Genitourinary cancer management during a severe pandemic: Utility of rapid communication tools and evidence‐based guidelines

Abstract Objectives: To determine the usefulness of social media for rapid communication with experts to discuss strategies for prioritization and safety of deferred treatment for urologic malignancies during COVID‐19 pandemic, and to determine whether the discourse and recommendations made through discussions on social media (Twitter) were consistent with the current peer‐reviewed literature regarding the safety of delayed treatment. Methods: We reviewed and compiled the responses to our questions on Twitter regarding the management and safety of deferred treatment in the setting of COVID‐19 related constraints on non‐urgent care. We chronicled the guidance published on this subject by various health authorities and professional organizations. Further, we analyzed peerreviewed literature on the safety of deferred treatment (surgery or systemic therapy) to make made evidence‐based recommendations. Results: Due to the rapidly changing information about epidemiology and infectious characteristics of COVID‐19, the health authorities and professional societies guidance required frequent revisions which by design take days or weeks to produce. Several active discussions on Twitter provided real‐time updates on the changing landscape of the restrictions being placed on non‐urgent care. For separate discussion threads on prostate cancer and bladder cancer, dozens of specialists with expertise in treating urologic cancers could be engaged in providing their expert opinions as well as share evidence to support their recommendations. Our analysis of published studies addressing the safety and extent to which delayed cancer care does not compromise oncological outcome revealed that most prostate cancer care and certain aspects of the bladder and kidney cancer care can be safely deferred for 2‐6 months. Urothelial bladder cancer and advanced kidney cancer require a higher priority for timely surgical care. We did not find evidence to support the idea of using nonsurgical therapies, such as hormone therapy for prostate cancer or chemotherapy for bladder cancer for safer deferment of previously planned surgery. We noted that the comments and recommendations made by the participants in the Twitter discussions were generally consistent with our evidence‐based recommendations for safely postponing cancer care for certain types of urologic cancers. Conclusion: The use of social media platforms, such as Twitter, where the comments and recommendations are subject to review and critique by other specialists is not only feasible but quite useful in addressing the situations requiring urgent resolution, often supported by published evidence. In circumstances such as natural disasters, this may be a preferable approach than the traditional expert panels due to its ability to harness the collective intellect to available experts to provide responses and solutions in real‐time. These real‐time communications via Twitter provided sound guidance which was readily available to the public and participants, and was generally in concordance with the peerreviewed data on safety of deferred treatment.


Abstract
Objectives: To determine the usefulness of social media for rapid communication with experts to discuss strategies for prioritization and safety of deferred treatment for urologic malignancies during COVID-19 pandemic, and to determine whether the discourse and recommendations made through discussions on social media (Twitter) were consistent with the current peer-reviewed literature regarding the safety of delayed treatment. Methods: We reviewed and compiled the responses to our questions on Twitter regarding the management and safety of deferred treatment in the setting of COVID-19 related constraints on non-urgent care. We chronicled the guidance published on this subject by various health authorities and professional organizations. Further, we analyzed peerreviewed literature on the safety of deferred treatment (surgery or systemic therapy) to make made evidence-based recommendations. Results: Due to the rapidly changing information about epidemiology and infectious characteristics of COVID-19, the health authorities and professional societies guidance required frequent revisions which by design take days or weeks to produce. Several active discussions on Twitter provided real-time updates on the changing landscape of the restrictions being placed on non-urgent care. For separate discussion threads on prostate cancer and bladder cancer, dozens of specialists with expertise in treating urologic cancers could be engaged in providing their expert opinions as well as share evidence to support their recommendations. Our analysis of published studies addressing the safety and extent to which delayed cancer care does not compromise oncological outcome revealed that most prostate cancer care and certain aspects of the bladder and kidney cancer care can be safely deferred for 2-6 months. Urothelial bladder cancer and advanced kidney cancer require a higher priority for timely surgical care. We did not find evidence to support the idea of using nonsurgical therapies, such as hormone therapy for prostate cancer or chemotherapy for bladder cancer for safer deferment of previously planned surgery. We noted that the comments and recommendations made by the participants in the Twitter discussions were generally consistent with our evidence-based recommendations

