Locally Advanced Head, Neck Cancers: Comparison
Please note this is a comparison between Version 1 by Camil Mirestean and Version 2 by Bruce Ren.

Locally advanced head and neck cancer is a unique challenge for cancer management in the Covid-19 situation. The negative consequences of delaying radio-chemotherapy treatment make it necessary to prioritize these patients, the continuation of radiotherapy being indicated even if SARS-CoV-2 infection is confirmed in the case of patients with moderate and mild symptoms.

  • head and neck cancer
  • non-surgical
  • radiotherapy
  • chemotherapy
  • Covid-19

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1. Introduction

The disease caused by the new coronavirus identified in Wuhan, China, Hubei province, has spread rapidly to all continents, causing a pandemic with severe consequences. The introduction of preventive measures including emergency restrictions on citizens’ freedoms, implementation of social distancing and wearing personal protective equipment (PPE) has limited the number of infections in most countries, a lesson learned from the experience of pandemic epicenters in China and Lombardy in Italy. After the pandemic epicenter in summer 2020 was Latin America, now India is tending to become the hottest spot in a second wave of infections affecting the whole world. Leung et al. draw attention to the increase in the rate of transmission of the SARS-CoV-2 virus associated with a possible second wave of infection in case of premature relaxation of the restrictions. On December 1st, 6,392,290 cases had been diagnosed since the beginning of the pandemic, of which 1,480,662 patients died and 44,230,469 were cured. Cancer patients were considered a high-risk group in developing severe forms of the disease with potential for worse outcome [1][2][3][1–3].

Among cancer patients, those diagnosed with head and neck cancers offer the multidisciplinary team one of the most extreme diagnostic and treatment challenges during the Covid-19 pandemic. The definition of locally advanced head and neck cancers generally refers to advanced tumor (T) and nodal (N) stages. Locally advanced head and neck cancer is a unique challenge for cancer management in the Covid-19 scenario, taking into account the complexity of the treatment that requires the involvement in at least one of the stages of treatment of both the head and neck surgical oncologist, the medical oncologist and the radiation oncologist. Although non-surgical treatment is the most common choice for these stages of disease evolution, the development of resection and reconstruction techniques has opened new horizons. Surgical treatments and the term “unresectable” are not currently superimposed on the “locally advanced” disease concept. Due to the risk of aerosolization associated with upper aerodigestive tract investigations taking into account the presence of virus in the respiratory mucosa of the naso- and oropharynx, but also due to increased mortality, the management of head and neck cancers is a challenge during a Covid-19 outbreak. Aerosolized droplets expelled during breathing, coughing or sneezing have a high risk of transmitting the disease. 85% of health care workers are exposed to SARS-CoV-2 infection, even if they wear a N95 filter mask which can provide adequate protection in this situation. Radiotherapy is essential as a treatment method, part of a multidisciplinary approach to locally advanced head and neck cancers offering a curative potential therapeutic approach. The physical presence of head and neck cancer patients in the radiotherapy department for approximately seven weeks significantly increases the risk of exposing them to a SARS-CoV-2 infection [3][4][5] [3–5].

2. Locally Advanced Head and Neck Cancer Treatment in Covid-19 Pandemic Outbreak—A Dance on a Slack Wire

Comorbidities coexist with head and neck cancers in 36.4%–88.9% and 65%–90% of cases diagnosed at an advanced stage. Being mostly heavy smokers, chronic obstructive pulmonary disease (COPD) is one of the most common comorbidities in this group of patients. All these factors significantly increase the risk of a severe outcome, including acute respiratory distress syndrome (ARDS), hospitalization in intensive care units (ICUs), mechanical ventilation, and even death. Sidaway et al. report 53.6% of cancer patients requiring mechanical ventilation and a 28.6% death rate in this category of patients, with most fatalities due to ARDS. Another specific aspect of head and neck cancer (HNC) is immunosuppressive treatment, an effect that is associated with a compromised immunity state generated by cancer, thus increasing the risk of a worse outcome in case of infection with the new coronavirus [6][7][8][6–8].

