Introduction

Chemoradiotherapy (CRT) with concurrent high-dose cisplatin (CDDP) is the gold standard of care as a non-surgical approach for patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) [1,2,3]. However, certain toxicities are commonly associated with CDDP administration, such as nausea and vomiting, renal insufficiency, ototoxicity, peripheral neuropathy, and cardiac overload due to large-volume infusion, which may cause serious adverse events especially in patients who are elderly or have several comorbidities.

The prevalence of head and neck cancer (HNC) is increasing among patients aged ≥ 60 years, and 20% of patients with HNC are aged ≥ 75 years [4,5,6]. Because the majority of HNC cases are associated with heavy smoking and drinking, HNC patients often have several comorbidities, including cardiovascular or cerebrovascular disease, chronic obstructive pulmonary disease, diabetes, and renal impairment, with poor performance status. Thus, only a limited number of fit patients can tolerate high-dose CDDP or are eligible for clinical trials in real-world HNC populations. Nonetheless, recently clinicians have had more opportunities to make challenging treatment decisions for patients for whom the optimal standard of care is less suitable.

In this review, we first emphasize the role of a surgical approach if patients cannot tolerate CRT as a non-surgical approach. We then briefly review the criteria used to determine eligibility for CDDP-based treatment. We focus on alternatives to definitive CRT, induction chemotherapy (ICT), and postoperative approaches for patients ineligible for standard treatment. This is a major unmet clinical need in the real-world practice of HNC.

Surgical or Non-surgical Approach?

One of the most critical decisions for patients with resectable LASCCHN is whether to undergo a surgical or non-surgical approach. The standard of care for organ preservation in patients with LASCCHN is CRT with high-dose CDDP. However, non-surgical approaches with systemic chemotherapy, such as CRT and BRT, are invariably associated not just with acute side effects, but also with late toxicities and delayed functional loss, including xerostomia, dysphagia, aspiration pneumonia, and prolonged dependence on a feeding tube [7]. In contrast, local therapy alone without systemic chemotherapy may sometimes be more tolerable and an option for patients with these risks. However, if radiotherapy (RT) alone is chosen as local therapy, there is concern about a poorer treatment outcome compared with the combined use of chemotherapy.

Upfront surgery is an important option with high curability, if de-intensification is estimated to be unavoidable in a non-surgical approach. Furthermore, upfront curative surgery may often be less toxic and more feasible than definitive CRT using high-dose CDDP, especially in patients whose postoperative pathological findings are expected to reflect no or moderate risk. Furthermore, total laryngectomy is often chosen for elderly patients with a high risk of aspiration pneumonia induced by definitive CRT because the risk of aspiration is extremely low due to complete separation of the airway from the gastrointestinal tract through total laryngectomy [8,9,10,11]. Interestingly, a retrospective study suggested that patients who underwent total laryngectomy were less dependent on a feeding tube and had less risk of aspiration pneumonia after adjuvant CRT than those who underwent other surgery [12]. Therefore, postoperative adjuvant CRT after total laryngectomy appears to be safe and feasible even in patients with high-risk pathological features.

Before discussing non-surgical approaches for patients for whom high-dose CDDP is unfeasible, the most preferable treatment option, including a surgical approach, should be considered taking into account patient and disease characteristics. Head and neck surgeons, radiation oncologists, and medical oncologists are in charge of decision-making on treatment modalities, such as surgery and reconstruction, radiotherapy, and chemotherapy, respectively. A multidisciplinary tumor board is the best setting to perform such critical decision-making in a consensual manner (Fig. 1).

Fig. 1
figure 1

Schematic representation of multidisciplinary approach to patients ineligible for standard treatment. The kinds of medical staff and their major roles are presented in the target list. Each member of the medical staff is in charge of decision-making on treatment modalities, subsequent treatment, or supportive care as a specialist. HNC head and neck cancer, CRT chemoradiotherapy

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Definition of Ineligibility for CDDP

Because CDDP plays a central role in concurrent CRT as well as in ICT for LASCCHN, ineligibility for CDDP also leads to ineligibility for the standard treatment. Unfortunately, some patients are considered to be “CDDP-ineligible” in the clinical practice of HNC.

