In December 2019, the novel coronavirus disease 2019 (COVID19) was first diagnosed in Wuhan, China, and initially presented in a small cluster of patients with severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) (1). Since its initial outbreak in the Hubei province of China, the disease has spread throughout the world, and it was formally declared a global pandemic by the World Health Organization (WHO) on March 11, 2020 . According to the Centers for Disease Control (CDC), as of the beginning of June 2020, nearly 6.3 million cases were diagnosed worldwide with 375,000 deaths. In the U.S., a total of 1.8 million cases were reported with nearly 110,000 deaths. It is interesting to note that the first case of COVID19 in the U.S. was diagnosed on January 20, 2020, which was the very same date as the first case of the disease reported in South Korea.
However, the subsequent course of the disease has taken dramatically different paths in the two countries, where a total of 12,003 COVID19 cases have been confirmed in South Korea with only 277 deaths reported as of June 12, 2020. In sharp contrast, in the U.S. nearly 2.1 million cases were recorded at that same date with nearly 120,000 deaths. Without question, COVID19 is a highly contagious disease, and it has dramatically affected the management of cancer patients in the U.S. and in countries around the world.
Cancer centers around the world have worked hard to modify their treatment strategies to appropriately manage their cancer patients during this pandemic. The two leading oncology associations in the U.S. and Europe, American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO), National Cancer Institute of Milan, Korean Cancer Association, and National Cancer Center, and an international collaborative group have published special reports on how to optimally manage and treat cancer patients during the COVID19 pandemic (2) (3) (4) (5) (6) (7) (8) . In this commentary, we provide a practical approach that was taken at our cancer center, the UPMC Hillman Cancer Center of the University of Pittsburgh, as representative of the strategies that have been adopted at other major cancer centers in the U.S.
There are currently two standard combined modality approaches to treat locally advanced rectal cancer. The first is to combine radiation therapy, usually administered over the course of about 5.5 weeks, with either infusional 5-FU or oral capecitabine. To avoid the need to come into the hospital for insertion of a central venous catheter and the potential complications associated with a central port, our approach during this pandemic has been to recommend oral capecitabine with radiation therapy. An alternative strategy would be to consider using shortcourse radiation therapy followed by neoadjuvant chemotherapy. In fact, at this year's ASCO 2020 Virtual Meeting, Hospers et al (9) presented the results of the RAPIDO trial (Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation), an international, multicenter, phase III randomized clinical trial comparing short-course radiotherapy followed by 18 weeks of either CAPOX or FOLFOX chemotherapy before total mesorectal excision (TME) to standard treatment with radiotherapy administered on weeks 1-6 combined with daily oral capecitabine for the duration of radiotherapy. This study showed an impressive doubling of the pCR rate from 14% to 28%, a 7% reduction in disease-related treatment failure and distant metastases, and an identical 3-year survival of 89% when compared to standard treatment. The potential advantage of this approach is that patients can significantly reduce the number of visits to the outpatient clinic for their daily radiation treatments, thereby avoiding unnecessary exposure to other patients and medical staff who may potentially be infected with COVID19. In addition, we would recommend the CAPOX regimen to be used as neoadjuvant chemotherapy, as opposed to FOLFOX, as this would eliminate the need for a central venous catheter.
The initiation of adjuvant chemotherapy for patients with early-stage colon cancer can be safely delayed for up to 8 weeks. However, studies from the Netherlands Cancer Institute and from a group of Chinese investigators showed that delayed adjuvant chemotherapy after 8 weeks was significantly associated with worse overall survival (10, 11) . For patients with stage II colon cancer, it is important for microsatellite instability (MSI) testing to be done to document the presence of MSI-high (MSI-H) disease as there is no clinical benefit from adjuvant chemotherapy in this particular patient subgroup. Thus, MSI testing can eliminate ineffective treatment, potential side effects, and unnecessary visits to the outpatient clinic that would increase the risk of exposure to COVID19. For patients with high-risk stage II and low-risk stage III colon cancer, the IDEA study has shown that 3 months of adjuvant therapy with CAPOX should be considered as non-inferior to 6 months (12). However, for patients with high-risk stage III colon cancer, it is clear that patients derive greater benefit with 6 months of adjuvant chemotherapy, whether it be CAPOX or FOLFOX. During this pandemic, the CAPOX regimen would certainly be preferred as it eliminates the need to insert a central venous catheter and an infusional pump, which would be required for the FOLFOX regimen.
