Individual lymph node position variation for rectal cancer patients treated with long course chemoradiotherapy.

Background and purpose: Delivery of high precision radiotherapy lymph node boosts requires detailed information on the interfraction positional variation of individual lymph nodes. In this study we characterized interfraction positional shifts of suspected malignant lymph nodes for rectal cancer patients receiving long course radiotherapy. Furthermore, we investigated parameters which could affect the magnitude of the position variation. Materials and Methods: Fourteen patients from a prospective clinical imaging study with a total of 61 suspected malignant lymph nodes in the mesorectum, presacral, and lateral regions, were included. The primary gross tumor volume (GTVp) and all suspected malignant lymph nodes were delineated on six magnetic resonance imaging scans per patient. Positional variation was calculated as systematic and random errors, based on shifts of center-of-mass, and estimated relative to either bony structures or the GTVp using a hierarchical linear mixed model. Results: Depending on location and direction, systematic and random variations (relative to bony structures) were within 0.6-2.8 mm and 0.6-2.9 mm, respectively. Systematic and random variations increased when evaluating position relative to GTVp (median increase of 0.6 mm and 0.5 mm, respectively). Correlations with scan time-point and relative bladder volume were found in some directions. Conclusions: Using linear mixed modeling, we estimated systematic and random positional variation for suspected malignant lymph nodes in rectal cancer patients treated with long course radiotherapy. Statistically significant correlations of the magnitude of the lymph node shifts were found related to scan time-point and relative bladder volume.

Extracting Systemic Anticancer Treatment Lines from the Danish National Patient Registry for Solid Tumour Patients Treated in the North Denmark Region Between 2009 and 2019.

Background: Reconstructing patient treatment trajectories is important to generate real-world evidence for epidemiological studies. The Danish National Patient Registry (DNPR) contains information about drug prescriptions and could therefore be used to reconstruct treatment trajectories. We aimed to evaluate and enhance two existing methods to reconstruct systemic anticancer treatment trajectories. Methods: This study was based on data from 8738 consecutive patients with solid tumors treated in the North Denmark Region between 2009 and 2019. Two approaches found in the literature as well as two new approaches were applied to the DNPR data. All methods relied on time intervals between two consecutive drug administrations to determine if they belonged to the same treatment line. MedOnc, a local dataset from the Department of Oncology, Aalborg University Hospital was used as a reference. To evaluate the performance of each method, F1-scores were calculated after matching the lines identified in both datasets. We used three different matching strategies: stringent matching, loose matching, and matching based on line numbers, controlling for overfitting. Results: Overall, the two new approaches outperformed the simpler and best performing of the two existing methods, with F1-scores of 0.47 and 0.45 vs 0.44 for stringent matching and 0.84 and 0.83 vs 0.82 for loose matching. Nevertheless, only one of the new methods outperformed the existing simpler method when matching on the number of lines (0.73 vs 0.72). Large differences were seen by cancer site, especially for the stringent and line number matchings. Performances were relatively stable by calendar year. Conclusion: The high F1-scores for the new methods confirm that they should be generally preferred to reconstruct systemic anticancer treatment trajectories using the DNPR.

Treatment planning for patients with low rectal cancer in a multicenter prospective organ preservation study.

BACKGROUND: Non-surgical management of rectal cancer relies on (chemo)radiotherapy as the definitive treatment modality. This study reports and evaluates the clinical high dose radiotherapy treatment plans delivered to patients with low resectable rectal cancer in a Danish multicenter trial. METHODS: The Danish prospective multicenter phase II Watchful Waiting 2 trial (NCT02438839) investigated definitive chemoradiation for non-surgical management of low rectal cancer. Three Danish centers participated in the trial and committed to protocol-specified treatment planning and delivery requirements. The protocol specified a dose of 50.4 Gy in 28 fractions to the elective volume (CTV-/PTV-E) and a concomitant boost of 62 Gy in 28 fractions to the primary target volume (CTV-/PTV-T). RESULTS: The trial included 108 patients, of which 106 treatment plans were available for retrospective analysis. Dose coverage planning goals for the main target structures were fulfilled for 94% of the treatment plans. However, large intercenter differences in doses to organs-at-risk (OARs) were seen, especially for the intestines. Five patients had a V60Gy>10 cm3 for the intestines and two patients for the bladder. CONCLUSION: Prescribed planning goals for target coverage were fulfilled for 94% of the treatment plans, however analysis of OAR doses and volumes indicated intercenter variations. Dose escalation to 62 Gy (as a concomitant boost to the primary tumor) introduced no substantial high dose volumes (>60 Gy) to the bladder and intestines. The treatment planning goals may be used for future prospective evaluation of highdose radiotherapy for organ preservation for low rectal cancer.

