Tamoxifen pharmacokinetics and pharmacodynamics in older patients with non-metastatic breast cancer.

BACKGROUND: We aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer. METHODS: Data for this analysis were derived from the CYPTAM study (NTR1509) database. Patients were stratified by age (age groups < 65 and 65 and older). Steady-state trough concentrations were measured of tamoxifen, N-desmethyltamoxifen, 4-hydroxy-tamoxifen, and endoxifen. CYP2D6 and CYP3A4 phenotypes were assessed for all patients by genotyping. Multiple linear regression models were used to analyze tamoxifen and endoxifen variability. Outcome data included recurrence-free survival at time of tamoxifen discontinuation (RFSt) and overall survival (OS). RESULTS: 668 patients were included, 141 (21%) were 65 and older. Demographics and treatment duration were similar across age groups. Older patients had significantly higher concentrations of tamoxifen 129.4 ng/ml (SD 53.7) versus 112.2 ng/ml (SD 42.0) and endoxifen 12.1 ng/ml (SD 6.6) versus 10.7 ng/ml (SD 5.7, p all < 0.05), independently of CYP2D6 and CYP3A4 gene polymorphisms. Age independently explained 5% of the variability of tamoxifen (b = 0.95, p < 0.001, R2 = 0.051) and 0.1% of the variability in endoxifen concentrations (b = 0.45, p = 0.12, R2 = 0.007). Older patients had worse RFSt (5.8 versus 7.3 years, p = 0.01) and worse OS (7.8 years versus 8.7 years, p = 0.01). This was not related to differences in endoxifen concentration (HR 1.0, 95% CI 0.96-1.04, p = 0.84) or CYP polymorphisms. CONCLUSION: Serum concentrations of tamoxifen and its demethylated metabolites are higher in older patients, independent of CYP2D6 or CYP3A4 gene polymorphisms. A higher bioavailability of tamoxifen in older patients may explain the observed differences. However, clinical relevance of these findings is limited and should not lead to a different tamoxifen dose in older patients.

The impact of geriatric characteristics and comorbidities on distant metastases and other cause mortality in older women with non-metastatic breast cancer treated with primary endocrine therapy.

INTRODUCTION: In recent years, primary surgical treatment of older women with non-metastatic breast cancer has decreased in favor of primary endocrine therapy (PET). PET can be considered in women with a remaining life expectancy of less than five years. The aim of this study was to (1) assess the risk of distant metastases and other cause mortality over ten years in women aged 65 and older with stage I-III breast cancer treated with PET, (2) whether this was associated with geriatric characteristics and comorbidities and to (3) describe the reasons on which the choice for PET was made. METHODS: Women were included from the retrospective FOCUS cohort, which comprises all incident women diagnosed with breast cancer aged 65 or older between January 1997 and December 2004 in the Comprehensive Cancer Center Region West in the Netherlands. We selected women (N = 257) with stage I-III breast cancer and treated with PET from this cohort. Patient characteristics (including comorbidity, polypharmacy, walking, cognitive and sensory impairment), treatment and tumor characteristics were retrospectively extracted from charts. Outcomes were distant metastasis and other cause mortality. Cumulative incidences were calculated using the Cumulative Incidence for Competing Risks method (CICR); and subdistribution hazard ratios (SHR) were tested between groups based on age, geriatric characteristics and comorbidity with the Fine and Gray model. RESULTS: Women treated with PET were on average 84 years old and 41% had one or more geriatric characteristics. Other cause mortality exceeded the cumulative incidence of distant metastasis over ten years (83 versus 5.6%). The risk of dying from another cause further increased in women with geriatric characteristics (SHR 2.06, p < 0.001) or two or more comorbidities (SHR 1.72, p < 0.001). Often the reason for omitting surgery was not recorded (52.9%), but if recorded surgery was omitted mainly at the patient's request (18.7%). DISCUSSION: This study shows that the cumulative incidence of distant metastasis is much lower than other cause mortality in older women with breast cancer treated with PET, especially in the presence of geriatric characteristics or comorbidities. This confirms the importance of assessment of geriatric characteristics to aid counseling of older women.

Predicting postoperative complications and their impact on quality of life and functional status in older patients with breast cancer.

