Short Course Radiotherapy Followed By Chemotherapy Before Total Mesorectal Excision (TME) Versus Preoperative Chemoradiotherapy, TME, And Optional Adjuvant Chemotherapy And Locally Advanced Rectal Cancer (RAPIDO): A Randomized, Open Label, Phase 3 Trial

The purpose of the RAPIDO trial was to minimize the risk of locoregional recurrence and distant failure in high risk rectal cancer patients, by delivering both radiotherapy and chemotherapy in the preoperative setting versus the adjuvant setting.

Investigators designed an open label, randomized multicenter phase 3 controlled clinical trial across 54 centers in Europe in the United States.  Patients had to be at least age 18 with an ECOG of 0-1.  Biopsy-proven newly diagnosed primary locally advanced rectal adenocarcinoma with high risk features on pelvic MRI including at least one of the following: Enlarged lateral lymph nodes, clinical N2 disease, mesorectal fascia involvement, extramural vascular invasion and clinical stage T4a or T4b disease) were included.  Patients were randomized in a one-to-one fashion to the experimental group which was comprised of 5X5 Gy of RT over a maximum of 8 days followed by 6 cycles of CAPOX capecitabine 1,000 mg/m² twice daily for 14 days, oxaliplatin 130 mg/m² intravenously on day 1 and a chemotherapy free interval between days 15-21 or 9 cycles of FOLFOX4, oxaliplatin 85 mg/m², IV on day 1, leucovorin 200 mg/m² IV on day 1 and 2, bolus 5-FU 400 mg/m² IV and 5-FU 600 mg/m² IV on day 1 and 2 with a chemo free interval between days 3-14.  Radiotherapy and chemotherapy was followed by total mesorectal excision.  The choice of chemotherapy was at the physician’s discretion.  Patients who were randomized to the standard of care group received 28 daily fractions of 1.8 Gy up to 50.4 Gy for 25 fractions of 2.0 Gy up to 50Gy with concomitant twice daily oral capecitabine 825 mg/m² followed by total mesorectal excision and adjuvant chemotherapy with 8 cycles of CAOPX or 12 cycles of FOLFOX4.  3-year disease related treatment failure was the primary endpoint.

920 patients were enrolled and randomized between June 2011 and June 2016.  912 were eligible for examination, 462 in the treatment arm and 415 the standard of care arm.  The median follow-up was 4.6 years.  After 3 years from randomization, the cumulative probability of disease-related treatment failure was 23.7% in the experimental group versus 30.4% in the standard of care group.  This translated to a hazard ratio of 0.75, with a P-value of 0.019.  The most common grade 3 or 4 adverse event in the preoperative group was diarrhea, at 18% versus 9% in the standard of care group.  Serious adverse events occurred in 38% and 34% respectively.  There were an equal number of treatment-related deaths in each group, for patients respectively.

The authors concluded ” the observed decrease probability of disease related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting.  Therefore, the experimental treatment can be considered as a new standard of care and high risk locally advanced rectal cancer”