International Validation of the Immunoscore Biopsy in Patients With Rectal Cancer Managed by a Watch-and-Wait Strategy.

PURPOSE: No biomarker capable of improving selection and monitoring of patients with rectal cancer managed by watch-and-wait (W&W) strategy is currently available. Prognostic performance of the Immunoscore biopsy (ISB) was recently suggested in a preliminary study. METHODS: This international validation study included 249 patients with clinical complete response (cCR) managed by W&W strategy. Intratumoral CD3+ and CD8+ T cells were quantified on pretreatment rectal biopsies by digital pathology and converted to ISB. The primary end point was time to recurrence (TTR; the time from the end of neoadjuvant treatment to the date of local regrowth or distant metastasis). Associations between ISB and outcomes were analyzed by stratified Cox regression adjusted for confounders. Immune status of tumor-draining lymph nodes (n = 161) of 17 additional patients treated by neoadjuvant chemoradiotherapy and surgery was investigated by 3'RNA-Seq and immunofluorescence. RESULTS: Recurrence-free rates at 5 years were 91.3% (82.4%-100.0%), 62.5% (53.2%-73.3%), and 53.1% (42.4%-66.5%) with ISB High, ISB Intermediate, and ISB Low, respectively (hazard ratio [HR; Low v High], 6.51; 95% CI, 1.99 to 21.28; log-rank P = .0004). ISB was also significantly associated with disease-free survival (log-rank P = .0002), and predicted both local regrowth and distant metastasis. In multivariate analysis, ISB was independent of patient age, sex, tumor location, cT stage (T, primary tumor; c, clinical), cN stage (N, regional lymph node; c, clinical), and was the strongest predictor for TTR (HR [ISB High v Low], 6.93; 95% CI, 2.08 to 23.15; P = .0017). The addition of ISB to a clinical-based model significantly improved the prediction of recurrence. Finally, B-cell proliferation and memory in draining lymph nodes was evidenced in the draining lymph nodes of patients with cCR. CONCLUSION: The ISB is validated as a biomarker to predict both local regrowth and distant metastasis, with a gradual scaling of the risk of pejorative outcome.

The role of immunotherapy in the treatment of colorectal cancer.

In Denmark, around 4,500 people are diagnosed with colorectal cancer (CRC) annually. This review investigates that while the efficacy of immunotherapy in CRC is still being studied, immunotherapy is currently only indicated in the treatment of mismatch-repair deficient (dMMR) metastatic CRC, which accounts for 10-15% of patients. Recent studies indicate high rates of pathologic response in dMMR CRC treated with pre-operative immunotherapy while large-scale studies on novel immunotherapy combinations are ongoing.

The effect of nutritional interventions in acute radiation-induced diarrhoea in patients with primary pelvic cancer: A systematic review.

Acute radiation-induced diarrhoea (RID) is a well-known side effect of external radiation therapy for pelvic cancer. Acute RID is an unresolved clinical problem in approximately 80% of patients. We investigated the effect of nutritional interventions on acute RID in patients with pelvic cancer treated with curative radiotherapy. A search was conducted using PubMed, Embase.com, CINAHL, and Cochrane Library, from 1 January 2005 until 10 October 2022. We included randomised controlled trials or prospective observational studies. Eleven of the 21 identified studies had low quality of evidence, mainly because of low patient numbers distributed among several cancer diagnoses, and non-systematic assessment of acute RID. Interventions included probiotics (n = 6), prebiotics (n = 6), glutamine (n = 4), and others (n = 5). Five studies, of which two provided high quality evidence, showed that probiotics improved acute RID. Future well-designed studies investigating the effects of probiotics on acute RID are warranted. PROSPERO ID: CRD42020209499).

