Discordance of COVID‐19 guidelines for patients with cancer: A systematic review

Abstract This review was aimed to systematically evaluate the available literature on the impact of COVID‐19 on cancer care and to critically analyze the diagnostic and therapeutic strategies suggested by various healthcare providers, societies, and institutions. Majority guidelines for various types of cancers favored a delay in treatment or a nonsurgical approach wherever feasible. These guidelines are based on a low level of evidence and have significant discordance for the role and timing of surgery, especially in early tumors.


| Search strategy
A comprehensive search strategy was developed following a consensus among the co-authors in collaboration with an external expert. The search strategy used variations in keywordscoronavirus, COVID, and cancer-to retrieve articles. Three electronic databases-Medline (Pubmed), Embase, and Scopus-were searched from their inception to 2nd May 2020. Full text of the pertinent articles was obtained and evaluated. The references of these articles were manually searched to look for any relevant studies. EndNote, version 9 (Clarivate Analytics), was used to facilitate the search process. The review has been done in accordance with the PRISMA guidelines.

| Timeline of publications
There has been a progressively rising trend over the last 4 months.
Of the total 212 publications analyzed in this review, the majority (n = 128, 60.3%) of them were published in April 2020.

| Country of origin
Based on the country of origin, majority of data originated from countries like the United States, China, and Italy, which were worst affected by this pandemic (Table S1).

Head and neck cancers
Forty-six articles fulfilled our inclusion criteria, addressing the effect of COVID-19 on head and neck cancers. Table 2 summarizes a few relevant recommendations/guidelines by various expert groups and societies. [8][9][10][11] All the guidelines consider surgery in head and neck region as a procedure with high-risk for viral aerosolization and recommend personal protective equipment usage mandatory in COVID-19 positive patients and patients undergoing aerosol-generating procedures like a tracheostomy. There is a uniform consensus regarding maintaining endotracheal intubation for up to 21 days before considering a tracheostomy to reduce the viral load. 9 Regarding the management of SARS-CoV-2 negative patients, there is discordance in the recommendations for treatment, especially for early stage    Routine nasal endoscopy to be deferred.  is a uniform consensus among all the groups to avoid or limit the number of face-to-face visits and consider virtual options like telemedicine. 10,12 Regarding the role of radiation therapy in the management of HNSCC in the current pandemic, the American Society of Radiation Oncology (ASTRO) and European Society for Radiotherapy and Oncology (ESTRO) 13 have issued a joint consensus statement, the salient features of which are listed in Table 2.  Guckenberger et al 16 Early pandemic scenario 1-risk mitigation: • Altered risk-benefit ratio of radiotherapy for patients with lung cancer in view of higher susceptibility for severe COVID-19 infection, and minimization of patient traveling and exposure of radiotherapy staff • Continue with standard recommended radiotherapy practice • Consider postponement or interruption of radiotherapy treatment of COVID-19 positive patients Later pandemic scenario 2-reduced radiotherapy resources • Triage patients requiring radiotherapy based on potential for cure, relative benefit of radiation, life expectancy, and performance status.  16,19 suggest to triage the patients based on the tumor stage, clinical condition, risk of SARS-CoV-2 infection, and availability of resources.
One guideline 17 addresses the management of lung nodules and suggests a delay in diagnostic testing.

Gynecological cancers
A total of nine articles addressing the effect of COVID-19 on gynecological cancers were retrieved. Two of them were not available in the English language. Table 5

Colorectal cancer
The impact of the COVID-19 epidemic over the management of col-  hypofractionation; Omit boost RT in patients with low risk for local relapse; Consider accelerated partial breast RT low-risk patients; consider omission of RT in elderly patients at low risk of recurrence 3. Systemic therapy: Avoid drugs with risk of immunosuppression; limit use of steroids; prefer 3 weekly regimen; recommend anti-HER2 agents for HER2 + ; follow usual international guidelines for adjuvant endocrine therapy; prefer oral formulations for adjuvant bisphosphonates. Advanced breast cancer: 1. Systemic therapy: consider dose reductions and dose interruptions; consider treatment holidays in prolonged treatments and stable disease; prefer endocrine-based therapy for ER + /HER2 negative; individualize the use of CDK 4/6 and mTOR inhibitors; prefer oral and liposomal formulations when using chemotherapy; consider use of prophylactic hematopoietic growth factors. 2. Radiation: urgent for spinal cord compression, brain and leptomeningeal metastases, and palliative treatments (eg of bone metastases) not responding to pharmaceutical interventions Dietz et al, 37 The COVID-19 pandemic breast cancer consortium Recommendations for prioritization, treatment, and triage of patients with breast cancer during the COVID-19 pandemic.Surgical oncology 1. Priority A (life threatening)-breast abscess in a septic patient, Expanding hematoma in a hemodynamically unstable patient 2. Priority B (not immediately life-threatening conditions but for whom treatment or services should not be indefinitely delayed until the end of the pandemic-most patients with breast cancer; a delay of 6-12 wk is unlikely to impact the overall survival. 3. Priority C (can be indefinitely deferred until the pandemic is over without adversely impacting outcomes)-pre-invasive cancer; breast reconstruction. Medical oncology 1. Priority A (life threatening)-oncologic emergencies requiring immediate treatment (eg febrile neutropenia, intractable pain) 2. Priority B-require systemic therapy but modified therapeutic approaches to minimize patient interactions with healthcare centers, maintain patient safety, and conserve resources while providing effective care 3. Priority C-delay interventions for many months without adverse impact on survival or quality of life. Radiation oncology 2 months-cancer curable with surgery without any adjuvant treatment, (c) Low priority cases to be deferred for more than 2 months-(i) Cancer amenable to radiation, pharmacological, and endoscopic treatment, and (ii) early cancer with good biology. The authors recommend that patients with a surgically curable disease but COVID-19 positive should be treated conservatively as much as possible without subjecting them to unnecessary risk.

