Overview

As discussed in the previous chapter detailing the evolution of neoadjuvant therapy in rectal cancer (Rationale and Evolution of Neoadjuvant Therapy), the surgical treatment of rectal cancer was historically associated with unacceptably high rates of local recurrence. The combination of neoadjuvant therapy and improved operative techniques, such as total mesorectal excision (TME), have drastically reduced local recurrence rates in properly trained surgeons.[1]

The seminal German Rectal Cancer Trial compared postoperative versus preoperative chemoradiation (CRT) and found that preoperative therapy was equivalent to postoperative therapy for overall survival even though CRT resulted in better treatment compliance and showed the added benefit of improved sphincter preservation.[2] Since then, a growing body of evidence supports the use of multimodality treatment in the neoadjuvant setting with increased utilization of chemotherapy in the neoadjuvant setting in addition to radiation therapy (known as “total neoadjuvant therapy” or TNT).[3][4]

The decision of whether a patient with rectal cancer should undergo neoadjuvant therapy depends upon two basic parameters: 1) the clinical stage of the tumor and 2) the tumor’s anatomic location in the rectum. Complete pathologic staging is not available when contemplating neoadjuvant therapy, so clinical staging using a combination of physical examination, endoscopy, and imaging studies is utilized in the decision-making process. These modalities can determine the clinical T and N stages as well as the exact location of the tumor, especially as the tumor relates to the anal sphincter complex, the peritoneal reflection, and other organs.[5][6][7]

The peritoneal reflection serves as an important landmark in treatment planning. The intraperitoneal, or upper third of the rectum, is covered in a serosa (Figure 1 and Figure 2); therefore, upper rectal cancers that are completely above the peritoneal reflection and biologically behave more like colon cancer with correspondingly lower local recurrence rates. Because local recurrences result from residual cancer left behind in the pelvic soft tissues, the extraperitoneal rectum is at specific risk for discontinuous spread of the tumor. Clinical stage II and III rectal cancer that involves the mid and distal rectum is therefore routinely treated with neoadjuvant therapy, while tumors that are completely above the peritoneal reflection are considered for neoadjuvant therapy on a case-by-case basis. Because proximal rectal cancers have local recurrence rates similar to colon cancers, the National Comprehensive Cancer Network® (NCCN®) notes that upper rectal cancers that are T3N0 can proceed directly to surgery without neoadjuvant treatment.[8]

Figure 1. Intraperitoneal Tumor MRI

Note relationship of the tumor with the sigmoid and small bowel loops, and the absence of an anterior mesorectum and mesorectal fascia.

MRI, magnetic resonance imaging.

Figure 2. Extraperitoneal Tumor MRI

Note the anterior mesorectum and mesorectal fascia.

Currently, the American Joint Commission on Cancer uses TNM staging to describe the clinical staging of rectal cancer. Using this framework, most rectal cancer with transmural invasion (T3) and tumors invading into surrounding organs (T4) should be considered for neoadjuvant therapy.[5][9]

In addition, patients with any mural invasion level and clinically positive regional nodal invasion (N1 or N2) should be considered for neoadjuvant treatment. The rationale for these recommendations lies in historical findings of increased local recurrence rates in higher-stage cancers with surgical treatment alone. Lower-stage cancers have low rates of local recurrence; therefore, the benefit of neoadjuvant therapy is limited in these patients, especially compared with the risk and cost of treatment.[8]