The treatment of colorectal cancer has always been something of an art—but never more so than during the COVID-19 pandemic. The ASCO Post asked three experts in this malignancy to share their concerns and their approaches to achieving good patient outcomes while minimizing the risk of COVID-19 exposure.
Axel Grothey, MD
Johanna C. Bendell, MD
Scott Kopetz, MD, PhD
Axel Grothey, MD, is Director of GI Cancer Research at the West Cancer Center, OneOncology, Memphis. Johanna C. Bendell, MD, is Director of the GI Cancer Research Program at Sarah Cannon Research Institute, Nashville. Scott Kopetz, MD, PhD, is Professor of Gastrointestinal Medical Oncology and Co-Leader of the Colorectal Cancer Moonshot at The University of Texas MD Anderson Cancer Center, Houston.
Several Key Concerns
First, as Dr. Grothey noted, a diagnosis of any kind of cancer places patients at risk for illness. Besides their underlying immunocompromised status, they can have other conditions that predispose them to complications—for example, hypercoagulability (also believed to also be a risk posed by COVID-19). Should they become infected, patients with cancer are likely to have worse outcomes than those of their peers without cancer.
Oncologists therefore must perfect the balancing act between exposing these already-susceptible persons to the virus and adequately treating their disease. “My main concern is trying to ensure that the intensity of therapy is appropriate for the patient, given the potential risks associated with treatment,” Dr. Kopetz said. “In general, it’s understanding when our treatments are of marginal benefit, for the incremental risk.”
Dr. Bendell said she becomes concerned even before she prescribes treatment. “It’s about getting our patients diagnosed in the first place,” she said. “A lot of ambulatory centers closed. Screening colonoscopies, for example, came to a pause (though patients with symptoms still received them). The health-care system was providing only essential care. We are now seeing these centers start to reopen.”
Surgical delays were also seen, she added. “There was confusion as to the wording of some of the guidance that was issued, and some cancer surgeries were pushed out,” she said. Dr. Bendell and colleagues worked to clarify the guidance on treatment to amend this situation.
Dr. Grothey echoed Dr. Bendell. “I worry that some patients are getting undertreated or not treated in a timely manner because their workup is delayed. For my patients, their cancer is real. Cancer doesn’t wait for coronavirus, and patients don’t want to wait for treatment,” he said.
What Dr. Bendell wants the health-care system to realize is this: “Treatment of cancer is Tier 3—high acuity—and it should proceed.”
Addressing Risk for Myelosuppression
Myelosuppression is always a concern with cancer treatment. “Patients with myelosuppression may be more vulnerable to potential COVID-19 complications, and there could be value in trying to prevent this in patients,” Dr. Kopetz said.
The panelists agreed on several approaches for mitigating this risk (with further elaboration below):
- In appropriate patients, shift away from intensive regimens to less intense therapy (ie, give a doublet, not a triplet).
- Switch from intravenous therapy to oral: use capecitabine where possible, instead of infusional fluorouracil (5-FU).
- If using FOLFOX (5-FU, leucovorin, oxaliplatin), eliminate the bolus 5-FU, which is the most myelosuppressive component.
- Modify irinotecan-based therapies by starting at a lower dose; irinotecan is myelosuppressive.
- Based on risk, jump-start treatment with single-agent capecitabine, possibly adding oxaliplatin later.
- Choose regorafenib over tipiracil/trifluridine (TAS-102); myelosuppression is the key toxicity of TAS-102.
- Consider giving treatment breaks.
“What’s important is to assess every patient’s needs and use the least amount of treatment that is necessary to control the disease,” Dr. Grothey emphasized.
Fewer Touch Points
Risk mitigation also involves reducing contact with others who might be infected and, to this end, scaling back on visits to infusion centers and clinics is important. Here are some suggestions for reducing contact:
- With FOLFOX and FOLFIRI (5-FU, leucovorin, irinotecan), stretch intervals from every 2 weeks to every 3 weeks in patients who have their disease under control.
- Consider CAPOX (capecitabine/oxaliplatin) rather than FOLFOX; it can be given every 3 weeks and for a shorter duration (3 months vs 6 months) as adjuvant therapy.
- Use short courses of radiation therapy (5 × 5 Gy), rather than standard schedules.
- Use telemedicine liberally for consultations and follow-up.
- Limit the time the patient is in the clinic; for example, allow patients to go home after coming in for labs or imaging, and contact them by phone or computer.