BACKGROUND: The percentage of older patients undergoing surgery for early-stage breast cancer has decreased over the past decade. This study aimed to develop a prediction model for postoperative complications to better inform patients about the benefits and risks of surgery, and to investigate the association between complications and functional status and quality of life (QoL). METHODS: Women aged at least 70 years who underwent surgery for Tis-3 N0 breast cancer were included between 2013 and 2018. The primary outcome was any postoperative complication within 30 days after surgery. Secondary outcomes included functional status and QoL during the first year after surgery, as assessed by the Groningen Activity Restriction Scale and the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23 questionnaires. A prediction model was developed using multivariable logistic regression and validated externally using data from the British Bridging the Age Gap Study. Linear mixed models were used to assess QoL and functional status over time. RESULTS: The development and validation cohorts included 547 and 2727 women respectively. The prediction model consisted of five predictors (age, polypharmacy, BMI, and type of breast and axillary surgery) and performed well in internal (area under curve (AUC) 0.76, 95 per cent c.i. 0.72 to 0.80) and external (AUC 0.70, 0.68 to 0.72) validations. Functional status and QoL were not affected by postoperative complication after adjustment for confounders. CONCLUSION: This validated prediction model can be used to counsel older patients with breast cancer about the postoperative phase. Postoperative complications did not affect functional status nor QoL within the first year after surgery even after adjustment for predefined confounders.

Surgery remains the standard of care for the majority of older patients with breast cancer. The percentage of older patients with breast cancer receiving surgery is decreasing. The reason for this decline is unknown, but it might be due to fear of complications. To better inform patients about the benefits and risks of surgery, the aim of this study was to develop a prediction model for complications after surgery. Another important aspect, especially for older adults with breast cancer, is quality of life, functional capacity, and ability to carry out daily tasks (functional status) after therapy. This study showed that quality of life and functional status did not decline after breast surgery, irrespective of the occurrence of postoperative complications.

Effect of omission of surgery on survival in patients aged 80 years and older with early-stage hormone receptor-positive breast cancer.

BACKGROUND: Surgery is increasingly being omitted in older patients with operable breast cancer in the Netherlands. Although omission of surgery can be considered in frail older patients, it may lead to inferior outcomes in non-frail patients. Therefore, the aim of this study was to evaluate the effect of omission of surgery on relative and overall survival in older patients with operable breast cancer. METHODS: Patients aged 80 years or older diagnosed with stage I-II hormone receptor-positive breast cancer between 2003 and 2009 were selected from the Netherlands Cancer Registry. An instrumental variable approach was applied to minimize confounding, using hospital variation in rate of primary surgery. Relative and overall survival was compared between patients treated in hospitals with different rates of surgery. RESULTS: Overall, 6464 patients were included. Relative survival was lower for patients treated in hospitals with lower compared with higher surgical rates (90·2 versus 92·4 per cent respectively after 5 years; 71·6 versus 88·2 per cent after 10 years). The relative excess risk for patients treated in hospitals with lower surgical rates was 2·00 (95 per cent c.i. 1·17 to 3·40). Overall survival rates were also lower among patients treated in hospitals with lower compared with higher surgical rates (48·3 versus 51·3 per cent after 5 years; 15·0 versus 19·7 per cent after 10 years respectively; adjusted hazard ratio 1·07, 95 per cent c.i. 1·00 to 1·14). CONCLUSION: Omission of surgery is associated with worse relative and overall survival in patients aged 80 years or more with stage I-II hormone receptor-positive breast cancer. Future research should focus on the effect on quality of life and physical functioning.

