Debating Pros and Cons of Total Neoadjuvant Therapy in Rectal Cancer

Simple Summary Rectal cancers represent one third of all colorectal tumours. Patients diagnosed with localised colon cancer undergo surgery upfront, likely followed by adjuvant chemotherapy. Those diagnosed with localised rectal cancer, however, frequently benefit from neoadjuvant treatments with either radiotherapy or chemoradiotherapy before undergoing surgery. On the other hand, the benefit of adjuvant chemotherapy in this setting is more controversial. The main challenges in treating patients affected by rectal cancer encompass: decreasing the risks of local relapse and distant metastases, preserving the sphincter and minimising treatment-associated functional sequelae, and improving overall survival. Some of these fuelled the concept of total neoadjuvant therapy, namely giving all available treatments including radiotherapy and systemic chemotherapy before surgery. Here, we critically review the pros and cons of such a treatment strategy, but also discuss the biological rational to support neoadjuvant treatment intensification. Recently, two large, randomised phase III clinical trials of total neoadjuvant therapy (TNT) in locally advanced rectal cancer were published (RAPIDO and PRODIGE 23). These two trials compared short-course radiotherapy (SCRT) followed by chemotherapy with standard chemoradiotherapy (CRT) and chemotherapy followed by CRT with standard CRT, respectively. They showed improvement in some of the outcomes such as distant recurrence and pathological complete response (pCR). No improvement, however, was observed in local disease control or the de-escalation of surgical procedures. Although it seems lawful to integrate TNT within the treatment algorithm of localised stage II and III rectal cancer, many questions remain unanswered, including which are the optimal criteria to identify patients who are most likely to benefit from this intensive treatment. Instead of providing a sterile summary of trial results, we put these in perspective in a pros and cons manner. Moreover, we discuss some biological aspects of rectal cancer, which may provide some insights into the current decision-making process, and represent the basis for the future development of alternative, more effective treatment strategies.