Critical Developments in Colorectal Cancer with Dr Mark Lewis
Presentation by Dr Mark Lewis, MD, Intermountain Health
At the 2023 Meeting of the Oncology Nursing Society, Metro Denver Chapter (MDONS) Dr Mark Lewis from Intermountain Health provided an overview of some of the most important developments in colorectal cancer (CRC), the third most prevalent cancer in the United States. He began by noting that with the women’s health movement, many women in his practice have been dutiful and diligent about screening with regular mammograms, PAP smears, and so on, but, on the other hand, have never had a colonoscopy – which he calls “a preventable tragedy… because everyone has a colon.”
Critical Considerations in CRC Treatment
Dr Lewis noted that, in the setting of CRC, patients will often ask, what is their clinical stage, and how long they are going to live. In this regard, he noted that all patients who are classified as stage IV disease are not necessarily the same. For example, while one patient may have stage IV disease that has completely overrun the liver at multiple sites (“widely metastatic disease”), another patient can have a single metastatic site and will still be classified as stage IV (“oligometastatic disease”). Another critical parameter to consider is in which side of the colon, right or left, did the cancer originate; this is important because during the early development, the colon originates from 2 different anatomical regions, the midgut and the hindgut, so essentially the colon can be considered 2 organs. It is now known that sidedness matters in CRC, with right sided CRC (midgut derived) being more prevalent in women and having a worse prognosis overall, and left sided CRC (hindgut derived) being more common in men and having an overall better prognosis. There are also key molecular differences related to sidedness which are relevant for CRC treatment. For example, he noted results from the CALGB/SWOG 80405 trial, which showed, initially, no difference in event-free survival (EFS) for patients with metastatic CRC who were treated with chemotherapy + cetuximab (an anti-EGFR agent) versus those treated with chemotherapy + bevacizumab (an anti-VEGF agent). In a subsequent analysis according to sidedness, however, there was a 20-month difference in EFS for patients with right versus left-sided CRC, showing that patients with right-sided disease should not receive treatment with cetuximab. He noted this was one of the most important concepts to emerge in CRC treatment over the past decade.
Another critical parameter to consider in the setting of CRC treatment which Dr Lewis noted is whether the patient is able to tolerate chemotherapy treatment which is typically assessed by their fitness, or performance status (PS). In this regard, he noted the pivotal results of the KEYNOTE-177 trial, which showed, remarkably, that in fact there are some CRC patients with metastatic disease that can be effectively treated using an immunotherapy (pembrolizumab) without any chemotherapy at all, specifically those patients with deficient mismatch repair (dMMR) and microsatellite instability high (MSI-H) status. He noted that some have suggested this can be a new standard of care for this type of CRC, and “If we can avoid giving chemo, as oncologists, we should absolutely avoid giving chemo…” Despite these findings, however, Dr Lewis reviewed data showing that the opportunity for a chemo-free treatment alternative is being overlooked in a sizable proportion of patients. For example, in one study, only two-thirds (66%) of patients with stage IV CRC disease had been screened for their MMR/MSI status. The prospect of missing a third of patients who may be candidates for a chemo-free approach Dr Lewis regards as “simply unacceptable”, and suggest this should be an ‘opt-out’ approach whereby all patients with metastatic CRC should be automatically screened for these markers unless they actively opt-out. Dr Lewis described a checklist of critical parameters which are absolutely essential to consider for patients with metastatic CRC (Box 1).
Box 1. Checklist of Critical Parameters in Metastatic CRC
Sidedness – Which side of the colon did the cancer originate (right or left)?
Mutational Status/Molecular Markers – What is the patient’s KRAS/NRAS/BRAF status?
Mismatch Repair (MMR)/Microsatellite Instability (MSI) Status – dMMR/MSI-high or low?
Human Epidermal Growth Factor Receptor 2 (HER2) Status – Positive or negative?
Patient Fitness/Performance Status – Are they able to tolerate chemotherapy?
