key: cord-0978190-t4fhmmn1 authors: Lou, Emil; Subramanian, Subbaya title: Changing oncology treatment paradigms in the COVID-19 pandemic date: 2020-05-14 journal: Clin Colorectal Cancer DOI: 10.1016/j.clcc.2020.05.002 sha: 0f41eb2da377dfb5715119a71c1be7b58ffcb7ab doc_id: 978190 cord_uid: t4fhmmn1 nan The COVID-19 pandemic has forced the oncology community to quickly reassess and adapt standard-of-care practices in an effort to minimize risk of COVID-specific infection-related morbidity to cancer patients. Newly released analysis confirms deep concerns that patients with cancer undergoing active treatment, and/or with intact metastatic disease 1 , are among the most particularly vulnerable patients amidst this pandemic. Physicians and care teams helping patients with cancer have had to make or at least consider difficult decisions, including how to best balance the risk-safety profile of cancer treatment with emerging and rapidly evolving risks associated with COVID-19 infection and the broad range of potentials sequelae of this infection. This overarching concern is especially present for patients with gastrointestinal (GI) cancers, which represent a particularly broad set of diverse disease entities that require multi-speciality input and management. Along with the significant delays in cancer treatment, colorectal cancer (CRC) screening has also dropped down to 86-94% 2 . Alarming data are emerging to support the hypothesis that the severity of COVID-19 increases in the elderly population and in patients with comorbidity. CRC generally affects people above 60 years of age, and COVID-19 further increases the risk for CRC patients, and patients with GI cancer in general, due to immunosuppressive treatments they receive. Our institution was one of ten cancer centers that recently published potential modifications that could be incorporated to help minimize patient safety for patients with GI cancers during this challenging time 3 symptoms. Although the overall times to ICU admission and mechanical ventilation were not as short as in the lung cancer population, nonetheless these statistics should sound the alarm to reexamine how our GI cancer patients can best be treated as safely as possible during this ongoing pandemic. This point is especially crucial considering the many unknowns we face as a society in the months (and perhaps years) to come, including impact on health care of cancer patients with anticipated second and third waves of infection, and beyond. With these significant risk and potential treatment delays, managing anxiety in CRC patients is critical during the COVID-19 pandemic. There are numerous practical adaptations and modifications for treating patients with GI cancer safely from a logistical point of view, expanded upon elsewhere 3 , that can help ease patient concerns. Transitioning patients to oral chemotherapeutic drugs in an effort to minimize in-clinic exposure to COVID-19 infection is just one specific example that can be easily implemented. However, from a broader and more strategic standpoint, now is the time to wholly reassess some strategies in this patient population, for standard-of-care but most especially for rational clinical trial design. We are and will continue to be forced to make this reassessment from every angle, including feasibility to avoid worsening already concerning extent of financial toxicity to patients, avoiding overburdening surgical staff due to a backlog of delayed surgeries, and ongoing concerns about availability of protective personal equipment (PPE), among many issues. For example, a specific patient subset that merits careful attention is the cohort of patients with localized and potentially resectable forms of cancer that were diagnosed just prior to or during the pandemic. Under normal circumstances such patients would routinely be scheduled for surgical resections as part of an intent-to-cure strategy for treatment; this is the case for multiple types of cancers, including early-to-mid stage forms of colorectal cancers, which have not to date met standards for the label of 'immunogenic' or otherwise 'hot' tumor targets for immunotherapy. However, the rapid expansion of the current crisis has not only forced cancellation of elective surgeries, but also made the need to assess risk/benefit ratio of proceeding with surgery during the pandemic vs. trying alternate strategies (e.g. chemotherapy prior to surgery) in order to delay surgery and thus minimize intra-and peri-operative risk of COVID-19 infection. Let us use the concept of neoadjuvant/upfront chemotherapy approaches, such as that used in the FOxTROT trial, as an example whose intent may be repurposed in the current setting. This trial, with results reported at the ASCO Annual Meeting in 2019 7 , was an attempt to examine the potential utility of 6 weeks of upfront/neoadjuvant-intent FOLFOX chemotherapy treatment for patients with non-metastatic resectable colon cancer in patients with advanced T stage (T3-T4), clinical N0-N2, and M0 disease prior to surgical resection. Although there was no significant improvement in overall survival compared to upfront surgery, the report of histological regression in 59% of patients who received neoadjuvant chemotherapy opened the door to consideration of alternative strategies and tactics, including sequence and timing of administration of standard as well as novel treatment modalities. [Note: the authors of this editorial were not involved in the design, administration, or any other aspect of this trial; we are citing the strategy as an example but not promoting its widespread use without further analysis]. While neoadjuvant chemotherapy may not be a current standard of care for resectable colon cancer, considering this approach for elderly patients, for example, and/or patients with other significant morbid conditions might confer potential benefit by postponing current risks of surgical intervention and potentially alleviate the congestion of OR schedules that many centers are facing and probably will face in the coming months. At least one group has published considerations of a similar strategy for patients with colonic (non-rectal) cancers 5 . Cancerdirected benefits would include potential for suppressing tumor growth while viably delaying surgery, and reducing the burden of micrometastasis, rationale that is the same for the growing adoption of this strategy for resectable pancreatic cancers 8 and with rectal cancer using the 'total neoadjuvant therapy' (TNT) approach 9, 10 . On the flip side, veering from the established standard of care also harbors risks, including progression of higher stage tumors that were resectable at time of diagnosis, and any neoadjuvant approach would be detrimental to any patients with near-obstructive or bleeding tumors at risk for colon perforation. Another drawback of the FOxTROT approach would be uncertain value without full lymph node sampling -the risk would be overtreating patients who ultimately were found to be 'downstaged' to