The lowest level of evidence is based on expert opinions, cross-sectional studies, case reports, and case series. Consequently, the assumptions underpinning low-dose weekly cisplatin in comparison with the high-dose regimen include a better shortand long-term tolerance without jeopardizing outcome, improved compliance, timely dose adjustments, enhanced radiosensitization, reduced risk of radioresistance, and lower costs due to outpatient administration [14]. Of them, those exploring effcacy, toxicity, and compliance were explored at higher levels of evidence and will be further discussed below. Radiobiological properties per se and logistical aspects have clinical relevance primarily if they infuence patient outcomes, and they have not been studied separately in prospective cohorts. Costeffectiveness issue have recently been gaining increasing attention, but data are mostly available for new medicines. Based on a small retrospective study of 62 patients, the incremental cost-effectiveness ratio (ICER) for the addition of threeweekly cisplatin to radiotherapy was calculated at \$3303-per-quality-adjusted life year (QALY) [29]. An analysis of healthcare expenditures in the cisplatin arm of the De-ESCALaTE trial revealed total costs of £13,517 per patient at 24 months posttreatment [30]. Unfortunately, similar analyses are neither available for a weekly regimen versus radiotherapy alone nor for a comparison between the two cisplatin schedules under question.

# *Level IV Evidence*

Retrospective cohort and case-control studies provide a higher level of evidence but are still diffcult to pool. As summarized in one of our publications, the results of such studies comparing weekly versus three-weekly cisplatin are conficting and do not allow us to make frm conclusions, albeit that an overall impression of their outcomes tends to endorse the high-dose regimen [14].

# *Level III Evidence*

Moving on to non-randomized prospective trials we present here the key results of the set of three meta-analyses mentioned above [14, 15]. In the adjuvant setting of conventionally fractionated chemoradiotherapy, data from nine trials could be retrieved, six on high-dose and three on low-dose cisplatin. While no differences in late toxicity (p = 0.5938) and compliance (p = 0.5747) were observed, severe acute toxicity favoured the weekly schedule with signifcantly less dysphagia (p = 0.0026) and weight loss (p < 0.0001). However, the latter fndings should be interpreted with caution as they are based on only one trial using weekly cisplatin. In the defnitive setting of conventionally fractionated chemoradiotherapy, 39 studies were included in the analysis, 25 in the high-dose and 14 in the low-dose cohort. There were clearly less severe acute toxicities with the weekly regimen as refected by signifcantly less myelotoxicity (leukopenia: p = 0.0083; neutropenia: p = 0.0024), nausea and/or vomiting (p < 0.0001), and severe nephrotoxicity (p = 0.0099). In line with that, also the compliance was better with the weekly cisplatin regimen. No data on late toxicity were available in the low-dose cohort, precluding thus further calculations. The effcacy outcomes provided interesting insights into the role of the cumulative cisplatin dose. Although no difference in overall survival was noted in either of these meta-analyses, only about two thirds of patients in the high-dose arm could receive all three cisplatin cycles, i.e. a cumulative dose of 300 mg/m2 . But what if the target dose was not 300 but 200 mg/m2 . In that case, would it still be possible to ensure suffcient effcacy but with notably lower acute toxicity?

As alluded to above, 200 mg/m2 might indeed provide an adequate exposition to the drug. Moreover, this is exactly the target cumulative dose used in the third metaanalysis run in the defnitive setting of altered fractionation chemoradiotherapy that involved 11 studies, seven with high-dose and four with low-dose cisplatin. Here, two cycles of the former regimen generated signifcantly less severe acute toxicity (mucositis and/or stomatitis: p = 0.0202, constipation: p = 0.0066) and short-term mortality (toxic deaths: p = 0.0168, 30-day mortality: p = 0.0154), but also less severe late adverse events (subcutaneous fbrosis: p < 0.0001) than observed with the low-dose cisplatin regimen. In line with an improved compliance (p = 0.0353), the vast majority of patients (95%) receiving the high-dose regimen could receive both planned cycles. Finally, patients on high-dose cisplatin during altered fractionation radiotherapy lived longer than those receiving the weekly regimen during altered fractionation radiotherapy (p = 0.0353). Albeit purely hypothetical, these results contribute to the ever-growing body of knowledge that supports a minimal cumulative dose of 200 mg/m2 .

# *Level of Evidence II*

Only two prospective trials randomly assigning LA-SCCHN patients to receive either the three-weekly high-dose or a weekly low-dose regimen have been published so far (Table 10.4) [31, 32]. Owing to an increased risk of bias arising from insuffcient power and cumulative dose issues, we have assigned them to level of evidence II. The frst study randomized 55 patients who were treated with the same mean radiotherapy and cisplatin doses (208.5 mg/m2 three-weekly versus 200.4 mg/ m2 weekly) but a cumulative dose of at least 200 mg/m2 could be delivered to signifcantly more patients in the high-dose arm (88.5% versus 62.5%, p = 0.047). In spite of that, the low dose regimen proved to be more toxic (p = 0.02), particularly with regard to severe mucositis (38.5% versus 75.0%, p = 0.012). No differences in overall survival were noted at median follow-up of 12 months [31]. The accrual in the second randomized study reached up to 300 patients but concerns were raised about the different cumulative doses with 180–210 mg/m2 being the target exposure in the weekly cisplatin arm and 300 mg/m2 in the three-weekly arm. In the end, it was not that surprising to see the three-weekly regimen generating better locoregional control at 2 years (58.5% versus 73.1%, p = 0.014) but at the cost of an

**Table 10.4** Phase III trials comparing radiotherapy given concurrently either to three-weekly high-dose or to weekly low-dose cisplatin

*nr* not reported

increment in severe acute toxicity (71.6% versus 84.6%, p = 0.006), namely vomiting, infection, hearing loss, hyponatremia, and myelotoxicity. Compliance and late toxicity were comparable [32].

# *Level of Evidence I*

Current evidence has not attained this level, and the presented meta-analyses do not qualify because they were not primarily based on randomized trials exploring the respective comparison. The situation may be changing soon when the results of the phase II/III non-inferiority trial of the Japan Clinical Oncology Group (JCOG1008) are shared. Aiming to enrol 260 participants in the post-operative setting, the study has been ongoing since October 2016 with the primary objective of overall survival. The target cumulative doses were set to 300 mg/m2 and 280 mg/m2 for three-weekly and weekly cisplatin, respectively [33].

# **Immunotherapy Trials**

After having defned new standards of care in the recurrent and/or metastatic setting, immune checkpoint inhibitors entered clinical trial design in LA-SCCHN challenging cisplatin-based chemoradiotherapy. In this respect, the majority of randomized trials are exploring immunotherapy on top of cisplatin by either intensifying defnitive or adjuvant treatment (dubbed for our purposes design concept "A") or by giving it right after the standard defnitive or adjuvant chemoradiotherapy (design concept "B"). Alternatively, immunotherapy can replace cisplatin creating thus pure immunoradiotherapy regimens. In the former type of trials, high-dose three-weekly cisplatin represents the preferred administration mode.

The design model "A" has been adopted for example by the following larger (> 100 participants) trials: JAVELINE Head & Neck (NCT02952586), KEYNOTE-412 (NCT03040999), KEYCHAIN (NCT03383094), ADRISK (NCT03480672), and NIVOPOSTOP (NCT03576417). Here, sometimes preceded by a short lead-in phase with one dose of immunotherapy in eligible patients, chemoradiotherapy, as already mentioned, is typically based on the high-dose three-weekly cisplatin schedule (weekly regimen allowed in ADRISK) and combined with a programmed death-1 (PD-1) inhibitor (pembrolizumab or nivolumab) or an anti-PD-1 ligand (PD-L1) agent (avelumab or atezolizumab) in the experimental arm. Afterwards, patients are started on a maintenance phase with or without the immune checkpoint inhibitor for six to 12 months. The design model "B" stands for a classic two-arm concept where patients are assigned either to 1 year of immunotherapy or the same period of placebo or observation after having completed curative treatment as seen in IMvoke010 (NCT03452137) and EA3161 (NCT03811015). Other notable mentions comprise IMSTAR-HN (NCT03700905) and KEYNOTE-689 (NCT03765918) which are combining both design models. Finally, cisplatin-based chemoradiotherapy has been challenged by non-chemotherapy approaches in the NRG-HN005 (NCT03952585) and REACH (NCT02999087) trials.

# **Concluding Remarks and Outlooks for the Future**

There are many drawbacks of high-dose cisplatin which is not by far the ideal solution to administer concurrently to curative radiotherapy. Particularly, toxicity has become an issue for many patients, sometimes with life-long consequences. And this is where a weekly regimen steps in with probably the greatest beneft in better short-term tolerance, such as less nausea, vomiting, transaminase elevations, ototoxicity, serum creatinine increase, and myelotoxicity. However, this might be offset by worse survival outcomes and no beneft in late toxicity. Three-weekly high-dose cisplatin should therefore remain the reference adjunct to radiotherapy with continuous efforts to fnd more effcacious and/or less toxic modalities. Unfortunately, weekly cisplatin has not convincingly met these requirements yet. Nevertheless, some clinical situation may indeed prioritize this approach.

Elderly people have often numerous comorbidities, impaired autonomy, decreased organ reserves, and a limited life expectancy. Geriatric assessment tools have been developed to help distinguish older patients who are ft and can be considered good candidates for standard treatment from those who are frail and should be directed towards palliative measures, but also from those who are in-between. Although the latter group, sometimes referred to as vulnerable, is typically excluded from registration trials, these patients may still be deemed suitable for curative therapy. Notwithstanding the lack of rigorous scientifc data, weekly cisplatin is one of the regimens that can be offered to them providing a compromise solution with less acute side effects and still a possible beneft in overall survival [34]. A single dose of 40 mg/m2 can be pursued since the usual six to seven applications ensure an effective (≥ 200 mg/m2 ) and at the same time safe (≤ 300 mg/m2 ) cumulative dose. In addition, lowering the peak concentration of cisplatin, either by prolonging the infusion time or reducing cisplatin dose, can be recommended also in the presence of other relative contraindications as explained elsewhere [22].

More recently, the attention of healthcare professionals and researchers has been largely shifted towards immunotherapy which holds promise of being not only a more effcacious but mainly less toxic modality, offering thus new opportunities for frail patients as well [35]. In LA-SCCHN, several large trials are already ongoing and believed by many to become practice-changing, albeit only in high-income countries. In any case, the frst results will not be available before 2021, and until then high-dose three-weekly cisplatin will retain its central position. But even later and in resource-limited regions, this schedule will not completely disappear from treatment protocols, and a choice between weekly and three-weekly cisplatin will maintain its signifcance for practicing physicians.

# **References**

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 11 Where and when to Use Induction Chemotherapy in Head and Neck Squamous Cell Cancer**

**Jan B. Vermorken**

# **Introduction**

Worldwide cancer incidence and mortality are rapidly growing, and this is also true for head and neck squamous cell cancer (HNSCC). The 2018 estimates point at more than 750.000 new cases and more than 380.000 deaths [1]. The reasons are complex but refect both aging and growth of the population, as well as changes in the prevalence and distribution of the main risk factors for cancer, several of which are associated with socioeconomic development [2, 3]. Sustained exposure to tobacco, tobacco-like products, and alcohol increase the risk of developing HNSCC [4]. Although HNSCC can arise within the oral cavity, oropharynx, hypopharynx, larynx, and nasopharynx, there has been a shift in primary site distribution, with a steady increase of oropharyngeal squamous cell carcinoma (OPSCC) and a decline in cancers of the larynx and hypopharynx, in particular in the Western world [5]. This change has been observed in parallel with a decrease in cigarette smoking and the identifcation of exposure to high-risk oncogenic human papillomavirus (HPV) as a risk factor for the development of OPSCC [6, 7]. This possible role for HPV in head and neck cancer was frst reported in the 1990s, while the proof for a causal association between HPV and OPSCC was delivered in 2000 [8, 9]. A systematic review and meta-analysis showed that the overall HPV prevalence in OPSCC is increasing signifcantly over time: from 40.5% (95% CI,35.1–46.1) before 2000, to 64.3% (95% CI, 56.7–71.3) between 2000 and 2004, and 72.2% (95% CI, 52.9–85.7) between 2005 and 2009 (p < .001) [10]. Prevalence increased signifcantly initially in North America and subsequently in Europe, and the signifcant gap between them that existed before 2000 (50.7% vs 35.3%, respectively, p = .008) has now disappeared (69.7% vs 73.1%, respectively, p = .8).

J. B. Vermorken (\*)

© The Author(s) 2021 155

Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium and Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium e-mail<EMAIL_ADDRESS>
J. B. Vermorken et al. (eds.), *Critical Issues in Head and Neck Oncology*, https://doi.org/10.1007/978-3-030-63234-2\_11

Many earlier studies have observed that patients with HPV-positive OPSCC had a distinct epidemiology when compared to patients with HPV-unrelated OPSCC, i.e. they were statistically younger, were more likely male, had fewer comorbidities, and reported less tobacco exposure but higher numbers of (oral) sex partners [11– 13]. The prognosis for these younger patients with HPV-positive OPSCC was substantially better than that for patients with HPV-negative tobacco-related cancers treated similarly [5]. However, more recently, several studies portend that the population of elderly patients with HPV-positive OPSCC is expanding [14–16]. In fact, the age at OPSCC diagnosis is increasing for both HPV-positive and HPV-negative patients, and a rising proportion of older patients have HPV-positive tumors. In an analysis of the National Cancer Database (with 119,611 OPSCC patients) Rettig et al. [14] showed that although patients of ≥70 years of age with HPV-positive OPSCC had improved survival compared to those with HPV-negative OPSCC (adjusted hazard ration [aHR] = 0.65, 95%CI = 0.55–0.76), the survival beneft of HPV-positive tumor status was signifcantly attenuated compared to younger HPVpositive patients (50–59 years: aHR = 0.45, 95%CI = 0.39–0.51; pinteraction < 0.001). The outcome of these older patients with HPV-positive OPSCC was in fact essentially similar to survival for the young HPV-negative patients [14]. These data will have implications for the therapeutic approach that clinicians need to consider for these elderly patients, taking into account the higher comorbidity score, the distinct disease characteristics, the higher rates of treatment-related toxicities, and the increased risk of non-cancer-related deaths [14].