ANTECEDENTES: En los Países Bajos cada vez es más frecuente descartar la cirugía en pacientes mayores con cáncer de mama operable. Aunque la omisión de la cirugía puede ser adecuada en pacientes mayores frágiles, ello puede determinar peores resultados en pacientes no frágiles. Por tanto, el objetivo de este estudio fue evaluar el efecto de omitir la cirugía en la supervivencia relativa y en la supervivencia global en pacientes mayores con cáncer de mama operable. MÉTODOS: A partir del Registro de Cáncer de los Países Bajos se seleccionaron las pacientes de ≥ 80 años de edad diagnosticadas de cáncer de mama entre 2003-2009 en estadios 1-2 y con receptores hormonales positivos. Se aplicó un método de variables instrumentales para minimizar los factores de confusión utilizando la tasa de variación hospitalaria de la cirugía primaria. Se compararon las supervivencias relativa y global de las pacientes tratadas en hospitales con diferentes tasas de cirugía. RESULTADOS: Se incluyeron 6.464 pacientes. La supervivencia relativa fue menor en las pacientes tratadas en hospitales con tasas quirúrgicas más bajas en comparación con las tratadas en hospitales con tasas altas (90,2% versus 92,4% a los 5 años y 71,6% versus 88,2% a los 10 años, respectivamente). El exceso de riesgo relativo para las pacientes tratadas en hospitales con tasas quirúrgicas más bajas fue de 2,00 (i.c. del 95% 1,17-3,40). La supervivencia global también fue menor para las pacientes tratadas en hospitales con tasas quirúrgicas más bajas en comparación con las más altas (48,3% versus 51,3% a los 5 años y 15,0% versus 19,7% a los 10 años, respectivamente, cociente de riesgos instantáneos, hazard ratio, HR, ajustado 1,07) i.c. del 95% 1,00-1,14)). CONCLUSIÓN: Omitir la cirugía se asocia con una peor supervivencia relativa y global en pacientes de ≥ 80 años con cáncer de mama en estadios 1-2 y receptores hormonales positivos. Las investigaciones futuras deberían centrarse en el efecto de este enfoque en la calidad de vida y la funcionalidad física.

Higher ER load is not associated with better outcome in stage 1-3 breast cancer: a descriptive overview of quantitative HR analysis in operable breast cancer.

PURPOSE: In breast cancer, hormone receptor (HR) status is generally a qualitative measure; positive or negative. Quantitatively measured oestrogen and progesterone receptors (ER and PR) are frequently proposed prognostic and predictive markers, some guidelines even provide different treatment options for patients with strong versus weak expression. AIM: To evaluate quantitative HR load assessed by immunohistochemistry as a prognostic and predictive measure in stage 1-3 breast cancer. METHODS: We reviewed all the available literature on quantitatively measured HRs using immunohistochemistry. RESULTS: All included studies (n = 19) comprised a cohort of 30,754 patients. Only 2 out of 17 studies found a clear correlation between higher quantitative ER and better disease outcome. Only one trial examined quantitative ER both as prognostic and predictive marker and found no association between ER% and survival. Ten studies examined quantitative PR load, only two of those found a significant correlation between higher PR load and better disease outcome. Two trials examined quantitative PR both as prognostic and predictive marker, neither found any association between PR% and disease outcome. CONCLUSIONS: There is no clear evidence for using quantitatively assessed ER and PR as prognostic nor predictive marker in patients with stage 1-3 breast cancer. We recommend only using a qualitative HR status in future guidelines and treatment considerations.

The Prognostic Value of a Geriatric Risk Score for Older Patients with Colorectal Cancer.

INTRODUCTION: VMS is a Dutch risk assessment tool for hospitalized older adults that includes a short evaluation of four geriatric domains: risk for delirium, risk for undernutrition, risk for physical impairments, and fall risk. We investigated whether the information derived from this tool has prognostic value for outcomes of colorectal surgery. METHODS: All consecutive patients over age 70 years who underwent elective colorectal cancer surgery in three Dutch hospitals (2014-2016) were studied. The presence of risk was scored prior to surgery and per geriatric domain as either 0 (risk absent) or 1 (risk present). The total number of geriatric risk factors was summed. The primary outcome was long-term survival. Secondary outcomes were postoperative complications, including delirium. Cox proportional hazards models were used to evaluate the sumscore and risk factors associated with overall survival. RESULTS: Five hundred fifty patients were included. Median age was 76.5 years, and median follow-up was 870 days. Patients with intermediate (1-2) or high (3-4) sumscore were independently associated with lower overall survival, with hazard ratio (HR) of 1.9 [95% confidence interval (CI) 1.1-3.5; p = 0.03] and 8.7 (95% CI 4.0-19.2; p < 0.001), respectively. Sumscores were also associated with postoperative complications (intermediate sumscore OR 1.8; 95% CI 1.2-2.7; high sumscore OR 2.4; 95% CI 1.02-5.5). CONCLUSIONS: This easy-to-use geriatric sumscore has strong associations with long-term outcome and morbidity after colorectal cancer surgery. This information may be included in risk models for morbidity and mortality and can be used in shared decision-making.

Treatment and outcome of elderly patients with advanced stage ovarian cancer: A nationwide analysis.