Nuanced Approach to De-intensification
Obviously, de-intensification measures are not safe for all patients with colorectal cancer. The oncologists offered some examples of how they make these decisions.
“We recognize that, in some settings, the benefits of treatment would be modest compared to the risks; in that case, the question is whether it’s still worth treating as initially planned or whether we should rethink the approach. When this is a patient who’s already 5 months into a 6-month adjuvant chemotherapy regimen, we may say ‘That’s enough,’ and stop therapy early or switch to a single-agent regimen,” Dr. Kopetz said. “In others, it may mean avoiding a more intense cytotoxic triplet, like FOLFOXIRI (5-FU, leucovorin, oxaliplatin, irinotecan). For patients we are considering for a more intense regimen, we may now be more likely to give a doublet. In an older patient, we may revisit whether the oxaliplatin is warranted.”
According to Dr. Bendell, stage of disease and risk of disease progression, as well as age and overall health (ie, risk for infection), guide treatment decisions. Data from the Surveillance, Epidemiology, and End Results registry, for older patients with stage III colorectal cancer (Medicare beneficiaries) showed the benefit of oxaliplatin is very small, relative to non–oxaliplatin-containing regimens.1 These patients are also those most likely to be at risk from COVID-19.
“So, for this group, there’s much more of a discussion,” she said. “Do we want to include oxaliplatin, which is more myelosuppressive and may not give significant benefit, or use single-agent capecitabine? Also, for stage III patients in general, we can use data from the IDEA trial2 to discuss treatment for 3 months, rather than 6. This may be a way to truncate therapy and lessen risk.”
A patient under the age of 50 or so, on the other hand, has less likelihood of a bad outcome from COVID-19 infection. For average-risk, stage II patients, the discussion remains whether to give adjuvant therapy; if the answer is yes, oral capecitabine is the best choice. For stage III disease, Dr. Bendell often opts for CAPOX for 3 months, though she may push for FOLFOX for 6 months in younger patients with high-risk disease.
Although some have suggested that adjuvant therapy could be delayed, she is not convinced this is a good idea. “I would modify treatment, rather than delay it significantly,” she said.
Metastatic Disease: Treatment Breaks and Delays
Since “not all tumors grow rapidly in 2 months,” Dr. Grothey maintained that treatment breaks can be acceptable for some patients. He referred to results from the CAIRO3 trial, which evaluated maintenance therapy with capecitabine/bevacizumab vs placebo after first-line CAPOX plus bevacizumab.3 Upon disease progression, patients in both groups were retreated with CAPOX/bevacizumab until second progression. The primary endpoint, progression-free survival at the second progression, was about 3 months longer with maintenance therapy, but the overall survival difference was not significant. “Maintenance therapy did have some effect, but patients who were given a break and retreated upon disease progression did not lose a lot,” he noted. “You are balancing that against the risk of the patient getting exposed…. You make a judgment call based on age, preexisting conditions, race, gender, and so forth.”
Treatment delays are also highly individualized decisions. “If the patient has a couple of lung metastases that are not immediately threatening, for example, and I know that even if they double in size, it’s not a clinical problem, then I may delay treatment for a couple of months,” Dr. Grothey offered.
But treatment delays should be considered cautiously, he added. “I recently participated in a webcast with oncologists from Wuhan, which as you know was completely locked down. Patients with cancer did not receive treatment at all for 3 months. When the lockdown was over and patients were restaged, 50% of them were found to have clinically meaningful disease progression. We need to be careful, but we can harm patients in two ways: by treating them too aggressively and also by not treating them enough.”
Oncologists are also tasked with balancing the timing of surgery for resectable metastases, Dr. Kopetz said. “We have patients who would probably go to surgery after 2 months of initial chemotherapy. We are extending that timeline for some of them, trying to minimize the risk of going to surgery during the peak of the surge—when the demand for ventilators is high—without overtreatment resulting in liver injury, which can happen after 4 to 6 months of chemotherapy.”
For Dr. Bendell, a key issue is curative potential. “Where there is a chance that a patient could respond to chemotherapy and be converted to a potentially curative surgical candidate, I’d treat aggressively. If a patient is symptomatic and needs a response, I would treat more aggressively for response to alleviate symptoms and then shift quickly to maintenance therapy. If the patient does not have a chance for conversion to cure, I would choose a less aggressive regimen, like capecitabine plus bevacizumab,” she said.