Ineligibility for treatment with CDDP has been well discussed in advanced urinary tract cancer [13, 14]. One consensus definition of CDDP ineligibility is inadequate renal function [creatinine clearance (CCR) < 60 mL/min], poor Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2, or pre-existing peripheral neuropathy or hearing loss. Similarly, an expert panel meeting sponsored by a pharmaceutical company developed clinical criteria for defining platinum-unsuitable patient populations in HNC [15]. Clinical criteria for patients for whom high-dose CDDP is unsuitable include poor PS (≥ 2), biological age > 70, renal dysfunction (50 < CCR < 60), and otologic and neurological dysfunction. Cardiovascular diseases including hypertension, unstable cardiac disease, diabetes, and recurrent pulmonary infections may also increase the risk of toxicity due to delayed hepatic metabolism and accelerating aging of the kidney. Weight loss (≥ 20%) and nutritional status may cause serious and dose-limiting side effects. Finally, socioeconomic status and family support are important factors affecting toxicity and treatment compliance. Taken together, when considering the administration of CDDP as part of a non-surgical approach, physicians should integrate such comprehensive physiological and socioeconomic factors into the decision-making for each patient.

What Are the Alternatives to Definitive CRT with High-Dose CDDP?

Approaches to reduce or avoid the toxicity of high-dose CDDP-based CRT include reduction of the CDDP dose, modified administration scheduling, or a change to alternative drugs (Table 1). New radiotherapy techniques, such as IMRT (intensity-modulated radiotherapy) and SW-IMRT (swallowing sparing IMRT), and stereotactic radiotherapy may also be associated with reduced toxicity. In this article, we focus on concurrent radiosensitizing chemotherapies for patients ineligible for treatment with high-dose CDDP.

Table 1 Alternatives to definitive CRT with high-dose CDDP
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RT Alone or Reduced Dose of CDDP plus RT

For patients ineligible for treatment with high-dose CDDP, RT alone or a reduced dose of CDDP plus RT might be alternative treatment regimens. RT alone is obviously less toxic than CDDP plus RT. However, a consensus has been reached that RT alone is clearly less effective than platinum-based CRT [3], with a complete response (CR) rate of 22–29% and 3-year survival of 7–45% [1, 16,17,18,19,20]. A meta-analysis showed a more pronounced survival benefit of concomitant chemotherapy than that of ICT. Furthermore, patients receiving a cumulative dose of < 200 mg/m2 had a significantly worse outcome than those receiving > 200 mg/m2 [21]. To achieve better therapeutic outcomes, concurrent use of any systemic chemotherapy more tolerable than CDDP should be identified in combination with RT without compromising efficacy for patients ineligible for CDDP.

Cetuximab plus Radiotherapy

Cetuximab is an epidermal growth factor receptor (EGFR)-targeting immunoglobulin G1 monoclonal antibody. A phase III trial conducted by Bonner et al. revealed that the addition of cetuximab to radiotherapy (BioRT) significantly improved the survival outcome and locoregional control compared with RT alone in patients with LASCCHN [19, 22, 23]. In that trial, there were few cases with gastrointestinal toxicity, renal dysfunction, and neurotoxicity and ototoxicity. Therefore, BioRT is considered as an option for patients ineligible for high-dose CDDP-based CRT. However, this trial enrolled highly selected patients with normal organ function, high Karnofsky performance status scores, and younger age. No prospective trials of BioRT have been conducted for patients who are ineligible for CDDP treatment.

Notably, BioRT has a specific toxicity profile, such as acneiform rash outside the radiation field, infusion reaction, and interstitial pneumonitis, which differs from that for CDDT plus RT. Other studies have also observed grade 3 or 4 radiation dermatitis in over 30% of patients treated with BioRT [24,25,26]. Although there was no difference in the incidence and severity of mucositis and dysphagia between BioRT and RT alone in the above phase III trial [19], the reported rates of mucositis in daily practice may be higher than those reported in the pivotal studies. For instance, Japanese real-world data have shown an occasionally worse outcome of BioRT versus RT alone, upon the occurrence of mucositis [27,28,29]. An Italian randomized phase II trial revealed that BioRT lowered compliance and increased acute toxicity rates compared with CRT, and the need for nutritional support more frequently arose in the BioRT arm than in CRT [30•]. Furthermore, the Radiation Therapy Oncology Group (RTOG) 1016 trial comparing BioRT with CRT for HPV-related oropharyngeal cancer also demonstrated the same frequencies of in-field toxicities and dependence on a feeding tube among the arms [31•, 32•]. These results suggest that the combination of cetuximab and RT may also impact the frequency of dependence on a feeding tube because of the high incidence of mucositis even in patients with a favorable general condition.

