key: cord-1024435-2e31a5b6 authors: Gulati, Shuchi; Muddasani, Ramya; Bergerot, Paulo; Pal, Sumanta Kumar title: Systemic therapy and COVID19: Immunotherapy and Chemotherapy date: 2020-12-26 journal: Urol Oncol DOI: 10.1016/j.urolonc.2020.12.022 sha: 15a21c7860a9a6eb05dc8297b3721b2150b9fc1f doc_id: 1024435 cord_uid: 2e31a5b6 As the novel severe acute respiratory syndrome coronavirus-2 related pandemic- Corona Virus Disease 2019 (COVID-19) has emerged, decision making in the context of cancer treatment has become more complex. The apprehension of using drugs that could adversely affect infected patients, the risk of not using life-saving treatments and the complexities related to the type of cancer itself, all must be taken into consideration before proceeding with treatment. Data from large registries such as COVID-19 and Cancer Consortium (CCC19), Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) and NCI COVID-19 in Cancer Patients Study (N-CCaPS) will hopefully provide granularity on the outcomes of patients with cancer who are infected with COVID-19. As these efforts are underway, this review aims to shed light on the management of patients with genitourinary malignancies being treated with systemic therapies while infected with COVID-19. A WHO-designated global pandemic of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged in 2020, infecting more than 20 million people worldwide and leading to more than half a million deaths as of August 14, 2020. [2] They reported higher rates of severe events among cancer patients, with clinically severe numerically higher among patients who underwent chemotherapy or surgery in the previous one month. [2] According to the COVID- 19 and Cancer Consortium (CCC19), the 30-day all-cause mortality in patients with active or prior cancer and confirmed COVID-19 infection was 13%. [3] The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry, which includes patients with only thoracic malignancies, reported an even higher mortality rate of 33%. [4] The proposed mechanisms that underlie the increased risk of COVID-19 complications among cancer patients include the immunosuppressive state related to cancer itself, the impact of multiple treatment regimens, as well as coexisting medical disease. Further, patients with genitourinary (GU) cancers are often older, smokers, are treated with drugs that have immunomodulatory effects (programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors) and possess unique needs in terms of surgery and perioperative chemotherapy, even in the localized setting. The current review will examine specific considerations to the treatment of GU malignancies in the context of the COVID-19 pandemic. The treatment of GU cancers has undergone a paradigm shift over the last few decades. Whereas chemotherapy remains important for specific indications, other forms of cancer treatment (targeted therapies, hormonal therapies and checkpoint inhibitors) now dominate this space. Several unique challenges exist in the treatment of patients with GU cancer suspected of being infected with COVID-19. Whereas a variety of options exist, chemotherapy continues to form the backbone of treatment in certain situations, including docetaxel for advanced prostate cancer or platinum-based chemotherapy for muscle-invasive and advanced bladder cancer. [5] -8 [6] For those diagnosed with advanced testicular cancer, chemotherapy remains the only option for patients seeking a potential cure. The effect of chemotherapy on disease outcomes among patients also infected with COVID-19 remains unclear, with conflicting results emerging from early studies. The aforementioned report from China by Zhang et al had shown a significantly increased the risk of adverse outcomes among those patients who had received cancer treatment within the previous 14 days (Table 1 ). [7] Notably however, this study reported data on only 28 patients, of which 10% had received chemotherapy. A further larger study from China reported data on 105 patients with cancer who also had a COVID-19 infection. The authors reported a higher rate of death and severe illness among patients who received immunotherapy or had undergone recent oncologic surgery, but not among patients who had received chemotherapy. [8] More recent data from the CCC-19 registry of an initial 928 patients has shown an increased risk of death among cancer patients; however, there was no significant association between systemic therapy in the past 4 weeks and the risk of death or serious complications. [3] Further analyses examining the association between type of systemic therapies and disease outcomes is yet to be published. In data presented from the TERAVOLT registry, univariate analysis suggested patients receiving treatment with chemotherapy alone were at an increased risk of death; however, this effect was not seen in follow-up multivariate analysis. [4] Whereas this data was limited to patients with thoracic malignancies, the final analysis found no association between type of systemic therapy (targeted agents, chemotherapy and immunotherapy) and survival. Finally, a study conducted by Tang The clinical conundrum related to the use of ICIs among patients infected with COVID-19 is more complex and nuanced as compared to the utilization of chemotherapy. This is likely due to the underlying mechanisms of immune modulation, as well as the concern for ICI related adverse events (perhaps most specifically pneumonitis) among those infected with COVID-19. There are varying data to describe the interaction between treatment with ICIs and viral illness. Pre-clinical data suggest that ICIs can activate cytotoxic T cells and reduce acute viral load in infected patients; however such models also showed the potential for hyperactivation of the immune system and secretion of inflammatory cytokines resulting in immune-mediated injury. [20] , [21] At the same time, ICI administration itself has also been reported to cause a induced immune activation may be a contributing factor in increasing mortality. [24] Theoretically, this could be augmented by ICIs. registry data concerning the impact of ICI based treatment and outcomes has not yet been presented, but will provide important insight and guidance given the large cohort size. The decision to treat patients with one-agent vs another is not a simple one. In a survey conducted among forty-one experts in treating patients with metastatic RCC, the