Adaptive Boost Radiotherapy to Primary Lesions and Positive Nodes in the Neoadjuvant Treatment of Locally Advanced Rectal Cancer

Locally advanced rectal cancer (LARC), typically stage II (cT3-4/N0) or stage III (cT1-4/N1-3), requires multimodal treatment. Surgical resection alone is associated with a high rate of local recurrence. Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME), on the other hand, can better control local recurrence in LARC patients. However, the overall pathological complete response (pCR) rate and clinical complete response (cCR) rate are still low, and there is an inconsistency between them, Therefore, the preservation of the anus is still a challenge. Optimizing neoadjuvant treatment strategies, including strategies such as increasing concurrent chemotherapy and increasing the dose of radiotherapy, is essential to improve tumor regression and anal preservation.

Radiotherapy is an important treatment for controlling local recurrence and downstaging LARC. A common cause of cancer recurrence in rectal cancer is that tumor cells metastasise nearby positive lymph nodes, such as the lateral pelvic lymph nodes These sites can serve as refuges where the cancer can regroup and either recur at the original site or spread to other areas. Various studies have also investigated the role of radiotherapy dose escalation in promoting tumor regression. Seldom have these studies examined dose escalation to both the primary lesions and positive lymph nodes. One of the major limiting factors is the tradeoff between destruction of the cancer itself and collateral damage to the neighboring healthy tissues. However, recent advances in the field have made great strides in overcoming this obstacle. Adaptive radiation therapy (ART), including magnetic resonance (MR)-guided, cone beam computed tomography (CBCT)-guided, and fan beam computed tomography (FBCT)-guided, allows direct imaging of the target and organs at risk (OAR), combined with optimization of the treatment plan for anatomical changes, to deliver high-quality dose escalation regimens to improve treatment response while protecting OAR such as the bladder, femoral heads, and small bowel.

We hypothesize that by implementing simultaneous integrated boost (SIB) or sequential boost (SB) radiotherapy to both the primary lesions and positive lymph nodes based on ART, we can improve the cCR and pCR rates without increasing surgical difficulty, while maintaining tolerable safety.

Against the above background, this study aims to conduct a multicenter, randomized, controlled phase III trial to evaluate the efficacy and safety of SIB or SB radiotherapy to the primary lesions and positive lymph nodes based on MR or CBCT or FBCT-guided ART in the neoadjuvant treatment of LARC. Eligible patients will be randomized 1:1 into experimental and control groups, both of which will undergo long course concurrent chemoradiotherapy (LCCRT), consolidation chemotherapy and TME surgery. During LCCRT, the experimental group will receive SIB or SB dose escalation based on MR or CBCT or FBCT-guided ART, while the control group will receive conventional dose without ART.