Keywords

Introduction

In squamous cell carcinoma of the head and neck (SCCHN), therapeutic decision making depends on several tumour-, patient-, and institution-related factors, the former being defined by a well-known categorization into localized (also known as early), locally (or locoregionally) advanced, and metastatic disease. According to the US Surveillance, Epidemiology, and End Results (SEER) Program data, about one third of newly diagnosed patients present with a localized tumour, almost half of them with locally advanced disease, and up to 20% may have distant dissemination. While cure rates of early disease surpass 80%, they almost halve in locally advanced SCCHN due to high rates of recurrences manifesting in about 60% of cases despite combined modality treatment instead of single-modality surgery or radiotherapy used in early disease [1, 2]. In oropharyngeal cancer, the decline in prognosis has been shown to be neutralized by human papillomavirus (HPV)-positivity [3]. On the other hand, even in developed countries, this favourable, viral-related subgroup represents only a minority of SCCHN [4]. Long-term survivorship is further halved in patients with distant metastases notwithstanding the introduction of targeted systemic agents and immunotherapy [5, 6]. The latter prognostic group consists of recurrent tumours as well, except for those that are salvaged with surgery or radiotherapy, particularly in the case of early larynx relapses and limited metastatic recurrences (oligorecurrences) of HPV-positive oropharyngeal cancer in the lungs [7, 8]. Relapses affect about 10-15% of patients with early disease, but they are up to 4 times more frequent in locally advanced disease [9,10,11,12]. Depending on primary tumour site, HPV-positivity in oropharyngeal cancer, primary treatment, and intensity of follow-up, the ratio between early, locoregional, and distant recurrences is roughly comparable with possibly a slight predominance of locoregional relapses [2, 13, 14]. According to disease stage at relapse, salvage surgery and/or (chemo)radiotherapy usually offered to the majority of patients without distant metastases yields five-year survival rates between 30 and 40% on average with even better outcomes after surgical resection [7, 14]. Importantly, these snapshot clinical scenarios need to be put in the context of gradual cancer progression towards more advanced stages, occurring at different rates in different individuals and both in the primary and recurrent disease settings. The respective treatment outcomes are summarized in Fig. 13.1.

Fig. 13.1
2 graphs depict long-term survival for primary and recurrence of a disease. Primary has the following labels, early, local and regional advanced, and metastatic with a decrease in trend from 80 to 0 percent. Recurrences has the following labels, early, local and regional advanced, and distant with an increase in trend from 80 to 0 percent.

In mucosal head and neck squamous cell carcinoma, survival outcomes differ according to clinical presentation. Disease progression is a continuous process, and recurrences are common. Apart from several exceptions, poorer prognosis correlates with more advanced stages both in the primary and recurrent settings. Long-term survival in local and regional stages corresponds to a period of at least 5 years, while in the metastatic setting we rely on the results of the Keynote-048 trial, as reported in 2019, with a median follow-up of 13 months in the immunochemotherapy arm and expect that mature data will probably show inferior outcomes as was the case of CheckMate-141

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Similarly entangled are therapeutic strategies defining antitumoral management of each of these disease categories. In this chapter, we will put the first-line palliative treatment in broader context and try to decipher this entanglement. Figure 13.2 illustrates the development of anticancer modalities in two temporal axes. The horizontal axe signifies historical evolution covering the modern era since 1970s, when the current concept of multimodality approach was grounded. Being one of the typical examples of a patient’s journey through the diagnosis and treatment of SCCHN as indicated above, the vertical axe demonstrates treatment sequencing models in a patient with initially locally advanced disease that later recurs and requires systemic therapy. Until the beginning of the 20th century, management of head and neck cancer was governed by surgery, albeit with generally very poor results and cure rates as low as 5%. Afterwards, radiotherapy began to develop, first independently and even replacing surgery as the mainstay between the two world wars but then gradually complementing resection and laying thus the foundation for treatment sequencing [15]. In the 1970s, adjuvant curative radiotherapy and low-dose methotrexate became the standard of care options in the primary and recurrent disease setting, respectively [16, 17]. At present, following 50 years of evolving multimodality management, median overall survival of these patients has significantly improved with a major impact of concurrent curative chemoradiation and advances in palliative therapy. The choice of the first-line systemic approach has thus a profound influence on patient outcomes, and we will discuss the role of patient- and disease-related factors in the context of the cancer care continuum.