Outcomes of emergency surgical interventions in right-sided colonic cancer: nationwide population-based study based on Danish Colorectal Cancer Group register.

AIM: The aim of this study was to investigate the trends in morbidity and mortality of patients with right-sided colonic cancer who had an emergency surgical procedure in Denmark after the introduction of quality index parameters. METHODS: This was a retrospective nationwide study based on a prospectively maintained Danish Colorectal Cancer Group database focused on right-sided colonic cancer in the interval from 1 May 2001 to 30 April 2018, who underwent emergency surgical intervention (within 48 h of hospital admission). The primary objective was to investigate the trends in morbidity and mortality throughout the study years. Multivariable estimates were adjusted for age, sex, smoking status, alcohol consumption, ASA score classification, tumour localization, type of access to abdominal cavity, surgeon's grade of specialization, and metastatic disease. RESULTS: Out of 2839 patients, a total of 2740 patients fulfilled the inclusion criteria, of whom 2464 underwent right or transverse colon resection (89.9 per cent). The 30-day and 90-day postoperative mortality rates were significantly reduced over the time of the study (OR 0.943, 95 per cent c.i. 0.922 to 0.965, P < 0.001 and OR 0.953, 95 per cent c.i. 0.934 to 0.972, P < 0.001 respectively); however, the complication rates did not follow this trend. Older patients (OR 1.032, 95 per cent c.i. 1.009 to 1.055, P = 0.005) and patients with high ASA scores (OR 1.61, 95 per cent c.i. 1.422 to 1.830, P < 0.001) had higher rates of severe grade 3b postoperative complications. A stoma was constructed in 276 patients (10 per cent), whereas a stent was used in only eight patients. Defunctioning procedures, including stoma construction or colonic stenting (without oncological resection), did not reduce the risk of complications compared with that of definitive surgery. CONCLUSION: The 30-day and 90-day postoperative mortality rates were significantly reduced over the time of the study. Age and ASA score were risk factors for severe postoperative complications.

Prognostic value of baseline functional status measures and geriatric screening in vulnerable older patients with metastatic colorectal cancer receiving palliative chemotherapy - The randomized NORDIC9-study.

INTRODUCTION: Appropriate patient selection based on functional status is crucial when considering older adults for palliative chemotherapy. This pre-planned analysis of the randomized NORDIC9-study explored the prognostic value of four functional status measures regarding progression-free survival (PFS) and overall survival (OS) in vulnerable older patients with metastatic colorectal cancer (mCRC) receiving first-line palliative chemotherapy. MATERIALS AND METHODS: Patients ≥70 years of age with mCRC not candidates for standard full-dose combination chemotherapy were randomized to receive full-dose S1 or reduced-dose S1 + oxaliplatin. At baseline, functional status was assessed using ECOG performance status (ECOG PS), frailty phenotype, Geriatric 8 (G8), and Vulnerable Elderly Survey-13 (VES-13). Multivariable regression models were applied and C-statistics were estimated. RESULTS: In total, 160 patients with a median age of 78 years (IQR: 76-81) were included. While in univariate analyses, ECOG PS, frailty phenotype, and VES-13 were statistically significantly associated with differences in OS between subgroups, G8 was not (HR = 1.55, 95%CI: 0.99-2.41, p = 0.050). In multivariable analyses adjusted for age, sex, body mass index, and treatment allocation, we found significant differences between subgroups for all applied tools and with C-statistics in the moderate range for ECOG PS and VES-13. Concerning PFS, statistically significant differences were observed between subgroups of ECOG PS, G8, and VES-13 both in uni- and multivariable analyses, but not for frailty phenotype. DISCUSSION: In this Nordic cohort of vulnerable older patients with mCRC, baseline ECOG PS, frailty phenotype, G8, and VES-13 showed prognostic value regarding overall survival, and moderate predictive value of models based on ECOG PS and VES-13 was demonstrated.

A phase II study of daily encorafenib in combination with biweekly cetuximab in patients with BRAF V600E mutated metastatic colorectal cancer: the NEW BEACON study.

