NSABP colorectal trials in the adjuvant and metastatic settings

NSABP trial C-08 is an adjuvant therapy study for patients with Stage II and III colon cancer. It uses the modified FOLFOX6 regimen as the chemotherapy platform and asks whether or not the addition of bevacizumab will increase the possibility of long-term, disease-free survival and cure. The study opened in October 2004.

NSABP-R-04 is a preoperative study for patients with clinical Stage II or III rectal cancer, which randomly assigns patients to continuous infusion 5-FU using an ambulatory infusion pump and central venous catheter or oral treatment with capecitabine. We’re currently in the process of amending that protocol to include a second question; namely, whether the addition of oxaliplatin along with either continuous infusion 5-FU or capecitabine could further increase the pathologic complete response rate and improve local control.

Another important trial is NSABP-C-09, which will focus on colorectal cancer that has metastasized to the liver. It’s being submitted to the National Cancer Institute for final approval, and we anticipate it will be open soon. The primary question is whether, following hepatic metastasectomy, we can improve the outcome by administering intra-arterial FUDR in addition to systemic treatment with capecitabine and oxaliplatin compared to the capecitabine and oxaliplatin combination alone.

We’re basically trying to confirm, in a multi-institutional setting, the data that Nancy Kemeny from Memorial Sloan-Kettering published some years ago in the New England Journal of Medicine, where the addition of intrahepatic FUDR seemed to decrease hepatic recurrences and improve two-year disease-free survival (Kemeny 1999a).

We have another study that has been approved by the National Cancer Institute, which will move forward in the first half of 2005 and which will evaluate the need for resection of an asymptomatic primary colon cancer in patients who present with metastatic disease. There’s been a lot of controversy about this in the literature. Approximately 25 percent of patients with metastatic colorectal cancer who have an unresected primary will develop a complication — primarily, obstruction — if that tumor isn’t resected.

Now that we have more effective systemic chemotherapy, our goal is to determine whether we can avoid the need for resection in patients who don’t have any symptoms related to the primary tumor but who have distant, unresectable metastatic disease. We’ll treat them all with the modified FOLFOX6 regimen plus bevacizumab. Our endpoint of this Phase II trial is to determine the local complication rates.

We will also be conducting a Phase II trial in patients with metastatic disease, where we will be evaluating capecitabine combined with oxaliplatin or capecitabine plus irinotecan, and adding bevacizumab to both of those oral combinations. Our rationale for this study is to obtain additional clinical evidence of activity and tolerability data in consideration of the next generation of adjuvant colon studies, because we have an interest in oral chemotherapy in the adjuvant setting.

NSABP trial C-06 compared oral UFT plus leucovorin versus intravenous 5-FU/leucovorin and was presented at ASCO last year (Wolmark 2004). The oral regimen was as effective as the intravenous, and there were improvements in quality of life. Unfortunately, that compound is not available in the US, so we will focus on capecitabine.

ASCO guidelines for treating Stage II disease

I believe the ASCO guidelines for adjuvant treatment of colorectal disease were reasonable (Benson 2004). They certainly recommended adjuvant therapy for patients with Stage III disease. For Stage II disease, they didn’t recommend it on a routine basis but did express that it would be a reasonable option to consider for high-risk patients. I think that’s fair. In my own practice, I certainly offer adjuvant therapy to patients with Stage II disease. I try to provide them with an assessment of the absolute magnitude of benefit from therapy. If they understand those numbers and prefer to undergo the therapy, then I do it.

X-ACT adjuvant trial: Capecitabine versus 5-FU/leucovorin

The X-ACT trial established the principle that oral chemotherapy could be effective in the adjuvant setting, compared to intravenous chemotherapy (Cassidy 2004; [3.1]). Capecitabine offers the patient the advantage of not requiring IV injections. The dosage level that was used is a bit higher than most oncologists in the United States have been able to administer to their patients, and it raises some interesting questions about possible pharmacogenetic differences between the populations in Europe and those in the United States.

I believe the data are very compelling and suggest that there might be an advantage for capecitabine over the Mayo Clinic method of administering 5-FU and leucovorin in the primary endpoint of disease-free survival, which practically reached statistical significance in favor of the capecitabine. The primary goal of the study was to demonstrate noninferiority. They certainly accomplished that. I now believe that in clinical practice, for a patient in whom fluoropyrimidine therapy is considered appropriate, capecitabine is a viable option.

Management of metastatic colorectal cancer

Selection of therapy for first-, second- and third-line therapy is an evolving process. Presently, I utilize FOLFOX plus bevacizumab for first-line nonprotocol therapy. We’re extending the survival times for our patients with this regimen, and they’re receiving more and more treatment. However, the neurotoxicity is becoming increasingly problematic. We’re approaching that problem in the same manner as in our Phase II trials of CAPOX or CAPIRI by administering a defined number of cycles of oxaliplatin or irinotecan with bevacizumab for approximately six months of therapy.

In those patients who are either responding or stable, we’ll continue the capecitabine and bevacizumab as maintenance therapy until the time of progression. That’s one way to provide the potential benefits of agents that do have cumulative toxicities — irinotecan and oxaliplatin — but then continue therapy with the agents that don’t have significant cumulative toxicities. Another approach that’s been utilized is the so-called “stop-and-go” technique of treating for several months to maximum response and perhaps a couple of additional cycles, and then simply stopping therapy and reinitiating treatment at a later time (3.2). I believe that is a reasonable alternative as well and I sometimes do that in my clinical practice.

Irinotecan and cetuximab would be very reasonable second-line options, whether it’s with single-agent irinotecan and adding in cetuximab at the time of progression or, taking out the reimbursement issues, starting with both cetuximab and irinotecan together, which would make sense. The third-line setting is wide open, and clinical trials would definitely have a value in identifying new agents.

Select publications

Dr O’Connell is a Professor of Human Oncology at Drexel University School of Medicine, Director of the Allegheny Cancer Center, Director of the Division of Medical Oncology at Allegheny General Hospital and Associate Chairman of the National Surgical Adjuvant Breast and Bowel Project in Pittsburgh, Pennsylvania.