Anti-cancer therapy and clinical trial considerations for gynecologic oncology patients during the COVID-19 pandemic crisis



# Introduction
The COVID-19 pandemic has rapidly and drastically changed the care of gynecologic cancer patients. Regardless of geographic location, COVID-19 will impact all practitioners; however, the degree will vary based on COVID-19 burden and available local resources. Given this variability, decisions regarding cancer care delivery should be individualized, and institutional and government mandates prioritized based on locoregional factors. Special considerations are needed with regard to decisions of systemic cancer-directed therapy and clinical trial enrollment during this unprecedented time. Chemotherapy and other anticancer treatments may result in significant immune compromise in patients, rendering them more susceptible to viral and other infectious illnesses. The recent Wuhan experience of 1524 patients reported in JAMA Oncology noted that the infection rate in cancer patients was double that of general population (OR, 2.31; 95% CI, 1.89-3.02) [bib_ref] SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in..., Yu [/bib_ref]. In addition, over 41% of COVID-19 infections were contracted in the hospital. Cancer patients admitted were at higher risk of severe events (composite endpoint: percentage of patients admitted to ICU, ventilated, or death) compared with patients without cancer (seven [39%] of 18 patients vs 124 [8%] of 1572 patients; Fisher's exact p = 0.0003). Lastly, patients who underwent chemotherapy or surgery within the previous month had a numerically higher risk of severe events [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref]. Though these were small series reported in China with differences in cancer care and no gynecologic cancer patients diagnosed with COVID-19 during the study period, the findings are informative in helping us understand the potential risks to our patients with cancer.
Given this information, we must carefully weigh the risk that COVID-19 presents to patients receiving anti-neoplastic therapy and participating on clinical trials. Traveling to treatment centers and interacting with the healthcare team increases patients' risk of COVID-19 exposure and transmission. Cancer treatment causes its own toxicities requiring acute care, and possibly hospitalization, and can increase severe COVID-19 infection risk via immunocompromise. Nonetheless, chemotherapy has a therapeutic benefit, and careful deliberation is required in the decision-making surrounding anti-cancer therapy and clinical trials management during this challenging time .

## Frontline considerations in covid-19 burdened regions
-Neoadjuvant chemotherapy for ovarian cancer compared with primary surgical debulking can reduce morbidity and reduce risk of hospitalization over primary surgical debulking especially in high COVID-19 burden areas [bib_ref] Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS):..., Kehoe [/bib_ref] [bib_ref] Neoadjuvant chemotherapy in advanced ovarian cancer: what kind of evidence is needed..., Vergote [/bib_ref]. -Delaying interval debulking surgery beyond 3-4 cycles of neoadjuvant chemotherapy can reduce morbidity and hospitalization for patients with ovarian cancer. -Choose regimens that necessitate the fewest infusion visits (i.e., q 3 week paclitaxel/carboplatin) [bib_ref] Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel..., Ozols [/bib_ref]. Consider avoiding/limiting the prescription of dose-dense, intraperitoneal, and HIPEC regimens. -Consider oral hormonal mono-therapy in patients with low-grade serous ovarian cancers. -For early endometrial cancer, treatment with progesterone therapy or a progesterone containing IUD may decrease bleeding and provide temporizing benefit if primary surgery is delayed for lower grade cancers [bib_ref] Updates on conservative management of endometrial cancer, Corzo [/bib_ref]. -For advanced/recurrent endometrial cancer consider the use of megestrol acetate, or megestrol acetate alternating with tamoxifen for endometrial cancer with endometrioid histology, or if estrogen/progesterone receptor status positive [bib_ref] Gynecologic Oncology Group s, Phase II trial of alternating courses of megestrol..., Fiorica [/bib_ref] [bib_ref] Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma:..., Thigpen [/bib_ref]. Oral everolimus/letrozole may have a better response rate compared to hormonal therapy alone but the impact of the increased toxicity and possible immunosuppression should be considered. -Avoid radiation if possible unless for curative intent (i.e., locally advanced cervical cancer) -For patients with recurrent cervical cancer who have received prior cisplatin, consider paclitaxel/carboplatin over paclitaxel/cisplatin based regimen due to shorter total time in infusion center and less toxicity [bib_ref] Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical..., Kitagawa [/bib_ref]. -For Stage IV primary high grade endometrial and cervical cancers, consider delaying/deferring non-curative treatment, especially if patients are older or possess significant co-morbidities unless to control symptoms that may necessitate/lead to hospitalization. Goals of care discussion are of paramount importance in this situation. General considerations for cancer directed therapy.
Prior to start of therapy -Consider goals of therapy: Frontline curative intent should be prioritized, maintenance therapy should be evaluated in terms of incremental survival benefit, and palliative treatment should be utilized to mitigate uncontrolled cancer symptoms that may lead to inpatient hospitalization -Transfer patients to infusion centers not at main hospital campuses where patients with COVID-19 are being evaluated and treated.
