Pan-Asian adaptation of the EHNSESMOESTRO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with squamous cell carcinoma of the head and neck



# Introduction
In 2020 an estimated 19.3 million new cases of cancer were diagnosed and almost 10 million cancer-related deaths recorded, worldwide. [bib_ref] Global cancer statistics 2020: GLO-BOCAN estimates of incidence and mortality worldwide for..., Sung [/bib_ref] Of these, squamous cell carcinomas of the head and neck (SCCHN) including carcinomas of the lip, oral cavity, larynx, oropharynx and hypopharynx, but excluding nasopharyngeal cancer, accounted for 3.9% (744 994) of new cases across both sexes, and 3.7% (357.339) of cancer deaths. [bib_ref] Global cancer statistics 2020: GLO-BOCAN estimates of incidence and mortality worldwide for..., Sung [/bib_ref] The highest incidence of head and neck cancer (HNC) is seen in Asia, with deaths from HNCs accounting for >5% of all cancer deaths. HNC comprises a heterogenous group of malignancies and the prevalences of the different types of HNCs vary from country to country across Asia. For example China and Taiwan have high incidences of oral cavity cancers, with the latter having increasing rates of human papilloma virus (HPV)-related oropharyngeal cancer. 2,3 India currently contributes w60% of the HNC cases worldwide with HNC the most common cancer in Indian men, and cancer of the oral cavity the most prevalent. In South Korea, laryngeal cancer is the commonest form of HNC with the incidence of all HNCs (tonsil, hypopharynx, oropharynx and larynx cancer) increasing, with a higher incidence in men than in women. [bib_ref] Trends in head and neck cancer in South Korea Between, Suh [/bib_ref] In Japan alone, there are >39 000 cases of HNC and w10 000 deaths from the disease, annually. [bib_ref] Cancer incidence and incidence rates in Japan in 2009: a study of..., Hori [/bib_ref] A report from the Japan Society for Head and Neck Cancer Registry Committee on 11 716 previously untreated HNC patients registered in 2016 showed w83% of the cases to be accounted for by tumours of the oral cavity (24.9%), larynx (20.4%), hypopharynx (21.4%) and oropharynx (16.9%).Although the incidence varies between countries and individual regions within countries, w80% of cases of SCCHN worldwide are attributable to tobacco use, excessive alcohol consumption or both, and in South Asia the use of smokeless tobacco and betel quid/areca nut products. [bib_ref] Head and neck squamous cell carcinoma, Johnson [/bib_ref] Betel quid/ areca nut use has been linked to high rates of cancers of the oral cavity in India, Taiwan and some provinces of mainland China. [bib_ref] Defining a global research and policy agenda for betel quid and areca..., Mehrtash [/bib_ref] Other risk factors include environmental pollutants, especially in countries with worsening air pollution such as India [bib_ref] Head and neck cancer: global burden and regional trends in India, Mishra [/bib_ref] and China, [bib_ref] Cancers of the lung, head and neck on the rise: perspectives on..., Wong [/bib_ref] and HPV infections in the aetiology of oropharyngeal cancer and cancers of the oral cavity. [bib_ref] The molecular landscape of head and neck cancer, Leemans [/bib_ref] A recent meta-analysis looking at the prevalence of HPVrelated oropharyngeal cancers in the Asia Pacific region reported an overall prevalence of 40.53% for oropharyngeal cancers. [bib_ref] HPV-associated head and neck cancers in the Asia Pacific: a critical literature..., Shaikh [/bib_ref] In a Malaysian study of 60 patients with oropharyngeal cancer of whom 53.3% were of Chinese ethnicity, 35% of Indian ethnicity and 11.7% of Malay ethnicity, all the Indian patients had p16-negative disease. [bib_ref] Clinico-pathological features of oropharyngeal squamous cell carcinomas in Malaysia with reference to..., Yap [/bib_ref] This was consistent with a study of 88 patients with SCCHN conducted in South India in which only 2.6% cases were HPV/p16positive. [bib_ref] Detection of human papilloma virus and risk factors among patients with head..., Bandhary [/bib_ref] Significantly, in the Malaysian study [bib_ref] Clinico-pathological features of oropharyngeal squamous cell carcinomas in Malaysia with reference to..., Yap [/bib_ref] 80% of the HPV-positive cases were in Chinese patients and the prevalence of p16-positive oropharyngeal squamous cell carcinomas (SCC) across all three ethnicities was half that of a matched UK cohort (25% versus 49%). [bib_ref] Clinico-pathological features of oropharyngeal squamous cell carcinomas in Malaysia with reference to..., Yap [/bib_ref] A study conducted in Singapore involving 159 urban, multiethnic, South East Asian patients with SCCHN demonstrated a high prevalence of high-risk HPV variants (HPV16, [bib_ref] Indian clinical practice consensus guidelines for the management of very advanced disease..., Prabhash [/bib_ref] [bib_ref] Randomized trial of radiation therapy with weekly cisplatin or cetuximab in low-risk..., Rischin [/bib_ref] [bib_ref] Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line..., Mesia [/bib_ref] and 68) and confirmed that HPV16 and p16 immunohistochemical expression were predominantly detected in the oropharyngeal carcinomas. [bib_ref] High-risk HPV genotypes and P16INK4a expression in a cohort of head and..., Tan [/bib_ref] Although an ethnic predisposition cannot be excluded, the differences in HPV positivity between the different Asian populations is probably due to differences in sexual practices.