| INTRODUC TI ON
Since the initial reports in late December 2019 of respiratory illness caused by a novel coronavirus  originating in Wuhan, China, the disease has made its way to over 200 countries. 1 In a short span of less than 5 weeks from its initial report to the WHO, COVID-19 infection was declared a public health emergency, and within 10 weeks, it was declared a global pandemic 2,3 on March 11, 2020. As of April 20, 2020, over 2 400 000 COVID-19 cases had been reported globally, resulting in over 165 000 deaths. 4 With such an exponential increase in COVID-19 infections, many counties were caught unprepared for the massive demand on their healthcare system, including parts of China, Europe, and the USA. Our inability to perform wide scale testing to identify asymptomatic cases and perform appropriate contact tracing further accelerated the spread of COVID-19.
The COVID-19 pandemic exposed a universal lack of planning to deal with a highly contagious pathogen. It has created an unprecedented healthcare crisis and has demonstrated the potential to overwhelm large healthcare systems worldwide. The stark reality of shortages in viral test kits, personal protective equipment (PPE), intensive care beds, ventilators, and trained personnel was quite apparent. In the absence of effective treatments or vaccines, social distancing has been most effective tool to curb the rapid spread of COVID-19. This concept of mitigative social distancing also applies to patients and healthcare workers. At the epicenters of the COVID-19 pandemic (such as New York City, Wuhan, China or Italy), mandated cancelation of all nonurgent medical care is the only logical option. Even, in the regions that currently are not severely affected, a precautionary stance of reducing all nonessential medical care to maintain capacity in the system (supplies, personnel) to handle a projected surge in COVID-19 infections is required. In certain situations, >80% of patients may fit into the category of nonurgent or elective care. While this approach is prudent, its open to interpretation as to what is considered "essential or necessary" medical care, leaving a large gray zone between emergency and elective care.
As the pandemic unfolded, it became abundantly clear that the public health authorities and professional organizations had not prepared any specific guidance for such an event. Due to its highly contagious nature, new evidence of infectious and epidemiologic characteristics of the virus was emerging so rapidly that many of the earlier COVID-19 related recommendations regarding elective procedures became outdated within days. The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and the European Association for Endoscopic Surgery (EAES) recommendations in response to COVID-19 crisis were published on March 21, required updates within 8 days. 5 An international, multi-institutional editorial on triage of elective urological surgery was made public around March 18, but 1 week later, the authors commented that some of the recommendations may no longer apply. 6,7 The Association of Surgeons of Great Britain & Ireland published guidance on March 25 which essentially prohibited laparoscopic surgery due to concerns over escape of viral particle-containing CO2 aerosol and potential exposure of the surgical staff. After questions were raised by fellow professionals about the rationale and data behind the statement, the inter-collegiate guidance on surgical procedures required updates by April 5. 8,9

| Rapid communication with experts via Twitter
In the weeks after declaration of a global pandemic when governmental agencies and professional organizations were struggling to provide safe and practical recommendations, the responsibility for weighing the risk of COVID-19 exposure to their patients (and staff) and the risks of deferred medical care was also taken up by the physicians. For rapid exchange of information and communication with fellow physicians and specialists with certain expertise, many were reliant on social media, especially Twitter. 6 Herein, we will summarize the views, concerns and priorities expressed by many experienced specialists during three different discussions that took place on Twitter within 4 days. Discussions included practice patterns for prostate cancer (PCa) and bladder cancer management in the context for safely postponing cancer care for certain types of urologic cancers. Conclusion: The use of social media platforms, such as Twitter, where the comments and recommendations are subject to review and critique by other specialists is not only feasible but quite useful in addressing the situations requiring urgent resolution, often supported by published evidence. In circumstances such as natural disasters, this may be a preferable approach than the traditional expert panels due to its ability to harness the collective intellect to available experts to provide responses and solutions in realtime. These real-time communications via Twitter provided sound guidance which was readily available to the public and participants, and was generally in concordance with the peerreviewed data on safety of deferred treatment.

