Salvage Surgery in Head and Neck Cancer

Salvage surgery (SS) in head and neck cancer is considered a last resort treatment after failure of organ preservation treatments. It offers challenges to the patients and the surgeon. The outcome of SS is often uncertain in terms of survival and quality of life. This paper offers an overview of evolution in SS, tumor and patient factors to be considered, challenges in reconstructive surgery, complications of SS and the changing landscape with regard to increasing incidence of human papillomavirus positive tumours, the role of transoral robotic surgery, the importance of multidisciplinary management and shared decision making.

Is there a Role for Neoadjuvant Targeted Therapy and Immunotherapy?

Neoadjuvant chemotherapy in head and neck cancer is the subject of much debate. Multiple trials have shown that the concomitant addition of targeted therapies, such as cetuximab to neoadjuvant chemotherapy (docetaxel, cisplatin, 5-fluorouracil), results in increased toxicity. Furthermore, no apparent significant benefit has been demonstrated in small randomized studies. Additional trials are currently being conducted to investigate the role of neoadjuvant immunotherapy, such as anti-PD-(L)1 inhibitors.On the other hand, window of opportunity studies are trials in which patients receive one investigational compound in the period between their cancer diagnosis and the start of standard therapy. The evaluation of new compounds using this approach enables translational research and provides information on molecular and clinical activity as well as predictive biomarkers.

High-Dose Three-Weekly or Low-Dose Weekly Cisplatin during Radiation, What to Prefer?

In locally advanced squamous cell carcinoma of the head and neck, adding three cycles of high-dose (100 mg/m2) cisplatin every three weeks to definitive or adjuvant radiotherapy can significantly improve locoregional control and survival. One of the major drawbacks is severe acute toxicity with about 40% of patients developing mucositis, up to one fourth suffering from dysphagia, and at least 20% having bone marrow suppression. Late toxicity has been under- and sometimes mis-reported and may even be responsible for an increase in non-cancer-related deaths in long-term survivors. Moreover, efficacy outcomes are still not satisfactory with 5-year overall survival rates ranging between 40% and 50%, excluding the growing minority of human papillomavirus-related oropharyngeal cancer cases with a markedly better prognosis. Consequently, alternative regimens have gained attention with the aim to reduce toxicity, improve adherence, and maintain adequate anti-tumour activity. Low-dose (usually 40 mg/m2) cisplatin given in weekly intervals emerged as the preferred alternative to the standard, high-dose regimen. But do we have enough evidence to support this approach and which patients might become suitable candidates? While the use of high-dose cisplatin is supported by the results of four large trials randomizing altogether 1539 patients between conventionally fractionated chemoradiation and radiotherapy alone, there are only three small, similarly designed but possibly biased studies favouring a weekly regimen. In addition, two other trials randomly assigning patients to receive either high-dose or low-dose cisplatin, provided evidence against routine administration of the latter schedule. Therefore, although weekly cisplatin may enhance short-term tolerance in terms of gastro-intestinal, hepatic, hearing, renal, and haematological side effects, it cannot be excluded that this improvement comes at the price of compromised survival with no benefit in late adverse events. We acknowledge that certain clinical scenarios, particularly in the presence of relative contraindications to high-dose cisplatin, may favour a less toxic cisplatin dose and/or administration schedule, among which the low-dose weekly regimen. In this respect, the ever-growing population of elderly patients is in particular benefitting from a careful decision, taking into account the pros and cons of such regimens.

New and Promising Targeted Therapies in First and Second-Line Settings

Deeper understanding of the molecular pathogenesis of malignancies, including head and neck squamous cell carcinoma (HNSCC), has led to the investigation of several novel targeted therapies. These therapeutic approaches may eventually replace or complement existing treatment modalities, such as surgery, radiation therapy, and traditional cytotoxic chemotherapy. Epidermal growth factor receptor (EGFR) inhibitors, and specifically cetuximab, are as of now the only class of targeted agents, excluding immune checkpoint inhibitors, with approval in the treatment of HNSCC. Beyond EGFR inhibition, novel therapies under evaluation are directed against vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR), PI3K/AKT/mTOR pathway, cell cycle regulation (for example, cyclin dependent kinases 4 and 6), HRAS, DNA repair mechanisms, and others. Development of new therapies has to take into consideration the complexity of solid tumors and their heterogeneity. Multitargeted combination therapy approaches may be required in certain cases in order to maximize antitumor effect. Ways to individualize treatment using validated biomarkers are likely to improve outcomes. We review the most relevant molecular targets in HNSCC and provide updates on clinical trial data with promising new targeted agents.