Taken together, the currently available data may not support the use of BioRT as a reasonable alternative to CRT in patients who cannot tolerate CDDP. It remains to be determined how best to select the patients with HNC who can benefit from BioRT. More importantly, multidisciplinary supportive care against radiation dermatitis and mucositis and nutritional intervention are still required for BioRT, and special care should be taken of elderly patients and those in a poor general condition.

Weekly Low-Dose and Fractionated Administration of CDDP plus RT

The recommended cumulative dose of CDDP is approximately 200 mg/m2 or more independent of the administration schedule [33, 34]. A modified schedule of CDDP dosing may be a reasonable alternative if the cumulative dose of CDDP has exceeded 200 mg/m2.

Several studies have reported on the use of weekly low-dose CDDP plus RT for LASCCHN. However, there are insufficient data on head-to-head prospective comparisons of tri-weekly CDDP plus RT with weekly CDDP plus RT for non-nasopharyngeal cancer (NPC). A randomized phase III trial comparing weekly versus tri-weekly CDDP failed to demonstrate the non-inferiority of weekly CDDP [35]. However, among the patients in this trial, only 7% intended to undergo definitive CRT. A comparison of concurrent CRT with tri-weekly versus weekly CDDP in patients with locally advanced NPC revealed similar acute toxicities and survival outcomes [36]. However, the statistical design of this trial is unclear. Notably, eligible patients in both trials needed to be feasible to tri-weekly 100 mg/m2 of CDDP.

Some clinicians have made use of the fractionated administration of a CDDP regimen for borderline cases with calculated creatinine clearance of 40–60 mL/min, in which 20 mg/m2 CDDP is separated across 4 treatment days. A prospective study targeted the fit patients with adequate hematological and organ function, including creatinine clearance of > 60 mL/min [37]. Therefore, it is still unclear whether the fractionated administration of CDDP plus RT is feasible and has comparable efficacy for patients for whom CDDP is unsuitable.

Carboplatin plus RT

Carboplatin (CBDCA) is a second-generation CDDP analog with lower gastrointestinal toxicity, nephrotoxicity, and neurotoxicity than CDDP [38]. Therefore, CBDCA has been selected as an alternative to CDDP in patients with solid tumors who are ineligible for treatment with CDDP. In HNC, the combination of CBDCA with RT was conventionally utilized after ICT in several large clinical trials, such as the TAX324 [39] and PARADIGM trials [40]. In a prospective randomized study in patients with locally advanced NPC, concurrent weekly CBDCA (100 mg/m2 on days 1, 8, 15, 22, 29, and 36) plus RT demonstrated comparable efficacy and better tolerability than high-dose tri-weekly CDDP plus RT [41]. There was no significant difference in survival outcome. For non-NPC, the Hellenic Cooperative Oncology Group Phase III Study showed that both high-dose CDDP and tri-weekly CBDCA-based CRT significantly prolonged 3-year survival compared with RT alone (52%, 42%, and 17.5% for CBDCA, CDDP, and RT alone, respectively) [42]. However, no prospective trials of CBDCA plus RT have been conducted in patients who are ineligible for CDDP.

A retrospective study from a single institution demonstrated the safety and efficacy of CBDCA plus RT in patients with LASCCHN ineligible for treatment with CDDP [43]. In that study, complete response was achieved in 70% of patients and the median PFS was 42.7 months. Furthermore, all patients received the planned total radiation dose of 70 Gy. These results suggest favorable compliance and efficacy of CBDCA plus RT even in CDDP-ineligible patients. Furthermore, a retrospective comparison between concomitant CBDCA and Cmab in patients ineligible for CDDP revealed that the survival outcome in CBDCA plus RT appeared to be better than that in Cmab plus RT: 42.7 months versus 11.6 months for PFS and 91.9 months versus 35.5 months for OS [44•].

However, CBDCA often causes grade 3 or 4 hematological toxicity, especially neutropenia and thrombocytopenia, and results in infection, which leads to unplanned breaks in RT and discontinuation or dose reduction of CBDCA. In the tri-weekly administration of CBDCA [area under the curve (AUC), 4–7], myelosuppression is more likely to occur than in its weekly administration (AUC, 1.5–2) [42, 43, 44•]. Although the antitumor effect of CBDCA is enhanced by increased AUC, myelosuppression is AUC dose-dependent. Therefore, low-dose weekly CBDCA plus RT may be more appropriate in patients who have a risk of myelosuppression.