Fig. 13.2
A diagram depicts the evolution of treatment. It has years categorized in the left as, 1970s to 1980s, 1990s, 2000s, and 2010s to 2020s, Curative setting in the middle has surgery followed by radiotherapy or chemoradiotherapy, and palliative setting which is further categorized as platinum-sensitive and platinum-resistant.

Evolution of treatment sequencing in mucosal head and neck squamous cell carcinoma. In any phase of the disease course, participation in well-designed clinical trials is recommended. Abbreviations: 5-FU, 5-fluorouracil; EXTREME, platinum/5-fluorouracil/cetuximab; TPEx, cisplatin/docetaxel/cetuximab; KN-048 combo, platinum/5-fluorouracil/pembrolizumab; anti-PD-1, anti-programmed cell death-1 (nivolumab or pembrolizumab)

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Defining the First Line

First-Line Setting: Where it Begins and Ends

Candidates for first-line palliative treatment can be divided into two groups. The smaller one consists of those presenting with newly diagnosed SCCHN ineligible for locoregional treatment due to synchronous metastases, and the larger one of those with disease relapse after one or more previous locoregional interventions and with no further possibility of such therapy [18]. Recurrent SCCHN is not a homogenous entity but differs according to previous anticancer treatment and site of recurrence with important implications for the choice of first-line systemic regimens. Previous therapeutic attempts can be locoregional only, such as surgery and radiotherapy for early disease and surgery followed by radiotherapy for locally advanced disease, but can also involve systemic drugs. Since the first-generation of larynx preservation trials, platinum agents (cisplatin and carboplatin) are the most commonly used drugs in the locally advanced setting. They have become the cornerstone of induction chemotherapy and concurrent chemoradiotherapy [2, 19].

However, owing to cumulative toxicity of cisplatin, prior exposure can be considered a relative contraindication for its retreatment (i.e., after previous use in the primary setting) or rechallenge (i.e., after previous use in the recurrent and/or metastatic setting), especially if the total administered dose exceeds 300 mg/m2 with up to 200 mg/m2 being considered relatively safe [20,21,22]. Albeit less toxic, the use of carboplatin comes with lower efficacy [23]. Moreover, a short platinum-free interval portends poor prognosis. Time to progression or relapse of less than 6 months after termination of previous platinum-based regimen has been adopted in clinical trials and routine practice to identify cases resistant to platinum retreatment. Although longer periods of disease control are a prerequisite for the term “platinum-sensitivity”, they do no guarantee a therapeutic success. Historically, one of the reasons for this categorization was the urgent need to allow a rapid access to reasonably effective drugs, which were very limited, to as many patients as possible. Nevertheless, this population is quite heterogenous comprising also patients who progress during platinum treatment, those who have a probably persisting locoregional disease after primary treatment that visibly progresses only 6 months later, and those who maintain remission of the primary tumour but present with new distant metastases. Here, we remind that in accordance with disease kinetics and tumour doubling time being usually in the order of several months, such new metastases must have already been subclinically present during the primary treatment, and contrary to induction chemotherapy, concomitant potentiation of radiotherapy by platinum agents does not diminish distant failure [2, 24]. Thus, there are differences in terms of the type of previous administration but also dose.