# **Milestones in Systemic Therapies for Locoregionally Advanced HNSCC**

Before 1980, the initial treatment of patients with locoregionally advanced stage III or IV (M0) was surgery and/or radiation therapy (RT), a choice that depended on the site of the disease, the resectability of the cancer, the performance status of the patients, and his/her comorbidities. However, with these "traditional" therapies outcome was quite poor, in particular in those with stage IV or unresectable disease. The milestones in systemic therapies are summarized in Fig. 11.1**.**

Single agent chemotherapy, in particular methotrexate was used for palliation in patients with recurrent or metastatic disease already in the 1960s. Systemic therapy was introduced as part of combined modality therapy for LA-HNSCC in the mid 1970s, initially as single agent chemotherapy with methotrexate or cisplatin, usually with palliative intent to patients with stage IV disease, M1 cancers or recurrent disease beyond salvage local treatment [17]. The utilization of cisplatin as a single agent produced a range of responses from 14% to 41% [18]. The higher response rates were seen in previously untreated patients. Subsequently, experience was obtained with combination chemotherapy, initially with cisplatin/bleomycin combinations, to which then methotrexate or vinca-alkaloids were added and ultimately

**Table 11.1** Induction chemotherapy in locoregionally advanced HNSCC\*

*MTX* metrotrexate, *BLM* bleomycin, *P* cisplatin, *PB* cisplatin/bleomycin, *PBM* PB + MTX, *Vinca* vinca alkaloid, *PF* cisplatin/infusional 5-FU, *CR* complete response, *PR* partial response, *OR* overall response. \*modifed from Choski et al. [19]

the cisplatin/infusional 5-fuorouracil (5-FU) regimen [19; Table 11.1). At Wayne State University in 1977, they initiated a pilot study for advanced previously untreated patients with head and neck cancer utilizing cisplatin, vincristine, and bleomycin. An overall response rate of 80% was achieved, with a 29% complete response (CR) rate [18]. With the known pulmonary toxicity of bleomycin and the in vitro synergism of 5-FU and cisplatin, they started a second pilot study with cisplatin (100 mg/m2 IV, day 1) and 5-FU (1000 mg/m2 /day by continuous IV infusion over 96 hours), the so-called PF regimen. The response rate with that regimen was 88% overall, with a 19% CR rate [20]. Increasing the infusion time of 5-FU to 120 hrs and the number of courses from 2 to 3, increased the overall response rate to 93% and the CR rate to 54% [21]. The feasibility of the latter scheme was established and the effcacy confrmed in a multi-institutional study within the Radiation Therapy Oncology Group (RTOG). An overall response rate of 86% was obtained, with a 38% CR rate [22]. An attempt to further improve the regimen by using higher dosages of cisplatin (40 → 30 mg/m2 /day x5 for 3 cycles), given in hypertonic saline, failed to show any further improvement over the 120 hrs PF regimen [23]. Although non-randomized trials were very promising with respect to response rate and sometimes also suggesting an improvement of survival, the impact on survival could only be assessed in randomized trials. Five randomized trials executed

between 1979 and 1987 using methotrexate as a single agent for induction before local treatment were, apart from one study, all negative with respect to survival beneft [24]. In the single positive study the methotrexate had been administered intra-arterially. Looking in more detail at that study, a difference in survival was present only in patients with oral cavity cancer. Further analysis of the oral cavity cases showed that the 5-year survival difference had signifcance only in stage II patients. The very high response rates, and in particular the very high CR rates stimulated investigators to do randomized trials with the hope to improve survival. However, the disappointment came rather fast when early randomized trials were all negative with respect to survival beneft, apart from one in patients with oral cavity cancer, in which again chemotherapy was administered by the intra-arterial route [24]. However, apart from a high response rate in untreated patients with locoregionally advanced HNSCC, it became clear that those patients that responded well to chemotherapy subsequently also responded more favorably to radiotherapy (RT) [25]. This observation formed the rationale for the frst-generation larynx preservation trials (see below).

In the 1990s, with the disappointing results with respect to survival gain in many randomized trials utilizing induction chemotherapy (ICT), the concept of concurrent chemotherapy with radiation therapy was revisited with the introduction of cisplatin given concurrently with radiation as the primary treatment for patients with inoperable and/or unresectable head and neck cancers [26]. The large individual patient-based meta-analysis, reported in 2000, demonstrated that cisplatin given concurrently with radiation (100 mg/m2 on days 1, 22, and 43 of the RT) achieved substantially more survival beneft versus RT alone when cisplatin was given sequentially (before or after the radiation) [27, 28; Table 11.2]. That is also true for the comparison versus the at that moment considered to be the best type of ICT, i.e. the PF regimen. Since that time enthusiasm to use ICT diminished strongly and colleagues on both sides of the Atlantic started to accept concurrent cisplatin-based chemoradiotherapy (CCRT) as the preferred treatment for both patients with resectable disease and those with inoperable or unresectable disease. For the frst category of patients, i.e. those with resectable disease, it was used as an adjuvant CCRT in case there were unfavorable features in the pathology specimen (positive margins and/or extracapsular extension), in the second category it was used as a defnitive nonsurgical treatment (defnitive CCRT). Determinative in this change of attitude

**Table 11.2** Summary of the meta-analysis of the MACH-NC collaborative Group [27, 28]

*PF* cisplatin +5-fuorouracil combination

were four large randomized controlled trials which irrefutably showed beneft of this combined modality approach [29–32].

The frst two decades in 2000 are fascinating in that new treatment approaches, initially targeted therapies, but later also immunotherapies came forward [33–40]. Both targeted therapies (in particular cetuximab) and immunotherapies (especially immune checkpoint inhibitors [CPIs]) have been practice changing. Not only were they extensively studied in the recurrent/metastatic (R/M) disease setting [34, 38– 40], they also found their way in patients with LA-HNSCC [35, 36], although for CPIs that has not been fully developed yet. There arose a renewed interest in ICT since the introduction of the taxanes, which proved to be active compounds for this disease [41, 42]. Two randomized controlled trials (RCTs), one in the US and one in Europe, showed that adding docetaxel to the PF combination made this regimen more effcacious, better tolerable for the patients, did not lead to a negative effect on quality of life (QoL), and was cost-effective [43–46]. This so-called TPF regimen is now considered standard for those situations in which ICT is indicated.

# **Comparison of the Practice Changing TPF Protocols (TAX 323/EORTC 24971 and TAX 324)**

The results of the European TPF regimen (protocol TAX 323/EORTC 24971) and the American TPF regimen (TAX 324) were published back to back in the New England Journal of Medicine in 2007 [43, 44]. In both phase III trials, LA-HNSCC patients were randomized to receive three (TAX 324) or four (TAX 323/EORTC 24971) cycles of TPF or PF as induction before local treatments. Details on the respective regimens can be found in Table 11.3. The studies were executed in different patient populations. TAX 323/EORTC 24971 included only patients with previously untreated, unresectable LA-HNSCC, while in TAX 324 there was a mixture of patients involved, i.e. those with either unresectable disease or disease of low surgical curability, as well as patients with LA-HNSCC who were candidates for organ preservation. Both studies also differed in the local treatment part of the protocol following the induction phase. In TAX 323/EORTC 24971, patients who did not have progressive disease underwent conventionally fractionated RT within 4 to 7 weeks after the completion of chemotherapy (total dose, 66 to 70 Gy) or accelerated or hyperfractionated regimens (total maximum dose 70 Gy for the accelerated

**Table 11.3** TPF regimens in accordance with TAX 323/E ORTC 24971 and TAX 324

regimen and 74 Gy for the hyperfractionated regimen), decided before the start of the protocol for each institution. Neck dissections could be performed, if indicated, before or after the RT. In TAX 324, all patients were assigned to receive CCRT beginning 3 to 8 weeks after the start of the third cycle of ICT (day 22 to day 56 of cycle 3). Weekly carboplatin at an area under the curve of 1.5 was given as an intravenous infusion during a 1-hour period for a maximum of seven weekly doses during the course of RT. The defnitive curative radiation dose administered to the primary tumor was between 70 and 74 Gy, administered as fractions of 2 Gy per day 5 days per week. The dose administered to uninvolved lymph nodes was at least 50 Gy. Involved lymph nodes were to receive 60 to 74 Gy, depending on whether an elective neck dissection was indicated after completion of treatment. Surgery was performed 6 to 12 weeks after completion of chemoradiotherapy in patients who had an initial nodal stage of N2 and a partial response to ICT or N3 disease, or residual disease after chemoradiotherapy. Surgery was also allowed for patients who did not complete chemoradiotherapy and had resectable residual disease at the primary site or in the neck.

Both trials concluded that the overall response rate with TPF was signifcantly (TAX 323/EORTC 24971) or numerically (TAX 324) higher than with PF. Both TPF regimens also clearly demonstrated survival beneft over PF ICT (Fig. 11.2). About three-quarters of the patients completed both TPF and RT per protocol and 24% to 29% had treatment delays during ICT. As mentioned above, the TAX 323/ EORTC 24971 regimen was associated with a more favorable safety profle than the previously standard PF regimen, likely owing to the lower overall doses of the cisplatin (75 mg/m2 instead of 100 mg/m2 on day 1) and 5-FU (750 mg/m2 /day x5 instead of 1000 mg/m2 /day x5). This resulted in a lower frequency of grade 3/4 stomatitis, nausea/vomiting, dysphagia, and thrombocytopenia [44]. Patients in the

**Fig. 11.2** Landmark trials of TPF versus PF in locoregionally advanced HNSCC

TPF arm had fewer treatment delays then did those in the PF group despite differences in peak neutropenia during ICT in the TPF group [43, 44]. The superiority of TPF over PF has been confrmed in a meta-analysis of pooled data from fve phase III studies, including the two mentioned above [47]. This analysis concluded that the TPF regimen, compared to the PF regimen, led to benefts in progression-free survival (PFS), overall survival (OS), locoregional failure rate (LFR) and distant failure rate (DFR). Nevertheless, despite the fact that this meta-analysis confrmed that TPF was a better ICT than PF, some critical remarks were made with respect to the pooling methodology used on the fve rather heterogeneous studies, the missing treatment failure data in the participating two Spanish trials [48, 49] and the EORTC trial [44], and the different follow-up treatments that were applied for the ICT responders and the ICT non-responders [50]. However, what this meta-analysis did not do, was changing the standard of care in patients with advanced HNSCC, i.e. concurrent chemoradiotherapy.

The main question that remained for most clinicians was not whether TPF was superior to PF, there was a unanimous feeling about that, but it was whether the sequential use of ICT and local therapy was superior to the concurrent use of chemotherapy and radiation. Although two previous phase III studies demonstrated beneft for ICT → RT versus RT alone, in particular in patients with inoperable/ unresectable disease [51, 52], the role of ICT in connection to CCRT in patients with inoperable/unresectable disease remained controversial, due to diffculties in trial design, execution or insuffcient patient accrual [53–57]. However, what most of these studies had in common was the fact that the toxicity with the combined approach was increased. Febrile neutropenia could be found as high as 11% [53] and toxic deaths have been reported even up to 6% [57]. Moreover, the use of ICT could compromise the completion of subsequent chemoradiation, which can have a deleterious effect, not only on local control, but also on survival [58]. Therefore, less toxic schemes have been investigated, such as a modifed TPF regimen [59], a weekly carboplatin (AUC2) and paclitaxel (135 mg/m2 ) regimen for six consecutive weeks [60] and the TPEx regimen (docetaxel and cisplatin both 75 mg/m2 every three weeks for three cycles plus weekly cetuximab 400/250 mg/m2 ) [61] are all of interest. A randomized controlled trial comparing TPF to modifed TPF in ft patients is currently ongoing [62].

# **When to Use Induction Chemotherapy in Head and Neck Squamous Cell Cancer**

# *For Larynx Preservation*

There is an established role for ICT in larynx preservation programs for patients who otherwise would be candidates for total laryngectomy. When Wayne State University published its positive experience with the PF regimen in previously untreated patients with head and neck cancers [21] and thereafter showed that responders nearly all (97%) were controlled by subsequent radiation, and the others did much less [25], an new concept of treatment was born, i.e. using ICT as a selection procedure. This concept was frst tested in randomized trials with in the control arm patients that received the standard of care at that time, i.e. total laryngectomy with postoperative RT, and in the experimental arm patients that were treated with PF ICT followed in responders by RT and salvage surgery if required. These frst generation trials are summarized in Table 11.4. The conclusions of these two trials were that the concept of larynx preservation, with the use of ICT as a selection procedure, was safe, kept the larynx in place in about two thirds of the patients and had no negative impact on survival [63–66]. The next generation of larynx preservation trials did not look only to how many larynxes could be kept in place, but took more notice of the function of the larynx. In that context a new defnition of larynx preservation came forward "laryngoesophageal dysfunction-free survival" that included death, local failure, salvage laryngectomy, tracheotomy, or feeding tube at 2 years or later [67].

With the milestone of concurrent chemoradiotherapy in the second half of the 1990s (see above) next trials compared ICT followed by RT with CCRT or with alternating CT and RT [68–71]. The results of these studies are summarized in Table 11.5.