K E Y W O R D S
bladder cancer, COVID-19, pandemic, prostate cancer, Twitter of COVID-19 related constraints on medical care. Some of the discussion and comments of the participants, with the strength or frequency of recommendations are presented graphically in Figure 1.

| Prostate cancer
One of the earlier discussion was initiated by an urologist seeking opinions about prioritization of treatment of a 56 year old with multifocal high-grade PCa, Grade group (GG) 4 and 3. The discussion was joined by a number of experts from various specialties with comments revolving around the timing and type of treatment, including the rationale for their particular approach. Within 1 day, there were over 60 responses from 15 specialists from the USA, Europe, and Australia. This discussion (and other discussions below) took place in mid-March and should be viewed in the context of early stages of COVID-19 in some countries relative to Italy and Spain (Table 1).

It was nearly uniformly agreed that intermediate risk PCa treatment
should be safe to defer for 6 months without any oncological harm.
For high-risk disease, the rationale provided by some participants for proceeding with surgery was that, at the moment, the healthcare system is not overburdened, and a minimally invasive procedure will not excessively strain the resources. Some participants were adamantly opposed to any intervention in this scenario so that all PPE could be preserved for the potential surge in COVID-19 cases.
Others expressed concerns over the potential risk of COVID-19 exposure during surgery to themselves and to the medical staff from an asymptomatic, untested patient. It was discussed that testing the patients for COVID-19 virus before surgery could relieve some of these concerns, however, the tests are in short supply and not available for wider use. Some raised concerns that while it may be safe for a young patient with high-grade cancer to wait 3 months, it's unclear how long the pandemic-related restrictions are going to last.
Their rationale to complete as much of the essential cancer treatment as possible before the anticipated surge in infections results in prolonged, open-ended delays. The discussion was not limited to only the opinions of the experts. Their rationale was supported by providing peer-reviewed literature and real-time data such as availability of beds and PPE supplies from various medical centers. 10,11 The opinions, ranged from absolute no PCa surgery to cautiously proceeding with surgery, with daily assessment of the local situation in that hospital or region.

| Change in practice pattern
Because of the variety of opinions noted during the above discussion, we asked urologic oncologists whether their own practice of PCa management had changed, or will change, due to COVID-19.
Specifically, would they consider delaying PCa surgery or consider radiation therapy (RT) instead of surgery or would they consider adding androgen deprivation therapy (ADT) when delaying surgery.
In addition to the initially invited 12 urologic oncologists, the discussion was soon joined by additional specialists including radiation F I G U R E 1 Frequency and strength of recommendations with the location of specialists responding to Twitter discussions about prostate cancer management in COVID-19 constraints in regions other than the pandemic hotspots. *References provided by the respondents; Green: in support of treatment; Orange: in support of postponement. Darker shades: stronger or frequent comments oncologists from US and Europe. The discussants generally agreed that surgery for patients with intermediate-risk PCa can be safely delayed for 6 months. Others opined that since the potential duration of this pandemic is unknown and for some patients, it may already be 3 months since diagnosis, waiting for another 3-6 months could lead to adverse outcomes. This concern was further amplified for patients with high-risk PCa. The proponents of delayed surgery pointed to publications that delayed surgery was not associated with increased risk of biochemical recurrence. 12 This was rebutted by another participant that only 5% of patients in that study had high-risk PCa and only 7% were delayed for more than 6 months. The question about using neoadjuvant ADT to make it safer to delay surgery was met with spirited discussion. Some viewed using ADT for delayed surgery as merely providing peace of mind for the patient and the physician, but without any oncological benefit, citing a lack of strong evidence of benefits of neoadjuvant ADT. It was suggested that using ADT for delaying surgery for high-risk PCa, especially if the anticipated delay is going to be more than 3 or 6 months, is a safe intermediary which could make it easier to accept the delays.
Concerns were raised about ADT-related adverse effects which can be quite pronounced in some patients. Other respondents viewed neoadjuvant ADT as comparable to the current standard of care of using ADT before RT. They referenced a randomized trial showing no significant adverse effects from using short-term neoadjuvant ADT before surgery. 13 Use of RT was discussed as an alternative to surgery to avoid the oncological risks of delayed treatment and the risk of COVID-19 to the surgical team. At a time when resource conservation and COVID-19 exposure mitigation are overriding concerns, it was debated whether the use of medical resources and risk of exposure was higher during roughly 40 visits to the facility for RT as compared to overnight hospitalization for minimally invasive surgery. While radiation oncology colleagues offered changing the practice to hypofractionated RT in 20 fractions, many discussants (mostly urologic oncologists) did not view that approach as having a lower risk of exposure or resource utilization. Within 12 hours, the discussion thread was engaged over a thousand times, yielding more than 100 suggestions and comments from over two dozen specialists ( Figure 2). Many participants suggested that for high-risk PCa, surgery or RT may proceed if local circumstances are permissive. But if anticipated delay is more than 6 months from diagnosis of highrisk PCA, some suggested that the use of ADT may be discussed for a possible, but unproven oncological benefit due to its well-understood safety profile.