preferred treatment in patients with favorable risk disease was pembrolizumab/axitinib for 53% independent of the pandemic, while only 35% of the experts chose an ICI based regimen during the COVID-19 pandemic. [25] RECOMMENDATIONS FOR PATIENTS WITH GU MALIGNANCIES (Figure 2 ) The management of patients with bladder cancer remains complex in the COVID-19 era due to the multiple treatment options, including chemotherapy and ICIs, that are approved by the FDA. There exists no granular data to help guide specific recommendations, however based on current data, it may be prudent to consider the following points. For muscle invasive bladder cancer (MIBC), immediate surgery may not be needed, however there are reports to suggest that a delay of more than 12 weeks in performing a radical cystectomy is associated with poorer outcomes. [26] Similarly, prospective data suggests that administering neoadjuvant chemotherapy prior to surgery is associated with improved survival in patients with locally advanced bladder cancer. [27] Therefore, it may be prudent to continue this treatment paradigm and administer neoadjuvant chemotherapy prior to surgery, with aggressive growth factor support to avoid hospitalizations and minimize the risk of exposure to COVID-19. If a bladder preservation technique is being considered for localized, muscle invasive bladder cancer, a hypofractionated radiation schedule may serve to reduce the duration of radiation treatment from ~6.5 weeks to 4 weeks; as these have been shown to be equivalent in a randomized controlled clinical trial. [28] Insufficient data exists regarding whether to utilize chemotherapy or ICI based therapy in the metastatic setting in the context of patients with a coexisting COVID-19 infection; however, the liberal use of growth factor among patients treated with chemotherapy is strongly recommend. In frail, elderly patients, it might be preferable to use ICI based treatments to avoid myelosuppression and repeat clinic visits or hospitalizations. In order to reduce the burden of repeat visits, one could consider administering pembrolizumab at a 400-mg/6-week dosing schedule, as this regimen is now FDA approved. Targeted agents, such as the FGFR inhibitor erdafitinib, should be the preferred agent among patients with FGFR2/3 alterations, given the low risk of myelosuppression with this agent. [29] In contrast, most myelosuppressive options, such as enfortumab, could be sequenced later. The management of RCC is similarly not clearly defined among patients also infected with study (avelumab/axitinib) was much lower, approximately 11%, however, the risk of exposure to COVID-19 must be balanced when making this choice, as avelumab requires administration every two weeks. A notable concern with high dose steroid administration for treatment of immune related adverse effects is patients may be at increased risk of contracting viral infections as a result of the immunosuppressive effects. [31] PROSTATE CANCER: The management of prostate cancer will also vary based on stage and risk categorization. In low-risk localized prostate cancer, it is likely appropriate to defer treatment. As disease staging advances, the use of drugs to inhibit androgen signaling become the backbone of prostate cancer management. There are conflicting reports regarding the benefit or harm of androgen suppression in patients infected with COVID-19. Both transmembrane serine protease 2 (TMPRSS2) and angiotensin converting enzyme 2 (ACE2) are known to be androgen dependent. While TMPRSS2 and ACE2 have been proposed as critical targets that enable the SARS-CoV-2 entry into host cells, further evidence is needed to clarify the role of androgen axis manipulation among patients with prostate cancer. [32] Recommendations from the National growth factor) to reduce the risk of complications and hospitalization incorporated as part of treatment. Systemic therapy recommendations for specific GU cancers in the COVID-19 era. As per NCCN guidelines, enrollment in clinical trials should be encouraged when feasible. In high-risk tumors types, the opportunity to participate in a clinical trial should not be overlooked. Examples of this include trials of adjuvant targeted therapy in FGFR3-mutated urothelial cancer, with an ongoing study exploring the FGFR3 inhibitor infigratinib in this setting. Given the high risk of recurrence among these patients, participation in trials such as this should still be encouraged. Type of treatment should also be given consideration in the context of clinical trial enrollment. one study from an academic medical center reported that none of their active study participants were required to stop protocol treatment as a consequence of the pandemic. [40] CONCLUSION In summary, the uncertainty and lack of clinical evidence regarding the management of patients with cancer and coexisting infection with COVID-19, has raised several important questions. Much of the data presented is based on the assumption that the virus will peak, however the current trends in both Europe and the US illustrate otherwise. As such, there is an urgent need to report cases to national registries so that information concerning clinical outcomes in the context of each cancer type and treatment can accumulate. Without this data, it will continue to be very difficult for clinicians to assess the safety and efficacy of various treatments in this complex and challenging time. Thus, as evidence builds, we must remain cognizant of how COVID-19 may affect a variety of patient outcomes and continue to refine treatment recommendations as such. Although COVID-19 vaccine trials have shown promise, their impact on the cancer demographic is yet to be understood. Patients with active cancer or a history of cancer are often excluded from a majority of vaccine studies. [41] Furthermore, there is much uncertainty as to whether treatment, especially immunosuppressive regimens, could affect the ideal time the vaccine should be administered or whether cancer patients will mount an adequate immune response. [42] Further, given this complex clinical picture, providers must engage with patients in a shared decision-making model. It is hoped that as more clinical and pre-clinical data emerges, and findings become more robust, the oncology community will be better prepared to manage the complex clinical scenarios brought forth by the COVID-19 pandemic. 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