FormalPara Key Summary Points

Head and neck squamous cell carcinoma (HNSCC) ranks among the most prevalent cancers with > 350,000 deaths annually and a 5-year overall survival of only 40–50%.

We examined the potential of established drugs as induction regimens to improve survival and reduce toxicity in locally advanced head and neck squamous cell carcinoma (LAHNSCC).

The TPF induction regimen was effective in LAHNSCC but had a high rate of adverse reactions.

Regimens for alternative induction therapy containing cetuximab are effective and reduce toxicity.

Immune checkpoint inhibitors combined with chemotherapy or double immunotherapy are promising for induction therapy of LAHNSCC.

Introduction

HNSCC ranks among the most prevalent cancers, with > 350,000 deaths annually and a 5-year overall survival (OS) rate of only 40–50% [1]. HNSCC is highly heterogeneous, and > 60% of patients are locally advanced when diagnosed [2]. Because the anatomical structure of head and neck is complex, and the neck contains many important organs, safer and more effective therapeutic strategies are imperative. The treatment should not only consider the therapeutic effect but also maximize the protection of organ function. Induction therapy is a viable treatment for patients in whom surgery is not suitable or who have a greater need for organ preservation, as it shrinks the volume of tumors and eliminates micro-metastases [3,4,5]. The classic TPF regimen (docetaxel, cisplatin, 5-fluorouracil) is a standard induction chemotherapy regimen, but the toxicity problem is the biggest limitation for patients choosing to use this regimen. The exploration for an effective, low-toxicity version of the induction regimen and its clinical testing are crucial to enhance the quality of life of patients as well as prolong their survival [6]. In this review, we collected data on LAHNSCC and examined the potential of established drugs in an induction regimen to improve survival and reduce toxicity in LAHNSCC.

Methods

For this narrative review, we searched Pubmed, ClinicalTrials.gov and Google Scholar databases for studies of induction therapy for LAHNSCC. The key terms used in this search were “locally advanced head and neck squamous cell carcinoma” or “head and neck squamous cell carcinoma” and “induction therapy” or “targeted therapy” or “ICIs therapy” or “radiation therapy.” No limitations on publication date or article type were specified, as the review covered previously conducted studies with human participants as well as some new studies. A total of 16,102 articles were retrieved through the above search terms; then, they were filtered by using specific keywords “locally advanced head and neck squamous cell carcinoma” to a final group of 352 and from the group we selected studies with reliable data. This article reviews the existing literature and does not contain any new studies with human participants or animals performed by any of the authors.

Induction Chemotherapy (ICT)

NCCN2022 defines ‘unresectable’ as the technical inability to obtain clear margins around a tumor and the presence of some sites associated with poor prognosis, organ function or T4b cancer [7]. In non-resectable LAHNSCC, concurrent chemoradiotherapy (CCRT) is the current standard of care, but the potential value of induction chemotherapy when followed by radiotherapy or CCRT in the management of LAHNSCC has generated considerable debate [7]. A meta-analysis showed that induction chemotherapy had a significantly better rate of progression-free survival (PFS) and complete response (CR) rate and a distinct survival advantage in patients with non-oropharyngeal LAHNSCC [8]. The H&N07 study [5] evaluated survival differences between patients with and without induction chemotherapy in non-resectable LASCCHN. Patients were randomly assigned to an ICT group or a non-ICT and subsequently received CCRT or cetuximab plus RT. The results showed that ICT had no influence on patients’ compliance to CCRT, and compared to the non-ICT, induction chemotherapy significantly improved the CR rate (77% vs 53%, p = 0.0028). The OS benefit of CCRT (HR = 0.83) or cetuximab combined with RT (HR = 0.57) after induction chemotherapy was better than that of CRT alone or cetuximab combined with RT. The degree of benefit from ICT could be different depending on the concomitant or subsequent therapeutic regimen. According to the Spanish TTCC trial [9], which used standard triweekly TPF regimen followed by concomitant CRT regimen, 30% of patients would never receive radiotherapy, 41% of patients needed dose reduction, and 17% of patients discontinued CRT treatment. The TTCC 2007-01 study [10] evaluated the efficacy and safety of cetuximab versus cisplatin after TPF induction therapy in patients with LASCCHN (T2-4, N2b +). The results showed that sequential targeted therapy combined with RT afforded good OS, PFS and LRC benefits after TPF induction therapy, and the survival benefits of the two treatment regimens were similar (OSHR 1.17, PFSHR 1.20, PFSHR 1.08). However, the rate of serious adverse events (SAEs) of any grade was numerically lower in the cetuximab plus RT group (22.8% vs 28.8%). This treatment method can be one of the effective options for patients with large tumor masses and high lymph node load. Sequential cetuximab plus RT benefited more from induction chemotherapy and had a numerically lower incidence of SAEs than sequential CRT. It should be noted that ICT is only suitable for patients with good performance status (PS) like PS ≤ 1.