OBJECTIVE: To provide an overview of treatment strategies for elderly patients with advanced stage epithelial ovarian cancer (EOC) in daily practice, evaluate changes over time and relate this to surgical mortality and survival. METHODS: All women diagnosed with advanced stage (FIGO IIB and higher) EOC between 2002 and 2013 were selected from the Netherlands Cancer Registry (n=10,440) and stratified by age, stage and period of diagnosis. Elderly patients were defined as aged ≥70years. Time trends in treatment patterns and postoperative mortality were described by age category and tested using multivariable logistic regression. Relative survival was calculated. RESULTS: With advancing age, less patients received ((neo-)adjuvant) treatment. Over time, elderly patients were less often treated (OR 2002-2004 versus 2011-2013: 0.73; 95%CI:0.58-0.92). But if treated, more often standard treatment was provided and 30-day postoperative mortality decreased from 4.5% to 1.9% between 2005 and 2007 and 2011-2013. In all age categories treatment shifted from primary surgery towards primary chemotherapy, in patients aged 70-79years combination therapy increased (+5%) between 2002 and 2004 and 2011-2013. Five-year relative survival for patients diagnosed in 2008-2010 aged <70years was 34% compared to 18% for elderly patients. CONCLUSION: Large treatment differences exist between younger and elderly patients. Over time, selection of elderly patients eligible for curative surgical treatment may have improved. More elderly patients were treated with neoadjuvant chemotherapy while less patients underwent surgery and simultaneously postoperative mortality decreased. However, the large and increasing number of elderly patients without treatment and the large survival gap suggests opportunities for further improvements in the care for elderly EOC patients.

Effect of low-dose aspirin use on survival of patients with gastrointestinal malignancies; an observational study.

BACKGROUND: Previous studies suggested a relationship between aspirin use and mortality reduction. The mechanism for the effect of aspirin on cancer outcomes remains unclear. The aim of this study was to evaluate aspirin use and survival in patients with gastrointestinal tract cancer. METHODS: Patients with gastrointestinal tract cancer diagnosed between 1998 and 2011 were included. The population-based Eindhoven Cancer Registry was linked to drug-dispensing data from the PHARMO Database Network. The association between aspirin use after diagnosis and overall survival was analysed using Cox regression models. RESULTS: In total, 13 715 patients were diagnosed with gastrointestinal cancer. A total of 1008 patients were identified as aspirin users, and 8278 patients were identified as nonusers. The adjusted hazard ratio for aspirin users vs nonusers was 0.52 (95% CI 0.44-0.63). A significant association between aspirin use and survival was observed for patients with oesophageal, hepatobiliary and colorectal cancer. CONCLUSIONS: Post-diagnosis use of aspirin in patients with gastrointestinal tract malignancies is associated with increased survival in cancers with different sites of origin and biology. This adds weight to the hypothesis that the anti-cancer effects of aspirin are not tumour-site specific and may be modulated through the tumour micro-environment.

The effect of a geriatric evaluation on treatment decisions for older patients with colorectal cancer.

BACKGROUND: Treating elderly colorectal cancer patients can be challenging. It is very important to carefully weigh the risks and benefits of potential treatments in individual patients. This treatment decision making can be guided by geriatric consultation. Our aim was to assess the effect of a geriatric evaluation on treatment decisions for older patients with colorectal cancer. METHODS: Colorectal cancer patients who were referred for a geriatric consultation between 2013 and 2015 in three Dutch teaching hospitals were included in a prospective database. The outcome of geriatric assessment, non-oncological interventions and geriatricians' treatment recommendations were evaluated. RESULTS: The total number of included referrals was 168. The median age was 81 years (range 60-94). Most patients (71%) had colon cancer and 49% had tumour stage III disease. The reason for geriatric consultation was uncertainty regarding the optimal oncologic treatment in 139 patients (83%). Overall 93% of patients suffered from geriatric impairments; non-oncological interventions that followed after geriatric consultation was mostly aimed at malnutrition. The geriatrician recommended the 'more intensive treatment' option in 69% and the 'less intensive treatment' option in 31% of which 63% 'supportive care only'. CONCLUSION: Geriatric consultation can be useful in treatment decision making in elderly patients with colorectal cancer. It may lead to changes in the treatment plan for individual cases and may result in an additional optimisation of patient's health status prior to treatment.

