A Phase I-II multicenter trial with Avelumab plus autologous dendritic cell vaccine in pre-treated mismatch repair-proficient (MSS) metastatic colorectal cancer patients; GEMCAD 1602 study.

BACKGROUND: Immune check-point blockade (ICB) has shown clinical benefit in mismatch repair-deficient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-proficient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic effects. METHODS: This was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor effects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efficacy of the combination. The primary end-point was 40% progression-free survival at 6 months with a 2 Simon Stage. RESULTS: A total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design first-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1-5.3 months] and overall survival was 12.2 months [3.2-23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted significant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, inflammation and oxidative stress pathways. CONCLUSIONS: The combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the first-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapy-induced tumor vulnerabilities.

Effect of aflibercept plus FOLFIRI and potential efficacy biomarkers in patients with metastatic colorectal cancer: the POLAF trial.

BACKGROUND: Aflibercept is an antiangiogenic drug against metastatic colorectal cancer (mCRC) combined with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI); however, no antiangiogenic biomarker has yet been validated. We assessed aflibercept plus FOLFIRI, investigating the biomarker role of baseline vascular endothelial growth factor A (VEGF-A) and angiotensin-converting enzyme (ACE). METHODS: Phase II trial in oxaliplatin-treated mCRC patients who received aflibercept plus FOLFIRI. The reported 135 ng/mL ACE cut-off was used and ROC analysis was performed to assess the optimal VEGF-A cut-off for progression-free survival (PFS). Overall survival (OS), time to progression (TTP), time to treatment failure (TTF), overall response rate (ORR) and disease control rate (DCR) were also assessed. RESULTS: In total, 101 patients were followed for a median of 12 (6-17) months. The 1941 pg/mL VEGF-A was an optimal cut-off, with a longer median PFS when VEGF-A was <1941 versus ≥1941 pg/mL (9 versus 4 months). Patients with VEGF-A < 1941 pg/mL showed longer median OS (19 versus 8 months), TTP (9 versus 4 months) and TTF (8 versus 4 months), along with higher ORR (26% versus 9%) and DCR (81% versus 55%). No differences were identified according to ACE levels. CONCLUSIONS: This study supports aflibercept plus FOLFIRI benefits, suggesting VEGF-A as a potential biomarker to predict better outcomes.

Prevalence and correlates of cancer-related fatigue in breast cancer survivors.

PURPOSE: To identify potential correlates of cancer-related fatigue (CRF) after curative breast cancer (BC) treatment. The hypothesis was that fatigue would be more severe among women treated with cardiotoxic drugs, with poor physical condition and those who exercised less. METHODS: Observational cross-sectional design. Fatigue was evaluated through PERFORM Questionnaire (multi-item, multi-dimensional). Patient-reported assessments and objective information regarding clinical data, physical activity (PA) and physical condition were analysed as potential correlates of CRF. RESULTS: One hundred eighty women who remained free of disease were recruited. The prevalence of fatigue interfering with quality of life was 43%. Weight, resting and recovery heart rate were positively associated with fatigue. Age and time from diagnosis were negatively associated. Previous therapies, objectively assessed weekly PA, cardiorespiratory condition, muscular strength and adherence to Mediterranean diet were not associated with CRF. CONCLUSIONS: CRF is a prevalent problem after BC treatment. Objectively assessed PA, cardiorespiratory fitness and muscular strength did not predict CRF. The association of heart rate and fatigue deserves a further insight. Future research should include longitudinal studies and determination of biomarkers. IMPLICATIONS FOR CANCER SURVIVORS: BC survivors, especially younger and overweight women, should be informed about fatigue as a potential persistent symptom through all stages of the cancer trajectory and into survivorship. They also should be routinely screened for CRF.

Is aflibercept an optimal treatment for wt RAS mCRC patients after progression to first line containing anti-EGFR?

