Tracks 1-15

Track 1 Molecular diagnostics to identify patients at high risk for colorectal cancer; potential chemoprevention agents Track 2 Use of neoadjuvant chemoradiation therapy to downstage rectal tumors Track 3 NSABP-R-04: Preoperative radiation therapy and either capecitabine or 5-FU, with or without oxaliplatin, for patients with operable rectal cancer Track 4 Off-protocol use of neoadjuvant oxaliplatin and capecitabine for rectal cancer Track 5 NSABP-C-08: A Phase III trial evaluating adjuvant FOLFOX with or without bevacizumab — Initial safety data Track 6 AVANT: A Phase III adjuvant trial comparing FOLFOX to FOLFOX/ bevacizumab and CAPOX/ bevacizumab for colon cancer Track 7 Bevacizumab versus cetuximab as first-line therapy for metastatic disease Track 8 K-ras mutation status and benefit in a clinical trial comparing panitumumab to best supportive care Track 9 Identifying predictors of response to anti-angiogenic agents Track 10 Interpreting the negative results of the PACCE trial of FOLFOX with bevacizumab and panitumumab Track 11 Clinical trials evaluating chemotherapy with bevacizumab and cetuximab Track 12 RT-PCR assay to identify patients with Stage II disease at high risk for recurrence Track 13 Development of future therapies based on molecular pathways and biologic profiles Track 14 Adjuvant Colon Cancer Endpoints (ACCENT) data: Survival after recurrence Track 15 ACCENT data on the recurrence pattern of colon cancer

Select Excerpts from the Interview

Track 3

DR LOVE: Would you discuss the background and design of the NSABPR-04 trial evaluating neoadjuvant treatment for rectal cancer?

DR O’CONNELL : The NSABP-R-04 study is evaluating different methods of combined-modality neoadjuvant treatment using continuous infusion 5-FU combined with radiation therapy preoperatively as the standard, and it’s investigating whether capecitabine would be equally effective as 5-FU in a noninferiority analysis.

The trial is also evaluating whether the addition of oxaliplatin in the preoperative setting might increase the pathological response rates and improve long term local control (1.1).

DR LOVE: Do you have any predictions about what we will see with the study?

DR O’CONNELL : We hope it will be possible to use an oral agent along with radiation therapy to be equally effective without the need for a central venous catheter and the ambulatory infusion pump.

With the known radiation-sensitizing effect of oxaliplatin and its activity combined with fluorinated pyrimidines in colorectal cancer, I believe it’s reasonable that the addition of oxaliplatin might improve local control. Obviously we have to run the trial and examine the results.

Track 4

DR LOVE: What are the key research issues surrounding adjuvant systemic therapy?

DR O’CONNELL : The major question is whether the addition of targeted agents — bevacizumab and the anti-endothelial growth factor receptor (EGFR) monoclonal antibodies cetuximab or panitumumab — to chemotherapy will improve the long-term therapeutic outcome. I believe we will have a definitive answer about whether bevacizumab adds to the adjuvant treatment of Stage II and Stage III colon cancer within the next two or three years.

The NSABP-C-08 study has randomly assigned about 2,700 patients with Stage II and III colon cancer to receive a modified FOLFOX6 regimen for six months, as the control, or the same treatment with bevacizumab for a year (1.2). The trial completed accrual a year ago. The primary endpoint is three-year disease free survival. Of course, if there’s a striking benefit, we might hear that early. But by 2009 at the latest we should have a definitive analysis of that trial.

DR LOVE: Where are we right now with safety data from that trial?

DR O’CONNELL : We will report this at ASCO 2008. We did not see an increase in GI perforations among these patients in the adjuvant setting, who are different from patients with advanced disease. Only two or three perforations were recorded in the entire study.

Second, we did not see an increase in arterial thrombotic strokes or heart attacks in this group of patients, who are more medically fit and younger than patients with advanced disease.

We did see a slight increase in wound infections, which was statistically significant and should be taken into consideration. It was of modest degree, perhaps two or three percent versus one percent, but with the numbers of patients we had, that difference was statistically significant.

Track 6

DR LOVE: Would you discuss the AVANT adjuvant study evaluating FOLFOX and CAPOX with bevacizumab?

DR O’CONNELL : AVANT is comparing FOLFOX alone, FOLFOX with bevacizumab or CAPOX with bevacizumab to learn whether substituting the oral agent, capecitabine, for the continuous infusion 5-FU/leucovorin will be as effective (1.3).

I understand that more than 3,500 patients have entered that trial and that the accrual was recently completed. Like the NSABP-C-08 trial, it’s also using a three-year disease-free survival endpoint, so it will be about three years before we have data from that study.

DR LOVE: Do you believe CAPOX is a reasonable clinical option in the adjuvant setting right now?

DR O’CONNELL : You could make that argument. My impression is that CAPOX is as effective as FOLFOX in the advanced-disease setting. That was proved by the NO16966 trial in the metastatic setting that’s been presented on several occasions (Cassidy 2006). The toxicity profiles are acceptable, and the efficacy in advanced disease is the same. Yes, I believe this would be a reasonable option in clinical practice now.

Track 14

DR LOVE: Can you summarize the ACCENT data you presented at the 2007 ASCO meeting?

DR O’CONNELL : The ACCENT database includes clinical data from 18 adjuvant therapy studies. Dan Sergeant, from the Mayo Clinic, is the coordinating statistician. The goal of the work I presented was to evaluate the combined data from these studies to determine if the characteristics of the primary tumor might predict the behavior of the cancer if it recurred months or years later.

We found that two factors turned out to be strongly prognostic. One of these was stage. Cancer that recurred years after patients with Stage II primary colon cancer had their tumors removed had a much more indolent natural history than the cancer recurring in patients who’d had Stage III cancer. Stage III — node-positive — cancer had a more rapid natural history when it recurred (O’Connell 2007; [1.4]).

What possibilities might explain this? One is that a difference exists in the biology of Stage II versus Stage III disease. If that were the case, you should be able to examine the patients with Stage II and III disease using a molecular analysis and observe different patterns. However, we haven’t observed this type of difference between Stage II and Stage III colon cancer.

DR LOVE: Then how do you explain what’s going on?

DR O’CONNELL : Perhaps patients with Stage III disease are further along in the natural history of their disease at the time of diagnosis. They may have more microscopic disease.

The results are profound — in fact, the difference in median survival from the time of diagnosis of metastatic disease, between earlier Stage II and Stage III, was 5.7 months (O’Connell 2007). That’s more than the difference made by any therapeutic regimen in any Phase III trial of chemotherapeutic agents in this disease.

The second major prognostic factor was the time it took for the original cancer to come back. If the tumor recurred quickly — within the first year — the prognosis was poor, suggesting aggressive disease.

However, if the tumor recurred four or five years later, the course of disease tended to be more indolent. We’ve observed this difference in our practices for many years (O’Connell 2007; [1.4]).

Select Publications

 

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