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The role of adjuvant chemotherapy for patients with rectal cancer after preoperative (chemo)radiotherapy and surgery is uncertain. We did a meta-analysis of individual patient data to compare adjuvant chemotherapy with observation for patients with rectal cancer. We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library, CENTRAL, and conference abstracts to identify European randomised, controlled, phase 3 trials comparing observation with adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with non-metastatic rectal cancer. The primary endpoint of interest was overall survival. We analysed data from four eligible trials, including data from 1196 patients with (y)pTNM stage II or III disease, who had an R0 resection, had a low anterior resection or an abdominoperineal resection, and had a tumour located within 15 cm of the anal verge. We found no significant differences in overall survival between patients who received adjuvant chemotherapy and those who underwent observation (hazard ratio [HR] 0·97, 95% CI 0·81–1·17; p=0·775); there were no significant differences in overall survival in subgroup analyses. Overall, adjuvant chemotherapy did not significantly improve disease-free survival (HR 0·91, 95% CI 0·77–1·07; p=0·230) or distant recurrences (0·94, 0·78–1·14; p=0·523) compared with observation. However, in subgroup analyses, patients with a tumour 10–15 cm from the anal verge had improved disease-free survival (0·59, 0·40–0·85; p=0·005, pinteraction=0·107) and fewer distant recurrences (0·61, 0·40–0·94; p=0·025, pinteraction=0·126) when treated with adjuvant chemotherapy compared with patients undergoing observation. Overall, adjuvant fluorouracil-based chemotherapy did not improve overall survival, disease-free survival, or distant recurrences. However, adjuvant chemotherapy might benefit patients with a tumour 10–15 cm from the anal verge in terms of disease-free survival and distant recurrence. Further studies of preoperative and postoperative treatment for this subgroup of patients are warranted. None.

PurposeThe number of older patients with breast cancer is rapidly increasing. A previous study showed that between 1990 and 2005, the survival of older patients with breast cancer did not improve in contrast to younger patients. In recent years, scientific evidence in the older age group has increased and specific guidelines for older women with breast cancer have been developed. The aim of this study was to assess changes in survival outcomes of older patients with breast cancer.Patients and methodsAll patients with breast cancer between 2000 and 2017 were included from the Netherlands cancer registry. We assessed changes in treatments using logistic regression. We calculated changes in relative survival as proxy for breast cancer mortality, stratified by age and stage.ResultsWe included 239,992 patients. Relative survival improved for patients < 65 for all stages. In patients aged 65–75 years, relative survival did not improve in stage I–II but did improve in stage III breast cancer (RER 0.98, 95% CI 0.96–1.00, p = 0.046). Concurrently, prescription of systemic treatments increased. In patients > 75, relative survival did not improve in patients with stage I/II or stage III disease, nor did treatment strategies change.ConclusionsThis study shows that relative survival of patients aged 65–75 years with advanced breast cancer has improved, and concurrently, prescription of systemic treatment increased. To improve survival of patients > 75 as well, future studies should focus on individualizing treatments based on concomitant comorbidity, geriatric parameters and the risk of competing mortality and toxicity of treatments.

BackgroundOlder patients are poorly represented in breast cancer research and guidelines do not provide evidence based recommendations for this specific group. We compared treatment strategies and survival outcomes between European countries and assessed whether variance in treatment patterns may be associated with variation in survival.MethodsPopulation-based study including patients aged ≥ 70 with non-metastatic BC from cancer registries from the Netherlands, Belgium, Ireland, England and Greater Poland. Proportions of local and systemic treatments, five-year relative survival and relative excess risks (RER) between countries were calculated.ResultsIn total, 236,015 patients were included. The proportion of stage I BC receiving endocrine therapy ranged from 19.6% (Netherlands) to 84.6% (Belgium). The proportion of stage III BC receiving no breast surgery varied between 22.0% (Belgium) and 50.8% (Ireland). For stage I BC, relative survival was lower in England compared with Belgium (RER 2.96, 95%CI 1.30–6.72, P < .001). For stage III BC, England, Ireland and Greater Poland showed significantly worse relative survival compared with Belgium.ConclusionsThere is substantial variation in treatment strategies and survival outcomes in elderly with BC in Europe. For early-stage BC, we observed large variation in endocrine therapy but no variation in relative survival, suggesting potential overtreatment. For advanced BC, we observed higher survival in countries with lower proportions of omission of surgery, suggesting potential undertreatment.

