Select Excerpts from the Interview

Track 3-4

DR LOVE: What have we learned over the past couple of years about staging rectal cancer?

DR TEPPER: First of all, I want to emphasize that we are in an age driven by molecular biology and elaborate ways of evaluating disease. However, what we have found is that some very standard, straightforward factors can make a real difference in terms of understanding the risks and outcomes of the disease. We need to emphasize the importance of what goes on both surgically and pathologically with the disease and how we interpret these data.

A series of articles has been published that has taken the lead in examining the impact of T stage and N stage on outcome for patients with rectal cancer (Gunderson 2002, 2004). It’s been known for years that N stage is important. In fact, many treatment algorithms for rectal cancer are based almost entirely on the premise that N stage dominates everything in terms of outcome.

However, the data from these studies show that both the T stage and the N stage of the tumor are important, and the impact of each on disease outcome is somewhat independent of the other. If you look at the data carefully, it is evident that someone with T2/N1 disease might have a slightly better prognosis than someone who has T3/N0 disease.

In a patient with N0 disease or, perhaps, N1 disease, the T stage is significant in determining the risk for both local and distant recurrence. So T stage has a big impact on survival differences, far larger than any impact that results from a therapeutic intervention additive to surgery, such as chemotherapy, radiation therapy, or a combination of the two.

In a study published several years ago, we evaluated tissue from patients with rectal cancer in terms of T and N staging (Tepper 2001). The study was based on an analysis of patients from the Gastrointestinal (GI) Intergroup study 0114, in which all patients with rectal cancer were treated postoperatively with chemotherapy and radiation/chemotherapy and then more chemotherapy. No difference appeared between the therapeutic interventions, so we were able to combine all of the treatment categories together.

When we looked at the data, we found that the number of lymph nodes examined had a great impact on outcome. More specifically, among patients with T3/N0 disease, the outcome was far worse if the pathologist found zero to eight nodes compared to finding 14 or more nodes in the specimen. Again, this difference was much bigger than the differences we see among therapeutic interventions.

This suggests to me the extreme importance of how we select patients who are at high risk, both in terms of how we define the outcomes of studies as well as how we define whom we should and shouldn’t treat with adjuvant therapies. For example, it is possible that a patient with T3/N0 disease, which has been well staged with many nodes that are negative, may not need adjuvant therapy, or at least not the same level of adjuvant therapy as he or she would need otherwise.

Another issue is whether nodal pathology outcomes are related to the surgeon’s skill and how well the operation was performed or to how well and how carefully the pathologist examined the specimen. We can’t answer this question definitively from this study, but the data suggest that the pathologist had a greater effect on outcomes than the surgeon. This is based on the fact that the number of nodes the pathologist found appeared to have a large effect on outcome for the patients with T3/N0 disease.

For patients with T3/N1 disease, there was a lesser effect, and for patients with T3/N2 disease, no discernible effect was visible. This suggests stage migration. If the effect was based simply on the surgeon performing a better operation, I would expect that the largest effect would be among the patients with N2 disease.

In reality, good surgery and good pathology probably both count, not just one or the other.

DR LOVE: What about the prognosis for patients who have received neoadjuvant radiation therapy and chemotherapy for rectal cancer? How do you interpret nodes?

DR TEPPER: It’s harder to interpret the node count for those patients. One still should be able to define nodes in those patients, but the gold standard of a minimum of 13 or 14 nodes probably doesn’t apply, and you probably can’t have that as a reasonable standard.

A couple of studies have examined this issue and found an increased difficulty in finding nodes in those patients (Wichmann 2002; Beresford 2005; Thorn 2004; Luna-Perez 2003).

Track 9

DR LOVE: What new clinical research approaches are currently under way for rectal cancer, including combined chemotherapy/radiation therapy regimens?

DR TEPPER: We’ve tried to coordinate the adjuvant trials in rectal cancer in the United States through a group previously called the GI Intergroup, which is now known as the GI Steering Committee of the National Cancer Institute’s Clinical Trials Working Group.

Two carefully designed trials have recently started that allow patients to enroll in both studies. The first is the NSABP-R-04 study that is evaluating preoperative radiation and chemotherapy for rectal cancer patients.

The study has a two-by-two randomization scheme in which patients are initially assigned either to continuous infusion 5-FU or to capecitabine plus or minus oxaliplatin, with radiation therapy.

The idea was to use oxaliplatin to increase the rate of pathologic complete response, improve the local control rate, and perhaps offer additional beneficial systemic effects (1.1).

After patients complete preoperative therapy and undergo surgery, they can be enrolled in an ECOG study in which patients are randomly assigned to FOLFOX either alone or with bevacizumab.

The entry criteria are basically what they’ve been for almost all of the rectal studies to date: The patients must have T3 and/or node-positive disease.

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