| Bladder cancer
A detailed discussion on March 20 was held to strategize about the safety and effectiveness of various therapeutic sequences to treat muscle invasive (MIBC) and non-muscle invasive (NMIBC) bladder cancer. Questions were asked about the best course of action for a patient with MIBC who finished neoadjuvant chemotherapy (NAC) 1 month ago and was scheduled for radical cystectomy in 2 weeks.
Should that surgery be postponed due to potential shortage of supplies or should the surgery proceed as scheduled, before there is a COVID-19 surge resulting in delay of 3-6 months? How best to quantify or justify the potential risk of COVID-19 exposure in the perioperative period or potentially worse oncological outcomes seen from the delay? Several of the uro-oncologists recommended proceeding with the definitive excision and utilize early recovery pathways for short hospitalization since the treatment offers the best chance at cure and delayed surgery is associated with worse survival outcomes.
In a follow-up discussion on March 22, participants from various sub-specialties were queried about their preferred therapeutic sequence for stage T2 MIBC including surgery and/or chemotherapy and/or RT. The discussants included a fair mix of urologists, medical oncologist and radiation oncologists from North America and Europe. Well over 100 responses within 1 day from dozens of experts about the rationale for their approach, and 320 votes were cast about the preferred initial management. Interestingly, 44% favored NAC alone (and defer surgery), 41% would proceed with radical cystectomy alone, and 12% choosing primary RT with chemotherapy. The recommendation for postponing radical cystectomy in favor of NAC was to mitigate the risk of COVID-19 exposure in the perioperative period. This idea was predicated on the significantly

| Communication with international urologists
Since mid-March several informal conversations were conducted via social media platforms including Facetime and WhatsApp with international urologists to obtain updates and learn how COVID-19 crisis had affected their lives, including scheduling of elective surgery. We also inquired whether there were deployments of urologists to different areas of the hospital that is, Emergency Department, Intensive Care Units, and other inpatient departments.

| Italy
After China, Italy hit the hardest in the early days of the pandemic.  22 These are likely to be followed by cancelation of other societies and regional conferences.
This will undoubtedly have a negative impact on the functions of professional societies, the research activities, the education of trainees, and on practitioners in both the academic and community setting for many months or even years to come. To mitigate some of the gap in educational activities many collaborative efforts have been initiated to provide distance learning via webinars and using surgical simulators to keep the trainees engaged in the learning process.
These efforts are great for didactic learning but the senior trainees in their final year will definitely be deprived of hands-on training as they look forward to opening a new chapter their careers as independent practitioners.