Guidelines and recommendations for the treatment and management of patients with SCCHN in Asia have been published for India, [bib_ref] Oncology Gold Standard practical consensus recommendations for the use of monoclonal antibodies..., Babu [/bib_ref] [bib_ref] Indian clinical practice consensus guidelines for the management of very advanced disease..., Prabhash [/bib_ref] China,Japan, [bib_ref] Japanese clinical practice guideline for head and neck cancer, Nibu [/bib_ref] [fig_ref] Table 1: from both a scientific [/fig_ref] [bib_ref] Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO..., Machiels [/bib_ref] This manuscript summarises the Pan-Asian adapted guidelines developed at the meeting accompanied by the level of evidence (LoE), grade of recommendation (GoR) and percentage consensus reached for each recommendation.

# Methodology
This Pan-Asian adaptation of the current ESMO Clinical Practice Guidelines 23 was prepared in accordance with the principles of ESMO standard operating procedures (http:// www.esmo.org/Guidelines/ESMO-Guidelines-Methodology) and was a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS.
Representatives from KSMO (n 14 4), ESMO (n 14 7), EHNS (n 14 1), ESTRO (n 14 2) and two experts from each of the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS) convened for the virtual 'face-to-face' meeting. Only two of the members from KSMO (HRK and YGL) were allowed to vote on the recommendations together with the experts from each of the six other Asian oncology societies (n 14 14).
A modified Delphi process was used to review, accept or adapt each of the individual recommendations in the latest EHNS-ESMO-ESTRO Clinical Practice Guidelines. [bib_ref] Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO..., Machiels [/bib_ref] [bib_ref] Infectious Diseases Society of America, American Society of Blood and Marrow Transplantation...., Dykewicz [/bib_ref] was used to define the LoE and strength (grade) of each recommendation. Any modifications to the initial recommendations were highlighted in bold text in a summary table of the final Asian recommendations and in the main text, if and as applicable. A consensus was considered to have been achieved when !80% of experts voted that a recommendation was acceptable.

# Results
In the initial pre-meeting survey, the 14 Asian experts reported on the 'acceptability' and 'applicability' of the 32 recommendations for the diagnosis treatment and followup of patients with SCCHN of the oral cavity, larynx, oropharynx and hypopharynx from the 2020 EHNS-ESMO-ESTRO Clinical Practice Guidelines. [bib_ref] Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO..., Machiels [/bib_ref]. After further consideration, however, the 'recommendations 3i and 3v', and 'recommendations 1d, 3a, 3e, 3f, 3k, 3l 3m, 3n, 3r, 3s, 3t and 4c' were identified for discussion during the 'face-to-face' meeting, based on the comments and feedback from the initial pre-meeting survey, as it was clear that some of the comments made in terms of applicability had scientific relevance. It was also decided that there was no need to discuss 'recommendations 1c, 1f, 3b and 3u' initially identified for discussion in terms of applicability.