**Table 11.4** Induction chemotherapy trials for larynx preservation: frst generation

*VA* Veterans Affairs Laryngeal Cancer Study Group, *LP* larynx preservation, *TL* total laryngectomy, *RND* radical neck dissection, *RT* radiotherapy, *PF* cisplatin 100 mg/m2 d1 + 5-FU 1000 mg/ m2 , d1-5

a The non-responders received surgery + RT b

N2c was excluded

**Table 11.5** Induction chemotherapy trials for larynx preservation: second generation

*LP* larynx preservation, *PF1* cisplatin 100 mg/m2 , d1 + 5-FU 1000 mg/m2 , d1–5, *CCRT* concurrent chemoradiotherapy, *RT* radiotherapy, *PF2* cisplatin 20 mg/m2 /d, d1–5 + 5-FU 200 mg/m2 /d1, d1–5, *T3+* with fxed cord involvement, *T3−* without cord fxation

a *LP* larynx in place, function (voice quality, swallowing function, QoL questionnaire) evaluated b *LP* larynx in place, no tumor, no tracheotomy, no feeding tube

The alternating arm in the EORTC trial had a lower dose of 5-FU (total 1000 mg/m2 instead of 5000 mg/m2 per cycle) and a lower total dose of radiation (60Gy instead of 70 Gy). This resulted in less grade 3 or 4 mucositis (32% in the sequential arm vs 21% in the alternating arm) and late severe edema and/or fbrosis was observed in 16% of the patients in the sequential arm versus 11% in the alternating arm. No signifcant differences in outcome between the two arms of the study were observed. Combined with the toxicity data the results favored slightly the alternating arm. However, due to the organizational diffculties in delivering this alternating regimen in daily practice, this regimen is rarely used [66, 68, 69]. RTOG 91–11 is a crucial trial, in that it is the only trial that compares sequential treatment (PF → RT) with cisplatin-based CCRT and a RT alone arm [70, 71]. There have been several analyses reported, all showing a higher larynx preservation rate with the CCRT arm compared with the ICT arm or the RT alone arm. At the long-term follow-up analysis, both chemotherapy regimens signifcantly improved laryngectomy-free survival (LFS; primary endpoint) compared with RT alone. Overall survival did not differ signifcantly, although there was a possibility of worse outcome with CCRT relative to ICT (HR, 1.25; 95% CI, 0.98 to 1.61; P = .08). No difference in late effects was detected, but for deaths not related to the study cancer, there was a signifcant disadvantage for the CCRT group compared to the ICT group (52.8% vs 69.8%, respectively, p = 0.03).

With the revival of ICT in the frst decade of the twenty-frst century, it was to expect that the comparison of TPF versus PF would also be studied in the larynx preservation setting. This was executed by the GORTEC (Groupe Oncologie Radiotherapie Tete Et Cou) in a phase III protocol [72]. Protocol 2000–1 was conducted in 220 patients with locoregionally advanced laryngeal and hypopharyngeal cancer, who were eligible for total laryngectomy. The European TPF schedule was compared with the standard PF regimen and three cycles at a 3-week interval were planned. The primary endpoint of the study was larynx preservation and larynx preservation was defned as a larynx in place without tumor, tracheostomy or feeding tube. Ultimately, 213 patients were treated with a median follow-up of 105 months [72, 73]. The larynx preservation rate was signifcantly higher with TPF than with PF (at 10 years 70.3% versus 46.5%, P = .01 in the TPF vs PF arms, respectively). The 10-year laryngeal dysfunction-free survival was 63.7% with TPF and 37.2% with PF, which was again signifcantly different [73]. There was no signifcant difference in 5-year or 10-years OS, or disease-free survival (DFS). Statistically fewer grade 3–4 late toxicities occurred with the TPF regimen compared with the PF arm (9.3% vs 17.1%, P = .038). Support for this observation comes from a subgroup analysis of the TAX 324 study, that included only patients with advanced laryngeal and hypopharyngeal cancer. Among those that had operable disease (TPF, n = 67; PF, n = 56), LFS was signifcantly greater with TPF (HR: 0.59; 95% CI: 0.37–0.95; P = 0.030). Three-year LFS with TPF was 52% versus 32% for PF [74].

**For larynx preservation ICT with TPF is one of the two approaches that can be considered as a standard approach for patients with advanced laryngeal or hypopharyngeal cancer, who are not eligible for partial laryngectomy. The**  **other approach is cisplatin-based CCRT. Overall, T4 disease and tumors extending to the post-cricoid area are not eligible for larynx preservation. It is unclear for the moment which option is best. The two approaches are presently being compared in the ongoing SALTORL trial (GORTEC 2014–03).**

# *For Treatment Intensifcation*

As mentioned earlier, the main question that remained for most clinicians was whether the use of TPF before the cisplatin-based CCRT would lead to survival beneft. The background for that can be found in the individual patient-based metaanalysis (MACH-NC) by Pignon et al., initially published in 2000, but updated in 2009 [75]. In that analysis, a 6.5% 5-year absolute survival beneft was demonstrated for the concurrent chemotherapy/RT approach [75]. No overall survival beneft was observed with the ICT schedules, although a marginal improvement was noticed in trials that made use of the PF combination. Patterns of failure differed between the two approaches. ICT signifcantly improved the rate of distant metastases (HR, 0.73; 95% confdence interval [CI] 0.61 to 0.88; p = .001), but did not infuence locoregional failure. However, CCRT markedly improved locoregional control (HR, 0.74; 95% 0.70 to 0.79; p < .001) with a signifcant but less impressive improvement in distant control (HR, 0.88; 95% CI, 0.77 to 1.00; p = .04). It seemed therefore reasonable to assume that combining both approaches could have a complementary effect on outcome. The fve randomized controlled trials that compared ICT → CCRT versus CCRT alone are summarized in Table 11.6 [53–57]. Four of the fve trials showed no impact of ICT on survival. The Italian study (with two types of concomitant regimens, cisplatin/5-FU + RT or cetuximab + RT) did show a survival beneft, but subgroup analysis did not show beneft for patients who received potentiation with cisplatin and fuorouracil. Two trials had accrual problems and stopped early before reaching the required number of patients, and two studies had diffculties in trial design or trial performance. Therefore, the role of ICT given before CCRT on the basis of these fve trials still remains controversial.

Two meta-analyses on the usefulness of ICT before CCRT in patients with LA-HNSCC concluded that, although ICT reduced the occurrence of distant failures, this did not translate into a signifcant survival beneft [76, 77]. However, the most recent systematic review and Bayesian network meta-analysis, comprising 57 trials and 15,723 patients indicated that IC with TPF was signifcantly superior against CCRT with cisplatin (HR 0.73 95% credible interval [CrI] 0.58–0.92) [78]. Therefore, it seems that over time, more data are pointing at a real value of the TPF regimen when used in addition to cisplatin-based CCRT. **However, as indicated above, individual randomized studies so far have not given an clear answer as to whether ICT is useful for treatment intensifcation in daily practice. Therefore, further positioning of ICT with CCRT as standard treatment for LA-SCCHN will come from more RCTs directly comparing ICT→ CCRT with CCRT in the appropriate patient population.**

**Table 11.6** Randomized trials of induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced HNSCC

*T* docetaxel, *P* cisplatin, *F* 5-fuorouracil, *CCRT* concurrent chemoradiotherapy, *C* carboplatin, *Doce* docetaxel, *Cet* cetuximab, *THFX* docetaxel, fuorouracil and hydroxyurea, *BRT* bioradiation with cetuximab

a PFS and OS were signifcantly better in the ICT arms, but subgroup analysis did not show any beneft for patients who received radiation with cisplatin and 5-FU after TPF

b More severe neutropenia in the ICT arms, other toxicities were not signifcantly different

Results from the DeCIDE trial and the GORTEC 2007–02, showing fewer distant metastases in the ICT arm of the studies, suggest that there still may be patients at very high risk for developing distant metastases who could beneft from ICT. Some improvement in the N-staging in the most recent American joint Committee in Cancer staging system has been made. Features such as low neck nodes and matted nodes (a proxy for extranodal extension) are of interest in that respect. In a retrospective analysis of 321 patients treated with three cycles docetaxel/cisplatin ICT followed by CCRT (weekly cisplatin), Kim et al. reported that lower neck node involvement (level IV, Vb, and supraclavicular regions) (p = 0.008) and poor response to ICT (p < 0.001) were associated with a signifcantly inferior distant metastasis-free survival [79].

In contrast to the patterns of failure seen in p16-negative disease, distant failure constitute a considerable portion of treatment failures in patients with p16-positive disease [80]. The Toronto group, in their analysis, pointed at patients with T4 and N3 disease being at high risk for distant failure. In a retrospective study, comprising patients with p16-positive OPSCC with low-neck (level IV and/or Vb) and/or N3 lymphadenopathy, being at high risk of distant failure, 44 receiving ICT (docetaxel/ platinum w/wo 5-FU) followed by CCRT (43 receiving platinum, 1 cetuximab) were compared with 44 patients receiving CCRT alone (38 receiving platinum, 6 cetuximab) [81]. The median age of the patients in the CCRT group was somewhat

higher (61 vs 56 years, p = 0.02). Disease control and survival outcomes were reported after adjusting for age, T-stage, N-stage and smoking status. A signifcant difference in distant metastases (adjusted HR 0.32, p = 0.02) and PFS (adjusted HR 0.46, p = 0.03) was observed, while OS showed a trend (adjusted HR 0.48, p = 0.09), all in favor of ICT at 3 years [81]. Finally, also protein expression biomarkers of aggressive disease could be of use in identifying patients who could beneft from ICT [82]. Examples are elevated expression of cyclin D1 and GDF15 expression as predictive markers for beneft of TPF, and acetylated tubulin as a marker for sensitivity to taxane chemotherapy [83–85]. There are also indications that excision repair cross-complementing 1 (ERCC1) expression may be of importance [86, 87]. Bišof et al. [86] reported, based on a meta-analysis of 1288 HNSCC patients who had been treated with platinum-based chemotherapy, that ERCC1 might be a predictive and prognostic factor for individualized therapies for HNSCC patients. In a study of 64 patients with oro- and hypoharyngeal cancers, who received PF induction chemotherapy before defnitive local treatment, Hasegawa et al. concluded that ERCC1 was predictive for response to PF and could select those who were candidates for organ preservation [87]. The study included four clinical variables (age, sex, T-class and N-class) and 22 biomarkers which were tested on pretreatment biopsies. In multivariate analysis, next to T-class, ERCC1 expression came forward as the only independent predictive marker for response. The investigators considered that both a DNA repair pathway and an apoptosis pathway are pivotal to the mechanism underlying response to chemotherapy and suggested that further studies on ERCC1 polymorphisms and mutations and assessing apoptotic response associated with p53 activation in HNSCC were needed to clarify genetic associations with response to chemotherapy in HNSCC patients [87].

# *For Borderline Resectable or Unresectable Oral Cavity Cancer*

Oral cavity cancer is one of the most common malignancies worldwide with geographic variation in incidence and mortality [88]. Higher incidence rates are observed in developing countries compared to developed countries. Bangladesh, Pakistan and India have the highest incidence rates of oral cavity cancer where it is the most common cancer in males and the second in females after breast cancer. As result of delay in presentation, most patients in these countries are diagnosed with advanced disease [89]. Surgery is usually the preferred upfront treatment in patients with oral cavity cancer. However, surgical resection cannot be achieved in many cases with advanced disease without major impact on patient's quality of life. The optimal care of these patients is challenging when surgical treatment is not possible. This is nicely summarized in the recent publication by Alzahrani et al. [89].

The role of induction chemotherapy in patients with resectable oral cavity cancer has been tested in two RTCs and both trials showed a negative outcome [90–92]. Licitra et al. [90] reported on 195 patients with resectable oral cavity cancer (stage T2-T4 (>3 cm), N0-N2, M0), who were randomized to receive three cycles of PF before surgery versus surgery alone. High-risk patients (positive resection margins, extracapsular nodal spread, nodal disease [N2 or N3], vascular invasion, or perineural invasion) underwent adjuvant RT. There were three toxic deaths in the chemotherapy arm, but ICT did not lead to an improvement in OS (at 5 years 55% in both arms), locoregional relapse or distant failure. An update of this study with a median follow-up of 11.5 years showed similar results with regard to clinical outcomes [91]. Interestingly, in the late follow-up of the patients in this trial, the control group showed a higher incidence of fbrosis (40% vs 22% in chemotherapy arm) and more grade 2 dysphagia (14% versus 5% in the chemotherapy arm), which the authors ascribed to less extensive surgery carried out in the chemotherapy group (31% versus 52% in control group) and less patients receiving postoperative RT (33% versus 46% in control group). Zhong et al. [92] randomized 256 patients with stage III or IVA oral squamous cell cancer to receive 2 cycles of TPF followed by surgery and adjuvant RT or surgery and adjuvant RT alone, again showing no difference in survival. A recent meta-analysis of individual patient data of these earlier mentioned two studies confrmed the lack of clinical beneft from ICT [93]. Contrary to that, for cN2 patients, an OS beneft was found in favor of ICT (p = 0.04)**. Taken together, it can be concluded that there is no evidence for routine use of ICT in resectable oral cavity cancer.**

The main goal of using induction chemotherapy before surgery is to convert borderline resectable disease or clearly unresectable disease to technically resectable disease. Although there are no randomized trials to prove this concept, there are studies, most of them coming from India (not surprising with 64% of patients have clinical stage IV disease versus 2.2% in the US), that lead to the same conclusion, i.e. about 30% will become resectable, and patients in whom this is possible will do better than those in whom this not possible [94–98]. Similar results have been reported by our colleagues in Taiwan [99]. Extension of the tumor to the base of skull, prevertebral muscles and encasement or invasion of the carotid artery are absolute contraindication to surgery. In addition, Patil et al. [96] adopted criteria specifcally for oral cavity cancer. These include: (1) buccal mucosa primary with diffuse margins and peritumoral edema, going up to or above the level of zygomatic arch and without any satellite nodules, (2) tongue primary (anterior two-thirds) with the tumor extending up to or below the level of the hyoid bone, (3) extension of tumor of anterior two-thirds of the oral tongue to the vallecula, (4) extension of tumor into the high infratemporal fossa, as defned by extension of tumor above an axial plane passing at the level of the sigmoid notch, and (5) extensive skin infltration impacting the achievement of negative margin. The Indian studies mentioned above are summarized in Table 11.7. Febrile neutropenia in some of these studies was reported to be a major problem. **Nevertheless, according to in particular our Indian colleagues, who see these far advanced stages of disease much more frequently than we do in the higher income countries, ICT may be considered in patients with unresectable or borderline resectable oral cavity cancers, as it may increase the chance of resectability and subsequently might improve outcomes.**

