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Purpose: This study aims to evaluate quality of life trajectory during the first year after surgical treatment in patients with resectable primary colon cancer., Methods: Patients with resectable primary colon cancer diagnosed between 2013 and 2019 who received surgical treatment and adjuvant chemotherapy if indicated were selected from the Prospective Dutch ColoRectal Cancer cohort study (PLCRC). Health-related quality of life (HR-QoL) was assessed using EORTC-QLQ-C30 questionnaire before surgery, and three and twelve months after surgery. HR-QoL scores varied between 0 and 100 and outcomes were compared according to age (< 70 years, ≥ 70 years), comorbidity (yes, no) and treatment type (adjuvant chemotherapy, surgical treatment only). The extent of resilience, defined as a recovery of HR-QoL to baseline level after a clinically relevant decline in HR-QoL at months, was calculated twelve months post-surgery., Results: For all 458 patients, the mean age was 66.4 years (SD 9.5), 40% were aged 70 years and older and 68% were men. Baseline level of HR-QoL summary score was relatively high with a mean of 87.9 (SD 11.5), and did not significantly differ between older and younger patients. The strongest decline of HR-QoL compared to baseline was observed at three months with a gradual recovery over time. Fourteen percent of all patients were non-resilient or showed a late decline at twelve months post-surgery. Compared to younger patients, older patients who received adjuvant chemotherapy were less resilient (respectively, 53 and 32%, p = 0.07) and at risk of a late decline in HR-QoL 1 year post-surgery (respectively, 3% versus 16%, p = 0.02). Comorbidity status had no significant impact on the HR-QoL trajectory., Conclusion: Colon cancer treatment was associated with a decline in HR-QoL three months post-surgery, but most patients return to baseline level within twelve months. Still, particularly older patients who received adjuvant chemotherapy were less resilient and at risk of a late decline in HR-QoL. These data could help in patients counselling regarding colon cancer treatment., (© 2023. The Author(s), under exclusive licence to European Geriatric Medicine Society.)

Objective: This study aims to evaluate changes in health-related quality of life (HR-QoL) 1 year after surgical treatment in patients with primary resectable colon cancer and to assess whether changes at group level differ from changes at individual level. In addition, we assess which characteristics are associated with a decline of HR-QoL., Methods: Patients with primary resectable colon cancer who received surgical treatment and adjuvant chemotherapy if indicated were selected from the Prospective Dutch ColoRectal Cancer cohort (PLCRC). HR-QoL was assessed using EORTC-QLQ-C30 questionnaire before surgery and 12 months post-surgery. Outcomes were assessed at group and individual levels. Logistic regression analysis was conducted to assess which socio-demographic and clinical characteristics were associated with a clinically relevant decline of HR-QoL at 12 months., Results: Of all 324 patients, the baseline level of HR-QoL summary score was relatively high with a mean of 88.1 (SD 11.4). On group level, the change of HR-QoL at 12 months varied between -2% for cognitive functioning and +9% for emotional functioning. On individual level, 15% of all patients experienced a clinically relevant decline in HR-QoL summary score at 12 months. Older age, comorbidity burden or the reception of adjuvant chemotherapy was independently associated with a decline of HR-QoL in one of the functional subscales of EORTC-QLQ-C30 at 12 months., Conclusion: Only trivial changes of HR-QoL were observed after colon cancer treatment on group level, whereas on individual level, at least 1 out of 10 patients experienced a decline of HR-QoL 12 months post-surgery. It is important to consider individual differences while making a treatment decision., (© 2022 John Wiley & Sons Ltd.)

