The Multimodal Management of Locally Advanced Rectal Cancer: Making Sense of the New Data

Abstract

In the past 40 years, the treatment of locally advanced rectal cancer has evolved with the addition of radiotherapy or chemoradiotherapy and providing (neo)adjuvant systemic chemotherapy to major surgery. However, recent trends have focused on improving our ability to risk-stratify patients and tailoring treatment to achieve the best oncologic outcome while limiting the impact on long-term quality of life. Therefore, there has been increasing interest in pursuing a watch-and-wait approach to achieve organ preservation. Several retro- and prospective studies suggest safety of the watch-and-wait approach, though it is still considered controversial due to limited clinical evidence, concerns about tumor regrowth, and subsequent distant progression. To further reduce treatment, MRI risk stratification, together with patient characteristics and patient preferences, can guide personalized treatment and reserve radiation and chemotherapy for a select patient population. Ultimately, improved options for reassessment during neoadjuvant treatment may allow for more adaptive therapy options based on treatment response. This article provides an overview of some major developments in the multimodal treatment of locally advanced rectal cancer. It reviews some relevant, controversial issues of the watch-and-wait approach and opportunities to personally tailor and reduce treatment. It also reviews the overall neoadjuvant treatment, including total neoadjuvant therapy trials, and how to best optimize for a potential complete response. Finally, it provides an algorithm as an example of how such a personalized, tailored, adaptive, and reduced treatment could look like in the future.

Evolution of therapy for locally advanced rectal cancer

“…Extramural venous invasion (EMVI) is tumor extension into veins beyond the muscularis propria and has been associated with poor prognosis. This finding on MRI is associated with local and distant recurrence 1–9 15 …”

“…This finding on MRI is associated with local and distant recurrence. [1][2][3][4][5][6][7][8][9] One study showed 85% agreement between MRIdetected EMVI and that determined by surgical pathology. 15 Nodal disease is differentiated by locoregional node (localized disease) and nonlocoregional node (metastatic disease) involvement.…”

“…In terms of stage at diagnosis, 37.2% of cases are diagnosed as localized, 34.8% are regionally spread, 19.6% with distant spread, and 8.5% are unstaged 5 . Locally advanced rectal cancer (LARC) is defined as stage T3−T4 (the tumor has invaded the mesorectal fat or adjacent organs, respectively) or tumors with spread to local lymph nodes 1,7,8 . Over recent years there have been advancements in both the medical and surgical management of LARC resulting in improved prognosis and survival for patients with rectal cancer.…”

Determining the optimal radiation‐surgery interval (RSI) for oncologic proctectomy following radiotherapy for rectal adenocarcinoma

“…Although various forms and courses of radiotherapy have been employed to treat rectal cancer for over 50 years, characterizing the optimal total dose, treatment course, and subsequent timing to oncological proctectomy remains contentious 7,13 . Moreover, recently popularized “total” neoadjuvant chemoradiotherapy (TNT) and nonoperative “watch and wait” (W&W) protocols add more variables to a complex and partially defined equation and often add substantial time to the interval between completing radiotherapy and surgical resection 5,14–17 …”

“…7,13 Moreover, recently popularized "total" neoadjuvant chemoradiotherapy (TNT) and nonoperative "watch and wait" (W&W) protocols add more variables to a complex and partially defined equation and often add substantial time to the interval between completing radiotherapy and surgical resection. 5,[14][15][16][17] Altering the radiation-surgery interval (RSI) offers a series of hypothetical trade-offs for patients requiring proctectomy following radiation. Since the tumoricidal effects of radiation increase over time from exposure, the rates of partial and complete tumor regression improve with longer RSI, which likely impart oncologic benefit.…”