Germ Cell Tumor Management in face of SARS-CoV-2:  Safe, Rational Modifications to Standard GCT Practice to Protect Public Health, GCT Outcomes, GCT Patients, and Health Systems.

This bulletin has been produced by a concerned group of international experts in germ cell tumors, has not undergone extensive peer-review and is not based on clinical data from germ cell tumor patients in the COVID-19. Keeping our obligations to public health, our patients and our health care systems in mind, these are our best recommendations for consideration gathered quickly across North America and Europe. We intend this to be a living document with regular updates as we gather more viewpoints and, critically, more clinical evidence as SARS-CoV-2 incidence of spread evolves stabilizes and declines. Ideas, comments and questions can be directed through theMednet and we hope to be able to aggregate and curate feedback on an ongoing basis. The contributors thank Drs Tandstad and Dahl for stimulating this urgent action.

Encouraging Millennial Public Health Champions- In this global challenge, older sicker populations will bear the brunt of the pandemic in terms of illness and death, but it is the younger generations that will be most important in “flattening the curve” through the current suggested public health interventions such as social distancing, reducing gathering size and hand and face hygiene.  GCT institutions and providers can use the special relationships between these providers and young GCT patients to encourage our grateful patients to play an outsized role promoting the public health solutions available to them. Institutions should be proactively and immediately communicating to current and past patients the opportunity and responsibility they have in becoming active partners in the solution, not the problem.

Current GCT patients without known exposures and without symptoms and past GCT patients. Little is known about increased susceptibility to SARS-CoV-2 infection or severity of COVID-19 illness in patients with a remote or current history of GCT. It is safest to assume that these patients are, at least, at the same or slightly higher risk of contracting the infection or having severe consequences of the illness as a similar age matched, non-cancer health matched risk group. There is no evidence that patients with prior exposure to bleomycin are at heightened risk of developing respiratory symptoms or have exaggerated symptoms compared to the general population. We would encourage open, forceful, and frequent communications of standard public health recommendations and specific and redundant instructions regarding contacting their health care providers should symptoms develop or there are prolonged known contacts with persons confirmed positive.

Current or past GCT patients with respiratory symptoms or fever. Create clear instructions regarding contacting oncology triage services for cancer patients with respiratory symptoms.  Reiterate communications plan with every necessary face to face visit. Communicate general public health recommendations through patient portals if available and other social media outlets. In patients requiring ongoing chemotherapy, specific patient education regarding bleomycin-related fevers which typically are managed with antipyretics +/-diphenhydramine and abate in almost patients within 24 hours of the bleomycin infusion. Patients who are receiving hematopoietic growth factors regarding recovery myalgias and management of these symptoms. Elimination or very judicious use of non-steroidals, use of alternative analgesics and non-pharmacologic approaches should receive special emphasis.

Considerations when planning GCT treatment or during active treatments. There are short term considerations that might improve the infectious profile for individual patients in active treatment or for the oncology care delivery system or both.

In creating a treatment plan, consideration should be given to, if possible, reduce the physical interface between the GCT patient and the physical oncology interface as well as decreasing periods of immunocompromise.

Early Stage GCT. In the short term, consider forgoing optional adjuvant treatments with adjuvant chemotherapy in CSI non-seminoma and seminoma or adjuvant EP or BEP after primary RPLND for small volume stage II seminoma or nonseminoma. Active surveillance is always a safe alternative and can reduce or delay prolonged contact with the oncology care delivery system. Such patients might be ideal candidates for management through telehealth and utilization of local laboratories and outpatient imaging facilities with video or telephonic evaluations and reporting of results

Newly diagnosed disseminated GCT requiring chemotherapy. The application of hematopoietic growth factors in GCT patients receiving chemotherapy is somewhat variable by region, availability, and IGCCC risk category. In the short term, in an abundance of caution, strong consideration of use of hematopoietic growth factors to diminish the incidence of neutropenia and infection should be made for all GCT patients receiving chemotherapy.

There is fairly strong consensus that patients with IGCCC intermediate and poor risk who require 4 cycles of three drug therapy should have consideration had for non-bleomycin containing regimens such as VIP with growth factor support. Advantages are avoidance of 360 units of bleomycin: a cumulative dose that is associated with a small but real incidence of bleomycin lung toxicity. Disadvantages are that VIP or TIP are typically more technically complex to deliver and is usually done as an inpatient and will reduce precious hospital capacity. Through the use of infusion pumps and home nursing, such regimens can be delivered as an outpatient, but it is challenging even at the best of times. Patients with IGCCC poor risk diseases are quite uncommon and, hopefully, there will be very few patients who have concurrent COVID-19 and a diagnosis of poor risk GCT. Such patients would be ideal to discuss with a high volume referral center. It is not an option to delay initiation of chemotherapy for IGCCC poor risk GCTs; SARS-CoV-2, COVID-19 or not. Certain patients with intermediate risk disease (intermediate risk by markers only without anatomic bulk disease) and concurrent significant viral illness might be observed very closely to allow symptoms to resolve and viral clearance to occur.