**Table 11.7** Induction chemotherapy in unresectable/borderline resectable locally advanced OSCC\*

*OSCC* oral squamous cell carcinoma, *TPF* docetaxel/cisplatin/5-FU, *TP* taxane/platinum, *mOS* median overall survival, *NST* nonsurgical treatment, *LRCT* locoregional control, *Resect*. resectable, \*Patil's criteria

# *As a Selection Tool for RT Dose de-Escalation in HPV-Positive OPSCC*

Treatment of patients with HPV-positive OPSCC is rapidly evolving and challenging the standard of care of defnitive RT with concurrent cisplatin [100]. Several de-escalation approaches are under study, among which are radiation alone instead of radiation combined with cisplatin, radiation combined with cetuximab instead of radiation combined with cisplatin, transoral surgery followed or not by postoperative RT and ICT followed by decreased radiation dose and/or volumes for good responders. In the latter setting, ICT is used as a tool to stratify patients by treatment response. De-escalation approaches are getting major attention in patients with locoregionally advanced OPSCC, because these patients have overall a better prognosis and if treated curatively with current standard treatment (CCRT), are confronted with possible long-term toxicity issues, such as feeding tube dependency ≥2 years post RT, pharyngeal dysfunction (dysphagia), laryngeal dysfunction, mucositis, or other toxicities (e.g. infection, fstula, weight loss etc). Three US trials have reported on ICT approaches, i.e. ECOG 1308 (NCT 01084083), the Quarterback trial (NCT 01706939) and the OPTIMA HPV trial (NCT 02258659).

ECOG 1308 was a single arm phase II study in which patients with HPVassociated OPSCC (the majority having T1-3N0-N2b disease and a history of ≤10 pack-years of smoking) were treated with three cycles paclitaxel, cisplatin and cetuximab, followed by cetuximab concurrently with intensity-modulated radiation therapy (IMRT). The purpose of the study was to evaluate whether a clinical CR to ICT could select patients for reduced radiation dose as a means of sparing late sequelae [101]. Patients with CR at the primary received a reduced RT dose (54 Gy instead of 69.3 Gy). Involved lymph nodes received 69.3 Gy unless they also were judged to have completely responded. The primary end point was 2-year PFS. Of the 90 patients enrolled, 80 were evaluable and 77 received three cycles of ICT. Fiftysix patients (70%) had a CR to the ÌCT at the primary site and 51 patients continued

to cetuximab with IMRT 54 Gy. At a median follow-up of 35.4 months, the 2-year PFS and OS rates were 80% and 94% among those 51 patients. These fgures were most promising (96% and 96%, respectively) for the more favorable group of patients (i.e. having <T4, < N2c and ≤ 10 pack-years of smoking). At 12 months, signifcantly fewer patients treated with the reduced RT dose had diffculty swallowing solids (40% v 89%; P = .011) or had impaired nutrition (10% v 44%; P = .025). The authors concluded that a reduced-dose IMRT with concurrent cetuximab was worthy of further study in favorable-risk patients with HPVassociated OPSCC.

The Quarterback trial, a phase III trial in patients with locally advanced p16 positive OPSCC and ≤ 20 pack years smoking, made use of three cycles of the American TPF regimen and clinical responders who were HPV-positive by typespecifc PCR were randomized 1:2 to standard-dosed (sd) IMRT (70 Gy) or reduceddosed (rd) IMRT (54 Gy), both combined with weekly carboplatin at AUC 1.5. The endpoints of the study were 3-year PFS and OS. The planned number of patients was 365 with 240 in the experimental arm. The original statistical plan was revised because of poor accrual. The trial terminated after 20 evaluable patients were randomized and treated (8 with sdCCRT and 12 rdCCRT). Sixteen (80%) were HPV16 positive and 4 (20%) had other high-risk (HR) variants. Fourteen (70%) had high risk features: T4, N2c, or N3. Median follow up was 56 months (range 42–70). Three-year PFS/OS for sdCCRT and rdCCRT were 87.5% vs 83.3% (log-rank test, p = 0.85), respectively. All three failures were locoregional within 4 months of completion of CCRT, 2 were in HR variants. As mentioned by the authors, the small sample size limits the interpretation of the outcome, but the study supports the potential clinical beneft of radiation dose reduction after ICT as a treatment strategy [102].

In the OPTIMA HPV trial, patients were classifed as low-risk (LR) (≤T3, ≤N2B, ≤10 pack year history) or high-risk (HR) (T4, ≥N2c, >10 pack year history). Patients received ICT of three cycles of dose dense carboplatin and nab-paclitaxel. LR patients with 50% response received 50 Gray (Gy) RT (RT50) while LR patients with 30%–50% response or HR patients with 50% response received 45 Gy CCRT (CCRT45). Patients with lesser response received standard-of-care 75 Gy CCRT (CCRT75). The primary end point was 2-year progression-free survival compared with a historical control of 85%. Secondary end points included overall survival and toxicity. Sixty-two patients (28 LR/34 HR) were enrolled [103]. Of the LR patients, 71% received RT50 while 21% received CRT45. Of the HR patients, 71% received CRT45. With a median follow-up of 29 months, 2-year PFS and OS were 95% and 100% for LR patients and 94% and 97% for HR patients, respectively. The overall 2-year PFS was 94.5% and within the 11% non-inferiority margin for the historical control. Grade ≥ 3 mucositis occurred in 30%, 63%, and 91% of the RT50, CCRT45, and CCRT75 groups, respectively (P = 0.004). Rates of any PEG-tube use were 0%, 31%, and 82% for RT50, CCRT45, and CCRT75 groups, respectively (P < 0.0001) [103]. This decreased over time, being at 12 months 0%, 4% and 9%, respectively. Updated information was presented at ASCO 2020, now including 107 patients that were treated according to the same lines and now with a median follow-up of

36 months [104]. Overall, 94% of patients were alive at last follow-up (98% LR; 89% HR). Three patients developed a recurrence (2 HR and 1 LR); 2 local and 1 at distance. This OPTIMA approach demonstrated excellent oncologic and functional outcomes with long-term follow-up.

**Despite these promising results, clinicians should refrain from de-escalation approaches outside clinical trials for this moment, because the safety of these approaches are still unclear. This has been reinforced by unexpected negative outcomes of two RCTs, in which cetuximab plus RT was compared with the standard-of-care cisplatin-based CCRT in p16-positive OPSCC** [105, 106]**.**

# *Oligometastatic Disease*

Another area of potential interest for the applicability of induction chemotherapy is oligometastatic disease. It is estimated that 5–47% (mean 15%) of patients will have distant metastases during the course of the disease [107]. The Surveillance Epidemiology and End Results (SEER) database revealed that 19% of patients with oral cavity or pharynx cancer presented with distant metastases at diagnosis [108]. The most common site of metastases from HNSCC is the lung accounting for up to 70% to 85%, followed by metastases to the bone (up to 20%) and liver (up to 10%). Other organs such as the brain, mediastinum, skin and bone marrow occur even more rarely [109]. There are different defnitions of oligometastases for different cancers, but a consensus defnition is fve or fewer sites of metastatic disease [109]. Patients with oligometastatic HNSCC can be divided in two groups; (1) those who present with metastatic disease at initial diagnosis, i.e. synchronous distant metastases, and (2) those who have developed the metastatic lesions during their surveillance after their defnitve treatment, the so-called metachronous distant metastases, with or without locoregional disease relapse.

Considering all patients with metastatic HNSCC as one group that should be treated with systemic therapy for palliation might not be correct. The contemporary standard of care systemic therapies result in a median survival of 10.1 to 13.6 months and it is unclear yet whether the treatment with immune checkpoint inhibitors will lead to cure [40, 110]. However, metastatic disease in HNSCC covers a wide range of disease presentations, depending not only on the site from which these metastases are originating, but also on the tumor biology and kinetics, whereby metastatic disease may vary from widely disseminated disease to oligometastatic disease.

Oligometastatic disease is a moving concept not only defned by its phenotypic metastatic burden but also by the ability to perform metastatic-directed treatments [107]. Advances in minimally invasive surgery and whole body stereotactic hypofractionated radiation therapy have opened an avenue to treat metastases in a safe, well-tolerated and relatively cost-effective manner. In a retrospective series from Germany, the authors noted a signifcant survival beneft for HNSCC patients who

received a specifc therapy regarding distant metastases irrespective of localization as compaired to a matched control cohort [111]. An analysis of patients with metastatic HNSCC in the National Cancer Database (NCDB) revealed that the patients who received high-intensity local treatment (defned as radiation doses ≥60 Gy or oncologic resection of the primary tumor) and systemic therapy had a 13% improvement in 2-year overall survival(OS) compared to patients receiving systemic therapy alone [112]. It is beyond the scope of this chapter on induction chemotherapy to discuss extensively the treatment of oligometastatic disease and the participation of local therapies therein. Suffce to say that currently, due to the lack of randomized but also suffciently powered prospective trials, no frm recommendations can be given on how to optimally treat oligometastatic disease. However, ablative techniques have already penetrated into routine clinical practices in high-volume centers [113].

The role of induction chemotherapy in this context is primarily concerning synchronous metastatic disease at frst diagnosis. Singular cases can be found in the literature were upfront chemotherapy is given with curative intent. Therefore strategies combining induction chemotherapy and upfront metastasis-directed treatments prior to locoregional therapy for the primary tumor can be anticipated [82].

# **Where to Use Induction Chemotherapy**

Toxicity is an issue of ICT, in particular when there is not much experience with the contemporary ICT regimens. With the European TPF regimen, as given in TAX 323/EORTC 24971 [44], i.e. with prophylactic antibiotics [ciprofoxacin from day 5–15] in each cycle and dexamethasone given before the start of each cycle to prevent docetaxel-related hypersensitivity reactions, skin toxicity and fuid retention, common (≥5%) grade 3–4 adverse events included: neutropenia (76.9%), leukopenia (41.6%), alopecia (11.6%), anemia (9.2%), infection (6.9%), febrile neutropenia (5.2%) and thrombocytopenia (5.2%). 6.2% of patients discontinued treatment due to adverse events and there were 2.3% toxic deaths. With the American TPF, as given in TAX 324 [43], premedication, prophylactic antibiotics and dexamethasone were given in the manner as in TAX 323/EORTC 24971, common (≥5%) grade 3–4 adverse events included: neutropenia (83%), stomatitis/mucositis (21%), nausea (14%), dysphagia (13%), anemia/febrile neutropenia/neutropenia infection/anorexia (each 12%), vomiting (8%), diarrhea (7%), infection (6%), and lethargy [5]. 6% of patients discontinued treatment due to adverse events related to treatment and there <1% deaths due to toxic effect of study medication.

Crucially in the safe use of TPF regimens is that it is being administered by experienced oncologists, familiar with the necessary protocols and supportive care requirements to ensure patient safety and maximize adherence throughout the treatment [114]. Adequate fuid management, especially on days 1–2 during TPF administration is crucial in preventing renal toxicity, hypovolemia, and severe fatigue. Discussing the patient in multidisciplinary team (MDT) meetings is strongly advised, considering also additional matters such as patient's psychological and nutritional status, potential for palliative care, addiction services, and speech therapy. The importance of MDT meetings have been extensively discussed during THNO-5 [115]. MDT meetings have emerged as a practical necessity for optimal coordination among health professionals and clear communication with patients, and increasingly more attention is paid to psychological aspects, quality of life, patient's rights and empowerment, and survivorship. Moreover, it has become more and more clear that treatment in higher volume centers, and experience of the center in trial participation correlate with outcomes [116, 117].

# **Conclusions**

For more than 10 years the PF regimen has been replaced by the TPF regimen as the standard ICT regimen [43, 44]. ICT has an established role for organ preservation in advanced laryngeal and hypopharyngeal cancer and the TPF regimen has been validated in that setting. There remains uncertainty about the beneft of the sequential approach of ICT followed by CCRT, despite the fact that ICT signifcantly reduces the occurrence of distant metastases. It seems therefore appropriate to further study ICT in patients who have the highest risk to develop distant metastases, in particular patients with low neck nodes and matted nodes. Moreover, further studies in patients with HPV-associated OPSCC at risk for distant failure (T4 or N3 disease) could be considered for that also. Retrospective data from India suggest that ICT may play an important role in converting borderline resectable disease or clearly unresectable disease to technically resectable disease. Therefore, larger randomized trials in patients with borderline resectable cancer of the oral cavity are needed to establish the beneft of induction chemotherapy in this setting. Data are available that suggest that ICT can be used as a tool to select HPV-associated OPSCC patients for dose and volume de-escalation of RT, and retaining excellent oncologic and functional outcomes. These approaches still need to be confrmed in adequately sized clinical trials. Outside clinical trials, the utility of ICT is restricted to uniquely pragmatic clinical scenarios, such as unavoidable delay in radiation or in the situation that RT is not tolerated or feasible. This can happen when there is severe pain from advanced disease or there is impending airway compromise or neurologic dysfunction that necessitates rapid initiation of treatment [82]. Future areas of research are the role of ICT in strategies whereby ICT is combined with upfront metastases-directed treatments, the usefulness of targeted agents or immune checkpoint inhibitors in the induction setting; studies in that direction have started. Finally, the application of radiographic, proteomic and genomic biomarkers will get attention to further defne prognostic groups and guide treatment selection with greater precision.