| Hematological malignancies
A total of six articles were retrieved on this topic of which full text of one article was in the Chinese language. Table S3 provides a brief overview of recommendations to help physicians to choose evidencebased information in light of the current scarcity of medical resources. The available literature also supports administering prophylactic antibacterial, antiviral medications, optimizing antiemetics and analgesic doses to reduce the hospital visits. 46

| Radiation therapy related
A total of eight articles concerning the various challenges observed while delivering radiation therapy was retrieved. Full texts of the two articles were not available in the English language. The remaining six articles were either recommendations, or suggestions, or opinions of expert groups to optimally deliver the radiation therapy while safeguarding the healthcare workers and limiting the effects of COVID-19 on the patients receiving radiation therapy.

| Cancer chemotherapy/immunotherapy related
A total of five articles addressing the cancer chemotherapy/immunotherapy were retrieved. Two of them were short communications/correspondences while one was an editorial. Out of the remaining two, one reviewed the literature to determine the association of cytotoxic chemotherapy and host immunity for COVID -19 and concluded that they do not have any beneficial action in mitigating the COVID-19-related effects. 47 Another was a survey con- The heterogeneity of articles providing various recommendations/suggestion to tackle the COVID-19, with differing level of evidence, can make it difficult for physicians, patients, and healthcare systems to adopt uniform strategies. As speculations continue over the possibility of further extension of the COVID-19 outbreak, the oncology community must be prepared for the fact that delivering a high level of care to cancer patients will become a daunting task.
Hence, there is an urgent need to strike a balance between delivering Patients to be evaluated within 2-4 wk-Cytology result of "squamous cell carcinoma," "atypical glandular cells, favor neoplastic," "endocervical adenocarcinoma in situ," or "adenocarcinoma"; histopathological diagnosis of suspected invasion from cervical/vaginal biopsy, or invasive disease after a cervical excision procedure, vaginal excision, or vulvar biopsy/excision; sudden onset of strongly suggestive symptoms for malignancyPatients to be evaluated within 3 mo-Patients with "high-grade squamous intraepithelial lesion (HSIL)," "atypical squamous cells that cannot exclude HSIL (ASC-H)," or "atypical glandular cells not otherwise specified (AGS-NOS)" at cervical cytology; Patients with a histopathological diagnosis of high-grade intraepithelial lesion without suspicion of invasion from a cervical biopsy (HSIL, CIN2-3), vaginal biopsy (HSIL, VAIN2-3), or a vulvar biopsy/excision (vulvar HSIL or differentiated VIN).Patients to be evaluated within 6-12 mo-Contact with patients with "positive high-risk HPV test with normal cervical cytology," "low-grade squamous intraepithelial lesion (LSIL)," or "atypical squamous cells of undetermined significance (ASC-US)" at cervical cytology 7 or with a histopathological diagnosis of low-grade intraepithelial lesion from a cervical, vaginal, or vulvar biopsy/ excision Society of European Robotic Gynaecological Surgery (SERGS) statement 41 Robot-assisted surgery may prove to be a safe surgical option if all the necessary precautions (protective kits and prevention of free escape of CO 2 and aerosol) are followed.
Remirez et al (Editorial Team of the International Journal of Gynecological Cancer) 42 Ovarian cancer: (a) Early disease, consideration of multiple factors, to assess risk of malignancy in adnexal mass. There is concordance in the guidelines suggesting a nonsurgical approach for patients with advanced cancers; however, there is discordance about the role of surgery in early-stage tumors. Delay in surgery for potentially curable early tumors is a major conflict among the guidelines. Table 6 highlights the likely reasons for these discordances among these guidelines.
There is an urgent need for formulating evidence-based practice guidelines for various domains of oncology practice so as to ensure the delivery of high-quality treatment. Global crowdsourcing 54 has the potential to help establish such evidence-based guidelines.

| Limitations of the review
Our search strategy, while systematic, did not include all published guidelines due to the rapid pace of publication. There is significant heterogeneity and limited data in the articles included.

| CONCLUSION
COVID-19 pandemic has posed dilemmas for the oncology community across the globe. Guidelines based on limited evidence show discordance and need to be interpreted with caution. "Crowdsourcing" could help collate the data related to COVID-19 and generate high-quality evidence-based guidelines.

ACKNOWLEDGMENT
The authors thank Mr Utsav Koul for graphical assistance.