BACKGROUND: Patients with BRAF V600E mutated metastatic colorectal cancer (mCRC) have a poor prognosis. The introduction of BRAF targeted therapy with encorafenib and weekly administered cetuximab have shown improved survival with a median progression free survival (PFS) of 4.3 months. However, a regimen with cetuximab given every second week may have comparable efficacy and is more convenient for patients. While BRAF targeted therapy is a new standard therapy in pre-treated patients with BRAF V600E mutated mCRC, resistance invariably occurs and is an emerging challenge. The aim of this study is to investigate the efficacy and tolerability of cetuximab given every second week in combination with daily encorafenib and to explore the correlation between markers of resistance and outcome. METHODS: The study is an open label, single arm, phase II study, investigating the efficacy and tolerability of cetuximab given every second week in combination with encorafenib in patients with BRAF V600E mutated mCRC. Furthermore, we will be investigating mechanisms of response and resistance against BRAF targeted therapy though comprehensive genomic profiling on tumor tissue and blood for circulating tumor DNA analysis. A total of 53 patients (19 + 34 in two steps) will be included according to Simon's optimal two stage design. The primary end point of the study is 2 months PFS rate. DISCUSSION: By combining BRAF inhibitor with cetuximab given every second week we can halve the number of visits in the hospital compared to the currently approved regimen with weekly cetuximab. This seems particularly relevant in a group of patients with a median overall survival of 9.3 months. Resistance after initial response to targeted therapy can be either adaptive (e.g., epigenetic, or transcriptomic alterations) or acquired (selective genetic alterations - e.g., activating de novo mutations) resistance. It is of great importance to untangle these complex mechanisms of resistance in patients with BRAF V600E mutated mCRC to improve treatment strategies in the future potentially even further. TRIAL REGISTRATION: EU Clinical Trial Register, Eudract no. 2020-003283-10 . Registered on 11 November 2020.

The Prognostic Value of Pre-Treatment Circulating Biomarkers of Systemic Inflammation (CRP, dNLR, YKL-40, and IL-6) in Vulnerable Older Patients with Metastatic Colorectal Cancer Receiving Palliative Chemotherapy-The Randomized NORDIC9-Study.

Appropriate patient selection for palliative chemotherapy is crucial in patients with metastatic colorectal cancer (mCRC). We investigated the prognostic value of C-reactive protein (CRP), derived neutrophil-to-lymphocyte ratio (dNLR), Interleukin (IL)-6, and YKL-40 on progression-free survival (PFS) and overall survival (OS) in the NORDIC9 cohort. The randomized NORDIC9-study included patients ≥70 years with mCRC not candidates for standard full-dose combination chemotherapy. Participants received either full-dose S1 (Teysuno) or a dose-reduced S1 plus oxaliplatin. Blood samples were collected at baseline and biomarkers were dichotomized according to standard cut-offs. Multivariable analyses adjusted for age, sex, ECOG performance status, and treatment allocation; furthermore, C-statistics were estimated. In total, 160 patients with a median age of 78 years (IQR: 76−81) were included between 2015 and 2017. All investigated biomarkers were significantly elevated in patients with either weight loss, ≥3 metastatic sites, or primary tumor in situ. In multivariable analyses, all markers showed significant association with OS; the highest HR was observed for CRP (HR = 3.40, 95%CI: 2.20−5.26, p < 0.001). Regarding PFS, statistically significant differences were found for CRP and IL-6, but not for dNLR and YKL-40. Applying C-statistics, CRP indicated a good prognostic model for OS (AUC = 0.72, 95%CI: 0.67−0.76). CRP is an easily available biomarker, which may support therapeutic decision-making in vulnerable older patients with mCRC.

High Validity of the Danish National Patient Registry for Systemic Anticancer Treatment Registration from 2009 to 2019.