-Consider local administration of chemotherapy if a patient lives far from the current infusion site or it requires traveling to a COVID-19 "hotspot".
-Test for COVID-19 prior to cancer directed therapy if testing capabilities allow -Try to limit frequency of infusions; avoid weekly infusions -Consider single agent therapy or holding cancer-directed therapy for patients N65 years old, patients at any age with significant co-morbidity (DM, chronic lung disease and cardiovascular disease) or ECOG status 2 [bib_ref] Preliminary estimates of the prevalence of selected underlying health conditions among patients..., -R [/bib_ref]. Patients with these co-morbid conditions appear to be at higher risk for severe COVID-19 disease than those without. Fatality was highest in persons 85 years old, ranging from 10% to 27%, followed by 3% to 11% among persons aged 65-84 years, 1% to 3% among persons aged 55-64 years, b1% among persons aged 20-54 years, and no fatalities among persons aged 19 years [bib_ref] Severe outcomes among patients with coronavirus disease 2019 (COVID-19) -United States, -R [/bib_ref]. More recent reports note very few fatalities in 19 years age group. -Consider oral therapies over infusion-based treatments when appropriate; be mindful that some oral regimens may have more toxicities than infusion-based therapies. -With select exceptions (i.e. high risk GTD), avoid inpatient administration of chemotherapy, when possible. -Screen all patients for symptoms of COVID-19 and ensure temperature b99.5 prior to treatment and consider testing if possible, prior to chemotherapy During therapy -Utilize telemedicine to reduce the frequency of in person evaluation and allow for patients to proceed directly to infusion center for treatment.
-Obtain local collection of labs whenever possible.
-Consider liberal use of granulocyte colony stimulating factor. Prioritize home administration or use of pegfilgrastim on-body injector in lieu of return for pegfilgrastim on day 2. -Consider outpatient management of neutropenic fever when clinically stable with moxifloxacin 400 mg po daily or ciprofloxacin po 500-750 mg BID and Augmentin 875 mg BID po. Maintain close follow-up with daily phone contact for at least 3 days to ensure no clinical deterioration [bib_ref] Oral antibiotics for fever in low-risk neutropenic patients with cancer: a double-blind,..., Kern [/bib_ref].
Post-therapy -Delay imaging during or after completion of treatment to a post-COVID surge timeframe unless critical to patients' immediate care.
-Ensure that goals of care discussions with patients (including DNR/DNI status) are prioritized prior to or shortly after admission, even if via telephone or telemedicine. -Increase interval for routine port flushes to 8-12 weeks.
The general considerations outlined in Tables 1 and 2 should be utilized when deliberating front-line anti-cancer therapy. For specific treatment options see [fig_ref] Table 3: Front-line cancer-specific chemotherapy considerations for women with early-stage gynecologic malignancies during the... [/fig_ref] in selecting primary treatment for early stage and late stage gynecologic malignancies, respectively.
In advanced ovarian cancer the decision between primary debulking surgery (PDS) and neoadjuvant chemotherapy (NACT) must be made with respect to COVID-19 burden and available resources. Careful decision-making regarding surgery should be utilized in older patients, those with significant medical co-morbidities, poor nutritional status, and those who may require prolonged ICU/hospital stay or require nursing home/facility placement post-surgery. While NACT can avoid many of these challenges, it does require a biopsy for pathologic confirmation, and chemotherapy will still result in an immunocompromised state. Randomized phase 3 trials, including EORTC and CHORUS, demonstrated that NACT is not inferior to primary surgical cytoreduction with respect to overall and progression-free survival, with lower morbidity [bib_ref] Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS):..., Kehoe [/bib_ref] [bib_ref] Neoadjuvant chemotherapy in advanced ovarian cancer: what kind of evidence is needed..., Vergote [/bib_ref]. NACT in patients with advanced stage disease is a viable alternative to PDS when resources for surgical intervention are restricted during the pandemic crisis.
For high-grade serous ovarian cancer, a 3 week taxane/platinum regimen is optimal and dose-dense and intraperitoneal regimens should probably be avoided [bib_ref] Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel..., Ozols [/bib_ref]. With NACT, consider delaying interval debulking surgery beyond 3-4 cycles to reduce surgical morbidity and hospitalization in high COVID burden areas. Hormonal therapy has demonstrated efficacy in low grade serous ovarian cancer; consider transitioning from chemotherapy to hormonal monotherapy.