PURPOSE: To determine the efficacy and safety data of aflibercept + FOLFIRI in wt RAS mCRC patients after progression to standard chemotherapy + anti-EGFR treatment. METHODS: Retrospective, observational study in real life conducted in wt RAS mCRC patients treated with FOLFIRI-aflibercept after progression to standard first line chemotherapy + anti-EGFR treatment. RESULTS: A total of 120 patients from 12 Spanish hospitals were enrolled. Median age is 60 years (62.5%/37.5%male/female). Primary tumor site is 24.1%/75.9% right/left-side colon, and 40.8% of patients had a prior resection. All patients had wild-type RAS tumors including 5% of patients with BRAF mutations and received anti-EGFR treatment. At the time aflibercept was initiated, ECOG PS is 0/1 in 96% of patients. Median number of FOLFIRI-aflibercept cycles is 12. Efficacy results: Overall response rate is 33%; progression-free survival (PFS) is 6.9 months (95%CI: 6.1-7.8). Primary tumor resection was the only significant variable related to PFS in the multivariate analysis. Median overall survival (OS) is 14.5 months (95%CI: 9.7-19.3). ECOG and number of metastatic sites were related to OS in multivariate analysis. About 54.1% of patients received a third-line therapy including TAS-102 (23%), regorafenib (18.5%), and capecitabine (9.2%). TOXICITY: Grade 3-4 toxicities were observed in 37.5% of the patients (hematologic 16.6%, hypertension 7.5%, asthenia 5.9%, and perforation 2.5%). Aflibercept dose was reduced in 18.3% of patients. CONCLUSIONS: The results show that patients with wt RAS mCRC who received an anti-EGFR as part of the first-line treatment achieved similar RR, PFS, OS, and toxicities to those reported in VELOUR trial. These results suggest that FOLFIRI-aflibercept after first-line treatment with anti-EGFR is an appropriated option for RAS wt mCRC.

Concurrent Exercise Interventions in Breast Cancer Survivors with Cancer-related Fatigue.

This study compared the effects of two supervised concurrent training interventions in breast cancer survivors with cancer-related fatigue at baseline. Twenty-three female breast cancer survivors (50±8 years) were randomized to a high- (n=13) or a moderate-intensity (n=10) training program. Both interventions lasted 16 weeks and included the same resistance exercises, but the aerobic component was supervised and more intense in the former (i.e., rating of perceived exertion of 7-8 vs. 6 on a 1-10 scale for the high and moderate-intensity intervention, respectively). The primary endpoint was fatigue perception. Endpoints were assessed at baseline and after 16 weeks. The p-value for statistical significance was set at 0.004 after Bonferroni correction for multiple comparisons. The high-intensity training program increased lower-limb muscle strength significantly (p=0.002) and tended to improve fatigue perception (p=0.006), waist circumference (p=0.013), neutrophil-to-lymphocyte ratio (p=0.028) and some quality of life items (p=0.011). Although the moderate-intensity training program did not provide such benefits in general (i.e., higher p-values for pre vs post-intervention comparisons), no significant differences were found between interventions (all p>0.004). Further research is needed to elucidate if the benefits provided by high-intensity concurrent training are superior to those elicited by moderate-intensity training in breast cancer survivors.

Cardiorespiratory fitness and adiposity in breast cancer survivors: is meeting current physical activity recommendations really enough?