## Diagnosis and pathology/molecular biologydrecommendations 1a-f
The Pan-Asian panel of experts agreed with and 'accepted' completely (100% consensus) the EHNS-ESMO-ESTRO recommendations on screening, 'recommendations 1a-f' from a scientific point of view (see below and [fig_ref] Table 1: from both a scientific [/fig_ref] 

## Staging and risk assessmentdrecommendation 2
The Pan-Asian panel of experts agreed with and 'accepted' completely (100% consensus) the EHNS-ESMO-ESTRO recommendations on staging and risk assessment, 'recommendation 2a' (below and

## Treatmentdrecommendations 3a-v
The Pan-Asian panel of experts agreed with and 'accepted' completely (100% consensus) the EHNS-ESMO-ESTRO recommendations on treatment, 'recommendations 3b-d, g, h, j, o-q and u,' from a scientific point of view (see below and [fig_ref] Table 1: from both a scientific [/fig_ref]. A lack of consensus in terms of 'acceptability' for recommendations 3i and 3v was identified, however, from the time of the pre-meeting survey and the need for discussion for 'recommendations 3a, e, f, k, l, m, n, r, s and t' from a scientific perspective only after consideration of the feedback comments , available at https://doi.org/10.1016/j.esmoop.2021.100309), as described above.
With regard to 'recommendation 3a' there was concern that not all centres in Asia have multidisciplinary teams (MDT) for the treatment of HNC, so the wording of the recommendation was revised slightly as per the bold text below with 100% consensus. After discussion at the 'face-to-face' meeting 'recommendations 3e and f' were accepted without change, with 100% consensus. 3a. Ideally the optimal treatment strategy should be discussed in an MDT including not only the treating physicians but all the supportive specialities [III, A; A lack of consensus in terms of 'acceptability' for 'recommendation 3i' below, however, was identified in the pre-meeting survey. The use of a hypoxic radiosensitiser has not been approved in China and is not practised in Singapore. The Asian experts agreed that the evidence was available to support this recommendation in the form of a meta-analysis, [bib_ref] Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and..., Overgaard [/bib_ref] A lack of consensus was also identified in the feedback comments about 'recommendations 3k, 3l, 3m and 3n'. With regard to 'recommendation 3k, there was concern over the statement that the standard of care was 100 mg/m 2 cisplatin given on days 1, 22 and 43 of concomitant RT (70 Gy), because a weekly dose of 40 mg/m 2 cisplatin is also a standard treatment option in Asian countries. Also, weekly low dose 40 mg/m 2 cisplatin plus RT has been shown to have similar survival to 100 mg/m 2 cisplatin plus RT every 3 weeks with lower toxicity. [bib_ref] Cisplatin every 3 weeks versus weekly with definitive concurrent radiotherapy for squamous..., Bauml [/bib_ref] A retrospective multicentre study failed to find any difference in survival between weekly versus 3-weekly cisplatin dosing and concomitant RT, [bib_ref] 3-weekly or weekly cisplatin concurrently with radiotherapy for patients with squamous cell..., Helfenstein [/bib_ref] although these findings are not universal, [bib_ref] Once-a-week versus once-every-3-weeks cisplatin chemoradiation for locally advanced head and neck cancer:..., Noronha [/bib_ref] [bib_ref] Weekly cisplatin concurrently with radiotherapy in head and neck squamous cell cancer:..., Osman [/bib_ref] and more prospective clinical studies are required. Also, in a separate study, weekly cisplatin plus RT versus cetuximab plus RT, showed weekly cisplatin plus concomitant RT to have superior outcomes to cetuximab plus RT. [bib_ref] Randomized trial of radiation therapy with weekly cisplatin or cetuximab in low-risk..., Rischin [/bib_ref] A Japanese study has also shown weekly cisplatin plus RT to be non-inferior to 3-weekly cisplatin plus RT post-operatively in Japanese patients with high-risk, locally advanced SCCHN. [bib_ref] Phase II/III trial of post-operative chemoradiotherapy comparing 3-weekly cisplatin with weekly cisplatin..., Kiyota [/bib_ref] Thus, an extra line was added to 'recommendation 3k' below (see bold text below and [fig_ref] Table 1: from both a scientific [/fig_ref] , with 100% consensus. There was also some discussion about 'recommendation 3l' and the use of cetuximab , available at https://doi. org/10.1016/j.esmoop.2021.100309), and the observation that Asian patients are more susceptible to RT-induced mucositis. 