Progesterone therapy with megestrol acetate or levonorgestrel intrauterine device for early stage, grade 1/2 endometrioid endometrial cancer can be utilized in lieu of surgery due to limited capability secondary to resource limitations [bib_ref] Updates on conservative management of endometrial cancer, Corzo [/bib_ref]. In advanced stage endometrioid and/or hormone receptor positive tumors, oral megestrol acetate, or megestrol acetate alternating with tamoxifen can be utilized [bib_ref] Gynecologic Oncology Group s, Phase II trial of alternating courses of megestrol..., Fiorica [/bib_ref] [bib_ref] Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma:..., Thigpen [/bib_ref]. Increased efficacy of oral everolimus and letrozole must be balanced with greater toxicity and immunosuppression.
Radiation therapy should be utilized for curative intent. Chemoradiation offers improved survival in locally advanced cervical cancer and should be prioritized [bib_ref] Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in..., Lanciano [/bib_ref] [bib_ref] Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for..., Morris [/bib_ref] [bib_ref] Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer, Rose [/bib_ref]. For metastatic cervical cancer, use of q 3-week paclitaxel and carboplatin can reduce total time in infusion center and toxicity [bib_ref] Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical..., Kitagawa [/bib_ref]. Consider the overall survival benefit with bevacizumab versus risk of fistula and hospitalization in cervical cancer [bib_ref] Improved survival with bevacizumab in advanced cervical cancer, Tewari [/bib_ref].

## Maintenance therapy considerations
-If utilizing maintenance therapy, consider the risk/benefit ratio with respect to exposure and infection during infusion versus the risk of immunosuppression with PARP inhibitor (PARPi) therapy -While bevacizumab can delay recurrence in the primary and recurrent settings this treatment does necessitate frequent visits to the cancer center -Oral PARPi should be considered in patients with high benefit to risk ratio (i.e. BRCA1/2 mutations and HRD)
-Patients should wait up to 8-12 weeks for recovery of blood counts from front line chemotherapy prior to starting maintenance PARPi; if not recovered, consider not starting PARPi maintenance -Consider deferring/delaying IV maintenance therapy -The risk benefit ratio should be considered based on resources available and the risk for infection at the time of infusion -For patients currently on IV maintenance therapy review individualized COVID-19 risk factors and benefit of continued maintenance -For those in prolonged remission, consider holding maintenance therapy during COVID-19 crisis. Issues to deliberate when starting/continuing anti-cancer therapy in gynecologic oncology patients during COVID-19.

## Issue consideration
What is the goal of treatment for your patient?
- Are you impacting OS? Cure?
- Are you expecting meaningful prolongation of PFS? What is the health status of your individual patient?
- Can you assess their overall morbidity and mortality due to cancer? Use of Geriatric Screening G8 for older patients (9) What is the likelihood of toxicity from anti-cancer treatment?
- Utilization of CARG toxicity tool to predict grade 3-5 toxicity - http://www.mycarg. org/Chemo_Toxicity_Calculator Are there alternatives of similar efficacy which minimize toxicity from anti-cancer therapy and/or risk from exposure to the health care system?
- Oral agents (oral = non-toxic)
- Fewer in-person visits - Treatment holidays Consideration of oral or intrauterine options, when available: levonorgestrel IUD [bib_ref] Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer, Ledermann [/bib_ref] or megestrol acetate (23) for Gr 1/2 endometrioid histology [bib_ref] Treatment of low-risk endometrial cancer and complex atypical hyperplasia with the levonorgestrel-releasing..., Pal [/bib_ref] [bib_ref] High-dose megestrol acetate in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology..., Lentz [/bib_ref] Consider for score 0-1: MTX weekly 50 mg/m2 IM [bib_ref] Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational..., Osborne [/bib_ref] Can also consider dactinomycin for all low risk GTD to reduce number of visits but must weigh against toxicity and need for central access [bib_ref] Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational..., Osborne [/bib_ref] Two main classes of maintenance therapies FDA approved for ovarian cancer include IV anti-angiogenic agent (bevacizumab) and oral PARPi (olaparib, niraparib, rucaparib), [bib_ref] OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or..., Aghajanian [/bib_ref] [bib_ref] Incorporation of bevacizumab in the primary treatment of ovarian cancer, Burger [/bib_ref] [bib_ref] Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer..., Coleman [/bib_ref] [bib_ref] Investigators PE-OG, Niraparib in patients with newly diagnosed advanced ovarian cancer, Gonzalez-Martin [/bib_ref] [bib_ref] Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer, Ledermann [/bib_ref] [bib_ref] Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer, Moore [/bib_ref] [bib_ref] investigators SOE-O, Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed..., Pujade-Lauraine [/bib_ref] [bib_ref] Olaparib plus bevacizumab as first-line maintenance in ovarian cancer, Ray-Coquard [/bib_ref]. While both agents prolong progression-free survival, one must consider incremental benefit and the risk of traveling for infusion as well as the risk of immunosuppression and COVID-19 infection when selecting use. Oral agents are preferred and PARPi can be utilized especially in biomarker positive (i.e. BRCA 1/2 mutation and HRD) patients. When utilizing PARPi maintenance adequate time should be allowed for bone marrow recovery and consideration should be given to delaying initiation of PARPi . Selection of PARPi should take into consideration the need for laboratory analysis, and ease of modifications for toxicity and dosing via telehealth modalities. Thoughtful incorporation of bevacizumab with chemotherapy in high-risk disease (stage IV, symptomatic pleural effusion/ascites) may decrease symptoms more quickly and keep patients from needing hospitalization or other interventions; the risk of added toxicity must be considered. In the maintenance setting, consider bevacizumab use based on assessment of COVID-19 exposure risk vs. benefit.