Aim: Some patients with stage I-III colorectal cancer (CRC) do not undergo tumor resection. Little is known about survival of these non-curatively managed patients. The aim of this study is to report all-cause mortality and to identify which factors are associated with survival in these patients., Methods: A retrospective review of electronic medical records was performed in two hospitals in the Netherlands. Patients diagnosed with CRC without distant metastases (radiologically determined stage I-III) and managed without tumor resection between 2011 and 2017 were included. The primary outcome was all-cause mortality. The effect of several variables on survival was evaluated with a multivariate logistic regression., Results: Of the 107 patients with stage I-III CRC that did not undergo resection of the primary tumor, 80% died within two years; median survival time was 8.5 months (IQR 2.5-22 months). Malnutrition risk (OR 6.36 (CI 1.21-33.25); p = 0.03) and comorbidity burden (OR 1.51 (CI 1.05-2.18 p = 0.03) were significantly associated with decreased survival after two years in a multivariate model. Age and disease stage were not. When treatment decision was mainly patient driven instead of based on the multi-disciplinary tumor board's decision, survival was longer (mean overall survival 16 months vs 10 months, respectively) p < 0.05., Conclusion: Survival of patients with radiologically determined stage I-III CRC who did not undergo surgical resection was approximately 20% at two years and associated with the number of comorbidities, malnutrition risk status and dependent living, but not with age or disease stage., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The treatment of cancer can have a significant impact on quality of life in older patients and this needs to be taken into account in decision making. However, quality of life can consist of many different components with varying importance between individuals. We set out to assess how older patients with cancer define quality of life and the components that are most significant to them. This was a single-centre, qualitative interview study. Patients aged 70 years or older with cancer were asked to answer open-ended questions: What makes life worthwhile? What does quality of life mean to you? What could affect your quality of life? Subsequently, they were asked to choose the five most important determinants of quality of life from a predefined list: cognition, contact with family or with community, independence, staying in your own home, helping others, having enough energy, emotional well-being, life satisfaction, religion and leisure activities. Afterwards, answers to the open-ended questions were independently categorized by two authors. The proportion of patients mentioning each category in the open-ended questions were compared to the predefined questions. Overall, 63 patients (median age 76 years) were included. When asked, "What makes life worthwhile?", patients identified social functioning (86%) most frequently. Moreover, to define quality of life, patients most frequently mentioned categories in the domains of physical functioning (70%) and physical health (48%). Maintaining cognition was mentioned in 17% of the open-ended questions and it was the most commonly chosen option from the list of determinants (72% of respondents). In conclusion, physical functioning, social functioning, physical health and cognition are important components in quality of life. When discussing treatment options, the impact of treatment on these aspects should be taken into consideration.

Purpose: We set out to determine study objectives of clinical trials which included older patients with the four most common malignancies, to assess the extent to which the inclusion of patient-related outcomes (PROs) has changed over the last fifteen years., Method: A search of the National Institutes of Health clinical trial registry was performed to identify currently recruiting or completed phase II or III clinical trials started between 2005 and 2020, which addressed chemotherapy or immunotherapy in patients aged > 65 years with the four most common solid malignancies. Trial characteristics and study objectives were extracted from the registry website., Results: Compared to disease- and treatment-related outcomes, PROs were the least measured outcomes. Of the 1,663 trials, PROs were addressed in only 21% of all trials, in which quality of life as primary objective was found in less than 1% of all trials. Compared to all trials, trials exclusively for older patients addressed more often PROs (respectively, 30% vs 21%, p < 0.001). Over the last fifteen years, there was an incremental trend in the reporting of PROs from 17 to 24% of all trials (p = 0.007)., Conclusion: Despite a slight incremental trend over the past 15 years, PROs appear to be underrepresented in clinical trials which include patients with a solid malignancy. In order to provide physicians and older patients with cancer realistic information about the impact of chemo- or immunotherapy on quality of life or functioning, researchers should strongly consider including PROs in their future clinical trials.

