Background and purpose: The RAPIDO trial demonstrated a decrease in disease-related treatment failure (DrTF) and an increase in pathological complete responses (pCR) in locally advanced rectal... Show moreBackground and purpose: The RAPIDO trial demonstrated a decrease in disease-related treatment failure (DrTF) and an increase in pathological complete responses (pCR) in locally advanced rectal cancer (LARC) patients receiving total neoadjuvant treatment (TNT) compared to conventional chemoradiotherapy. This study examines health-related quality of life (HRQL), bowel function, and late toxicity in patients in the trial.Materials and methods: Patients were randomized between short-course radiotherapy followed by pre-operative chemotherapy (EXP), or chemoradiotherapy and optional post-operative chemotherapy (STD). The STD group was divided into patients who did (STD+) and did not (STD-) receive post-operative chemotherapy. Three years after surgery patients received HRQL (EORTC QLQ-C30, QLQ-CR29 and QLQ-CIPN20) and LARS questionnaires. Patients who experienced a DrTF event before the toxicity assessments (6, 12, 24, or 36 months) were excluded from analyses.Results: Of 574 eligible patients, 495 questionnaires were returned (86%) and 453 analyzed (79% com-pleted within time limits). No significant differences were observed between the groups regarding QLQ-C30, QLQ-CR29 or LARS scores. Sensory-related symptoms occurred significantly more often in the EXP group compared to all STD patients, but not compared to STD+ patients. Any toxicity of any grade and grade > 3 toxicity was comparable between the EXP and STD groups at all time-points. Neurotoxicity grade 1-2 occurred significantly more often in the EXP and STD+ group at all time-points compared to the STD-group.Conclusion: The results demonstrate that TNT for LARC, yielding improved DrTF and pCRs, does not com-promise HRQL, bowel functional or results in more grade >3 toxicity compared to standard chemoradio-therapy at three years after surgery in DrTF-free patients.(c) 2022 The Authors. Published by Elsevier B.V. Radiotherapy and Oncology 171 (2022) 69-76 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
Background: The evaluation of health-related quality of life (HRQoL) in clinical trials has become increasingly important because it addresses the impact of treatment from the patient's perspective... Show moreBackground: The evaluation of health-related quality of life (HRQoL) in clinical trials has become increasingly important because it addresses the impact of treatment from the patient's perspective. The primary aim of this study was to investigate the effect of postoperative chemotherapy and chemoradiotherapy (CRT) after neoadjuvant chemotherapy and surgery with extended (D2) lymphadenectomy on HRQoL in the CRITICS trial. Second, we investigated the potential prognostic value of pretreatment HRQoL on event-free survival (EFS) and overall survival (OS). Patients and Methods: Patients in the CRITICS trial were asked to complete HRQoL questionnaires (EORTC Quality-of-Life Questionnaire-Core 30 and Quality-of-Life Questionnaire gastric cancer-specific module) at baseline, after preoperative chemotherapy, after surgery, after postoperative chemotherapy or CRT, and at 12 months follow-up. Patients with at least 1 evaluable questionnaire (645 of 788 randomized patients) were included in the HRQoL analyses. The predefined endpoints included dysphagia, pain, physical functioning, fatigue, and Quality-of-Life Questionnaire-Core 30 summary score. Linear mixed modeling was used to assess differences over time and at each time point. Associations of baseline HRQoL with EFS and OS were investigated using multivariate Cox proportional hazards analyses. Results: At completion of postoperative chemo(radio)therapy, the chemotherapy group had significantly better physical functioning (P=.02; Cohen's effect size = 0.42) and less dysphagia (P=.01; Cohen's effect size = 0.38) compared with the CRT group. At baseline, worse social functioning (hazard ratio [HR], 2.20; 95% CI, 1.36-3.55; P=.001), nausea (HR, 1.89; 95% CI, 1.39-2.56; P<.001), worse WHO performance status (HR, 1.55; 95% CI, 1.13-2.13; P=.007), and histologic subtype (diffuse vs intestinal: HR, 1.94; 95% CI, 1.42-2.67; P<.001; mixed vs intestinal: HR, 2.35; 95% CI, 1.35-4.12; P=.003) were significantly associated with worse EFS and OS. Conclusions: In the CRITICS trial, the chemotherapy group had significantly better physical functioning and less dysphagia after postoperative treatment. HRQoL scales at baseline were significantly associated with EFS and OS. Show less