BACKGROUND: The Danish National Patient Registry is a major resource for Danish epidemiology. Only a few studies have been conducted to check the validity of the reporting of systemic anticancer treatments. In this study, we assessed this validity for a range of cancer types over a long period of time. PATIENTS AND METHODS: We extracted systemic anticancer treatment procedures from the Danish National Patient Registry for patients with solid malignant tumors treated at the Department of Oncology at Aalborg University Hospital between 2009 and 2019 (12,014 patients with 215,293 drug records). These data were compared to records obtained from the antineoplastic prescription database used at the department. We estimated the sensitivity, positive predictive value (PPV), and F1-score defined as the harmonic mean of the sensitivity and the PPV. RESULTS: There was an overall high concordance between the two datasets with a sensitivity and a PPV >92%. Treatments for brain, ovarian and endometrial cancers displayed lower concordance (81-89%). The validity was stable over the study period, with a slight drop during 2016-2017. Most drugs had a high validity with F1-scores above 90%. Fluorouracil, gemcitabine, pemetrexed, pembrolizumab, and nivolumab had F1-scores above 97%. Drugs that were introduced in the study period, such as lapatinib, palbociclib, erlotinib, pertuzumab, and panitumumab, yielded lower F1-scores due to the absence of specific registry codes early after introduction. CONCLUSION: The Danish National Patient Registry can be used to reliably obtain information about systemic anticancer treatments, keeping in mind limitations for recently introduced drugs and for some types of cancer.

Quality of Life in Vulnerable Older Patients with Metastatic Colorectal Cancer Receiving Palliative Chemotherapy-The Randomized NORDIC9-Study.

Quality of life data from randomized trials are lacking in older patients with metastatic colorectal cancer (mCRC). In the randomized NORDIC9-study, reduced-dose S1+oxaliplatin (SOx) showed superior efficacy compared to full-dose S1 monotherapy. We hypothesized that treatment with SOx does not result in inferior quality of life. Patients with mCRC aged ≥70 years and that were not a candidate for standard combination chemotherapy were included and randomly assigned to receive either S1 or SOx. The EORTC QLQ-C30 questionnaire was completed at baseline, after 9, and 18 weeks. The primary endpoint was global Quality of Life (QoL) at 9 weeks. For statistical analysis, a non-inferiority design was chosen applying linear mixed effects models for repeated measurements. The results were interpreted according to statistical significance and anchor-based, clinically relevant between-group minimally important differences (MID). A total of 160 patients aged (median (Interquartile range (IQR))) 78 years (76-81) were included. The QLQ-C30 questionnaire was completed by 150, 100, and 60 patients at baseline, at 9, and 18 weeks, respectively. The difference at 9 weeks in global QoL was 6.85 (95%CI-1.94; 15.65) and 7.37 (0.70; 14.05) in the physical functioning domain in favor of SOx exceeding the threshold for MID. At 18 weeks, the between-group MID in physical functioning was preserved. Dose-reduced combination chemotherapy may be recommended in vulnerable older patients with mCRC, rather than full-dose monotherapy.

Risk for Myocardial Infarction Following 5-Fluorouracil Treatment in Patients With Gastrointestinal Cancer: A Nationwide Registry-Based Study.

BACKGROUND: Myocardial infarction is a cardiac adverse event associated with 5-fluorouracil (5-FU). There are limited data on the incidence, risk, and prognosis of 5-FU-associated myocardial infarction. OBJECTIVES: The aim of this study was to examine the risk for myocardial infarction in patients with gastrointestinal (GI) cancer treated with 5-FU compared with age- and sex-matched population control subjects without cancer (1:2 ratio). METHODS: Patients with GI cancer treated with 5-FU between 2004 and 2016 were identified within the Danish National Patient Registry. Prevalent ischemic heart disease in both groups was excluded. Cumulative incidences were calculated, and multivariable regression and competing risk analyses were performed. RESULTS: A total of 30,870 patients were included in the final analysis, of whom 10,290 had GI cancer and were treated with 5-FU and 20,580 were population control subjects without cancer. Differences in comorbid conditions and select antianginal medications were nonsignificant (P > 0.05 for all). The 6-month cumulative incidence of myocardial infarction was significantly higher for 5-FU patients at 0.7% (95% CI: 0.5%-0.9%) versus 0.3% (95% CI: 0.3%-0.4%) in population control subjects, with a competing risk for death of 12.1% versus 0.6%. The 1-year cumulative incidence of myocardial infarction for 5-FU patients was 0.9% (95% CI: 0.7%-1.0%) versus 0.6% (95% CI: 0.5%-0.7%) among population control subjects, with a competing risk for death of 26.5% versus 1.4%. When accounting for competing risks, the corresponding subdistribution hazard ratios suggested an increased risk for myocardial infarction in 5-FU patients, compared with control subjects, at both 6 months (hazard ratio: 2.10; 95% CI: 1.50-2.95; P < 0.001) and 12 months (hazard ratio: 1.39; 95% CI: 1.05-1.84; P = 0.022). CONCLUSIONS: Despite a statistically significantly higher 6- and 12-month risk for myocardial infarction among 5-FU patients compared with population control subjects, the absolute risk for myocardial infarction was low, and the clinical significance of these differences appears to be limited in the context of the significant competing risk for death in this population.

TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial.

BACKGROUND: TAS-102 (trifluridine-tipiracil) has shown a significant overall survival benefit compared with placebo in patients with chemorefractory metastatic colorectal cancer. Inspired by the encouraging results of a small phase 1-2 study, C-TASK FORCE, which evaluated the combination of TAS-102 plus bevacizumab in patients with chemorefractory metastatic colorectal cancer, we aimed to compare the efficacy of TAS-102 plus bevacizumab versus TAS-102 monotherapy in patients receiving refractory therapy for metastatic colorectal cancer . METHODS: This investigator-initiated, open-label, randomised, phase 2 study enrolled patients (aged ≥18 years) with metastatic colorectal from four cancer centres in Denmark. The main inclusion criteria were histopathologically confirmed metastatic colorectal cancer refractory or intolerant to a fluoropyrimidine, irinotecan, oxaliplatin, and cetuximab or panitumumab (only for RAS wild-type), and WHO performance status of 0 or 1. Previous therapy with bevacizumab, aflibercept, ramucirumab, or regorafenib was allowed but not mandatory. Participants were enrolled and randomly assigned (1:1) in block sizes of two, four, or six by a web-based tool to receive oral TAS-102 (35 mg/m2 twice daily on days 1-5 and 8-12 every 28 days) alone or combined with intravenous bevacizumab (5 mg/kg on days 1 and 15) until progression, unacceptable toxicity, or patient decision to withdraw. Treatment assignment was not masked, and randomisation was stratified by institution and RAS mutation status. The primary endpoint was investigator-evaluated progression-free survival. All analyses were based on intention to treat. This trial is registered with EudraCT, 2016-005241-23. FINDINGS: From Aug 24, 2017, to Oct 31, 2018, 93 patients were enrolled and randomly assigned to TAS-102 (n=47) or TAS-102 plus bevacizumab (n=46). The clinical cut-off date was Feb 15, 2019, after a median follow-up of 10·0 months (IQR 6·8-14·0). Median progression-free survival was 2·6 months (95% CI 1·6-3·5) in the TAS-102 group versus 4·6 months (3·5-6·5) in the TAS-102 plus bevacizumab group (hazard ratio 0·45 [95% CI 0·29-0·72]; p=0·0015). The most frequent grade 3 or worse adverse event was neutropenia (18 [38%] of 47 in the TAS-102 monotherapy group vs 31 [67%] of 46 in the TAS-102 plus bevacizumab group). Serious adverse events were observed in 21 (45%) patients in the TAS-102 group and 19 (41%) in the TAS-102 plus bevacizumab group. No deaths were deemed treatment related. INTERPRETATION: In patients with chemorefractory metastatic colorectal cancer, TAS-102 plus bevacizumab, as compared with TAS-102 monotherapy, was associated with a significant and clinically relevant improvement in progression-free survival with tolerable toxicity. The combination of TAS-102 plus bevacizumab could be a new treatment option for patients with refractory metastatic colorectal cancer and could be a practice-changing development. FUNDING: Servier.

Reduced-dose combination chemotherapy (S-1 plus oxaliplatin) versus full-dose monotherapy (S-1) in older vulnerable patients with metastatic colorectal cancer (NORDIC9): a randomised, open-label phase 2 trial.

