß1. The induction of the overexpression of MUC4 increased the effects of TGF-ß1 on mesenchymal/myofibroblast transformations and cell senescence. MUC4 overexpression and siRNA-MUC4 gene silencing increased or decreased, respectively, the phosphorylation of TGFßRI and SMAD3, contributing to smad-binding element activation. Immunoprecipitation analysis and confocal immunofluorescence showed the formation of a protein complex between MUC4ß/p-TGFßRI and p-SMAD3 in the cell membrane after TGF-ß1 stimulation and in lung tissue from IPF patients. Bleomycin-induced lung fibrosis was reduced in mice transiently transfected with siRNA-MUC4. This study shows that MUC4 expression is enhanced in IPF and promotes fibrotic processes in collaboration with TGF-ß1 canonical pathway that could be an attractive druggable target for human IPF.

Controversies in the treatment of RAS wild-type metastatic colorectal cancer.

OBJECTIVE: To provide guidance for the management of RAS wild-type (wt) metastatic colorectal cancer (mCRC) in daily practice. METHODS: Nominal group and Delphi techniques were used. A steering committee of seven experts analyzed the current management of RAS wt mCRC, through which they identified controversies, critically analyzed the available evidence, and formulated several guiding statements for clinicians. Subsequently, a group of 30 experts (the expert panel) was selected to test agreement with the statements, through two Delphi rounds. The following response categories were established in both rounds: 1 = totally agree, 2 = basically agree, 3 = basically disagree, 4 = totally disagree. Agreement was defined if ≥ 75% of answers were in categories 1 and 2 (consensus with the agreement) or 3 and 4 (consensus with the disagreement). RESULTS: Overall, 71 statements were proposed, which incorporated the following areas: (1) overarching principles; (2) tumor location; (3) triplets; (4) maintenance; (5) second-line and beyond treatments; (6) Rechallenge and liquid biopsy. After the two Delphi rounds, only six statements maintained a lack of clear consensus. CONCLUSIONS: This document aims to describe the expert's attitude when dealing with several common clinical questions regarding patients with RAS wt mCRC.

Gender influence on work satisfaction and leadership for medical oncologists: a survey of the Spanish Society of Medical Oncology (SEOM).

BACKGROUND: Women represent an increasing proportion of the oncology workforce; however, globally this does not translate into leadership roles, reflecting disparities in career opportunities between men and women. The Spanish Society of Medical Oncology (SEOM) undertook a survey to investigate gender disparity in the Spanish oncology context. DESIGN: An online survey was made available to SEOM medical oncologists between February and May 2019. It included demographics, professional context and achievements, parenthood and family conciliation issues, workplace gender bias, and approaches to address disparities. RESULTS: Of the 316 eligible respondents, 71.5% were women, 59.5% were aged 45 or younger, and 66.1% had children. Among women, 12.4% were division or unit heads, compared with 45.5% of men, with most women (74.3%) being attending medical oncologists, compared with 45.5% of men. More males were professors (34.4% versus 14.2% of females), had a PhD (46.7% versus 28.8%), and/or had led clinical research groups (41.1% versus 9.7%). Spending time overseas after completing a residency was also more common for men than women (34.4% versus 20.4%). Professional satisfaction was similar between genders, driven primarily by patient care and intellectual stimulation. More women (40.7%) considered parenthood to have a strong negative impact on their career, compared with men (9.0%). Main perceived barriers to gender equality included a lack of work-life balance (72.6% women, 44.4% men), bias of peers and superiors (50.0% women, 18.9% men), and different career goals (41.2% women, 24.4% men). Preferred solutions included educational programs and scholarships (52.9%), communication and leadership training (35.8%), childcare at conferences (33.2%), and postmaternity return-to-work incentives (32.0%). CONCLUSION: There is a clear paucity of equal opportunities for female oncologists in Spain. This can be addressed by encouraging professional development and merit recognition particularly for younger female oncologists, and empowering women to be involved in management and leadership of institutions and professional societies.

Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study.

BACKGROUND: We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF/PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI [irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. RESULTS: Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. CONCLUSIONS: BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy.

Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer.

BACKGROUND: The efficacy and safety of capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer (mCRC) considered unsuitable for receiving first-line chemotherapy with an irinotecan or oxaliplatin-based combination were assessed in a phase II, open, multicentre, uncontrolled study. METHODS: Treatment consisted of capecitabine 1250 mg m(-2) (or 950 mg m(-2) for patients with a creatinine clearance of 30-50 ml min(-1)) twice daily on days 1-14 and bevacizumab (7.5 mg kg(-1)) on day 1 every 3 weeks. RESULTS: A total of 59 patients aged >or=70 years with mCRC were enrolled. In an intention-to-treat analysis, the overall response rate was 34%, with 71% of patients achieving disease control. Median progression-free survival and overall survival were 10.8 months and 18 months, respectively. In all, 32 patients (54%) had grade 3/4 adverse events (AEs), the most common being hand-foot syndrome (19%), diarrhoea (9%) and deep venous thrombosis (7%). Four patients died because of treatment-related AEs. A relationship was detected between creatinine clearance

[Self-evaluation of a clinical pathway to improve the results of rectal cancer]. / Autoevaluación de una vía clínica para mejora del proceso quirúrgico carcinoma de recto.