In the field of germ cell tumor management, there has been strong opinion both ways about the appropriateness of EP x 4 versus BEP x 3 in good risk germ cell tumors. Even our group was clearly split on this issue and we all firmly feel that now is not the time to try to resolve this definitively using SARS-CoV-2 to bolster the arguments one way or another and/or make complex decisions based on speculation or projections on what may or may not represent the biologic and clinical reality. It is a significant challenge to sort this considering the “known knowns”, the “known unknowns” and the “unknown unknowns.” The majority opinion forwarded by the North American and Australian contingents base the argument on the belief that there is a strong evidence base pointing to superior therapeutic outcomes for good risk GCT patients and easily managed short- and long-term toxicity for BEP X 3 compared to EP X 4. What is known is that EP X 4 adds at least a 25% increase to the duration of immunocompromise with the obligate 4^th course and the associated neutropenia and lymphopenia. What is obviously unknown is whether that additional duration of immunocompromise leads to higher rates of SARS-CoV-2 infections and illness.

In patients without SARS-CoV-2 and COVID-19, BEP x 3 in IGCCC good risk is preferred unless there is an ironclad contra-indication to bleomycin. In patients with concurrent good risk disease and COVID-19, there are no data and the majority of our group would recommend that proceeding with standard BEP or if you are uncomfortable with that, VIP X 3. It also must be remembered that patients with good risk disease can often have chemotherapy initiation be safely delayed to allow a week or two for viral clearance and resolution of symptoms

A minority of our group in North America and Europe favored a more cautious posture regarding bleomycin in good risk GCT patients and is as follows:

If SARS-CoV-2 is found in patients planning to start chemotherapy for good prognosis metastatic disease, we recommend that initiation of treatment may be postponed until symptoms are in regression. The patients should be closely monitored during this time with e.g. weekly checkups, weekly measurement of tumor markers, and biweekly imaging until initiation of treatment. It is important for patients not to have their prognosis worsen by moving from good prognosis to intermediate prognosis. Treatment should be given without bleomycin to reduce the risk of pulmonary toxicity and we recommend VIP x 4 in intermediate and poor prognosis patients. In good prognosis patients, we recommend EP x 4 or VIP x 3. Treatment should be given with hematopoietic growth factors.

If SARS-CoV-2 is found in patients already initiated chemotherapy for metastatic disease there is little evidence as to what is the correct treatment. In asymptomatic patients, treatment may be continued as planned with very close follow-up. Bleomycin should be omitted for the remainder of the treatment. Treatment should be given with hematopoietic growth factors. Patients with symptoms in this situation should be discussed on an individual basis with a high volume center/collaborative group.

Delays in surgical management should be kept to a minimum if possible. Outpatient procedures such as diagnostic biopsies or excision should not be delayed if possible. Judicious delays in post-chemotherapy surgery may be considered on a region by region basis and patient risk of delay.  Expert high-volume centers should develop strategies for surge capacity if required.

Curative-intent salvage chemotherapy and surgery should proceed as possible as appropriate to the regional medical environment. Regions or nations should develop short term strategies for consolidating these important technologies and experience to high volume centers e.g. high dose chemotherapy complex salvage surgery. Insurers should break down network and payment barriers in the short term to facilitate distributed expert management.

Palliative, non-curative approaches should seek to minimize contact with inpatient or outpatient services and include oral chemotherapy management, non-chemotherapy management and single dose radiation for bone metastases.

Active Surveillance/post treatment surveillance. Early stage patients on active surveillance and those who are on surveillance schedules after active treatment should, as much as possible be encouraged to stay on the selected surveillance schedule but to do it with as little physical contact with the cancer care delivery system as possible. Patients when at all possible can have blood work done remotely as well as cancer imaging in local facilities. Teleoncology solutions should be employed as much as possible to minimize physical interactions with health systems.

Patients with respiratory symptoms and scheduled for regular GCT imaging or blood work can be safely delayed for a week or two until resolution of symptoms or identification of cause.

Communications, Telehealth and Research

One likely short-term casualty of SARS-CoV-2 will be referrals to high volume experienced centers for second opinions or complex technologies. It is imperative that experts and high volume centers promote and communicate virtual and no cost visibility to our community partners. Formalized electronic consultative services should be opened up or developed de novo. Contact information and offers of remote access should be widely and frequently distributed.

In the short term, consideration of putting complex research protocols on hiatus particularly if participation in research increases contact with the oncology care delivery system or research staff.  In particular, clinical investigations exploring approaches that increase time within the system such as combined modality radio-chemotherapy in stage II seminoma might be safely put on hold until health care system capacity stabilizes.

The academic GCT community should develop an open clearinghouse for ideas, experiences, complications and communications regarding this challenging era in the history of management.  Rapid communication and dissemination techniques need to be refined and engagement with the cancer education and training system elements are paramount.

Contributors and Location:

Nabil Adra, Indiana USA

Hamed Ahmadi, California, USA

Doug Bank, Illinois, USA

Aditya Bagrodia Texas USA

Phillipe Bedard  Ontario Canada

Olav Dahl, Norway

Siamak Daneshmand, California USA

@Lawrence H. Einhorn, Indiana USA

Peter Grimison, Australia

Robert Hamilton, Ontario, Canada

@Andrea L. Harzstark, California USA

@Nadine Housri, New York, USA

@Rebecca H. Johnson, Washington, USA

Christian Kollmannsberger, British Columbia, Canada

@Mark A. Lewis, Utah, USA

Lucia Nappi, British Columbia, Canada

@Craig R. Nichols, Oregon, USA

@Bruce J. Roth Missouri, USA

Ben Tran, Australia

Torgrim Tandstad, Norway

Guy Toner, Australia

@David J. Vaughn, Pennsylvania, USA