Until recently, the standard of care for locally advanced rectal cancer (LARC) consisted of neoadjuvant chemoradiotherapy, followed by surgery according to the total mesorectal excision principles. This strategy has decreased the rates of local recurrences below 10% at 5 years. To improve quality of life, interest in organ preservation has increased, even in patients with locally advanced disease.
Unfortunately, distant recurrences still remain a problem, with 5-year disease free survival rates of about 65% for locally advanced rectal cancer patients. The beneficial effect of postoperative adjuvant chemotherapy in rectal cancer is limited, especially after neoadjuvant (chemo)radiotherapy (CRT). One possible explanation is the poor compliance to chemotherapy after major surgery. In addition, the long interval between diagnosis and start of postoperative chemotherapy may facilitate outgrowth of micrometastases. Introducing chemotherapy before surgery, may therefore improve compliance and efficacy. Chemotherapy in a total neoadjuvant treatment (TNT) regimen can be given either as induction or as consolidation chemotherapy. In the last decade, several large, randomized trials have been performed in order to prove the beneficial effect of TNT. The Polish, STELLAR and RAPIDO trial evaluated regimens with short course RT (5x5 Gy) combined with consolidation chemotherapy and compared this with standard CRT with or without adjuvant chemotherapy1–3. In contrast, the PRODIGE 23 trial compared CRT combined with consolidation chemotherapy with standard CRT followed by adjuvant chemotherapy 4. Furthermore, the CAO/ARO/AIO-12 and OPRA study evaluated the difference between induction and consolidation chemotherapy in combination with CRT5,6.
In general, it can be concluded that TNT appears to improve disease free survival (DFS) in some studies (RAPIDO, PRODIGE 23), but not in others (STELLAR, Polish study) when compared to standard CRT. Overall survival (OS) benefit was not seen in any of these studies. The comparison between induction and consolidation chemotherapy did not reveal a difference in DFS or OS.
However, all studies comparing TNT with standard chemoradiotherapy demonstrated a significant increase in the number of patients that achieved a pathological complete response (pCR). This was confirmed in a recent meta-analysis7 and may open a window of opportunity for organ preservation in this locally advanced patient group. Additionally, consolidation chemotherapy after CRT seems more effective in achieving a pCR than induction chemotherapy before CRT.
Despite these results, the optimal treatment strategy is still not clear. All above mentioned trials used different chemotherapy regimens, with variation in the number of courses as well as in the choice for doublet or triplet therapy. Also, the interval from start of treatment to evaluation varied in the different trials, hampering a firm conclusion about the best strategy.
Given that no improvement in overall survival is observed in any of the trials, one has to be cautious about the increase in toxicity that is unavoidable with intensified treatment. The optimal neoadjuvant chemotherapy should therefore be balanced between efficacy and toxicity. Adequate patient selection is a prerequisite in this neoadjuvant setting to avoid unneccessary overtreatment and toxicity. Further insight in optimal strategy, patient selection and toxicity profiles will be provided during this talk.
Referrences
1. Bujko, K. et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer. Ann. Oncol. 27, 834–842 (2016).
2. Bahadoer, R. R. 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). Lancet Oncol. 22, 29–42 (2021).
3. Jin, J. et al. Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR). J. Clin. Oncol. 40, 1681–1692 (2022).
4. Conroy, T. et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23). Lancet Oncol. 22, 702–715 (2021).
5. Fokas, E. et al. Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12. J. Clin. Oncol. JCO.(2019).
6. Garcia-Aguilar, J. et al. Organ Preservation in Patients with Rectal Adenocarcinoma Treated with Total Neoadjuvant Therapy. J. Clin. Oncol. 18, (2022).
7. Zhang, X., Ma, S., Guo, Y., Luo, Y. & Li, L. Total neoadjuvant therapy versus standard therapy in locally advanced rectal cancer: A systematic review and meta-analysis of 15 trials. PLoS One 17, e0276599 (2022).