The optimal strategy for induction chemotherapy has not been fully determined. Several studies have confirmed that the TPF regimen is superior to the PF regimen for induction therapy of LASCCHN. The TAX323 study [11] showed that compared to the PF (cisplatin, 5-fluorouracil) regimen, the TPF regimen significantly prolonged PFS and OS. Similarly, the TAX324 study [12] showed that induction chemotherapy with TPF provided greater PFS and OS benefits for locally advanced SCCHN compared to PF. However, while the TPF induction regimen had greater efficacy, it also suffered from a higher rate of adverse reactions. Therefore, pretreatment and toxicity management are a crucial part of selecting appropriate patients for induction therapy.

In addition, many trials have shown the effectiveness of induction chemotherapy in organ preservation [13,14,15]. Pointreau et al. [16] recruited patients who had larynx and hypopharynx cancer that required total laryngectomy and randomly assigned patients to receive three cycles of TPF or PF induction therapy. Patients who responded to chemotherapy received radiotherapy and who did not respond to chemotherapy underwent total laryngectomy. With a median follow-up of 36 months, the 3-year actuarial larynx preservation rate was 70.3% with TPF vs 57.5% with PF (difference = 12.8%; P = 0.03). However, as Robert [17] said, from the trial, people are only given results for larynx preservation as an indicator of a successful laryngeal outcome without laryngectomy-free survival. Laryngectomy-free survival (LFS) accounts for those patients who survived with an intact and functional larynx instead of only focusing on those with a preserved larynx. In sequential therapy for the locally advanced larynx and hypopharynx cancer subgroup in TAX 324, we could see among operable patients (TPF, n = 67; PF, n = 56) that LFS was significantly greater with TPF (HR: 0.59; 95% CI: 0.37–0.95; P = 0.030). Three-year LFS with TPF was 52% vs 32% for PF. Results of the study and TAX324 support the use of sequential TPF followed by chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced laryngeal and hypopharyngeal cancers (LHC) [18].

Induction of Targeted Therapy Combined with Chemotherapy

In the targeted treatment of HNSCC, a monoclonal antibody against EGFR is the first antibody applied [19]. Cetuximab as a representative drug is the first monoclonal antibody in the treatment of HNSCC [20]. Targeted therapy with cetuximab blocks intracellular signal transduction pathways by competitively binding to EGFR tyrosine kinase, thus inhibiting the proliferation of cancer cells and inducing their apoptosis (Fig. 1) [21]. In 80–90% of HNSCC cases, EGFR overexpression promotes tumor cell survival, proliferation, invasion and angiogenesis [22].

Fig. 1
figure 1

Mechanism of cetuximab action. Cetuximab blocks PI3K-AKT and RAS-ERK1/2 transduction pathways by competitively binding to epidermal growth factor receptor (EGFR) tyrosine kinase, thus inducing apoptosis and inhibiting the proliferation of cancer cells

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Cetuximab is mostly used concurrently with radiotherapy either as a definitive bioradiation approach or preceded by ICT in a sequential approach, i.e., ICT followed by cetuximab/RT, and its role in induction therapy has also been studied. The TPC (docetaxel, cisplatin, cetuximab) regimen with cetuximab instead of 5-FU and the ACPF (albumin paclitaxel, cetuximab, cisplatin, 5-FU) regimen with albumin paclitaxel instead of traditional paclitaxel were more effective and better tolerated compared with the TPF regimen and could be used as an alternative to induction therapy [6]. The AGMT study [6] compared the effectiveness and safety of docetaxel combined with cisplatin and cetuximab (TPC) with TPF in the induction of LASCCHN. The results showed that the overall response rate (ORR) at 3 months (74.5% vs 64.3%) and OS rate at 400 days (86.1% vs 78.5%) in the TPC group were higher than those in the TPF group. In addition, the incidence of SAEs and haematological toxicities was slightly lower in the TPC group, but TPC resulted in more skin toxicities [6]. Collectively, TPC is effective and well tolerated as an induction therapy, and the 1-day regimen (TPC) is clinically more convenient than the 5-day regimen (TPF). Adkins [23] investigated the efficacy and safety of ACPF induction therapy followed by CCRT in patients newly diagnosed with LASCCHN. The results showed that for the primary endpoint, the overall 2-year PFS rate and 2-year OS rate with ACPF treatment were 65% and 84%, respectively. The number of occurrences of grade 3, 4 and 5 AE was 33%, 3% and 3%, respectively [23]. The study indicated that ACPF induction therapy produced a high CRR in the primary tumor location that did not affect subsequent CCRT, and the adverse reactions were controllable [23].