Unfortunately, the topic of platinum-resistance is still far from being fully understood, and for example addressing local and systemic platinum-resistance, if there is such a distinction, merits special attention. In addition, determining the actual disease-free interval may be challenging. Primary response assessment after chemoradiotherapy is recommended at 3 months with no further imaging being required in the majority of patients in case of complete remission. Thus, it is not that uncommon that imaging at 6 months is performed if suspicious findings are detected already at 3 months. Subsequently, if a recurrence is confirmed at 6 months, its attribution to the designation “platinum-sensitive” may be problematic because its inception was earlier than thought. This type of diagnostic pitfall and the fact that the armamentarium of systemic therapy has broadened during the past 15 years advocate the pertinence of increasing the time span of platinum-resistance or introducing the term of “partial platinum-sensitivity/resistance” as in ovarian cancer [25].

Taken together, cisplatin ineligibility may be either due to toxicity reasons or treatment resistance. The most common alternative regimens comprise a carboplatin/5-fluorouracil doublet, sharing the same platinum resistance issues, and cetuximab [22]. Justified by a hypothetically increasing number of sensitive cells in a growing tumour that recurred, cetuximab may in principle be subjected to retreatment or rechallenge after previous failure (e.g., first in concomitance with curative radiotherapy and then in the palliative setting), but data are still limited [26]. Even less evidence exists for retreatment or rechallenge with the same class of immune checkpoint inhibitors, which currently dominate the recurrent and/or metastatic setting and are increasingly incorporated in ongoing clinical trials in the locally advanced setting. Here, some efficacy can be expected, but an off-immunotherapy period is obviously warranted [27, 28]. Disease-free interval prior to first-line palliative systemic treatment represents, therefore, a crucial indicator impacting on the drug choice. A short disease-free interval is a poor prognosticator, and the outcomes are almost uniformly worse than if the same treatment is given later. A cut-off of 6 months can still be reasonably used in clinical practice, but the relation is probably stochastic and not categorical.

As alluded to above, relapsing SCCHN differs according to the site of recurrence and can thus be classified into locoregional recurrence only, locoregional recurrence with metachronous (with respect to the primary tumour) metastases, and distant failure only. Intriguingly, locoregional relapse eligible neither for salvage surgery nor radiotherapy may not require the same systemic drugs as a widespread disseminated disease. In fact, the use of first-line immunotherapy, particularly as a single-agent regimen, is accompanied by an increased risk of progression in more than one third of patients and in some of them even in the form of hyperprogression, which is an abnormally accelerated tumour growth described in about one quarter of patients receiving immune checkpoint inhibitors and being more frequent in those presenting with locoregional recurrence relative to those with exclusively distant dissemination [29]. Keeping in mind the typical head and neck tumour location in a very sensitive area near vital structures, the increased risk of progression could explain a lack of survival benefit seen in subgroup analyses of the registration Keynote-048 trial in patients presenting with locoregional recurrence only [30]. On the other hand, this is exactly the group of patients in which a non-immunotherapy alternative for the first-line setting consisting of cetuximab/platinum/5-fluorouracil triplet seem to have a major effect (hazard ratio for death 0.65 [0.49, 0.87] in locoregional recurrence only versus 0.99 [0.72, 1.36] in metastatic tumours including also locoregional recurrences) [31]. Furthermore, a post-hoc pooled analysis of both arms of the TPExtreme trial (see below) showed a significantly improved progression-free survival in patients with a locoregional recurrence only [18].

About half of all patients starting with standard-of-care first-line treatment (see below) will also receive second-line therapy, where the drug choice is proportionally restricted. Importantly, the majority of these patients experience progression while on treatment, so there is no disease-free interval as could be the case after primary therapy. Although we might feel intuitively driven towards giving the most comprehensive therapy at the earliest possible opportunity, allowing thus the majority of patients to benefit from it, emerging evidence suggests that treatment sequencing may be the key of success. Illustrative to that are also the very recent results of three large randomized trials in first-line metastatic melanoma. Despite initial excitement and even FDA approval, they did not in the end confirm any significant clinical benefit of combining two of the most potent regimens, i.e., immune checkpoint inhibitors of programmed cell death-1 receptor (PD-1) or its ligand (PD-L1) with RAF and MEK inhibitors [32].