stage I or II colon carcinoma, leaving uncertainty as to whether their cancer had already been at that stage, and negative nodal status, at the time of diagnosis. It would further be more challenging to adequately assess response to therapy, unless it were done via endoscopy to complement radiologic assessment, and biomarker assessment of carcinoembryonic antigen which may not be of much utility in half of patients who have normal baseline values at diagnosis 11 . The trial investigators noted that, while initial analysis was performed of the study population unselected for KRAS-status, there was an improvement of the hazard ratio when excluding patients with mismatch repair deficiency; the investigators' conclusion was that the neoadjuvant approach proposed by FOxTROT would be of most utility in patients with tumors without mismatch repair deficiency 7 . The trial is not yet published in its entirety, so some questions remain about the validity of this approach in larger cohorts and also among evolving changes in molecular targeted approaches for non-metastatic forms of colon cancer currently under investigation in other trials. Meanwhile, trial examining first-line treatment of patients with metastatic colorectal cancers with deficient mismatch repair may provide further insight; such trials were scheduled to be presented at the 2020 Annual Meeting of the American Society of Clinical Oncology, and are now expected to be presented May 29-31, 2020 in the form of a virtual meeting. If positive for significant response rate, that treatment strategy (checkpoint immune inhibitor for resectable dMMR tumors might be an alternate method to consider in future trial design as well, especially for vulnerable populations in vulnerable times. There are non-chemotherapy based timing strategies that also could be evaluated, and in turn better incorporated into rational clinical trial design in addition to validated tissue-based and blood-based biomarkers. Validated assessments that could predict 'aggressiveness' and growth curves of tumors would be a helpful tool in clinical decision-making, helping to determine which patients would not be harmed by delaying surgery during this pandemic, which patients would at least not be harmed by administering neoadjuvant chemotherapy until a safer time to perform surgery, and identifying those patients in whom the risk/benefit ratio tips toward benefit for not delaying surgery due to inherent risk of rapid tumor growth. The current pandemic has forced us to reexamine these questions in new light of more practical and non-biologic questions, most prominently in recent weeks the question of how to best ration personal protective equipment (PPE) to preserve it for the most crucial, necessary, and most urgent of medical cases. Many cancer-related surgeries are required as part of an intent-to-treat strategy; the challenge will be balancing the urgency with timing that would still serve the patient for best possible outcome, and still preserve the safety of healthcare workers. With the hanging possibility that the current wave of COVID-19 infections may not be the last in the months and years to come, this is a question that will recur and be necessary to address for the future as well as the immediate present. For this reason alone we must think creatively and proactively to question and reassess rational strategies for standard-of-care treatment approaches and also for clinical trial design taking all of these factors into account using available data. While such validated assessments may not exist currently, past studies may pave the way for such decision-making tools 12 . Such studies include biophysical and mathematical models of cancer cell behavior that identify patterns of tumor cell expansion, even occurring on the individual patient level 13 . At the convergence of mathematical oncology, cancer cell biology and immunology, there may be a meeting point that will help solve modern and urgent problems in practical cancer treatment by informing better timing of cancer treatment [14] [15] [16] . An adaptive therapy strategy and clinical trial design, based on prediction models of the evolution of cancer cell growth and response to drugs, are already being utilized for clinical trials in metastatic castrate-resistant prostate cancer 17 . There is opportunity to leverage the evolution of the field of medical oncology as well to better incorporate perspectives from experts in mathematical oncology and bioengineering to likewise address this important aspect colon cancer biology into the way we design trials with therapeutic intent, with arms that reflect appropriate changes based on changes in tumors identified using serial liquid biopsies (e.g. ctDNA, pharmacogenomically profiled circulating tumor cells, etc.) and other biologic tools. The sequence and timing of treatment administration should also be closely be reexamined, as the efficacy of treatment of MSI-H tumors in this immuno-oncology era may be enhanced by staggering timing with chemotherapy. For example, our recent preclinical studies showed that resecting tumor-draining lymph nodes in early-stage tumor significantly reduces anti-tumor immune response, and that sequential treatments with chemotherapies and immunotherapies improve tumor control 18 . This finding will require further extensive investigation but provides Routine cancer screenings have plummeted during the pandemic, medical records data show Modifying Practices in GI Oncology in the Face of COVID-19: Recommendations From Expert Oncologists on Minimizing Patient Risk Guidance for management of cancer surgery during the COVID-19 pandemic Strategy for the practice of digestive and oncological surgery during the Covid-19 epidemic Coronavirus pandemic and Colorectal surgery: practical advice based on the Italian experience FOxTROT: an international randomised controlled trial in 1052 patients (pts) evaluating neoadjuvant chemotherapy (NAC) for colon cancer Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial The impact of total neo-adjuvant treatment on nonoperative management in patients with locally advanced rectal cancer: The evaluation of 66 cases Rectal Cancer C: Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management The Goldilocks Window of Personalized Chemotherapy: Getting the Immune Response Just Right Different growth patterns of a cancer cell population as a function of its starting growth characteristics: analysis by mathematical modelling Metastases Growth Patterns in vivo-A Unique Test Case of a Metastatic Colorectal Cancer Patient Mathematical modeling of cell population dynamics in the colonic crypt and in colorectal cancer A Review of Cell-Based Computational Modeling in Cancer Biology Multidrug Cancer Therapy in Metastatic Castrate-Resistant Prostate Cancer: An Evolution-Based Strategy Chemotherapy but Not the Tumor Draining Lymph Nodes Determine the Immunotherapy Response in Secondary Tumors The authors have no competing interests to disclose.