# **References**

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 12 Prognostic Role of p16/HPV in Nonoropharyngeal Head and Neck Squamous Cell Cancer (HNSCC)**

**Stavros Gkolfnopoulos, Panagiota Economopoulou, and Amanda Psyrri**

# **Introduction**

HPV infection has been established as an etiologic and prognostic factor for a subset of oropharyngeal squamous cell carcinoma (OPC) with distinct clinical and pathologic characteristics [1]. Also established is that the expression of p16/INK4A gene correlates with HPV infection in the oropharynx and, consequently, the product of this gene, detected with immunohistochemistry (IHC), can be used as a surrogate biomarker for HPV-related OPC [2]. This information is vital for properly staging HPV(+) OPC, for determining the prognosis of the disease, and for implementing de-intensifcation strategies in the context of clinical trials. On the contrary, conficting evidence exists regarding the role of p16/HPV as a biomarker in non-OPC head and neck cancer, more specifcally for oral, for laryngeal and for hypopharyngeal primaries. Most of the relevant data are inconsistent and derive from retrospective and heterogeneous series of patients. Herein, a brief review of the existing information regarding the utility of p16 as a surrogate marker for HPV in non-OPC HNSCC is presented, and the potential prognostic role of p16/HPV in non-OPC primaries is analyzed.

Medical School, National and Kapodistrian University of Athens, Athens, Greece

S. Gkolfnopoulos · P. Economopoulou

Oncology Section, 2nd Department of Internal Medicine-Propaedeutic, University General Hospital "Attikon", Chaidari, Greece

A. Psyrri (\*)

Oncology Section, 2nd Department of Internal Medicine-Propaedeutic, University General Hospital "Attikon", Chaidari, Greece

J. B. Vermorken et al. (eds.), *Critical Issues in Head and Neck Oncology*, https://doi.org/10.1007/978-3-030-63234-2\_12

# **HPV Life Cycle**

HPV is a small, non-enveloped, double-stranded DNA virus that encodes a total of 8–9 proteins in approximately 8000 base pairs and has the ability to infect cutaneous or mucosal tissues. The viral genome consists of three distinct regions that have specifc functional properties. The early (E) region encodes proteins regulating viral transcription (E2), viral DNA replication (E1, E2), cell proliferation (E5, E6, E7), and viral particle release (E4). E6 and E7 viral oncogenes also encode proteins associated with malignant lesions that are capable of immortalizing primary human keratinocytes. The continuous expression of E6 and E7 is crucial in maintaining the cancer phenotype in infected cells, as repression of their expression reverses the malignant phenotype of HPV(+) cancer cells. The late (L) region encodes for two structural viral capsid proteins (L1 and L2). Finally, the long control (LCR) or noncoding region (NCR) regulates viral gene expression and replication [3].

HPV has a complex gene expression that requires a synchronization of transcription, mRNA stability, splicing, and polyadenylation with keratinocyte differentiation and distinct phases of the viral life cycle. The life cycle of HPV is directly related to the cellular differentiation program of the host cell. In the initial phase of the HPV life cycle, keratinocytes of the basal cell layer are infected by the virus that has passed through the above epidermal barrier through erosions and microwounds. For effcient establishment of infection from the high-risk subtypes it is vital that they infect actively dividing basal, or stem epithelial cells. Initial infection is followed by a phase of viral genome amplifcation; subsequently, the viral genome is maintained as an extrachromosomal circular element, known as episome, at a low copy number. Alternatively, it can be integrated into the host-cell genome. This integration usually occurs downstream of the early genes E6 and E7, often in the E1 or E2 region. HPV uses the host cell replication machinery to initiate viral DNA replication. In the case of high risk HPVs, proteins E6 and E7 promote cell-cycle progression and viral DNA replication in differentiated keratinocytes as they move towards the surface epithelium. As a result, HPV DNA replicates in a high copy number in differentiated cells located near the epithelial surface. Both E7 and E6 have a vital role in manipulating the cellular replication mechanisms in order to create the optimal environment for viral genome replication. Viral protein E6 is required for episomal genome maintenance, while E7 forces the infected cell to re-enter S-phase. The integration of HPV DNA into the host genome disrupts the expression of the main viral transcription/replication factor E2, which acts as transcriptional repressor of E6 and E7 viral oncogenes. Furthermore, the E6 protein causes degradation of the p53 tumor suppressor protein via a ubiquitin-mediated process, while the HPV-E7 protein binds cullin 2 ubiquitin ligase complex and ubiquitinates the retinoblastoma (Rb) tumor suppressor protein. Consequently, the p53 and pRb tumor suppressor pathways are dormant but active in cancer cells due to the continuous expression of E6 and E7 oncogenes. Degradation of Rb induces expression of p16INK4A, which is the hallmark of HPV(+) OPC. pRb downregulates p16 protein at the transcriptional level and low pRb levels, inversely, lead to p16 upregulation. This is the reason why HPV-associated cancers contain high p16 protein levels. The fnal stage of the life cycle of HPVinvolves the exit from the cell and the expression of late viral proteins L1 and L2 to enable packing of the viral genome [4].

# **Risk Factors for HPV(+) Non-OPC**

HPV(+) OPC has distinct risk factors that are different from the common risk factors of HPV(−) OPC, e.g. excessive exposure to tobacco and alcohol.  It is, however, unclear, whether these same demographic variables apply for HPV(+) non-OPC as well.

To our knowledge, there is only one study that has tried to answer that query. In a multicenter, case-control study of SCCs called the Papillomavirus Role in Oral Cancer Viral Etiology study (PROVE), Windon et al. have discovered that HPV(−) non-OPC patients were more likely to be ever smokers than HPV(+) OPC (n = 185, OR 3.28, 95%CI 1.10–10.2). Also, compared with their HPV(+) OPC counterparts, HPV(+) non-OPC were less likely to have had over 3 oral sexual partners (OR 0.29, 95%CI 0.06–0.9), more likely to have multimorbidity (OR 3.30, 95%CI 1.04–10.5), and less likely to have antibodies to HPV16 E6 (90% vs 28%, OR 0.05, 95%CI 0.02–0.2). Although this was a small study, it provided potential evidence that HPV is not an adequate factor to promote carcinogenesis in non-OPC sites, in contrast to OPC, but rather a second hit of chemical-induced carcinogenesis is required for cancer progression in these cases, as it also happens in HPV(−) HNSCC [6].

# **p16 as a Surrogate Biomarker for a Transcriptionally Active HPV Infection in Non-OPC**

The gold standard for determining that HPV is actively contributing to the oncogenic process in OPC is the detection of the E6/E7 viral oncogene expression through quantitative reverse transcriptase–PCR (qRT-PCR) [3, 4]. Detection of HPV mRNA, however, in formalin-fxed paraffn-embedded (FFPE) tissue has variable sensitivity depending on the quality of the clinical sample. Moreover, many HPV(+) patients identifed in the next-generation sequencing study by Parfenov et al. had low levels of E6/E7 expression and could be misclassifed by E6/E7mRNA detection [7]. A method that is commonly used is HPV DNA detection by either in situ hybridization (ISH) or polymerase chain reaction (PCR) [2]. DNA ISH can differentiate between integrated and episomal forms of HPV in tumors but lacks sensitivity. HPV DNA PCR is a sensitive method for determination of HPV status but it lacks specifcity. HPV DNA presence in tumors per se cannot prove causality, as HPV is ubiquitously present in humans. Also, as has already been mentioned, the detection of p16 protein expression by IHC staining is used as a surrogate marker of oncogenic HPV infection. A negative autoregulatory loop between p16 and pRb has been described and degradation of pRb by HPVE7 oncoprotein leads to p16 upregulation in HPV(+) cancers [8]. p16 IHC followed by PCR for HPV DNA detection in p16(+) cases has been proposed as a reliable algorithm for determination of HPV status in paraffn-embedded OPC specimens. p16 protein expression, however, is not a reliable surrogate biomarker for HPV infection outside the oropharynx.

Using these methods, it has been found that in OPC, HPV positivity ranges between 57% and 72%, with the variation attributed to differences in assay selection and study populations [9–11]. In addition, a high concordance rate of approximately 90% is noted between HPV ISH and p16 IHC in OPC, and this is partly a result of the high rates of active and persistent HPV infection in this site [12].

In non-OPC sites, however, the rates of active HPV infection are substantially lower, as only 1.3% to 7% of non-OPCs, including cancers of the oral cavity, hypopharynx, and larynx, are HPV positive [13–15]. Similarly, the concordance rates between these two methods of HPV detection also seem to be lower. For example, in oral cavity squamous cell cancer, sensitivity of p16 IHC compared with high-risk HPV E6/E7 mRNA expression is 79%, specifcity is 93%, positive predictive value (PPV) is 41%, and negative predictive value is 99% [14].

Harris et al. examined biomolecular profles in a cohort of 25 young adults with squamous cell cancers (SCCs) of the oral tongue diagnosed between 1989 and 2007. Median age at diagnosis was 30 years (range: 20–39 years). Patients with non-squamous histology, prior history of malignancy and distant metastatic disease at presentation were excluded. Further demonstrating the discrepancy between p16 expression and HPV DNA positivity in non-OPC, p16 overexpression was observed in 11 of 25 patients, whereas HPV-16 DNA positivity was observed in none of the tumor samples by ISH and 2 of the tumor samples by PCR. Interestingly, neither of these HPV DNA(+) patients were found to be p16(+) as well. In this study, p16INK4a positivity was correlated with improved relapse-free survival (HR = 0.23, p = 0.01) and overall survival (OS) (HR = 0.28, P = 0.05). In this trial p16 positivity was correlated with favorable prognosis, while p16INK4a overexpression was not a reliable predictor of HPV positivity. The authors concluded that a mechanism alternative to HPV infection that is leading to p16 positivity may exist in this particular subset of tumors, and that p16INK4a status is the truly important prognosticmarker in HNSCC, independent of HPV infection. However, the small cohort size and the selected patient populationare serious limitations for generalization of these results [16].

Furthermore, in a study by Chung et al. p16 expression and high-risk HPV status in non-OPCs from RTOG 0129, 0234, and 0522 studies were determined by IHC for p16 and HPV DNA ISH for high-risk HPV DNA. A total of 683 eligible patients with non-OPSCC tumors, including primary sites in the oral cavity, hypopharynx, and larynx, were identifed among the 1921 patients enrolled onto the abovementioned trials. Tumors from 356 (52.1%) of 683 patients with non-OPSCC were tested for p16 expression, which could be determined in 90.4% (322 of 356) of the

tumors. HPV status could be determined in 95.5% (297 of 311). Overall, 19.3% (62 of 322) of non-OPC were p16 positive and 9.4% (28 of 297) were HPV ISH positive. p16 expression was positive in 14.1% (12 of 85), 24.2% (23 of 95), and 19.0% (27 of 142) and HPV ISH was positive in 6.5% (six of 93), 14.6% (15 of 103), and 6.9% (seven of 101) of non-OPCsfrom RTOG 0129, 0234, and 0522 studies, respectively. Cancer of the oral cavity had the highest rate of p16 positivity (21 [26.3%] of 80), followed by the larynx (31 [17.1%] of 181) and hypopharynx (10 [16.4%] of 61). Also, cancer of the oral cavity had the highest rate of HPV ISH positivity (13[14.6%] of 89), followed by the larynx (12 [7.9%] of 151) and hypopharynx (three [5.3%] of 57). HR for p16 expression were 0.63 (95% CI, 0.42 to 0.95; P = 0.03) and 0.56 (95% CI, 0.35 to 0.89, P = 0.01) for progression-free (PFS) and OS, respectively. Poor concordance was observed between p16 and HPV ISH among the subsites of the oral cavity, hypopharynx, and larynx, where oral cavity tumors had the worst concordance. Although this trial also showed that patients with p16-negative non-OPC have worse outcomes than patients with p16-positive non-OPC, HPV status was not found to be prognostic, so once again it was demonstrated that p16 was not a good surrogate biomarker for HPV positivity [17].

Finally, in a retrospective study of 409 cases of oral cavity SCC treated at 4 North American Hospitals, ffteen high-risk HPV types were detected in tumors by consensus PCR followed by type-specifc HR-HPV E6/7 oncogene expression by quantitative reverse-transcriptase PCR. P16 expression was evaluated by IHC. Twenty-four (5.9%) were high-risk HPV E6/7 expression positive; 3.7% (95%CI 1.8–5.5) for HPV16 and 2.2% (95%CI 0.8–3.6) for other high-risk HPV types. HPV(+) tumors originated from throughout the oral cavity (foor of mouth [n = 9], anterior tongue [6], alveolar process [4], hard palate [3], gingiva [1] and lip [1]) and were signifcantly correlated with male gender, small tumor stage, poor tumor differentiation, and basaloid histopathology. In this trial, p16 IHC had very good-to-excellent sensitivity (79.2%, 95%CI 57.9–92.9), specifcity (93.0%, 95%CI 90.0–95.3), and negative-predictive value (98.6%,95%CI 96.8–99.6), but poor positive-predictive value (41.3%, 95%CI 27.0–56.8) for HR-HPV E6/7 expression in oral cavity SCC [14].

Conclusively, the data at our disposal suggest that p16 is a poor surrogate marker for transcriptionally active HPV infection in non-OPC sites.