PURPOSE: Breast cancer (BC) survivors are becoming increasingly predisposed to cardiovascular disease (CVD) mortality. Low cardiorespiratory fitness and physical activity (PA) levels, as well as high values of adiposity indices, contribute to CVD risk. We evaluated adiposity, cardiorespiratory profile, and PA levels in two independent cohorts of BC survivors. METHODS: Data were collected from two groups (99% women) from different areas of Madrid (Spain): group 1, n = 110, age 51.4 ± 9.7 years, median time from diagnosis 365 days (95% confidence interval [CI], 354-401), and group 2, n = 93, age 54.7 ± 8.9 years, 1714 days (95% CI, 1502-1938). We estimated peak oxygen uptake (VO2peak) and measured body mass index (BMI), waist circumference (WC), waist-to-hip index, and accelerometry-determined PA. RESULTS: Both groups had values of BMI in the overweight range (25.3 ± 4.3 and 27.1 ± 5.1 kg/m2, p = 0.003). Estimated VO2peak levels were lower in group 2 than in group 1 (28.1 ± 9.1 and 23.7 ± 8.8 ml/kg/min, p < 0.001), although levels in both groups were low. Yet, the majority of participants in both groups (81 and 88%, p = 0.234) met international PA recommendations (235 ± 196 and 351 ± 173 min/week of moderate-vigorous PA, p < 0.001). Both groups had very low levels of vigorous PA. These results were essentially independent of type of treatment (anthracycline/radiotherapy). CONCLUSIONS: We found a poor cardiorespiratory profile in two independent BC cohorts that differed in median time from diagnosis (as well in socioeconomic status), supporting the notion that implementation of PA (possibly focusing on vigorous PA) and dietary intervention is urgently needed in this patient population.

Clinical audit of multidisciplinary care at a medium-sized hospital in Spain.

BACKGROUND: Multidisciplinary care is a key enabler in the provision of high quality care for cancer patients. Despite compelling evidence supporting their benefit to patients and for providers, multidisciplinary cancer conferences (MCC) are not universally occurring. Team composition of MCC reflects the multidisciplinary nature of the body. Lack of nursing input can have a negative impact on team decision making. The objective of this study was to evaluate multidisciplinary care and adherence to national recommendations at a medium-sized hospital through a clinical audit of cancer conferences and clinical records. METHODS: A total of 77 multidisciplinary cancer conferences were visited and 496 electronic health records were reviewed. The regularity of meetings and multidisciplinary attendance were evaluated. Each electronic health record was checked to verify documented prospective discussion before any treatment was started. RESULTS: Nine multidisciplinary teams meet on a weekly or biweekly basis at the hospital with an average number of ten people and six different specialties represented. Average duration of meetings was 46.8 min. Though most patients (64.5%) were discussed at some point at the relevant cancer conference, only 40% had a documented multidisciplinary team discussion prior to the first treatment. Pathological stage (pTNM) was documented in 53.6% of clinical records. CONCLUSIONS: Nursing representatives should be included as usual attendees at cancer conferences. Prospective discussion of all cancer cases should be encouraged. Use of checklists and systematic collection of key information, specifically cancer staging, could improve clinical documentation in the electronic clinical record.

Autonomy support in an exercise intervention with colorectal cancer patients during chemotherapy: a qualitative perspective.

OBJECTIVE: Physical activity (PA) has emerged as an important element of supportive care for cancer patients, but few patients engage with exercise. Considering that autonomy support is associated with healthy lifestyles, it would be useful to know the specific autonomy-supportive techniques that can help to encourage PA in colorectal cancer (CRC) patients. This study aims to qualitatively explore autonomy support perceptions through a self-determination-theory-based exercise program (FIT-CANCER) with CRC patients during chemotherapy treatment. METHODS AND MEASURES: A total of 27 participants were included, 16 CRC patients, six relatives, and five healthcare professionals. Qualitative data from semi-structured interviews and observational field notes were analyzed with thematic analysis. RESULTS: Three main themes were identified: Healthcare professionals encouraging enrollment in the exercise program, Relatives supporting attendance to the exercise sessions, Exercise instructor favoring adherence to the exercise program. The different subthemes showed autonomy-supportive techniques from these social agents to promote CRC patients' participation in the exercise program. CONCLUSION: The present research showed the importance of autonomy support from healthcare professionals, relatives and the exercise instructor to promote the initiation and maintenance of CRC patients' PA behavior and improve their quality of life, health and well-being.

SEOM-GEMCAD-TTD clinical guidelines for the adjuvant treatment of colon cancer (2023).