In a systematic review and meta-analysis that evaluated the effect of oncological therapies on the course of Covid-19 disease, Yekedüz et al. identified chemotherapy as a risk factor for SARS-CoV-2 infection mortality without a consensus on safety in surgery, radiation therapy, target molecular therapy, and immunotherapy. A systematic review and meta-analysis by Wang et al. concluded that these therapies do not increase the risk of death in combination with Covid-19, chemotherapy being in this case too considered the only cancer therapy at risk. Cancer is considered due to its immunosuppressive status a risk factor in association with SARS-CoV-2 infection, the rate of possible severe complications, not only ARDS, considered to be 33%. In the new context created by the Covid-19 pandemic, it is necessary to adapt the treatment guidelines in order to limit as much as possible the risk of infection, both for the medical staff and the patients, given the unpredictable variation of hospital resources, as well as the fluctuation of the spread of the virus, expected to have an “in waves” evolution for several months or even longer. The effect of the pandemic is disproportionate, the most affected being the countries with health systems that will become overburdened, with the risk of exacerbating socioeconomic inequalities. There is a consensus on the protection of patients and medical staff, the use of telemedicine services is recommended in the departments involved in the treatment of head and neck cancers, and an individualized decision should be taken after assessment of the benefit and risk of treatment, whether it is surgical followed by adjuvant treatment, or definitive radio-chemotherapy [9][10][11][9–11].

An international multicenter study that included 1137 patients treated with curative intent during the Covid-19 pandemic identified, in the group analyzed, positive SARS-CoV-2 test rates of 3% and an overall mortality of 1.2% 30 days after surgery. Tracheostomization and oral tumor surgery is considered to be at increased risk of staff contamination, a factor that cannot be overlooked given the reportedly unfavorable pathways, the high death rate among otolaryngologists and head neck surgeons being probably correlated with a high viral load. The authors consider the non-surgical treatment of cancers of the salivary glands and oral cavity suboptimal, considering only for oropharyngeal and laryngeal cancers the option of treatment with radio-chemotherapy. However, the lung complication rate of 51.2% with a death rate of 23.8% is another argument that advocates avoiding surgery in the upper aerodigestive tract [12][13][14] [12–14].

SARS-CoV-2 has had effects on HNC management in choosing optimal treatment, taking into account that resources available in each department involved are essential. The multidisciplinary team (MDT) has an essential role in evaluating the optimal option and is also involved in patient evaluation and follow-up during this pandemic period [15][16][15,16].

Bowman et al. consider the Covid-19 pandemic to be similar to Hurricane Katrina, with reduced access to cancer care following this disaster. During these periods, there is an argument that the evaluation of a patient should be delayed. Limiting hospital visits by using telemedicine services, using PPE including face masks and patient testing, and reducing patients’ stay time in the waiting room through telephone scheduling are strategies that can limit the risk of contamination during radiotherapy treatment. Patients with dysphagia and dyspnea require percutaneous gastrostomy or tracheostomy tubes which have an increased risk of aerosolization and spread of the virus, so testing HNC patients and staff involved in their treatment is a priority. For these reasons, given the difficulties in identifying cough as a consequence of oncological disease or as determined by Covid-19 infection, H&N and lung cancers patients require triage and correct evaluation of the etiology of symptoms. The need to travel daily for long distances and possible lack of telemedicine services create additional difficulties in providing health care to HNC patients. This situation is exacerbated by the fear of patients not contacting treatment services, which has the consequence of delaying treatment. Considering mortality is in the 4%0-50% range, much higher than Covid-19 mortality estimated at 1%–2% in the United States, HNC treatment is a priority. However, the high mortality rate in cancer patients who become infected with the new coronavirus must be taken into account. Afshar et al. consider the fatality rate as between 5.5% and 60% in this group of patients without specifying the type of cancer [17][18][19][20][21][22][17–22].

Surgery services are the most affected by the risk of contaminating staff when treating patients with HNC, given the need for procedures that require aerosolization. Under these conditions, it is recommended to delay the treatment of benign tumors, but also of low-grade carcinomas such as mucoepidermoid carcinoma, acinar cell carcinoma and polymorphic adenocarcinoma as long as the COVID-19 pandemic exposes patients and medical staff to the risk of contamination. In the case of low grade malignancies, follow-up by computer tomography (CT) or magnetic resonance imaging (MRI) is recommended [19].

