Short-course radiation followed by mFOLFOX-6 plus avelumab for locally-advanced rectal adenocarcinoma.
BACKGROUND
Current standard practice for locally advanced rectal cancer (LARC) entails a multidisciplinary approach that includes preoperative chemoradiotherapy, followed by total mesorectal excision, and then adjuvant chemotherapy. The latter has been accompanied by low compliance rates and no survival benefit in phase III randomized trials, so the strategy of administering neoadjuvant, rather than adjuvant, chemotherapy has been adapted by many trials, with improvement in pathologic complete response. Induction chemotherapy with oxaliplatin has been shown to have increased efficacy in rectal cancer, while short-course radiation therapy with consolidation chemotherapy increased short-term overall survival rate and decreased toxicity levels, making it cheaper and more convenient than long-course radiation therapy. This led to recognition of total neoadjuvant therapy as a valid treatment approach in many guidelines despite limited available survival data. With the upregulation (PDL-1) expression in rectal tumors after radiotherapy and the increased use of in malignant melanoma, the novel approach of combining immunotherapy with chemotherapy after radiation may have a role in further increasing pCR and improving overall outcomes in rectal cancer.


METHODS
The study is an open label single arm multi- center phase II trial. Forty-four recruited LARC patients will receive 5Gy x 5fractions of SCRT, followed by 6 cycles of mFOLFOX-6 plus avelumab, before TME is performed. The hypothesis is that the addition of avelumab to mFOLFOX-6, administered following SCRT, will improve pCR and overall outcomes. The primary outcome measure is the proportion of patients who achieve a pCR, defined as no viable tumor cells on the excised specimen. Secondary objectives are to evaluate 3-year progression-free survival, tumor response to treatment (tumor regression grades 0 & 1), density of tumor-infiltrating lymphocytes, correlation of baseline Immunoscore with pCR rates and changes in PD-L1 expression.


DISCUSSION
Recent studies show an increase in PD-L1 expression and density of CD8+ TILs after CRT in rectal cancer patients, implying a potential role for combinatory strategies using PD-L1- and programmed-death- 1 inhibiting drugs. We aim through this study to evaluate pCR following SCRT, followed by mFOLFOX-6 with avelumab, and then TME procedure in patients with LARC.


TRIAL REGISTRATION
Trial Registration Number and Date of Registration: ClinicalTrials.gov NCT03503630, April 20, 2018.
['Shamseddine|Ali|A|', 'Zeidan|Youssef H|YH|', 'Kreidieh|Malek|M|', 'Khalifeh|Ibrahim|I|', 'Turfa|Rim|R|', 'Kattan|Joseph|J|', 'Mukherji|Deborah|D|', 'Temraz|Sally|S|', 'Alqasem|Kholoud|K|', 'Amarin|Rula|R|', 'Al Awabdeh|Tala|T|', 'Deeba|Samer|S|', 'Jamali|Faek|F|', 'Mohamad|Issa|I|', 'Elkhaldi|Mousa|M|', 'Daoud|Faiez|F|', 'Al Masri|Mahmoud|M|', 'Dabous|Ali|A|', 'Hushki|Ahmad|A|', 'Jaber|Omar|O|', 'Khoury|Clement|C|', 'El Husseini|Ziad|Z|', 'Charafeddine|Maya|M|', 'Al Darazi|Monita|M|', 'Geara|Fady|F|']
D000230:Adenocarcinoma D000293:Adolescent D000328:Adult D000368:Aged D000369:Aged, 80 and over D061067:Antibodies, Monoclonal, Humanized D000074322:Antineoplastic Agents, Immunological D000971:Antineoplastic Combined Chemotherapy Protocols D017322:Clinical Trials, Phase II as Topic D005260:Female D005472:Fluorouracil D005500:Follow-Up Studies D006801:Humans D007167:Immunotherapy D002955:Leucovorin D008297:Male D008875:Middle Aged D015337:Multicenter Studies as Topic D020360:Neoadjuvant Therapy D009944:Organoplatinum Compounds D000077982:Progression-Free Survival D011446:Prospective Studies D012004:Rectal Neoplasms D055815:Young Adult
Rectal cancer Chemotherapy Neoadjuvant Radiotherapy Immunotherapy