# **p16/HPV as a Prognostic Factor in Non-OPC**

In addition to the above-mentioned studies, several other trials have attempted to elucidate the prognostic role of p16 and/or HPV status in non-OPC disease sites. Young et al. evaluated a cohort of 324 laryngeal SCC patients for the expression of p16 by IHC and for high-risk HPV E6 and E7 mRNA transcripts by RNA ISH. The median age of patients at diagnosis was 66 years (range 36–88 years). Males comprised 94% of the patients, with 95% being current or former smokers. p16 expression and HPV status were correlated with clinicopathological features and outcomes. In this trial, 6.5% of the patients were p16(+) and only 7 cases were HPV RNA(+), all of which were also p16 IHC positive. There was no difference in OS between p16-positive and p16-negative patients with 2-year survival of 79% in each group (HR = 0.83, 95% CI 0.36–1.89, P = 0.65). Also, no statistically signifcant difference in OS was found between patients with HPV RNA ISH-positive tumors compared with ISH-negative tumors with 2-year survival of 86% and 71%, respectively (HR = 0.76, 95% CI 0.23–2.5, P = 0.65). The most signifcant strength of this study is the large cohort consisting of a single site of head and neck cancer only, namely the larynx, while its major limitation is its retrospective nature. The researchers concluded that p16 overexpression in laryngeal cancer is infrequent as are the proportion of cases with high-risk HPV transcripts, and there are no statistically signifcant correlations with survival outcomes [18].

Furthermore, in a retrospective, multi-institution study by Fakhry et al. 239 patients with OPC and 621 patients with non-OPC of the oral cavity, larynx, and nasopharynx, diagnosed from 1995 to 2012, were centrally tested for p16 and HPV by HPV16 DNA and high-risk HPV E6/E7mRNA ISH. The prevalence of HPV(+) tumors among cancers of the oropharynx, oral cavity, larynx, and nasopharynx was 56%, 2%, 5%, and 10%, respectively. The tumor HPV status and p16 were not of prognostic signifcance in HNSCCs of the oral cavity (n = 253; P = 0.22), larynx (n = 243; P = 0.72), or nasopharynx (n = 125; P = 0.23). Also, the study did not fnd any correlation of p16 with OS for non-OPC (P = 0.26) [19].

Also, D′ Souza et al. analyzed data from 1362 HNSCC cases diagnosed between 2002–2011 and registered in epidemiologic studies in Brazil (GENCAPO study, n = 388), U.S. (CHANCE study, n = 472), and Europe (ARCAGE study, n = 502). Tumors were centrally tested for p16 and HPV16 DNA by PCR. In total, 517 OPC and 845 non-OPC cases (397 laryngeal, 382 oral cavity, and 66 hypopharyngeal SCC) were identifed. Although HPV-related OPC had similar survival benefts across these three regions, among non-OPC, neither p16 (aHR = 0.83, 95%CI = 0.60–1.14), HPV16 DNA (aHR = 1.20, 95%CI = 0.89–1.63), or p16(+)/ HPV16(+) (aHR = 0.59, 95%CI = 0.32–1.08) were statistically signifcant predictors of mortality. The researchers concluded that the prognostic utility of HPV among non-OPC patients is limited and, although cases with dual p16 and HPV positivity appeared to have better outcome, tumor HPV/p16 testing should not be routinely done in non-OPC [20].

In addition, Lassen et al. analyzed retrospectively p16 expression via IHC in a cohort of 1294 patients enrolled in previously conducted DAHANCA-trials between 1992 and 2012. The study included patients with stage III–IV pharynx and larynx cancer treated with primary CRT. Thirty-eight percent (490/1294) of the tumors were p16-positive with a signifcantly higher frequency in OPC (425/815) than in non-OPC (65/479) (p < 0.0001). As expected, in OPC p16-positivity correlated with signifcantly improved locoregional control (LRC), event-free survival (EFS) and OS. However, in non-OPC no prognostic impact of p16-status was found for either endpoint: LRC (HR = 1.13 [0.75–1.70]), EFS (HR = 1.06 [0.76–1.47]), and OS (HR = 0.82 [0.59–1.16]). This trial further suggests that, in non-OPC sites, p16 positivity is rare and does not carry any prognostic signifcance [21].

On the contrary, results from a retrospective analysis of 19,993 non-OPC patients registered in the National Cancer Data Base (NCDB), of whom 5070 were positive for HPV via PCR, revealed that OS was signifcantly higher for patients with HPV(+) versus HPV(−) non-OPC, and that the robust survival advantage of HPV was maintained in all subsites. Improved outcomes were more pronounced in patients with locally advanced compared to early stage disease. The main limitation of this trial is that, since routine HPV testing in non-OPC is not standard of care, selection bias must exist in the data set. Therefore, factors driving the decision to test for HPV status may be contributing to the improved outcomes of the HPV(+) non-OPC cohort [22].

Moreover, high-risk HPV positivity was associated with OS in certain non-OPC primaries in a large analysis of 24,470 patients diagnosed with HNSCC between 2010 and 2013 who had been registered in the NCDB. Of these patients, 9907 patients had been diagnosed with non-OPC SCCs: 1085 with SCC of the hypopharynx, 4804 with SCC of the larynx, and 4018 with SCC of the oral cavity. The rate of high-risk HPV positivity for those patients varied by primary tumor site: 17.7% of patients with SCCs of the hypopharynx were high-risk HPV(+), as were 11% and 10.6%, respectively, of those with SCCs of the larynx and oral cavity. HPV status was found to be prognostic in multiple unadjusted and propensity-adjusted non-OPC populations. HPV positivity was associated with superior OS in patients with hypopharyngeal SCC with a HR of 0.61 (P < 0.001), in patients with AJCC stage III to IVB laryngeal SCC (HR = 0.79; P = 0.019), and in patients with AJCC stage III to IVB SCC of the oral cavity (HR = 0.78; P = 0.03). However, as the researchers themselves have pointed out, there are certain serious limitations in this trial. First of all, the results of this trial derive from retrospective, administratively collected data. Then, important information such as patterns of response/failure to treatment, salvage therapies, cause of death and smoking status are not captured by NCDB. Finally, the method of testing is not prespecifedby the NCDB, so HPV testing wasperformed as part of clinical care and was, therefore, heterogeneous. The results of this study, therefore, should be interpreted with caution [23].

# **Conclusions**

The studies evaluating the prognostic impact of HPV infection in non-oropharyngeal head and neck cancers have shown conficting results (Table 12.1). Variations in sample sizes, geography, the method of HPV detection and other factors may have contributed to this fact. It seems that p16 is a poor surrogate biomarker for oncogenic HPV infection for non-OPC disease sites. The majority of studies so far suggest that the prognostic impact of HPV positivity is reserved for the oropharynx, so routine HPV testing is not recommended for other sites.

**Table 12.1**Clinical Trials investigating the prognostic role of p16/HPV in non-OPC

oropharyngeal cancer; *NCDB* National Cancer Data Base

# **References**

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 13 Is there a Role for Neoadjuvant Targeted Therapy and Immunotherapy?**

**Simon Beyaert and Jean-Pascal Machiels**

# **Abbreviations**

# **Introduction**

The role of induction or neoadjuvant therapy to treat locally advanced squamous cell carcinoma of the head and neck (SCCHN) is controversial [1, 2]. Standard treatment remains concomitant chemoradiation with high-dose (100 mg/m2 ) cisplatin when a non-surgical approach is preferred [1, 2]. The only recognized indication for induction chemotherapy is larynx preservation, and the oncological outcome is similar to that of concomitant chemoradiation in this particular setting [3]. Taxane/ platinum/5-Fluorouracil (TPF) combinations have proven to be superior to

J.-P. Machiels (\*)

S. Beyaert

Institut de Recherche Expérimentale et Clinique (Pôle MIRO), Université Catholique de Louvain (UCLouvain), Brussels, Belgium e-mail<EMAIL_ADDRESS>
Institut de Recherche Expérimentale et Clinique (Pôle MIRO), Université Catholique de Louvain (UCLouvain), Brussels, Belgium

Service d'Oncologie Médicale, Institut Roi Albert II, Cliniques universitaires Saint-Luc, Brussels, Belgium e-mail<EMAIL_ADDRESS>
platinum/5-fuorouracil schedules, and TPF is therefore now the accepted standard for induction [4, 5].

In this chapter, we review if there is a role forneoadjuvant targeted therapy or immunotherapy in the treatment of SCCHN. We discuss two different approaches: neoadjuvant or induction studies and window of opportunity trials.

# **Induction Therapy with Targeted Therapy and Immune Checkpoint Inhibitors**

In a neoadjuvant or induction approach, the defnitive standard treatment (i.e. surgery or (chemo)radiation) is delayed to allow enough time for the neoadjuvant agent(s) to produce a therapeutic response and improve overall treatment effcacy. In this setting, the use of drugs targeting the epidermal growth factor receptor (EGFR) has been largely investigated in combination with chemotherapy.

Three trials have studied the safety and feasibility of combining cetuximab with TPF [6–8]. Specenier et al. investigated four cycles of TPF plus cetuximab (TPF-E) (cisplatin and docetaxel 75 mg/m2 on day 1 followed by 5-fuoruracil (5-FU) 750 mg/m2 /day as a continuous infusion on days 1–5 plus cetuximab at a loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2 ), with prophylactic antibiotics but no growth factors [6]. Induction TPF-E was discontinued in 13% of patients due to toxicity, and three out of 46 patients developed a bowel perforation. Only 65% of the patients in this study started chemoradiation. Mesia et al., using the same TPF regimen but with prophylactic granulocyte-colony stimulating factor (G-CSF) and antibiotics, observed febrile neutropenia, grade III/IV diarrhea and toxic death in 24%, 20% and 6% of patients, respectively [7]. It was therefore deemed that TPF-E leads to unacceptable toxicities. In contrast, Haddad et al. found that it was feasible to give three cycles of TPF-E with cisplatin 100 mg/m2 day 1, docetaxel 75 mg/m2 day 1 and 5-FU 850 mg/m2 /day as a continuous infusion on days 1–4 plus cetuximab for a total of six weeks given on days 1 and 8 of each cycle of TPF [8]. Similarly, a phase I trial combined lapatinib with TPF, but this combination also resulted in prohibitive toxicities [9].

Therefore, several single arm phase II trials evaluated the combination of cetuximab with a platinum compound and a taxane but without 5-FU [10–14]. In most of the trials, these combinations were found to be feasible, and observed objective response rates of between 70% and 97% were promising (Table 13.1).

A small number of randomized trials have compared cetuximab/platinum/ taxane-based induction chemotherapy versus TP(F) [15–17]. No clinically signifcant differences were observed between the cetuximab-based regimens and the controls (Table 13.2). Therefore, the role of induction therapy with a targeted agent to treat SCCHN remains purely investigational.

**Table 13.1** Single arm phase II trials investigating cetuximab with a platinum compound and a taxane

*NA* not-available; *AUC* area under the curve: *ORR* objective response rate; *PFS* progression-free survival; *OS* overall survival; *y* year

**Table 13.2** Randomized phase II trials investigating cetuximab with a platinum compound and a taxane

*NA* not-available; *AUC* area under the curve: *ORR* objective response rate; *PFS* progression-free survival; *LFS* laryngectomy-free survival: *OS* overall survival; *y*:year

Based on the promising effcacy of some window trials, immune checkpoint inhibitors are also under evaluation. A phase III trial is currently investigating the standard of care versus two cycles of neoadjuvant pembrolizumab (200 mg every 3 weeks) followed by curative-intent surgery and postoperative pembrolizumabbased (chemo)radiation [18]. One of the primary endpoints is pathological response after neoadjuvant therapy (<10% of tumor cells within the resected primary tumor and lymph nodes). The study design is depicted in Fig. 13.1.

**Fig. 13.1** KEYNOTE-689: Phase III study of adjuvant and neoadjuvant pembrolizumab combined with standard of care in patients with resectable, locally advanced head and neck squamous cell carcinoma

# **Window of Opportunity Trials with Targeted Therapy and Immune Checkpoint Inhibitors**

Window of opportunity studies are trials in which patients receive one new compound in the period between their cancer diagnosis and the start of standard therapy. The primary objective of this approach is not treatment effcacy but translational research. Standard treatment is usually surgery. Tumor biopsies and anatomic and functional imaging are performed before and after investigational treatment for translational research (Fig. 13.2). The main advantage of this study design is the ability to investigate new molecules in patients who have not yet been treated by multiple anti-cancer therapies. Traditionally, drugs are often tested in patients with locoregional or metastatic recurrence whose tumors are predominantly resistant and there is a risk that the activity of these agents may be underestimated. Furthermore, the understanding of the biological and molecular effects of these tested drugs may be limited in palliative patients because it could be perceived unethical to perform additional biopsies for research purposes only. In head and neck cancer window studies, pretreatment biopsies during diagnostic endoscopy and post-treatment biopsies on the day of surgery can be performed, taking advantage of general anesthesia. The evaluation of new compounds using this approach prior to classical curative treatment provides information about molecular and clinical activity as well as predictive biomarkers [19, 20].

Window of opportunity studies aim to maximize the information gain whilst minimizing the risk to patients who are awaiting potentially curative treatment. Standard treatment should therefore not be delayed due to the investigational drugs' study procedures or side effects. Some studies have shown that curative treatment in head and neck cancer should be carried out within 20 to 28 days after diagnosis [21, 22],

**Fig. 13.2** Example of a window of opportunity study design. *FDG-PET* fuorodeoxyglucosepositron emission tomography; *DCE* dynamic contrast enhanced; *DWI-MRI diffusion-*weighted magnetic resonance imaging

making trial organization one of the main challenges for this type of study. To achieve this goal, we recommend that patients with SCCHN be included in window studies at the time of clinical diagnosis, that the time points for biopsies and imaging are prospectively pre-defned, and that the schedule, dose, and duration of the preoperative treatment are standardized and the same for all patients. Finally, to validate translational research, patients should also be randomized against a control/ placebo group. If macroscopic tumor reduction is observed with the investigational compound, surgery should be performed as initially planned to ensure that the extracted surgical specimen has clear margins without microscopic tumor invasion.

Several PD1/PD-L1 monoclonal antibodies and anti-EGFR agents have been investigated in this setting (Tables 13.3 and 13.4). Interestingly, and aside from molecular activity, clinical effcacy has sometimes been detected even if the treatment period was short (<4 weeks). We will discuss some examples to highlight the advantages and drawbacks of this research approach.

