The impact of surgery and adjuvant chemotherapy on health-related quality of life in patients with colon cancer: Changes at group level versus individual level.

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.

The G8 frailty screening tool and the decision-making process in older breast cancer patients.

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.

Chemotherapy in the oldest old: Choices and outcomes.

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.

Severe fluoropyrimidine toxicity due to novel and rare DPYD missense mutations, deletion and genomic amplification affecting DPD activity and mRNA splicing.

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.

Clinical validation study of genetic markers for capecitabine efficacy in metastatic colorectal cancer patients.

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.

Excision Repair Cross-Complementation group 1 (ERCC1) C118T SNP does not affect cellular response to oxaliplatin.

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.

MTHFR polymorphisms and capecitabine-induced toxicity in patients with metastatic colorectal cancer.

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.

What Defines Quality of Life for Older Patients Diagnosed with Cancer? A Qualitative Study.

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.

Factors associated with survival in older patients with stage I-III colorectal carcinoma who were not managed curatively in the Netherlands.

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.

[Patient or disease in oncology?] / Zieke of ziekte in de oncologie?

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.

Optimizing the geriatrician's contribution to cancer care for older patients.

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.

Do age and comorbidity impair recovery during two years after treatment for endometrial cancer?

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.

Clinical judgment versus geriatric assessment for frailty in older patients with cancer.

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.

Development of a self-reported version of the G8 screening tool.

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.