Updates on rectal cancer treatment

There have been major shifts in rectal cancer treatment in the last few years. The old paradigm established by a German trial 20 years ago involved a sequence of chemoradiation, surgery and, if needed, adjuvant chemotherapy as standard of care. Now, many doctors are administering total neoadjuvant therapy (TNT), which moves chemotherapy to the neoadjuvant space in the appropriate patients. 

Benefits and risks of TNT

TNT offers several advantages:

• Targets micrometastases early
• Improves treatment adherence
• Reduces time with an ostomy
• Increases complete response rates and disease-free survival

Patients undergoing TNT can receive either:

• Doublet chemotherapy (FOLFOX or CAPEOX)
• Triplet chemotherapy (FOLFIRINOX, as studied in PRODIGE23)

They also have options regarding radiation and surgery:

• Short-course radiation (RAPIDO, POLISH II) vs. standard radiation
• Surgery vs. watch-and-wait approach (OPRA trial)

However, TNT has the risk of overtreating some patients since not all patients with locally advanced rectal cancer need chemotherapy after chemoradiation. Additionally, it is important to remember the limitations of MRI in staging some patients.

Key clinical trials

OPRA trial

The OPRA trial randomized patients with distal rectal cancer stage II and III into two different TNT regimens:

1. Induction chemotherapy with chemoradiation
2. Consolidation chemotherapy after chemoradiation

Patients with complete clinical responses were offered nonoperative management (watch and wait). Results showed impressive organ preservation rates at five years:

• 54% for consolidation chemotherapy
• 39% for induction chemotherapy

PROSPECT trial

This large study included patients who had clinical T2N+ and T3N-/+ rectal cancer who were candidates for chemoradiation and sphincter-sparing surgery. It compared:

1. Standard treatment: Chemoradiation, surgery and adjuvant chemotherapy (FOLFOX or CAPEOX)
2. Alternative approach: Three months of neoadjuvant FOLFOX, with surgery only for those showing at least a 20% response (otherwise, they received chemoradiation before surgery)

The results showed no difference in:

• Disease-free survival
• Overall survival
• Local recurrence at five years

Only 9% of patients required selective radiation after surgery, and overall quality of life was not different between the two arms.

Role of immunotherapy in MMR-deficient rectal cancer

About 5% of rectal cancers have mismatch repair (MMR) deficiency. Even though it is a very small patient population, it is an extremely important one to identify and it is the standard of care now to test for MMR in all rectal cancer patients.

A small 2022 trial treated MMR-deficient rectal cancer patients with six months of neoadjuvant anti-PD1 therapy (dostarlimab). Patients with complete clinical responses (based on radiologic, endoscopic, and rectal exam assessments) followed a nonoperative management strategy.

This trial suggests that immunotherapy alone may be enough for these patients. However, key questions remain, such as:

• Which immunotherapy drugs should be used?
• Should monotherapy or dual checkpoint inhibitors be preferred?
• How long should immunotherapy be given?

Balancing treatment efficacy and quality of life

So, there’s a lot to consider when balancing efficacy with morbidity when trying to help our patients have the best treatment plan, especially considering that the multimodality treatments have significant long-term bowel, bladder and sexual dysfunction side effects.

• Patients who want to avoid radiation (without T4 or N2 tumors and eligible for sphincter-sparing surgery) can receive FOLFOX with selective radiation. This improves sexual health, bowel function, and fertility without harming oncologic outcomes.
• Patients seeking nonoperative management or those with T4 tumors, threatened margins, or distal tumors can be treated with TNT using either doublet or triplet chemotherapy. This approach:
  • Increases pathologic complete response rates
  • Improves disease-free survival and reduces disease-related treatment failure
  • Enhances overall survival without reducing long-term quality of life

Future research

The JANUS rectal trial will compare different TNT regimens (doublet or triplet chemotherapy combined with long-course chemoradiation) followed by either surgery or observation. This study aims to clarify the optimal treatment approach.

Conclusion

Advances in rectal cancer treatment provide more options for patients. Whether prioritizing organ preservation, avoiding radiation, or achieving the best oncologic outcomes, individualized treatment planning is essential to balance efficacy with quality of life.