ObjectiveMany treatment decisions are preference-sensitive and call for shared decision-making, notably when benefits are limited or uncertain, and harms impact quality of life. We explored if clinical practice guidelines (CPGs) acknowledge preference-sensitive decisions in how they motivate and phrase their recommendations.DesignWe performed a qualitative analysis of the content of CPGs and verified the results in semistructured interviews with CPG panel members.SettingDutch oncology CPGs issued in 2010 or later, concerning primary treatment with curative intent.Participants14 CPG panel members.Main outcomesFor treatment recommendations from six CPG modules, two researchers extracted the following: strength of recommendation in terms of the Grading of Recommendations Assessment, Development and Evaluation and its consistency with the CPG text; completeness of presentation of benefits and harms; incorporation of patient preferences; statements on the panel’s benefits–harm trade-off underlying recommendation; and advice on patient involvement in decision-making.ResultsWe identified 32 recommendations, 18 were acknowledged preference-sensitive decisions. Three of 14 strong recommendations should have been weak based on the module text. The reporting of benefits and harms, and their probabilities, was sufficiently complete and clear to inform the strength of the recommendation in one of the six modules only. Numerical probabilities were seldom presented. None of the modules presented information on patient preferences. CPG panel’s preferences were not made explicit, but appeared to have impacted 15 of 32 recommendations. Advice to involve patients and their preferences in decision-making was given for 20 recommendations (14 weak). Interviewees confirmed these findings. Explanations for lack of information were, for example, that clinicians know the information and that CPGs must be short. Explanations for trade-offs made were cultural-historical preferences, compliance with daily care, presumed role of CPGs and lack of time.ConclusionsThe motivation and phrasing of CPG recommendations do not stimulate choice awareness and a neutral presentation of options, thus hindering shared decision-making.

Importance Although older patients are at increased risk of developing grade 3 or higher chemotherapy-related toxic effects, no studies, to our knowledge, have focused on the association between toxic effects and quality of life (QOL) and physical functioning. Objective To investigate the association between grade 3 or higher chemotherapy-related toxic effects and QOL and physical functioning over time in older patients. Design, Setting, and Participants In this prospective, multicenter cohort study, patients aged 70 years or older who were scheduled to receive chemotherapy with curative or palliative intent and a geriatric assessment were included. Patients were treated with chemotherapy between December 2015 and December 2021. Quality of life and physical functioning were analyzed at baseline and after 6 months and 12 months. Exposures Common Terminology Criteria for Adverse Events grade 3 or higher chemotherapy-related toxic effects. Main Outcomes and Measures The main outcome was a composite end point, defined as a decline in QOL and/or physical functioning or mortality at 6 months and 12 months after chemotherapy initiation. Associations between toxic effects and the composite end point were analyzed with multivariable logistic regression models. Results Of the 276 patients, the median age was 74 years (IQR, 72-77 years), 177 (64%) were male, 196 (71%) received chemotherapy with curative intent, and 157 (57%) had gastrointestinal cancers. Among the total patients, 145 (53%) had deficits in 2 or more of the 4 domains of the geriatric assessment and were classified as frail. Grade 3 or higher toxic effects were observed in 94 patients (65%) with frailty and 66 (50%) of those without frailty (P = .01). Decline in QOL and/or physical functioning or death was observed in 76% of patients with frailty and in 64% to 68% of those without frailty. Among patients with frailty, grade 3 or higher toxic effects were associated with the composite end point at 6 months (odds ratio [OR], 2.62; 95% CI, 1.14-6.05) but not at 12 months (OR, 1.09; 95% CI, 0.45-2.64) and were associated with mortality at 12 months (OR, 3.54; 95% CI, 1.50-8.33). Toxic effects were not associated with the composite end point in patients without frailty (6 months: OR, 0.76; 95% CI, 0.36-1.64; 12 months: OR, 1.06; 95% CI, 0.46-2.43). Conclusions and Relevance In this prospective cohort study of 276 patients aged 70 or older who were treated with chemotherapy, patients with frailty had more grade 3 or higher toxic effects than those without frailty, and the occurrence of toxic effects was associated with a decline in QOL and/or physical functioning or mortality after 1 year. Toxic effects were not associated with poor outcomes in patients without frailty. Pretreatment frailty screening and individualized treatment adaptions could prevent a treatment-related decline of remaining health.

