Treatment Intensification in Locoregionally Advanced Head and Neck Squamous Cell Carcinoma: What Are the Options and for Whom?

Abstract

Current treatment guidelines for patients with locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC) recommend multimodal treatment, including concurrent chemoradiotherapy (CCRT) or surgery followed by radiotherapy (RT), with/without chemotherapy (CT). Induction chemotherapy followed by (chemo)-RT has also level I evidence for larynx preservation procedures in patients with advanced laryngeal or hypopharyngeal cancer. The CT part of the CCRT consists of platinum-based chemotherapy, most often single agent cisplatin. Although for a long time high-dose cisplatin (100 mg/m²) three-times every three weeks during RT has been the standard of care, recent prospective randomized studies have indicated that weekly low-dose cisplatin (40 mg/m²) is a good alternative with less toxicity. For patients not eligible or not tolerating cisplatin there are other alternatives (such as carboplatin with or without 5-fluorouracil, taxanes or cetuximab). However, none of these have shown superior results over the use of cisplatin in randomized trials. Late toxicity is a major downside of CCRT, and this is most worrying for those with the highest chance of cure, i.e. low-risk human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). De-escalation approaches have priority in these patients, but this needs to be done with the utmost caution. In the remaining patient populations (high-risk HPV-positive OPSCC, HPV-negative OPSCC and non-OPSCC patients) there is room for improvement in both locoregional control and in distant control. Recent strategies of potential interest above and beyond CCRT are adding (1) more cytotoxic chemotherapy, (2) targeted therapy, (3) hypoxic sensitizers, (4) immunotherapy and (5) hyperthermia. Many of those options are being investigated in prospective randomized trials and will hopefully lead to further improvement in outcome for these less favorable HNSCC patient categories.

Introduction

About two-thirds of the patients with head and neck squamous cell carcinoma present with locoregionally advanced disease (LA-HNSCC). These patients have a 5-year overall survival (OS) of approximately 50% and improved tailoring of existing treatment modalities is thought to have important influence on outcome [1]. For unselected patients with LA-HNSCC current treatment guidelines recommend multimodal treatment, including concurrent chemoradiotherapy (CCRT) or surgery followed by radiotherapy (RT) with/without chemotherapy (CT). Moreover, induction chemotherapy (ICT) followed by RT/CCRT is an alternative larynx preservation approach in patients with advanced laryngeal or hypopharyngeal carcinomas [2, 3]. The choice of treatment largely depends on primary tumor site, resectability and the expertise of the hospital where the patient is being treated.

For the CT part of the CCRT, the National Comprehensive Cancer Network (NCCN) guidelines categorize two systemic therapies during conventionally fractionated RT as “category 1” in the definitive CCRT setting: high-dose cisplatin (100 mg/m² for 3 cycles) and 3 cycles of carboplatin/5-fluorouracil. In the postoperative setting, CCRT with “cisplatin” without further specification is recommended for high-risk non-oropharyngeal cancer patients. Although weekly low-dose cisplatin for a long time was classified as a category 2B category, recent prospective randomized studies have shown that weekly low-dose cisplatin (40 mg/m² for 7 cycles) is a good alternative for the high-dose cisplatin regimen, i.e. showing the same efficacy, but with less toxicity [4, 5]. For patients not eligible or not tolerating cisplatin there are other alternatives, such as carboplatin with or without fluorouracil, taxanes or cetuximab, although with uncertainty about equal efficacy [6,7,8]. Independent prognostic factors include performance status, tumor (T) stage, nodal (N) stage, human papillomavirus (HPV) status (in oropharyngeal cancer) and the treatment itself.

Standard of Care Concurrent Chemoradiotherapy (CCRT)

The individual patient-based Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) was practice-changing in 2000 in that it became clear that concurrent chemoradiation had more impact on outcome than sequential use of chemotherapy and RT (whether as neoadjuvant or adjuvant), showing an absolute survival benefit of 8% at 5 years with CCRT [9]. Further updates of this MACH-NC, with a different statistical approach (Peto analysis), showed an absolute benefit of 6.5% at 5 years (26.1% → 33.6%) and 3.6% at 10 years (17.3% → 20.9%) and a decreasing effect with increasing age [10, 11]. Using single agent platin showed the strongest relative risk reduction in comparison to RT alone (hazard ratio [HR] 0.74, 95% confidence interval [CI, 0.67; 0.82], p = 0.006).

Both accelerated and hyperfractionated RT have been proposed as an alternative for adding chemotherapy to RT, thereby avoiding the typical chemotherapy-induced toxicities and possibly reducing the RT enhancing effect of CT on normal tissues. The individualized patient-based Meta-Analysis of Radiotherapy in squamous cell carcinoma of Head and Neck (MARCH) showed a survival benefit with altered fractionation (3.4% at 5 years; hazard ratio [HR] 0.92, 95% CI, 0.86; 0.97, p = 0.003) with hyperfractionated RT showing the greatest benefit and again showing a decreasing effect with increasing age [12]. A further update of MARCH confirmed the survival benefit with altered fractionation versus standard fractionating (absolute benefit at 5 years 3.1%, at 10 years of 1.2%). However, that analysis showed that survival benefit was restricted to hyperfractionated RT with an absolute benefit of 8.1% at 5 years [13]. In the same update, conventionally fractionated RT plus concomitant CT versus altered fractionation RT alone showed a significantly worse OS with altered fractionation radiotherapy (HR 1·22, 1·05–1·42; p = 0·0098), with absolute differences at 5 years of −5·8% (−11·9 to 0·3) and at 10 years of −5·1% (−13·0 to 2·8). Both moderately accelerated chemoradiotherapy (70 Gy in 6 weeks plus 2 cycles of 5 days’ concomitant carboplatin and 5-fluorouracil regimen) and very accelerated RT alone (64.8 Gy [1.8 Gy twice daily] in 3.5 weeks) were inferior to conventional CCRT (70 Gy in 7 weeks plus 3 cycles of 4 days’ concomitant carboplatin and 5-fluorouracil regimen) in a prospective randomized phase III study of the Groupe d'Oncologie Radiothérapie Tête Et Cou (GORTEC-99–02) [14]. For the moment, it is unclear whether hyperfractionated RT equals cisplatin-based CCRT.

Toxicity of Standard of Care Concurrent Chemoradiotherapy

Acute Toxicities

Using single day fractionation RT alone (70 Gy at 2 Gy/day; arm A) versus the same RT plus high-dose cisplatin (100 mg/m² every 3 weeks on days 1, 22 and 43; arm B) versus a third arm with 3 cycles of cisplatin/5-fluorouracil and split course RT (arm C) in an Intergroup phase III trial in patients with unresectable HNSCC, grade 3–5 acute toxicity was significantly higher in arm B versus arm A (89 vs. 52%). This mostly concerned nausea/vomiting (16%), mucositis/dysphagia (45%), leukopenia (42%), anemia (18%), renal toxicity (8%) and skin toxicity (7%). Feeding tubes were needed in 52% [15]. In that study all four disease sites were represented, but 50–60% of disease sites in the different arms consisted of oropharyngeal squamous cell carcinomas (OPSCC).

To determine the contributions of chemotherapy and radiotherapy to larynx-preserving treatment, the Radiation Therapy Oncology Group (RTOG) and the Head and Neck Intergroup conducted a randomized trial (RTOG 91–11) in patients with advanced laryngeal cancer to investigate three radiation-based treatments: induction cisplatin plus 5-fluorouracil followed by RT if there was a response to the CT, RT with concurrent cisplatin (100 mg/m² three-times every three weeks) and RT alone [16]. The rate of high toxic effects (grade 3–4) was highest in the CCRT arm (82%) versus 81% in the ICT arm and 61% with RT alone. This mostly concerned nausea/vomiting (20%), mucositis/stomatitis (43%), hematologic toxicity (47%), pharyngeal or esophageal toxicity (35%), skin reaction in the radiation field (7%), renal or genitourinary (4%) and neurologic side effects (5%).

We explored the efficacy, toxicity and compliance of three-weekly high-dose cisplatin in three meta-analyses of aggregate data, separately evaluating chemoradiotherapy based on conventional and on altered fractionations in the definitive and the post-operative settings [17, 18]. Among 31 prospective trials utilizing conventionally fractionated RT, model-based estimates of 5-years OS were 39 and 51% in the definitive and adjuvant setting, respectively. Relative to RT alone, patients treated with the combined regimen experienced more grade 3–4 acute toxicity [17]. Of those treated in the definitive setting, about 40% developed severe mucositis, about 25% had severe swallowing problems and at least 20% showed severe bone marrow suppression. As a result of that, only about two-thirds of these patients could receive all three planned cycles of high-dose cisplatin, while 92% received at least two cisplatin cycles [17]. In the same setting, the outcome with altered fractionation and high-dose cisplatin was better, showing an estimated 5-year survival of 57%. In this situation 92% of all planned cisplatin cycles (i.e. two) could be given. Also with altered fractionation RT severe mucositis occurred in around 40%, but severe dysphagia occurred in 40%, and again around 20% had severe bone suppression [18]. The early toxic effects are typically transient, but for a number of tissues data have been presented supporting the concept that severe early effects may be causally related to the subsequent late effects [19].