Colorectal cancer (CRC) has a 5-year overall survival rate of over 60%. The decrease in the rate of metastatic disease is due to screening programs and the population's awareness of healthy lifestyle. Similarly, advancements in surgical methods and the use of adjuvant chemotherapy have contributed to a decrease in the recurrence of resected disease. Before evaluating a patient's treatment, it is recommended to be discussed in a multidisciplinary tumor board. In stage II tumors, the pathologic characteristics of poor prognosis must be known (T4, number of lymph nodes analyzed less than 12, lymphovascular or perineural invasion, obstruction or perforation, poor histologic grade, presence of tumor budding) and it is mandatory to determine the MSI/MMR status for avoiding administering fluoropyridimidines in monotherapy to patients with MSI-H/dMMR tumors. In stage III tumors, the standard treatment consists of a combination of fluoropyrimidine (oral or intravenous) with oxaliplatin for 6 months although the administration of CAPOX can be considered for 3 months in low-risk tumors. Neoadjuvant treatment is not consolidated yet although immunotherapy is achieving very good preliminary results in MSI-H patients. The use of ctDNA to define the treatment and monitoring of resected tumors is only recommended within studies. These guidelines are intended to help decision-making to offer the best management of patients with non-metastatic colon cancer.

Cancer-Related Fatigue and Circulating Biomarkers in Breast Cancer Survivors.

PURPOSE: Cancer-related fatigue (CRF) is the most common and disruptive symptom experienced by cancer survivors and because of its frequency and severity is especially worrisome in breast cancer survivors (BCS). Despite a great deal of research, the mechanisms underlying CRF have not been determined. The present study aims to describe associations between CRF in BCS and different blood biomarkers. METHODS: A descriptive and cross-sectional study was conducted. A set of biomarkers assessing inflammation were measured in BCS: C-reactive protein (CRP), neutrophil-lymphocyte ratio (NLR), IL-1ß, IL-6, IL-8, IL-10, tumor necrosis factor (TNF); HPA axis dysfunction (cortisol), autonomic dysfunction (noradrenaline); oxidative stress (8-OH deoxyguanosine); insulin resistance markers (insulin, IGF-I, IGFBP3) and sexual hormones (estrogens, progesterone, testosterone). RESULTS: NLR (p = .00) and cortisol (p = .02) were positive and negatively associated with CRF, respectively. The rest of the blood markers were not associated with CRF. CONCLUSION: Our results increase the evidence on pathophysiological mechanisms driving CRF in BCS. However, longitudinal studies are needed to explore the role of these factors as potential causal mechanisms.

Biological mechanisms of cancer-related fatigue in breast cancer survivors after treatment: a scoping review.

PURPOSE: Cancer-related fatigue (CRF) is the most common symptom experienced by cancer survivors. It is a multidimensional symptom affecting physical, emotional, and/or cognitive spheres, different from other types of fatigue. Characteristically is not alleviated by sleep or rest. CRF could have specific features in breast cancer survivors (BCS), because of sex, hormones, and distinct treatments. On the other hand, more than 25% of BCS report persistent CRF for 10 years or more after the diagnosis. The present study aims to recapitulate the knowledge about the biological mechanisms that potentially drive CRF in BCS after treatment. METHODS: To answer a broad question, a scoping review methodology was used. Data were collated from three bibliographic databases: PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). Studies were selected if they had included more than 20 BCS, after finishing their treatment, fatigue was measured with a quantitative scale and biomarkers were analyzed. RESULTS: The final database was composed of 1896 records. Sixty-four studies finally met the eligibility criteria. Inflammation (61%), hypothalamic-pituitary-adrenal (HPA) axis dysregulation (14%), autonomic nervous system (ANS) dysfunction (11%), and diet (9%) were the biological pathways most frequently studied. Unfortunately, results from studies about inflammation and HPA axis show many inconsistencies. CONCLUSION: More research about the role of ANS dysfunction and diet on the pathogenesis of CRF would be warranted according to the results of the review. There are some fields such as endocannabinoid systems, mitochondrial dysfunction, gut microbiota, and oxidative stress that have been insufficiently explored. IMPLICATIONS FOR CANCER SURVIVORS: To widen the scope of future research in the physiopathology of CRF, it is necessary to identify mechanisms that would be potentially involved and have been insufficiently explored. Because of the high prevalence of CRF in BCS and the tremendous impact that fatigue has in their quality of life, it is essential to improve the efficacy of the treatments through a good knowledge of the biological basis of CRF.