Schell et al. [24] compared survival outcomes with APF + C versus TPF + C induction therapy for LASCCHN. Their study, which updated the results of Adkins’ study [23] and compared them with the historical controls, found that the APF + C group had significantly higher 2-year disease-specific survival (DSS), 2-year PFS rate, 2-year OS rate and ORR, with significantly lower toxicity. These studies suggest that regimens containing cetuximab (TPC) and/or albumin paclitaxel (ACPF) can improve efficacy and reduce toxicity and are beneficial alternative induction therapies.

Induction of Immune Checkpoint Inhibitors Combined with Chemotherapy

The use of immune checkpoint inhibitors (ICIs) affords effective immunotherapies. The main mechanism is to block the signaling pathway that inhibits immune checkpoints and leads to the reactivation of the immune response against tumor cells [25]. Cells active in the immune system express inhibitory receptors, such as cytotoxic T lymphocyte associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) and its ligands programmed cell death-ligand 1 (PD-L1) and PD-L2, which are crucial in the tumor microenvironment (TME) [26]. The change of immune function status in HNSCC patients is a process of immunosuppression, which is mainly manifested as a decrease in total white blood cell count and an increase in the proportion of regulatory T cells (Tregs), while tumor-infiltrating lymphocytes (TILs) in tumor tissues contain more inhibitory Tregs. Therefore, blocking these immune checkpoints can restore T cell function in patients [27, 28]. HNSCC is a kind of immunosuppressive tumor, and immune escape and destruction of T cell signaling are important mechanisms of its occurrence and development [2]. ICI therapy has become another important treatment method for HNSCC through its unique mechanism of action.

The main ICIs have been tested in many trials, not only as monotherapeutic agents but also in combination therapy [29]. TPF induction chemotherapy has been found to increase the expression of PD-L1 in tumor tissue and the numbers of immune cells infiltrating tumors in LAHNSCC [30, 31], indicating that tumors sensitive to induction chemotherapy may activate immune regulatory pathways that promote PD-L1 expression. Increased PD-L1 expression by tumor cells and immune cells may also be a part of the underlying resistance mechanism mediated by the immune system to induction chemotherapy; high levels of PD-L1 in patients may readily interact with ICIs [32]. This indicates that the combination of induction chemotherapy and immunotherapy is suitable for LAHNSCC patients [32], and more studies have focused on this aspect. NCT02952586 is a phase-3 trial with avelumab plus standard-of-care chemoradiotherapy compared with chemoradiotherapy alone in LAHNSCC patients. In the study, the median follow-up for progression-free survival was 14.6 (IQR 8.5–19.6) months in the avelumab-treated group of patients and 14.8 (11.6–18.8) months in the placebo group, which meant that the primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance was not met [33]. Xia Li [34] found that the addition of sintilimab provided longer PFS duration with no increase in toxic events compared to conventional chemotherapy regimens in LAHNSCC patients. The KEYNOTE-412 study evaluated the efficacy and safety of pembrolizumab vs placebo given concomitantly with CRT followed by maintenance pembrolizumab therapy or placebo in patients with LAHNSCC [35]. Compared with the placebo + CRT group, pembrolizumab + CRT showed benefits in improving EFS (event-free survival) of LAHNSCC patients (HR 0.83; P = 0.0429). The 2-year EFS rates of the two groups were 63.2% and 56.2%, respectively, but there was no associated statistical significance. Although the primary endpoint of the KEYNOTE-412 study (EFS) did not reach statistical significance, the results provide some important insights for the treatment of LAHNSCC [36]. The data from ICIs combined with chemotherapy in the induction therapy of LAHNSCC are insufficient to change the guidelines, but the data for the treatment of HNSCC are still promising.