Background Epstein-Barr virus positivity (EBV+) and microsatellite instability (MSI-high) are positive prognostic factors for survival in resectable gastric cancer (GC). However, benefit of... Show moreBackground Epstein-Barr virus positivity (EBV+) and microsatellite instability (MSI-high) are positive prognostic factors for survival in resectable gastric cancer (GC). However, benefit of perioperative treatment in patients with MSI-high tumors remains topic of discussion. Here, we present the clinicopathological outcomes of patients with EBV+, MSI-high, and EBV-/MSS GCs who received either surgery only or perioperative treatment. Methods EBV and MSI status were determined on tumor samples collected from 447 patients treated with surgery only in the D1/D2 trial, and from 451 patients treated perioperatively in the CRITICS trial. Results were correlated to histopathological response, morphological tumor characteristics, and survival. Results In the D1/D2 trial, 5-year cancer-related survival was 65.2% in 47 patients with EBV+, 56.7% in 47 patients with MSI-high, and 47.6% in 353 patients with EBV-/MSS tumors. In the CRITICS trial, 5-year cancer-related survival was 69.8% in 25 patients with EBV+, 51.7% in 27 patients with MSI-high, and 38.6% in 402 patients with EBV-/MSS tumors. Interestingly, all three MSI-high tumors with moderate to complete histopathological response (3/27, 11.1%) had substantial mucinous differentiation. No EBV+ tumors had a mucinous phenotype. 115/402 (28.6%) of EBV-/MSS tumors had moderate to complete histopathological response, of which 23/115 (20.0%) had a mucinous phenotype. Conclusions In resectable GC, MSI-high had favorable outcome compared to EBV-/MSS, both in patients treated with surgery only, and in those treated with perioperative chemo(radio)therapy. Substantial histopathological response was restricted to mucinous MSI-high tumors. The mucinous phenotype might be a relevant parameter in future clinical trials for MSI-high patients. Show less
Background: Young-onset rectal cancer, in patients less than 50 years, is expected to increase in the coming years. A watch-and-wait strategy is nowadays increasingly practised in patients with a... Show moreBackground: Young-onset rectal cancer, in patients less than 50 years, is expected to increase in the coming years. A watch-and-wait strategy is nowadays increasingly practised in patients with a clinical complete response (cCR) after neoadjuvant treatment. Nevertheless, there may be reluctance to offer organ preservation treatment to young patients owing to a potentially higher oncological risk. This study compared patients aged less than 50 years with those aged 50 years or more to identify possible differences in oncological outcomes of watch and wait.Methods: The study analysed data from patients with a cCR after neoadjuvant therapy in whom surgery was omitted, registered in the retrospective-prospective, multicentre International Watch & Wait Database (IWWD).Results: In the IWWD, 1552 patients met the inclusion criteria, of whom 199 (12.8 per cent) were aged less than 50 years. Patients younger than 50 years had a higher T category of disease at diagnosis (P = 0.011). The disease-specific survival rate at 3 years was 98 (95 per cent c.i. 93 to 99) per cent in this group, compared with 97 (95 to 98) per cent in patients aged over 50 years (hazard ratio (HR) 1.67, 95 per cent c.i. 0.76 to 3.64; P = 0.199). The cumulative probability of local regrowth at 3 years was 24 (95 per cent c.i. 18 to 31) per cent in patients less than 50 years and 26 (23 to 29) per cent among those aged 50 years or more (HR 1.09, 0.79 to 1.49; P = 0.603). Both groups had a cumulative probability of distant metastases of 10 per cent at 3 years (HR 1.00, 0.62 to 1.62; P = 0.998).Conclusion: There is no additional oncological risk in young patients compared with their older counterparts when following a watch-and-wait strategy after a cCR. In light of a shared decision-making process, watch and wait should be also be discussed with young patients who have a cCR after neoadjuvant treatment. Show less
Background Young-onset rectal cancer, in patients less than 50 years, is expected to increase in the coming years. A watch-and-wait strategy is nowadays increasingly practised in patients with a... Show moreBackground Young-onset rectal cancer, in patients less than 50 years, is expected to increase in the coming years. A watch-and-wait strategy is nowadays increasingly practised in patients with a clinical complete response (cCR) after neoadjuvant treatment. Nevertheless, there may be reluctance to offer organ preservation treatment to young patients owing to a potentially higher oncological risk. This study compared patients aged less than 50 years with those aged 50 years or more to identify possible differences in oncological outcomes of watch and wait. Methods The study analysed data from patients with a cCR after neoadjuvant therapy in whom surgery was omitted, registered in the retrospective-prospective, multicentre International Watch & Wait Database (IWWD). Results In the IWWD, 1552 patients met the inclusion criteria, of whom 199 (12.8 per cent) were