Schmitz et al. [21, 23, 24] investigated cetuximab versus controls in the two weeks before curative surgery in treatment-naïve patients with SCCHN. The primary endpoint of safety was reached with cetuximab prior to surgery. Cetuximab also induced a high rate of response based on 18-fuorodeoxyglucose-positron emission tomography (18FDG-PET) evaluation and a decrease in tumor cellularity, which signifcantly correlated with18FDG-PET response. Four patients out of 20 also had a

Window of opportunity studies with targeted therapies in SCCHN (non-exhaustive list)

\* Window study before curative (chemo)radiotherapy

\*\* in the second part of the trial

*NA* not available; *18FDG-PET* 18-fuorodeoxyglucose-positron emission tomography; *MRI* magnetic resonance imaging

199

\* According to the abstract of ASCO 2017

macroscopic reduction in the size of their tumor. Gene expression analyses showed that in some patients cetuximab increased the expression of genes involved in epithelial to mesenchymal transition and activation of cancer-associated fbroblasts.

Afatinib, an irreversible pan-ErbB inhibitor, has also been investigated in a multicenter randomized window study of 25 treated patients versus fve controls [25]. The primary endpoint was 18FDG-PET response. Seventy percent of the patients showed a partial metabolic response and 22% of patients had a partial response according to RECIST v1.1. A high cluster 3-hypoxia score and wild *TP53* status were predictive of treatment activity. The investigational compound was considered safe even though three patients experienced surgical delay. Among them, two delays (3 and 24 days, respectively) were related to drug toxicity. We therefore believe that it is preferable to use drugs that have already proven to be safe in phase I studies in order to maximize patient safety and to protect the initiation of standard treatment. To the best of our knowledge, very few window studies in head and neck oncology have had to deal with grade ≥ 4 or unexpected side effects.

In 2017, Ferris et al. [26] conducted a window study with nivolumab, a monoclonal antibody targeting PD-1, in 29 SCCHN patients. Patients received two doses prior to surgery that was planned on day 29 ± 7. The primary endpoint was safety. The publication is still pending, but according to the ESMO 2017 abstract, grade 3–4 treatment-related adverse events occurred in four patients without delaying surgery. Tumor shrinkage, assessed by computer tomography (CT)-scan just before surgery, was observed in 48% of evaluable patients. Three patients experienced tumor reduction ≥40% (largest reduction = 75%). However, 11 patients also showed an increase in tumor size (the largest by 100%). At this stage, it is not possible to differentiate between true tumor progression or pseudo-progression.

 The main challenge for vaccines using this trial design is the limited period of time that short-term vaccination has available to show effective immunological effects. In this context, we recommend the use of minimally invasive samples (e.g. blood tests) to investigate the therapeutic effect of these vaccines after standard curative treatment, for example four weeks after surgery, as shown in Fig. 13.2. A metaanalysis of 239 phase I therapeutic cancer vaccine trials, conducted by Rahma et al. [27], concluded that the risk of severe adverse events (SAEs) when testing therapeutic cancer vaccines is extremely low and that AEs did not correlate with dose levels. Several window studies investigating the use of short-term therapeutic vaccination in head and neck cancers are currently in progress. First results are pending.

# **Conclusion**

Targeted and immune therapies as induction or neoadjuvant therapy are not standard of care and should be reserved for clinical trials. In this context, a phase III trial is investigating neoadjuvant and adjuvant pembrolizumab in patients selected for a primary surgical treatment. Window of opportunity trials are important translational research tools that require careful design and an experienced team.

# **References**

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 14 Is there a Role for Adjuvant Targeted and Immunotherapies in Patients with Locoregionally-Advanced Head and Neck Cancer?**

**Kevin J. Harrington**

# **Introduction**

Although surgery and radiotherapy are the main curative treatment modalities in patients with locoregionally-advanced squamous cell cancers of the head and neck (LA-SCCHN), their use as single modality therapies or combined as dual modality (surgery and adjuvant post-operative radiotherapy) treatment is associated with unacceptably poor outcomes for many patients. Consequently, the development of curative therapies for LA-SCCHN has seen an inexorable shift towards combinatorial approaches that include systemic treatments delivered alongside surgery and/or radiotherapy.

As is frequently the case in oncology, clinicians have used the lessons learned in treating patients in the context of relapsed and/or metastatic head and neck cancer to provide useful indicators towards therapeutic approaches that can be employed effectively in the locoregionally-advanced setting. Building on data demonstrating the beneft of systemic platin-based chemotherapy [1, 2] with or without epidermal growth factor receptor (EGFR) inhibition [3, 4] in patients with relapsed and/or metastatic head and neck cancer, clinicians have established a robust body of evidence to support the use of systemic agents in the context of treating LA-SCCHN. Thus, multimodality regimens in which radiotherapy is delivered with the addition of concomitant platin-based chemotherapy [5, 6] or a monoclonal antibody that targets EGFR [7, 8] have become standards-of-care in younger patients of good performance status. However, similar approaches involving the use of either chemotherapy or EGFR inhibition in the context of adjuvant therapy delivered after defnitive or post-operative (chemo)radiotherapy have not, as yet, resulted in practice-changing outcomes.

Head of Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK e-mail<EMAIL_ADDRESS>
K. J. Harrington (\*)

In the case of immune checkpoint inhibitors (ICPI), there have also been attempts to extend the principle of applying that which is effective in the relapsed and/or metastatic setting to earlier time points within the patient pathway. ICPIs have been shown to be more effective than standard-of-care chemotherapy in both frst- [9] and second-line [10–13] treatment of relapsed and/or metastatic head and neck cancer and have become new global gold-standard therapies. Importantly, in each of the practice-changing trials of ICPIs in head and neck cancer, patients have received prolonged dosing with immunotherapy and many have achieved durable and possibly permanent remissions. In many ways, the use of prolonged dosing regimens with ICPIs, even in patients who have achieved radiological complete remissions, can be seen as mimicking a course of adjuvant therapy. It is, therefore, no surprise that a number of clinical trials are currently addressing the question of using ICPIs in the adjuvant setting after the delivery of curative-intent treatment regimens, including studies involving adjuvant therapy after defnitive chemoradiotherapy or surgery followed by post-operative chemoradiotherapy.

Therefore, in this chapter, we will discuss the potential role of adjuvant therapies in patients with LA-SCCHN. Data on the use of cytotoxic chemotherapy agents will be reviewed frst in order to provide a context for more recent attempts to develop effective adjuvant approaches based on EGFR-targeted therapies and ICPIs.

# **Adjuvant Post-Operative Chemoradiotherapy Improves Outcomes in LA-SCCHN**

Post-operative radiotherapy (PORT) is considered when the risk of recurrence of disease above the clavicles exceeds 20% (either at the mucosal site or in surgicallytreated and -untreated nodal levels). Absolute indications for PORT include close (less than 5 mm) or involved (positive) margins at the primary tumour resection site, two or more involved cervical lymph nodes, extracapsular spread and invasion of the soft tissues of the neck. The presence of lymphovascular space invasion and perineurial invasion are relative indications for PORT that are considered in association with other factors [14].

The role of adjuvant post-operative chemoradiotherapy (POCRT), as opposed to PORT, was clarifed in two seminal studies published in 2004 [15, 16] and summarised in Fig. 14.1. It is important to emphasise that, in both of these trials, the delivery of chemotherapy was restricted solely to the period of time during which the patient received adjuvant post-operative radiotherapy. In other words, there was no use of chemotherapy in a fashion that might be considered as true adjuvant therapy. The inclusion criteria for the RTOG 9501 [15] and EORTC 22931 [16] studies were slightly different, but the overall fndings were remarkably similar. In the RTOG study, loco-regional control and disease-free survival were increased by the addition of concomitant cisplatin to PORT. There was a 10% improvement in 2-year loco-regional control (82% vs 72%) in favour of POCRT. In the EORTC study,

**Fig. 14.1** Trial designs and main fndings of the RTOG 9501 and EORTC 22931 trials of postoperative radiotherapy versus post-operative chemoradiotherapy

5-year progression-free and overall survival rates were increased by the addition of concomitant cisplatin to PORT.

The authors of those two studies subsequently amalgamated the datasets to derive consensus indications for POCRT [17]. They found that extracapsular spread in lymph node disease and the presence of microscopically involved resection margins were the only risk factors for which the impact of POCRT was signifcant in both trials. Therefore, these two factors have been widely adopted as absolute indications for POCRT across the globe. The combined analysis also suggested a trend in favour of POCRT in patients with stage III/IV disease, those with perineurial invasion, lymphovascular space emboli or level IV and V lymph nodes in the case of oral cavity or oropharyngeal cancers. These factors have not been accepted widely as absolute indications for POCRT.

# **Adjuvant Chemotherapy Is Not Effective in LA-SCCHN**

The Meta-Analysis of Chemotherapy on Head and Neck Cancer (MACH-NC) collaborative group was originally published in 2000 and represented a landmark study that fundamentally changed the standard-of-care treatment paradigms for patients with stage III/IV disease [5]. That meta-analysis addressed three specifc issues: (i) the effect on survival outcomes of adding chemotherapy to locoregional treatment; (ii) the effect of different chemotherapy schedules; and (iii) the role of induction/

neoadjuvant chemotherapy in laryngeal preservation. Data relating to the frst two questions have provided clear guidance on the absence of a defned role for adjuvant cytotoxic chemotherapy in LA-SCCHN. Thus, although the meta-analysis, which included 63 trials involving 10,741 patients, demonstrated that survival following defnitive local therapy was signifcantly improved with the addition of chemotherapy, neither induction nor adjuvant chemotherapy was seen to have had a signifcant effect on survival outcomes.

In view of the heterogeneity of the studies included in the original MACH-NC meta-analysis, a further study was conducted in which the group updated their results by including individual patient data from randomised trials that were conducted between 1994 and 2000 [6]. Data from a total of 87 randomised trials were available for the analyses. Because some trial arms were used more than once in the analysis, the total number of comparisons in the updated meta-analysis was 108 comprising data on 17,493 patients. The majority of new trial data were specifcally related to the use of concomitant chemotherapy and resulted in the meta-analysis being able to draw much clearer conclusions about the value of this treatment approach. As with the previous analysis, there was a signifcant effect of the timing of chemotherapy with concomitant chemotherapy clearly offering the greatest beneft (hazard ratio 0.81 (95% CI 0.78–0.86). Once again, neither induction (hazard ratio 0.96 (95% CI 0.90–1.02) nor adjuvant (hazard ratio 1.06 (95% CI 0.95–1.18) chemotherapy was found to be better than locoregional therapy alone. As a consequence, there is broad agreement across the globe that adjuvant chemotherapy has no established role when delivered after defnitive surgery, radiotherapy, or radical/ post-operative chemoradiotherapy.

# **Epidermal Growth Factor Receptor-Targeted Therapies in LA-SCCHN**

SCCHN very frequently show upregulated EGFR signalling. EGFR is a member of the c-erbB/HER family of transmembrane type I receptor tyrosine kinases, which comprises a total of four members (EGFR/c-erbB-1/HER1, c-erbB-2/neu/HER-2, c-erbB-3/HER-3, c-erbB-4/HER-4 [18, 19]). HER-family receptor proteins share a common structure, consisting of a glycosylated extracellular ligand-binding domain, a hydrophobic trans-membrane component and an intracellular domain with tyrosine kinase activity. When the specifc (cognate) ligand binds to its ligand-binding domain on the extracellular component of a HER-family member, it causes receptor dimerization and activation of the kinase domain. This, in turn, mediates phosphorylation of target proteins, which triggers a cascade of intracellular secondary messengers that alter patterns of gene expression. In this way, binding of a protein on the cell surface can infuence the cell's behaviour. It is important to note that there is no ligand for the c-erbB2/HER2 receptor and that the c-erbB3/HER3 receptor has no kinase activity. Nonetheless, these receptors are able to participate in signalling

by dimerizing with appropriate partners. For example, EGFR:c-erbB3 (HER1/ HER3) and c-erbB-2:c-erbB-3 (HER2/HER3) heterodimers can exploit ligand binding to the HER3 component and kinase-mediated signalling from the EGFR or HER2 component of the partnership.

Normally, activation of HER-family receptors by their cognate ligands (growth factors) is very tightly controlled—through regulation of the expression of the receptor, the availability of the ligand and the ability of the cell to de-phosphorylate activated receptors. In this way, proliferation of normal tissues is carefully regulated to avoid unnecessary or unscheduled cell growth. In contrast, in SCCHN there is very frequently a state of independence from normal regulatory mechanisms that is driven through a number of different processes. These include: (i) manufacture and release of growth factors that stimulate HER-family receptors on the malignant cell (autocrine signalling) and on neighbouring malignant (and normal) cells (paracrine signalling); (ii) altering the number, structure or function of the surface growth factor receptors expressed on tumour cells; and (iii) by altering the signalling pathways downstream of the receptor. In contrast to other tumour types, in which EGFR gene amplifcation or mutation is common (e.g. lung adenocarcinoma), overexpression of the receptor, without gene amplifcation, is the dominant process whereby EGFR affects the pathobiology of SCCHN. The roles of HER2, HER3 and HER4 in SCCHN remain unclear. However, it is known that HER2/HER3 heterodimers are potent inducers of the PI3-kinase anti-apoptotic pathway [20] and this may be relevant to particular subsets of SCCHN, including human papillomavirus (HPV) related disease37.

Irrespective of the fact that SCCHN rarely shows evidence of EGFR mutation, the evidence of single-agent responses to HER-family-targeted therapies strongly supports the notion that these tumours can be reliant on signalling through these pathways in order to maintain the malignant phenotype. This reliance on activation of an oncogenic driver has been called "oncogene addiction" [21] and is seen as a potential point of therapeutic attack against a range of tumour types. Therefore, HER-family receptors represent attractive therapeutic targets in SCCHN and two main classes of drugs, monoclonal antibodies (MAB) and small molecule tyrosine kinase inhibitors (smTKI), have been developed. MAB are large molecules directed against the extracellular domain of the receptor, while smTKI inhibit the intracellular kinase domain of the receptor.