Taking the above findings together, CBDCA as a concurrent systemic therapy with RT is well tolerated and may be a treatment option for LASCCHN patients ineligible for CDDP, although attention should be paid to hematological toxicity.

S-1 plus RT

The combination of non-platinum agents could be a reasonable option for patients ineligible for CDDP. S-1 is an oral anticancer drug that combines tegafur, a prodrug of fluorouracil, with 5-chloro-2,4-dihydropyrimidine and potassium oxonate at a molar ratio of 1:0.4:1. Various dose and administration schedules of S-1 were investigated for concurrent use with RT in Japanese phase 1 and 2 trials [45,46,47,48,49,50,51,52,53]. The major adverse events were mucositis and dermatitis in all reports. However, care should be taken regarding the potential for renal toxicity when using S-1 for patients with decreased CCR.

S-1 plus RT has been mainly used to target early laryngeal cancer (T2N0M0) in several retrospective and prospective trials [45, 47, 49, 51,52,53]. These studies revealed that the 5-year overall survival rate for the RT plus S-1 group was significantly better than that of the RT alone group, and a significantly lower incidence of distant metastasis was observed in the RT plus S-1 group than in RT alone. However, it is still unclear whether this combination has a survival benefit compared with RT alone in locally advanced stage III or IV HNC. More importantly, no data are available for patients for whom CDDP is unfeasible, since all of these studies excluded patients with comorbidity or poor PS.

PTX plus RT

A prospective study was conducted to compare concomitant CRT using CDDP with that using paclitaxel in stage III and IV advanced HNC [54]. However, no definitive findings have been obtained about the superiority or inferiority of each regimen, and it is unclear whether paclitaxel can be substituted for CDDP in patients ineligible for standard treatment. In stage IB–III esophageal cancer, a phase I/II study of CRT with paclitaxel is ongoing for elderly patients older than 70.

Clinical Trials

At present, there are no available data from prospective studies on alternative treatments for LASCCHN patients in whom CDDP is contraindicated. However, recent advances in immune checkpoint inhibitors (ICIs) have expanded their indication as definitive treatments in LASCCHN. Over the past few years, ICIs targeting programmed cell death protein 1 (PD-1) (nivolumab, pembrolizumab) and programmed cell death ligand 1 (PD-L1) (atezolizumab, avelumab, durvalumab) have changed treatment paradigms in many malignancies. Previous phase 2 studies demonstrated that pembrolizumab and atezolizumab had antitumor activity and acceptable tolerability in CDDP-ineligible patients with locally advanced and metastatic urothelial carcinoma [55,56,57].

Combinations of ICIs with RT/CRT are currently under investigation in the treatment of LASCCHN. RT modulates the immune system, such as antigen presentation, effector T cell recruitment, and the expression of immune checkpoint receptors [58]. Localized RT also induces the regression of disease at distant sites [59], which is known as the abscopal effect. Therefore, combined therapy with RT and ICIs works synergistically to improve treatment outcomes. Importantly, some of the clinical trials on ICIs for LASCCHN have evaluated ICIs plus RT alone in the specific cohort of patients ineligible for standard treatment using high-dose CDDP (Table 2). Some trials involving head-to-head comparison of ICIs (pembrolizumab or durvalumab) plus RT versus BioRT have been established. There are also phase 3 trials investigating whether the addition of ICIs (nivolumab, avelumab) to BioRT significantly improves the survival outcome compared with BioRT. However, it is unclear whether the combination of ICIs with RT alone without concurrent platinum agents is comparable with standard high-dose CDDP-based CRT in terms of treatment outcome.

Table 2 Ongoing clinical trials of definitive and postoperative radiotherapy for patients ineligible for CDDP plus RT
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Alternatives to Induction Chemotherapy-TPF

Although CRT is a standard treatment for patients with LASCCHN, ICT is a useful tool for laryngeal preservation in resectable laryngeal and hypopharyngeal cancers. Another purpose of ICT is to improve overall survival through the control of distant metastasis. The patients with multiple or bilateral cervical nodal metastases are at high risk of distant metastases and have poor prognosis [60, 61]. It has been reported that the addition of ICT to locoregional treatment significantly reduces distant metastases compared with locoregional treatment alone [2, 3, 62], while several prospective clinical trials have failed to demonstrate the survival benefit of ICT compared with CRT alone due to difficulties in trial design or execution, or insufficient patient accrual [40, 60, 63]. Thus, the role of ICT in unresectable disease remains controversial, and the exact patient populations who gain the most benefit from ICT remain to be comprehensively defined.