aged less than 50 years. Patients younger than 50 years had a higher T category of disease at diagnosis (P = 0.011). The disease-specific survival rate at 3 years was 98 (95 per cent c.i. 93 to 99) per cent in this group, compared with 97 (95 to 98) per cent in patients aged over 50 years (hazard ratio (HR) 1.67, 95 per cent c.i. 0.76 to 3.64; P = 0.199). The cumulative probability of local regrowth at 3 years was 24 (95 per cent c.i. 18 to 31) per cent in patients less than 50 years and 26 (23 to 29) per cent among those aged 50 years or more (HR 1.09, 0.79 to 1.49; P = 0.603). Both groups had a cumulative probability of distant metastases of 10 per cent at 3 years (HR 1.00, 0.62 to 1.62; P = 0.998). Conclusion There is no additional oncological risk in young patients compared with their older counterparts when following a watch-and-wait strategy after a cCR. In light of a shared decision-making process, watch and wait should be also be discussed with young patients who have a cCR after neoadjuvant treatment.Data from the International Watch and Wait Database have been analysed. There is no additional oncological risk in patients younger than 50 years compared with their older counterparts when following watch and wait after the achievement of a clinical complete response following neoadjuvant treatment for rectal cancer. Show less
Patients undergoing complex gastrointestinal surgery are at high risk of major postoperative complications (e.g., anastomotic leakage, sepsis), classified as Clavien-Dindo (CD) >= IIIa.... Show morePatients undergoing complex gastrointestinal surgery are at high risk of major postoperative complications (e.g., anastomotic leakage, sepsis), classified as Clavien-Dindo (CD) >= IIIa. Identification of preoperative risk factors can lead to the identification of high-risk patients. These risk factors can also be used to design personalized perioperative care. This systematic review focuses on the identification of these factors. The Medline and Embase databases were searched for prospective, retrospective cohort studies and randomized controlled trials investigating the effect of risk factors on the occurrence of major postoperative complications and/or mortality after complex gastrointestinal cancer surgery. Risk of bias was assessed using the Quality in Prognostic Studies tool. The level of evidence was graded based on the number of studies reporting a significant association between risk factors and major complications. A total of 207 eligible studies were retrieved, identifying 33 risk factors for major postoperative complications and 13 preoperative laboratory results associated with postoperative complications. The present systematic review provides a comprehensive overview of preoperative risk factors associated with major postoperative complications. A wide range of risk factors are amenable to actions in perioperative care and prehabilitation programs, which may lead to improved outcomes for high-risk patients. Additionally, the knowledge of this study is important for benchmarking surgical outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd. Show less
Aim To evaluate the prognostic value of tumor markers in a European cohort of patients with resectable gastric cancer. Methods We performed a post hoc analysis of the CRITICS trial, in which 788... Show moreAim To evaluate the prognostic value of tumor markers in a European cohort of patients with resectable gastric cancer. Methods We performed a post hoc analysis of the CRITICS trial, in which 788 patients received perioperative therapy. Association between survival and pretreatment CEA, CA 19-9, alkaline phosphatase, neutrophils, hemoglobin and lactate dehydrogenase were explored in uni- and multivariable Cox regression analyses. Likelihoods to receive potentially curative surgery were investigated for patients without elevated tumor markers versus one of the tumor markers elevated versus both tumor markers elevated. The association between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 patients with available ctDNA data. Results In multivariable analysis, in which we corrected for allocated treatment and other baseline characteristics, elevated pretreatment CEA (HR 1.43; 95% CI 1.11-1.85, p < 0.001) and CA 19-9 (HR 1.79; 95% CI 1.42-2.25, p < 0.001) were associated with worse OS. Likelihoods to receive potentially curative surgery were 86%, 77% and 60% for patients without elevated tumor marker versus either elevated CEA or CA 19-9 versus both elevated, respectively (p < 0.001). Although both preoperative presence of ctDNA and tumor markers were prognostic for survival, no association was found between these two parameters. Conclusion CEA and CA 19-9 were independent prognostic factors for survival in a large cohort of European patients with resectable gastric cancer. No relationship was found between tumor markers and ctDNA. These factors could potentially guide treatment choices and should be included in future trials to determine their definitive position. Show less
