Despite advances in detection and treatment, colorectal cancer remains the third deadliest cancer among men and women in the United States. To get a better understanding of the current state of this disease and what lies ahead, The ASCO Post recently spoke with colorectal cancer expert John L. Marshall, MD, Director, Ruesch Center for the Cure of GI Cancers, Washington, DC.
Major Advance
What has been the most important advance in colorectal cancer during your career in the field?
I believe the biggest advance is the recognition that colon cancer is more than one disease, which was not yet understood when I began my career. Back then we treated every colon cancer in the same way; we bunched young people and old people and right side and left side into colon cancer buckets of the same disease. We now know it is not one disease, and our approach to treatment and research has changed accordingly.
Certainly, factors such as discovering the role of RAS mutations and detecting microsatellite instability in colon tumors have helped us recognize the diverse nature of colorectal cancer. And this knowledge is going to transform colorectal cancer care and expedite the discovery of promising new agents that will revolutionize the way we treat our patients.
Screening Issues
Screening methods in various cancers such as breast and prostate have come under scrutiny for their effectiveness in mortality reduction. Where are we with colorectal screening with regard to compliance and reduction in mortality?
We are clearly seeing—at least in the United States—a drop in the incidence and mortality in colon cancer, and we attribute this, in large part, to screening with colonoscopy. That said, we have fallen far short of doing a good job in screening our populations for colon cancer. There are several reasons for this failure to achieve comprehensive screening, but much of the blame falls on the cancer community, because we haven’t taken the time to properly study how to deliver the most cost-effective population-based colon cancer screening.
It’s quite simple. Colonoscopy is a prevention tool, and if we increase screening compliance, we will see the incidence and mortality of colon cancer decrease markedly. However, the other piece to this story is that we are failing to incorporate the shifting demographics in our screening populations. For example, it is recommended that African Americans begin screening at the age of 45, but that recommendation is not widely recognized or conformed to at the primary care level.
Interestingly, we’ve seen a decrease in the incidence of colon cancer, but we’re also seeing the incidence shifting toward younger people. To that end, we’re not seeing any studies or research looking at this trend and perhaps adjusting age-specific screening guidelines accordingly.
Even though it is widely publicized that we’re overscreening in breast cancer, mammography compliance among women is solid across the board, whereas in colonoscopy, which is proven as the gold standard for prevention, we only see a meager 30% to 40% rate of compliance in the target populations.
This is a huge disconnect between the medical community and its patients. Part of the problem lies in advocacy and messaging. It’s uncool not to have had your mammogram. But everyone seems to put off having a regular colonoscopy. This is an issue that needs to be addressed by all the stakeholders. We simply have to do a better job of getting the message out there that a timely colonoscopy could save your life.
That said, even if we had perfect screening and compliance, there would still be a large number of people who are going to develop colon cancer and die of it. So while it is imperative to continue to screen and decrease incidence, we need to aggressively pursue the development of new treatments for this disease.
Biologic Agents
What are some of the unanswered questions about the use of biologic agents in earlier-stage disease?
When we talk about biologics in colon cancer, there are really only two: vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors. We have miles to go in this area of therapeutics.
In earlier-stage disease, I think we’ve been asking the wrong questions. We’ve been aiming our therapeutic approach at traditional metastatic adenocarcinoma under the mindset that if the drugs work in that setting, they’ll work in every disease stage. And that has not held true in colon cancer, probably because the target cell in the adjuvant setting may be a different cell that doesn’t respond the same way. While fluorouracil (5FU) cures some of these cancers and oxaliplatin cures others, traditional use of systemic therapy has not proven effective in dealing with that adjuvant cell.
That’s why advancing the science in biologics in this setting is vital. I also feel that immunotherapies will have an important role in early-stage disease. As yet, we haven’t seen the results with immunotherapy in colon cancer that have been seen in kidney cancer and melanoma, but we’ll keep working hard in this promising area.
To pull all these new therapeutic directions together, we need better molecular profiling and specific RAS testing. As we get more specific around EGFR targeting and understand which pathways and mutations really matter, we are getting better response rates and longer survival times for our patients. We’re also learning which patients need treatment and which patients do not.
Promising Strategies
Is there any current trial or study looking at a therapeutic avenue that could change the standard-of-care in colorectal cancer?
Well, we have TAS-102, which in a sense is a new 5-FU (in that it has a similar mechanism of action), a novel antimetabolite after all these years.
I think the biggest impact in how we treat our patients will be seen by using different treatments for different molecular subgroups, which is how we’ll shift our standard or care. In short, it will move us away from the one-size-fits-all strategy with our drugs.
Cost and Value
In today’s new world of cost-effectiveness and value, are we delivering cost-effective care in colorectal cancer?
Cost-effectiveness is a relative term. If you ask people in the United States, they would probably answer yes to that question, because patients who were once living for a year with colorectal cancer are now living close to 3 years. To most Americans, spending $25,000 a month for that added survival is cost-effective use of our resources. In most other countries around the world, our colorectal cancer care would not be deemed cost-effective because the gains would not outweigh the costs.
So I think the important tensions between cost and value are now hitting our shores, as we begin to wrestle with health-care cost issues. Moving forward, our health-care delivery will be judged not by our rate of consumption, but by the outcomes of our care delivery. As international markets begin to grow and compete with each other, we will see a leveling off of the prices of these very expensive compounds. Just as cost-effectiveness is a relative term, so is value.
Closing Thoughts
Any last words on a disease that you’ve devoted much of your career to?
If we look at colorectal cancer, and more broadly, gastrointestinal cancers, they are the most common and most fatal cancers on the planet. Furthermore, we haven’t yet seen the huge wave of increased incidence due to people living longer and more people around the world being diagnosed.
We have a huge challenge ahead in colorectal cancer. But given the rapid advances we’re seeing, especially in molecular profiling and promising new areas of research, such as immunotherapy, we will be able to make significant strides in reducing mortality and increasing survival. ■
Disclosure: Dr. Marshall reported no potential conflicts of interest.