First-Line Treatment: Pros and Cons

Since 2008, the standard first-line treatment has been biochemotherapy according to the EXTREME trial combining the epidermal growth factor receptor inhibitor cetuximab with a platinum-doublet (cisplatin or carboplatin with 5-fluorouracil) in platinum-sensitive SCCHN patients. In comparison with the platinum-doublet alone, the EXTREME regimen significantly improved overall survival from 7.4 to 10.1 months, progression-free survival, and response rate, and all this without compromising quality of life [33, 34]. However, the regimen had several shortcomings including a high rate of severe acute adverse events observed in 82% of patients, poor long-term results with less than 5% of patients being alive at 5 years, absence of significant benefit in patients with distant dissemination according to a subgroup analysis, a lack of predictive biomarkers, and an inconvenient continuous administration of 5-fluorouracil [31, 33, 35]. Nonetheless, EXTREME dominated the first line for more than 10 years and withstood multiple challenges to be dethroned by other promising regimens.

Validating the first predictive molecular marker in SCCHN, the Keynote-048 trial introduced immunotherapy to the first line and demonstrated its superiority over EXTREME in patients with platinum-sensitive tumours marked positively for PD-L1 expressed as combined positive score (CPS). Immunochemotherapy (anti-PD-1 inhibitor pembrolizumab with a platinum doublet) significantly improved overall survival from 10.4 to 13.6 months and from 11 to 14.7 months in the in CPS ≥1 and CPS ≥20 subgroups, respectively. Immunotherapy alone proved such benefit only in the CPS ≥20 subgroup (10.7 versus 14.9 months) [36]. In the PD-L1 negative subgroup accounting for 15% of the study population, EXTREME defended its position. In the subgroup with low PD-L1 expression (CPS 1-19), immunotherapy should be combined with chemotherapy [37]. Furthermore, pembrolizumab prolonged median duration of response by more than 16 months, was substantially less toxic than EXTREME, and retained its efficacy in the elderly subgroup suggesting possible benefits in less fit patients as well [36, 38]. However, even this new schedule has its downsides. In comparison with EXTREME, both pembrolizumab alone and pembrolizumab with chemotherapy improved neither progression-free survival nor response rate, and progressions were more common, probably leading to a lack of overall survival benefit in locoregionally recurrent cases as mentioned above. In the immunochemotherapy arm, more treatment-related deaths than with EXTREME were noted, severe acute adverse events occurred in 74% of participants, and the inconvenient necessity of a continuous administration of 5-fluorouracil remained [36].

The third pivotal trial challenging EXTREME in patients with platinum-sensitive disease was TPExtreme (Fig. 13.3). Although the survival benefit of the better tolerated experimental TPEx arm (cetuximab/platinum/docetaxel) did not reach statistical significance, the trial provided us with valuable data that could improve the delivery of EXTREME, such as validation of biweekly administration of cetuximab in the maintenance phase, growth factor support to maximize dose intensity if tumour shrinkage is the main goal, or deintensification of cisplatin to decrease toxicity and subsequently enhance efficacy [18, 39]. Besides that, impressive outcomes were yielded in patients receiving second-line immunotherapy with overall survival reaching up to 21.9 and 19.4 months in the TPEx and EXTREME arms, respectively. Altogether, the TPEx regimen can be recommended as an alternative to EXTREME, but the eligibility criteria according to the study protocol are more restrictive (maximum age of 70 years, obligatory growth factor support and cisplatin use) [18].

Fig. 13.3
A flow chart depicts pivotal trials for platinum-sensitive patients in first line palliative care. The trials are, EXTREME in 2008 has P F and EXTREME. KEYNOTE, 048 in 2019 has pembrolizumab, EXTREME, and Pembro P F. T P Extreme in 2021 has EXTREME and T P Ex.