Late Toxicities

Late toxic effects in patients become manifest after latent periods ranging from months to years and include radiation-induced fibrosis, atrophy, vascular damage, neural damage, and a range of endocrine and growth-related effects [20]. There has been a lack of adequate reporting on late toxicities [17, 21]. Despite this limitation, the earlier mentioned meta-analysis on prospective trials reported an overall prevalence of grade 3–4 late toxicity of 20% with the use of conventionally fractionated RT in combination with concurrent high-dose cisplatin (10% xerostomia, 10% dysphagia and 5% subcutaneous fibrosis) [17]. For altered fractionation RT plus high-dose cisplatin the overall prevalence of grade 3–4 late toxicity was 43% (6% xerostomia, 12% dysphagia and 2% subcutaneous fibrosis).

In a study that was specifically set up to report on late toxicities in a subset of patients who participated in three previously reported RTOG trials of CCRT for LA-HNSCC, all being cisplatin-based (RTOG 91–11, 97–03 and 99–14), the data were more impressive [22]. Of the 230 assessable patients, 99 (43%) experienced severe late toxicities (grade 3–5), 27% showed pharyngeal dysfunction, 13% were feeding-tube dependent >2 years post-RT and 12% showed laryngeal dysfunction. Extremely worrying was the fact that there were 10% (unexplained) deaths. The long-term follow-up data from RTOG 91–11 showed that the survival curves were diverging after 4.5 years of observation in favor of the ICT arm and showed more noncancer-related deaths with CCRT, which likely related to the more frequently occurring and more severe late toxic effects with this treatment approach [16]. In the above mentioned RTOG analysis of Machtay et al., older age, advanced T-stage and larynx/hypopharynx primary site were strong independent risk factors and neck dissection after CCRT was associated with an increased risk of these complications. In a later analysis, additionally, it was found that higher point dose estimates to the hypopharynx (superior and/or inferior) were also associated with an increased risk of severe late toxicity [23].

In support of the Machtay data are the data of the long-term outcome and morbidity after treatment with accelerated RT to a dose of 68 Gy and weekly cisplatin (40 mg/m²) in 77 LA-HNSCC patients treated between May 2003 and December 2007 at the departments of Radiation Oncology and Medical Oncology of the Radboud University Nijmegen Medical Center in the Netherlands [24]. The radiation treatment technique used was three-dimensional (3D) conformal radiotherapy (from May 2003 to July 2006) and thereafter intensity-modulated radiation therapy with simultaneous integrated boost (IMRT-SIB). In that study, surviving patients were invited to a multidisciplinary late morbidity clinic to evaluate late toxicity. Of the 43 patients still alive, 32 participated in the late morbidity evaluation, with a median follow-up of 44 months (range, 14–68 months). The majority of patients had a least one RTOG/European Organization for Research and Treatment of Cancer (EORTC) grade 2 late toxicity (53%). Grade 3 toxicity of one or more organs or tissues was observed in 12 patients (38%), mostly fibrosis of subcutaneous tissue and xerostomia. Five patients (16%) experienced grade 4 toxicity, 2 laryngeal necrosis, 3 osteoradionecorisis of the mandible. The 5-year actuarial rates of overall grade 3–4 toxicity were 52 and 25%, respectively. Toxicity was significantly correlated with tumor site, with oropharyngeal and oral cavity tumors having more grade 3–4 toxicity than hypopharyngeal tumors. There was also a significant correlation with T-stage, higher T-stages having more grade 3–4 toxicity. Radiologic evaluation demonstrated impaired swallowing in 57% of the patients, including 23% with silent aspiration. Both studies stress the dangers of swallowing difficulties with dysphagia and aspiration following CCRT [22, 24]. These side effects are being seen as major obstacles in intensifying treatment from RT to CCRT (with cisplatin). Identifying those patients as early as possible seems pertinent [25]. Subjective assessment using a systematic scoring system in the Dutch study indicated normalcy of diet in only 15.6% of the patients. Nevertheless, despite all this, quality-of-life questionnaires used in the Dutch study showed that the overall quality-of-life was good; yet, the majority of the patients had a high score on the symptom scale “dry mouth” and “sticky saliva”. The study also showed a significant correlation between dysphagia and xerostomia and subcutaneous fibrosis. Therefore, prevention of xerostomia by sparing the parotid and/or submandibular glands might reduce the incidence of dysphagia. It is expected that with contemporary studies utilizing IMRT these late side effects might be less. Examples of that are the two recent prospective randomized phase III de-escalation studies in p16-positive OPSCC, using normofractionation RT in the De-ESCALaTE study and accelerated IMRT in RTOG 1016, and high-dose cisplatin in the control arm and cetuximab in the experimental arm [26, 27]. Apart from 13% ear and labyrinth disorders and 12% gastrointestinal disorders, all remaining severe late toxicities in the control arm of the De-ESCALaTE study occurred in 1–3% (at 24 months). In the control arm of the RTOG 1016 study, overall prevalence of grade 3–4 late toxicity was 20%, with only 2% severe xerostomia, 4% severe dysphagia and no subcutaneous fibrosis at a median follow-up of 4.5 years. The lower overall prevalence of severe late toxicity in RTOG 1016 than in the meta-analysis (20 vs. 43%) may pertain to the use of IMRT in this study.

Is Single Day Three-Weekly High-Dose Cisplatin Optimal to Enhance the Effect of Radiation?

This has remained the most crucial question. The use of high-dose cisplatin during RT has been built on the results of four large phase III trials published between 2003 and 2004 and these data have been supported by the outcome of the two above mentioned de-escalation trials (De-ESCALaTE and RTOG 1016), all showing superiority of this high-dose cisplatin-based CCRT approach versus RT alone or versus cetuximab plus RT [28]. However, the disadvantage of this high-dose cisplatin regimen during RT is that a substantial proportion of patients do not receive the planned number of three cycles due to toxicity issues and therefore alternative cisplatin administration schedules have been studied, and for those patients ineligible for cisplatin, other cytotoxics (e.g. carboplatin, taxanes, low dose gemcitabine), targeted agents (e.g. cetuximab, despite inferior outcome) or hypoxic modification have been investigated.

An important aspect in this discussion is the impact of the cumulative dose of cisplatin. In a recent systematic review, Strojan et al. [29] showed that the cumulative delivered dose of cisplatin is prognostic for survival, even beyond the 200 mg/m². Although the critical cumulative dose is not exactly known, several other studies have suggested or indicated that minimally a cumulative dose of 200 mg/m² is needed for obtaining a survival benefit [21]. Strojan’s additional observation that the benefit of a higher cumulative dose was independent from the type of cisplatin schedule is intriguing in light of data from clinical pharmacology studies showing cisplatin-induced toxicities are not only dose related, but at a specific dose also peak dose related [30, 31], i.e. the higher the dose and the shorter the infusion time, the more toxicity was experienced. Vermorken et al. found free platinum clearance correlating with creatinine clearance and, in addition, observed that patients experiencing nephrotoxicity also showed an increased incidence of ototoxicity [31, 32]. In their studies in patients with normal renal and hepatic functions, these investigators found the area under the concentration–time curves (AUCs) of free platinum species (the active component) to be identical for cisplatin infusions of different duration when utilizing the same dose [32, 33]. These observations support the clinical impression that, contrary to toxicity, antitumor activity of cisplatin is not dependent on the method of administration. In that context prolonged infusion over 24 h, or splitting up the dose over 4 or 5 days are worth studying with the hope to induce less toxicity.

The German ARO 96–3 trial, comprising 440 patients with high-risk HNSCC, compared CCRT with cisplatin (20 mg/m²/day, on days 1–5 and 29–33) plus 5-fluorouracil (600 mg/m²/day, on days 1–5 and 29–33) to RT alone (66 Gy/33 fractions/6.6 weeks) in the postoperative setting [34]. The incidence of grade 3 or higher acute toxicity was higher during CCRT than during RT alone, but lower when compared with the grade 3 or higher acute toxicity observed in the earlier mentioned meta-analysis utilizing high-dose cisplatin and conventionally fractionated RT: mucositis 20.8% versus 42% and leucopenia 4.4% versus 19% in the meta-analysis [17]. However, it should be realized that, contrary to the meta-analysis, the cumulative cisplatin dose in the ARO 96–3 study did not go beyond the 200 mg/m². Moreover, although the 5-year OS favored CCRT over RT alone (58.1 vs. 48.6%), this did not reach significance. A second study of interest in that respect is the GORTEC 2015–2 study [35]. The trial, stratified for postoperative or definitive CCRT, compared standard of care (SOC) cisplatin dose (100 mg/m² three-times every three weeks) to fractionated high dose (FHD) cisplatin (25 mg/m²/day, on days 1–4 three-times every three weeks) concomitantly with RT in 124 patients with LA-HNSCC (oropharynx 51%, p16+: 43%). Definitive RT included 70 Gy/7 weeks, postoperative RT 66 Gy/6.5 weeks. The median delivered cumulative dose (primary endpoint) was 291 mg/m² (interquartile: 256–298) with FHD cisplatin and 280 mg/m² with SOC cisplatin (p = 0.03). Overall, 50 (35%) grade 3–4 acute toxicities occurred with FHD cisplatin versus 91 (65%) with SOC cisplatin (p < 0.001). Efficacy endpoints OS, progression-free survival (PFS) and locoregional control (LRC) were identical. The authors considered FHD cisplatin concomitantly with RT worth further study.

