Indications for Preoperative Neoadjuvant Therapy

Local recurrence in rectal cancer is most commonly the result of residual malignant tissue left behind in the pelvic soft tissues after surgical resection. Historically, the surgical treatment of rectal cancer was associated with unacceptably high rates of local recurrence. Improved operative techniques such as total mesorectal excision (TME) have drastically reduced local recurrence rates in properly trained hands, even without the use of neoadjuvant and/or adjuvant therapy. However, these results are not reproducible at all centers. When clinical trials in the United States began to address the issue of local recurrence in rectal cancer, rates after surgical treatment alone were 25% or higher.[1] The use of chemotherapy, radiation therapy, and a combination of the two was proposed and studied in an attempt to reduce these rates. At first, postoperative or adjuvant therapy was advised. However, concerns over increased morbidity, delays in instituting therapy, and diminished intestinal function led to the comparison of adjuvant therapy and neoadjuvant (i.e., preoperative) therapy. The seminal German Rectal Cancer Trial addressed the comparison of postoperative versus preoperative combined chemotherapy and radiation therapy (CRT), finding preoperative therapy equivalent to postoperative therapy with better treatment compliance and the added benefit of improved sphincter preservation.[2] Therefore, the preponderance of evidence currently supports the use of multi-modality treatment in the neoadjuvant setting.

The choice of neoadjuvant therapy in rectal cancer focuses upon two basic parameters: the stage of the tumor and its anatomic location in the rectum. Pathologic staging is not commonly available especially when contemplating neoadjuvant CRT, so clinical staging using a combination of physical examination, endoscopy, and imaging studies is utilized in the decision-making process. These modalities can also determine the exact location of the tumor, especially as it relates to the anal sphincter complex, the peritoneal reflection, and other organs. Since 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. The intraperitoneal, or upper third of the rectum, is covered in a serosa, which thwarts the local spread of cancer cells (Figure 3.1 a. intraperitoneal tumor, and b. extraperitoneal tumor). Therefore, upper rectal cancers that are completely above the peritoneal reflection biologically behave like colon cancer with correspondingly lower local recurrence rates. Thus, clinical stage II and III rectal cancer that involve the extraperitoneal rectum to any extent are routinely given neoadjuvant therapy, while tumors that are completely above the peritoneal reflection are considered for neoadjuvant therapy on a case-by-case basis. The factors considered by the multidisciplinary team when considering neoadjuvant therapy include the location within the pelvis, distance from the anal verge, and tumor T and N stages.

Figure 3.1a
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MRI showing a intraperitoneal tumor. Note relationship of the tumor with the sigmoid and small bowel loops, and an absence of an anterior mesorectum and mesorectal fascia.
Figure 3.1b
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Extraperitoneal tumor MRI. Note anterior mesorectum and mesorectal fascia.

Currently, the American Joint Commission on Cancer (AJCC) staging is used to describe clinical staging of rectal cancer. Utilizing this framework, rectal cancer with transmural invasion (T3) or tumors invading into surrounding organs (T4) should be considered for neoadjuvant CRT. In addition, patients with any mural invasion level and clinically positive regional nodal disease (N1 or N2) should be considered for 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 already have low rates of local recurrence; therefore, the benefit of CRT is limited in these patients, especially as compared to the risk and cost of treatment.

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Last updated: September 17, 2021