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| 2. |
- Bahadoer, Renu R., et al.
(author)
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Risk and location of distant metastases in patients with locally advanced rectal cancer after total neoadjuvant treatment or chemoradiotherapy in the RAPIDO trial
- 2023
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In: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 185, s. 139-149
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Journal article (peer-reviewed)abstract
- Introduction: Although optimising rectal cancer treatment has reduced local recurrence rates, many patients develop distant metastases (DM). The current study investigated whether a total neoadjuvant treatment strategy influences the development, location, and timing of metastases in patients diagnosed with high-risk locally advanced rectal cancer included in the Rectal cancer And Pre-operative Induction therapy followed by Dedicated Operation (RAPIDO) trial.Material and methods: Patients were randomly assigned to short-course radiotherapy fol-lowed by 18 weeks of CAPOX or FOLFOX4 before surgery (EXP), or long-course che-moradiotherapy with optional postoperative chemotherapy (SC-G). Assessments for metastatic disease were performed pre-and post-treatment, during surgery, and 6, 12, 24, 36, and 60 months postoperatively. From randomisation, differences in the occurrence of DM and first site of metastasis were evaluated.Results: In total, 462 patients were evaluated in the EXP and 450 patients in the SC-G groups. The cumulative probability of DM at 5 years after randomisation was 23% [95% CI 19-27] and 30% [95% CI 26-35] (HR 0.72 [95% CI 0.56-0.93]; P = 0.011) in the EXP and SC -G, respectively. The median time to DM was 1.4 (EXP) and 1.3 years (SC-G). After diagnosis of DM, median survival was 2.6 years [95% CI 2.0-3.1] in the EXP and 3.2 years [95% CI 2.3-4.1] in the SC-G groups (HR 1.39 [95% CI 1.01-1.92]; P = 0.04). First occurrence of DM was most often in the lungs (60/462 [13%] EXP and 55/450 [12%] SC-G) or the liver (40/462 [9%] EXP and 69/450 [15%] SC-G). A hospital policy of postoperative chemotherapy did not influence the development of DM.Conclusions: Compared to long-course chemoradiotherapy, total neoadjuvant treatment with short-course radiotherapy and chemotherapy significantly decreased the occurrence of me-tastases, particularly liver metastases.
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- Bahadoer, Renu R., et al.
(author)
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Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO) : a randomised, open-label, phase 3 trial
- 2021
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In: The Lancet Oncology. - : Elsevier. - 1470-2045 .- 1474-5488. ; 22:1, s. 29-42
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Journal article (peer-reviewed)abstract
- 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 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.
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- Bakker, M. Els, et al.
(author)
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Assessment of Regional Progression of Pulmonary Emphysema With CT Densitometry
- 2008
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In: Chest. - : Elsevier BV. - 1931-3543 .- 0012-3692. ; 134:5, s. 931-937
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Journal article (peer-reviewed)abstract
- Background: Lung densitometry is an effective method to assess overall progression of emphysema, but generally the location of the progression is not estimated. We hypothesized that progression of emphysema is the result of extension from affected areas toward less affected areas in the lung. To test this hypothesis, a method was developed to assess emphysema severity at different levels in the lungs in order to estimate regional changes. Methods: Fifty subjects with emphysema due to alpha(1)-antitrypsin deficiency (AATD) [AATD deficiency of phenotype PiZZ (PiZ) group] and 16 subjects with general emphysema (general emphysema without phenotype PiZZ [non-.PiZ] group) were scanned with CT at baseline and after 30 months. Densitometry was performed in 12 axial partitions of equal volumes. To indicate predominant location, craniocaudal locallity was defined as the slope in the plot of densities against partitions. Regional progression of emphysema was calculated after volume correction, and its slope identifies the area of predominant progression. The hypothesis was tested by investigating the correlation between predominant location and predominant progression. Results: As expected, the PiZ patients showed more basal emphysema than the non-PiZ group (craniocaudal locality, -40.0 g/L vs -6.2 g/L). Overall progression rate in PiZ patients was lower than in non-PiZ subjects. A significant correlation was found between craniocaudal locality and progression slope in PiZ subjects (R = 0.566, p < 0.001). In the non-PiZ group, no correlation was found. Conclusions: In the PiZ group, the more emphysema is distributed basally, the more progression was found in the basal area. This finding suggests that emphysema due to AATD spreads out from affected areas. (CHEST 2008; 134:931-937)
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- den Dulk, Marcel, et al.