Introduction. Pretreatment enlarged lateral lymph nodes (LLN) in patients with locally advanced low rectal cancer are predictive for local recurrences after neoadjuvant (chemo)radiotherapy (n(C)RT)... Show moreIntroduction. Pretreatment enlarged lateral lymph nodes (LLN) in patients with locally advanced low rectal cancer are predictive for local recurrences after neoadjuvant (chemo)radiotherapy (n(C)RT) followed by total mesorectal excision (TME). Not much is known of the impact on oncological outcomes when in addition malignant features are present in enlarged LLN.Patients and Methods. A multicenter retrospective cohort study was conducted at five tertiary referral centers in the Netherlands and Australia. All patients were diagnosed with locally advanced low rectal cancer with LLN on pretreatment magnetic resonance imaging (MRI) and underwent n(C)RT followed by TME. LLN were considered enlarged with a short axis of >= 5 mm. Malignant features were defined as nodes with internal heterogeneity and/or border irregularity. Outcomes of interest were local recurrence-free survival (LRFS), distant metastatic-free survival (DMFS), and overall survival (OS).Results. Out of 115 patients, the majority was male (75%) and the median age was 64 years (range 26-85 years). Median pretreatment LLN short axis was 7 mm (range 5-28 mm), and 60 patients (52%) had malignant features. After a median follow-up of 47 months, patients with larger LLN (7 + mm) had a worse LRFS (p = 0.01) but no difference in DMFS (p = 0.37) and OS (p = 0.54) compared with patients with smaller LLN (5-6 mm). LLN patients with malignant features had no difference in LRFS (p = 0.20) but worse DMFS (p = 0.004) and OS (p = 0.006) compared with patients without malignant features in the LLN. Cox regression analysis identified LLN short axis as an independent factor for LR. Malignant features in LLN were an independent factor for DMFS.Conclusion. The current study suggests that pre-treatment enlarged LLN that also harbor malignant features are predictive of a worse MMES. More studies will be required to further explore the role of malignant features in LLN. Show less
Simple Summary Around 20% of gastric cancer patients develop peritoneal metastasis after preoperative chemotherapy and curative surgery. Patients with peritoneal metastasis as a single site of... Show moreSimple Summary Around 20% of gastric cancer patients develop peritoneal metastasis after preoperative chemotherapy and curative surgery. Patients with peritoneal metastasis as a single site of metastasis may potentially benefit from prophylactic strategies. In this post-hoc analysis of the international phase III CRITICS trial, we aim to identify factors that can distinguish patients at high risk for developing peritoneal metastasis as a single site. Diffuse or mixed histological subtype, tumors with serosal involvement (ypT4) and advanced lymph node stage (ypN3 or a tumor positive lymph node ratio >20%) were independent risk factors for isolated peritoneal metastasis after preoperative chemotherapy and curative surgery. The combination of these risk factors identifies a subgroup that may benefit from treatment strategies that aim to prevent peritoneal metastasis. Gastric cancer (GC) patients at high risk of developing peritoneal metastasis (PM) as a single site of metastasis after curative treatment may be candidates for adjuvant prophylactic strategies. Here we investigated risk factors for metachronous isolated PM in patients who were treated in the CRITICS trial (NCT00407186). Univariable and multivariable analyses on both metachronous isolated PM and 'other events', i.e., (concurrent) distant metastasis, locoregional recurrence or death, were performed using a competing risk model and summarized by cumulative incidences. Isolated PM occurred in 64 of the 606 (11%) included patients. Diffuse or mixed histological subtype, ypT4 tumor stage and LNhigh (ypN3 lymph node stage or a lymph node ratio >20%) were independent risk factors for isolated PM in both univariable and multivariable analyses. Likewise, LNhigh was an independent risk factor for 'other events'. Patients with tumors who were positive for all three independent risk factors had the highest two-year cumulative incidence of 43% for isolated PM development. In conclusion, diffuse or mixed histological subtype, ypT4 and LNhigh were identified as independent risk factors for isolated PM in patients treated with preoperative chemotherapy followed by surgical resection. The combination of these factors may identify a subgroup that may benefit from PM-preventing treatment strategies. Show less