'Recommendation 3l' was left unchanged with 100% consensus. In relation to 'recommendation 3m' the Asian experts were concerned that it should be made clear that induction chemotherapy was only to be administered for up to three cycles, according to response, with the patient's disease evaluated after every cycle. The text of 'recommendation 3m' was thus revised accordingly (see bold text), with 100% consensus. In the case of 'recommendation 3n' it was noted that although induction chemotherapy was not used routinely with larynx preservation, the Japanese experts considered induction chemotherapy an option in the A lack of consensus was also identified in the feedback comments with regard to 'recommendations 3r-t, and 3v'. The Asian experts recommended that the text of 'recommendation 3r' below was revised (see bold text) to make it clear that every effort should be made to ensure that patients receive RT or CRT within 6 weeks of surgery, and definitely no later than 8 weeks after surgery. Emphasis was placed on the importance of liaising with the surgeon in an MDT environment, where and whenever possible. In relation to 'recommendation 3s' there was much discussion about the PD-L1 combined positive score (CPS) as an indicator of response to pembrolizumab based on the data from the phase III KEYNOTE (KN)-048 trial in which previously untreated patients with recurrent or metastatic SCCHN (R/M SCCHN) were randomised to receive pembrolizumab alone or chemotherapy plus either pembrolizumab or cetuximab. [bib_ref] Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or..., Burtness [/bib_ref] Pembrolizumab alone improved overall survival versus chemotherapy plus cetuximab (EXTREME regimen [bib_ref] Platinum-based chemotherapy plus cetuximab in head and neck cancer, Vermorken [/bib_ref] [bib_ref] Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or..., Burtness [/bib_ref] Pembrolizumab plus chemotherapy was also superior to cetuximab plus chemotherapy in terms of overall survival in the total population [13.0 months versus 10.7 months, HR 0.77 (95% confidence interval 0.63-0.93), P 14 0.0034] with the benefit again slightly greater in patients with a CPS !20 than in those with a CPS !1 and therefore the wording of 'recommendation 3s' was revised to reflect this, and reference made to the publication by Kiyota and Imamura 2020 35 in relation to 'recommendations 3s and 3t'. Although support for the EXTREME regimen first line has been shown in a Chinese phase III study [bib_ref] First-line treatment with chemotherapy plus cetuximab in Chinese patients with recurrent and/or..., Guo [/bib_ref] and a Japanese observational study, [bib_ref] Real-world clinical outcomes and prognostic factors in Japanese patients with recurrent or..., Yokota [/bib_ref] the Asian experts considered pembrolizumab plus chemotherapy to also be a valid option for the treatment of PD-L1-negative disease based on the data from the KN-048 trial, [bib_ref] Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or..., Burtness [/bib_ref] for the total patient population, especially as in some countries in Asia the EXTREME regimen is not reimbursed. Docetaxel, cisplatin and cetuximab (TPeX) (although the safety data are only available for induction therapy in Asian patients), [bib_ref] A multicenter phase II trial of docetaxel, cisplatin, and cetuximab (TPEx) followed..., Zenda [/bib_ref] and paclitaxel and carboplatin plus cetuximab (PCE) which has shown promising activity in Japanese patients, [bib_ref] Phase II trial of combination treatment with paclitaxel, carboplatin and cetuximab (PCE)..., Tahara [/bib_ref] are alternative treatment options, and the wording of 'recommendation 3t' below was amended to reflect this with 100% consensus. 3r. Every effort should be made to ensure that the administration of post-operative RT or CRT starts This score relates to a planned subgroup illustrating enhanced benefit among a subset of the approved cohort with CPS PD-L1 expression !20. e QoL evaluated as exploratory endpoint (as distinct from primary or secondary endpoint) is not eligible for ESMO-MCBS grading. f European Medicines Agency (EMA) approval is restricted to PD-L1 !50% tumour proportion score (TPS). PD-L1 !1 CPS was a secondary endpoint eligible for ESMO-MCBS scoring. g EMA indication is restricted to recurrent or metastatic head and neck cancer with PD-L1 !50% TPS. This approval is based on an exploratory analysis with no adjustment for multiplicity in which the median OS control arm was 6.6 months, with a gain of 5.0 months HR 0.53 (95% CI 0.35-0.81). Although exploratory analyses can be the basis for hypothesis generation or conjecture or even licensing approvals by regulatory authorities, since they are exploratory (as distinct from primary or secondary endpoints), they are not eligible for grading using ESMO-MCBS.