The low-dose weekly cisplatin during RT has gained ground also in the Western world, now that some recent prospective randomized trials have indicated this treatment schedule to be noninferior to the SOC high-dose cisplatin during RT [4, 5]. This is particularly the case for high-risk patients treated in the postoperative setting (see below). The data are still premature for the definitive setting. Moreover, the comparison of high-dose three-weekly cisplatin versus low-dose weekly cisplatin concomitantly with RT in HPV-associated OPSCC was still not reported (see below). Nevertheless, this regimen, at least the weekly dose of 40 mg/m² is now recommended in official guidelines [2]. Crucial in this comparison of three-weekly high-dose cisplatin versus weekly low-dose cisplatin is whether the cumulative dose at the end of treatment is comparable or not (Table 10.1).

Table 10.1 Phase III trials comparing radiotherapy given concurrently either with three-weekly high-dose or with weekly low-dose cisplatin (non-exhaustive list)

We learnt from the meta-analysis on studies using conventionally fractionated RT, both in the adjuvant setting and in the definitive setting that severe acute toxicities with the weekly regimen occurred significantly less frequently than with the high-dose three-weekly cisplatin regimen and there was no suggestion of any difference in outcome [17]. The two prospective randomized trials reported at the previous THNO meeting were, as described, not conclusive [28]. In the small randomized study, reported by Tsan et al. [36] a cumulative dose of 200 mg/m² could be delivered to significantly more patients in the high-dose arm. Nevertheless, the weekly low-dose regimen was found more toxic, in particular with respect to severe mucositis (38.5 vs. 75.0%, p = 0.012). However, contrary to the patients in the three-weekly high-dose treatment arm, those in the weekly low-dose cisplatin arm did not receive adequate hydration schemes. The Indian phase III study, reported by Noronha et al. [37], made use of a weekly low-dose of 30 mg/m² during RT and compared this with a three-weekly high-dose cisplatin regimen during RT. This led to a difference in cumulative cisplatin dose between both arms of the study (Table 10.1). Two hundred seventy-nine of the 300 enrolled patients (93%) received chemoradiotherapy in the adjuvant setting. After a median follow-up of 22 months, OS was not significantly different between both arms, but the three-weekly regimen did generate a better LRC (58.5 vs. 73.1%, p = 0.014). This was obtained at the cost of more severe acute toxicity (71.6 vs. 84.6%, p = 0.006), in particular, vomiting, infection, hearing loss, hyponatremia and myelotoxicity.

The Japanese Clinical Oncology Group (JCOG) performed a multi-institutional open-label phase II/III study, in which patients with postoperative high-risk LA-HNSCC were randomly assigned to receive either chemoradiotherapy with three-weekly cisplatin (100 mg/m²) or weekly cisplatin (40 mg/m²) to confirm the noninferiority of the weekly regimen [4]. Primary endpoint of the phase II part of this study was the proportion of treatment completion, and that of the phase III part was OS. After a median follow-up of 2.2 years, CCRT with weekly low-dose cisplatin proved to be noninferior to three-weekly high-dose cisplatin in terms of OS with a HR of 0.69 (99.1% confidence interval [CI], 0.374 to 1.273, p < 1.32, one-sided p for noninferiority = 0.0027). As expected, grade 3 or more neutropenia and infection were less frequent in the weekly cisplatin arm, as was any grade of hearing impairment, including tinnitus and renal impairment. Grade 3–4 dysphagia occurred in 12% in the weekly cisplatin arm and in 19% in the three-weekly cisplatin arm. This academic trial will change practice for high-risk patients in the postoperative setting. However, there is insufficient data on the p16-positive OPSCC patients to make a firm statement on that subset of patients.

Another study of interest on this topic was recently presented at the 2022 Annual meeting of the American Society of Clinical Oncology (ASCO) by Sharma and colleagues [5]. This concerned a multicentric Indian non-inferiority study, comparing three-weekly high-dose cisplatin to weekly 40 mg/m² cisplatin in the definitive CCRT setting (Table 10.1). Among the primary disease sites, OPSCC comprised 59.6%, with 13% of those tested for p16 being positive. The primary objective was the comparison of the 2-year LRC rates. Two hundred seventy-eight patients were randomized. Treatment interruptions (p = 0.035), hospitalizations (p = 0.004), use of additional intravenous fluids (p < 0.001), mucositis (p = 0.029), myelosuppression (p = 0.0212), renal toxicity (p < 0.001), vomiting (p = 0.002) and hyponatremia (p = 0.004) were all significantly more frequent in the high-dose cisplatin arm. LRC rates at 2 years were 57.69% in the high-dose cisplatin arm and 61.53% in the weekly cisplatin arm of the study. There was no significant difference in median time to locoregional failure, OS, and PFS. Again, no information could be given on the p16-positive OPSCC patients. Moreover, a large number of patients were treated with 2D radiotherapy in this study. The study needs further update and finally peer-review.

Both studies are not conclusive on what is the best CCRT option for patients with HPV/p16-positive OPSCC. This aspect is being covered in the ongoing NRG-HN009 study. In this phase II/III study two cohorts will be assessed for this important question, i.e. patients with p16-positive OPSCC/cancer of unknown primary (target number of patients in phase III is 500) and patients with non-OPSCC/p16-negative OPSCC (target number in phase III is 750), and should be able to definitively answer this important question (Fig. 10.1).

Fig. 10.1

NRG-HN009: Randomized phase II/III trial of radiation with high-dose cisplatin every three weeks versus radiation with low-dose weekly cisplatin for patients with LA-HNSCC

Concurrent Chemoradiotherapy in HPV-Positive Oropharyngeal Cancer Patients

After the first description of a causative association between infection with high-risk HPV and oral squamous cell cancer in 1983 by Syrjanen et al., it was Maura Gillison who clearly indicated that HPV-positive OPSCC was a distinct molecular, clinical and pathologic entity with a markedly improved prognosis [38, 39]. This observation was further substantiated by the retrospective subgroup analysis of the OPSCC patients in the RTOG 0129 study (a study in which all LA-HNSCC patients were treated with high-dose cisplatin based CCRT), showing that the HPV-positive OPSCC patients had a considerably better survival than the HPV-negative OPSCC patients [40]. In that study, Ang et al., using a recursive-partitioning analysis, could classify the patients on the basis of four factors (HPV-status, pack-years of tobacco smoking, tumor stage and nodal stage) in three risk groups: a low-risk category with a 3-year survival rate of 93%, an intermediate category with a 3-year survival rate of 70.8% and a high-risk category with a 3-year survival rate 46.2%. Low-risk was defined as HPV-positive with low tobacco exposure (≤10 pack-years, regardless of T- or N-classification) or >10 pack-years and one ipsilateral node <6 cm (regardless of T-classification); intermediate-risk was defined as both HPV-positive and >10 pack-years and advanced nodal disease (multiple ipsilateral, ≥1 contralateral or any node >6 cm), as well as HPV-negative with low tobacco exposure and <T4; high-risk was reserved for HPV-negative with >10 pack-years or T4. Basically, it can be summarized that all HPV-positive OPSCC are either low- or intermediate-risk. The observed differences in the RTOG-0129 trial remained consistent with longer follow-up (5-year estimates of OS and PFS in low-risk group 87.6% and 80.3%, respectively). External validation of the risk groups in RTOG-0552 showed similar results, i.e. significant differences between the three risk groups, but the 5-year estimate of the PFS in the low-risk group in RTOG-0522 was lower than in RTOG-0129 (5-year estimates in RTOG-0522 were for OS 88.1%, for PFS 72.9%). However, in a subgroup of very good-risk patients in RTOG-0522 (p16-positive, ≤10 pack years and T1-2 with ipsilateral ≤6 cm nodes or T3 without contralateral or >6 cm nodes), 5-year OS and PFS were 93.8% and PFS 82.2%, respectively [41]. These data suggest that caution is indicated in selecting patients for treatment de-escalation and support a more stringent definition of low-risk than that defined by RTOG-0129.