3. Covid-19 “Tsunami”—The Urgent Need for Recommendations

The standard treatment with potentially curative effect for locally advanced HNC is concomitant chemo-radiotherapy. Any delay of treatment increases the risk of death by 16% for each month. A protocol for radiotherapy in the case of a Covid-19 pandemic outbreak has been proposed by a panel of international experts from the American Society of Radiation Oncology (ASTRO) and the European Society of Radiation Oncology (ESTRO). Cutoffs chosen for strong agreement and agreement were 80% and 66%, respectively, taking into account two possible pandemic scenarios.

The first, “early” scenario of risk mitigation is characterized by the aim to reduce risk infection for patients and staff and also focuses on the evaluation of serious infection risk for patients receiving chemotherapy and radiation therapy. This scenario takes into account the necessity to avoid repeated hospital visits. In this scenario, the risk of complications and severe toxicities associated with intensive chemo-radiotherapy treatments is also a cause of concern.

In the second “late” scenario, the resources of radiotherapy services are severely reduced and some patients cannot benefit from treatment.

A panel of experts chose five different cases for which they proposed a multidisciplinary approach. For all cases that were proposed for definitive non-surgical treatment, the experts voted by “strong agreement” not to postpone treatment except for a T1b node negative glottic cancer case. In this case the consensus vote was validated by “agreement”. Oropharyngeal Human Papilloma Virus (HPV) positive (+) and negative (−) and locally advanced larynx cancer were considered as having a high priority for treatment, followed by the T1N0 glottic larynx cancer. In a very limited resource scenario, HPV+ oropharynx was considered a top priority and locally advanced larynx was chosen before HPV-oropharynx cases for priority treatment. By positive margins, operated oral cavity cases were prioritized before early glottic cancer. SARS-CoV-2 infection and symptomatic benefit, followed by curative option, were the criteria considered relevant for the beginning of treatment in less than one week. Not postponing HNC radiotherapy for more than four–six weeks and considering radical treatment for these cases as a high priority were recommendations with “strong agreement”. For all cases proposed for radio-chemotherapy treatment, there is a consensus to postpone treatment in the case of SARS-CoV-2 infections until a negative real-time polymerase chain reaction (RT-PCR) test. The consensus was not to discontinue treatment if the patient had started radiotherapy treatment at the time of Covid-19 diagnosis. If, during treatment, the patient presents cough, chest pain, or requires oxygen support due to respiratory problems, the consensus is to discontinue treatment, considering the risk of hospitalization in the ICU department with a potentially fatal evolution, the risk in this case being considered higher than the benefit of radio-chemotherapy. A 10-14 day waiting period is recommended after repeated negative tests for this category of patient before treatment restarts. The risk of contaminating staff or other patients, the possibility of worsening of the general condition with the need for an emergency room presentation and the need for a feeding tube may be arguments for discontinuation the treatment in patients diagnosed with SARS-CoV-2 with mild symptoms. A cutoff of two weeks from the start of treatment is considered significant in order not to interrupt treatment in case of SARS-CoV-2 infection, in the case of mild symptoms without any additional risks.

Regarding the fractionation scheme in the first pandemic scenario, there was a strong agreement to keep the same fractionation scheme in all cases proposed for potentially curative treatment. In the scenario of limited resources, hypofractionation was proposed with a strong agreement consensus. Cisplatin-based chemotherapy 80–100 mg/m2 every three weeks or 30–40 mg/m2 weekly are the most common regimens for a concurrent approach, with a preference 6/4 ratio for the three-week regimen. If in the first scenario there was consensus for chemotherapy administration in all cases that had guideline indications, in the scenario of limited resources there was a consensus to de-escalate chemotherapy for HPV+ oropharyngeal cancer, but for other cases there were opinions on omitting concomitant chemotherapy. Conventional radiotherapy or moderate hypofractionation with a maximum 2.4 Gy per fraction were accepted in concurrent radio-chemotherapy protocol.

Induction chemotherapy was not considered as an option by most experts, only 10% considering this as a therapeutic standard, and only 27% considering it as an option for the timing of radiotherapy. The rationale for avoiding induction chemotherapy was based on the immunosuppressive potential associated with an increased risk of contracting Covid-19 disease, but also of developing severe clinical evolution to ARDS or even death [19][20][19,20].

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