Objective: This study aims to assess age-related treatment patterns and primary reasons for adjusted treatment in patients with colorectal cancer., Methods: Patients with colorectal cancer stage II or III diagnosed between 2015 and 2018 in the Netherlands were eligible for this study. Data were provided by the Netherlands Cancer Registry and included socio-demographics, clinical characteristics, treatment patterns and primary reasons for adjusted treatment. Treatment patterns and reasons for adjusted treatment were analysed according to age groups., Results: Of all 29,620 patients, 30% were aged <65 years (n = 8994), 34% between 65 and 75 years (n = 10,173), 27% between 75 and 85 years (n = 8102) and 8% were ≥85 years (n = 2349). Irrespective of cancer location or stage, older patients received less frequently a combination of surgery and (neo)adjuvant therapy compared to younger patients (decreasing from 55% to 1% in colon cancer patients, and from 71% to 23% in rectal cancer patients aged <65 years and ≥85 years respectively). Omission of surgical treatment increased with age in both patients with colon cancer (ranging from 1% in patients aged <65 years to 16% in those ≥85 years) and rectal cancer (ranging from 12% in patients aged <65 years to 56% in those ≥85 years). The most common reasons for adjusted treatment were patient preference (27%) and functional status (20%), both reasons increased with advancing age., Conclusions: Guideline non-adherence increased with advancing age and omission of standard treatment was mainly based on patient preference and functional status. These findings provides insight in the treatment decision-making process in patients with colorectal cancer. Future research is necessary to further assess patient's role in the treatment decision-making process., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Patients need to be well informed about those outcomes that matter most to them to be able to make good decisions between different oncologic treatment options. Research shows that patient-centred data on quality of life and physical, social and cognitive functions are important to patients besides the more commonly used disease-centred outcomes. Current design and reporting of outcomes in oncologic studies does not provide enough information on these necessary patient-centred outcomes. Optimizing oncologic care and research requires a patient-centred focus instead of a disease-centred focus.

Objective: Social support may reduce the amount of psychological distress and increase quality of life. This study assessed whether socio-demographic, personality, and clinical characteristics predict the level of perceived social support in patients with endometrial or ovarian cancer., Methods: Patients with endometrial or ovarian cancer who participated in the ROGY Care study and completed the Multidimensional Scale of Perceived Social Support(MSPSS) 12 months after inclusion were eligible for this study (n=238). Logistic regression analysis was conducted to determine the predictive value of socio-demographic characteristics, personality and clinical characteristics after initial treatment on the perceived level of social support after 12 months., Results: Of the 238 patients (mean age 64.8 ± 9.4 years), 139 patients had endometrial cancer (58%) and 99 patients had ovarian cancer (42%). One year after inclusion, the level of perceived social support was high in 79% of all patients (n=189). Patients experiencing low level of perceived social support (n=49) less often had a partner (69% versus 83% in patients with high level of perceived social support; p=0.029), had a higher education level (24% versus 15% respectively; p=0.013) and a distressed (type D) personality was more common (40% versus 16% respectively; p<0.001). In multivariable analysis, a type D personality, characterized by negative affect and social inhibition, was the only independent predictor of a low level of perceived social support (OR 2.96; 95% CI 1.37-6.37; p=0.006)., Conclusions: In patients with endometrial or ovarian cancer, the level of perceived social support is mainly associated with a distressed (type D) personality. Those patients can be at risk of experiencing less social support. Future research is needed to assess whether they might benefit from additional support during cancer diagnosis and treatment., Competing Interests: Declaration of Competing Interest Dr. Ezendam reports grants from Dutch Cancer Society, during the conduct of the study. All other authors declared no conflicts of interest., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To assess the decision-making process in fit and frail older breast cancer patients., Methods: Breast cancer patients aged ≥70 years who completed the G8 frailty screening tool (G8) were included in this retrospective study. Socio-demographic and clinical characteristics were collected, as well as information from geriatric assessment (GA). Treatment decisions were compared with national guidelines., Results: Of 177 patients, 85 patients were considered fit by the G8 (G8-fit) and 92 patients frail (G8-frail). All G8-fit and 53 G8-frail were proposed for surgery. GA was performed in 34 patients (9 G8-fit; 25 G8-frail) of whom 16 (2 G8-fit;14 G8-frail) were considered frail (GA-frail). 28 out of these 34 patients were considered fit for surgery (including 11 GA-frail); their impairments were unlikely to interfere with surgery or life expectancy. Reasons for adjusting treatment were physical/cognitive condition and patient preference. Ultimately, 123 patients underwent surgery in accordance with guidelines (81 G8-fit;42 G8-frail, p < 0.001). Survival was reduced in G8-frail compared to G8-fit (p = 0.001), but G8 lost its association with mortality in multivariable survival analysis. Among patients undergoing surgery, no difference in mortality was seen between G8-fit and G8-frail (p = 0.996)., Conclusion: The G8 is associated with treatment decisions and did not affect survival in patients undergoing surgery. In the decision-making process, the G8 may help and estimates the need for adaptive care., (© 2020 John Wiley & Sons Ltd.)