## Considerations for surveillance and recurrent disease
-Routine surveillance of asymptomatic patients should be postponed as appropriate, or conducted via telemedicine. -Consider delaying start of new therapy for patients with asymptomatic recurrence (and/or CA125 only recurrence for ovarian cancer patients). -For patients with symptomatic, recurrent disease, choice of therapy should be predicated on minimizing exposure to other contacts, risk from therapy, and life expectancy/prognosis. -Consider lower dosing intensity and less myelosuppressive regimens to reduce lymphopenia and neutropenia. While the exact role of lymphopenia and neutropenia in COVID-19 infections remains unclear, lymphopenia has been described to be associated with poor outcome or more severe disease for patients with COVID-19 infections [bib_ref] Clinical and immunologic features in severe and moderate coronavirus disease, Chen [/bib_ref] [bib_ref] Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study, Tan [/bib_ref].
-In certain patients, oral therapies may be a preferred alternative to minimize visits and exposure to the medical setting. In patients with grade 1/2 endometrioid endometrial cancers, oral hormonal therapy regimens such as megestrol acetate or alternating megestrol acetate/tamoxifen can be considered [bib_ref] Gynecologic Oncology Group s, Phase II trial of alternating courses of megestrol..., Fiorica [/bib_ref] [bib_ref] Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma:..., Thigpen [/bib_ref]. PARPi can be used as treatment for BRCA associated or platinum-sensitive HRD ovarian cancers [bib_ref] Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation, Kaufman [/bib_ref] [bib_ref] Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label,..., Moore [/bib_ref]. Oral chemotherapies (etoposide or cyclophosphamide) are other options for patients with ovarian cancer [bib_ref] Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in..., Garcia [/bib_ref] [bib_ref] Sequential prolonged oral topotecan and prolonged oral etoposide as second-line therapy in..., Rose [/bib_ref]. -One should be cognizant of the risks and benefits of further therapy, considering the risk for potential COVID-19 complications. Best supportive care may provide better outcomes for patients in whom the likelihood of benefit from further therapy is low (e.g., platinumrefractory ovarian cancer).
Principles surrounding surveillance and treatment of recurrent gynecologic malignancies mirror considerations for front-line therapy and center around minimizing the risk of COVID-19 exposure and the risk of toxicity from therapy in these patients . While prospective data regarding early treatment of asymptomatic recurrence are limited, a randomized trial of 527 patients treated for recurrent ovarian cancer based on CA125 level alone compared to clinical or symptomatic relapse demonstrated no difference in overall survival between these two groups. Additionally, case series have reported that between 41 and 83% of endometrial cancer patients and between 46 and 95% of cervical cancer patients will have symptoms at the time of recurrence, even in the setting of surveillance, suggesting that remote telemedicine visits can identify many patients with potential recurrence [bib_ref] An update on posttreatment surveillance and diagnosis of recurrence in women with..., Salani [/bib_ref]. For patients in whom chemotherapy is being considered, emerging data have reported both higher rate of COVID-19 infection in cancer patients as well as increased risk of severe events, especially in patients who have received recent cancer-directed therapy [bib_ref] SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in..., Yu [/bib_ref] [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref]. As such, when making decisions about proceeding with therapy for recurrent disease and choice of therapy regimen, careful consideration must be made regarding the benefits of therapy in terms of symptomatic relief, survival, and prevention of hospitalization, compared to the risks of [bib_ref] Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel..., Ozols [/bib_ref] ; consider thoughtful incorporation of bevacizumab (i.e., stage IV, significant ascites) [bib_ref] Incorporation of bevacizumab in the primary treatment of ovarian cancer, Burger [/bib_ref] Chemotherapy followed by aromatase inhibitor therapy vs. aromatase inhibitor monotherapy [bib_ref] Hormonal maintenance therapy for women with low-grade serous cancer of the ovary..., Gershenson [/bib_ref] Platinum/taxane Chemotherapy every 3 weeksChemoradiation for curative cases [bib_ref] Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in..., Lanciano [/bib_ref] [bib_ref] Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for..., Morris [/bib_ref] [bib_ref] Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer, Rose [/bib_ref] Neoadjuvant chemoradiation [bib_ref] Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the..., Moore [/bib_ref] Inpatient EMA-CO for choriocarcinoma [bib_ref] EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272..., Bower [/bib_ref] EMA-EP for placental site trophoblastic tumor (PSTT) [bib_ref] Etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EMA) chemotherapy for patients with..., Newlands [/bib_ref] Single agent doxorubicin q 3 wks [bib_ref] Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced..., Seddon [/bib_ref] Preferred oral maintenance PARPi vs. bevacizumab use based on assessment of COVID 19 exposure risk vs. benefit or observation only Low threshold to transition to oral hormonal maintenance Avoid radiation unless indicated for curative intent Paclitaxel/carboplatin [bib_ref] Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical..., Kitagawa [/bib_ref] or taxane/platinum with bevacizumab every 3 weeks (weigh survival benefit versus risk of fistula) [bib_ref] Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical..., Kitagawa [/bib_ref] [bib_ref] Improved survival with bevacizumab in advanced cervical cancer, Tewari [/bib_ref] Aromatase inhibitors in ER + uLMS [bib_ref] Phase 2 trial of aromatase inhibition with letrozole in patients with uterine..., George [/bib_ref] Oral pazopanib [bib_ref] Outcome of uterine sarcoma patients treated with pazopanib: a retrospective analysis based..., Benson [/bib_ref] Consideration of oral options: megestrol acetate, or megestrol acetate alternating tamoxifen, oral everolimus/ letrozole, weigh increased toxicity over above hormone regimens [bib_ref] Gynecologic Oncology Group s, Phase II trial of alternating courses of megestrol..., Fiorica [/bib_ref] [bib_ref] Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma:..., Thigpen [/bib_ref] Stage IV and high risk for COVID-19 morbidity consider delaying/deferring non-curative intent treatment; goals of care discussion
Stage IV (high grade) and high risk for COVID-19 morbidity -consider delaying/deferring non-curative intent treatment; goals of care discussion increased exposure to the medical setting for therapy, possible complications of therapy, and potential for increased risk of COVID-19 infection or severity. Immunotherapy is increasingly used to treat gynecologic cancers [bib_ref] Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results..., Chung [/bib_ref] [bib_ref] Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer, Makker [/bib_ref]. Currently no evidence demonstrates that immunotherapy, in cancer patients, increases COVID-19 susceptibility. Strong overlap between immune-related (IR) pneumonitis and COVID-19 infection exists, including cough, dyspnea, fever and CT findings of ground-glass opacities and interstitial changes.

## Considerations for immunotherapy
Patients on immunotherapy with unexplained fever and pulmonary symptoms or new CT findings (symptomatic or undergoing bronchoscopy and/or corticosteroid intervention) should have COVID-19 testing. While corticosteroids are a mainstay of treatment of IR-related pneumonitis, steroids can prolong immunosuppression; increase risk of infections; delay viral clearance; and increase viral pneumonitis mortality [bib_ref] On the use of corticosteroids for 2019-nCoV pneumonia, Shang [/bib_ref]. Currently, the WHO and CDC recommend that corticosteroids not be used in treatment of COVID-19 viral pneumonia or ARDS unless indicated for another reason (asthma, COPD, septic shock).
Carefully evaluate anticipated benefit before starting immunotherapy. Pre-existing lymphopenia is associated with lower immunotherapy response and predicts more severe COVID-19 infections [bib_ref] Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study, Tan [/bib_ref] [bib_ref] Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients..., Diehl [/bib_ref]. Immunotherapy administration at higher dose and longer treatment intervals can decrease clinic visit frequency [bib_ref] A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R)..., Lala [/bib_ref].

## Considerations for older and medically vulnerable patients
-Consider the goals of care for the patient with respect to relief of symptoms or improvement in overall survival. -Evaluation of the patient's health status with respect to COVID-19 morbidity will help determine treatment -Determine how the toxicity from treatment will put the patient at risk -Decrease the frequency of visits to reduce the risk with less frequent schedules or oral alternatives
Older patients (65) and/or those with medical comorbidities are at significantly increased risk of morbidity and mortality if the contract COVID-19. In addition to general considerations to mitigate COVID-19 infections , consider assessment of frailty and prediction of toxicity risk in this most vulnerable population. The Geriatric 8 panel (G8) is a concise version of the geriatric assessment tool (18 items) and assesses frailty. The lower the score (b 14), the more frail the patient may be and the higher the risk for chemotherapy related toxicities. The 8-item scale may be completed by phone using the patient's reported weight [bib_ref] Detection of frailty in elderly cancer patients: improvement of the G8 screening..., Petit-Moneger [/bib_ref]. The Cancer Aging Research Group (CARG) toxicity calculator (http://www.mycarg.org/Chemo_Toxicity_Calculator) is a simple, complimentary, online tool that provides a percentage of chemotherapy related toxicity (grade 3-5) based on patient information and selected regimens. These assessments, combined with candid goals of therapy discussions, can help counsel older patients and assist with treatment decisions.

