Survival and disease relapse after surgery alone1–9,13
or combined with adjuvant treatment10–12,14
for rectal cancer patients are a function of both degree of bowel wall penetration of the primary lesion and nodal status. However, nodal involvement alone does not determine survival and relapse rates. Invasion through the bowel wall and number of involved lymph nodes are independent high-risk factors for both relapse and survival.
For patients with a single high-risk factor of either direct tumor extension beyond the wall, nodes negative (T3N0), or positive nodes but primary tumor confined to the wall (T1-2N1-2), local relapse rates published in older surgical series have ranged from 20% to 40%.2–7
For patients with both positive nodes and extension beyond the wall (T3-4N1-2), the risk of pelvic relapse was nearly additive (40% to 65% in clinical series and 70% in a reoperative series).2–7
The rate of systemic metastases is significantly higher for patients with both high-risk pathologic factors (extension beyond rectal wall and positive nodes; T3-4N1-2), as opposed to patients with only a single risk factor (T3-4N0, T1-2N1). In published data from adjuvant rectal cancer patients irradiated at either Massachusetts General Hospital10,11
or Mayo Clinic,12
the incidence of subsequent systemic relapse was approximately 20% for patients with T3-4N0 and T1-2N+ lesions versus 40% to 60% for patients with T3-4N+ lesions.
Single-institution analyses from Massachusetts General Hospital10
and Mayo Clinic12
had previously suggested that patients with T1-2N1-2 lesions who were treated with postoperative irradiation alone or combined with chemotherapy had outcomes similar to T3N0 and T4N0 patients, but patient numbers in each stage subset were small. In the rectal pooled analyses with larger numbers of patients, the 5-year OS rate observed for the T1-2N1 patients was similar to that for T3N0 patients, and the 5-year survival for T1-2N2 patients was similar to that for patients with T4N0 or T3N1 lesions ().15,16
Results by N2 category were rarely available before the first pooled analysis,15
and results by T subcategory for patients with N2 disease (ie, T1-2N2, T3N2, T4N2) were nonexistent.
Data from the rectal cancer pooled analyses ()15,16
strongly supported substaging of TNM stages II and III, as accomplished in the sixth edition (2002) of TNM staging.14,18
As shown in , for TNM stage III patients, three separate prognostic subgroups of lesions exist (intermediate risk, T1-2N1; moderately high risk, T1-2N2 and T3N1; and high risk, T3N2 and T4N1-2). To combine or merge all of these patients into TNM stage III (Dukes C) does not provide full prognostic information for patients or physicians. However, patients with T1-2N1-2 disease had a more favorable prognosis than previously thought, and patients with T4N1 lesions (stage IIIB, AJCC sixth edition, along with T3N1 lesions) had prognoses more akin to those of patients with T3-4N2 lesions (stage IIIC, sixth edition).
For patients with N2 disease, data from the rectal pooled analyses demonstrated that N2 disease does not by itself confer poor prognosis.15,16
Substaging by T category influenced both 5-year OS (N2T1-2, 67%; N2T3, 44%; and N2T4, 37%; P
< .001; ) and 5-year disease-free survival (N2T1-2, 58%; N2T3, 36%; and N2T4, 30%; P
< .001). Placement of all N2 patients in AJCC IIIC substage in the sixth edition16a
did not reflect the markedly different prognosis of N2 patients observed in the rectal pooled analyses.
As shown in , data in the current large SEER population-based rectal cancer analysis validates the rectal pooled analyses with regard to the more favorable prognosis of patients with T1-2N1-2 lesions (stage IIIC, AJCC sixth edition) and less favorable prognosis of patients with T4N1 cancers (stage IIIB, sixth edition). Both SEER and rectal pooled analyses data support the shift of T1-2N2 lesions from stage IIIC to an earlier stage of disease (IIIA/IIIB) and T4N1 lesions from stage IIIB to IIIC ( and ).