Background: A better understanding of the impact of age and comorbidity on health-related quality of life (HRQoL) may improve treatment decision-making in patients with endometrial cancer. We investigated whether either age or comorbidity is more strongly associated with changes in HRQoL over time., Methods: Endometrial cancer patients (n = 296) were invited to complete questionnaires after initial treatment and after 6, 12 and 24 months follow-up. Patients were divided into subgroups according to age (<60, 60-75 and ≥75 years) and according to comorbidity (0, 1, 2 or ≥3). HRQoL was measured with the five EORTC QLQ-C30 functioning scales. Linear mixed models were performed for the different subgroups to assess changes in HRQoL over time. HRQoL was also compared to longitudinal outcomes from an age- and gender-matched normative population., Results: The first questionnaire was returned by 221 patients (75%) of whom six were excluded due to progressive disease. Changes in HRQoL were mainly associated with cumulative comorbidity burden and not with age. Patients with comorbidity reported deterioration of physical and role functioning between 12 and 24 months. Compared to the normative population, patients initially scored higher on physical and role functioning, but at 24 months outcomes were no longer different., Conclusion: Cumulative comorbidity burden was more strongly associated with deterioration of HRQoL than patient's age. Therefore, patients with endometrial cancer and multiple comorbid conditions require careful follow-up of HRQoL after treatment., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Geriatric assessment (GA) is an appropriate method for identifying frailty in older patients with cancer, but a shorter instrument may be easier to use in clinical practice. Clinical judgment is always available and requires no investments in time or resources. The purpose of this study was to assess correlations between clinical judgment for frailty of the cancer specialist, the general practitioner and patient's self-assessment, and the correlation between clinical judgment and GA., Methods: This was a dual-center inception cohort study of patients with cancer aged ≥70 years starting curative or first-line palliative chemotherapy. GA included the following domains: (instrumental) activities of daily living, nutrition, mobility, cognition, mood, and polypharmacy. Clinical judgment for frailty was rated on a scale from 0 to 10 (0 = not frail, 10 = frail). Correlation was tested using Kendall's tau-b correlation coefficient., Results: Of all 55 patients, 76% had ≥2 geriatric impairments. Median clinical judgment frailty score was 3 (range 1-10 for cancer specialist and patient and range 0-10 for general practitioner) and did not vary much according to the number of impaired geriatric domains (ranging from 2 for 0-1 impaired domains to 4 for ≥3 impaired domains). Correlations between mutual clinical judgment scores and between clinical judgment and GA were negligible or low., Conclusion: Correlations between clinical judgment scores and between clinical judgment and GA were poor. Most patients with multiple geriatric impairments had low 'subjective' frailty scores. Other frailty assessments, such as frailty screening tools or GA, should be considered in addition to clinical judgment when selecting older patients for potential treatment with chemotherapy., Competing Interests: Declaration of Competing Interest All authors have declared no conflicts of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Objective: This study aims to assess the reasons for guideline non-adherence in women with advanced stage ovarian cancer and whether these reasons differ according to age., Methods: All women diagnosed with advanced stage ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) IIb-IV, between 2015 and 2018 were selected from the Netherlands Cancer Registry. Treatment patterns and reasons for guideline non-adherence were analyzed according to age groups., Results: 4210 women were included, of whom 34%, 33%, 26%, and 8% were aged <65, 65-75, 75-85, and ≥85 years respectively. With advancing age, less women received guideline-adherent treatment (decreasing from 70% to 2% in women aged <65 and ≥85 years respectively) and more women received best supportive care only (ranging from 4% to 69% in women aged <65 and ≥85 years respectively). The most prevalent reasons for guideline non-adherence differed according to age and included patient preference in older women, and functional status and extent of disease in younger women., Conclusions: Most older women did not receive guideline-adherent care and patient preference was the most common reason for this decision. This knowledge provides insight in the current treatment decision-making process and highlights the importance of eliciting patient treatment preferences. Further prospective