The treatment and diagnosis of patients with head and neck cancers are a challenge in the SARS-CoV-2 pandemic context due to the therapeutic and prognostic features, with a risk of evolution to more advanced stages and, consequently, with a high mortality in case of delayed treatment, by limiting the resources of the medical systems that were prioritized for the treatment of COVID-19 patients. The increased risk, up to two times, to develop severe forms of disease also contributes to the limitation of medical care of cancer patients in this context. Due to the risk of SARS-CoV-2 contamination of both medical staff involved and patients, associated with invasive procedures, but also because of the frequency of disease complications associated with frequent visits to the emergency room, this category of patients present some peculiarities. Also, the higher rate of disease complications associated with frequent visits to the emergency room is a factor that associates patients with head and neck cancers with a high risk of SARS-CoV-2 contamination. The concept of using telemedicine services as much as possible, limiting outpatient visits and postponing elective surgery, is also applied to these patients. Although the recommendations of the World Health Organization (WHO) mention the need to regulate the diagnostic and therapeutic approach of cancer patients in this context, the pandemic interaction between cancer and SARS-CoV-2 infection remains unknown, and the factors determining the severity of a possible concomitant evolution are still being investigated. Given the contradiction between the risk of providing treatment for cancer and the risk of disease progresses in the absence of adequate treatment, the concept of ensuring a balance between benefits and risks in terms of cancer treatment during the SARS-CoV-2 pandemic has been implemented. Current data on anticancer treatments and the risk of mortality from COVID-19 causes are contradictory(1,2).
COVID-19 and cancer –
from pathophysiological mechanisms
and interactions to clinical reality
The clinical evolution of SARS-CoV-2 infection is different from one case to another and may have the appearance of a subclinical syndrome or a more severe evolution similar to influenza. In some cases, the evolution is towards severe pneumonia, with respiratory failure and multiple organ dysfunction (MOTD) or even death. Although advanced age, obesity, diabetes and preexisting cardiovascular disease are already known to be associated with a risk of a severe form of COVID-19, the association of cancer with the SARS-CoV-2 infection remains unknown. It is difficult to estimate whether cancer is an independent risk factor or the combination of other risk factors and repeated patient exposure through complex treatments in pandemic outbreaks are in fact factors leading to severe developments in these patients. The delay of both surgical and adjuvant oncological treatments has certainly led to a worsening of the condition of these patients, and the effects of these treatments may be a significant factor for a potential severity of SARS-CoV-2 co-infection. Also, biological factors related to cancer and the immunosuppressive status associated with this disease, as well as the expressions of transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2), proinflammatory cytokines and procoagulant and prothrombotic status increase the risk of complications associated with SARS-CoV-2 infection in cancer patients. While it is unanimously accepted that recent cancer surgery increases the risk of contracting the infection by more than 5% (above the level of risk of contracting the infection in the general population), the evidence for the risk associated with adjuvant treatment is still controversial. Unexpectedly, the higher levels of ACE2 or ACE1/ACE2 rebalancing might improve the outcome of COVID-19 in both sexes by reducing inflammation, thrombosis, and death(3-6).
Some authors consider recent oncological surgery to be associated with an increased rate of mortality and active oncological treatments during the pandemic as being associated with an increased rate (over 5%) of contracting the infection, higher than in the general population. However, there are also opinions that cancer surgery does not increase the risk of COVID-19 mortality in gynecological cancers, but recent immunotherapy treatment may be associated with a high mortality. However, given the heterogeneity of cancer, a generalized hypothesis that cancer patients would have an unfavorable prognosis for SARS-CoV-2 infection might be exaggerated. Comparatively evaluating COVID-19 and non-COVID-19 adult patients in the UK, the authors evaluated the effect of tumor type, age and sex on patients on the prevalence and mortality of COVID-19 using univariate and multivariable models. 1044 patients with active cancer and documented SARS-CoV-2 infection or COVID-19 disease were registered in the UKCCMP database(1,7).
From the first reports of the pandemic, patients with thoracic tumors are considered at high risk of unfavorable evolution. Old age, a history of smoking and possible preexisting cardiovascular comorbidities make these patients sensitive to the association of SARS-CoV-2 infection with cancer. A multicenter observational study included 200 patients from eight countries, diagnosed or suspected of SARS-CoV-2 infection, between March 26 and 12 April 2020, with all types of chest tumors, who tested positive at the real-time polymerase chain reaction (RT-PCR) or who presented computed tomography imaging (CT) suggestive of COVID-19. The median age of the evaluated patients was 68 years old, of which 81% were smokers and 76% were on active cancer treatment at the time of diagnosis of COVID-19. The hospitalization rate was 33% and the death rate was 10% in the lot of patients evaluated in the study. The multivariate analysis showed an increased risk of death associated with age over 65, smoker status and chemotherapy at the time of diagnosis of COVID-19, but the univariate analysis showed only smoking as a risk factor. The authors noted a low rate of hospitalization in intensive care units (ICUs), considering that a prediction of severe evolutionary risk and a multidisciplinary approach in order to prioritize the access of these patients to ICUs would reduce the mortality rate(8).
COVID-19 and head and neck cancers
In order to estimate the risk of the association of COVID-19 with head and neck cancers, we must start from some well-known premises. COVID-19 is highly contagious, transmissible and by localizing the virus during the period with the maximum risk of contagion in the nasopharynx and oropharynx, the treatment of head and neck cancers becomes a challenge in the pandemic context. The assessed mortality of COVID-19 during the pandemic outbreak from the USA is approximately 1-2%. Considering that the mortality of head and neck cancers not treated properly is 40-50%, it becomes obvious the priority of a cancer treatment even in the pandemic context. However, the procedures that include aerosolization are at high risk of contamination and require special measures, and in case of patients with head and neck cancer the risk is maintained even after performing the procedure by wearing nasogastric tubes, tracheostomy tubes or percutaneous gastrostomy. The association of severe limitation of the access to the specialized medical services, as well as to the hospital beds from ICU will favor the progression of the oncological disease and will lead to the increase in the number of serious cases, candidates for a more aggressive treatment(9-10).
