Can we use a simple blood test to reduce unnecessary adverse effects from radiotherapy by timely identification of radiotherapy-resistant rectal cancers? MeD-Seq rectal study protocol.

BACKGROUND: Chemoradiation therapy (CRT) followed by surgery is currently the standard of care to treat patients with locally advanced rectal cancer (LARC). CRT reduces local recurrences, but is associated with significant damage to the surrounding healthy tissue that can severely impact patients quality of life. Additionally, a proportion of patients (hardly) benefit from CRT. We aim to develop a diagnostic innovation, using DNA-methylation, which can enable a more selective and thereby more effective use of the available therapies for rectal cancer patients. METHODS: MeD-Seq Rectal is a prospective single centre, observational study. 75 patients diagnosed with rectal cancer and will receive CRT as neoadjuvant treatment are will be included. DNA-methylation profiling will be performed on liquid biopsies to predict pathological response to CRT. DISCUSSION: To data no clinical or image-based features were found that predict response to CRT. we hypothesize that DNA methylation patterns in liquid biopsies may provide a promising and patient-friendly strategy to predict CRT resistance upfront. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT06035471).

Locally recurrent rectal cancer and distant metastases: is there still a chance ofcure?

INTRODUCTION: Patients with locally recurrent rectal cancer (LRRC) generally have poor prognosis, especially those who have (a history of) distant metastases. The aim of this study was to investigate the impact of distant metastases on oncological outcomes in LRRC patients undergoing curative treatment. METHODS: Consecutive patients with surgically treated LRRC between 2005 and 2019 in two tertiary referral hospitals were retrospectively analysed. Oncological survival of patients without distant metastases were compared with outcomes of patients with synchronous distant metastases with the primary tumour, patients with distant metastases in the primary-recurrence interval, and patients with synchronous LRRC distant metastases. RESULTS: A total of 535 LRRC patients were analysed, of whom 398 (74%) had no (history of) metastases, 22 (4%) had synchronous metastases with the primary tumour, 44 (8%) had metachronous metastases, and 71 (13%) had synchronous LRRC metastases. Patients with synchronous LRRC metastases had worse survival compared to patients without metastases (adjusted hazard ratio: 1.56 [1.15-2.12]), whilst survival of patients with synchronous primary metastases and metachronous metastases of the primary tumour was similar as those patients who had no metastases. In LRRC patients who had metastases in primary-recurrence interval, patients with early metachronous metastases had better disease-free survival as patients with late metachronous metastases (3-year disease-free survival: 48% vs 22%, p = 0.039). CONCLUSION: LRRC patients with synchronous distant metastases undergoing curative surgery have relatively poor prognosis. However, LRRC patients with a history of distant metastases diagnosed nearby the primary tumour have comparable (oncological) survival as LRRC patients without distant metastases.

Relation between body composition and severe diarrhea in patients treated with preoperative chemoradiation with capecitabine for rectal cancer: a single-centre cohort study.

BACKGROUND: Chemoradiation with capecitabine followed by surgery is standard care for locally advanced rectal cancer (LARC). Severe diarrhea is considered a dose-limiting toxicity of adding capecitabine to radiation therapy. The aim of this study was to describe the risk factors and the impact of body composition on severe diarrhea in patients with LARC during preoperative chemoradiation with capecitabine. METHODS: A single centre retrospective cohort study was conducted in a tertiary referral centre. All patients treated with preoperative chemoradiation with capecitabine for LARC from 2009 to 2015 were included. Patients with locally recurrent rectal cancer who received chemoradiation for the first time were included as well. Logistic regression analyses were performed to identify risk factors for severe diarrhea. RESULTS: A total of 746 patients were included. Median age was 64 years (interquartile range 57-71) and 477 patients (64%) were male. All patients received a radiation dosage of 25 × 2 Gy during a period of five weeks with either concomitant capecitabine administered on radiation days or continuously during radiotherapy. In this cohort 70 patients (9%) developed severe diarrhea. In multivariable logistic regression analyses female sex (OR: 4.42, 95% CI 2.54-7.91) and age ≥ 65 (OR: 3.25, 95% CI 1.85-5.87) were the only risk factors for severe diarrhea. CONCLUSIONS: Female patients and patients aged sixty-five or older had an increased risk of developing severe diarrhea during preoperative chemoradiation therapy with capecitabine. No relation was found between body composition and severe diarrhea.

The clinical relevance of indeterminate lung nodules in patients with locally recurrent rectal cancer.

AIM: To evaluate the clinical relevance of indeterminate lung nodules (ILN) in patients with locally recurrent rectal cancer (LRRC) treated in a tertiary referral centre. METHODS: All patients with LRRC diagnosed between 2000 and 2017 were retrospectively reviewed. Reports of staging chest CT-scans were evaluated for ILN. Patients with distant metastases including lung metastases at time of LRRC diagnosis were excluded. Overall (OS), progression-free survival (PFS) and the cumulative incidence of lung metastases were compared between patients with and without ILN. RESULTS: In total 556 patients with LRRC were treated during the study period. In the 243 patients eligible for analysis, 68 (28%) had ILN at LRRC diagnosis. Median OS was 37 months for both the patients with and without ILN (p = 0.37). Median PFS was 14 months for the patients with ILN and 16 months for patients without ILN (p = 0.80). After correction for potential confounding, ILN present at LRRC diagnosis was not associated with impaired OS or PFS (adjusted hazards ratio [95% confidence interval]: 0.81 [0.54-1.22] and 1.09 [0.75-1.59]). The 5-year cumulative incidence of lung metastases was 31% in patients with ILN and 28% in patients without ILN (p = 0.19). CONCLUSION: Our study shows that ILN are present in roughly a quarter of patients with LRRC. No differences in OS, PFS, or the cumulative incidence of lung metastases were found between patients with and without ILN at LRRC diagnosis. These results suggest that ILN are of little to no clinical relevance in patients with LRRC.

Locally recurrent rectal cancer; long-term outcome of curative surgical and non-surgical treatment of 447 consecutive patients in a tertiary referral centre.

INTRODUCTION: The majority of patients with locally recurrent rectal cancer (LRRC) present with extensive metastatic disease or an unresectable recurrence, and will be treated palliatively. Only a minority of patients will be eligible for potential cure by surgical treatment. The aim of this study is to evaluate the long-term outcome of surgical treatment and non-surgical treatment of patients with LRRC. METHODS: All patients with LRRC referred to our tertiary institute between 2000 and 2015 were retrospectively analysed. Patients were discussed in a multidisciplinary tumour board (MDT) and eventually received curative surgical or non-surgical treatment. Overall survival (OS) was compared by resection margin status and non-surgical treatment. RESULTS: A total of 447 patients were discussed in our MDT of which 193 patients underwent surgical treatment and 254 patients received non-surgical treatment. Surgically treated patients were significantly younger, received less neoadjuvant therapy for the primary tumour, had less metastasis at diagnosis and more central recurrences. The 5-year OS was 51% for R0-resections and 34% for R1-resections. Although numbers with R2-resections were too small to implicate prognostic significance, there was no difference in 5-year OS between R2-resections and non-surgical treatment (10% vs. 4%, p = 0.282). In a subgroup analysis the OS of R2-patients was even poorer compared to optimal palliative treated patients with combined chemotherapy and radiotherapy (22 vs 29 months, p = 0.413). CONCLUSION: R2-resections do not result in a survival benefit compared to non-surgical treatment in this non-randomized series. Patients with a high chance on a R2-resection could be offered non-surgical treatment, without local resection.