Induction of Chemo-Free Therapy

Because the residual toxicity from induction chemotherapy may have effects on subsequent treatments for LASCCHN [7], researchers have considered the induction of chemo-free therapy, such as double immunotherapy or targeting therapy combined with immunotherapy for this disease.

Double Immunotherapy

CTLA-4 and PD-1/PD-L1 mediate different inhibiting pathways, and their activation mechanisms do not overlap. Therefore, it was hypothesized that combined inhibition of CTLA-4 and PD-1/PD-L1 may achieve better results than either alone, which was indeed proved in preclinical studies in mouse models [37]. Combination therapies using antibodies against CTLA-4 and PD-1/PD-L1 have been investigated by various researchers, and the large volume of data suggests that the combined treatment may overcome the defects of monotherapy. For example, anti-CTLA-4 leads to a rise in the numbers of T cells and an increase in IFN-γ, which in turn can induce the expression of PD-L1 in the tumor microenvironment, thereby inhibiting the anti-tumor response of T cells, but this process increases the therapeutic effects of anti-PD-1 and anti-PD-L1 as well [38] (Fig. 2). Hence, the combination of anti-CTLA-4 with anti-PD-1 or anti-PD-L1 therapy may be able to create an immunogenic tumor microenvironment and lead to improved outcomes for patients.

Fig. 2
figure 2

Antitumor mechanism of anti-PD-1 antibody combined with anti-CTLA-4 antibody. Anti-CTLA-4 leads to a rise in the numbers of T cells and an increase in IFN-γ. In turn, this can induce the expression of PD-L1 in the tumor microenvironment, thereby inhibiting the anti-tumor response of T cells, but this process increases the therapeutic effects of anti-PD-1 and anti-PD-L1. CTLA4 cytotoxic T-lymphocyte antigen 4, IFN-γ interferon-gamma, PD-L1 programmed death ligand-1 and PD-1 programmed cell death protein 1

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Durvalumab and tremelimumab were compared with the EXTREME treatment regimen [39], and it was found that this resulted in a higher rate of response than either treatment alone. However, the adverse reactions of PD-L1 blockades, including colitis, diarrhea, hypophysitis and adrenal insufficiency, may increase when combined with CTLA-4 therapy [40,41,42]. Jonathan et al. [42] compared nivolumab plus ipilimumab (N + I) and nivolumab (N). There was evidence of response in both the N and N + I arms (volumetric response 50%, 53%; pathologic down-staging 53%, 69%; RECIST response 13%, 38%; pathologic response 54%, 73%, respectively) in their study, but there were toxic effects potentially related to the study treatment in 21 patients, including grade 3 to 4 events in 2 (N), and 5 (N + I) patients [42]. Therefore, monitoring and reducing adverse reactions to this type of immunotherapy are essential if this combination is to be used in practice in the future.

EGFR-Targeting Agents Combined with Major ICIs

The effectiveness of cetuximab used alone in HNSCC patients is < 15%, which may be a result of its multiple functions in immune cells, like enhancing the cytotoxic function of effector T cells and promoting the increase of CTLA-4+ Tregs [43]. Therefore, the addition of a CTLA-4 inhibitor to the cetuximab treatment regimen may promote the consumption of Tregs and increase the expression of CTLA-4 and PD-1/PD-L1 to obtain better therapeutic effects [44, 45]. Also, it is known that cetuximab not only blocks EGFR signaling, but can stimulate NK cells and CTLs to secrete IFN-γ, which induces the expression of PD-L1 in tumor cells [46] (Fig. 3). As further evidence of the efficacy of combination therapy, cetuximab increased the number of new immune cells in the TME and could be used to activate the immune system for treatment with ICIs. While ICIs inhibit existing cells, in a way that is complementary to the congenital adaptive immune system, they also interact with a variety of immune cells, thus enhancing the synergistic effect [47].

