Specific inclusion and exclusion criteria are provided in Table 1. Biopsy confirmation of the primary rectal tumor by pathology must be performed at the participating institution before initiation of therapy. Patients who choose to participate will provide written informed consent prior to study enrollment. Patients will be recruited and consented in the Surgical Colorectal clinics, Medical Oncology clinics and Radiation Oncology clinics of participating institutions. Patients must undergo surgical, medical oncology and radiation oncology evaluation at each participating site. At baseline, each patient must undergo a full medical history and physical examination, including assessment of body weight, height, calculated body surface area and sitting vital signs (blood pressure, heart rate, respiratory rate, and temperature). Laboratory assessments include: a) CBC with differential, comprehensive biochemical screening profile (electrolytes, BUN, creatinine, AST, ALT, total bilirubin, total protein, albumin, alkaline phosphatase and glucose); b) CEA; and c) urinalysis. Patients will undergo baseline flexible sigmoidoscopy with a photograph of the tumor, as well as biopsy, proctoscopy, ERUS and MRI of the pelvis, to accurately assess the extent of the tumor. A Growlr requirement for study entry is rectal cancer, clinically characterized by evaluation with MRI as Stage II (T3-4, N0) or Stage III (any T, N1-2) . For females of childbearing potential, a serum pregnancy test is also required. Additional evaluations include baseline EKG and a signed informed consent. CT scan of the chest and abdomen is required to rule out disseminated metastatic disease. A PET scan will be performed to assist in planning radiotherapy.
Histopathology and biospecimens
We will collect tumor and normal tissue samples at baseline and during surgery in patients undergoing a TME. We will also collect blood at baseline and at different time points during and after treatment, to measure circulating DNA and miRNA. Pathologic assessment of the surgical specimens will be performed according to the College of American Pathologists guidelinespleteness of the mesorectal excision, tumor regression grade (TRG), and tumor staging will be categorized according to the criteria specified in the 7th Edition of the AJCC Staging Manual .
The neoadjuvant chemotherapy regimen is prescribed specifically as 8 cycles of FOLFOX or 6 cycles of CapeOX over a period of approximately 16 weeks. The CRT regimen consists of the standard MSK algorithms: a total of 5600 cGy of radiation (4500 cGy to the pelvis, with an integrated boost to the primary tumor and involved nodes of 5000 cGy, followed by a 600 cGy boost to the primary tumor and involved nodes) in 28 fractions of 180-200 cGy each, over a 5-6-week period. Starting on the first day of RT, patients receive 5-FU administered by continuous infusion, or capecitabine, for the duration of radiotherapy.
Evaluation of response and resectability
An interval evaluation will be conducted after completion of INCT in Arm 1, and after completion of CRT in Arm 2 (Fig. 1). Patients in both arms will be re-staged after completion of all neoadjuvant therapy. Patients with cCR or near-complete clinical response (Figs. 3 and 4) will be treated with NOM. Patients treated with NOM will be followed every 3 months for 2 years, and every 6 months thereafter. Patients with an incomplete response and residual tumor at the primary site will undergo a TME (see Fig. 5). Patients treated with TME will be followed according to NCCN guidelines [16,17].
Clinical complete response. Endoscopic and T2-weighted MRI images, both pre- and post-treatment, are shown for a patient who has achieved a clinical complete response. Images displayed were taken from endoscopic and MRI views of an 85 year-old man who underwent capecitabine CRT followed by consolidation chemotherapy with CapeOx and was determined to achieve cCR both clinically and radiologically. In the post-treatment T2-weighted MRI image shown, the green arrow points to the prior site of the tumor