Pivotal randomized trials in platinum-sensitive patients in the first-line palliative setting

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In platinum-resistant disease, the current standard of care has been defined by two phase III trials, CheckMate-141 and Keynote-040, primarily focusing on the second-line setting but also including patients with confirmed progression within the first 6 months (22%) and between 3 and 6 months (15%) after primary treatment completion, respectively (Fig. 13.4). Both studies had a similar design exploring the anti-PD-1 inhibitors nivolumab and pembrolizumab, respectively, with almost the same comparator arms containing investigator’s choice between single-agent cetuximab, methotrexate, and docetaxel [40, 41]. For Checkmate-141, a subgroup analysis of overall survival in platinum-refractory patients confirmed the benefit in this difficult-to-treat population even at 2-year follow-up (median of 7.7 versus 3.3 months) [42]. Interestingly, another subgroup analysis performed in both trials suggested that single-agent docetaxel is more effective than monotherapies with either methotrexate or cetuximab and that it may even be as effective as immunotherapy. Nevertheless, such conclusions are speculative and biased by small numbers of patients in the respective analyses [43].

Fig. 13.4
A flow chart. The second line has trials of checkmate 141 in 2016 and keynote 040 in 2019. They further split into 2 components. In curative settings, 22 percent of patients are treated with 0 to 6 months after platinum, and 15 percent are treated with 3 to 6 months after platinum.

Pivotal randomized trials in platinum-resistant patients in the first-line palliative setting

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Decision-Making Factors

Some of them have already been addressed. Here, we will provide a summary, and interested readers are advised to refer to our previous publication presenting a decision-making algorithm [44]. Except for the first two, all factors are continuous variables ranging from minimum to maximum values.

Categorical Variables

Platinum Eligibility

In patients with platinum-sensitive tumours, three treatment options are supported by randomized data: biochemotherapy (the preferred EXTREME regimen or alternatively TPEx), immunochemotherapy (Keynote-048 combination regimen), and immunotherapy alone (pembrolizumab according to Keynote-048). Patients with platinum-resistant tumours should preferentially receive immunotherapy (nivolumab or pembrolizumab) or chemotherapy. For the latter option, no standard-of-care has been defined but taxanes (paclitaxel or docetaxel) with or without cetuximab can be recommended if immune checkpoint inhibitors are not accessible.

Reflecting compromised organ functions, patient’s general health status, previously administered dose, and some other specific situations, contraindications to cisplatin have been summarised elsewhere [22]. Contraindications to carboplatin are much less frequent, being mostly linked to impaired bone marrow capacity, hypersensitivity, first trimester of pregnancy, and lactation.

Disease Site

We have already indicated the caveat of locoregional recurrence in patients treated with immune checkpoint inhibitors and that distant dissemination may preclude efficacy of biochemotherapy [30, 31]. Another recent discovery points towards possibly restrained efficacy of immunotherapy in liver metastases owing to altered antitumour immunity and CD8+ T cell depletion [45].

Continuous Variables

Overall Health Status (From Fitness to Frailty)

In comparison to later stages of the disease course, treatment-naive patients are usually in a better overall condition, and their treatment tolerance and outcomes are superior. However, the majority of candidates for first-line systemic therapy present with a recurrence after multimodality management of locally advanced SCCHN and they may present with various adverse consequences thereof, especially if the disease relapses shortly after a platinum-based regimen.

Patient’s health status can be appraised at two levels. The first is more general and corresponds to the well-known performance status, being one of the most commonly used measures in clinical practice to estimate overall survival and treatment toxicity. However, it has several downsides. The correlation between toxicity and performance status pertains to conventional chemotherapy based on data from the 1980s. Thus, extrapolation to the current setting is problematic, primarily due to advances in supportive care and introduction of new medicines because targeted therapies, particularly modern immunotherapy with immune checkpoint inhibitors, might fit less to this model [46, 47]. Another disadvantage is that performance status is not an equal replacement of functional status comprising patient ability to complete activities of daily living (ADLs like washing, dressing, feeding, mobility etc.) and instrumental ADLs (IADLs like housework, shopping, taking medicines etc.), and it is even a less suitable surrogate of comorbidity scales. This holds true mainly for the elderly population, in which comorbidities rank among the most common indispositions followed by impaired IADLs, nutritional compromise, depression, cognitive dysfunction, impaired ADLs, and deteriorated performance status (grade ≥2 according to the Eastern Cooperative Oncology Group scale), the latter of which is found only in about 20% [48, 49]. Although performance status continues to be a widely accepted stratification factor for clinical trials and has real-world applicability in many young patients, it does not unfortunately play this role in the elderly.

