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Background: The watch and wait (W&W) strategy is proposed for patients with locally advanced rectal cancer (LARC) achieving clinical complete response (cCR) after neoadjuvant radiotherapy. cCR is only in partial concordance with pathological complete response (pCR) due to persisting viable tumour cells. The aim was to investigate circulating-free-deoxyribonucleic-acid (cfDNA) as a biomarker for prediction of pCR., Materials and Methods: Patients treated with neoadjuvant radiotherapy for LARC, were included in a prospective biomarker study in Aarhus, Denmark from 2017 to 2020. Plasma cfDNA levels were analysed by a direct fluorescent assay (DFA). Surgical specimens were reviewed by pathologists to categorize response to cytotoxic therapy., Results: In total, 76 patients were included with plasma available at baseline (n = 70), mid therapy (n = 50), and end of therapy (n = 54). Higher cfDNA levels were observed in LARC patients compared with healthy subjects (p < 0.01). By ROC analysis (AUC: 0.87 (95% CI, 0.81-0.92)) the optimal cut-off was 0.71 ng/µL for differentiation between healthy subjects and LARC patients. Thirteen patients obtained pCR with a median cfDNA level of 0.57 ng/µL at end of therapy. Patients with cfDNA levels at end of therapy below the cut-off (p < 0.02) and 'cfDNA responders' with descending levels greater than the 75th percentile during therapy had a significantly higher chance of pCR (p < 0.01)., Conclusion: This hypothesis generating study indicates that low cfDNA levels at end of treatment or ´cfDNA responderś might be associated with pCR. Quantification of cfDNA by the rapid and feasible DFA analysis could potentially facilitate personalized follow-up as a complementary tool to identify candidates for a W&W strategy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Purpose: Neoadjuvant radiotherapy with or without chemotherapy decreases the risk of local recurrence after surgery for rectal cancer. Emerging data suggest that diabetic patients on metformin may have improved cancer outcome after radiotherapy. A single institutional pilot study was performed to determine if metformin given concurrently with long course chemoradiation (CRT) may improve pathologic complete response (pCR) in non-diabetic rectal cancer patients. The study was designed to construct a confidence interval (CI) for the pCR rate to determine the sample size for a phase 2 trial., Methods: Non-diabetic patients with biopsy confirmed rectal cancer deemed candidates for long course neoadjuvant CRT were invited to participate. Radiation consisted of 50.4 Gy in 28 daily fractions with concurrent daily capecitabine (825 mg/m 2 twice daily). Participants self-administered metformin (500 mg of twice daily) 2 weeks prior to, during and for 4 weeks after CRT., Results: A total of 16 patients were accrued. One patient withdrew from the study. Only grade 1 or 2 adverse events were observed. Three patients had a clinical complete response (cCR) and did not undergo surgery. Of the 12 patients who underwent surgery, there were two pCRs. For the combined pCR/cCR rate of 33% (95% CI 19-47%), a total of 85 patients will be required to yield a 95% CI with a 10% margin of error., Conclusions: Adding metformin to neoadjuvant CRT for rectal cancer does not appear to enhance toxicities. These results will be used to refine the design and conduct of a future phase 2 trial to determine whether adding metformin to CRT improves pCR/cCR rates., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Purpose: Anal squamous cell carcinomas (ASCC) are increasing in frequency across the developed world. The 3-year disease-free survival (DFS) in patients with locally-advanced disease is approximately 60% after primary radiochemotherapy (RCT). There is a strong rationale for combining immunotherapy with RCT in patients with ASCC due to its association with human papilloma virus (HPV) infection., Methods/design: RADIANCE is an investigator initiated, prospective, multicenter, randomized phase II trial testing the addition of Durvalumab, a PD-L1 immune checkpoint inhibitor, to standard RCT in 178 patients with locally advanced ASCC (T2 ≥ 4 cm Nany, cT3-4 and/or cN+). In the control arm, patients will be treated with standard mitomycin C (MMC)/5-fluorouracil (5-FU)-based RCT. Intensity-modulated radiotherapy (IMRT) will be applied as follows: PTV&#95;A (primary tumor) T1-T2 < 4 cm N+: 28 × 1.9 Gy = 53.2 Gy; or T2 ≥ 4 cm, T3-4 Nany: 31 × 1.9 Gy = 58.9 Gy; PTV&#95;N (involved node): 28 × 1.8 Gy = 50.4 Gy ; and PTV&#95;Elec (elective node): 28 × 1.43 Gy = 40.0 Gy over a period of 5,5-6 weeks. Concomitant chemotherapy will be administered using MMC with 5-FU during weeks 1 and 5 of radiotherapy (MMC 12 mg/m 2 , day 1 [maximum single dose 20 mg]; 5-FU 1000 mg/m 2 days 1-4 and 29-32). In the experimental arm, Durvalmab (1500 mg absolute dose, intravenously) will be combined with the same RCT as in the control arm. Immunotherapy with Durvalumab will start 14 days before initiation of standard RCT, administered every four weeks (q4w) thereafter for a total of twelve doses. The primary endpoint is disease-free survival (DFS) after 3 years., Discussion: As ASCC is considered an immunogenically "hot" tumor due to its association with HPV infection, the combination of RCT with Durvalumab may improve tumor control and long-term clinical outcome in this patient collective compared to RCT alone., Competing Interests: The trial is funded by the German Cancer Aid (Deutsche Krebshilfe, DKH; Funding Project Number: 70113615; PI: Emmanouil Fokas). The study drug and the pharmacy costs (Funding Project Number: ESR-17-13077) are provided by Astra Zeneca. The authors have no further conflicts of interest to declare., (© 2020 The Author(s).)