## Considerations for uterine leiomyosarcoma
-There is no proven benefit from adjuvant therapy in early stage uterine leiomyosarcoma -Single agent doxorubicin requires less frequent visits and may represent the best choice to limit visits during treatment -Oral tyrosine-kinase inhibitor, pazopanib is an approved treatment option for sarcoma [bib_ref] Outcome of uterine sarcoma patients treated with pazopanib: a retrospective analysis based..., Benson [/bib_ref].
The doxorubicin, ifosfamide, and the combination of gemcitabine and docetaxel represent the mainstays of front-line treatment for those patients with advanced or recurrent uterine leiomyosarcoma (uLMS). There is no proven benefit to adjuvant therapy in stage I or stage II uLMS [bib_ref] Difficult choices in stage I uterine leiomyosarcoma -it's okay to "stand there, Hensley [/bib_ref]. For advanced or recurrent uLMS the gemcitabine/docetaxel doublet has demonstrated activity in prior trials, but requires administration on days 1 and 8 of a 21 day cycle and is associated with significant hematologic toxicity, including neutropenia, necessitating use of granulocyte colony stimulating factors [bib_ref] Fixeddose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma:..., Hensley [/bib_ref] [bib_ref] Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV high grade uterine..., Hensley [/bib_ref] [bib_ref] Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase..., Hensley [/bib_ref]. Single agent doxorubicin is probably the optimal first-line treatment option during the COVID-19 crisis. In a phase III trial comparing doxorubicin q 21 days to the combination of gemcitabine and docetaxel every three weeks in patients with unresectable or metastatic soft tissue sarcoma, response rates, progression-free survival and overall survival were similar in both arms [bib_ref] Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced..., Seddon [/bib_ref]. Dose delays and dose reductions were frequent in both groups, with the main reason being febrile neutropenia. Singleagent doxorubicin in the front-line setting should be considered, after balancing these risks with gemcitabine/docetaxel and the patient's risk of cardiac dysfunction with doxorubicin during the COVID-19 crisis. Pazopanib is an oral tyrosine-kinase which represents an option with activity in uLMS [bib_ref] Outcome of uterine sarcoma patients treated with pazopanib: a retrospective analysis based..., Benson [/bib_ref]. Aromatase inhibitors have limited toxicity and can result in stable disease in patients with ER positive uLMS [bib_ref] Phase 2 trial of aromatase inhibition with letrozole in patients with uterine..., George [/bib_ref]. With all of these non-curative therapies, the toxicity and risk of viral infection during treatment must be weighed against the potential benefit of these therapies.

## Considerations for malignant germ cell tumors
-Stage I grade 1 immature teratomas can be followed without treatment
[59] -Stage I dysgerminomas can be followed without treatment but tumor markers including LDH, hCG, and AFP should be checked to exclude a mixed tumor [59] -Active surveillance could be considered in patients with complete staging who have a stage IA, grade 2/3 immature teratoma [60] -The risks and benefits of bleomycin should be considered due to the concern for pulmonary toxicity and the risk of respiratory failure with COVID-19 [bib_ref] Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized..., De Wit [/bib_ref] Malignant germ cell tumors are chemo-sensitive and curable tumors that occur in young healthy patients and should be high priority if resources are limited. Conservative therapy can be considered but complete surgical staging including omentectomy and lymph node assessment is critical if adjuvant therapy is omitted. Active surveillance in grade 2/3 immature teratomas is currently being investigated in pediatric studies. However, there is some indication that pediatric tumors may have a less aggressive biology [bib_ref] Prognostic factors in children with extragonadal malignant germ cell tumors: a pediatric..., Marina [/bib_ref]. Stage IA yolk sac tumors and embryonal carcinoma could possibly be followed without treatment in extremely resource limited settings. In all cases of active surveillance, tumor markers should be followed to make sure they decline appropriately.
Bleomycin can cause pulmonary toxicity in about 10% of patients and there is concern that this could increase the risk with co-existing COVID-19 infection [bib_ref] Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized..., De Wit [/bib_ref]. Bleomycin can be safely omitted in dysgerminomas with no detriment in survival [bib_ref] Adjuvant therapy of completely resected dysgerminoma with carboplatin and etoposide: a trial..., Williams [/bib_ref]. Based on the experience with non-seminomatous testicular cancers, the relapse rate increases by about 8% when bleomycin is not included in the chemotherapy regimen [bib_ref] Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized..., De Wit [/bib_ref]. Therefore, the risks and benefits as well as the resources and rate of viral infection should be carefully considered when considering this chemotherapy regimen.

