“Forgotten Lessons” May Help Advance Colorectal Cancer Care

Alan P. Venook, MD, shares insight into the evolving treatment paradigm for colorectal cancer.

Alan P. Venook, MD

In 2015, the FDA approvals of ramucirumab (Cyramza) and TAS-102 (Lonsurf) led to updates to the NCCN treatment guidelines for colorectal cancer (CRC).

Although these new agents have shown great promise, Alan P. Venook, MD, cautions against ignoring established therapies, such as 5-fluorouracil (5-FU).

At the 2016 NCCN Annual Meeting, Venook, delivered a presentation on treatment strategies in metastatic CRC (mCRC) and recent changes to the guidelines.

OncLive: What were the key points you made in today's talk?

For further insight into the evolving treatment paradigm for CRC, OncLive sat down at the NCCN meeting with Venook, who is The Madden Family Distinguished Professor of Medical Oncology and Translational Research at the Helen Diller Family Comprehensive Cancer Center.Venook: This was a view from 30,000 feet. I talked about how we got to where we are today in the treatment of mCRC. As we're learning about new drugs and new strategies, we need to remember that some of the things we figured out years ago still apply and, maybe, we've forgotten some lessons.

I also talked about how to think about the disease and think about subsets of patients. There's no magical formula for how to treat patients or use drugs, but we need to think about goals for a patient when you start on a therapy—getting from point A to point B.

As we look at our numbers, patients appear to be doing much better, but it's a bit of a fake out. We've learned how to select therapies for the best patients. It's reporting bias. We need to up our game for those patients doing poorly and maximize outcomes for patients who will do well.

You mentioned there might be some “forgotten lessons” in treating patients with mCRC. What are these lessons?

During a talk I was giving about 15 years ago, I had a slide that had 5-FU in the rearview mirror, as if we'd be moving beyond it. Today, though, it still does the heavy lifting in colorectal cancer. It's the most effective drug we have. We can still maximize the way we use 5-FU and we're not really doing that right now.

We also need to think about which side the primary cancer is located on—right or left—in metastatic disease. It was demonstrated 20 years ago in a study that this matters, but we never really followed it. I'll be presenting data at the 2016 ASCO Annual Meeting that may suggest it does make a difference. We used to talk a lot about the microbiome and how it affects the absorption of chemotherapy.

These are simple things, but sometimes we get amazed with genetic testing and the ability to look at the genome. We need to remember that there may be older, simpler snippets of information that should be kept in play today.

Beyond testing, do you think that researchers and physicians are too focused on new types of therapies, as well?

In my talk, I joked that the future of colon cancer is immunotherapy—as if that's all we have to do. It's a hot topic, but it's not the answer in colon cancer generically.

What should a community oncologist know about curable disease?

New technology is great and it will open up new territory for us, but we're not going to throw out chemotherapy and other old methods. There's a misconception, too, that targeted therapies cause no side effects.Colon cancer is curable in selected patients with stage IV disease—maybe 5% to 20% of patients. The reason behind a cure is inexplicable, but physicians need to think about it. If you don't look for that curable patient, you may miss the opportunity.

What point did you hope to drive home in discussing different subsets of patients with CRC?

We know that patients with a BRAF mutation do poorly and should go on a clinical trial. We also know the pattern of how BRAF-mutated disease looks—it tends to be peritoneal disease, right-sided primary cancers, women—these are just tendencies. For years, we knew that patients with this kind of disease did poorly, but now we have a molecular explanation.

A lot of your talk seems to have implications with clinical trials. Is there a need for change in CRC trials?

Those of us that do just colon or gastrointestinal cancers have an amazing bank of experience to make these calls. The average oncologist doesn't have that opportunity. As we move forward, there will be a need for more specialization.We have been slower than we would like in making progress, because we can't make global decisions quickly if only 3% of patients are participating in clinical trials. It's a challenge to bring more patients on clinical trials, but we need to do it. Essentially, what we'd be doing is dividing colon cancer into many rare diseases. Once you do that, it's difficult to design clinical trials. We need to be more nimble in reaching out to patients and institutions.

What's the effect of all this on the guidelines for CRC?

Let's say you have a marker that predicts for excellent results with a given treatment. Then, you need to enrich for that marker and have off-the-charts effectiveness. Conducting a 700-patient study to show a 3-week benefit is ridiculous, in my opinion, and the era of those trials should end.I've been on the panel for the NCCN guidelines since its inception in 1996. Then, the document was 4 pages. Today, the guidelines are 40 pages.

In just the past year, TAS-102 and ramucirumab changed the guidelines, but we made other changes, too. As a panel, we're always looking at things that we accepted many years ago and ask ourselves about the reasons.

Our guidelines have historically required US data to drive decision-making. I think we should start considering outside data, even though there are big questions about cost and value.

It's a living document and it's always a work in progress.

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