Nevertheless, ICT may be required for certain patient subgroups with high-risk disease or those for whom organ preservation is a key end goal. Indeed, ICT has been occasionally performed before CRT or BRT in clinical practice.

Docetaxel plus CDDP and 5-fluorouracil (TPF) is an evidence-based standard ICT regimen in LASCCHN, and confers benefits in fit patients when it is administered safely. However, TPF frequently induces myelotoxicity, such as severe neutropenia or febrile neutropenia (FN), which may lead to discontinuation of subsequent TPF chemotherapy and treatment-related death. FN occurred in 5–29% of patients with LASCCHN who received TPF [39, 64, 65]. The TPF regimen has also been reported to cause severe gastrointestinal, renal, and neural toxicities. These events occurred especially in patients who were elderly or had cardiac, renal, or neurogenic dysfunction. Therefore, an alternative to TPF as ICT should be considered for LASCCHN patients ineligible for the TPF regimen.

To prevent unacceptable toxicity, other triplet regimens without the 5-fluorouracil component were investigated. For instance, the results of studies using TPE (taxane, platinum, and cetuximab) have been encouraging [66,67,68,69], although no randomized trials comparing TPE with TPF have been completed. However, TPE contains the combination of 75–100 mg/m2 CDDP and docetaxel, and is still associated with severe myelosuppression and mucositis. Therefore, TPE-ICT is not a feasible treatment option for the CDDP-ineligible population.

Although there is no standard ICT regimen for LASCCHN patients who are ineligible for TPF, one of the most appropriate alternative ICT regimens may be the paclitaxel plus carboplatin and cetuximab (PCE) regimen, in which CDDP and docetaxel are exchanged for carboplatin and paclitaxel, respectively [70]. A phase II prospective trial of the PCE regimen revealed that the overall response rate (ORR) was 96%, and the most common grade 3 or 4 toxicity was skin rash (45%), followed by neutropenia (21%) without fever [71]. However, the oropharynx was the main primary site of disease in this study, which is particularly sensitive to chemotherapy. Furthermore, this study enrolled CDDP-eligible patients alone. A retrospective study on the ICT regimen for LASCCHN patients ineligible for TPF treatment showed promising efficacy of the PCE regimen as ICT, with an ORR of 87% [72]. While the PCE regimen was well tolerated in this population, care must be taken regarding the possibility of myelosuppression, oral mucositis, and dermatological reactions. Therefore, appropriate modification of the initial dose may be needed according to the patient’s characteristics.

Although the PCE regimen could represent a safer option than TPF for patients ineligible for high-dose CDDP, there is no consensus regarding the optimal locoregional treatments after PCE-ICT. Because evidence obtained to date suggests that ICT followed by CRT confers high toxicity without additional benefit, future investigations must determine the optimal local therapy after ICT, namely, RT alone or RT plus either carboplatin or cetuximab, for patients ineligible for TPF.

Alternatives to Postoperative CRT with High-Dose CDDP

There is no evidence on alternatives to postoperative CRT for patients ineligible for high-dose CDDP. Experiences in the definitive setting have mostly been extrapolated to the adjuvant setting.

In this context, the alternative scheduling of CDDP administration may be an option. Bachaud et al. conducted a small phase 2 study to investigate postoperative CRT concurrently using weekly CDDP [73, 74]. However, the dose of CDDP was 50 mg/m2 once weekly seven times, which exceeded the level in current practice and caused more severe acute adverse events. Aforementioned phase III randomized trial comparing weekly versus tri-weekly CDDP mostly included the patients who intended to enter the postoperative adjuvant setting due to high-risk features [35]. The results revealed that tri-weekly CDDP at 100 mg/m2 resulted in superior locoregional control compared with weekly CDDP at 30 mg/m2, despite more toxicity. However, the criticism has been raised that the dose of CDDP in the weekly arm was only 30 mg/m2 and that the majority of patients were young and had oral cancer. A prospective randomized controlled trial (JCOG1008) is underway in Japan, in which weekly CDDP/RT is being compared with high-dose tri-weekly CDDP/RT as postoperative adjuvant CRT for high-risk patients. However, all of the above trials targeted patients for whom high-dose CDDP was feasible. Therefore, these trials cannot resolve whether weekly CDDP is safe and efficacious for patients ineligible for high-dose CDDP.