research is necessary to study the underlying motivation for women to decline guideline care and the extent to which shared decision-making influences treatment choice., Competing Interests: Declaration of competing interest JA Louwers is consultant for DySISmedical. All other authors have declared no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cancer specialists and geriatricians can struggle to find the best form for their collaboration within geriatric oncology and do not always benefit optimally from the experience and knowledge the other has to offer. To optimize the yield of a geriatric consultation for older patients with cancer, the geriatrician needs to know the specific purpose of the consultation, the expected disease trajectory, and some information on the potential benefits and risks of treatment options including best supportive care only. The geriatrician should subsequently focus primarily on the patient, their preferences and priorities with regards to oncologic and non-oncologic outcomes and assess their overall health status through a geriatric assessment that includes at minimum comorbidities, medication review, basic and instrument activities of daily living, mobility, falls, nutritional status, cognition, mood and social support. Reporting back to the cancer specialist should be concise, objective whenever possible and to the point. Within the multidisciplinary team, the geriatrician can contribute with information on health status and reserves, remaining life-expectancy and toxicity risks, and by creating awareness of the limitations of evidence regarding the older population. This will help in reaching a well-tailored treatment decision that balances cancer-related and patient-centred outcome measures and fits within the patient's own preferences for treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: The G8 is a widely used frailty screening tool in patients with cancer that was designed to be completed by healthcare professionals. A patient-reported version would enable a broader application. Aim of this study was to develop a self-reported version of the G8 and to assess its agreement with the original G8., Materials and Methods: A self-reported version of the G8 was developed with the aid of communication specialists. Patients aged ≥ 70 years from two different study populations were included: 1. Patients with cancer and 2. Patients visiting the geriatric outpatient clinic. The original G8 was completed by an oncology nurse or clinical research assistant and patients completed the self-reported G8. Patients were blinded to results of the original G8. Kappas were calculated to measure the agreement between the self-reported and original G8 for both the individual items as well as for the cut-off for potential frailty (≤14)., Results: 161 patients participated, of whom 104 had cancer (65%). Patients with cancer more frequently completed all items than geriatric patients (all items completed in 94% versus 72%, p < 0.001). The agreement for potential frailty was substantial for patients with cancer (Kappa 0.63) and poor for geriatric patients (Kappa 0.05)., Conclusion: Completion of the self-reported G8 is feasible and agreement of its outcome with the original G8 outcome is sufficient for patients with cancer but not for geriatric patients. The self-reported G8 may therefore be a useful alternative to the original G8 in older patients with cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Treatment decision-making in older patients with cancer is difficult due to a paucity of data evaluating chemotherapy tolerability in this population. We investigated the feasibility of chemotherapy in the oldest old and performed a singl-centre retrospective analysis of patients aged ≥80 years initiating chemotherapy for one of five common solid malignancies or non-Hodgkin lymphoma between 2010 and 2016. Treatment plan and course were extracted from medical files. Primary outcome was whether chemotherapy was completed according to plan, defined as a calculated relative dose intensity (RDI) ≥85%. A total of 104 patients receiving 129 chemotherapy lines were included. Median age at diagnosis was 82 years (range 80-94 years). Most patients (64%) received palliative intent chemotherapy. Primary and secondary chemotherapy adaptations were implemented in 63% and 65% of the cases, and hospitalisation occurred in a quarter. 52% of all cases completed chemotherapy according to plan. Almost half of the chemotherapy regimens started in the oldest old were not completed according to plan, despite frequently implemented upfront adaptations. The decision to start chemotherapy in these patients should be carefully considered. To improve decision-making in current practice, there is a need for the implementation of validated tools assessing chemotherapy feasibility in these patients., (© 2019 John Wiley & Sons Ltd.)

