Author: By Laura Cowen, medwireNews Reporter
medwireNews: Individuals with newly diagnosed locally advanced rectal adenocarcinoma are less likely to experience treatment failure when given an experimental regimen of short-course radiotherapy followed by chemotherapy prior to surgery compared with standard care, phase III study data show.
“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”, write Geke Hospers, from University Medical Center Groningen in the Netherlands, and co-authors in The Lancet Oncology.
They add: “Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer.”
The international RAPIDO trial included 912 patients with newly diagnosed, locally advanced rectal adenocarcinoma that was classified as high risk on pelvic magnetic resonance imaging.
Of these, 462 patients were randomly assigned to the experimental treatment group, which involved short-course radiotherapy (five fractions of 5.0 Gy over a maximum of 8 days) followed by physician’s choice of six cycles of CAPOX chemotherapy (99% of patients) or nine cycles of FOLFOX4 (1%) then total mesorectal excision. The median time between conclusion of radiotherapy and start of chemotherapy was 14 days.
The remaining 450 patients received standard care with physician’s choice of 28 daily fractions of 1.8 Gy up to 50.4 Gy or 25 fractions of 2.0 Gy up to 50.0 Gy, with concomitant twice-daily oral capecitabine 825 mg/m2 followed by total mesorectal excision. This was given along with adjuvant chemotherapy consisting of eight cycles of CAPOX or 12 cycles of FOLFOX4, where appropriate.
The researchers report that, at 3 years, individuals who received the experimental treatment had a significant 25% lower risk of disease-related treatment failure than those who received standard care, with cumulative rates of 23.7% and 30.4%, respectively. Treatment failure was defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death.
Geke Hospers and team note that most disease-related treatment failures were due to distant metastases; the rates at 3 years were 20.0% in the experimental arm and 26.8% in the standard care arm, corresponding to a significant 31% reduction in risk.
There was no significant difference between the two groups in locoregional failure rates at 3 years, but the rate was numerically higher with the experimental treatment (8.3 vs 6.0%), which the investigators suggest could be due to “the presence of a small proportion of nonresponding tumours that might actually progress during preoperative treatment.”
“Hence, early response imaging could be advocated, enabling alterations in therapeutic approach”, they add.
The pathologic complete response rate was a significant 2.37 times higher with the experimental treatment (28.4 vs 14.3%) but there was no difference in overall survival between the two groups at 3 years (89.1 vs 88.8%).
Almost half (48%) of patients in the experimental treatment group experienced a grade 3 or higher adverse event (AE) before surgery, most commonly diarrhoea (18%), compared with a quarter in the standard care group. In addition, 34% of the 187 patients who received adjuvant therapy experienced a grade 3 or higher AE, most commonly neurological toxicity (9%).
Geke Hospers et al conclude that their data, alongside findings from the PRODIGE 23 trial, “add strong evidence to support the proposal that total neoadjuvant therapy should replace the current standard treatment since it decreases the risk of systemic relapse and could potentially improve overall survival.”
In an accompanying comment, Avanish Saklani, from Homi Bhabha National Institute in Mumbai, India, and co-authors agree. They say: “The landscape of total neoadjuvant therapy for locally advanced rectal cancers looks promising, and the RAPIDO protocol is likely to be the new standard of care, especially in resource-limited settings and the current climate of the COVID-19 pandemic, when fewer visits to health-care centres are desirable.”
They add: “This treatment protocol is also likely to increase the number of patients being offered organ preservation with the watch and wait policy due to the increase in pathological complete response and likely subsequent increase in clinical complete response rate.”
- Bahadoer RR, Dijkstra EA, van Etten B, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol 2020; 7 December 2020. doi:10.1016/ S1470-2045(20)30555-6
- Saklani A, Pandey D, Patel S. RAPIDO protocol: a promising approach for high-risk locally advanced rectal cancers. Lancet Oncol 2020; 7 December 2020. doi:10.1016/ S1470-2045(20)30643-4
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