Background: In the West, low rectal cancer patients with abnormal lateral lymph nodes (LLNs) are commonly treated with neoadjuvant (chemo)radiotherapy (nCRT) followed by total mesorectal excision ... Show moreBackground: In the West, low rectal cancer patients with abnormal lateral lymph nodes (LLNs) are commonly treated with neoadjuvant (chemo)radiotherapy (nCRT) followed by total mesorectal excision (TME). Additionally, some perform a lateral lymph node dissection (LLND). To date, no comparative data (nCRT vs. nCRT + LLND) are available in Western patients. Methods: An international multi-centre cohort study was conducted at six centres from the Netherlands, US and Australia. Patients with low rectal cancers from the Netherlands and Australia with abnormal LLNs (>5 mm short-axis in the obturator, internal iliac, external iliac and/or common iliac basin) who underwent nCRT and TME (LLND-group) were compared to similarly staged patients from the US who underwent a LLND in addition to nCRT and TME (LLND + group). Results: LLND + patients (n = 44) were younger with higher ASA-classifications and ypN-stages compared to LLND-patients (n = 115). LLND + patients had larger median LLNs short-axes and received more adjuvant chemotherapy (100 vs. 30%; p < 0.0001). Between groups, the local recurrence rate (LRR) was 3% for LLND + vs. 11% for LLND-(p = 0.13). Disease-free survival (DFS, p = 0.94) and overall survival (OS, p = 0.42) were similar. On multivariable analysis, LLND was an independent sig-nificant factor for local recurrences (p = 0.01). Sub-analysis of patients who underwent long-course nCRT and had adjuvant chemotherapy (LLND-n = 30, LLND + n = 44) demonstrated a lower LRR for LLND + patients (3% vs. 16% for LLND-; p = 0.04). DFS (p = 0.10) and OS (p = 0.11) were similar between groups. Conclusion: A LLND in addition to nCRT may improve loco-regional control in Western patients with low rectal cancer and abnormal LLNs. Larger studies in Western patients are required to evaluate its contribution. (c) 2021 Elsevier Ltd, BASO -The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. Show less
Vuijk, F.A.; Water, C. van de; Lent-van Vliet, S.; Valk, M.J.M. van der; Simmer, F.; Velde, C.J.H. van de; ... ; Hilling, D.E. 2021
Simple SummaryA subset of patients with rectal cancer are treated before surgery with chemoradiation. Unfortunately, this neoadjuvant chemoradiotherapy does not have the preferred effect of tumor... Show moreSimple SummaryA subset of patients with rectal cancer are treated before surgery with chemoradiation. Unfortunately, this neoadjuvant chemoradiotherapy does not have the preferred effect of tumor downstaging in all patients, but does bring substantial side effects and possible complications. A pre-treatment prediction based on available parameters might provide a means to better select therapy for individual patients. Genomic mutational status of pre-treatment biopsies may provide prognostic information, however, it also might be influenced by tumor heterogeneity. This study investigates whether pre-treatment biopsy material is a reliable way of defining mutational status in rectal cancer.Neoadjuvant therapy before surgical resection is indicated for patients with locally advanced rectal cancer. However, a significant number of patients show minimal or no response to neoadjuvant therapy. Unfortunately, we are currently unable to predict response and identify non-responding patients before neoadjuvant treatment is given. Genomic mutational status might provide valuable prognostic information. However, it is unclear whether predictions based on genomic mutational status in single preoperative biopsies are reliable due to intra-tumoral heterogeneity. In this study we aim to investigate the reliability of genomic mutations found in single pre-operative biopsies by comparing genomic mutations to four other locations within the same tumor using next generation sequencing. Rectal cancer patients undergoing primary resection without neoadjuvant therapy were included. From each patient, one biopsy, two deep and two superficial samples were obtained and sequenced using a targeted next generation sequencing gene panel. Concordance between these five samples was assessed. In this feasibility study we included 11 patients. In 7 out of 11 (64%) patients, all 5 samples showed concordant mutations. In 4 out of 11 patients (36%) discordant mutations were observed. In conclusion, assessment of mutational status on a single pre-operative biopsy shows discordance with tumor tissue from other locations in 36% of cases. These results warrant careful interpretation of biopsy material analysis, as these might be influenced by tumor heterogeneity. Show less
Flanagan, M.; Clancy, C.; Sorensen, J.; Thompson, L.; Kranenbarg, E.M.K.; Velde, C.J.H. van de; ... ; Burke, J. 2021