Administration of adjuvant chemotherapy in older patients with Stage III colon cancer: an observational study.

AIM: According to established guidelines, patients with Stage III colon cancer should receive adjuvant chemotherapy. However, a significant proportion do not. This study assessed factors associated with the administration of adjuvant chemotherapy and causes of death. METHODS: Patients with Stage III colon cancer who underwent surgery between 2000 and 2009 were selected from two hospitals in the Netherlands. Patient characteristics including comorbidities and treatment preferences, tumour characteristics and follow-up were extracted from the medical records. The patient and tumour characteristics of patients who did receive chemotherapy were compared with those who did not using chi-squared analysis. Differences between the groups in causes of death were recorded together with the duration of follow-up. RESULTS: A total of 348 patients were included. The median age was 73 years (range 33-93). Over half of the patients received adjuvant chemotherapy (50.6%). Patients who did not receive adjuvant chemotherapy were significantly older (P < 0.001), had more comorbidities (P < 0.001) and were more often living alone (P < 0.001). Patients who received no adjuvant chemotherapy had a reduced overall survival, and the cause of death was more often attributed to other causes (60%) than colon cancer (40%). For patients who received chemotherapy, the cause of death was usually attributed to colon cancer (71%). CONCLUSION: Patients who did not receive adjuvant chemotherapy had a worse overall survival and the majority died due to other causes than colon cancer. In our aging society it will become even more important to develop tools to estimate remaining life expectancy in order to improve the selection of older patients for adjuvant treatments.

Validity of the online PREDICT tool in older patients with breast cancer: a population-based study.

BACKGROUND: Predicting breast cancer outcome in older patients is challenging, as it has been shown that the available tools are not accurate in older patients. The PREDICT tool may serve as an alternative tool, as it was developed in a cohort that included almost 1800 women aged 65 years or over. The aim of this study was to assess the validity of the online PREDICT tool in a population-based cohort of unselected older patients with breast cancer. METHODS: Patients were included from the population-based FOCUS-cohort. Observed 5- and 10-year overall survival were estimated using the Kaplan-Meier method, and compared with predicted outcomes. Calibration was tested by composing calibration plots and Poisson Regression. Discriminatory accuracy was assessed by composing receiver-operator-curves and corresponding c-indices. RESULTS: In all 2012 included patients, observed and predicted overall survival differed by 1.7%, 95% confidence interval (CI)=-0.3-3.7, for 5-year overall survival, and 4.5%, 95% CI=2.3-6.6, for 10-year overall survival. Poisson regression showed that 5-year overall survival did not significantly differ from the ideal line (standardised mortality ratio (SMR)=1.07, 95% CI=0.98-1.16, P=0.133), but 10-year overall survival was significantly different from the perfect calibration (SMR=1.12, 95% CI=1.05-1.20, P=0.0004). The c-index for 5-year overall survival was 0.73, 95% CI=0.70-0.75, and 0.74, 95% CI=0.72-0.76, for 10-year overall survival. CONCLUSIONS: PREDICT can accurately predict 5-year overall survival in older patients with breast cancer. Ten-year predicted overall survival was, however, slightly overestimated.

Association Between the Most Frequent Complications After Surgery for Stage I-III Colon Cancer and Short-Term Survival, Long-Term Survival, and Recurrences.

BACKGROUND: The purpose of this study was to identify the ten most frequent complications after surgery for stage I-III colon cancer and to assess the association between these complications and overall survival, conditional overall survival, and recurrences. METHODS: All patients who underwent surgery for stage I-III colon cancer in five hospitals in the Western region of the Netherlands were identified. Crude and adjusted Cox proportional hazards models were used to study the association between complications and 1-year overall survival, 5-year overall survival, 5-year conditional overall survival, and 5-year disease-free period. RESULTS: Data from 761 patients were used for the analyses. Complications were associated with decreased 1-year overall survival (hazard ratio (HR) 2.87, 95 % confidence interval (CI) 1.82-4.51; p < 0.001), 5-year overall survival (HR 1.59, 95 % CI 1.25-2.04; p < 0.001), and 5-year conditional overall survival (HR 1.34, 95 % CI 1.06-1.69; p = 0.016), whereas an increasing number of complications had no additional impact. Anastomotic leakage, excessive blood loss, and (abdominal) sepsis were associated with reduced 1-year overall survival, anastomotic leakage, delirium, abscess, and (abdominal) sepsis with reduced 5-year overall survival, and anastomotic leakage, delirium, and abscess with reduced 5-year conditional overall survival. Anastomotic leakage, electrolyte disorders, and abscess were risk factors for recurrence within five years. CONCLUSIONS: Our results demonstrate the serious impact of the most frequent complications after surgery for colon cancer on short-term and long-term outcomes. This study confirms the prolonged impact of surgery and demonstrates that complications result not only in reduced 1-year survival, but also in reduced long-term outcomes.