Objective: To assess long-term differences in health-related quality of life (HRQoL) of older ovarian cancer survivors compared to both an age-matched normative population and to younger survivors. In addition, the differential effect of chemotherapy on HRQoL between older and younger survivors was compared., Methods: Ovarian cancer survivors (n = 348) diagnosed between 2000 and 2010, as registered by the Dutch population-based Eindhoven Cancer Registry, were invited to complete the EORTC QLQ-C30 HRQoL questionnaire in 2012. HRQoL outcomes of survivors were compared with an age-matched normative population and older survivors (≥70 years) were compared with younger survivors., Results: The questionnaire was returned by 191 ovarian cancer survivors (55%), 31% were aged ≥70 years (n = 59). Compared to the normative population, survivors ≥70 years scored lower on global health status and all functioning subscales except emotional functioning, and they reported more symptoms. Survivors aged <70 years only reported worse physical and cognitive functioning in comparison with the normative population. Most differences were of medium to small clinical relevance. Age appeared to moderate the effect of chemotherapy on HRQoL. Older survivors who had received chemotherapy experienced better physical functioning and less pain and insomnia while the opposite was found in younger survivors., Conclusion: In comparison with an age-matched normative population, older ovarian cancer survivors report lower HRQoL scores than younger survivors. As this represents a selection of long-term survivors, future research should focus on the trajectory of HRQoL from diagnosis throughout treatment and follow-up to identify which factors are related to worse HRQoL in the entire older ovarian cancer population and whether timely interventions are able to improve HRQoL., (Copyright © 2019. Published by Elsevier Inc.)

Objective: To investigate treatment choices and outcomes in women with ovarian cancer, comparing elderly (≥75 years) and younger patients (<75 years)., Methods: A single-center retrospective analysis of patients diagnosed with ovarian cancer between 2010 and 2015. The initial treatment plan and course of treatment were extracted from medical files., Results: Of 128 included patients, 34% were aged ≥75 years. The initial treatment plan consisted of the combination of cytoreductive surgery and platinum-based doublet chemotherapy (ie, standard treatment) in only 10% of the elderly patients with an indication for this treatment. 5% of these patients completed this treatment without adaptations (compared with 85% and 48%, respectively, in younger patients). 38% of the elderly patients with an indication for cytoreductive surgery and chemotherapy received best supportive care only. Patient preference was an important reason to withhold standard treatment. Surgery- and chemotherapy-related complications and hospital admissions did not differ between groups. Median survival was lower in the elderly (p=0.002) and in patients receiving best supportive care (p<0.001)., Conclusions: Elderly patients were less frequently treated in accordance with the treatment guideline. To select those older patients who may benefit from (adapted) treatment is challenging. Future studies should evaluate determinants associated with treatment completion to improve outcomes in this vulnerable population., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Genetic variations in DPD have emerged as predictive risk factors for severe fluoropyrimidine toxicity. Here, we report novel and rare genetic variants underlying DPD deficiency in 9 cancer patients presenting with severe fluoropyrimidine-associated toxicity. All patients possessed a strongly reduced DPD activity, ranging from 9 to 53% of controls. Analysis of the DPD gene (DPYD) showed the presence of 21 variable sites including 4 novel and 4 very rare aberrations: 3 missense mutations, 2 splice-site mutations, 1 intronic mutation, a deletion of 21 nucleotides and a genomic amplification of exons 9-12. Two novel/rare variants (c.2843T>C, c.321+1G>A) were present in multiple, unrelated patients. Functional analysis of recombinantly-expressed DPD mutants carrying the p.I948T and p.G284V mutation showed residual DPD activities of 30% and 0.5%, respectively. Analysis of a DPD homology model indicated that the p.I948T and p.G284V mutations may affect electron transfer and the binding of FAD, respectively. cDNA analysis showed that the c.321+1G>A mutation in DPYD leads to skipping of exon 4 immediately upstream of the mutated splice-donor site in the process of DPD pre-mRNA splicing. A lethal toxicity in two DPD patients suggests that fluoropyrimidines combined with other therapies such as radiotherapy might be particularly toxic for DPD deficient patients. Our study advocates a more comprehensive genotyping approach combined with phenotyping strategies for upfront screening for DPD deficiency to ensure the safe administration of fluoropyrimidines., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background and Aim: Pharmacogenetic studies continue to search for pretreatment predictors of chemotherapeutic efficacy and toxicity in metastatic colorectal cancer. Both genome-wide association studies and candidate gene studies have yielded potential genetic markers for chemosensitivity. We conducted a clinical association study, validating the effect of specific genetic markers cited in recently published papers on the efficacy of the oral 5-fluoro-uracil prodrug capecitabine., Patients and Methods: Germline DNA was collected for 268 metastatic colorectal cancer patients from the CAIRO trial, a multicenter phase III trial, randomizing between combined or sequential first-line treatment with capecitabine, irinotecan, and oxaliplatin. Genotyping was performed for eight single-nucleotide polymorphisms (SNPs), using high-resolution melting curves. Four SNPs are located in the MTRR gene, and another four SNPs showed significant association with 5-fluoro-uracil cytotoxicity in a recent in-vitro genome-wide association study. The primary endpoint was progression-free survival (PFS); secondary endpoints were objective response and overall survival., Results: In patients receiving capecitabine monotherapy, rs4702484, located in ADCY2 and close to MTRR, was associated with slightly reduced PFS for homozygous wild-type patients (CC 6.2 vs. CT 8.0 months; P=0.018). For the other selected genetic markers, we found no association with PFS, overall survival, or radiologic response upon treatment with capecitabine, either in the total study population or in the capecitabine monotherapy subgroup., Conclusion: With the exception of rs4702484, we found no evidence of an effect on capecitabine chemosensitivity for any of the studied SNPs. More specifically, variants in methionine synthase reductase (MTRR) are not likely associated with capecitabine efficacy.