Can also be considered, but role is less clear at present:
Tumor Mutational Burden (TMB)
Consensus Molecular Subtype (CMS)
Adjuvant Therapy and Circulating Tumor DNA
Dr Lewis then moved into a discussion of using adjuvant therapy for CRC, which he considers “the hardest sell in oncology…” He noted that, while surgeons can be very thorough and use phrases like “they got it all”, there is always a chance for microscopic residual disease to be present, and “a cell left behind is a cell that, over time, can have a chance to grow…” He noted that, in stage III colon cancer, many, perhaps 50% or more of patients, can be cured with surgery alone, but because not all patients are, the default recommendation is to give adjuvant chemotherapy to all patients, a guideline which inevitably results in overtreatment for many patients. One development which Dr Lewis noted could be a path to resolving this clinical dilemma is the use of circulating tumor DNA (ctDNA), a marker which can be used to detect residual disease present in the blood following surgery. Dr Lewis noted that ctDNA can be a much more sensitive marker of residual cancer than, for example, carcinoembryonic antigen (CEA), which is frequently used as a CRC marker. The reason for this is that CEA is not cancer specific and can be elevated, for example, in cases of food poisoning. While the technology is new and there are benefits and risks at present to using ctDNA as a means to guide treatment decisions in CRC, Dr Lewis noted it may nonetheless offer patients the opportunity to possibly forgo the use of chemotherapy in the near future.
Dr Lewis then reviewed some of the key data for using ctDNA in CRC, which clearly show the utility of ctDNA as a prognostic marker, meaning that, for patients whose ctDNA test is positive after surgery (indicating the presence of residual disease) the probability for their cancer to recur is much higher than for those with a negative ctDNA test after surgery (indicating the absence of residual disease). Results from a large Japanese study of over 1000 patients (CIRCULATE) further show that for patients with resected stage I through IV disease who have a negative ctDNA test, the disease-free survival is nearly 100%, meaning that even stage IV patients could possibly be cured with surgery alone. Dr Lewis also reviewed data for high-risk stage II, and stage III CRC patients with a positive ctDNA test after surgery, showing that there is a clear and significant benefit of using adjuvant chemotherapy versus not. By comparison, Dr Lewis reviewed data showing that, for patients with a negative ctDNA test after surgery, there was no discernable benefit of using adjuvant chemotherapy versus not. The major caveat of using ctDNA which Dr Lewis highlighted was the significant psychological impact that a positive ctDNA could entail for the patient. Owing to the sensitivity of the ctDNA test, it may become positive up to one year prior to any radiologic evidence of a cancer recurrence, and it is not yet known whether intervening for these patients, with chemotherapy for example, would have any meaningful impact on their outcome. From this perspective, Dr Lewis emphasized the treatment principle of ‘never doing a test unless you know how to act on the result’. He further noted two ongoing trials that are investigating the potential for acting on a ctDNA test or not, including one in Japan, and one in the US, which offer the potential for stage II and stage III patients with a negative ctDNA test after surgery (who would otherwise have received adjuvant chemotherapy) to not receive any chemotherapy treatment. Forthcoming results from these trials, Dr Lewis noted, have the potential to change the current standard of care with adjuvant chemotherapy on the basis of ctDNA testing results.
Quick Summary
For patients with metastatic colorectal cancer (CRC), there are certain critical parameters which must be assessed for appropriate treatment (Box 1).
o Sidedness of cancer origin (right or left) is a critical determinant of treatment.
o Patient fitness for chemotherapy must be considered.
o Certain patients with metastatic CRC (dMMR/MSI-H) may never require chemotherapy.
The role of newer diagnostic tests in CRC, such as circulating tumor DNA (ctDNA), remains under investigation, and at present requires shared decision making with the patient.
ctDNA testing offers a real possibility to uphold the first standard of medical ethics in CRC treatment, “first do no harm”:
o “Treat the right people, don’t overtreat the wrong people…”
Speaker Disclosure Information: Dr Lewis reported no disclosures for this presentation.