Not only account elderly patients for the majority of cancer patients, more than half of them are frail or vulnerable and only less than one third fit [1, 50]. Comprehensive geriatric assessment (CGA) addresses the multifaceted health characteristics of elderly people summarized as biological age. In routine practice, geriatric screening tests (e.g., G8) are less time-consuming but still appropriate to select those who are not fit and require a full CGA to conclude on their biological age. Fit elderly persons should receive full-dose standard therapy because they derive the same anticancer benefit as their younger counterparts, albeit still with a potentially higher risk of toxicity due to physiological changes in metabolism; vulnerable patients may need alternative regimens or dose reductions and frailty precludes conventional treatment [50, 51]. Nevertheless, immune checkpoint inhibitors may still be a good option in frail or poor performance patients irrespective of age [38, 47].

The second level of health appraisal focuses specifically on comorbidities that besides their impact on general well-being, can also imply distinct contraindications for some drugs such as renal insufficiency for cisplatin, coronary artery disease for 5-fluorouracil, solid organ transplantation for immune checkpoint inhibitors, and many more [22, 52, 53]. In these cases, alternative regimens are required. Cisplatin/5-fluorouracil doublet may be replaced by carboplatin/5-fluorouracil in the EXTREME and Keynote-048 regimens. The TPEx schedule substitutes 5-fluorouracil for docetaxel, and treating physicians can opt either for cisplatin/docetaxel or carboplatin/docetaxel. If no third agent is added, both cisplatin/paclitaxel or carboplatin/paclitaxel are viable options [18, 33, 36, 54]. Instead of immune checkpoint inhibitor monotherapy in the second line, patients may receive single-agent taxane, methotrexate, or cetuximab [40, 41]. Every deviation entails changes in toxicity profile with some of them being also linked to decreased efficacy as in the above-mentioned cases of carboplatin or single-agent substitutions for immunotherapy [23, 40, 41].

Tumour Burden (From High to Low)

Mounting evidence suggests that increasing tumour size negatively correlates with response to immune checkpoint inhibitors and other types of immunotherapy. The underlying mechanism relates to local and systemic changes induced by large tumours leading to formation of a more immunosuppressive microenvironment [55]. Another implication of tumour volume is the corresponding probability to elicit symptoms. Here, three treatment characteristics have a key relevance, involving objective response rate, rate of progressive disease, and time to response. They inform us about the potential of a given systemic therapy to counteract increasing tumour size menacing to cause symptoms [56]. While a chemotherapy component is crucial to assure high response rates both in biochemotherapy and immunochemotherapy regimens, the immunotherapy component, either given alone or with chemotherapy, may have deleterious effects in terms of higher rates of progressions as we discussed earlier and probably also on time to response when given as monotherapy. Theoretically, due to its indirect action through mobilisation of immune cells, more time is needed to obtain tumour shrinkage with immunotherapy. This has been only partially reproduced in clinical practice so far because median time to response was comparable between immunotherapy and chemotherapy arms in CheckMate-141 and Keynote-048 but was longer in the pembrolizumab arm in Keynote-040 (4.5 versus 2.2 months) [36, 40, 41]. Of note, administration of only two doses of nivolumab prior to curative resection of locally advanced SCCHN (i.e., already at one month from nivolumab initiation) yielded radiographic tumour reduction from baseline in about 50% of patients [57].