## Considerations for gestational trophoblastic disease (gtd)
-Hysterectomy can be considered if fertility is not desired to reduce the need for chemotherapy if resources allow [64] -A second D&C will result in remission in 38% of patients [bib_ref] Second curettage for low-risk nonmetastatic gestational trophoblastic neoplasia, Osborne [/bib_ref] -Standard 5-day or 8-day methotrexate regimens are preferred in low risk GTD (WHO  6) [66,67] -A 5-day oral regimen has been described in low risk GTD with similar efficacy to IM regimens [bib_ref] Treatment of nonmetastatic gestational trophoblastic disease with oral methotrexate, Barter [/bib_ref] -Weekly methotrexate at 50 mg/m2 can be considered for very low risk disease (WHO 0-1) -Dactinomycin at 1.25 mg/m2 has been shown to be more efficacious than weekly methotrexate in patients with a WHO score  6 [69] -EMA-CO should be given to patients with a WHO score  6 even though this regimen requires hospitalization [bib_ref] Etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EMA) chemotherapy for patients with..., Newlands [/bib_ref] GTD is a chemo-sensitive and curable disease that occurs in premenopausal patients. A second D&C would be recommended to avoid chemotherapy in 38% of patients [bib_ref] Second curettage for low-risk nonmetastatic gestational trophoblastic neoplasia, Osborne [/bib_ref]. Either the 8-day or 5-day regimens are acceptable for women with a WHO score of 6 but both regimens require frequent visits for the injections which may increase exposure to viral infection [bib_ref] The role of low-dose methotrexate and folinic acid in gestational trophoblastic tumours..., Bagshawe [/bib_ref] [bib_ref] Single-agent methotrexate chemotherapy for the treatment of nonmetastatic gestational trophoblastic tumors, Lurain [/bib_ref]. A small series of an oral 5-day regimen has been described with outcomes that are similar to those reported with methotrexate injections and could be considered to reduce the risk of exposure or when infusion resources are limited [bib_ref] Treatment of nonmetastatic gestational trophoblastic disease with oral methotrexate, Barter [/bib_ref]. Dactinomycin at 1.25 mg/m2 has the advantage of every 2 week dosing and has been shown to be superior to weekly methotrexate [bib_ref] Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational..., Osborne [/bib_ref]. However, the success rate for this regimen was only 44% in women with a WHO score of 5-6 and generally should be given through a central line to reduce the risk of extravasation injury. All regimens should be continued until 3 treatments past a normal hCG defined as (b5 mIU/ml) [bib_ref] 15 years of progress in gestational trophoblastic disease: scoring, standardization, and salvage, Brown [/bib_ref]. The inpatient EMA-CO regimen is recommended for patients with high risk disease (WHO N 6).

## Clinical trial considerations
-Prioritize Tier 1 studies where there is high potential benefit (i.e., trial that offers drug where alternative treatments are limited) in resourcestratified environments. -Identify and inform sponsors when there will be deviations for visits/ labs/physical exam/radiology tests that are not essential such as pharmacokinetics tests -Be aware of your institutional regulatory guidelines regarding how COVID-19-related deviations should be tracked and reported. -Prioritize shipping oral drugs to patients to minimize in-person visits.
-Consider COVID-19 burden and ability to enroll new patients on trial (safety, staffing resources including clinical trial nurses, data mangers, and regulatory staff)
Conducting clinical trials during the COVID-19 crisis is challenging and will vary based on geographic location and institutional resources.
Clinical trial guidelines are available from the FDA, National Cancer Institute, NRG Oncology, and local institutions. Develop COVID-19 guidelines for investigator-initiated trials internally and distribute to participating sites. Clinical trials should be prioritized based on the study type and benefit potential [fig_ref] Table 5: Prioritization criteria for clinical trials during the COVID-19 pandemic [/fig_ref]. Tier 2 and non-essential Tier 3 (tissue and non-therapeutic studies) are not enrolling at many centers. Before enrolling new patients consider COVID-19 burden and trial conduct capability including staffing, imaging, procedures, and research labs acquisition. Minimize non-critical visits and patient interactions between physicians and research coordinators using telemedicine to conduct visits and assessment of toxicity, symptoms, and concomitant medications. Arrange for delivery of investigative oral drugs directly to patients if possible and obtain labs and imaging locally. Inform and follow sponsor and IRB guidelines regarding deviations and patients diagnosed with COVID-19 while on study.

# Author contributions

## Declaration of competing interest
Dr. Huh has nothing to disclose. Dr. Armstrong reports grants from Astra Zeneca, Clovis, Pfizer, Tesary, Syndax, Esai/Morphotek, from null, outside the submitted work.
Dr. Naumann reports personal fees from Astra-Zeneca, grants and personal fees from BioSutro, grants from Bristol-Myers-Squib, personal fees from Clovis, grants and personal fees from Merck, personal fees from Eisai, grants and personal fees from Tesaro/GSK, grants and personal fees from GOG Foundation, grants from OncoMed, outside the submitted work.
Dr. Kesterson reports personal fees from GSK/Tesaro, personal fees from Clovis Oncology, outside the submitted work.