Choosing relevant endpoints for older breast cancer patients in clinical trials: an overview of all current clinical trials on breast cancer treatment.

With the ongoing ageing of western societies, the proportion of older breast cancer patients will increase. For several years, clinicians and researchers in geriatric oncology have urged for new clinical trials that address patient-related endpoints such as functional decline after treatment of older patients. The aim of this study was to present an overview of trial characteristics and endpoints of all currently running clinical trials in breast cancer, particularly in older patients. The clinical trial register of the United States National Institutes of Health Differences was searched for all current clinical trials on breast cancer treatment. Trial characteristics and endpoints were retrieved from the register and differences in characteristics between studies in older patients specifically (defined as a lower age-limit of 60 years or older) and trials in all patients were assessed using χ(2) tests. We included 463 clinical trials. Nine trials (2 %) specifically investigated breast cancer treatment in older patients. Ninety-one breast cancer trials included any patient-related endpoint (20 %), while five trials specifically addressing older patients included any patient-related endpoint (56 %, P = 0.02). Five of the trials in older patients incorporated a geriatric assessment (56 %). Clinical trials still rarely incorporate patient-related endpoints, even in trials that specifically address older patients. Trials that are specifically designed for older patients do not often incorporate a geriatric assessment in their design. This implicates that current clinical studies are not expected to fill the gap in knowledge concerning treatment of older breast cancer patients in the next decade.

Impact of omission of surgery on survival of older patients with breast cancer.

BACKGROUND: Older patients with breast cancer are often not treated in accordance with guidelines. With the emergence of endocrine therapy, omission of surgery can be considered in some patients. The aim of this population-based study was to investigate time trends in surgical treatment between 1995 and 2011, and to evaluate the effects of omitting surgery on overall and relative survival in older patients with resectable breast cancer. METHODS: Patients aged 75 years and older with stage I-III breast cancer diagnosed between 1995 and 2011 were selected from the Netherlands Cancer Registry. Time trends of all treatment modalities were evaluated using linear regression models. Changes in overall survival were calculated by Cox regression. Relative survival was calculated using the Ederer II method. RESULTS: Overall, 26 292 patients were included. The proportion of patients receiving surgical treatment decreased significantly, from 90·8 per cent in 1995 to 69·9 per cent in 2011 (P < 0·001). Multivariable analysis showed that overall survival did not change over time (hazard ratio 1·00 (95 per cent confidence interval (c.i.) 0·99 to 1·00) per year); nor did relative survival (relative excess risk 1·00 (0·98 to 1·02) per year). CONCLUSION: Omission of surgery has become more common in older patients with breast cancer during the past 15 years in the Netherlands, but this has not altered overall or relative survival.

Geriatric oncology in the Netherlands: a survey of medical oncology specialists and oncology nursing specialists.

To identify ways to improve cancer care for older patients, we set out to examine how older patients in the Netherlands are currently being evaluated prior to oncological treatment and to explore the potential obstacles in the incorporation of a geriatric evaluation, using a web-based survey sent to Dutch medical oncology specialists and oncology nursing specialists. The response rate was 34% (183 out of 544). Two-thirds of respondents reported that a geriatric evaluation was being used, although primarily on an ad hoc basis only. Most respondents expressed a desire for a routine evaluation or more intensive collaboration with the geriatrician and 86% of respondents who were not using a geriatric evaluation expressed their interest to do so. The most important obstacles were a lack of time or personnel and insufficient availability of a geriatrician to perform the assessment. Thus, over 30% of oncology professionals in the Netherlands express an interest in geriatric oncology. Important obstacles to a routine implementation of a geriatric evaluation are a lack of time, or insufficient availability of geriatricians; this could be overcome with policies that acknowledge that quality cancer care for older patients requires the investment of time and personnel.