Aims: ERCC1 is involved in the repair of oxaliplatin-induced DNA damage. Studies for the association of the C118T SNP with clinical response to treatment with platinum drugs have rendered inconsistent results. We investigated the ERCC1 C118T SNP with respect to overall and progression-free survival in patients with advanced colorectal cancer (ACC) treated with oxaliplatin and in vitro DNA repair capacity after oxaliplatin exposure. In addition we discuss discrepancies from other studies concerning ERCC1 C118T., Materials and Methods: Progression-free survival was determined in 145 ACC patients treated with oxaliplatin-based chemotherapy in a phase 3 trial. For the in vitro studies regarding ERCC1 functionality, we transfected an ERCC1 negative cell line with 118C or 118T ERCC1. Cellular sensitivity and DNA repair capacity after exposure to oxaliplatin was examined by Sulphorodamine B growth inhibition assay, COMET assay and Rad51 foci staining., Results: We found no association between ERCC1 C118T and progression-free or overall survival. In addition, transfection of either 118C or 118T restores DNA-repair capacity of UV20 cells to the same level and chemosensitivity to oxaliplatin was similar in ERCC1 118C and 118T transfected cells., Conclusion: This study shows that the ERCC1 C118T variants are not associated with survival in ACC patients treated with oxaliplatin or the in vitro sensitivity and DNA-repair capacity in 118C and 118T transfected cell lines. Therefore, ERCC1 C118T genotyping seems of no value in individualizing oxaliplatin based chemotherapy in ACC., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: The availability of current chemotherapeutic options for metastatic colorectal cancer (mCRC) has increased survival, but it is also accompanied by considerable morbidity. Fluoropyrimidines are the mainstay of systemic therapy. Germline pharmacogenetic markers involved in 5-fluorouracil pharmacodynamics could provide individualized pretreatment tools for predicting toxicity. Research on methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and fluoropyrimidine treatment outcome has focused on intravenous 5-fluorouracil and has yielded inconclusive results. The literature on pharmacogenetics in capecitabine-based chemotherapy is scarce. Therefore, we analysed the association of MTHFR gene polymorphisms and the occurrence of serious toxicity of first-line capecitabine monotherapy and combination therapy., Methods: One hundred and twenty-seven patients treated with first-line monotherapy capecitabine and 141 patients on capecitabine-irinotecan combination therapy were recruited from the CAIRO trial, an open-label phase III randomized trial, comparing sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in mCRC. All patients were genotyped for MTHFR 1298A>C and 677C>T polymorphisms and analysed in both cohorts separately for the association between the MTHFR genotype and incidence of grade 3-4 overall toxicity and specific adverse events, as well as efficacy parameters., Results: MTHFR 1298A>C and 677C>T genotypes were not associated with grade 3-4 overall toxicity, febrile neutropenia or hand-foot syndrome. MTHFR 1298CC homozygotes showed a borderline significantly higher incidence of grade 3-4 diarrhoea compared with MTHFR 1298AC or AA individuals (25 vs. 5%, P=0.041) in the monotherapy cohort. No significant association was found between the MTHFR genotypes and efficacy parameters in either treatment cohort., Conclusion: MTHFR polymorphisms are not associated with toxicity or efficacy in mCRC patients treated with capecitabine-based chemotherapy.