Stroma tissue surrounding cancer cells plays an important role in tumor development and behavior. In colorectal cancer, it has been found that the amount of stroma within the primary tumor is of prognostic value. We therefore have evaluated the prognostic value of this tumor–stroma ratio for breast cancer. A cohort of 574 early breast cancer patients, primarily treated with surgery between 1985 and 1994 was analyzed for the tumor–stroma ratio. The percentage of stroma was visually estimated on Haematoxylin-Eosin (H&E) stained histological sections. Patients with more than 50% intra-tumor stroma were quantified as stroma rich and patients with less than 50% as stroma poor. For the total group of patients, stroma-rich tumors had a shorter relapse-free period (RFP) ( P  = 0.001) and overall survival (OS) ( P  = 0.025) compared to stroma-poor tumors. Tumor–stroma ratio was an independent prognostic parameter for the total group of patients ( P  < 0.001) and also in stratified analysis based on systemic treatment. Importantly, in the triple-negative cancer subpopulation, patients with stroma-rich tumors had a 2.92 times higher risk of relapse ( P  = 0.006) compared to those with stroma-poor tumors, independently of other clinico-pathological parameters. Five-year RFP-rates for triple-negative cancer patients with stroma-rich compared to stroma-poor tumors were 56 and 81%, respectively. Tumor–stroma ratio has proven to be an independent prognostic factor for RFP in breast cancer patients and especially in the triple-negative cancer subpopulation. Tumor–stroma ratio could be easily implemented in routine daily pathology diagnostics, as it is simple to determine, reproducible, and performed in quick time.

After 5 years of median follow-up, the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial reported no difference in disease-free survival between exemestane monotherapy and a sequential scheme of tamoxifen followed by exemestane in postmenopausal patients with early-stage, hormone receptor-positive breast cancer. As recurrence risk in hormone receptor-positive breast cancer remains linear beyond 5 years after diagnosis, we analysed long-term follow-up outcomes of this trial. The TEAM trial, a multicentre, open-label, randomised, controlled, phase 3 trial, included postmenopausal patients with early-stage hormone receptor-positive breast cancer from nine countries. Patients were randomly allocated (1:1) by a computer-generated random permuted block method (block sizes 4–8) to either 5 years of oral exemestane monotherapy (25 mg once a day) or a sequential scheme of oral tamoxifen (20 mg once a day) followed by exemestane for a total duration of 5 years. After the publication of the IES trial, the protocol was amended (Dec 13, 2004). Patients assigned to tamoxifen were switched after 2·5–3·0 years to exemestane therapy for a total duration of 5·0 years of treatment. Randomisation was done centrally in each country. Long-term follow-up data for disease recurrence and survival was collected in six participating countries and analysed by intention to treat. The primary endpoint was disease-free survival at 10 years of follow-up. The trial is registered with ClinicalTrials.gov, numbers NCT00279448 and NCT00032136; with Netherlands Trial Register, number NTR 267; and the Ethics Commission Trial, number 27/2001. 6120 patients of the original 9776 patients in the TEAM trial were included in the current intention-to-treat analysis. Median follow-up was 9·8 years (IQR 8·0–10·3). During follow-up, 921 (30%) of 3075 patients in the exemestane group and 929 (31%) of 3045 patients in the sequential group had a disease-free survival event. Disease-free survival at 10 years was 67% (95% CI 65–69) for the exemestane group and 67% (65–69) for the sequential group (hazard ratio 0·96, 0·88–1·05; p=0·39). The long-term findings of the TEAM trial confirm that both exemestane alone and sequential treatment with tamoxifen followed by exemestane are reasonable options as adjuvant endocrine therapy in postmenopausal patients with hormone receptor-positive early breast cancer. These results suggest that the opportunity to individualise adjuvant endocrine strategy accordingly, based on patient preferences, comorbidities, and tolerability might be possible. Pfizer, Dutch Cancer Foundation.