# **Anti-EGFR Monoclonal Antibodies Are Not Used as Adjuvant Therapies for LA-SCCHN**

Anti-EGFR-targeted monoclonal antibodies (cetuximab, zalutumumab, panitumumab, nimotuzumab) have been extensively tested in patients with relapsed and/ or metastatic head and neck cancers. Cetuximab has been shown to improve the outcome of frst-line palliative chemotherapy [3]. In the EXTREME study, 442 eligible patients with untreated recurrent and/or metastatic SCCHN received cisplatin or carboplatin plus 5-fuorouracil every 3 weeks for a maximum of 6 cycles. Cetuximab (400 mg/m2 loading dose, then 250 mg/m2 per week) was administered to 222 randomly selected patients. Patients in the cetuximab arm who showed stable disease or treatment response were planned to continue with maintenance cetuximab until disease progression or unacceptable toxicity. This study showed that the cetuximab/platinum/5-fuorouracil combination prolonged median overall survival from 7.4 months to 10.1 months (P = 0.04). There were also increases in the median progression-free survival time (3.3 to 5.6 months; P < 0.001) and the response rate (20% to 36%; P < 0.001) [3]. Consequently, the EXTREME regimen was adopted as a gold-standard treatment for relapsed/metastatic head and neck cancer. In contrast, neither panitumumab [22] nor zalutumumab [23] has been registered for the treatment of relapsed and/or metastatic head and neck cancer following negative phase III trials, although the data from those trials was strongly suggestive of activity of those agents. The use of nimotuzumab is largely restricted to India and there are very limited data relating to its use in recurrent and/or metastatic SCCHN [24].

Cetuximab has also been approved as part of a curative regimen for LA-SCCHN. In a phase III study of 424 subjects with locally or regionally advanced SCCHN, locoregional control (median 24.4 vs. 14.9 months; hazard ratio: 0.68; P = 0.005) and overall survival (median 49.0 vs. 29.3 months; hazard ratio: 0.74; P = 0.03) were signifcantly prolonged in patients receiving radiotherapy and cetuximab compared to those treated with radiotherapy alone [7, 8]. However, in this study, there was no continued, adjuvant use of cetuximab beyond the completion of radiotherapy. In addition, both zalutumumab and panitumumab have been tested in combination with radiation/chemoradiation, again without any attempt to use them in an adjuvant phase beyond the completion of defnitive treatment. Neither of these agents improved outcomes when compared to the standard therapy arms and they have not been approved in the context of LA-SCCHN [25–27]. Nimotuzumab is widely used with chemoradiotherapy in India, following the publication of a positive randomised phase III trial. However, once again, there was no use of nimotuzumab following completion of defnitive loco-regional therapy [28] and, therefore, there is no evidential basis on which to deliver this therapy in an adjuvant setting.

# **Small Tyrosine Kinase Inhibitors Are Not Effective Adjuvant Therapies in LA-SCCHN**

A number of agents have been developed to target HER-family members across a variety of different tumour types. In the context of head and neck cancer, geftinib and erlotinib (EGFR/HER1 inhibitors) [29–31], lapatinib (HER1/HER2 inhibitor) [32, 33] and afatinib (pan-HER inhibitor) [34] have been most extensively investigated. Studies have included assessments of agents in the palliative setting for relapsed and/or metastatic disease. Despite the fact that these agents demonstrate

single-agent activity in phase I/II trials, randomised studies have failed to demonstrate clinically meaningful survival advantage relative to standard-of-care treatment and none of them is in routine clinical use for patients with relapsed and/or metastatic disease. Specifcally, a randomised phase III study was conducted to compare survival in 486 patients with recurrent or metastatic SCCHN treated with geftinib 250 or 500 mg/day or standard-of-care single-agent weekly methotrexate [35]. Neither of the geftinib doses improved overall survival compared with methotrexate (hazard ratios 1.22 (95% CI 0.95–1.57 and 1.12 (95% CI, 0.87–1.43), respectively. The median overall survivals were 5.6, 6.0, and 6.7 months for geftinib 250 mg/day, geftinib 500 mg/day, and intravenous methotrexate, respectively. Afatinib has been assessed in the phase III LUX head and neck-1 study in patients receiving second-line therapy for relapsed/metastatic SCCHN [36]. A total of 583 patients were treated with afatinib (322 patients) or methotrexate ((161 patients). Afatinib signifcantly increased median progression-free survival (2.6 versus 1.7 months, p = 0.03) but did not improve median overall survival (6.8 versus 6.0 months) relative to methotrexate. In an integrated analysis of quality of life, afatinib showed a delay in deterioration of global health status, pain and swallowing problems (all p ≤ 0.03) but such data were of insuffcient weight to lead to regula-

tory approval of this therapy.

In the context of adjuvant maintenance therapy using HER-family-targeted therapies, there have been signifcant attempts to develop lapatinib and afatinib. A randomised phase III study of lapatinib administered concomitantly with chemoradiotherapy and as maintenance monotherapy in patients with high-risk surgically-treated SCCHN has been reported [37, 38]. Patients with resected stage II-IVA SCCHN, with a surgical margin ≤5 mm and/or extracapsular extension in metastatic cervical nodal disease were randomized to chemoradiotherapy (66 Gy total dose and 100 mg/m2 cisplatin administered on days 1, 22 and 43) plus placebo or lapatinib (1500 mg/day) prior to and during chemoradiotherapy, followed by 12 months of maintenance monotherapy (either placebo or lapatinib). Six hundred and eighty-eight patients were enrolled; 346 received lapatinib and 342 received placebo. With a median follow-up of 35.3 months, the study was terminated early due to the apparent plateauing of disease-free survival events. Median disease-free survivals were 53.6 months and "not reached" for lapatinib and placebo, respectively; hazard ratio 1.10 (95% CI 0.85–1.43). No signifcant differences in diseasefree survival by HPV status or overall survival were observed between the two treatment arms. Similar numbers of patients in both treatment arms experienced adverse events, with more patients in the lapatinib arm experiencing serious events (48% vs 40%). This study demonstrated that adding lapatinib to chemoradiotherapy and its use as long-term adjuvant therapy was safe, but did not offer any effcacy benefts compared with placebo in patients with surgically-treated high-risk SCCHN.

In the LUX head and neck-2 study, 617 patients were randomised to treatment (411 to afatinib and 206 to placebo) in a true adjuvant context [39, 40]. Eligible patients had histologically or cytologically confrmed LA HNSCC (Stage III, IVa or IVb SCC of the oral cavity, oropharynx or hypopharynx, or Stage IVa or IVb SCC of the larynx). Since HPV status was not determined for eligibility, unfavourable risk was defned as non-oropharynx primary site or oropharynx cancer in heavy smokers (>10 pack years). Patients were required to have unresected disease prior to chemoradiotherapy. Concomitant defnitive chemoradiotherapy had to have been completed no longer than 24 weeks prior to randomisation, comprising radiotherapy with curative intent to a minimum dose of 66 Gy in 33 fractions, and cisplatin or carboplatin. No evidence of disease was required on clinical and radiographic examinations (defned as no residual tumour after chemoradiotherapy (with or without R0 resection at the primary site or neck dissection). A pre-planned futility analysis, showed the study was unlikely to demonstrate a signifcant advantage with afatinib and the trial was halted early on the recommendation of the independent data-monitoring committee. Patients were discontinued from treatment and followup for disease recurrence and survival was stopped. The percentage of patients taking at least 80% of the planned study medication was lower for the afatinib group (85.3%) than the placebo group (98.5%), almost certainly refecting the appreciable toxicity associated with chronic administration of this pan-HER-targeted oral medication. Median disease-free survival (DFS) by investigator review was 43.4 months (95% CI 37.4–not estimable) with afatinib versus "not estimable" (95% CI 40.1–not estimable) with placebo (HR 1.13, 95% CI 0.81–1.57; stratifed log-rank test p = 0.48). The DFS rate at 2 years was evaluated using the Kaplan-Meier method; the probability of being disease-free at 2 years was 67.2% in the afatinib group and 73.5% in the placebo group (estimated difference: −6.3%, 95% CI -15.0–2.5; p = 0.16). At the time of data cut-off for the futility analysis, overall survival data were immature. The effect of afatinib versus placebo on DFS was explored in preplanned subgroup analyses based on stratifcation factors, biomarker status, demographics, baseline disease characteristics and prior anti-cancer chemotherapy. These subgroup analyses were generally consistent with the primary analysis and showed no clear trend of beneft in any subgroup, although there was a slight beneft for afatinib patients with nodal status N2b–N3 (HR 0.82, 95% CI 0.55–1.21).

# **Immune Checkpoint Inhibitors as Adjuvant Therapies in LA-SCCHN**

In recent years, immunotherapy has emerged as a new pillar in the treatment of many solid cancers [41]. This renewed interest in immunotherapy has been underscored by huge advances in our understanding of the fundamental biological principles that guide the activity of the immune system. In particular, specifc immune checkpoints have been discovered that are integral components of normal immune responses. In normal health, these checkpoints function as negative regulators or "brakes" on the normal immune response and prevent T cells from becoming chronically activated or aberrantly targeted against normal tissues. Many cancers exploit these inhibitory pathways in order to escape from immunosurveillance.

Proteins that are expressed on activated T cells, such as cytotoxic T-lymphocyteassociated protein-4 (CTLA-4) and programmed death-1 (PD-1), are key players that allow many cancers to evade anti-tumour immunity by interfering with the activation and effector phases of immune responses, respectively. In the context of relapsed and/or metastatic head and neck cancer, we have clear evidence that blockade of signalling through the PD-1 pathway (mediated by programmed death ligand-1 (PD-L1) expressed on the surface of cancer and other cells) can yield signifcant clinical responses. Indeed, we now have positive phase III trial data, initially in the second-line and, more recently, in the frst-line setting, to show that anti-PD-1-targeted therapies are capable of signifcantly improving overall survival in patients with relapsed and/or metastatic head and neck cancers [9–13]. As with chemotherapy and HER-family-targeted therapies, such data have spurred on investigators to investigate the potential value of immune checkpoint inhibitors (ICPI) as adjuvant therapies for cancer.

A number of lines of evidence can be invoked to support the hypothesis that adjuvant ICPI therapy might be benefcial in patients treated for LA-SCCHN. First, there are data in patients with melanoma that demonstrate that the "baseline tumour size" is an independent, statistically signifcant predictor of overall survival in patients treated with anti-PD-1 ICPI [42]. In addition, phase III clinical trials have shown improvement in progression-free and overall survival endpoints for tumour types such as melanoma and lung cancer [43–46]. As a guide to the management of SCCHN, the data from the PACIFIC trial in lung cancer are most compelling because the patient population comprised those with locally-advanced, stage III non-small-cell lung cancer who had not progressed on chemoradiotherapy delivered with curative intent [45, 46]. Interestingly, patients were required to commence adjuvant anti-PD-L1 therapy (durvalumab) within 42 days of completion of chemoradiotherapy.

At the time of writing, there are at least 3 major trials that have either completed recruitment or are still ongoing that address the question of adjuvant/maintenance ICPI in locally-advanced head and neck cancer. The designs of these trials are summarised in Figs. 14.2, 14.3 and 14.4.

**Key:** F/U – follow-up; HPV – human papillomavirus; LA-SCCHN – locally-advanced squamous cell cancer of the head and neck; q2w – every 2 weeks; R – randomisation; RT - radiotherapy

**Fig. 14.2** Javelin Head and Neck-100 study design. Key: *F/U* follow-up; *HPV* human papillomavirus; *LA-SCCHN* locally-advanced squamous cell cancer of the head and neck; *q2w* every 2 weeks; *R* randomisation; *RT* radiotherapy

\*\* Expression of P16 is highly correlated with HPV in oropharyngeal cancer. Tumors outside the

**Fig. 14.3** KEYNOTE-412 clinical trial design. \*\*Expression of P16 is highly correlated with HPV in oropharyngeal cancer. Tumors outside the oropharynx are considered HPV negative regardless of results of p16 staining. *+ Chemotherapy* Cisplatin 100 mg/m2 × 3; *RT* AFX – 200 cGY/6 per week, SFX – 200 cGy/5 per week. Key: *AFX* accelerated fractination; *p16-positive/negative* surrogate measure for human papillomavirus; *R* randomisation; *RT* radiotherapy; *SFX* standard fractionation

**Key:** CR – complete remission; DLT – definitive local treatment; HPV – human papillomavirus; PR – partial remission; Q3w – every 3 weeks; R – randomisation; RT - radiotherapy ; SD – stable disease

**Fig. 14.4** IMvoke010 clinical trial design. Key: *CR* complete remission; *DLT* defnitive local treatment; *HPV* human papillomavirus; *PR* partial remission; *Q3w* every 3 weeks; *R* randomisation; *RT* radiotherapy; *SD* stable disease

The Javelin Head and Neck 100 study was a randomized, double-blind, placebocontrolled, parallel-arm, superiority study of the anti-PD-L1 agent, avelumab, versus placebo. Patients with LA-SCCHN (oral cavity, oropharynx, larynx, or hypopharynx) who were eligible for defnitive chemoradiotherapy were enrolled (details of patient groups are provided in Fig. 14.2). Patients were randomized to receive either avelumab or placebo plus standard-of-care chemoradiotherapy. Randomization was stratifed by tumour stage (<T4 vs T4), nodal stage (N0/ N1/2aN2b vs N2c/N3), and HPV status (positive vs negative). There were three treatment phases in the study: lead-in phase; treatment phase; and maintenance phase. The primary endpoint of Javelin Head and Neck 100 is the progression-free survival (PFS) per modifed Response Evaluation Criteria in Solid Tumours