[formula] consensus [ 100%].Available Y/N Available Y/N Available Y/N Available Y/N Available Y/N Available Y/N Available Y/N Imaging PET/PET/CT Y Y Y Y Y Y Y Assays p16 IHC Y Y Y Y Y Y Y HPV test such as DNA, RNA or ISH Y Y N Y Y Y Y EBER Y Y Y Y Y Y Y PD-L1 IHC Y Y Y Y Y Y Y DPD testing N Y N N N Y N Radiotherapy IMRT or VMAT Y Y Y Y Y Y Y Drugs Pembrolizumab Y Y Y Y Y Y Y Nivolumab Y Y Y Y Y Y Y Cetuximab Y Y Y Y Y Y Y CSCO, [/formula]
Deficiencies in the functioning of dihydropyrimidine dehydrogenase (DPD), the main enzyme involved in fluoropyrimidine metabolism, due to genetic polymorphisms, occur in 3%-5% of Western/European patients and can lead to lethal fluoropyrimidine toxicity. [bib_ref] DPYD genotypeguided dose individualisation of fluoropyrimidine therapy in patients with cancer: a..., Henricks [/bib_ref] Due to the low incidence of DPD deficiency in Asian patients, however, DPD genotyping and phenotyping is not carried out in routine daily practice in Asia, but is recommended for patients, who experience severe 5-FU toxicity during and after their first cycle of chemotherapy. The original 'recommendation 3v' below was thus revised completely, to the version in bold text and [fig_ref] Table 1: from both a scientific [/fig_ref] , to reflect this. 3v. DPD testing is recommended before initiating 5-FU. 3v. According to the specific genetic profile of the Asian patient population, DPD genotyping or phenotyping may be considered before initiating fluoropyrimidine-

## Drug and testing availability
The drug and testing availability for each of the seven Asian countries is summarised in, and the ESMO-Magnitude of Clinical Benefit Scales (ESMO-MCBSs) for the different systemic therapy options for the treatment of SCCHN are presented in [fig_ref] Table 3: ESMO-MCBS table for new therapies/indications in SCCHN CI, confidence interval [/fig_ref]. Resource limitations are the most important barrier to offering optimal diagnosis and treatment to patients with SCCHN across the different Asian countries.

# Conclusions
The recommendations listed in [fig_ref] Table 1: from both a scientific [/fig_ref] can be considered to constitute the consensus Clinical Practice Guidelines for the treatment of patients with SSCHN (excluding nasopharyngeal cancer) in Asia, and are the result of voting by the Asian experts both before and during the virtual 'face-toface' meeting hosted by KSMO, to adapt the recently published EHNS-ESMO-ESTRO Clinical Practice Guidelines. [bib_ref] Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO..., Machiels [/bib_ref] Following 'face-to-face' discussions during the virtual meeting, the revisions highlighted in bold text in [fig_ref] Table 1: from both a scientific [/fig_ref] were made to the wording of the recent EHNS-ESMO-ESTRO Clinical Practice Guideline 'recommendations' initially identified in the pre-meeting survey as not having the agreement of all the Asian experts, and resulted in a 100% consensus, being achieved for all the recommendations listed.
Despite these changes, these Pan-Asian adapted recommendations show high concordance with the original EHNS-ESMO-ESTRO Clinical Practice Guideline recommendations for the treatment of patients with SCCHN, [bib_ref] Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO..., Machiels [/bib_ref] with the acceptance of each recommendation by each of the Asian experts based on the available scientific evidence independently of the approval and reimbursement status of certain drugs in their individual countries.
A summary of the availability of the recommended treatment modalities and recommended drugs, as of July 2021, is presented for each participating Asian country inand will obviously impact on some of the disease and patient management strategies that can be adopted.