"To be myself again": Perceived benefits of group-based exercise for colorectal cancer patients.

PURPOSE: To explore the perceived benefits of a group-based exercise program for patients with colorectal cancer (CRC) undergoing chemotherapy treatment. METHODS: In-depth semi-structured interviews were conducted with all participants (n = 27) at the end of the exercise program (patients, relatives and healthcare professionals). The exercise instructor in charge of the exercise program with CRC patients also collected observational field notes throughout a research diary. RESULTS: Three main themes related to exercise as a coping strategy were obtained: (a) physical recovery; (b) psychosocial well-being, and (c) reconnection with their embodied selves and normal lives. Physical recovery included a perceived increase in fitness and a reduction in physical side-effects. Psychosocial well-being included perceived benefits in self-confidence, sense of control, reduced fear, feeling of being useful, sense of achievement, positive thinking and avoiding depression. All the physical and psychosocial benefits helped patients reconnect with their embodied selves, engage in activities practised before the diagnoses, improve their body image, avoid stigma, and increase their social life beyond cancer diagnoses. In this sense, some patients held on to their past selves, trying to keep or recover normality in their lives, while others acknowledged that they might not be the same person anymore, with exercise being part of this new identity. CONCLUSIONS: This study shows that exercise is a coping strategy that benefitted CRC patients in several ways related to their physical and psychosocial quality of life.

Impact of the COVID-19 Lockdown on Physical Activity Levels and Health Parameters in Young Adults with Cancer.

The lockdown of the COVID-19 pandemic impacted physical activity (PA) levels around the world, affecting health parameters in young adults with cancer (YAC). To our knowledge, there is no evidence of the impact of the lockdown on the Spanish YAC. To analyse the changes in PA levels before, during, and after the lockdown of the YAC and its impact on health metrics in Spain, in this study, we utilized a self-reported web survey. PA levels decreased during the lockdown, and a significant increase in PA was observed after the lockdown. Moderate PA had the largest reduction (49%). Significant increases in moderate PA were noted after the lockdown (85.2%). Participants self-reported more than 9 h of sitting per day. HQoL and fatigue levels were significantly worse during the lockdown. The impact of the COVID-19 pandemic in this cohort of Spanish YAC showed a decrease in PA levels during the lockdown, affecting sedentarism, fatigue and HQoL. After lockdown, PA levels partially recovered, while HQoL and fatigue levels remained altered. This may have long-term physical effects such as cardiovascular comorbidities associated with sedentarism and psychosocial effects. It is necessary to implement strategies such as cardio-oncology rehabilitation (CORE), an intervention that can be delivered online, potentially improving participants' health behaviours and outcomes.

ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated BRAFV600E-Mutant Metastatic Colorectal Cancer.

PURPOSE: The positive BEACON colorectal cancer (CRC) safety lead-in, evaluating encorafenib + cetuximab + binimetinib in previously treated patients with BRAFV600E-mutated metastatic CRC (mCRC), prompted the design of the phase II ANCHOR CRC study (ClinicalTrails.gov identifier: NCT03693170). ANCHOR CRC aimed to evaluate efficacy, safety, and quality of life with first-line encorafenib + binimetinib + cetuximab in BRAFV600E-mutated mCRC. METHODS: In this multicenter, open-label, single-arm study, patients with BRAFV600E-mutated mCRC received oral encorafenib 300 mg once daily and binimetinib 45 mg twice daily in 28-day cycles, plus intravenous cetuximab 400 mg/m2 once on day 1 of cycle 1, then 250 mg/m2 once weekly for the first seven cycles, and 500 mg/m2 once on Days 1 and 15 from cycle 8 onward. The primary end point was locally assessed confirmed objective response rate (cORR), and secondary end points included centrally assessed cORR, progression-free survival, overall survival (OS), quality of life, and safety and tolerability. RESULTS: Among 95 patients, the locally assessed cORR was 47.4% (95% CI, 37.0 to 57.9) with all partial responses. Since the lower limit of the 95% CI exceeded 30%, the primary end point was met. With a median follow-up duration of 20.1 months, the median progression-free survival on the basis of local assessments was 5.8 months and the median OS was 18.3 months. Treatment was well tolerated, with no unexpected toxicities. Using Patient Global Impression of Changes, substantial improvement in symptoms was consistently reported in ≥ 30% of patients from cycle 3 to cycle 10. CONCLUSION: The ANCHOR CRC study showed that the scientifically driven combination of encorafenib + binimetinib + cetuximab was active in the first-line setting of BRAFV600E-mutated mCRC with a manageable safety profile. Further first-line evaluation is ongoing (ClinicalTrails.gov identifier: NCT04607421).