Background Thirty-day mortality after surgery for colorectal cancer may vastly underestimate 1-year mortality. This study aimed to quantify the excess mortality in the first postoperative year of stage I–III colorectal cancer patients and to identify risk factors for excess mortality. Methods All 2,131 patients who were operated with curative intent for stage I–III colorectal cancer in the western region of the Netherlands between January 1, 2006, and December 31, 2008, were analyzed. Thirty-day mortality and relative survival were calculated. In addition, relative excess risk (RER) of death was estimated by a multivariable model. Results Thirty-day mortality was 4.9%. One-year mortality was 12.4%. Risk factors for excess mortality in the first postoperative year for colon cancer patients were emergency surgery (excess mortality 29.7%, RER 2.5, 95% confidence interval 2.5–5.0), a Charlson score of >1 (excess mortality 12.6%, RER 2.3, 95% confidence interval 1.5–3.7), stage II or III disease (excess mortality 14.9%, RER 3.9, 95% confidence interval 1.9–8.1), and postoperative adverse events (excess mortality 22.6%, RER 2.1, 95% confidence interval 1.4–3.2). Conclusions The 30-day mortality rate highly underestimates the risk of dying in the first year after surgery, with excess 1-year mortality rates varying from 15 to 30%. This excess mortality was especially prominent in patients with comorbidities, higher stages of disease, emergency surgery, and postoperative surgical complications.

Adjuvant! Online is a prediction tool that can be used to aid clinical decision making in patients with breast cancer. It was developed in a patient population aged 69 years or younger, and subsequent validation studies included small numbers of older patients. Since older patients with breast cancer differ from younger patients in many aspects, the aim of this study was to investigate the validity of Adjuvant! Online in a large cohort of unselected older patients. We included patients from the population-based FOCUS cohort, which included all consecutive patients aged 65 years or older who were diagnosed with invasive or in-situ breast cancer between Jan 1, 1997, and Dec 31, 2004, in the southwestern part of the Netherlands. We included all patients who fulfilled the criteria as stated by Adjuvant! Online: patients with unilateral, unicentric, invasive adenocarcinoma; no evidence of metastatic or residual disease; no evidence of T4 features; and no evidence of inflammatory breast cancer. We entered data from all patients with the “average for age” comorbidity status (model 1) and with an individualised comorbidity status (model 2). We included 2012 patients. Median age of patients in the cohort was 74·0 years (IQR 69·0–79·0). 904 (45%) of 2012 patients died during follow-up, whereas 326 (16%) patients had recurrence. Median follow-up for overall survival was 9·0 years (IQR 7·4–10·7), and 6·6 years (4·4–6·6) for patients without recurrence. Using model 1, Adjuvant! Online overestimated 10-year overall survival by 9·8% ([95% CI 5·9–13·7], p<0·0001) and 10-year cumulative recurrence survival by 8·7% ([6·7–10·7], p<0·0001). By contrast, when using model 2, Adjuvant! Online underestimated the 10-year overall survival by −17·1% ([95% CI −21·0 to −13·2], p<0·0001). However, when using model 2, Adjuvant! Online predicted cumulative recurrence accurately in all patients (–0·7% [95% CI −2·7–1·3], p=0·48). Adjuvant! Online does not accurately predict overall survival and recurrence in older patients with early breast cancer. Dutch Cancer Foundation.

Immune checkpoint inhibitors (ICIs) have strongly improved the survival of melanoma patients. However, as durable response to ICIs are only seen in a minority, there is an unmet need to identify biomarkers that predict response. Therefore, we provide a systematic review that evaluates all biomarkers studied in association with outcomes of melanoma patients receiving ICIs. We searched Pubmed, COCHRANE Library, Embase, Emcare, and Web of Science for relevant articles that were published before June 2020 and studied blood, tumor, or fecal biomarkers that predicted response or survival in melanoma patients treated with ICIs. Of the 2536 identified reports, 177 were included in our review. Risk of bias was high in 40%, moderate in 50% and low in 10% of all studies. Biomarkers that correlated with response were myeloid-derived suppressor cells (MDSCs), circulating tumor cells (CTCs), CD8+ memory T-cells, T-cell receptor (TCR) diversity, tumor-infiltrating lymphocytes (TILs), gene expression profiling (GEP), and a favorable gut microbiome. This review shows that biomarkers for ICIs in melanoma patients are widely studied, but heterogeneity between studies is high, average sample sizes are low, and validation is often lacking. Future studies are needed to further investigate the predictive utility of some promising candidate biomarkers.