Mechanisms of Cetuximab Resistance and How to Overcome It

Deregulated or increased signalling of the epidermal growth factor receptor (EGFR) plays an integral role in the development of various cancer types, including head and neck squamous cell carcinoma (HNSCC), making it a compelling drug target. However, after initially promising results of EGFR-targeted therapies, such as the monoclonal antibody cetuximab, it became clear that both intrinsic and acquired therapeutic resistance are major roadblocks in the field of personalised cancer treatments.In order to unravel and overcome resistance to cetuximab, at least two strategies can be adopted.Firstly, therapeutic resistance to anti-EGFR therapy may arise from mechanisms that can compensate for reduced EGFR signalling and/or mechanisms that can modulate EGFR-dependent signalling. In this chapter, we discuss which mechanisms of cetuximab resistance are already known and which ones deserve further investigation. This enhanced knowledge will guide us to rationally design and test novel combination therapies that overcome resistance to EGFR-targeting agents in cancer treatment.Secondly, an urgent need remains to develop novel targeted treatments for single-agent or combined therapy use. In this view, due to the particular mode of activation of the EGFR receptor, involving ligand-induced homo- and heterodimerization of the four HER receptors, an increased inhibition scope of HER receptors most likely results in a more potent blockade of the HER network, preventing premature emergence of resistance and leading to a more pronounced therapeutic benefit. We discuss two multitargeted compounds, being MEHD7945A (duligotuzumab) and afatinib, in this chapter.Despite the huge efforts to unravel the molecular landscape of HNSCC, the main clinically validated target remains EGFR. However, immune checkpoints, like programmed cell death protein 1 (PD-1), are gaining clinical approvals as well. We underscore the importance of adopting rational drug combinations to enhance the therapeutic effect of the EGFR-inhibitor cetuximab and highlight the ongoing search for predictive biomarkers, with the ultimate goal of delivering individualized cancer therapy to HNSCC patients.

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

Despite significant technical improvements in the management of patients with locoregionally-advanced head and neck cancers, too many patients fail to achieve durable remissions that ultimately translate into cures. Loco-regional recurrence and/or metastatic relapse after intensive local therapies remain the scourge of those who suffer from this disease, and the surgeons and physicians who treat them. Regrettably, until now, we have failed to develop effective adjuvant therapies that can be delivered after the completion of definitive loco-regional treatment in order to reduce the risk of disease relapse. In this chapter, approaches based on cytotoxic chemotherapy, targeted therapies directed against c-erbB/HER receptors and immune checkpoint inhibition will be discussed. Neither cytotoxic chemotherapy nor anti-HER-family targeted therapies have proven to be successful as adjuvant therapies for locoregionally-advanced head and neck cancers, but there is significant hope that anti-PD1/anti-PD-L1-targeted antibody therapies may deliver progress in this area for the first time.

Patients with Rare Head Neck Cancers: Do They Need a Different Approach?

A cancer is considered rare when the annual cancer incidence is less than 6 per 100,000 inhabitants. In absolute numbers more than 500,000 patients per year are diagnosed with a rare cancer, and 4,300,000 rare cancer patients are prevalent in Europe. The definition is widely adopted among the different scientific international societies like ESMO and ESTRO. This means that 22% of all diagnosed cancers are rare and out of the 260 cancer types identified (www.rarecare), 223 (86%) are rare. The European Network for Rare Solid Cancers (EURACAN) uses this definition to create reference networks in order to improve rare cancer care.In Europe rare cancer patients have poorer survival as compared to common cancer patients. Moreover, the survival of rare cancer patients in the Netherlands has barely increased over time (from 50% in 1995–2000 to 56% in 2012–2016), in contrast to the common cancers (from 59% in 1995–2012 to 72% in 2012–2016). Clinical decision-making is more problematic in the case of a rare cancer because clinical studies on that tumor will be more difficult to do; so, the quality of available evidence tends to be limited. Furthermore, the decreased survival is partly caused by a delay in the diagnostic trajectory and found to be related to more advanced staging resulting in less effective treatment options.Examples of rare cancers in the head and neck region are salivary gland cancers, which can be divided in 22 histological subtypes, and epithelial tumors of the nasal cavity and sinuses, e.g. intestinal type adenocarcinoma. Furthermore, soft tissue sarcoma and bone sarcoma and Merkel cell carcinoma, which are rare and frequently located in the head and neck area (Table 20.1).New developments in the treatment of (recurrent/metastatic) salivary gland cancer, especially salivary duct cancer, will be discussed. By unraveling tumor characteristics, such as genetic alterations and protein expression profiles, therapeutic strategies tailored to the patient’s tumor can be rationalized. This genomic profiling and mapping of immunohistochemical expression profiles is essential in the search for a suitable treatment or study approach. Thereby, it alleviates the paucity in systemic treatment options and can significantly alter the prognosis of patients with rare cancers.