Dr. Fader reports personal fees and other from Mersana, personal fees from Merck, outside the submitted work.
Dr. Liu reports advisory board participation for AstraZeneca, Clovis Oncology, Tesaro/GSK, Genentech, Merck, and Mersana Therapeutics, outside the submitted work; and Institutional PI on industrysponsored trials from Acetylon Pharmaceuticals, Aravive Biologics, Arch Oncology, AstraZeneca, Atara Biotherapeutics, Boston Biomedical, Bristol-Myers Squibb, Agenus, Clovis Oncology, CytomX Therapeutics, Genentech/Roche, Regeneron Pharmaceuticals, Surface Oncology, Tesaro/GSK, and Vigeo Therapeutics.
Dr. Westin reports grants and personal fees from AstraZeneca, grants and personal fees from Clovis Oncology, grants and personal fees from GSK/Tesaro, grants and personal fees from Roche/ Genentech, grants and personal fees from Novartis, personal fees from Merck, personal fees from Pfizer, personal fees from Eisai, grants from Cotinga Pharmaceuticals, grants from Bayer, grants from ArQule, personal fees from CIrculogene, outside the submitted work.
Dr. Pothuri reports grants, personal fees and non-financial support outside the submitted work; Institutional PI for industry sponsored trials from Tesaro/GSK, AstraZeneca, Merck, Genetech/Roche, and Clovis Oncology. Compensated advisory boards include Tesaro/GSK, AstraZeneca, and Eisai.
Dr. Moore reports personal fees and other from Astra Zeneca, grants, personal fees and other from Genentech/Roche, grants, personal fees and other from Immunogen, grants, personal fees and other from Clovis, grants, personal fees and other from Tesaro, personal fees and other from Pfizer, personal fees from Janssen, personal fees from Aravive, personal fees from VBL Therapeutics, personal fees and other from Onco Med, personal fees from Samumed, grants and other from Lilly, personal fees from Eisai, personal fees from Vavotar, personal fees from Abbvie, personal fees from Tarveda, outside the submitted work.
Dr. Alvarez Secord reports grants from AbbVie, Amgen, Astra Zeneca, Clovis, Astellas Pharma Inc., Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Endocyte, Exelixis, Incyte, Merck, PharmaMar, Immutep Ltd., Roche/Genentech, Seattle Genetics, Inc., Tesaro/GSK, VBL Therapeutics, National Cancer Trial Network; honoraria from Aravive, Astra Zeneca, Clovis, Cordgenics, Eisai, Janssen/Johnson & Johnson, Merck, Mersana, OncoQuest, Roche/Genentech, Tesaro/ GSK Advisory Boards; participation on Clinical Trial Steering Committees (uncompensated) for Roche/Genentech, and VBL Therapeutics; and member of GOG-Foundation Board of Directors, outside the submitted work.
Dr. Chan reports personal fees from Acerta, personal fees from Aravive, personal fees from Biodesix, personal fees from Clovis, personal fees from Janssen/J and J, personal fees from Oxigene/Mateon, grants and personal fees from Roche/Genentech, grants and personal fees from Glaxosmithkline/Tesaro, grants and personal fees from Astra Zeneca, personal fees from Eisai, outside the submitted work.
[table] Table 3: Front-line cancer-specific chemotherapy considerations for women with early-stage gynecologic malignancies during the COVID-19 pandemic. Study of Active Surveillance for Low Risk and a Randomized Trial of Carboplatin vs. Cisplatin for Standard Risk Pediatric and Adult Patients with Germ Cell Tumors) [60] [/table]
[table] Table 4: Front-line cancer-specific chemotherapy considerations for women with advanced-stage gynecologic malignancies during the COVID-19 pandemic. [/table]
[table] - Immunotherapy: COVID-19 infection and early immunotherapyrelated pneumonitis have similar presentations. In the case of suspected pneumonitis, test for COVID-19 prior to start of steroids and collaborate with pulmonary consultants.-Access to PFTs and bronchoscopy may be limited and decisions may need to be determined based on clinical findings and severity of symptoms. -Consider utilizing less frequent dosing intervals for immune checkpoint inhibitors [/table]
[table] Table 5: Prioritization criteria for clinical trials during the COVID-19 pandemic. Clinical research protocols (1) involving treatments for acute, life threatening health conditions (i.e., some cancer trials) or(2) where stopping the intervention could be harmful (i.e., some investigational drugs, or vaccines or preventative drug).b Clinical research protocols (1) evaluating treatments for chronic conditions or(2)involving assessment of the safety or efficacy of an intervention in which, if stopped, the potential societal benefit of the science would be significantly and adversely impacted, for example where a research assessment (blood collection or imaging study) is only valuable if at a very specific time.R. Wendel Naumann: Conceptualization, Methodology, Writingoriginal draft, Writing -review & editing. [/table]