Rectal SEER Analysis: 5-Year Relative and Observed Survival by TN Category of Disease in Patients With Invasive Cancer and Evaluable TN Category
Rectal Cancer: Proposed Changes in Substaging of AJCC Stages II and III Based on Rectal Pooled and SEER Analyses
Expanded SEER rectal cancer outcomes data ( to ) also support subdividing T4, N1, and N2 categories of disease. Patients with T4a lesions (penetrates to the surface of visceral peritoneum [revised definition, AJCC seventh edition]) have a better prognosis than patients with T4b lesions (directly invades or is adherent to other organs or structures) for each N category of disease (N0, N1, and N2). For patients with N0T4a versus N0T4b lesions, there is an approximately 10% improvement in absolute 5-year relative survival and OS, and for patients with N1T4a versus N1T4b and N2T4a versus N2T4b disease, there is a nearly 20% improvement in 5-year survival. Patients with one positive node (N1a) have a better prognosis than patients with two to three positive nodes (N1b), and patients with four to five positive nodes (N2a) have a better prognosis than patients with ≥ seven positive nodes (N2b) by T category.
Previous analyses with much smaller data sets had suggested that patients with perforated T4 lesions may have a worse prognosis than patients with invasion of or adherence to other organs or structures.45,46
However, as shown in the current SEER analysis with large data sets for each TN category of disease, patients with T4 lesions that penetrate to the surface of visceral peritoneum (T4a in AJCC seventh edition) have a more favorable prognosis than patients with invasion of or adherence to other organs or structures (T4b in AJCC seventh edition).
Data in the current SEER analyses combined with rectal pooled analyses data support revised substaging of stages II and III ( and ). The AJCC seventh edition HTF recommended the following changes (): subdivide IIB into IIB (T4aN0) and IIC (T4bN0); shift more favorable TN2 categories to either IIIA (T1N2a) or IIIB (T2N2a, T1-2N2b, T3N2a); and shift less favorable T4N1 lesions from IIIB to IIIC (T4bN1).
Survival outcomes by TN/NT category in the rectal pooled analyses15,16
and the current SEER rectal cancer analysis suggest a complex biologic interaction between depth of invasion and nodal status. As shown in to , some TN categories of patients with positive nodes (T1-2N1 and T1-2N2) have a similar or better prognosis than patients with negative nodes with regard to both relapse (rectal pooled) and survival (SEER, rectal pooled). Patients with T1-2N1 lesions have better 5-year OS (rectal pooled), relative survival, and observed survival (SEER) than patients with T3N0 or T4N0 cancers ( to ), with outcomes more akin to patients with T2N0 lesions ( to ). Accordingly, the indications for adjuvant chemoradiotherapy or chemotherapy in patients with T1-2N1 disease should continue to be evaluated. Patients with N2a category (four to six involved nodes) but limited invasion have 5-year survival outcomes similar to those of patients with T2N0 and T3N0 cancers (T1N2a) or T4aN0 cancers (T2N2a) in the current analysis.
Survival outcomes by TN category of disease in the SEER rectal cancer analysis are more similar to SEER colon cancer outcomes than expected.16a
Because of the similarities, the AJCC seventh edition HTF recommended continuance of a common staging system for patients with rectal and colon cancers. These similarities may be the result of common tumor biology, the impact of adjuvant chemoradiotherapy (preoperative or postoperative), and/or adjuvant chemotherapy or other factors.
This revision of TNM classification for rectal cancer demonstrates the critical role of formulating postulates and then assessing them in data sets that are larger than single-institution series. As the AJCC proceeds to the next edition, it will be important to collect data on other points of consideration that include, but are not limited to, the number of peritumoral deposits, the number of positive and total nodes examined, and the magnitude of the circumferential radial margin. Only through prospective data collection will usable data exist that can guide decisions relative to the next edition of the staging manual, when hopefully several molecular markers can be incorporated as an adjunct or modifier to the TNM categories of disease.