BACKGROUND: Older or vulnerable patients with metastatic colorectal cancer are seldom included in randomised trials. The multicentre NORDIC9 trial evaluated reduced-dose combination chemotherapy compared with full-dose monotherapy in older, vulnerable patients. METHODS: This randomised, open-label phase 2 trial was done in 23 Nordic oncology clinics and included patients aged 70 years or older with previously untreated metastatic colorectal cancer who were not candidates for full-dose combination chemotherapy. Patients were block randomised (1:1) using a web-based tool to full-dose S-1 (30 mg/m2 orally twice daily on days 1-14 every 3 weeks) followed by second-line treatment at progression with irinotecan (250 mg/m2 intravenously on day 1 every 3 weeks or 180 mg/m2 intravenously on day 1 every 2 weeks) or reduced-dose combination chemotherapy with S-1 (20 mg/m2 orally twice daily on days 1-14) and oxaliplatin (100 mg/m2 intravenously on day 1 every 3 weeks) followed by second-line treatment at progression with S-1 (20 mg/m2 orally twice daily on days 1-14) and irinotecan (180 mg/m2 intravenously on day 1 every 3 weeks). Use of bevacizumab (7·5 mg/kg intravenously on day 1 of each cycle) was optional. Treatment allocation was not masked and randomisation was stratified for institution and bevacizumab. The primary outcome was progression-free survival. Survival analyses were by intention to treat and safety analyses were done on the treated population. This trial is registered with EudraCT, number 2014-000394-39, and is closed to new participants. FINDINGS: From March 9, 2015, to Oct 11, 2017, 160 patients with a median age of 78 years (IQR 76-81) were randomly assigned to full-dose monotherapy (n=83) or reduced-dose combination chemotherapy (n=77). At data cutoff (Sept 1, 2018; median follow-up 23·8 months [IQR 18·8-30·9]), 81 (98%) patients in the full-dose monotherapy group and 71 (92%) patients in the reduced-dose combination group had progressed or died. Median progression-free survival was significantly longer with reduced-dose combination chemotherapy (6·2 months [95% CI 5·3-8·3]) than with full-dose monotherapy (5·3 months [4·1-6·8]; hazard ratio [HR] 0·72 [95% CI 0·52-0·99]; p=0·047). Toxicity was evaluated in 157 patients who received treatment. Significantly more patients in the full-dose monotherapy group (51 [62%] of 82 patients) experienced at least one grade 3-4 adverse event than in the reduced-dose combination group (32 [43%] of 75 patients; p=0·014). Grade 3-4 diarrhoea (12 [15%] vs two [3%]; p=0·018), fatigue (ten [12%] vs three [4%]; p=0·083), and dehydration (five [6%] vs none; p=0·060) were more frequent in the full-dose monotherapy group than in the reduced-dose combination group. Treatment-related deaths occurred in three patients during first-line treatment and three patients during second-line treatment (two in the full-dose monotherapy group vs one in the reduced-dose combination group in both cases). INTERPRETATION: Reduced-dose combination chemotherapy with S-1 and oxaliplatin for older, vulnerable patients with metastatic colorectal cancer was more effective and resulted in less toxicity than full-dose monotherapy with S-1. Reduced-dose combination chemotherapy could be a preferred treatment for this population. FUNDING: Taiho Pharmaceuticals, Nordic Group, the Danish Cancer Society, the Swedish Cancer Society, Academy of Geriatric Research (AgeCare), and Region of Southern Denmark.

Is the accuracy of preoperative MRI stage in rectal adenocarcinoma influenced by tumour height?

AIM: To our knowledge, no prior studies have addressed the possible effects of tumour height on the accuracy of preoperative magnetic resonance imaging (MRI)-based staging relative to postoperative histopathological assessments in patients with adenocarcinoma of the rectum (RC). This study aimed to investigate whether the accuracy of preoperative MRI stage in RC is influenced by tumour height. METHODS: A total of 489 consecutive RC patients scheduled for curative treatment between 2009 and 2013 were included. Of the 489 patients, 133 patients had preoperative chemoradiotherapy (CRT), and 356 patients underwent primary surgery. Low, mid and high RC were defined as a tumour <5 cm, 5-10 cm and >10 cm from the anal verge, respectively. Diagnostic MRI and, for patients with CRT, re-staging MRI features including tumour T-stage (mrT), distance between the tumour border and the distance to the mesorectal fascia (mrMRF), extramural tumour depth (mrEMD), extramural vascular invasion (mrEMVI) and nodal involvement (mrN) were correlated with the corresponding postoperative histopathological findings. RESULTS: There were 115, 186 and 188 patients with low RC, mid RC and high RC, respectively. For all patients, the correlations between mrT and pT and between mrMRF and pCRM were not influenced by tumour height. None of the correlations between mrEMD, mrEMVI and mrN and the corresponding postoperative histopathological findings significantly differed for tumours of different heights. For patients with CRT, a remarkable proportion with low RC were overstaged as ymrT3 compared to ypT0-2. CONCLUSIONS: The ability to preoperatively use MRI to accurately stage is not influenced by tumour height. For patients with preoperative CRT, low RC may be MRI overstaged due to post-radiation fibrosis. We found that mrEMD predicts pEMD reliably and should therefore be considered in treatment decisions. Although new MRI techniques are emerging, preoperative RC staging remains incompletely definitive in daily clinical practice.