Disease Pace (From Fast to Slow)

The speed of tumour-cell proliferation measured as tumour doubling time and the speed of tumour-cell shedding leading to formation of new regional or distant metastases are two principal events defining tumour kinetics. It ranges from indolent cases over faster progressing cancers to cases of hyperprogression [29, 56]. A fast growing disease needs a similar approach as large tumours aiming at high response rates, low rates of progression, and a short time to response, whereas in a slowly growing disease we may prioritize less intensive regimens similarly to small tumours (e.g., local ablation, immunotherapy alone) or even periods of watchful waiting [44]. Recently, we introduced the term argometastases delineating slowly developing distant metastases which can be cured with local ablation [58].

PD-L1 Expression (From High to Low)

Tumours exposing this ligand on cell surfaces derive better outcomes from immune checkpoint inhibitors. At present, this statement holds true for a survival advantage shown with pembrolizumab in the first-line setting according to Keynote-048 where the expression was measured as CPS, i.e., including also non-tumoural cells, mostly lymphocytes and macrophages [36]. In Keynote-040, better survival and response rate were associated with a higher PD-L1 expression measured solely on tumour cells as tumour proportion score (TPS) of 50% or more. Importantly, CPS was not predictive in Keynote-040, and no correlation with either CPS or TPS was found in CheckMate-141 [40, 41]. Nevertheless, PD-L1 expression remains the only validated molecular marker in recurrent and/or metastatic SCCHN warranting further research to improve its predictive value.

Treatment Sequencing

Acknowledging the continuous process of malignant development from early to advanced stages, both in the primary and recurrent disease settings, as well as the inherent propensity of SCCHN to relapse (Fig. 13.1), therapeutic decision making should always look farther into the natural disease course and respond to questions as of what will be the next best step in case of failure. Treatment sequencing is therefore not a series of ad hoc decisions each time a new treatment is required but a comprehensive pre-planned individualized analysis of anticancer management divided into several consequential therapeutic blocks that are employed at disease progression or relapse (Fig. 13.2). In SCCHN, it represents an emerging new concept evolving along with the introduction of new treatment options or combinations.

Illustrative to this is a sequential administration of immune checkpoint inhibitors in the recurrent and/or metastatic setting as opposed to the standard concomitant approach proposed by Keynote-048. Median progression-free survival of biochemotherapy is 5.6 months according to EXTREME [33]. If patients who progress receive single-agent nivolumab according to CheckMate-141, it takes about 3 months for the survival advantage of immunotherapy to manifest which is actually the time needed for a separation of survival curves between nivolumab and the comparator arm [40]. Taken together, patients starting biochemotherapy may be benefiting from immunotherapy after about 8 months. Interestingly, this seems to be the same period necessary for a separation of survival curves in the Keynote-048 trial. Moreover, median overall survival of concomitant immunochemotherapy is about 14 months [36]. In the TPExtreme trial, patients treated initially with biochemotherapy and then second-line immunotherapy had a median overall survival of almost 20 months [18]. There were such sequentially treated patients also in the standard arm of Keynote-048 but only about 25% [36]. In summary, these results suggest comparable or even better outcomes of a sequential versus concomitant approach. However, when translating them to clinical practice, further elements should be considered such as toxicity (not excluding immune-related adverse events), risk of progression (locoregional recurrence versus asymptomatic distant metastases or the presence of already symptomatic distant metastases), quality of life, and patient’s perspective.

Conclusions

Growing knowledge from clinical trials and the real-world setting help us understand the natural course of head and neck cancer, predictors of its outcome, and principles of treatment sequencing. The above mentioned six factors should all be integrated in the decision-making algorithm but some of them may be prioritized while others brought to background, particularly if conflicting results are yielded (e.g., high disease burden with high PD-L1 expression or a locoregional recurrence with high PD-L1 expression).

Treatment sequencing with deferral of immunotherapy to the second line should also be part of the decision-making algorithm but may still be difficult to explain to patients confronted with the general assumption about a universal benefit of immunotherapy. In these situations, presenting the therapeutic model as a comprehensive approach with clearly defined turning points and available options may help pave the way towards an optimal solution for each patient.