Efficacy and Toxicity of Total Neoadjuvant Sandwich Treatment Via Short Course Radiotherapy in the Treatment of Stage II and III Rectal Cancer Patients

Rectal cancer is a common malignancy that often requires multimodal treatment approaches for optimal outcomes. Neoadjuvant chemoradiotherapy is a standard of care for stage II-III rectal cancer, with total neoadjuvant treatment (TNT) being an emerging strategy. Long-course chemoradiotherapy (CRT) and short-course radiotherapy (SCRT) are both commonly used as neoadjuvant treatments for stage II-III rectal cancer. SCRT consists of 5 fractions of 5 Gy followed by surgery, which can be performed 1 to 8 weeks later [1-3]. Studies have shown that both approaches have similar survival rates, toxicity levels, and patient-reported outcomes [4-6].

The Uppsala trial was the starting point for the acceptance of preoperative SCRT [7], with the Stockholm I trial running in parallel [8]. The subsequent Swedish Rectal Cancer Trial, which randomized patients between surgery alone and preoperative SCRT, showed not only improved local control but also a survival benefit [9]. Although criticism was raised regarding the quality of surgery performed in these trials, the Dutch TME trial confirmed that preoperative SCRT improved local control, with certain subgroups showing a survival benefit [10,11]. Randomized data also suggest that SCRT should be preferred in resectable rectal cancer, as it leads to decreased short-term toxicity and no differences in long-term oncologic outcomes and late toxicity compared to preoperative CRT [12].

The risk of developing metachronous metastases in intermediate and locally advanced rectal cancer is high (25-65%), and systemic chemotherapy aims to treat the occult or micrometastatic disease that may later appear as distant metastases [13-15]. However, there are at least two arguments against postoperative delivery of chemotherapy. Firstly, rectal cancer surgery is associated with a substantial risk of postoperative complications that may prevent patients from tolerating postoperative chemotherapy [16,17]. Secondly, in the early stages of the disease when microscopic dissemination is limited, systemic chemotherapy would theoretically be expected to be most effective. Additionally, surgery, particularly if extensive, may accelerate tumor growth [18,19].

Recent studies have shown promising results with a strategy of delivering preoperative SCRT followed by delayed surgery [20-22]. Moreover, (SCRT)-including TNT strategy was investigated in several large trials. A Dutch phase II trial has reported high response rates and radical resection in patients with resectable metastatic rectal cancer who received SCRT followed by preoperative chemotherapy including bevacizumab [23]. The Polish II study included patients with locally advanced rectal cancer and compared preoperative SCRT followed by chemotherapy with CRT. They reported decreased acute toxicities and better overall survival (OS) [24]. Additionally the RAPIDO trial has concluded that SCRT followed by preoperative chemotherapy showed lower risk of disease related treatment failure and comparable toxicity profile when compared with preoperative CRT [25].

The above mentioned factors highlight the need for effective neoadjuvant treatment strategies that incorporate systemic chemotherapy and minimize the risk of postoperative complications. Two trials have explored the use of TNT using CRT where chemotherapy is delivered before and after radiotherapy (via a sandwich technique), one trial offered adjuvant chemotherapy as well. Both trials showed that neoadjuvant CRT based sandwich technique is well tolerated and highly effective in terms of PCR rate [26-27].

The timing of chemotherapy delivery remains a topic of debate, with concerns over postoperative complications. Both SCRT and CRT have been shown to have similar efficacy and safety profiles, SCRT has gained acceptance as a preferred option due to its decreased short-term toxicity and similar long-term outcomes. Moreover access to radiotherapy treatment in some developing countries can be limited, leading to delays in treatment initiation [28]. In this setting a TNT strategy utilizing systemic chemotherapy delivered before and after SCRT (known as a "sandwich" treatment) could provide equivalent outcomes while avoiding delays in treatment initiation and being more cost-effective compared to a CRT-based TNT approach.

The primary end point is to assess the rate of pathological complete response (pCR) after total mesorectal excision (TME). The secondary end points are to explore radiotherapy-related toxicities, post-operative complications and median disease free survival of systemic chemotherapy delivered before and after short course radiotherapy (SCRT) according to a "sandwich" technique.