Background There is no consensus on the use of neoadjuvant radiotherapy for tumors of the upper third of the rectum. Due to conflicting findings in high-quality trials and significant long-term... Show moreBackground There is no consensus on the use of neoadjuvant radiotherapy for tumors of the upper third of the rectum. Due to conflicting findings in high-quality trials and significant long-term side effects associated with neoadjuvant radiotherapy, the benefit of neoadjuvant radiotherapy for upper third rectal tumors is less certain than for lower two third rectal tumors. This metaanalysis compares oncological outcomes with neoadjuvant radiotherapy and surgery versus surgery alone for upper third rectal tumors. Patients and Methods PubMed, Embase, and the Cochrane library databases were searched. Randomized controlled trials (RCT) comparing neoadjuvant radiotherapy and surgery versus surgery alone for resectable rectal cancer were included. Individual patient data were sought from the principal investigator of each eligible trial for comparative data on patients with upper third rectal tumors. The main outcomes measured were survival outcomes, oncological outcomes, postoperative morbidity, and late toxicity. Results Individual patient data from two RCTs examining outcomes in 758 patients were obtained. Published data from one further RCT containing comparable data on upper third rectal tumors were included in analysis of local recurrence. In patients with curative surgery, there was no significant reduction in local recurrence or significant improvement in overall survival or disease-free survival with neoadjuvant radiotherapy (LR RR: 0.38, 95% CI 0.14-1.04, p = 0.06) (OS RR: 1.10, 95% CI 0.98-1.24, p = 0.11) (DFS RR: 1.11, 95% CI 0.97-1.26, p = 0.13). Conclusions The benefit of neoadjuvant radiotherapy for upper third rectal tumors is not certain, and surgery alone for patients with potentially curative disease at preoperative staging may be sufficient. Show less
Background: The Intergroup 0116 and the MAGIC trials changed clinical practice for resectable gastric cancer in the Western world. In these trials, overall survival improved with post-operative... Show moreBackground: The Intergroup 0116 and the MAGIC trials changed clinical practice for resectable gastric cancer in the Western world. In these trials, overall survival improved with post-operative chemoradiotherapy (CRT) and perioperative chemotherapy (CT). Intention-to-treat analysis in the CRITICS trial of post-operative CT or post-operative CRT did not show a survival difference. The current study reports on the per-protocol (PP) analysis of the CRITICS trial.Patients and methods: The CRITICS trial was a randomized, controlled trial in which 788 patients with stage Ib-Iva resectable gastric or esophagogastric adenocarcinoma were included. Before start of preoperative CT, patients from the Netherlands, Sweden and Denmark were randomly assigned to receive post-operative CT or CRT. For the current analysis, only patients who started their allocated post-operative treatment were included. Since it is uncertain that the two treatment arms are balanced in such PP analysis, adjusted proportional hazards regression analysis and inverse probability weighted analysis were used to minimize the risk of selection bias and to estimate and compare overall and event-free survival.Results: Of the 788 patients, 478 started post-operative treatment according to protocol, 233 (59%) patients in the CT group and 245 (62%) patients in the CRT group. Patient and tumor characteristics between the groups before start of the post-operative treatment were not different. After a median follow-up of 6.7 years since the start of post-operative treatment, the 5-year overall survival was 57.9% (95% confidence interval: 51.4% to 64.3%) in the CT group versus 45.5% (95% confidence interval: 39.2% to 51.8%) in the CRT group (adjusted hazard ratio CRT versus CT: 1.62 (1.24-2.12), P = 0.0004). Inverse probability weighted analysis resulted in similar hazard ratios.Conclusion: After adjustment for all known confounding factors, the PP analysis of patients who started the allocated post-operative treatment in the CRITICS trial showed that the CT group had a significantly better 5-year overall survival than the CRT group (NCT00407186). Show less
Houtsma, D.; Groot, S. de; Baak-Pablo, R.; Kranenbarg, E.M.K.; Seynaeve, C.M.; Velde, C.J.H. van de; ... ; Gelderblom, H. 2021