Considering that future treatment of patients with HPV-positive OPSCC might become different from those with HPV-negative OPSCC, selection of the ideal candidates for treatment-de-escalation and treatment intensification become imperative. In that respect, future novel approaches will likely feature radiographic, proteomic and genomic biomarkers to define prognostic groups and guide treatment selection with greater precision. In the same line of thinking, the availability of a diagnostic test that can reliably select OPSCC tumors that are caused by HPV, becomes indispensable. This has been highlighted in the Key Concepts from the Sixth THNO meeting [42]. Several de-escalation approaches are under study, and will not be further discussed in the current chapter. However, an important question remains “which cisplatin regimen in the control arms of de-escalation studies should be applied, should it be the three-weekly high-dose cisplatin approach or the weekly low dose cisplatin approach?” and”which regimen should be preferred when evaluating treatment intensification approaches in selected locoregionally advanced OPSCC patients and non-OPSCC patients?”.

As mentioned earlier, there have been two recent randomized de-escalation trials reported (De-ESCALaTE and RTOG 1016) in which high-dose cisplatin/RT was compared to cetuximab/RT [26, 27]. A third study, contrary to the first two, included only low-risk patients with HPV-positive OPSCC [43]. This randomized trial, comparing cisplatin/IMRT to cetuximab/IMRT, was executed by the Trans-Tasman Radiation Oncology Group (TROG 12.01, Table 10.2). The TROG 12.01 study included patients with American Joint Committee on Cancer (AJCC)/tumor, node, metastasis (TNM) 7th edition stage III (excluding T1-2N1) or stage IV (excluding T4 and/or N3 and/or N2b-c if smoking history >10 pack years and/or distant metastases). The primary outcome was symptom severity assessed by the MD Anderson Symptom Inventory—Head and Neck (MDASI-HN) questionnaire. Quality-of-life was assessed with the Functional Assessment of Cancer Therapy—Head and Neck (FACT-HN) questionnaire. There proved to be neither a significant difference between the arms in symptom severity, nor were there significant differences between both arms in the FACT-HN total score or any of the FACT-HN subscales. With respect to acute toxicity, more dermatitis and acneiform rash were seen in the cetuximab arm and more febrile neutropenia, emesis, dry mouth and fatigue in the cisplatin arm. The number of grade 3 or higher acute events per patient as measured by the T-score (using the TAME method of reporting, [44]) was higher with cisplatin (4.35 vs. 3.82 in the cetuximab arm), but this was not statistically significant. Although there was more grade 2 or higher hearing impairment and tinnitus in the cisplatin arm, the Hearing Handicap Inventory (HHIA-S) did not reveal a significant difference between the arms, though there was a statistically significant deterioration in both arms over time. It is interesting to compare these data with the observations in the De-ESCALaTE study (using 3 × 100 mg/m²) and in RTOG 1016 (using 2 × 100 mg/m²). In De-ESCALaTE, late severe ear and labyrinth disorders occurred in 13% of patients with high-dose cisplatin (versus 5% with cetuximab) while in RTOG 1016 late severe hearing impairment was recorded in only 6.3% with high-dose cisplatin (versus 2.1% with cetuximab). Quality-of-life studies done in these trials did not show a striking difference between the cisplatin containing arms and the cetuximab containing arms. In De-ESCALaTE, the mean quality-of-life score measured by the EORTC Core Quality of Life questionnaire (QLQ C30) showed substantial drop at 3 months but that recovered rapidly. At 12 months and 24 months, a significant difference in role functioning was observed in favour of cisplatin (difference in mean scores of 8.32 points, p = 0.0173). However, none of the differences reached the minimal clinically important difference of 10 points. Of interest is the observation in a substudy of the TROG 02.02 study [45]. TROG 02.02/HeadSTART compared RT (70 Gy/7 weeks) given concurrently with three cycles of either cisplatin (100 mg/m²) or cisplatin (75 mg/m²) plus tirapazamine, a bioreductive agent that can enhance the cytotoxic effects of ionizing radiation in hypoxic cells. Quality-of-life was comparable between both arms of the study. However, Ringash et al. noticed in a subset of 200 OPSCC patients with known p16 status that p16-positive OPSCC patients overall had a better quality-of-life at baseline but showed a more dramatic drop in quality-of-life at 2 months, which was recovered by 12 months, with even superior scores than observed among the p16-negative patients. It was speculated whether this effect was primarily related to physical injury or to the shock of the diagnosis and change in lifestyle and self-image associated with the quite aggressive cancer therapy.

Table 10.2 Concurrent chemoradiotherapy with cisplatin in HPV (p16) associated locoregionally advanced oropharyngeal squamous cell carcinoma

The survival data, as shown in Table 10.2, clearly show the unprecedented favorable outcome of the HPV-associated locoregionally advanced OPSCC patients. O’Sullivan and colleagues demonstrated that patients with T4 and N3 disease had poorer survival due to a high rate of distant metastases that ultimately led to these patients being classified as stage 3 in the AJCC/TNM version 8 HPV-related OPSCC staging. The investigators in the De-ESCALaTE study performed a post-hoc subgroup sensitivity analysis. In 276 patients with AJCC/TNM version 8 stage I or II disease, a significant difference in 2-year OS was observed: 98.4% for the cisplatin group and 93.2% for the cetuximab group. (p = 0.0431). The 58 patients with AJCC/TNM 8 stage III (T4 or N3) disease that were allowed in this study showed a larger 2-year OS detriment with cetuximab (67.1%) than with cisplatin (93.3%; p = 0.0304). Interestingly, the study overall showed significantly fewer distant metastases with high-dose cisplatin (3 vs. 9%, log rank p = 0.0092). That was also the case in the TROG 12.01 study, showing a 3-year freedom from distant failure rate with cisplatin 97%, with cetuximab 88% (HR, 4.1; 95% CI 1.2–14.9; p = 0.018). So, seemingly there is not much difference in the effect on distant metastases whether using three-weekly high dose cisplatin or weekly low-dose cisplatin, albeit moderate.

Taking together, the above-mentioned data indicate that cisplatin-containing CCRT is the standard approach for fit patients with LA-HNSCC when there are no absolute contra-indications for cisplatin. This is true for both non-OPSCC primary disease sites, HPV-negative OPSCC as well as HPV-positive OPSCC. Weekly low-dose cisplatin (40 mg/m² × 7) is not inferior to three-weekly high-dose cisplatin (100 mg/m² × 3) in the postoperative setting, but the available data (abstract only) in the definitive setting needs to be peer-reviewed first. Although there are no direct comparisons between the two approaches in HPV/p16-positive OPSCC, the suggestion is that both are effective (also for the effect on distant metastases). Overall, the data suggest that acute toxicity is worse with the tri-weekly high dose, both hematologic (neutropenia) and nonhematologic (severe nausea/vomiting, nephrotoxicity), but in some studies more dysphagia and weight loss have been encountered with the weekly regimen. Overall, late toxicity seems to be lower with the weekly regimen (ototoxicity, renal toxicity). Late pharyngeal toxicity is a major threat with both CCRT regimens, and early detection and taking early measures to reduce the risk of aspiration pneumonia is essential. A direct comparison of both approaches in HPV/p16-positive tumor would still be of academic interest.

Treatment Intensification Beyond Concurrent Cisplatin-Based Chemoradiotherapy (summarized in Table 10.3)

Candidates for treatment intensification are fit LA-HNSCC patients, both in the definitive setting and in the adjuvant setting who are candidates for CCRT without absolute contra-indication for cisplatin [46] but still have a poor outcome:

• 1. HPV/p16-positive OPSCC patients who do not belong to the category with the most favorable outcome (who are candidates for de-escalation approaches).

• 2. HPV/p16-negative OPSCC patients and non-OPSCC LA-HNSCC patients.

A separate group are the patients with LA-HNSCC with oligometastatic disease.

Table 10.3 Intensification strategies of potential interest, beyond cisplatin/RT

Combining Altered Fractionation Radiotherapy with Chemotherapy

As discussed earlier, the MARCH meta-analysis showed that altered fractionation RT was associated with a significant OS benefit compared with conventional fractionation RT [13]. However, the OS benefit was restricted to hyperfractionated radiotherapy. A recent updated individual patient data network meta-analysis, evaluating both MACH-NC and MARCH combined, comprised 115 randomized trials, in a patient population that in great majority was HPV/p16-negative. It compared 16 different treatments, and of those different approaches hyperfractionated RT with concomitant chemotherapy (HFCRT) ranked as the best treatment, when compared with locoregional therapy alone (P score for OS 97%; HR 0.63 [95% CI 0.51–0.77] [47]. In the comparison of HFCRT versus conventionally fractionated platinum-based CCRT (the present standard), the HR was 0.82 (95% CI 0.66–1.01) for OS and the corresponding HR for event-free survival (EFS) was significant with a HR of 0.80 (95% CI 0.65–0.98). The investigators did not analyze toxicity data because the data available in MACH-NC and MARCH were different, with very few toxicities in common [47]. It is therefore important to mention here, that the meta-analysis on altered fractionation with weekly low-dose cisplatin versus two times 100 mg/m² showed that compared to the weekly low-dose cisplatin, the high-dose cisplatin regimen not only improved OS (p = 0.0185), but was more compliant with respect to receiving all planned cycles of cisplatin (71 vs. 95%, p = 0.0353) and demonstrated less complications in terms of severe (grade 3–4) acute mucositis and/or stomatitis (75 vs. 40%, p = 0.0202) and constipation (8 vs. 1%, p = 0.0066) and severe late subcutaneous fibrosis (21 vs. 2%, p < 0.0001) [18].

