The invited discussant for the RAPIDO and PRODIGE 23 trials, Christopher Leigh Hallemeier, MD, Associate Professor of Radiation Oncology at the Mayo Clinic, Rochester, noted the standard approach to locally advanced rectal cancer has been, for the past 2 decades, a long course of chemoradiotherapy followed by total mesorectal excision and then adjuvant chemotherapy, usually FOLFOX. Many other strategies are being evaluated to improve outcomes.

Christopher Leigh Hallemeier, MD

Reflections on RAPIDO

The RAPIDO trial focused on a cohort of patients deemed at high risk of local recurrence and distant metastatic disease. The experimental arm involved short-course radiotherapy (25 Gy in 5 fractions) followed by consolidative chemotherapy and then total mesorectal excision. This approach yielded a significantly higher rate of pathologic complete response and a reduction in treatment failures and distant metastases, although overall survival and quality of life were similar to those with standard treatment.

“The question is, why do we see a reduction in distant metastases with no difference in overall survival?” Dr. Hallemeier asked. “Could it be we’re merely delaying distant metastases vs preventing them by more consistent use of systemic therapy sooner? Longer term follow-up will be needed to determine whether that’s the case.”

“Should we be concerned about a trend toward higher risk of loco­regional failure with the experimental arm in this trial?” he further asked. Dr. Hallemeier noted the recent Polish II trial, which had a similar randomization, also showed a numerically higher risk of local failure with short-course radiotherapy and consolidative chemotherapy compared with standard chemoradiotherapy.¹ Since locoregional failures continue to emerge over time, longer follow-up will be important.

Dr. Hallemeier agreed with the authors’ conclusion that short-course radiotherapy and consolidative chemotherapy represents a new standard of care, a stance further supported by the Polish II trial, which, with longer follow-up, showed this approach to be at least as effective as standard long-course chemoradiotherapy. Short-course radiotherapy is also supported by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines^®). “I should also point out that five fractions of radiotherapy is COVID-19–friendly, in that it reduces the number of visits to the health-care facility,” he added.

PRODIGE 23: ‘More Questions Than Answers’

The PRODIGE 23 trial investigated induction modified ­FOLFIRINOX as part of a total neoadjuvant therapy package. It showed a 92% compliance rate with this regimen and a reduction in grade 3 or 4 adverse hematologic toxicity and peripheral neuropathy. It also demonstrated the potential for higher rates of pathologic complete response, disease-free survival, and metastasis-free survival and a trend toward better overall survival. “But this trial provides more questions than answers,” maintained Dr. Hallemeier.

Mature overall survival data will help determine “whether we are preventing recurrences vs merely delaying them.” Could there be utility of using this intensified neoadjuvant regimen in subsets of patients at higher risk for locoregional or distant recurrence? Other questions pertain to the optimal sequencing of a neoadjuvant FOLFIRINOX regimen: before vs after radiotherapy? Will this approach facilitate nonoperative management? Could radiotherapy be eliminated in some patients? “These concepts are being tested in ongoing trials,” noted Dr. ­Hallemeier.

“For the treatment of rectal cancer, we seem to be moving away from a one-size-fits-all approach and moving toward a tailored or personalized approach, adjusting the available dials and switches in terms of radiotherapy, systemic therapy, and surgical intensity … depending on the clinical scenario to achieve the optimal outcome,” Dr. Hallemeier stated. “The holy grail would be to identify predictive markers to tell us which patients will respond to which treatment.” 

DISCLOSURE: Dr. Hallemeier reported no conflicts of interest.

REFERENCE

1. Ciseł B, Pietrzak L, Michalski W, et al: Long-course preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: Long-term results of the randomized Polish II study. Ann Oncol 30:1298-1303, 2019.