Adjuvant immunotherapy in older patients with stage III and resected stage IV melanoma: Toxicity and recurrence-free survival outcomes from the Dutch melanoma treatment registry.

BACKGROUND: Adjuvant anti-PD-1 therapy improves relapse free survival in stage III melanoma, but also leads to immune-related adverse events (irAEs). Older patients are of particular interest due to comorbidities and frailty, which may impact their ability to tolerate irAEs and benefit from anti-PD-1 therapy. This study aimed to explore associations between clinical parameters and the occurrence of grade ≥ 3 irAEs and recurrence-free survival (RFS) in older patients with radically resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy. METHODS: Patients aged ≥ 65 with resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy between 2018 and 2022 were selected using real-world data from the nationwide Dutch Melanoma Treatment Registry (DMTR). A univariate and multivariable logistic regression was used to compare determinants of grade ≥ 3 irAEs, and univariate and multivariable Cox-proportional hazard models were fitted to identify factors influencing RFS. RESULTS: The study included 885 patients, with 280 aged 75 and older. The incidence of grade ≥ 3 irAEs was 15.5 % in the 65-74 age group and 13.9 % in the ≥ 75 age group. No significant correlation was found between age and grade ≥ 3 irAEs. However, an increasing number of comorbidities was associated with a higher risk of grade ≥ 3 irAEs (multivariable analyses: OR 1.83, 95 % C.I. 0.99-3.40). The 1-year RFS rate of 80.0 % of this study was comparable to those reported in previous registration trials and real-world data. Having ≥ 3 comorbidities was significantly associated with a decrease in RFS (HR: 1.68, 95 % C.I. 1.15-2.44). CONCLUSION: Older patients had similar benefit of adjuvant immunotherapy compared to older subgroups in previous trials. However, patients with multiple comorbidities were at increased risk of grade ≥ 3 irAEs and had a lower RFS. This should be considered when deciding upon adjuvant treatment.

Diabetes in relation to breast cancer relapse and all-cause mortality in elderly breast cancer patients: a FOCUS study analysis.

BACKGROUND: In developed countries, 40% of breast cancer patients are >65 years of age at diagnosis, of whom 16% additionally suffer from diabetes. The aim of this study was to assess the impact of diabetes on relapse-free period (RFP) and overall mortality in elderly breast cancer patients. PATIENTS AND METHODS: Patients were selected from the retrospective FOCUS cohort, which contains detailed information of elderly breast cancer patients. RFP was calculated using Fine and Gray competing risk regression models for patients with diabetes versus patients without diabetes. Overall survival was calculated by Cox regression models, in which patients were divided into four groups: no comorbidity, diabetes only, diabetes and other comorbidity or other comorbidity without diabetes. RESULTS: Overall, 3124 patients with non-metastasized breast cancer were included. RFP was better for patients with diabetes compared with patients without diabetes (multivariable HR 0.77, 95% CI 0.59-1.01), irrespective of other comorbidity and most evident in patients aged ≥75 years (HR 0.67, 95% CI 0.45-0.98). The overall survival was similar for patients with diabetes only compared with patients without comorbidity (HR 0.86, 95% CI 0.45-0.98), while patients with diabetes and additional comorbidity had the worst overall survival (HR 1.70, 95% CI 1.44-2.01). CONCLUSION: When taking competing mortality into account, RFP was better in elderly breast cancer patients with diabetes compared with patients without diabetes. Moreover, patients with diabetes without other comorbidity had a similar overall survival as patients without any comorbidity. Possibly, unfavourable effects of (complications of) diabetes on overall survival are counterbalanced by beneficial effects of metformin on the occurrence of breast cancer recurrences.

Complicated postoperative recovery increases omission, delay and discontinuation of adjuvant chemotherapy in patients with Stage III colon cancer.