(author)
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The abdominoperineal resection itself is associated with an adverse outcome : The European experience based on a pooled analysis of five European randomised clinical trials on rectal cancer
- 2009
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In: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 45:7, s. 1175-1183
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Journal article (peer-reviewed)abstract
- PURPOSE: The aim of this study is to identify factors associated with the decision to perform an abdominoperineal resection (APR) and to assess if these factors or the surgical procedure itself is associated with circumferential resection margin (CRM) involvement, local recurrence (LR), overall survival (OS) and cancer-specific survival (CSS). PATIENTS AND METHODS: The Swedish Rectal Cancer Trial (SRCT), TME trial, CAO/ARO/AIO-94 trial, EORTC 22921 trial and Polish Rectal Cancer Trial (PRCT) were pooled. A propensity score was calculated, which indicated the predicted probability of undergoing an APR given gender, age and distance, and used in the multivariate analyses. RESULTS: An APR procedure was associated with an increased risk of CRM involvement [odd ratio (OR) 2.52, p<0.001], increased LR rate [hazard ratio (HR) 1.53, p=0.001] and decreased CSS rate (HR 1.31, p=0.002), whereas the propensity score was not. CONCLUSION: The results suggest that the APR procedure itself is a significant predictor for non-radical resections and increased risk of LR and death due to cancer for patients with advanced rectal cancer.
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- Dijkstra, Esmee A., et al.
(author)
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Locoregional Failure During and After Short-course Radiotherapy Followed by Chemotherapy and Surgery Compared With Long-course Chemoradiotherapy and Surgery
- 2023
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In: Annals of Surgery. - : Lippincott Williams & Wilkins. - 0003-4932 .- 1528-1140. ; 278:4, s. E766-E772
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Journal article (peer-reviewed)abstract
- Objective:To analyze risk and patterns of locoregional failure (LRF) in patients of the RAPIDO trial at 5 years.Background:Multimodality treatment improves local control in rectal cancer. Total neoadjuvant treatment (TNT) aims to improve systemic control while local control is maintained. At 3 years, LRF rate was comparable between TNT and chemoradiotherapy in the RAPIDO trial.Methods:A total of 920 patients were randomized between an experimental (EXP, short-course radiotherapy, chemotherapy, and surgery) and a standard-care group (STD, chemoradiotherapy, surgery, and optional postoperative chemotherapy). LRFs, including early LRF (no resection except for organ preservation/R2 resection) and locoregional recurrence (LRR) after an R0/R1 resection, were analyzed.Results:Totally, 460 EXP and 446 STD patients were eligible. At 5.6 years (median follow-up), LRF was detected in 54/460 (12%) and 36/446 (8%) patients in the EXP and STD groups, respectively (P=0.07), in which EXP patients were more often treated with 3-dimensional-conformed radiotherapy (P=0.029). In the EXP group, LRR was detected more often [44/431 (10%) vs. 26/428 (6%); P=0.027], with more often a breached mesorectum (9/44 (21%) vs. 1/26 (4); P=0.048). The EXP treatment, enlarged lateral lymph nodes, positive circumferential resection margin, tumor deposits, and node positivity at pathology were the significant predictors for developing LRR. Location of the LRRs was similar between groups. Overall survival after LRF was comparable [hazard ratio: 0.76 (95% CI, 0.46-1.26); P=0.29].Conclusions:The EXP treatment was associated with an increased risk of LRR, whereas the reduction in disease-related treatment failure and distant metastases remained after 5 years. Further refinement of the TNT in rectal cancer is mandated.
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| 8. |
- Dijkstra, Esmee A., et al.
(author)
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Quality of life and late toxicity after short-course radiotherapy followed by chemotherapy or chemoradiotherapy for locally advanced rectal cancer - The RAPIDO trial
- 2022
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In: Radiotherapy and Oncology. - : Elsevier. - 0167-8140 .- 1879-0887. ; 171, s. 69-76
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Journal article (peer-reviewed)abstract
- 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 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/).
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- Oonk, Maaike H. M., et al.
(author)
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Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients With Micrometastases in the Sentinel Node : Results of GROINSS-V II
- 2021
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In: Journal of Clinical Oncology. - : Lippincott, Williams & Wilkins. - 0732-183X .- 1527-7755. ; 39:32, s. 3623-3632
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Journal article (peer-reviewed)abstract
- PURPOSE The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (<= 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL (P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL.
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