For patients who present with advanced, metastatic CRC, there are several important factors that must be taken into account, and they include performance status, co-morbidities, tumor-related symptoms, tumor bulk, and site-limited disease with the goal of curative surgical resection. As has been previously noted, during this pandemic, we recommend using oral capecitabine, in place of infusional 5-FU, to serve as the fluoropyrimidine backbone for combination regimens with oxaliplatin and irinotecan. The use of oral capecitabine will help in reducing the frequency of in-hospital and outpatient infusional procedures. While patient preferences for experiencing certain toxicities such as neuropathy versus GI toxicity should be considered, during this pandemic an oxaliplatin-based regimen may be preferred, as the potential risk of serious GI toxicities and even myelosuppression may be lower when compared to irinotecan-based chemotherapy. In patients who are symptomatic and for whom a more immediate reduction in tumor bulk is required, an anti-EGFR antibody, either cetuximab or panitumumab, is recommended in the setting of wild-type RAS and BRAF disease. For patients with mutant RAS or BRAF disease, the anti-VEGF antibody bevacizumab is entirely appropriate. With respect to metastatic disease that is specifically confined to the liver or lungs and for which surgical resection is being considered after conversion therapy, it is still entirely reasonable to be aggressive. In this regard, the triplet regimen of FOLFOXIRI plus or minus cetuximab or bevacizumab is entirely appropriate. Obviously, one concern is the potential myelosuppressive effects of this regimen, which might then place patients at increased risk of infectious complications. To address this issue, a modified schedule of FOLFOXIRI can be considered with a reduced dose of infusional 5-FU from 3200 mg/m 2 to 2400 mg/m 2 and a reduced dose of irinotecan from 165 mg/m 2 to 150 mg/m 2 . In addition, the use of G-CSF should be considered as a prophylactic measure to reduce the risk of myelosuppression and the potential for infectious complications.
In the second-line setting, the main goal is to maintain clinical efficacy while minimizing toxicity. If a patient had been previously treated with a bevacizumab-containing regimen, continuation with bevacizumab at the time of disease progression is entirely reasonable and the use of alternative anti-VEGF therapies, such as aflibercept and ramucirumab should not be considered. The rationale for avoiding these other anti-VEGF agents is that they are clearly associated with more significant side effects, including myelosuppression and GI toxicity, when compared to bevacizumab. For sure, these side effects are to be avoided so as not to place patients at increased risk for developing COVID19 infection. In patients with BRAF V600E mutations, the updated results of the BEACON phase III clinical trial shows that the doublet combination of encorafenib plus cetuximab yields the same improvement in progression-free survival and overall survival when compared to the triplet regimen of encorafenib, cetuximab, and binimetinib (13) . While the overall response rate with the triplet regimen is better than the doublet (27% vs 20%), this is at the expense of increased overall grade 3/4 toxicity and, in particular, GI toxicity and anemia. For this reason, we recommend using the doublet combination of cetuximab plus encorafenib in the setting of BRAF V600E mutant mCRC.
In the third-line, disease-refractory setting, a key factor to consider is the overall performance status of the patient as well as whether there are symptoms associated with the disease. In the absence of tumor-related symptoms, it is entirely reasonable to proceed with best supportive care and to hold off on active treatments. If treatment is to be initiated, one possibility to consider is an anti-EGFR antibody therapy with either cetuximab or panitumumab, if not previously used and only in the setting of wild-type RAS and BRAF. While regorafenib or the oral fluoropyrimidine TAS-102 have equal clinical efficacy in this disease-refractory setting, regorafenib is preferred as it is not associated with myelosuppression, as is seen with TAS-102. To reduce the potential side effects observed with regorafenib, it would be important to consider alternative dosing schedules such as the ReDOS strategy (14) , the 120 mg/day 3-weeks on and 1-week off schedule, or an intermittent dosing regimen of 160 mg once daily for 1-week on and one-week off.
The COVID-19 pandemic has presented an unparalleled challenge to the delivery of clinical care to our cancer patients. In just the past 3-4 months, medical oncologists and other healthcare professionals involved in cancer care of patients with colorectal cancer have had to modify their approach to ensure patient safety while, at the same time, not compromising clinical efficacy. This commentary provides practical recommendations on how to approach patients with colorectal cancer during COVID19. While the hope is for the U.S. to return to the normal, pre-COVID19 practices, the on-going concern is that so many states in the U.S. are experiencing a continued rise in COVID19 cases. As a result, it is conceivable that we may need to continue with a modified approach for the foreseeable future until there is a significant reduction in the incidence of COVID19 infections.