C-Reactive Protein Is Associated with Physical Fitness in Breast Cancer Survivors.

Background: Physical fitness (PF) is an expression of the physiological functioning of multiple body components. PF is an important prognostic factor in terms of cardiovascular mortality, cancer mortality, and all-cause mortality. PF has been related to some biomarkers in the general population but not in breast cancer survivors (BCS). Purpose: To evaluate the effects of PF on biomarkers potentially related to physical activity (PA) in a sample of BCS. Methods: Cross-sectional study. A total of 84 BCS (mean age 54) who had finished their treatment were recruited. Different components of PF were evaluated, namely body composition (anthropometry), cardiorespiratory fitness (one-mile walk test), muscular (handgrip and sit-to-stand timed test), and motor (gait speed) components. Sexual hormones, inflammation, and insulin resistance biomarkers were measured. Results: C-Reactive Protein (CRP) was associated with every component of physical fitness: cardiorespiratory fitness (p-value = 0.002), muscular (sit-to-stand timed test, p-value = 0.002) and motor (gait speed, p-value = 0.004) components, and body composition (body mass index, p-value = 0.003; waist, p-value < 0.000; and waist-to-hip index, p-value = 0.012). CRP also was associated with "poor physical condition," a constructed variable that encompasses all components of physical fitness (p-value < 0.001). Insulin was associated with cardiorespiratory fitness and gait speed (p-values = 0.002 and 0.024, respectively). Insulin-like Growth Factor-1 was negatively associated with waist perimeter and waist-to-hip ratio. Conclusions: CRP can also be considered an indicator of poor PF in BCS. Implications for cancer survivors: in case of elevation of CRP indicating cardiovascular risk, health professionals should recommend lifestyle changes to improve BCS physical condition.

Cancer-related Fatigue in Breast Cancer Survivors: A Review.

Fatigue has been the most distressing and frequent symptom in breast cancer (BC) survivors after treatment. Although fatigue can occur in other cancer survivors, women with a history of BC might share some distinctive features. The present study aimed to recapitulate the knowledge about risk factors and correlates of cancer-related fatigue (CRF) in BC survivors after oncologic therapy. An electronic data search was conducted in PubMed using the terms "fatigue," "breast," "cancer," and "survivors." Records were included if they were original articles, available in English, had used a quantitative scale, had > 100 participants, and had excluded women with BC relapse. BC survivors were required to have finished their treatments ≥ 2 months before, except for hormonal therapy. The physiopathology and other interventions were considered beyond the scope of our review. The correlates were subsequently classified into 7 main categories: (1) sociodemographic data, (2) physical variables, (3) tumor- and treatment-related variables, (4) comorbidities, (5) other symptoms, (6) psychological issues, and (7) lifestyle factors. Fatigue was consistently greater in younger, obese, and diabetic women. Women reporting fatigue often communicated symptoms such as pain, depression, insomnia, and cognitive dysfunction. Coping strategies such as catastrophizing could play an important role in the persistence of fatigue. However, tumor characteristics, previous treatments received, and physical activity were not consistently reported. CRF was a strong predictor of the quality of life of BC survivors after treatment. In conclusion, we found CRF was a frequent and serious symptom that severely affects the quality of life of BC survivors after treatment. Health practitioners require more awareness and information about CRF.