OBJECTIVES: To analyse whether the self-evaluation of a clinical pathway improves the results of rectal cancer (RC) treatment. PATIENTS AND METHOD: Patients operated on for RC were divided into 3 groups according to biannual modifications of a clinical pathway analysing several indicators. RESULTS: 166 patients: Group A: 2002-3 n=50, B: 2004-5 n=53 and C: 2006-7 n=63, without any differences in age, gender or comorbidity. Preoperative study improved with the introduction of CT scan: 76% in Group C vs. 6% in Group A (P<0.001). All Group C tumours were staged using MR, rectal ultrasound or both, compared to 84% in Group A (P<0.001). The rate of abdominal-perineal resections was reduced from 42% (Group A) to 17% (Group C); (P=0.007) and about 48% of surgeons in Group A vs. 94% in the C had a specific activity in coloproctology (P<0.001). The average lymph node count was: Group A=6.2+/-4.5 vs. 13+/-6.5 in the C and circumferential margin analysis was reported in 24% of Group A vs. 76% in Group C (P<0.001). Parameters such as perioperative blood transfusion, ICU admission, use of nasogastric tube, early feeding or epidural analgesia also improved progressively. Operative mortality decreased non-significantly to 4.7% and anastomotic leaks from 24% to 9.5% with a reduction in postoperative stay from 15 to 11 days during the period analysed (P=0.029). CONCLUSIONS: Several indicators have significantly improved in a relatively short period of time due to self-evaluations of the process.

Analysis of the elderly patient population in a tertiary-care university hospital.

A progressively ageing population and the high association between advanced age and cancer has resulted in an increased interest in the field of geriatric oncology with the objective being a more effective diagnosis and treatment of these patients. We performed an epidemiological analysis on an intent-to-treat of elderly population within our healthcare unit. This is a retrospective study of all patients attended in our Medical Oncology Department during the year 2002. A total 667 patients were assessed, 42% older than 70 years of age. The most frequent tumour sites were lung, colorectal and breast. The most frequent histology was adenocarcinoma. The diagnosis in advanced stages was significantly higher in older age group (76% vs. 59%). The use of symptom-control follow-up and palliative-care, compared with radio- and chemo-therapy, was higher in older age group. However, we observed no statistically significant differences with respect to inclusion in clinical trials. In conclusion, the elderly represents an important percentage of patients receiving cancer care. The distributions by sites and histology types are similar in both groups of age. Although the election of palliative treatment is more frequent in elderly population, the most frequently used treatments in both groups, were radiotherapy and chemotherapy. We didn't observe any significant differences about the inclusion in clinical trials.

First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: Phase II randomised MACRO2 TTD study.

BACKGROUND: This multicentre, randomised, and phase II study evaluated mFOLFOX+cetuximab followed by maintenance mFOLFOX+cetuximab or single-agent cetuximab in metastatic colorectal cancer (mCRC) patients (NCT01161316). PATIENTS AND METHODS: Previously, untreated mCRC patients (wild-type KRAS) were randomised to receive cetuximab+mFOLFOX-6 (8 cycles for 2 weeks) followed by maintenance therapy: single-agent cetuximab (Arm-A) or mFOLFOX-6 + cetuximab (Arm-B) until progression. Primary endpoint was progression-free survival (PFS) at 9 months. RESULTS: One hundred ninety-three patients (median [range] age 60 [33-74] years) were randomised (2:1): 129 Arm-A versus 64 Arm-B. PFS at 9 months (95% confidence interval) showed non-inferiority between arms (Arm-A/Arm-B: 60 [52, 69]%/72 [61, 83]%, p [non-inferiority]<0.1). There were no statistically significant differences in the PFS (Arm-A/Arm-B: 9 [95% CI 7, 10] months/10 [7,13] months, hazard ratio [HR] = 1.19 [0.80, 1.79]) or overall survival (23 [19, 28] months/27 [18, 36] months, HR = 1.24 [0.85, 1.79]) between arms. The objective response rate was also similar (48 [39, 57]%/39 [27, 52]%). The safety profile was similar between arms, and all patients experienced at least one adverse event (AE) (Arm-A/Arm-B grade ≥III AEs: 70%/68%). The most common grade ≥III AEs were as follows: neutropenia (Arm-A/Arm-B: 28%/26%), rash acneiform (15%/24%) and sensory neuropathy (2%/15%) in any group. Arm-A was associated with less grade ≥III rash and sensory neuropathy and a lower rate of serious AEs (20%/27%). CONCLUSION(S): This phase II exploratory trial with a non-inferiority design suggests that maintenance therapy with single-agent cetuximab following mFOLFOX+cetuximab induction could be a valuable option compared with mFOLFOX+cetuximab treatment continuation. We await phase III trials to confirm single-agent cetuximab as maintenance therapy in mCRC patients.

Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines

5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.

Controversies in the treatment of RAS wild-type metastatic colorectal cancer

Objective To provide guidance for the management of RAS wild-type (wt) metastatic colorectal cancer (mCRC) in daily practice. Methods Nominal group and Delphi techniques were used. A steering committee of seven experts analyzed the current management of RAS wt mCRC, through which they identified controversies, critically analyzed the available evidence, and formulated several guiding statements for clinicians. Subsequently, a group of 30 experts (the expert panel) was selected to test agreement with the statements, through two Delphi rounds. The following response categories were established in both rounds: 1 = totally agree, 2 = basically agree, 3 = basically disagree, 4 = totally disagree. Agreement was defined if ≥ 75% of answers were in categories 1 and 2 (consensus with the agreement) or 3 and 4 (consensus with the disagreement). Results Overall, 71 statements were proposed, which incorporated the following areas: (1) overarching principles; (2) tumor location; (3) triplets; (4) maintenance; (5) second-line and beyond treatments; (6) Rechallenge and liquid biopsy. After the two Delphi rounds, only six statements maintained a lack of clear consensus. Conclusions This document aims to describe the expert’s attitude when dealing with several common clinical questions regarding patients with RAS wt mCRC (AU)

SEOM Clinical Guideline of localized rectal cancer (2016).

Localized rectal adenocarcinoma is a heterogeneous disease and current treatment recommendations are based on a preoperative multidisciplinary evaluation. High-resolution magnetic resonance imaging and endoscopic ultrasound are complementary to do a locoregional accurate staging. Surgery remains the mainstay of treatment and preoperative therapies with chemoradiation (CRT) or short-course radiation (SCRT) must be considered in more locally advanced cases. Novel strategies with induction chemotherapy alone or preceding or after CRT (SCRT) and surgery are in development.

Current controversies in the management of metastatic colorectal cancer.

The factors affecting the decisions for the treatment for patients with metastatic colorectal cancer (mCRC) are related to the patient, the tumor, and the treatment itself. Both cetuximab and panitumumab are anti-EGFR monoclonal antibody options for patients with RAS wild-type tumors. Several trials comparing these agents with bevacizumab are analyzed in this paper. The liver is the most common site of metastases in patients with CRC, and perioperative chemotherapy has been shown to yield benefits in this setting. In the second-line treatment for mCRC, maintenance with bevacizumab after progression following first-line treatment is convenient in some groups of patients with mCRC. Also, aflibercept has demonstrated benefits in response rate, progression-free survival, and overall survival in second-line treatment, whereas regorafenib provides benefits to patients progressing on all standard therapies. Several novel therapeutic options for patients with mCRC are under development, and these are discussed.

First-line single-agent panitumumab in frail elderly patients with wild-type KRAS metastatic colorectal cancer and poor prognostic factors: A phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumours.

BACKGROUND: Frail elderly patients with metastatic colorectal cancer (mCRC) are not candidates for chemotherapy. Monotherapy with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies may be an option for these patients with few systemic toxic effects. PATIENTS AND METHODS: Single-arm, multicentre, phase II trial including patients ⩾ 70y ears with wild-type (WT) KRAS (exon 2) mCRC, Eastern Cooperative Oncology Group (ECOG) status ⩽ 3, KPC (Köhne Prognostic Classification)--defined intermediate or high risk status, frailty and/or ineligibility for chemotherapy. Patients received panitumumab until progression or unacceptable toxicity. The primary end-point was progression free survival (PFS) rate at 6 months. RESULTS: The study included 33 patients (intention-to-treat (ITT) population). Median age: 81 years; sex: 66.7% male; high-risk KPC status: 45.4%. Median treatment duration was 14 weeks and 6-month PFS rate was 36.4% (95% confidence interval (CI): 20.0-52.8). The objective response rate: 9.1% (95% CI: 0-18.9) (all partial responses), and there were 18 stable diseases (54.5%). Median PFS was 4.3 months (95% CI: 2.8-6.4) and median overall survival (OS) was 7.1 months (95% CI: 5.0-12.3). There were no deaths or grade 4-5 adverse events (AEs) related to panitumumab and the most common grade 3-related AE was rash acneiform (15.2%). A significant association between clinical response and RAS status was observed (P=0.037). In the WT RAS subgroup (WT exons 2, 3, and 4 of KRAS and NRAS, N = 15), 6-month PFS rate was 53.3% (95% CI: 30.1-75.2) and median PFS and OS were 7.9 and 12.3 months, respectively. CONCLUSIONS: Single-agent panitumumab is active and well tolerated and may be a therapeutic option for high-risk frail elderly patients with WT RAS tumours considered not candidates for chemotherapy (clinicaltrials.gov identifier NCT01126112).