The PvuII (rs2234693) Single Nucleotide Polymorphism (SNP) in the gene coding for the estrogen receptor-1 (ESR1), has been found associated with outcome in tamoxifen treated patients with early... Show moreThe PvuII (rs2234693) Single Nucleotide Polymorphism (SNP) in the gene coding for the estrogen receptor-1 (ESR1), has been found associated with outcome in tamoxifen treated patients with early hormone-receptor positive breast cancer. However, it remains unclear whether this SNP is a predictive marker for tamoxifen efficacy or a prognostic marker for breast cancer outcome. The aim of this study was to examine the prognostic potential of this SNP in postmenopausal early breast cancer patients treated with adjuvant exemestane. Dutch postmenopausal patients randomised to 5 years of adjuvant exemestane of whom tissue was available (N=807) were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial database. The SNP rs2234693 in the ESR1 gene was genotyped on DNA from formalin-fixed paraffin embedded (FFPE) tumor tissue using Taqman assays and related to the primary endpoint disease-free survival (DFS) and secondary endpoint overall survival (OS). Survival analyses were performed using Cox regression analysis. In total 805 patients were included in the analyses (median follow up of 5.22 years) and genotypes were obtained in 97% of the samples. The variant T allele of PvuII in ESR1 (rs2234693) was associated with a better DFS (hazard ratio (HR) 0.689, 95% confidence interval (CI) 0.480-0.989, P=0.044) in univariate analysis only, and a better OS in both univariate (HR 0.616, 95%, CI 0.411-0.923, P=0.019) and multivariate analyses (HR 0.571, 95% CI 0.380-0.856, P=0.007), consistent with a prognostic rather than a predictive drug response effect. Variation of PvuII in the ESR1 gene is related to OS in postmenopausal, early HR+breast cancer patients treated with exemestane in the TEAM study. Variation in the ESR1 gene may therefore be a prognostic marker of early breast cancer survival, and warrants further research. Show less
Weixler, B.; Cunha, S.T. da; Warschkow, R.; Demartines, N.; Guller, U.; Zettl, A.; ... ; Zuber, M. 2021
Background Molecular lymph node workup with one-step nucleic acid amplification (OSNA) is a validated diagnostic adjunct in breast cancer and also appealing for colon cancer (CC) staging. This... Show moreBackground Molecular lymph node workup with one-step nucleic acid amplification (OSNA) is a validated diagnostic adjunct in breast cancer and also appealing for colon cancer (CC) staging. This study, for the first time, evaluates the prognostic value of OSNA in CC. Patients and methods The retrospective study includes patients with stage I-III CC from three centres. Lymph nodes were investigated with haematoxylin and eosin (H&E) and with OSNA, applying a 250 copies/mu L threshold of CK19 mRNA. Diagnostic value of H&E and OSNA was assessed by survival analysis, sensitivity, specificity and time-dependent receiver operating characteristic curves. Results Eighty-seven patients were included [mean follow-up 53.4 months (+/- 24.9)]. Disease recurrence occurred in 16.1% after 19.8 months (+/- 12.3). Staging with H&E independently predicted worse cancer-specific survival in multivariate analysis (HR = 10.77, 95% CI 1.07-108.7, p = 0.019) but not OSNA (HR = 3.08, 95% CI 0.26-36.07, p = 0.197). With cancer-specific death or recurrence as gold standard, H&E sensitivity was 46.7% (95% CI 21.3-73.4%) and specificity 84.7% (95% CI 74.3-92.1%). OSNA sensitivity and specificity were 60.0% (95% CI 32.3-83.7%) and 75.0% (95% CI 63.4-84.5%), respectively. Conclusions In patients with CC, OSNA does not add relevant prognostic value to conventional H&E contrasting findings in other cancers. Further studies should assess lower thresholds for OSNA (< 250 copies/mu L). Show less
Background Watch and wait is a novel management strategy in patients with rectal cancer who have a clinical complete response after neoadjuvant chemoradiotherapy. Surveillance of these patients is... Show moreBackground Watch and wait is a novel management strategy in patients with rectal cancer who have a clinical complete response after neoadjuvant chemoradiotherapy. Surveillance of these patients is generally intensive, because local regrowth (with the potential for salvage) occurs in 25% of patients, and distant metastases occur in 10% of patients. It is unclear for how long these patients should be followed up. To address this issue, we did conditional survival modelling using the International Watch & Wait Database (IWWD), which is a large-scale registry of patients with a clinical complete response after neoadjuvant chemotherapy who have been managed by a watch-and-wait strategy.Methods We did a retrospective, multicentre registry study using a dataset from the IWWD, which includes data from 47 clinics across 15 countries. We selected patients (aged >= 18 years) with rectal cancer who had a clinical complete response after neoadjuvant chemotherapy, and who were subsequently managed by a watch-and-wait strategy between Nov 25,1991, and Dec 31,2015. Patients who had not achieved a clinical complete response or who had undergone any surgical procedure were excluded. The criteria used for defining a clinical complete response and the specific surveillance strategies were at the discretion of each participating centre. We used conditional survival modelling to estimate the probability of patients remaining free of local regrowth or distant metastasis for an additional 2 years after sustaining a clinical complete