Although in the above mentioned network meta-analysis, ICT with TPF (docetaxel, cisplatin and 5-fluorouracil) followed by conventionally fractionated platinum-based CCRT ranked fourth for OS, according to a sensitivity analysis restricted to trials mandating the use of granulocyte colony-stimulating factor, ICT with TPF followed by CCRT ranked second after HFCRT for OS and first for EFS. As TPF followed by CCRT probably is more commonly used in clinical practice than HFCRT, this network meta-analysis partly supported the use of ICT with TPF followed by CCRT in practice for selected patients with advanced disease, in good clinical condition and minor comorbidities. However, it should be further tested in clinical trials. Clearly, as stated by the authors, the results of this network meta-analysis are a decision-supporting tool rather than a decision-making tool [47].

Adding More Cytotoxic Chemotherapy

Induction Chemotherapy

The original MACH-NC analysis and also the two later updated versions did not suggest a major role for induction chemotherapy in the treatment of patients with LA-HNSCC [9,10,11]. However, in the two more recent network meta-analyses, in particular with the use of the TPF regimen, the position of this so-called sequential approach has become stronger [47, 48]. Only one of five moderately sized individual trials comparing TPF followed by CCRT versus CCRT alone, presented at THNO-7, showed survival benefit of the sequential approach over CCRT alone, but all five trials showed an increase in toxic events with the sequential approach [49]. Only two of the five studies showed fewer distant metastases in the ICT arms. This positive effect on distant metastases was also confirmed in two meta-analyses, but still did not lead to a significant effect on OS [50, 51]. A better selection of patients who are at risk for developing distant metastases therefore seems appropriate. Features such as low neck nodes and matted nodes (a proxy for extranodal extension) are of interest. Burningham et al. [52] reported on the prognostic impact of matted lymphadenopathy (ML) in 417 OPSCC patients treated with definitive CCRT. Patients were stratified into favorable OPSCC (p16-positive with ≤10 pack-years smoking history, n = 220) and unfavorable OPSCC (p16-negative and/or >10 pack-years, n = 197). ML had only a significant negative impact on OS and PFS in the unfavorable group, with a 3-year OS for patients with and without matted nodes being at 56% and 74%, respectively (HR 1.61, 95%CI 1.01–2.58). On multivariate Cox regression, patients with ML experienced significantly worsened OS (HR 1.65, 95% CI 1.03–2.65) and PFS (HR 1.94, 95% CI 1.28–2.93). The cumulative incidence of distant metastases was also higher with ML (31 vs. 9%, adjusted HR 3.3, 95% CI 1.71–6.48). ML had no prognostic importance in patients with favorable OPSCC. Similar results had been reported in a retrospective analysis of 321 patients treated with three cycles of docetaxel/cisplatin followed by CCRT (with weekly cisplatin) [53]. Lower neck node involvement (level IV, Vb and supraclavicular regions, p = 0.008) and poor response to ICT (p < 0.001) were associated with significantly inferior distant metastases-free survival [53].

Huang et al. very elegantly discusses the prognostic significance of the different forms of extranodal extension (pathologically [pENE], radiologically [rENE] and clinically [cENE]) in Chap. 7 of this book. Emerging data have consistently shown that ENE is one of the most powerful prognostic factors for all head and neck cancers, including OPSCC (HPV/p16-positive and HPV/p16-negative) and nasopharyngeal cancer (NPC). The role of rENE is becoming more prominent in selecting patients that need additional systemic treatment to have sufficient effect on distant metastases. Huang et al. were not impressed by the effect of cisplatin on negating distant metastases in patients with ENE. Therefore, additional systemic therapy for that purpose needs to be explored, whether cytotoxic, targeted or immunologic, whether in the induction setting or in the adjuvant setting. For protein expression biomarkers of aggressive disease that could help in a better selection of those that may benefit from ICT, see also Chap. 11 of 7th Critical Issues in Head and Neck Oncology, 2021 [49].

Roughly 15% of head and neck cancer patients will present initially with distant metastases, but a portion of these will have only few discrete lesions. A review of this so-called oligometastatic disease status is beyond the scope of this chapter. Suffice to say, there are no specific treatment guidelines for oligometastatic HNSCC patients [54]. However, the increasing sophistication and clinical experience with stereotactic body radiotherapy has made definitive local treatment to these sites a reasonable option (see also Nevens and Szturz, Chap. 15). When it concerns patients with synchronous oligometastatic disease, aggressive treatment of the primary disease site is essential, leading to better survival outcome compared to patients treated with systemic therapy alone. With that in mind, strategies may emerge combining ICT and upfront metastasis-directed treatment prior to locoregional therapy for the primary tumor [55]. However, for the moment there is a lack of data on this.

Adjuvant Chemotherapy

The data on adjuvant chemotherapy is very scarce. Patients who were given cytotoxic therapy in the adjuvant setting after CCRT had difficulties to tolerate that and 50% or more had to stop treatment early. The original MACH-NC analysis in 2000 and the later updated versions in 2009 and 2021 clearly indicated that adjuvant chemotherapy had no established role [9,10,11]. However, recent reports on the benefit of adjuvant capecitabine after CCRT (with/without prior ICT) in patients with locoregionally advanced NPC have reactivated the discussion [56, 57], (Table 10.4). In particular, the data on the use of metronomic capecitabine in that respect was intriguing, showing only 17% grade 3 or higher adverse events associated with this approach [57], which seems less than what is usually seen with cisplatin/5-fluorouracil in the adjuvant setting after CCRT (43%, [58]) or with cisplatin/gemcitabine after CCRT (80%, [59]).

Table 10.4 Capecitabine as adjuvant therapy after concurrent chemoradiotherapy in patients with high-risk locoregionally advanced nasopharyngeal carcinoma

Metronomic chemotherapy is the chronic administration of chemotherapeutic agents at relatively low, minimally toxic dose (one tenth to one third of the maximum tolerated dose [MTD]) with no prolonged drug-free breaks. Several mechanisms of actions have been proposed, including inhibition of the nutrition supply for tumor growth, inhibition of tumor angiogenesis, immune system modulation and cellular dormancy mechanisms [60].

There have been several promising reports suggesting a beneficial effect of maintenance metronomic chemotherapy, also in non-NPC HNSCC patients, most of them being retrospective data [61,62,63,64,65]. In these studies, use has been made most frequently of fluoropyrimidine derivatives, such as tegafur-uracil (UFT) and S-1, which can be given orally. Another popular combination is low dose oral methotrexate (15 mg/m²) once a week and celecoxib 200 mg twice daily. All these treatments are mostly applied for a duration of one year to 18 months. So far, there have been no solid data of prospective randomized phase III trials and there are no meta-analyses on the use of these agents in the adjuvant setting. Nevertheless, it seems worth continuing to investigate this further.

Adding Targeted Therapy

Targeting the Epidermal Growth Factor Receptor (EGFR)

The epidermal growth factor receptor (EGFR) is a cell-surface receptor belonging to the ErbB family of receptor tyrosine kinases. Overexpression of EGFR, which is frequently found in HNSCC, is correlated with poor outcome [66, 67]. Advances in understanding of the EGFR signaling pathways in cancer have led to the development of anti-EGFR agents including monoclonal antibodies (mAbs) and small-molecule tyrosine kinase inhibitors (Table 10.5).

Table 10.5 EGFR-targeting agents investigated in patients with HNSCC (non-exhaustive list)

Cetuximab is a recombinant human/mouse chimeric mAb that binds the extracellular portion of the EGFR and interferes with binding and receptor activation by the natural ligands of EGFR. In addition, cetuximab not only hinders the binding of the natural ligands of EGFR, thereby inhibiting downstream signaling pathways and inducing apoptosis, but also has an immunological effect (antibody-dependent cellular cytotoxicity [ADCC]), thereby acting as a bridge between tumor cells expressing EGFR and immune cells such as CD16-positive natural killer (NK) and dendritic cells [68, 69]. Cetuximab is the only anti-EGFR mAb approved for the treatment of HNSCC in the US and Europe. The approval was based on the results of the EXTREME study in first-line recurrent/metastatic (R/M) HNSCC setting, comparing the platinum/5-fluorouracil combination (PF) versus PF plus cetuximab and the IMCL-9815 phase III registration trial in LA-HNSCC, comparing RT plus weekly cetuximab versus RT alone, both showing significant survival benefit [70,71,72]. At the time that these trials were performed there was no recognition of the important role of HPV, and stratification by HPV/p16 status had not been done. Subsequent p16 and HPV substudies performed in these two trials showed that, while p16 and HPV are prognostic biomarkers in patients with LA-HNSCC and R/M-HNSCC, it could not be shown that they are predictive for the outcomes of the described cetuximab-containing trial regimens [73]. This is remarkable, considering there is evidence that EGFR inhibitors, including cetuximab have minimal activity as single agents in R/M HPV-positive OPSCC compared with HPV-negative HNSCC [74].