AIM: The study included investigation of factors determining suboptimal adjuvant chemotherapy of patients diagnosed with Stage III colon cancer. METHOD: All 606 patients diagnosed with Stage III colon cancer between 2006 and 2008 in the western part of the Netherlands were included. Patient [gender, age, comorbidity and socio-economic status (SES)], tumour (location, stage and grade) and treatment (emergency surgery, laparoscopic surgery, reoperation, hospital stay and multidisciplinary meeting) factors were examined in logistic regression analyses predicting a complicated postoperative period and omission, delay and discontinuation of adjuvant chemotherapy. RESULTS: Overall, 27% of all patients experienced a complicated postoperative period, which was independently associated with emergency surgery, older age, multiple comorbidity, male gender and poor tumour grade. Of patients who survived this period, 60% received chemotherapy. Chemotherapy was omitted more often in women, the elderly and in patients with Stage IIIB, reoperation, prolonged hospital stay and (borderline) after open surgery. Of patients who received chemotherapy, 86% started within 8 weeks after surgery. Patients with a higher SES, reoperation and prolonged hospital stay had a higher probability of a delayed start. Sixty-seven per cent of patients completed their chemotherapy. For women, elderly patients and patients with prolonged hospital stay a higher probability of discontinuation was noted. CONCLUSION: Age was the most important predictive factor for receiving adjuvant chemotherapy. However, at all ages, complicated postoperative recovery negatively influenced the administration of chemotherapy to Stage III colon cancer patients, as well as a timely start and completion of chemotherapy.

Gene expression signatures in older patients with breast cancer: A systematic review.

BACKGROUND: Gene expression signatures have emerged to predict prognosis and guide the use of adjuvant therapy in patients with hormone receptor-positive breast cancer. The objective of this systematic review was to evaluate the prognostic and predictive value of commercially available gene expression signatures as a tool in adjuvant treatment decision-making in older patients with breast cancer. METHODS: PubMed, MEDLINE, Embase, Web of Science, Cochrane Library, and Emcare were reviewed for relevant articles published before December 2021. Eligible studies were randomised trials and cohort studies that externally validated commercially available gene expression signatures in patients aged 65 years and older, including studies that presented subanalyses of this age group. Data extraction and risk of bias assessment was performed independently by two investigators. RESULTS: Fifteen studies were included. Most studies investigated Oncotype DX, while results from other gene expression signatures were limited. Several studies underlined the prognostic performance of Oncotype DX and Prosigna Risk of Recurrence in older patients. Moreover, Oncotype DX was predictive for older patients with an intermediate-risk recurrence score; chemotherapy could be spared in both lymph node-positive and lymph node-negative disease. CONCLUSIONS: Prognostic performance has been demonstrated in older patients for several gene expression signatures. However, additional validation in patients with high-risk tumours is needed before gene expression signatures can be implemented in clinical practice as a prediction tool for adjuvant chemotherapy decision-making in the older age group.

Biomarkers of the ageing immune system and their association with frailty - A systematic review.

INTRODUCTION: Ageing is associated with several physiological changes, including changes in the immune system. Age-related changes in the innate and adaptive immune system are thought to contribute to frailty. Understanding the immunological determinants of frailty could help to develop and deliver more effective care to older people. This systematic review aims to study the association between biomarkers of the ageing immune system and frailty. METHODS: The search strategy was performed in PubMed and Embase, using the keywords "immunosenescence", "inflammation", "inflammaging" and "frailty". We included studies that investigated the association of biomarkers of the ageing immune system and frailty cross-sectionally in older adults, without an active disease that affects immune parameters. Three independent researchers selected the studies and performed data extraction. Study quality was assessed using the Newcastle-Ottawa scale adapted for cross-sectional studies. RESULTS: A total of 44 studies, with a median number of 184 participants, was included. Study quality was good in 16 (36 %), moderate in 25 (57 %) and poor in 3 (7 %) of studies. The most frequently studied inflammaging biomarkers were IL-6, CRP and TNF-α. Associations with frailty were observed for increased levels of (i) IL-6 in 12 of 24 studies, (ii) CRP in 7 of 19 studies, and (ii) TNF-α in 4 of 13 studies. In none of the other studies were associations observed of frailty with these biomarkers. Different types of T-lymphocyte subpopulations were studied but each subset was studied only once, and the study sample sizes were low. CONCLUSION: Our review of 44 studies on the relation between immune biomarkers and frailty identified IL-6 and CRP as the biomarkers that were most consistently associated with frailty. T-lymphocyte subpopulations were investigated but too infrequently to draw strong conclusions yet, although initial results are promising. Additional studies are required in order to further validate these immune biomarkers in larger cohorts. Furthermore, prospective studies in more uniform settings and larger cohorts are needed to further investigate the association with immune candidate biomarkers for which potential associations with ageing and frailty were previously observed, before these can be used in clinical practice to help assess frailty and improve the care treatments of older patients.