Since the mid-1980s, rates of colorectal cancer (CRC) have doubled in individuals ages 20 to 39. Just as notorious as the disease itself are the treatments patients must endure to become cancer-free. Case in point: After undergoing surgery to remove a tumor, high-risk stage II CRC patients and all stage III CRC patients are recommended for chemotherapy, a treatment regimen that has been used since the 1940s, along with other treatments, such as radiotherapy, to remove any cancer that may be remaining after surgery.
Yet, despite the widespread use of chemotherapy, there are several drawbacks – chief among them, its potentially debilitating side effects. Additionally, there can be a significant financial burden impacting patients long after their cancer has cleared. In the end, going through chemotherapy may not be worth the side effects or the financial costs since not every patient benefits from it. For example, in situations involving stage III CRC patients for whom chemotherapy is automatically recommended, up to 40 percent have already been cured from surgery.
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What is needed are more precise tools for assessing a CRC patient’s need for – and response to – chemotherapy. And to this point, molecular-level detection methods, which are already being used in the clinic, could help provide the clarity needed to better inform these treatment decisions.
Opportunities to improve the standard of care
There are two key opportunities for improvement in the way oncologists prescribe chemotherapy for stage II and III CRC patients. The first is in assigning cancer stage, which is currently determined by the results of physical exams, imaging tests (x-rays, CT scans, etc.), endoscopy exams, and any biopsies that are done before treatment starts. However, these methods are not sensitive enough to detect residual traces of cancer.
Because staging the cancer plays a large role in determining a patient’s need for chemotherapy – as previously mentioned, high-risk stage II patients and all stage III CRC patients receive chemotherapy – molecular detection tools, which can provide more accurate information about risk of recurrence, should be a key factor in the staging decision. Without molecular-based detection methods, CRC patients risk receiving post-surgical treatment that may be unnecessary, expensive, and physically taxing, or conversely, forgoing treatment when intervention would benefit the patient.
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The second opportunity for improvement is during treatment monitoring. After starting chemotherapy, oncologists try to determine whether a patient’s cancer is growing or shrinking. Instead of observing the cancer’s response to chemotherapy in real time, clinicians must wait for a cancer response to be detected by established methods such as imaging and microscopy. This can take months, and be challenging or impossible to tailor personalized care. Molecular testing could provide an easier way to monitor treatment response in real time and help oncologists to halt chemotherapy treatments as soon as they have cleared the cancer.
Circulating-tumor DNA can lead the way
One promising molecular detection tool that could improve our current approach to CRC is circulating tumor DNA (ctDNA), which is shed into the bloodstream by cancerous cells. Since it measures the total amount of ctDNA in a patient’s bloodstream using a simple blood draw, ctDNA liquid biopsy tests offers oncologists with an accurate, molecular, real-time cancer detection tool.
In cancer staging, such a tool would offer clinicians a more precise way to determine the true stage of cancer. From that point, they would also be better able to assess how aggressive the treatment regimen should be. Moreover, in treatment monitoring, a molecular-level detection method could help oncologists observe the cancer’s behavior in real time and would enable clinicians to discontinue a therapeutic that is either not working or when the cancer has been cleared. Further, it could help oncologists select which patients are cured of cancer by surgery, and, therefore, do not need chemotherapy at all.
Current research in ctDNA in CRC
Supporting this claim is a growing body of evidence that shows ctDNA is a viable supplement to oncologists’ current strategy for assessing the need and efficacy of chemotherapy, such as the 2019 paper in the Journal of American Medical Association (JAMA) that suggests that ctDNA may have implications for postoperative management of CRC that includes guiding chemotherapy patient selection and optimizing chemotherapy duration. Another study published in 2021 from the Zhejiang University School of Medicine and the Sun Yat-sen University Cancer Center found a strong correlation between positive ctDNA test results and risk of recurrence. Even stage III CRC patients with negative ctDNA after surgery where the standard of care is automatically adjuvant treatment – may not need chemotherapy and can instead wait to see if their ctDNA results turn positive. As a significant percentage of stage III CRC patients could be cured by surgery alone, a ctDNA-guided approach to treatment may spare patients from the unnecessary drug toxicity and the financial burden of chemotherapy.
Another example is the GALAXY study in CIRCULATE Japan, where I am the principal investigator, which found that the presence of ctDNA post-surgery was more predictive of who would benefit from adjuvant chemotherapy (ACT) than any other factor, regardless of cancer stage. These results suggest that stratifying post-surgical treatment decisions based on the presence of ctDNA can identify patients more likely to benefit from ACT across all stages, including stage II, which would be an improvement to the current standard of care.
Barriers to adoption
In spite of growing clinical evidence, the adoption of molecular testing as a supplement to the current standard of care has a long way to go and must overcome a couple of hurdles. First, while early research is promising, more data demonstrating that patient outcomes may be improved through the use of these early molecular-based detection tools is needed.
Additionally, as the body of evidence increases, ctDNA testing must be incorporated into official guidelines. Current American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines do not address the clinical utility of molecular testing in guiding decisions about postoperative cancer treatment in CRC. Instead, they cite risk-based factors as the basis upon which treatment decisions are made, despite the fact that personalized cancer-detection tests are already clinically validated and now covered by Medicare in the U.S. Especially for stage II CRC, for which molecular testing could improve the standard of care – as demonstrated in the GALAXY study mentioned earlier, molecular testing could improve the standard of care for stage II CRC patients and could potentially spare many patients from the unnecessary physical and financial toxicities of ACT.
Though the cure for cancer is still many years away, sensitive and reliable molecular detection tools may be used to help alleviate the burden of a cancer diagnosis. As resources are poured into finding cures, we should be mindful of the lives that are currently being impacted by the disease and how we can improve how we care for this population now – which, in CRC alone, is about 1.5 million people. Helping patients reclaim their lives from cancer sooner should be a top priority, and by implementing tools such as molecular testing can help get the job done.
Photo: Main_sail, Getty Images
Dr. Takayuki Yoshino, M.D. PhD. currently works at the National Cancer Center Hospital East (NCCE) in Kashiwa, Japan, where he is the Deputy Director of Hospital and the Director for the Department of Gastrointestinal Oncology.
Dr. Yoshino has had over 250 peer-review scholar journal publications on CRC, with several articles published in the Lancet Journal, Journal of Clinical Oncology, the New England Journal of Medicine and Nature Medicine. In addition, he holds several professional appointments, serving on a Guidelines Steering Committee member of the European Society for Medical Oncology (ESMO), a chair of Pan-Asian adapted ESMO Guideline for CRC, an advisory committee member of American Society of Clinical Oncology (ASCO) Breakthrough, Editorial Board of ESMO/ASCO Global Curriculum, the Vice President of Japan Society of Clinical Oncology (JSCO) and the administrative board & a chair of international affairs committee of Japanese Society of Medical Oncology (JSMO).