The number of studies evaluating CCRT plus anti-EGFR treatment (with anti-EGFR given in the concurrent or adjuvant settings or in both) versus CCRT alone is limited [75,76,77,78,79,80,81]. Anti-EGFR mAbs are not used as adjuvant therapies for LA-HNSCC and small tyrosine kinase inhibitors are not effective adjuvant therapies, as shown in two large phase III trials [78, 80]. A systematic review and meta-analysis of randomized trials published between 2005 and 2016 (not including the more recent nimotuzumab trials) concluded that for stage III/IV patients, anti-EGFR mAb plus RT can improve OS compared with RT alone, while replacement of chemotherapy with EGFR mAb or adding EGFR mAb to combined chemotherapy and RT did not [82]. Nimotuzumab, originally developed in Cuba, now approved in 30 countries, including countries in Asia, South America and Africa, is a humanized immunoglobulin G1 (IgG1) mAb that has demonstrated a unique clinical profile, where antitumor activity was observed in absence of severe skin, renal or gastrointestinal mucosa toxicities, commonly associated with anti-EGFR targeting antibodies. It is hypothesized that higher binding and internalization of mAbs in the tumor together with a low level of internalization in nontumor tissue is obtained when there is intermediate affinity (10^–9 to 10^–8 M) to the receptor [84]. For panitumumab and cetuximab this binding is high (5 × 10^–11 and 1 × 10^–10 M for panitumumab and cetuximab, respectively), while for nimotuzumab there is an intermediate binding capacity (about 1 × 10^–9 M). In addition, this mAb also induces ADCC and complement dependent cytotoxicity.

The largest component in the above-mentioned meta-analysis of anti-EGFR agents administered concurrently with standard therapies was the RTOG 0522 study [75]. Patients included in RTOG 0522 had stage III & IV (excluded T1N+ , T2N1) squamous cell cancer of the oropharynx, larynx and hypopharynx and were randomized to receive altered fractionation with concomitant boost (AFX-CB: 72 Gy/42 fractions/6 weeks) and cisplatin (100 mg/m², twice every 3 weeks) or the same CCRT plus cetuximab (400 mg/m² × 1, then 250 mg/m²/week). Details on outcome are in Table 10.6. Patients were stratified by tumor site (larynx vs other), nodal stage (N0 vs N1-N2b vs N2c-N3), Zubrod performance status, use of IMRT (yes vs. no) and receipt of pretreatment fused positron emission tomography/computed tomography scan (PET-CT, yes vs. no). The combined treatment led to more interruptions (26.9 vs. 15.1%) of the RT and induced more grade 3–4 mucositis (43.2 vs. 33.3%), rash, fatigue, anorexia and hypokalemia than CCRT alone, but not more late toxicity. There were no significant differences in outcome between the two arms, with the exception of a better OS for younger patients with the addition of cetuximab. Moreover, when the investigators looked specifically in the OPSCC cohort for whom p16 status was known, there was a trend in better outcome with the addition of cetuximab in the p16-negative cohort, but not (or even the opposite) in the p16-positive cohort, and this was true for both PFS and OS.

Table 10.6 Anti-EGFR monoclonal antibodies plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced HNSCC: results of two large phase III trials

In the Tata Memorial Center trial [81], patients with oral cavity tumors were also allowed into the study, as were patients with a Karnofsky performance status ≥70. Stratification occurred for primary disease site (OPSCC vs. other), stage (stage III versus IV), age (≤60 vs. >60 years) and radiation technique (conventional vs. other). Radiation techniques included the standard 2D technique, a 3D conformal technique and IMRT. Gross tumor and lymph node disease received 70 Gy/35 fractions/7 weeks, and in both arms of the study cisplatin was dosed at 30 mg/m² weekly during RT. In the combined arm, nimotuzumab was administered weekly intravenously as a 200 mg flat dose in 250 mL normal saline over 60 min without premedication.

The primary endpoint of the Tata Memorial Center trial was PFS and that endpoint was reached (Table 10.6). The addition of nimotuzumab improved also LRC (HR 0.67; 95% CI 0.50–0.89; p = 0.006) and disease-free survival (DFS) (HR 0.71; 95% CI 0.55–0.92; p = 0.008) and showed a trend towards improved OS. Grade 3–5 adverse events were similar between the two arms, except for a higher incidence of mucositis in the combined arm (66.7 vs. 55.8%, p = 0.01).

Although the patient and treatment characteristic differed between both trials (in the Indian trial there were more younger patients, less OPSCC patients, more p16-negative OPSCC patients [69.5 vs. 26.8%]), there seemed to be a trend in having a positive effect on survival with the addition of both cetuximab and nimotuzumab in p16-negative OPSCC patients. This positive effect became more clear in a subgroup analysis which has been reported separately for the Tata Memorial trial [84]. Of the 269 patients in the Patil study with OPSCC (see Table 10.6), p16 testing was feasible in 212, of whom 187 were p16 negative (88.2%). Of these 187 patients, 91 were in the CCRT arm and 97 in the CCRT plus nimotuzumab arm. The arms were balanced for patient and disease characteristics. The interaction test for HPV status (positive and negative) was significant for PFS (p = 0.000), LRC (p = 0.007) and OS (p = 0.002), but not for DFS (p = 0.072). The 2-year PFS was 31.5% in the CCRT arm versus 57.2% in the combined arm (HR 0.54; 95% CI 0.36–0.79, p = 0.002). The 2-year LRC was 41.4% in the CCRT arm versus 60.4% in the combined arm (HR 0.61; 95% CI 0.40–0.94, p = 0.024). The addition of nimotuzumab also led to an improved OS at 2 years from 39.0 to 57.6% (HR −0.63, 95% CI 0.43–0.92, p = 0.018). This trial seems to indicate that treatment intensification in HPV-negative OPSCC patients with the use of nimotuzumab is feasible when using very low weekly cisplatin doses. It is unclear whether this also works when high-dose cisplatin during RT is utilized. In order to further identify patients who might benefit from this combined treatment, Patil et al. [85] performed a biomarker study in a subgroup (n = 404, 206 treated with CCRT, 198 with CCRT + nimotuzumab) of the 536 patients enrolled in the Tata Memorial trial (Table 10.6). This cohort consisted only of HPV-negative cases. The investigators assessed the expression of EGFR, phosphorylated EGFR dimers (pEGFR; a surrogate marker of EGFR activity) and hypoxia-inducible factor 1α (HIF1α; because of increased sensitivity of HNSCC cells to cetuximab under hypoxia in vitro) by immunohistochemistry and EGFR gene copy change by fluorescence in situ hybridization (FISH). Multivariate analysis revealed HIF1α as an independent negative prognostic factor. Moreover, interestingly, outcomes (PFS, LCR, OS) were significantly improved with the addition of nimotuzumab in patients with high HIF1α, but not in those with a low HIF1α expression [85].

The addition of anti-EGFR mAbs to CCRT in patients with locoregionally advanced HPV/p16-negative OPSCC and non-OPSCC seems of interest, and this may be true for both cetuximab and nimotuzumab. Further selection of patients by using molecular markers might be the way to proceed.

Targeting the Inhibitor of Apoptosis Proteins

Inhibitors of apoptosis proteins (IAPs) are a class of proteins that negatively regulate apoptosis and modulate immune and inflammatory responses, processes that are frequently dysregulated in cancer [86]. IAPs are frequently overexpressed in various cancers, including HNSCC, and have been shown to increase the resistance of cancer cells to apoptosis and prevent cell death induced by anticancer treatments, such as chemotherapy and radiotherapy. Cellular IAPs, including cIAP1 and cIAP2, play a critical role in regulating death receptor-mediated apoptosis and modulating nuclear factor kappa B (NF-ҡB) pathways, driving immune and inflammatory responses. X chromosome-linked IAP (XIAP) plays a central role in the inhibition of apoptosis in both death receptor-mediated and mitochondria-mediated pathways by directly inhibiting members of the caspase family. The critical role of IAPs in primary and secondary resistance to anticancer agents has led to evaluation of IAP inhibitors as therapeutic targets.