Management of BRAF-Mutated Disease
BRAF-mutated tumors tend to carry a worse prognosis and therefore deserve intensive therapy. These patients are probably not good candidates for de-escalation of treatment or treatment delays.
“We still tend to be fairly aggressive in initiating treatment for BRAF-mutated colorectal cancer,” Dr. Kopetz said. While first-line FOLFOXIRI could be used, he currently favors FOLFOX, “trying to minimize use of a triplet,” he said. The BEACON trial, for which Dr. Kopetz was an investigator, found an overall survival benefit for encorafenib plus cetuximab, but the doublet is not yet approved in the front-line setting.4 It is possible to use the regimen in patients who have disease progression shortly after adjuvant therapy, he added.
Rectal Cancer: Neoadjuvant Therapy, Short-Course Radiation
For these colorectal cancer specialists, the treatment of rectal cancer has not changed considerably. Neoadjuvant therapy has become standard treatment in most cancer centers; therefore, many patients are already some time out from surgery. Radiation therapy, however, has changed and now tends to be delivered in shorter courses. This is a trend that is likely to stick, once the pandemic has passed.
Standard radiotherapy for locally advanced rectal cancer is 50.4 Gy delivered in 25 to 28 fractions, which requires patients to come for treatment 28 times in 5.5 weeks. Short-course radiotherapy totals 25 Gy in doses of 5 Gy over 5 days.
“There has been a shift (before the pandemic) toward recognition that a short course of five fractions may be as effective as standard radiotherapy, in certain settings,” Dr. Kopetz said. “During this period of time, the decision was made at MD Anderson to use a short course for all these patients.”
Crisis Prompts Reflection
COVID-19 has “prompted discussions by patients with cancer to have ‘what if’ conversations and to make living wills,” Dr. Kopetz observed. “It’s a positive to have those conversations sooner and more frequently with family and the care team, and I’m hopeful that trend will continue. I also think it forces us to look at everything we are providing in a new light and reassess the risk, benefit, and value of all components of care. If we’ve always done something one way, does that mean it’s the right way when the risks change?”
“COVID-19 will change the practice of oncology,” Dr. Bendell predicted, “but we want to maintain our standards.” This means the de-intensification of regimens, as described here, will likely not become routine practice, although one change will stick: the broader use of telemedicine.
Telemedicine Is Here to Stay
All three colorectal cancer specialists found these “remote visits” to be acceptable for general purposes. The need for the technology and, finally, its reimbursement by the Centers for Medicare & Medicaid Services, has assured that this technology will become an integral part of cancer care.
“I think there are certainly visits we can replace efficiently with telemedicine,” Dr. Kopetz has concluded. “My hope is that telemedicine will become an important part of delivering the right care in a way that’s convenient for the patient.”
Still, face-to-face at the computer is not the same as face-to-face in the office, the oncologists agreed. As Dr. Kopetz remarked, “We are so used to seeing patients face-to-face to get a sense of how they’re doing and to pick up on nonverbal cues that are important for reading between the lines. There are also nuances to symptoms that are very difficult to fully evaluate from a distance and, as a result, I never quite feel like I have the same sense of understanding of the patient’s current situation. While many visits can be conducted remotely, there are lots of conversations—like end-of-life discussions—that are difficult to have without being in the room with the patient.”
