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Radiotherapy and Chemotherapy Before Total Mesorectal Excision for Locally Advanced Rectal Cancer: Comparison of Regimens


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As reported in The Lancet Oncology by Bahadoer et al, the phase III RAPIDO trial has shown improved 3-year disease-related treatment failure with preoperative short-course radiotherapy followed by chemotherapy and total mesorectal excision (TME) vs preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in patients with locally advanced rectal cancer.

Study Details

The open-label trial included 912 eligible newly diagnosed patients from sites in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the United States. Patients were randomly assigned between June 2011 and June 2016 to receive short-course radiotherapy followed by chemotherapy and TME (experimental group, n = 462) or preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy (standard of care group, n = 450). Patients had to have high-risk disease defined as at least one of following criteria: clinical tumor stage cT4a or cT4b, extramural vascular invasion, clinical nodal stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes.

Patients in the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX (capecitabine and oxaliplatin) on days 1–14 with a chemotherapy-free interval between days 15–21 or nine cycles of FOLFOX4 (oxaliplatin, leucovorin, fluorouracil) on days 1 and 2 with a chemotherapy-free interval between days 3­­–14 followed by TME; the choice of CAPOX or FOLFOX4 was left to physician’s discretion. Patients in the standard-of-care group received radiotherapy at (per physician discretion or hospital policy) 28 daily fractions (1.8 Gy up to 50.4 Gy) or 25 fractions (2.0 Gy up to 50.0 Gy) with concomitant twice-daily oral capecitabine, followed by TME and optional adjuvant chemotherapy (according to hospital policy) with 8 cycles of CAPOX or 12 cycles of FOLFOX4 (n = 187). The primary endpoint was 3-year disease-related treatment failure—defined as first occurrence of locoregional failure, distant metastasis, new primary colorectal tumor, or treatment-related death—in the intention-to-treat population.

Disease-Related Treatment Failure

KEY POINTS

  • Preoperative short-course radiotherapy followed by chemotherapy and TME was associated with reduced disease-related treatment failure vs preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy.
  • The 3-year cumulative incidence of disease-related treatment failure was 23.7% vs 30.4%.

Median follow-up was 4.6 years (interquartile range = 3.5–5.5 years). At 3 years after random assignment, the cumulative probability of disease-related treatment failure was 23.7% (95% confidence interval [CI] = 19.8%­–27.6%) in the experimental group vs 30.4% (95% CI = 26.1%–34.6%) in the standard-of-care group (hazard ratio [HR] = 0.75, 95% CI = 0.60–0.95, P = .019).

At 3 years, the cumulative probability of distant metastases was 20.0% (95% CI = 16.4%–23.7%) vs 26.8% (95% CI = 22.7%–0.9%; HR = 0.69, 95% CI = 0.54–0.90, P = .0048) and the cumulative probability of locoregional failure was 8.3% (95% CI = 5.8%–10.8%) vs 6.0% (95% CI = 3.8%–8.2%; HR = 1.42, 95% CI = 0.91–2.21, P = .12). A new primary colorectal tumor occurred in 2% vs 3% of patients.

Among evaluable patients, pathologic complete response was achieved in 120 (28%) of 423 patients in the experimental group vs 57 (14%) of 398 in the standard-of-care group (odds ratio = 2.37, 95% CI = 1.67–3.37, P < .0001). Overall survival at 3 years was 89.1% (95% CI = 86.3%–92.0%) vs 88.8% (95% CI = 85.9%–91.7%; HR = 0.92, 95% CI = 0.67–1.25, P = .59).

Adverse Events

The most commonly reported grade ≥ 3 adverse events during preoperative therapy were diarrhea in both groups (18% vs 9%), and neurologic toxicity during adjuvant chemotherapy in the standard-of-care group (9%). Serious adverse events occurred in 38% vs 34% of patients who did not receive adjuvant chemotherapy and in 34% of 187 patients who did receive adjuvant chemotherapy. Treatment-related deaths occurred in four patients in the experimental group (due to cardiac arrest and pulmonary embolism in one patient each and infectious complications in two) and in four patients in the standard-of-care group (due to pulmonary embolism, neutropenic sepsis, aspiration, and suicide in 1 patient each).

The investigators concluded, “The observed decreased 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 in high-risk locally advanced rectal cancer.”

Geke A.P. Hospers, MD, of the Department of Medical Oncology, University Medical Center Groningen, Netherlands, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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