Xevinapant (Debio 1143, also known as AT-406 and SM-406) is a first-in-class, potent, oral, small-molecule antagonist of IAPs, including XIAP, cIAP1 and cIAP2, with the potential to enhance the antitumor activity of cisplatin and radiotherapy. The radiosensitizing effect of xevinapant is mediated through caspase activation and tumor necrosis factor (TNF), interferon gamma (IFN_γ), CD8 T cell-dependent pathways [86, 87], (Fig. 10.2). Used as a single agent at doses up to 900 mg/day on days 1–5 or 400 mg/day on days 1–14 every 3 weeks could be given without reaching a MTD. Dose limiting toxicities (DLT) included elevations of transaminases, which were not dose-related [88]. When the drug was given in combination with CCRT (with high-dose cisplatin) in a phase I study, doses were escalated from 100 to 200 mg and to 300 mg, given for 14 days every 3 weeks. Two of the six patients treated at the 200 mg dose level experienced DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia and grade 3 lipase increase). This dose was therefore considered the MTD and the recommend dose for phase II studies. The next step was a randomized phase II study, which was executed by the GORTEC [87]. The patients included in this study were aged 18–75 years, had histologically confirmed treatment naïve LA-HNSCC (stage III, IVa and IVb, limited to T ≥ 2, N0-3 and M0 (AJCC/TNM 7th edition) originating from the oral cavity, pharynx (OPSCC p16-positive or p16-negative) and larynx, Eastern Cooperative Oncology Group (ECOG) performance status 0–1, a tobacco smoking history of more than 10 pack-years, no diseases or conditions associated with chronic inflammation and adequate organ functions. The protocol design is shown in Fig. 10.3. The primary endpoint was the proportion of patients with LRC at 18 months after chemoradiotherapy termination, and the aim was reaching >20% difference in LRC rate at that time (with 0.8 power at 0.2 significance level). In the first report, the median follow-up was 25 months [87]. LRC at 18 months after chemoradiation was achieved in 26 of 48 patients (54%) in the xevinapant arm and in 16 of 48 patients (33%) in the placebo arm. Grade 3 or more toxicity was reported in 85% of patients in the xevinapant arm and in 87% in the placebo arm. Most common grade 3–4 adverse events were dysphagia (59 vs. 21%), mucositis (31 vs. 21%) and anemia (35 vs. 23%) in the xevinapant and placebo arms, respectively. Median PFS (secondary endpoint) was not reached for the xevinapant group and was 16.9 months for the placebo group (HR 0.37 [95% CI 0.18–0.76], p = 0.0069). There was no significant difference in OS between both groups at 24 months (73% with xevinapant versus 65%; HR 0.65 [0.32–1.33], p = 0.243). However, the data became even more promising at 3 years follow-up with at that time also a significant difference in survival (66% for the xevinapant group and 51% for the placebo group (HR 0.49 [95% CI 0.26; 0.92], p = 0.0261) (Fig. 10.4A and B) [89].

Fig. 10.2

Xevinapant unleashes the cancer cell death cascade and enhances antitumor immune response

Fig. 10.3

Xevinapant randomised phase II trial: study design. A double-blind, placebo-controlled multicenter study [87]

Fig. 10.4

A Locoregional control at 18-month timepoint. Sun et al. Lancet Oncol 2020 [87]. B Progression-free survival and overall survival at 3 years. Bourhis et al. Ann Oncol 2020 [89]

In conclusion: these differences are unprecedented for this poor-risk patient population and needs further study. A phase III trial (TrilynX study; NCT04459715) is recruiting similar poor risk patients to confirm these promising data. Details on the study can be obtained in a recent publication [90].

Adding Approaches that Increase the Radio-Sensitivity of Hypoxic Cells

Adding Hypoxic Sensitizers (Nimorazole)

One of the major hurdles in radiation oncology is radioresistance due to heterogeneous hypoxic areas in most solid tumors, including HNSCC, irrespective of their size and histological characteristics [91]. Various efforts and methods to overcome hypoxia-induced radiation resistance have been summarized by Elming et al. in 2019 [92] (Table 10.7). Basically, as indicated, they include improving oxygen availability, increasing radiosensitivity of hypoxic cells, killing the hypoxic cell population or modifying the radiation treatment either by increasing the dose to the hypoxic areas (dose painting) or utilizing radiation of a higher LET (linear energy transfer) in which the oxygen enhancement ratio is reduced [92]. Hyperthermia (HT; heat treatments of 39–45 °C) induces many of these effects and is therefore being considered as one of the best agents for eliminating hypoxia.

Table 10.7 Approaches for dealing with hypoxia^a

The beneficial effect of giving radiotherapy with hypoxic modification is supported by a meta-analysis [93]. Criteria for inclusion in that meta-analysis included curative treatment with RT alone with randomization to a hypoxic modifier which should be known only to influence hypoxic radioresistance and have no other cytotoxic effect. Thus, studies involving chemotherapy, either as part of primary therapy or as intended hypoxic modifier or HT were not included. The same was true for studies with hemoglobin modification, these were also not included. Overall, hypoxic modification did result in a significant benefit in LRC (odds ratio [OR] 0.71, 95% CI 0.63–0.80, p < 0.001), disease-specific survival (OR: 0.73, 95% CI 0.64–0.82, p < 0.001) and to a lesser extent in OS (OR: 0.87, 95% CI 0.77–0.98, p = 0.03). The risk of distant metastases was not significantly influenced. Important was the observation that the radiation related late complications were not influenced by the overall use of hypoxic modification (Fig. 10.5).

Fig. 10.5

Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck. Overgaard J. Radiother Oncol 2011; 100: 22–32 [93]

After a first experience with misonidazole in the Danish Head and Neck Cancer Study Group (DAHANCA 2), showing better LRC with RT plus misonidazole than RT alone in patients with pharynx and supraglottic larynx carcinoma (no benefit in glottic lesions) at the cost of unacceptable peripheral neurotoxicity in 26% of the patients, nimorazole (1-(N-β-ethyllmorpholine)-5-nitro-imidazole) was tested in the DAHANCA 5 study [94]. This concerned a randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary RT in supraglottic larynx and pharynx cancers. Overall, the nimorazole group (n = 219) showed a significantly better LRC rate (primary endpoint) than the placebo group (n = 195), 49% versus 33% (p = 0.002) and also disease specific survival was significantly improved (52 vs. 41% at 5 years, p = 0.01). However, OS was not significantly different and late RT-related morbidity occurred in 10% of surviving patients, irrespective of nimorazole treatment [94]. Although these observations are promising, hypoxic modification found little following [95], except for the use of nimorazole in Denmark. As tumors display variable degrees of hypoxia, it is becoming increasingly clear that patient selection is an important factor in the evaluation and interpretation of clinical trials. Of the several different methods for measuring hypoxia, fluoromisonidazole (FMISO) and Fluoroazomycin arabinoside (FAZA)-PET are examples of functional, non-invasive imaging techniques, and PET measured hypoxia proved to be robust and showed a strong impact on LRC and OS in HNSCC patients treated with (chemo)radiotherapy [96]. Other methods include oxygen electrode measurements, exogenous hypoxia markers and endogenous hypoxia markers [97, 98]. Toustrup et al. developed a 15-gene hypoxia classifier, which was validated in 323 DAHANCA 5 patients of whom they had access to sufficient formalin-fixed paraffin-embedded (FFPE) pre-treatment tumor biopsies for gene expression classification. On the basis of this classifier, tumors were classified as either “more” hypoxic (n = 114 [35%]) and as “less” hypoxic (n = 209 [65%]). Patient characteristics in the two groups were grosso modo comparable and the relative number of p16-positive tumors was equally distributed between the two groups [97]. The “more” hypoxic group had a significant benefit of hypoxic modification with nimorazole compared with placebo in terms of LRC (5-year actuarial values of 49 vs. 18%, p = 0.001) and disease specific survival (48 vs. 30%, p = 0.04). “Less” hypoxic tumors had no significant effect of hypoxic modification. Contrary to HPV-negative tumors, HPV-positive tumors had a substantially better outcome in response to RT, which was irrespective of hypoxic modification [97].

The DAHANCA group has further tested the feasibility of hyperfractionated, accelerated RT with concomitant weekly low-dose cisplatin and nimorazole (HART-CN) in locoregionally advanced, HPV-negative squamous cell carcinoma of the oropharynx, hypopharynx, larynx and oral cavity (DAHANCA 28) and will explore this approach also in hypoxic tumors. Of interest in that respect is the observation by DeSchuymer et al. [99] that by using the 15 gene hypoxia classifier in patients treated with accelerated CCRT, no significant outcome differences were observed between “more” and “less” hypoxic tumors.