[fig] 100 Recommendation 4: Follow-up 4a. Clinical follow-up including head and neck examination by flexible endoscopy should be carried out every 2-3 months during the first 2 years, every 6 months for years 3-5 and annually thereafter [III, A]. 100 4b. Imaging should be carried out if symptoms occur or in cases of abnormalities found at the clinical examination [III, A]. 100 4c. FDG-PET/CT is recommended 3 months after CRT for patients with node-positive disease to assess the necessity of neck dissection [I, A]. [/fig]
[fig] 100: CE-CT, contrast-enhanced-computed tomography; CPS, combined positive score; CRT, chemoradiotherapy; CT, computed tomography; DOI, depth of invasion; DPD, dihydropyrimidine dehydrogenase; EMA, European Medicines Agency; EBER, EpsteineBarr-encoded RNA; ESMO-MCBS, ESMO-Magnitude of Clinical Benefit Scale; FDA, Food and Drug Administration; FDG-PET, 2-fluoro-2-deoxy-D-glucose-positron emission tomography; 5-FU, 5-fluorouracil; HPV, human papilloma virus; IHC, immunohistochemistry; IMRT, intensity modulated radiotherapy; MDT, multidisciplinary team; MRI, magnetic resonance imaging; PCE, paclitaxel, carboplatin and cetuximab; PD-L1, programmed death-ligand 1; R/M, recurrent/metastatic; RT, radiotherapy; SCCHN, squamous cell carcinoma of the head and neck; TNM, tumour, node and metastasis; TPeX, taxane, cisplatin and cetuximab; TPF, docetaxel, cisplatin and 5 -FU; UICC, Union for International Cancer Control; VMAT, volumetric modulated arc therapy. [/fig]
[fig] Figure 3: Management of oropharyngeal cancer (p16-negative stage ILIVB; p16-positive stage ILIII). c, clinical; CRT, chemoradiotherapy; M, metastasis; N, node; RT, radiotherapy; T, tumour. a Altered fractionation (accelerated or hyperfractionated) RT is a valid option for T1AN1, T2AN0 or T2AN1. b Altered fractionation (accelerated or hyperfractionated) RT is a valid option for T1AN1 or T2AN1. c Altered fractionation (accelerated or hyperfractionated) RT is a valid option for T1AN1 or T2AN1. [/fig]
[fig] Figure 4: Management of hypopharyngeal cancer (stage ILIVB). BSC, best supportive care; c, clinical; ChT, chemotherapy; CRT, chemoradiotherapy; M, metastasis; N, node; RT, radiotherapy; T, tumour. a In the case of patients unfit for curative treatment. However, curative treatment should be considered for most patients. [/fig]
[fig] Figure 5: Management of recurrent and/or metastatic disease not amenable to curative RT or surgery. BSC, best supportive care; c, clinical; ChT, chemotherapy; CRT, chemoradiotherapy; 5-FU, 5-fluorouracil; M, metastasis; MCBS, Magnitude of Clinical Benefit Scale; N, node; PCE, paclitaxel, carboplatin and cetuximab; PD-L1, programmed death-ligand 1; RT, radiotherapy; T, tumour; TPeX, cisplatin/docetaxel/cetuximab. [/fig]
[table] Table 1: from both a scientific (acceptability) and applicability point of view (see also Supplementary Table S2, available at https://doi.org/10. 1016/j.esmoop.2021.100309). 2a. The UICC TNM 8th edition staging system should be used (Supplementary Table S4, available at https:// doi.org/10.1016/j.esmoop.2021.100309). 25 [/table]
[table] 3e: The recommended treatment option should be based on patient-and treatment-related factors (e.g. sideeffects, complications, etc.) since conservative surgery and RT may often provide similar locoregional control [IV, A; consensus [ 100%]. 3f. Early disease should be treated as much as possible with a single-modality treatment [IV, A; consensus [ [/table]
[table] Table 3: ESMO-MCBS table for new therapies/indications in SCCHN CI, confidence interval; CPS, combined positive score; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; 5-FU, 5-fluorouracil; HR, hazard ratio; OS, overall survival; PD-L1, programmed death-ligand 1; QoL, quality of life; R/M, recurrent/metastatic; SCCHN, squamous cell carcinoma of the head and neck. a ESMO-MCBS version 1.1. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee. b QoL exploratory endpoint, therefore, not creditable. c Three-arm trial comparing chemotherapy plus cetuximab versus chemotherapy plus pembrolizumab versus pembrolizumab monotherapy. d The licensed indication is for CPS PD-L1 expression !1. [/table]