DISCLOSURE: Dr. Grothey has received honoraria from Aptitude Health, Elsevier, and Imedex; has served in a consulting or advisory role for Genentech/Roche; has served in an institutional consulting or advisory role for Amgen, Array BioPharma, Bayer, Bristol-Myers Squibb, Boston Biomedical, Daiichi Sankyo, and Lilly; has received institutional research funding from Array BioPharma, Bayer, Boston Biomedical, Daiichi Sankyo, Eisai, Genentech/Roche, Lilly, and Pfizer; and has been reimbursed for travel, accommodations, or other expenses by Amgen, Array BioPharma, Bayer, Boston Biomedical, Bristol-Myers Squibb, and Genentech/Roche. Dr. Bendell has served in an institutional consulting or advisory role for Amgen, Apexigen, Arch Oncology, Armo BioSciences, Array BioPharma, AstraZeneca, Bayer, BeiGene, Bicycle Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Cerulean Pharma, Continuum Clinical, Cyteir, Daiichi Sankyo, EMD Serono, Evelo Therapeutics, Five Prime Therapeutics, Forma Therapeutics, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Incyte, Innate Pharma, Ipsen, Janssen, Kyn Therapeutics, Leap Therapeutics, Lilly, Macrogenics, MedImmune, Merck, Merrimack, Moderna Therapeutics, Molecular Partners, Novartis, Oncogenex, OncoMed, Phoenix Biotech, Prelude Therapeutics, Relay Therapeutics, Sanofi, Seattle Genetics, Taiho Pharmaceuticals, Tanabe Research, TD2, TG Therapeutics, Tizona Therapeutics, Tolero Pharmaceuticals, and Torque; has received institutional research funding from Abbott/AbbVie, Acerta Pharma, ADC Therapeutics, Agios, Amgen, Apexigen, Arch Oncology, Arcus Biosciences, Array BioPharma, Arrys Therapeutics, AstraZeneca/MedImmune, Armo BioSciences, Bayer, BeiGene, Bellicum, Bicycle Therapeutics, Blueprint Medicines, Boehringer Ingelheim, Boston Biomedical, Bristol-Myers Squibb, Calithera Biosciences, Celgene, Celldex, Cyteir, CytomX Therapeutics, Daiichi Sankyo, Effector Therapeutics, Eisai, EMD Serono, Evelo Biosciences, Five Prime Therapeutics, Forma Therapeutics, Forty Seven, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Gossamer Biopharma, Gritstone Oncology, Harpoon Therapeutics, ImClone Systems, Incyte, Innate Pharma, Ipsen, Jacobio, Janssen, Kolltan Pharmaceuticals, Leap Therapeutics, Lilly, Macrogenics, Marshall Edwards, Merck, Merrimack, Mersana, Merus, Millennium Pharmaceuticals, Molecular Partners, Nektar, NGM, Novartis, Novocure, Oncogenex, OncoMed, Onyx, Pfizer, Pieris Pharmaceuticals, Phoenix Biotech, Prelude Therapeutics, Revolution Medicines, Relay Therapeutics, Rgenix, Sanofi, Scholar Rock, Seattle Genetics, Shattuck Labs, Sierra Oncology, Sorrento Therapeutics, Stem CentRx, SynDevRx, Synthorx, Taiho Pharmaceutical, Takeda, Tarveda Therapeutics, Tempest Therapeutics, TG Therapeutics, Tizona Therapeutics, Torque, Tracon Pharma, Tyrogenex, Unum Therapeutics, Vyriad, and Zymeworks; and has been reimbursed for travel, accommodations, or other expenses by Armo BioSciences, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Forma Therapeutics, Gilead Sciences, Ipsen, Lilly, MedImmune, Merck, Novartis, OncoMed, Roche/Genentech, and Taiho Pharmaceutical. Dr. Kopetz owns stock or ownership interests in MolecularMatch and Navire; has served in a consulting or advisory role for Amal Therapeutics, Amgen, AstraZeneca/MedImmune, Bayer Health, Biocartis, Boehringer Ingelheim, Boston Biomedical, Daiichi Sankyo, EMD Serono, Genentech, Holy Stone, Ipsen, Karyopharm Therapeutics, Lilly, Merck, Natera, Navire Pharma, Novartis, Pierre Fabre, Redx Pharma, Roche, and Symphogen; and has received institutional research funding from Amgen, Array BioPharma, Biocartis, Daiichi Sankyo, EMD Serono, Genentech/Roche, Guardant Health, Lilly, MedImmune, Novartis, Sanofi.
REFERENCES
1. Sanoff HK, Carpenter WR, Freburger J, et al: Comparison of adverse events during 5-fluorouracil vs 5-fluorouracil/oxaliplatin adjuvant chemotherapy for stage III colon cancer: A population-based analysis. Cancer 118:4309-4320, 2012.
2. Shi Q, Sobrero AF, Shields AF, et al: Prospective pooled analysis of 6 phase III trials investigating duration of adjuvant oxaliplatin-based therapy (3 vs 6 months) for patients with stage III colon cancer: The IDEA (International Duration Evaluation of Adjuvant Chemotherapy). 2017 ASCO Annual Meeting. Abstract LBA1. Presented June 4, 2017.
3. Simkens LHJ, van Tinteren H, May A, et al: Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): A phase III randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 385:1843-1852, 2015.
4. Kopetz S, Grothey A, Yaeger R, et al: Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med 381:1632-1643, 2019.