Finally, the DAHANCA 29–EORTC 1219 study, tried to confirm the Danish data outside Denmark. The objectives of that trial were to demonstrate the benefit of nimorazole with accelerated CCRT and the predictive value of the hypoxic gene signature. Quality controlled accelerated RT was delivered using IMRT up to a dose of 70 Gy in 6 weeks. Cisplatin was delivered either weekly 40 mg/m² on weeks 1 to 6 or three-weekly 100 mg/m² on weeks 1 and 4. Nimorazole or placebo were delivered orally with a daily dose of 1.2 mg/m². The two co-primary endpoints were LRC for the entire population and the hypoxic-gene population (Fig. 10.6). Thirty-three percent of the tumors were hypoxic-gene positive. After two safety reviews, the Independent Data Monitoring Committee (IDMC) recommended to only use the weekly cisplatin regimen based on nephrotoxicity in the three-weekly arm, with more toxicity in the nimorazole arm (27 vs. 11.4% with the placebo arm). Overall, grade 3 or higher adverse events occurred in more than 90% of patients in both arms. Unfortunately, at the last review, the IDMC recommended early closure of the trial based on weak conditional power for the hypothesized treatment effect. At 2 years, the LRC probability was not clinically different between the two arms, neither in the entire population (63.8% with nimorazole and 72.1% with placebo) nor in the hypoxic-gene positive patients [100].

Fig. 10.6

DAHANCA 29–EORTC 1219 trial: study design. Gregoire V. et al. Radiother Oncol 2021 [100]

Hyperthermia

As mentioned in Elming’s paper in Cancers (see also Table 10.7), HT induces many of the effects that are playing a role in handling the negative effects of tumor hypoxia and in that sense it has the potential to be one of the best agents for eliminating hypoxia [92]. Locoregional HT, at 40–44 °C, has been shown to be a potential radiosensitizer, a chemosensitizer and an immunomodulator with no significantly added side effects [101]. The thermodynamic changes are initiated at around 38 °C and result in a gradual increase in tumor blood flow and subsequent oxygenation, while the thermoradiobiological mechanisms lead to direct cell kill, thermal sensitization and inhibition of DNA repair between 39 °C and 45 °C [101, 102]. Thus, at the usual clinically achievable temperature of 40–42 °C, HT can lead to appreciable radiosensitization, chemosensitization and immunomodulation along with RT with or without chemotherapy. In a meta-analysis of six clinical trials comprising 451 cases of LA-HNSCC the combination of RT and HT improved the overall complete response rate by 25.5% over RT alone (p < 0.0001) without an excess of acute or late morbidity [103]. A narrative review of regional HT updating the period 2010–2019 reported data on three studies in NPC comparing CCRT versus CCRT with HT [104]. Two of the three studies showed improved complete response (CR), PFS and OS with the combined approach, while improved DFS was reported in the third study. There are no randomized trials of CCRT with HT versus CCRT alone in patients with LA-HNSCC. However, retrospective studies reported promising results, both in terms of efficacy and toxicity, when applying CCRT with weekly cisplatin and weekly HT in head and neck cancer patients [105, 106]. In particular, no enhanced mucosa and thermal toxicity was reported.

Contrary to the situation in head and neck cancer, randomized trials on CCRT with HT versus CCRT alone are available for patients with locally advanced cervical cancer (LACC), a cancer sharing similar histology with head and neck cancer, and showing a lot of similarities with LA-HNSCC in terms of treatment evolution. A first randomized trial in the Netherlands (the Dutch Deep Hyperthermia Trial), completed in 1996, showed significant benefit of adding HT to RT (3-year OS of 51 vs. 27%, p = 0.009) [107]. The results of this trial have led to the acceptance of RT plus HT as standard treatment for advanced cervical cancer in the Netherlands. However, the standard treatment of LACC nowadays, based on at least five randomized trials worldwide, consists of CCRT with weekly cisplatin (40 mg/m²). In retrospect, the outcome data with RT plus HT were quite similar to those that can be obtained with CCRT (with cisplatin). A randomized trial (the RADCHOC trial), in which patients with LACC were randomized to RT plus HT or RT plus cisplatin, reported comparable outcome and comparable grade 3 or higher late radiation-related toxicity between the two treatment arms, suggesting HT might have a role to play as an alternative treatment if chemotherapy tolerance is an issue [92, 108]. It was therefore of interest to see whether HT to CCRT would further improve outcome and it did. In a systematic review and meta-analysis, the risk difference from three randomized clinical trials (total number of patients 738) for LCR and OS showed an advantage for CCRT plus HT over CCRT alone of 10.1% (p = 0.03) and 5.6% (p = 0.07), respectively [109, 110]. This beneficial effect was also confirmed in a network meta-analysis, in which all 13 different therapeutic approaches for treating LACC from 49 clinical trials totalling 9894 patients were evaluated [111].

Crucial for such a set up for LA-HNSCC is having a proper HT unit for the head and neck region that would allow adequate heating and monitoring of HT during individual treatment sessions. In Rotterdam (The Netherlands), such a HT delivery system (The HYPERcollar: a novel applicator delivering heat at 433 MHz to the head and neck) has been further developed and is currently being validated in clinics for HT delivery in the head and neck region. Presently, a magnetic resonance (MR)-compatible version of this applicator is being used with a 1.5 T MR system, allowing an online monitoring of the temperature using non-invasive thermometry with the proton resonance frequency shift method [112, 113].

In conclusion, there is at present no proof that treatment intensification with the use of hypoxic sensitizers added to conventionally fractionated or accelerated cisplatin-based CCRT leads to better outcome in patients with LA-HNSCC. However, considering the strong background data, further studies guided by molecular markers of hypoxia seem appropriate. Since HT can effectively target hypoxia via a variety of different mechanisms and showed improved outcome when combined with RT in a number of solid tumor sites, among which NPC, there is potential that it may further improve outcome in LA-HNSCC over CCRT alone also in the non-NPC sites.

Adding Immunotherapy (Immune Checkpoint Inhibitors)

As mentioned by Machiels et al. in two THNO chapters (Chap. 13 in the 7th Critical Issues in Head and Neck Oncology, 2021 and Chap. 11 in the present issue) the integration of immune checkpoint inhibitors (ICIs) in the primary treatment of patients with LA-HNSCC so far has not reached the same success that has been seen when immune checkpoint inhibitors were used in the R/M disease setting. The reader is referred to these chapters for details. No improvement in outcome of patients treated with ICIs during chemoradiotherapy has been reported. The cause of this is not completely clear. One of the options mentioned as an explanation for the lack of benefit of anti-programmed death-1 (PD-1)/PD-Ligand-1 (PD-L1) mAbs in combination with (chemo)radiation is the large field of irradiation to regional lymph nodes that might neutralize immune competent cells. Unfortunately, some of these studies have more than one question at the same time, which complicates outcome data. So far, ICIs in the neoadjuvant setting, either alone or in combination with chemotherapy have shown promising results (high pathological response rates) in window of opportunity studies, but no data from randomized phase III trials exploring this option have been reported. Data on ICIs used as adjuvant therapy per se are eagerly awaited, because of its simplicity and purity.

Conclusions

Current treatment guidelines for patients with LA-HNSCC recommend multimodal treatment, including CCRT or surgery followed by RT, with/without CT. ICT followed by (chemo)-RT is an alternative approach for larynx preservation procedures in patients with locoregionally advanced laryngeal or hypopharyngeal cancer. The CT part of the CCRT consists of platinum-based chemotherapy, most often single agent cisplatin. Although for a long time high-dose cisplatin (100 mg/m²) three-times every three weeks during RT has been the standard of care, recent prospective randomized studies have indicated that the weekly low-dose cisplatin (40 mg/m²) is a good alternative with less toxicity, in particular in the postoperative (adjuvant) setting. For patients not eligible or not tolerating cisplatin there are other alternatives (such as carboplatin with or without 5-fluorouracil, taxanes or cetuximab). However, none of these have shown superior results over the use of cisplatin in randomized trials. Late toxicity is a major downside of CCRT, and this is most worrying for those with the highest chance of cure, i.e. low-risk HPV-positive OPSCC. De-escalation approaches have priority in these patients, but this needs to be done with the utmost caution. In the remaining patient populations (high-risk HPV-positive OPSCC, HPV-negative OPSCC and non-OPSCC patients) there is room for improvement in both locoregional control and in distant control. Recent strategies of potential interest above and beyond cisplatin-based CCRT are adding (1) more cytotoxic chemotherapy (both neoadjuvant and adjuvant), (2) targeted therapy (concomitant cetuximab, nimotuzumab, xevinapant) (3) hypoxic sensitizers (nimorazole), including hyperthermia, and, (4) immunological approaches (immune checkpoint inhibitors). However, these approaches are not applicable for all poor-risk LA-HNSCC patients and radiographic, proteomic and genomic biomarkers will play an increasing role in better defining prognostic groups and guide treatment selection with greater precision. Apart from hyperthermia, all these approaches beyond CCRT will be accompanied by an increase in toxicity. Therefore, taking into account the already existing toxicity profile of cisplatin-based CCRT, these treatment intensification options can only be considered in patients in a good general condition, with adequate organ functions and without prohibitive co-morbidities. Many of the above mentioned options are being investigated in prospective randomized trials and will hopefully lead to further improvement in outcome for these less favorable HNSCC patient categories.