| E VIDEN CE FOR SAFE T Y OF DEL AYED SU RG ERY
Recent policies pertaining to elective surgery, generally set forth by administrative bodies, are meant to serve the communal interests of the population over the interests of an individual. Current guidance statements on elective surgery utilize equivocal terms such as "non-essential" or "non-critical," language that invites interpretation by individuals to identify those procedures needing prioritization vs those that may be safely delayed. 23

| High-risk disease
A more relevant question under current circumstances is about the optimal timing of intervention for high-risk PCa, and whether delays in therapy will impact oncologic outcomes. Several studies have evaluated the impact of delayed treatment for patients with high-risk disease. 36,37 A recent retrospective evaluation of 2,303 mean with GG 3 or higher clinically localized PCa compared pathologic and clinical outcomes among men who underwent radical prostatectomy within 3 months of diagnosis to those whose surgery occurred between 3 and 6 months after diagnosis. 37  In fact, a review of the National Cancer Database reveals that the contemporary use of neoadjuvant hormonal therapy prior to radical prostatectomy has increased slightly over recent years, particularly for high-risk cancer. 40 It is important to note that a therapeutic benefit for neoadjuvant androgen deprivation has only been definitively demonstrated in the setting of primary radiation. 41 Role of ADT before radical prostatectomy for high-risk disease remains undetermined. While several trials have demonstrated a pathologic benefit to neoadjuvant treatment among surgical patients, specifically reduced rates of positive surgical margin, 42 consistent improvement in recurrence-free or cancer-specific survival remains to be shown. 13,43 In circumstances prolonged delay in surgery is anticipated and concerns about oncological control exist, a short course of neoadjuvant ADT may be offered as a temporizing measure after careful consideration. It is unlikely that ADT prior to surgery for high-risk PCa will results in any more significant adverse effects than those noted during ADT and RT.  46 Theses findings are consistent with the results of a more recent prospective study which demonstrated a cancer-specific survival of 100% with AS for SRM. 47 Thus, in times of deferred elective surgery, physicians should integrate surveillance strategies for SRM into decision-making algorithms. 48 For patients in whom primary treatment for SRM is recommended or desired (younger, healthier) these data serve to provide reassurance to patients and physicians that deferred intervention for over 6 months is highly unlikely to compromise survival outcomes.

| Inferior vena cava tumor thrombus
On the opposite end of kidney cancer spectrum are renal cell carcinomas exhibiting tumor thrombus extension into the renal vein or inferior vena cava. These tumors should be regarded as high-risk because without treatment, the median survival for these patients is only 5 months and 1-year cancer-specific mortality over 70%. 49 Treatment delays pose potential for tumor thrombus propagation, which not only increases the complexity of the surgery, but also heightens the risk for venous thromboembolic events to as high as 6% prior to surgery. 50