Postoperative BioRT was retrospectively studied in patients with locally advanced cutaneous SCC deemed poor candidates for CDDP [75]. The specific reasons for patients’ ineligibility for CDDP included old age, medical comorbidities, and poor performance status. Because the toxicities induced by BioRT were not systematically identified, this study does not support the routine use of BioRT in patients with high-risk pathological features. Ongoing randomized trials are comparing RT versus BioRT in patients with SCCHN with intermediate-risk features after resection with curative intent (RTOG 0920). Furthermore, according to results of a randomized phase II trial (RTOG 0234) [76] examining concurrent CRT (CDDP or docetaxel) and cetuximab, the addition of weekly docetaxel (15 mg/m2) to BioRT might be an option.

Concurrent high-dose CDDP may possibly be substituted by CBDCA in a postoperative setting in clinical practice. Two prospective randomized trials of postoperative RT with or without CBDCA have been performed. Both trials included patients with ECOG performance status 2 and calculated CCR (Cockcroft–Gault) of < 60 but > 40 mL/min. However, both trials failed to demonstrate any benefit of the addition of weekly carboplatin to adjuvant RT. A trial by Argiris et al. was prematurely terminated because of slow patient accrual [77]. Another randomized phase III trial, the Trans-Tasman Radiation Oncology Group (TROG) 05.01 study, showed that weekly low-dose CBDCA had no effect on survival, although this trial targeted cutaneous SCCHN but not the mucosal type [78••]. Thus, there is currently insufficient evidence to support the combination of CBDCA with RT for patients for whom CDDP is unfeasible.

The combination of CBDCA/5-fluorouracil doublet with RT has generally been accepted as a surrogate for definitive CRT concurrently using high-dose CDDP, especially in the EU [79]. Although this combination has never been prospectively tested after curative resection, it may be applied in the adjuvant setting. However, a concern is that RT-induced mucositis may be enhanced by 5-fluorouracil.

Postoperative adjuvant immunotherapy combining PD-1/PD-L1 antibody and/or CTLA-4 antibody with RT/CRT is also currently under investigation. For instance, a phase II study of durvalumab with or without tremelimumab in combination with RT targeting intermediate-risk HNSCC patients is currently ongoing (NCT03529422). If the obtained results are favorable, this combination may be applied to CDDP-ineligible patients in the future.

Supportive Care

To pursue successful treatment outcomes in patients with HNC ineligible for standard treatment, multidisciplinary supportive care via collaboration between medical staff members is indispensable (Fig. 1). For instance, based on nutritional assessment and support initiated by a dietician [80, 81], physicians should prepare nutritional access, such as a feeding tube. Oral intake and swallowing are among the most important functions impaired by CRT. A program providing evaluation of swallowing function using video-fluoroscopic examination is helpful in addition to rehabilitation. Dentists and dental hygienists are also involved in routine oral screening, oral care, and continuous follow-up of RT-related late toxicity. Furthermore, psychiatric support and economic consultation may be required for some patients and their families. Thus, medical staff with many different specialties play roles in supportive care. However, their roles are not restricted to one task. For instance, medical oncologists and radiation oncologists should be involved not just in deciding treatment modalities, but also in supportive care in CRT. On the other hand, nurses also support patients’ decision-making regarding treatment modalities.

Conclusions

Since HNC patients are often elderly and have several comorbidities, a limited number of patients tolerate high-dose CDDP in real-world HNC populations. The major issue in determining the treatment strategy in patients ineligible for the standard of care is to assess the individual benefit-to-risk ratio of each treatment option, and to propose personalized treatment. Upfront surgery is an important option with high curability, if a de-intensified non-surgical approach is estimated to be unavoidable. When considering CDDP-based definitive/postoperative CRT or ICT as part of a non-surgical approach, precise evaluation of the patient’s physical condition, nutritional status, and comorbidities is needed when deciding on the treatment of HNC. In clinical practice, there are no standard alternatives to definitive CRT, ICT, and postoperative approaches using high-dose CDDP for patients ineligible for standard treatment, because no prospective data are currently available. The combination of ICIs with RT may be a promising novel approach, and some trials are currently targeting the specific patients ineligible for high-dose CDDP. Regardless of the alternative treatment chosen, a multidisciplinary approach is essential for these patients, from the perspective not just of physical supportive care, but also of socioeconomic support.