response or being distant metastasis-free for 1,3, and 5 years from the date of the decision to commence watch and wait. The primary outcomes were conditional local regrowth-free survival at 3 years, and conditional distant metastasis-free survival at 5 years.Findings We identified 793 patients in the IWWD with clinical complete response who had been managed by a watch-and-wait strategy. Median follow-up was 55.2 months (IQR 36.0-75.6). The probability of remaining free from local regrowth for an additional 2 years if a patient had a sustained clinical complete response for 1 year was 88.1% (95% CI 85.8-90.9), for 3 years was 97.3% (95.2-98.6), and for 5 years was 98.6% (97.6-100.0). The probably of remaining free from distant metastasis for a further 2 years in patients who had a clinical complete response without distant metastasis for 1 year was 93.8% (92.3-95.9), for 3 years was 97.8% (96.6-99.3), and for 5 years was 96.6% (94.0-98.9).Interpretation These results suggest that the intensity of active surveillance in patients with rectal cancer managed by a watch-and-wait approach could be reduced if they achieve and maintain a clinical complete response within the first 3 years of starting this approach. Copyright (C) 2020 Elsevier Ltd. All rights reserved. Show less
Purpose: Individualized selection of patients with early-stage hormone receptor-positive (HR+) breast cancer for extended endocrine therapy (EET) is required to balance modest gains in outcome with... Show morePurpose: Individualized selection of patients with early-stage hormone receptor-positive (HR+) breast cancer for extended endocrine therapy (EET) is required to balance modest gains in outcome with toxicities of prolonged use. This study examined the Breast Cancer Index [BCI; HOXB13/IL17BR ratio (H/I)] as a predictive biomarker of EET benefit in patients from the Investigation on the Duration of Extended Adjuvant Letrozole trial.Experimental Design: BCI was tested in primary tumor specimens from 908 patients randomized to receive 2.5 versus 5 years of extended letrozole. The primary endpoint was recurrence-free interval. Cox models and likelihood ratios tested the interaction between HET and BCI (H/I).Results: BCI (H/I)-high significantly predicted benefit from extended letrozole in the overall cohort [HR 0.42; 95% confidence interval (CI), 0.21-0.84; P = 0.011] and any aromatase inhibitor subset [HR 0.34; 95% CI, 0.16-0.73; P - 0.004), whereas BCI (H/I)-low patients did not derive significant benefit (HR 0.95; 95% CI, 0.58-1.56; P - 0.84 and HR 0.90; 95% CI, 053-1.55; P - 0.71, respectively) treatment to hiomarker interaction was significant (P = 0.045, P = 0.025, respectively). BCI identified approximately 50% of patients with clinically high-risk disease that did not benefit, and with clinically low-risk disease that derived significant benefit, from an additional 2.5 years of EEL.Conclusions: BCI (H/I) predicted preferential benefit from 5 versus 2.5 years of EET and identified patients with improved outcomes from completing 10 years of adjuvant endocrine therapy. Findings expand the clinical utility of BCI (H/I) to a broader range of patients and beyond prognostic risk factors as a predictive endocrine response biomarker for early-stage HR+ breast cancer. Show less
Background Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And... Show moreBackground Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control.Methods In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocardnoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within S weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 x 5 Gy over a maximum of 8 days) followed by six cycles of CAPDX chemotherapy (capecitabine 1000 mg/m(2) orally twice daily on days 1-14, oxaliplatin 130 mg/m(2) intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m(2) intravenously on day 1, leucovorin [folinic acid] 200 mg/m 2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m(2) intravenously and fluorouracil 600 mg/m 2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPDX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1.8 Gy up to 50.4 Gy or 25 fractions of 2.0 Gy up to 50.0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m(2) followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPDX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov , NCT01558921, and is now complete.Findings Between June 21,2011, and June 2,2016,920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4.6 years (IQR 3.5-5.5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23.7% (95% CI 19.8-27.6) in the experimental group versus 30.4% (26.1-34.6) in the standard of care group (hazard ratio 0.75, 95% CI 0.60-0-95; p=0-019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression).Interpretation The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer. Copyright (C) 2020 Elsevier Ltd. All rights reserved. Show less