The Pocketable Electronic Devices in Radiation Oncology (PEDRO) Project: How the Use of Tools in Medical Decision Making is Changing?

PURPOSE: To analyze the impact of mobile electronic devices (MEDs) and apps in the daily clinical activity of young radiation or clinical oncologists in 5 Western European countries (Italy, Germany, Spain, Portugal, and Denmark). METHODS: A web-based questionnaire was sent to 462 young (≤40 years) members of the national radiation or clinical oncology associations of the countries involved in the study. The 15 items investigated diffusion of MEDs (smartphones and/or tablets), their impact on daily clinical activity, and the differences perceived by participants along time. RESULTS: A total of 386 (83.5%) of the 462 correctly filled questionnaires were statistically evaluated. Up to 65% of respondents declared to use an electronic device during their clinical activity. Conversely, 72% considered low to moderate impact of smartphones/tables on their daily practice. The daily use significantly increased from 2009 to 2012: users reporting a use ≥6 times/d raised from 5% to 39.9%. Professional needs fulfillment was declared by less than 68% of respondents and compliance to apps indications by 66%. Significant differences were seen among the countries, in particular concerning the feeling of usefulness of MEDs in the daily clinical life. The perception of the need of a comprehensive Web site containing a variety of applications (apps) for clinical use significantly differed among countries in 2009, while it was comparable in 2012. CONCLUSIONS: This survey showed a large diffusion of MEDs in young professionals working in radiation oncology. Looking at these data, it is important to verify the consistency of information found within apps, in order to avoid potential errors eventually detrimental for patients. "Quality assurance" criteria should be specifically developed for medical apps and a comprehensive Web site gathering all reliable applications and tools might be useful for daily clinical practice.

Significance of age and comorbidity on treatment modality, treatment adherence, and prognosis in elderly ovarian cancer patients.

BACKGROUND: Age is associated with poor prognosis in ovarian cancer patients. Reasons could be increased comorbidity, more advanced stage, or nonoptimal surgery or chemotherapy. Objectives of this study were to evaluate the significance of comorbidity and age ≥70 years on receiving cytoreductive surgery, standard combination chemotherapy (TC), adherence to TC treatment, and prognosis. METHODS: A retrospective cohort study of all women registered in a nation-wide database with ovarian or peritoneal cancer in 2005-2006. Logistic regression was employed for determining the predictive value of age and comorbidity (ASA score) on receiving cytoreductive surgery and TC, and on adhering to TC. Kaplan-Meier method and Cox proportional hazards analysis were employed for survival analyses. RESULTS: Of 961 patients, 348 (36.2%) were elderly. Age ≥70 years was independently predictive of not receiving surgery, OR 0.2(95% CI 0.1-0.5) and TC treatment, OR 0.03 (95% CI 0.01-0.1). Comorbidity was also independently predictive of not receiving standard treatment: OR for receiving surgery with ASA score of ≥3 was 0.2 (95% CI 0.1-0.5), and for receiving TC it was 0.03 (95% CI 0.01-0.1). Overall, age ≥70 was a poor prognostic factor in OS and PFS, but the effect of age ceased after 16 months. Comorbidity was a poor prognostic factor throughout the study period but with time-varying effect. For patients treated with TC, age was not a prognostic factor, whereas ASA score ≥3 was. CONCLUSION: Elderly patients and patients with comorbidity less often receive optimal surgical and medical treatment. For those receiving optimal treatment, age ≥70 is not an independent poor prognostic factor, whereas severe comorbidity is.