Early Clinical Experience with Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: The ROS Study.

Trifluridine/tipiracil is currently approved for metastatic colorectal cancer (mCRC) refractory to available therapies. However, there is no consensus on factors that predict treatment outcomes in daily practice. We assessed the early clinical experience with trifluridine/tipiracil in Spain and potential survival markers. This was a retrospective cohort study of mCRC patients who participated in the trifluridine/tipiracil early clinical experience programme in Spain. The primary outcome was overall survival (OS). Associations between OS and patient characteristics were assessed using multivariate Cox regression analyses. A total of 379 patients were included in the study. Trifluridine/tipiracil was administered for a median of 3.0 cycles and discontinued mainly due to disease progression (79.2%). The median OS was 7.9 months, with a 12-month OS rate of 30.5%. Cox analyses revealed that the following variables independently enhanced OS: ≤2 metastatic sites, no liver metastasis, alkaline phosphatase < 300 IU, trifluridine/tipiracil dose reductions, and neutrophil/lymphocyte ratio < 5. Grade ≥ 3 toxicities were reported in 141 (37.2%) patients, including mainly afebrile neutropaenia (23.2%), anaemia (12.1%), and thrombocytopaenia (5.3%). This study supports the real-life efficacy and safety of trifluridine/tipiracil for refractory mCRC and identifies tumour burden, liver metastasis, alkaline phosphatase, dose reductions, and neutrophil/lymphocyte ratio as survival markers.

Metastatic Colorectal Cancer. First Line Therapy for Unresectable Disease.

Colorectal cancer (CRC) is a commonly diagnosed malignancy. The prognosis of patients with unresectable, metastatic colorectal cancer (mCRC) is dismal and medical treatment is mainly palliative in nature. Although chemotherapy remains the backbone of treatment, the landscape is changing with the understanding of its heterogeneity and molecular biology. First-line therapy relies on a combination of chemotherapy and targeted therapies, according to clinical patient characteristics and tumor molecular profile. Here we review current evidence from randomized clinical trials for using chemotherapy doublets or triplets, and for the addition of bevacizumab or anti-epidermal growth factor receptor (EGFR) agents. Novel therapies developed for small, selected populations are also discussed.

Safety and Effectiveness of Aflibercept + Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) for the Treatment of Patients with Metastatic Colorectal Cancer (mCRC) in Current Clinical Practice: OZONE Study.

For patients with metastatic colorectal cancer (mCRC) that have failed a first-line oxaliplatin-based regimen, the preferred treatment option is an irinotecan-based regimen. This prospective, observational, noncomparative, post-authorization safety study (OZONE) evaluated the safety and effectiveness of aflibercept plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) in patients with mCRC treated in daily practice after failure of an oxaliplatin-based regimen. Patients were grouped by age, renal impairment, hepatic impairment, race, number, and type of prior anticancer therapy. Of 766 treated patients enrolled, 59.5% were male, 94.8% had an Eastern Cooperative Oncology Group performance status of 0-1, all received previous chemotherapy (97.8% including oxaliplatin), and 58.6% had prior exposure to bevacizumab. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 68.3% of patients. Neutropenia, hypertension, diarrhea, and asthenia were the most frequently occurring grade ≥ 3 TEAEs. Antivascular endothelial growth factor class events were infrequent. Subgroup analyses did not reveal major differences in the safety profile according to age, renal and hepatic status, race, or prior anticancer therapy. For the total population, median overall survival was 12.5 months, median progression-free survival was 6.1 months, and overall response rate was 16.3%. Aflibercept in combination with FOLFIRI is a safe and efficacious regimen administered in current clinical practice to patients with mCRC previously treated with oxaliplatin. The study results, conducted in real-world clinical practice with a less selected patient population, are aligned with the VELOUR (NCT00561470) trial and no new safety issues were identified.