There is a "survival paradox" in colon cancer ― patients with a lower-stage malignancy have poorer survival than patients with higher-stage disease ― and a new study confirms the phenomenon.
This is a paradox because it is in opposition to the usual pattern of staging categories, say senior author Prakash Peddi, MD, a medical oncologist at the Feist-Weill Cancer Center of the Louisiana State University Health Sciences Center in Shreveport, and colleagues.
"In general, high-stage malignancies have a poorer survival than low-stage tumors," they write.
But stage IIB/C and stage IIIA colon cancers defy this rule, which is a finding that has been repeatedly demonstrated in studies since 2004.
The Louisiana team decided to reinvestigate this well-documented paradox, as "there is no proven factor" that explains the conundrum. Their report was published online July 14 in Surgery.
"We feel that there is still lack of understanding as to why these T4N0 tumors have poor outcomes and behave different than their counterparts T2-T3N1 tumors," Dr Peddi told Medscape Medical News.
The team reviewed outcomes from a cohort of 16,471 patients with stage IIB/C and stage IIIA colon cancer diagnosed from 2003 to 2012 in the National Cancer Data Base. Notably, all patients received chemotherapy. Also, all patients with stage IIB/C disease had ≥12 lymph nodes retrieved. The stage IIIA patients were split into two groups: those with <12 and="" lymph="" more.="" nodes="" p="" those="" with="">
As other studies have found, the investigators report that patients with the lower-stage cancer had a worse median survival than those with higher-stage disease.
Specifically, the 5-year overall survival rate was 70.8% for stage IIB/C. This compared unfavorably both with the 81.6% survival rate for stage IIIA with <12 85.6="" and="" for="" i="" iiia="" lymph="" nodes="" stage="" with="">P
The team from Louisiana also found that independent predictors (P <.01) of poor overall survival included stage IIB/C, advanced age, African American ethnicity, treatment at a community cancer program, being uninsured or being insured with Medicaid, low education level, high comorbidity index, and positive surgical margins.
These independent predictors of survival would apply to many cancers. But the authors focused on the surgical margins in this case, as the other variables are out of the control of surgeons
They explained that for stage IIIA colon cancer (and its associated T1-T2 lesions), achieving negative margins status can be accomplished with "minimal difficulties." But for bulkier lesions of stage IIB/C (and its T4 tumor), a more extensive resection might require resection of an adjacent organ, which is a "more difficult operation."
Indeed, in the study, among patients with stage IIIA disease, only 1% had residual tumor, compared with 19% for stage IIB/C patients (P < .0001) — which is evidence that the lower- stage surgeries are more challenging
The authors call upon surgeons to step up their performance in stage IIB/C patients. "The implication is that surgeons should make every attempt to resect T4 lesions [in patients with stage IIB/C disease] adequately to achieve a negative margin," they write.
The status of a margin may be a significant contributing factor to outcomes in these colon cancer patients, suggest the authors.
An expert not involved in the study agreed and said that this conclusion does not tell enough of the story.
"While positive margins are likely a contributing factor, it is clearly not the only factor accounting for the worse outcomes," said Patrick Boland, MD, a medical oncologist at the Roswell Park Cancer Institute in Buffalo, New York.
Patients with stage IIB/C disease with negative margins also demonstrated worse survival compared to the higher-stage patients, he pointed out.
The 5-year overall survival rate was 84.3% for stage IIIA with no residual tumor and 73.3% for stage IIB/C with no residual tumor.
Furthermore, a lot of the study data have an important limitation, said Dr Boland in an email to Medscape Medical News.
Namely, among the stage II tumors evaluated (5670) in the database, a large proportion (3456; 61%) were only described as T4 (no T4a or T4b assignment).
Dr Boland explained that stages IIB and IIC comprise the most deeply penetrating tumors, T4a and T4b, respectively. Among the updates in the seventh edition of American Joint Committee on Cancer (AJCC) Tumor, Node, and Metastasis (TNM) staging system was the addition of stage IIC, which differentiates between T4aN0 (IIB) and T4bN0 (IIC) tumors.
"This is important, because T4b tumors penetrate other organs and carry a substantially worse prognosis than T4a tumors that only penetrate through the visceral peritoneum. However, both are significantly worse than early stage IIA (T3N0) cancers," he said.
Thus, the incomplete data in the National Cancer Data Base limit the insights from the study. "It is very difficult to determine which features contribute to T4b tumors having the much worse outcome than T4a tumors. The two should be important distinctions," Dr Boland pointed out.
He also said that the study is provocative in another way.
"Perhaps most importantly, what this database analysis cannot answer is the question of why stage IIIA cancers do so well; outcomes for these tumors rival or even exceed those of stage IIA cancers," he said.
"Presumably there is something biologically favorable surrounding a smaller/less deeply invasive tumor that has limited lymph node spread as compared to a more deeply invading tumor, whether or not nodes are involved," Dr Boland commented.
Nevertheless, the study authors would like to see the AJCC staging change further to accommodate the fact that stage IIB/C colon cancers (and their associated T4 lesions) are more aggressive than stage IIIA cancers.
"Future iteration of the AJCC TNM staging system should consider this observation and upstage T4 lesions to stage III," they write.
"We would like to see if T4 tumors can be finally placed into stage III rather than stage II," said Dr Peddi.
The authors and Dr Boland report no relevant financial relationships.
Surgery. Published online July 14, 2016. Abstract
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