Fig. 3
figure 3

Mechanism of action of cetuximab combined with immune therapy. Cetuximab used alone in HNSCC enhanced the cytotoxic function of effector T cells and promoted an increase in the number of CTLA-4 + Tregs. The addition of a CTLA-4 inhibitor to the cetuximab treatment regimen promotes the consumption of Tregs and increases the expression of CTLA-4 and PD-1/PD-L1 to obtain better therapeutic effects. Cetuximab stimulates NK cells and CTL to secrete IFN-γ, which induces the expression of PD-L1 in tumor cells. HNSCC head and neck squamous cell carcinoma, NK cells natural killer cells, CTLs cytotoxic T lymphocytes

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Ferris et al. conducted a phase I trial (NCT01935921) of cetuximab plus radiotherapy combined with ipilimumab (CTLA-4 mab) for LAHNSCC [48]. It was the first time that radiotherapy plus double target immunotherapy (cetuximab plus ipilimumab) was tested in LAHNSCC patients, who received conventional cetuximab plus radiotherapy, with an additional dose of ipilimumab (1 mg/kg) at 5, 8, 11 and 14 weeks of treatment [48]. The 3-year DFS and OS were 72% (90% CI 57–92%) and 72% (90% CI 56–92%), respectively [48]. No dose-limiting toxicity (DLT) was observed [48]. Afatinib, an inhibitor of both EGFR and human EGFR 2 tyrosine kinase, was combined with pembrolizumab in a phase II single-arm trial (ALPHA, NCT03695510) and was found to improve the tumor microenvironment in HNSCC patients, enhancing the effectiveness of pembrolizumab treatment [49]. Therefore, we can look forward to the development of this treatment in the future.

Biomarkers for HNSCC

At present, domestic and foreign guidelines for treating HNSCC recommend monitoring PD-L1 levels to evaluate the efficacy of ICIs. The expression of PD-L1 on immune cells in tumor biopsies before treatment confirms the previously elicited adaptive antitumor immune response and correlates with efficacy [50, 51]. Thus, blocking the PD-1/PD-L1 interaction promotes the immune response, bringing long-lasting antitumor effects for a subset of cancer patients. Multiple studies have shown [52,53,54,55] that TMB is a promising biomarker for responsiveness to immunotherapy in non-small cell lung cancer (NSCLC) and melanoma. Type I interferons (IFNs) are involved in the mechanism of induction of the antitumor innate immune response leading to the recruitment of spontaneously toxic T cells, which is a key step in determining the type of TME inflammation [56,57,58].

Conclusions and Future Prospects

In conclusion, CCRT is the standard treatment for patients with LAHNSCC, but because of the high toxicity of TPF, rational induction therapy with its lower incidence of adverse effects is very attractive; combining targeted therapy and immunotherapy or even radiotherapy is being tried and evaluated in prospective studies. Leidner et al. [59] were the first to test combined stereotactic body radiation therapy (SBRT) with immunotherapy as a neoadjuvant therapy for LAHNSCC. In their trial, 20 of 21 patients did not require the 6-week course of adjuvant radiation therapy, and the extent of surgical resection was reduced. The results of this trial are encouraging, but at the same time, postoperative adjuvant therapy after neoadjuvant radiotherapy remains controversial [60]. The NCCN guidelines indicate that residual toxicity from induction chemotherapy may have an adverse effect on subsequent treatment for LASCCHN [7]. Nevertheless, interest in ICT endures for several reasons [7]. First, ICT is beneficial for decreasing distant metastases [61, 62]. Second, with the application of targeted therapy and immunotherapy in LASCCHN, clinicians can use treatments with fewer long-term side effects to improve prognosis [63]. ASCO and ESMO presented some promising data in 2022, and these data also provided us with some ideas for induction therapy of LAHNSCC (Table 1). ICI induction therapy has shown good results in clinical trials. The results of CHECKMATE-141 [64, 65] and KEYNOTE-048 [66, 67] demonstrated the efficacy of ICI therapy in recurrent and metastatic HNSCC; therefore, we can expect ICI therapy to play a more prominent role in LAHNSCC. As we showed here, there have been many research studies and clinical trials of neoadjuvant therapy, but the development of the neoadjuvant therapy with ICIs and other immunological approaches in LAHNSCC have just begun. Several LAHNSCC induction therapy studies are under way (Table 2). A number of variables need to be examined, including timing, duration of administration and relevance to conventional treatment. We look forward to the results of ongoing clinical trials. The clinical benefits of induction therapy may be offset by lower patient adherence to the subsequent therapy or the use of concurrent regimens, which are better tolerated but less effective [7]. Because of this, patients are encouraged to participate in appropriate clinical trials. Meanwhile, better patient selection based on clinical and molecular biomarkers could reveal the mechanism behind this treatment strategy in the appropriate context.

Table 1 New data from ASCO and ESMO (2022)
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Table 2 Ongoing clinical trial of LAHNSCC
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