What are the indications for adjuvant radiotherapy (RT) in pancreatic cancer (ca pancreas)?

Indications for Adjuvant Radiotherapy in Pancreatic Cancer

Adjuvant radiotherapy (RT) in pancreatic cancer should be reserved primarily for patients with high-risk features including R1 resection (positive microscopic margins) and/or lymph node positive disease, following completion of 4-6 months of systemic adjuvant chemotherapy. 1

Primary Indications for Adjuvant RT

• Patients with R1 resection (microscopic positive margins) may benefit from adjuvant chemoradiotherapy after completion of systemic chemotherapy 2, 1
• Patients with positive lymph nodes show improved survival with adjuvant RT compared to those with negative nodes 2, 1
• Patients with lymphovascular invasion may obtain survival benefits from adjuvant chemoradiotherapy 3

Evidence Supporting RT in High-Risk Subgroups

• A meta-analysis of 4 randomized controlled trials found increased survival benefit with adjuvant chemoradiotherapy in the R1 subset (HR for death, 0.72) compared to the R0 subset (HR for death, 1.19) 2
• A large multi-institutional study of 747 patients with resected pancreatic cancer demonstrated significant improvement in survival with chemoradiotherapy only in patients with lymph node-positive disease 2
• A retrospective review from Johns Hopkins Hospital comparing outcomes of 94 patients who underwent distal pancreatectomy showed that patients with positive lymph nodes derived greater benefit from adjuvant chemoradiotherapy than those with negative nodes 2

Timing and Sequencing of RT

• When chemoradiotherapy is considered as adjuvant therapy, it should be administered after an adequate course (up to 4 months) of systemic chemotherapy 2
• This sequencing approach is supported by emerging data in locally advanced disease suggesting that a period of chemotherapy followed by consolidated chemoradiotherapy may be preferable to up-front chemoradiotherapy 2
• Treatment should ideally be initiated within 4-8 weeks after surgery, assuming adequate recovery 2, 1

RT Technical Considerations

• When postoperative RT is given, it should be administered at a dose of 45-54 Gy (1.8-2.0 Gy/day) 2
• CT simulation and 3-dimensional treatment planning are strongly encouraged 2
• Treatment volumes should be based on preoperative CT scans and surgical clips (when placed), targeting the location of the primary tumor and regional lymph nodes 2
• RT is typically given in combination with concurrent fluoropyrimidine-based chemotherapy (continuous infusion 5-FU or capecitabine) 2

Limitations and Controversies

• Most data comparing chemotherapy versus chemoradiotherapy do not generally show a survival advantage for the addition of RT 2, 4
• The ESPAC-1 trial suggested that the addition of RT to adjuvant 5-FU chemotherapy may be unnecessary and potentially harmful (OS of 13.9 months for CRT vs. 21.6 months for chemotherapy alone) 2
• However, this trial has been criticized for lack of attention to quality control for RT, among other concerns 2
• The RTOG 97-04 study, which used daily fractionated RT with prospective quality assurance, showed a non-statistically significant increase in OS in the gemcitabine arm compared with the 5-FU arm for pancreatic head tumors 2

Practical Algorithm for Adjuvant RT Decision-Making

1. Complete surgical resection of pancreatic cancer 1
2. Assess pathological risk factors:
   • Margin status (R0 vs. R1)
   • Lymph node status (positive vs. negative)
   • Presence of lymphovascular invasion 3
3. Initiate adjuvant chemotherapy within 8 weeks after resection 1
4. Complete 4-6 months of adjuvant chemotherapy 1
5. Consider adding chemoradiotherapy for patients with:
   • R1 resection
   • Positive lymph nodes (especially ≥5 positive nodes) 5
   • Lymphovascular invasion 3
6. For patients receiving RT, use 45-54 Gy with concurrent fluoropyrimidine-based chemotherapy 2

Conclusion

While the role of adjuvant RT in pancreatic cancer remains somewhat controversial, current evidence suggests it may provide benefit in specific high-risk subgroups, particularly patients with R1 resections and/or positive lymph nodes. The ongoing ADJUPANC trial (NCT06427447) aims to provide more definitive evidence regarding the role of adjuvant chemoradiotherapy versus chemotherapy alone in these high-risk patients 3.