| Muscle-invasive disease
Muscle-invasive bladder cancer (MIBC) is an aggressive disease that carries high risk for metastatic progression, including a relatively high incidence of relapse even after radical cystectomy. 63 Given the association with occult metastases at time of diagnosis, the accepted standard of care currently involves administration of platinum-based NAC based on evidence of 5% overall survival benefit and 9% disease-free survival benefit, especially if initiated within 2 months of diagnosis. 64,65 Nevertheless, many patients are not candidates for NAC, particularly those with compromised renal function or unfavorable comorbid status. These individuals should be prioritized for radical cystectomy. Several studies have demonstrated that surgical delay of 2 or 3 months can adversely impact survival outcomes, thus allowing a narrow window of flexibility. 66,67 In a study of patients undergoing upfront radical cystectomy, surgical delay ranging between 60 to 90 days from time of bladder cancer diagnosis to surgery or from time of transurethral resection to surgery were associated with a 34% and 18% increase in risk of death, respectively. 66 For patients completingNAC, surgery should similarly be performed in a timely manner as delays in radical cystectomy have also been shown to confer poorer prognosis in this cohort. 67 Its critically important that while we consider the sequence of treatment, we must also balance the direct risk to the patients from treatment, either upfront cystectomy or NAC, the frequency of medical encounters, the risk of readmission or ER visits, and the risk of COVID-19 infection in the perioperative period or during 3-4 cycles of cisplatin-based chemotherapy. In this regard, we must carefully consider the net survival benefit from NAC, which appears to be relatively modest, and cystectomy which is the primary curative treatment. Radical cystectomy requires hospitalization for an average of 6 days and utilizes additional resources such as anesthesia services and PPEs, with roughly 25%-30% risk of readmission. 68 Use of NAC requires multiple medical encounters, for infusions and laboratory testing, requiring multiple PPEs for each encounter. As noted above, cisplatin-based chemotherapy regimens are associated with immunosuppression, neutropenia, chemo-induced GI symptoms all of which result in ER visits and hospital admission in up to 20% of patients.
Further, the demographics of MIBC patients are of particular concern for COVID-19 infection because, even at baseline, these include all of the high-risk features including age, co-morbidities, and malignancy. Thus, adding immunosuppressive therapies such as cisplatin-based NAC will increase the risk of acquiring COVID-19 infection. A computational oncology modeling study estimated that the now well-established age-related COVID-19 case fatality rate (CFR) could increase by 3-to 12-fold in patients receiving chemotherapy. 14 The authors estimated that with a 5% benefit from chemotherapy, the age-related baseline CFR for a 70-year patient who acquired COVID-19 infection would be higher than the 5% benefit from chemotherapy and could increase threefold by adding the effects of cancer and chemotherapy. Thus, using NAC to defer surgery may not the best option for most patients. Combination of RT and chemotherapy has been used quite successfully, especially in European centers, and are likely less immunosuppressive than cisplatin-based NAC. While the protocols vary, however, these bladder-preservation protocols are no less labor-intensive as these require dozens of visits to the hospital and are challenged by the same factors mentioned above for NAC.
In treating MIBC, the guiding principle is that we should employ the most effective single therapy first which provides the best survival outcomes. Both NAC and adjuvant chemotherapy provide important but limited survival benefit, thus may be offered on case by case basis to those who are strong candidate to receive cisplatin. RT and chemotherapy can be offered as an alternative, if cystectomy is not desired or possible, especially if these can be delivered in facilities that are separate from the main hospitals to reduce personal contacts and COVID-19 exposure. The desired sequence of treatment is subject to the COVID-19 related constraints placed at hospitals in that region, at that moment in time.

| Non-muscle invasive disease
Non-muscle invasive bladder cancer (NMIBC) is a more heterogenous entity, sub-stratified further into low-and high-risk groups. The cumulative incidence of progression to high-risk NMIBC was only 8%, whereas that to muscle-invasive disease was 1.8% over a median 7-year follow-up period. 69   Post chemotherapy residual retroperitoneal mass may be managed based on size and histologic criteria. Small mass (<3 cm) after chemotherapy, especially seminoma, is safe to observe and a period of monitoring with serial imaging can risk-stratify these patients.

| Metastatic germ cell cancer
Larger residual retroperitoneal masses require retroperitoneal lymph node dissection (RPLND) to consolidate the curative intent.
Due to the low incidence of this disease, the data on the safety of decayed RPLND is scant but delays in surgical care, particularly exceeding 3 months, have been shown to significantly compromise survival. 86 Due to the favorable demographics of this cohort (young, healthy), absence of alternative therapies at this stage, and the curative nature of these interventions, RPLND for residual mass should be prioritized.  Interestingly, while performing our review of evidence-based safety of deferred treatment, we found that the discussion and responses during Twitter discussions were generally concordant with the evidence-based recommendations presented above.

| SUMMARY
Thus, during times of crisis when urgent exchange of information is desired, real-time discussions on a public forum, such as Twitter, with experts in their fields appears to be quite feasible and useful.
Because of the open format, the responses are subject to rebuttal and critique. Such a discourse can potentially yield a robust set of recommendations.
Within GU oncology, there exists a sufficient degree of heterogeneity in cancer biology among our most commonly encountered malignancies. This allows us to prioritize the surgical (and non-surgical) care, utilizing an evidence-based approach for safely deferring certain treatment. Further, it is likely that deferred medical care will identify certain postponed interventions (ie, surveillance, frequency, radiology, labs) which resulted in no harm. These low value interventions may no longer be considered essential, requiring us to adjust the clinical guidelines. Our recommendations are subject to change as the landscape of COVID-19 pandemic changes in different regions. As more accurate testing, effective treatment and vaccines become available, cancer care will be ramped up on a regional basis, depending upon the COVID-19 burden at that time.