The Role of Liquid Biopsies for Monitoring Disease Evolution

Body fluids of cancer patients have attracted increasing attention in biomedical research within the last 15 years since—as so-called liquid biopsies—they represent a non-invasive source of clinically exploitable biomarkers, including circulating tumor cells (CTCs) and cell-free tumor DNA (ctDNA). Assessment of CTCs in peripheral blood from solid cancer patients has proven useful for detection of subclinical disease which otherwise remains invisible for current staging techniques. Based on results from large cohort studies in breast and colon cancer, diagnostic tests for enumeration of CTCs have been developed which can be used for tumor staging, prognosis, and post-treatment surveillance. Circulating plasma DNA derived from Epstein–Barr or human papilloma viruses has been established as a sensitive and highly specific biomarker for early cancer detection and disease monitoring. More recently, first studies have been initiated for studying the diagnostic value of mutant variants in plasma-derived ctDNA for treatment selection, response assessment and early detection of treatment failure.Advanced Head and Neck Squamous Cell Carcinoma (HNSCC) represents a malignancy associated with locoregionally advanced stage at presentation, dismal prognosis and little improvement in treatment outcome over the past decade, especially for patients with metastatic disease. HNSCC patients might therefore benefit from incorporation of liquid biopsy-based assays in clinical management. In the following chapters, I will summarize current evidence of the diagnostic value of liquid biopsies in HNSCC and give examples of potential clinical applications.

Optimal Supportive Measures during Primary Treatment

Supportive care during curative treatment of head and neck cancer patients has different scopes: reducing the burden of acute toxicities and limiting the risk of developing late adverse effects; increasing the quality of life of the patients; allowing to perform optimal curative therapy, maintaining treatment dose intensity; preventing higher grade toxicities so to reduce also the costs associated with hospitalization, examinations, visits and use of drugs. At the same time, it is necessary to give uniformity in the supportive care protocols, as these preventive and therapeutic measures may influence the results of oncological treatments and their efficacy should be evaluated in a consistent manner. Several preventive and therapeutic interventions are available, particularly in the context of chemoradiotherapy, where the adverse events are more prominent. An accurate evaluation of the patient and a tailored approach with preventative indications and therapeutic interventions represent key factors. This approach could be easily identified within a “simultaneous care” strategy, as the optimal supportive measures are provided concurrently to the best therapeutic approach since the beginning of the treatment.

Epidemiological Aspects in Nasopharyngeal Cancer

Nasopharyngeal cancer (NPC) is an uncommon cancer. According to the Global Cancer Observatory, of the 129,000 new diagnoses in 2018, 85% has been made in the Asiatic population. In males the annual age adjusted rate of incidence (per 100,000) dramatically varied between 8 in South-Eastern Asia and <1 in Europe. In Europe (period of diagnosis 1999–2007), the annual incidence rate varied between 0.7 (South of Europe) and 0.2 (North of Europe). Incidence is three time higher in men than women. Elderly are more affected than young people. Five-year survival, from European population based cancer registries was 49% (period 1999–2007), survival was better in younger than in older patients (73% vs. 31%), prognosis was more favorable in women than men (54% vs. 47%). Geographical variation of survival was reported, with poor 5-year in the Eastern European countries (36%).Incidence and population based survival are crucial for public health and planning clinical study. Lifestyle and environmental factors are responsible of the decreasing trend of incidence in quite all the world countries.Being one of the rare diseases, NPC need to be centralized for diagnosis and treatment. In Europe, the European Joint Action of Rare Cancers and the European Reference Network for rare disease will play an important role to make progress and reduce geographical disparities.