Most studies that have discussed the problem of head and neck cancers in the pandemic context from the point of view of the surgical approach have evaluated the safety of surgery, given the associated risk of contamination of patients and staff, without analyzing in detail the interaction between cancer and COVID-19. Because this issue has affected most oncology departments, not only of head and neck cancers, but of cancer in general, a situation clearly highlighted in the title of the article “From high volume to zero: Italian experience in the COVID era”, published by Mascangi et al., Baird et al. formulates some basic concepts that should lead the surgical approach to head and neck cancers in the current pandemic context. Given particularly the biological features of squamous cell carcinoma of the head and neck and the aggressive tumor biology at risk of rapid evolution from early-stage disease to local advanced or even metastatic cancer, the context of COVID-19 should not be the cause. In the surgical therapeutic decision of head and neck cancers, factors such as the severity of the disease, the patient’s comorbidities and the local situation of the risk of SARS-CoV-2 infection should be evaluated. The authors also recommend a safe tracheostomy and according to the indications, considering the risk of prolonged intubation or severe sequelae of a possible association of COVID-19.
Retrospectively analyzing data obtained from 1137 patients from 26 countries with head and neck cancer who underwent primary surgery with curative intent, the authors identified a 30-day mortality of 1.2% and a positive SARS-CoV-2 test rate of 3%. Among positive patients, the death rate was estimated at 10.3%, the severe evolution being associated with an advanced disease and ICU admission. The positive SARS-CoV-2 test rate among the surgical team was 3% at 30 days after surgery. These data partially contradict the concept of limiting head and neck surgery during the pandemic, with the authors considering oncological head and neck surgery as safe even in cases where cancer management requires a complex approach. The risk of staff contamination was significantly higher for patients who presented with oral tumors or tracheostomies. A Danish study evaluated the prevalence of SARS-CoV-2 infection in a tertiary otorhinolaryngology clinic for both patients with suspected acute upper airway and head and neck cancer patients, and the rate of positive patients was 0% in the group including 96 patients operated for head and neck cancer. Thus, in the first six weeks of the first pandemic wave, the authors considered head and neck cancer surgery safe, without any reason to postpone the procedures(14-15).
Day and collaborators recommend managing these surgical risks and evaluating the appropriateness of the nonsurgical treatment option. If traditional surgery is preferred, the authors recommend the use of perioperative protocols in the context of COVID-19 pandemic, in order to reduce the risk of contamination of both patients and staff. Another plea against postponing head and neck cancer surgery is offered by Gupta el al. Referring to the situation in India, a country with an increased incidence of these cancers, they noted that a 1- or 2-month delay in surgery will lead to a high rate of inoperability and the need for extensive oncological surgery of the head and neck. In the context of limiting the diagnostic and therapeutic procedure of this type of cancer, it is foreseeable an increase in the number of cases, social distancing measures being estimated to also have as a consequence a shift to a more advanced disease at the time of the first presentation to the ENT physician(16-20).
The same pathophysiological mechanism involving ACE2 in the pathogenesis of COVID-19 is currently being reported in the case of head and neck cancers by Chauhan et al. The authors also present the SARS-CoV-2 infection mechanism that describes the role of Furin host enzymes in the interaction with the protein S and ACE2 receptor, mentioning the increase in FURIN and ACE2 expression in oral cancer and paracarcinoma tissue. Thus, the hypothesis of an increased risk of infection can be issued through these mechanisms in patients with cancers of the oral cavity. The lack of concrete systematized data regarding the possible impact of the association of COVID-19 makes Sean Dolan ask a rhetorical question about the impact of SARS-CoV-2 infection on patients with squamous cell carcinoma. The author mentions a possible increased risk of combining the two diseases but recommends avoiding smoking, alcohol ingestion, as well as rigorous oral hygiene as safe measures that can help reduce the synergistic impact of cancer and COVID-19. Silverman and collaborators add to these measures the aggressive management of associated comorbidities and note the risk of respiratory complications in this group of patients(21-22).
Due to the risk of shift towards an increased preva lence of more advanced stages and consequently towards an increased mortality in case of postponement of surgical treatment, but also of adjuvant treatment, head and neck cancer, and in particular HNSCC, is an oncological pathology that must be prioritized from the point of view of assessment and treatment, even at the time of possible pandemic outbreaks. It is thus estimated an increase in the need for more extensive surgical treatments and definitive nonsurgical treatments. Data on the association of SARS-CoV-2 infection with head and neck cancer are limited to case studies, with more severe progression anticipated by possible severe pneumonia and associated diseases decompensation, and less by the effects associated with a “cytokine storm”, given the immunosuppressive status associated with cancer. An increased attention to the risk of SARS-CoV-2 infection is needed for oral cavity cancers, taking into account the possible molecular mechanisms involved. Measures to reduce alcohol consumption, smoking and strict oral hygiene, as well as the aggressive management of comorbidities and the immediate practice of tracheostomy in the case of a clear indication – head and neck cancer patients risking a possible prolonged hospitalization in the ICU in case of a SARS-CoV-2 infection – are measures that can reduce the mortality. It is necessary to evaluate in clinical trials lots of patients who associate head and neck cancer with COVID-19 in order to elucidate both hypotheses based on pathophysiological concepts and to assess the risk of severe complications of the possible synergistic effects in case of head and neck cancer association with COVID-19.