Traugott, Amber

BACKGROUND: Obstructed defecation syndrome and posterior compartment (rectal) prolapse significantly impact patients’ quality of life. Pelvic floor physical therapy is a critical part of multidisciplinary management for these conditions, yet there is little guidance or standardization to guide providers’ referral practices, diagnostic approaches, or treatment. OBJECTIVE: To develop multidisciplinary consensus-based recommendations for incorporating pelvic floor physical therapy into the treatment of obstructed defecation syndrome and posterior compartment prolapse. DATA SOURCES: MEDLINE, PubMed, Embase, and the Cochrane Database of Systematic Reviews were searched for English-language studies on pelvic floor physical therapy, obstructed defecation, diagnostic criteria, imaging, and pelvic organ prolapse. STUDY SELECTION: Studies identified in the literature search were reviewed by multidisciplinary expert subgroups, who formulated draft statements based on the available evidence. INTERVENTION: Consensus meetings were conducted and included experts from colorectal surgery, urogynecology, physical therapy, gastroenterology, radiology, and urology. Statements were evaluated via structured discussions and voting processes. Those reaching more than 70% consensus were adopted for inclusion. Statements underwent final review and editing by the leadership of the American Society of Colon and Rectal Surgeons and the International Urogynecological Association. MAIN OUTCOME MEASURES: Consensus statements addressed referral criteria, diagnostic evaluations, therapy protocols, timing, coordination with surgery, and management of anatomical abnormalities. RESULTS: Fifteen statements reached consensus. Key recommendations included prompt referral to pelvic floor physical therapy for patients without contraindications, individualized therapy based on appropriate diagnostic evaluation and patient goals, timing of pelvic floor physical therapy relative to surgery, and trauma-informed patient care. LIMITATIONS: Recommendations primarily reflect expert consensus due to limited high-quality evidence. Variability in practitioner expertise and geographic access to trained therapists are barriers to consistent implementation. CONCLUSIONS: These recommendations provide structured guidance for integrating pelvic floor physical therapy into the management of obstructed defecation syndrome and rectal prolapse. Additional research and standardized training are essential to optimize patient outcomes.

3612 Background: The RAS/RAF/MEK signal transduction pathway is critical to the development of colorectal cancer, and tumors harboring KRAS, NRAS, and BRAF mutations were shown to be resistant to radiation. Thus, we conducted a phase I study of trametinib, a potent MEK1/2 inhibitor, in combination with CRT in patients with LARC. Methods: Phase I trial for patients with Stage II/III rectal cancers with a 3+3 design, and an expansion cohort of 12 patients at the maximum tolerated dose (MTD). Trametinib is given orally at 3 dose levels: 0.5mg, 1mg, and 2mg (Mon-Fri). CRT regimen is infusional 5-flourouracil (5FU) 225mg/m2/day (Mon-Fri) and daily fractions of 1.8 Gy (total 50.4Gy). There is a 5-day trametinib lead-in followed by trametinib and CRT. Six to 10 weeks after completion of CRT, patients then proceed to their surgery and adjuvant therapy. The primary endpoint is to identify the MTD and recommended phase 2 dose of trametinib with CRT. Immunohistochemistry staining for phosphorylated –ERK (pERK) and genomic profiling is performed on the tumor samples. Results: Enrollment is complete at all dose levels with18 patients, and 15 patients evaluable for toxicity and response as of Feb 6. One dose-limiting toxicity of diarrhea was observed at the 2mg dose. Grade 3 and most common toxicities are shown in Table 1. No grade 4/5 toxicities have been observed. At 2mg dose level, 3/9 (33%) patients had pathological complete response (pCR) and 2/9 (22%) had a near pCR. Correlative studies confirm decrease in pERK levels with increasing doses of trametinib. Correlation of genomic mutational status with toxicity, response, and outcomes is being analyzed. Conclusions: The combination of trametinib with 5FU CRT is tolerable with promising preliminary activity. Final results will be presented at the meeting. Toxicities. Clinical trial information: NCT01740648. [Table: see text]

685 Background: RAS/BRAF mutations constitutively activate the MAPK pathway in colorectal cancer, and may promote resistance to CRT. We propose that trametinib, a MEK1/2 inhibitor, in combination with 5FU CRT for patients with LARC will improve outcome. Methods: Phase I study with standard 3+3 design in patients with Stage II/III rectal cancer with 3 dose levels of trametinib: 0.5, 1, and 2mg daily with 5FU 225mg/m2/day and 50.4 Gy. Trametinib was given over a 5-day lead-in and continued through the course of CRT. Patients undergo surgery 6-10 weeks after the completion of CRT. An expansion cohort at the maximum tolerated dose (MTD) with 12 patients is ongoing. Tumor tissue is collected prior to therapy, at day 4/5 of trametinib, and at surgery. The primary endpoint is to determine the MTD of trametinib with CRT. Results: 15 patients (10 males, 5 females) have been enrolled and 14 patients are evaluable for toxicities to date. Median age is 53 years (range 35-74). Patients have completed enrollment to all dose levels, with 1 dose-limiting toxicity of diarrhea attributed to 5FU CRT. No grade 4/5 toxicities, and toxicities are shown in the table. Generalized skin rash led to trametinib discontinuation after 2 weeks of therapy for 1 patient, and was held 3 days for 2 patients. At the trametinib dose level of 2mg, 3 out of 7 (43%) patients had a pathological complete response and the average neoadjuvant rectal (NAR) score is 8.1. Tumor RAS/BRAF mutation status is determined. Analysis of tumor tissue shows dose-dependent decrease in phosphorylated-ERK1/2 with increasing doses of trametinib. Conclusions: Initial evaluation shows that the combination of trametinib with 5FU CRT is tolerable and effective, and warrants further investigation in LARC. Clinical trial information: NCT01740648. [Table: see text]