Approximately 41,000 cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed annually in the United States, of which approximately one-third arises within the oropharynx. ¹ Located posterior to the oral cavity and between the nasopharynx and larynx, the oropharynx is critical in maintaining normal speech and swallowing. Its main components include the soft palate, posterior and lateral pharyngeal walls, faucial arches, tonsillar fossa, as well as the base of tongue (which anchors to the hyoid bone at the inferior border of the oropharynx). Its nonrestraining soft tissue boundaries as well as its rich lymphatic supply allow the escape of malignant cells, resulting in the majority of patients presenting with advanced disease (stage III or IV). ¹ Treatment often consists of surgical resection followed by adjuvant radiotherapy (RT) with or without chemotherapy; however, successful nonsurgical strategies have been developed over recent years through the refinement of RT techniques and/or the use of combination chemoradiotherapy (CRT). ² Recently, however, the introduction of minimally invasive techniques has rekindled interest in surgical therapy.

While the incidence of the majority of head and neck malignancies has decreased in parallel with the reduction in smoking, this trend has not been observed in cancers of the oropharynx. This coincides with an increased understanding of the contribution of the human papillomavirus (HPV), especially that of HPV16, to the oncogenic process. It is estimated that over the last two decades, HPV-related oropharyngeal malignancies have increased from 50% to now approximately 80% of all oropharyngeal cancers. ^3,4 While the biology is not fully elucidated, there are defining clinicopathologic features that are exemplified in this patient population. For instance, HPV-associated tumors predominately arise in the base of tongue or tonsils and are often associated with an early-stage (T1/T2) primary tumor yet advanced (N2/3) and cystic neck disease. In contrast to patients with HPV-negative oropharynx squamous cell carcinoma (SCC), those with virus-mediated disease are often younger by 10 years. ^5,6 While outcomes are improved compared to those anticipated in treating smoking-related oropharyngeal cancers, the changing nature of the disease creates challenges in terms of maximizing tumor control while reducing late-occurring side effects. ^3,7

This chapter focuses on how an increased understanding of the pathogenesis of oropharyngeal malignancies has informed therapeutic approaches as well as the technological advancements that aim to not only improve oncologic outcomes but also maintain functional integrity of the oropharynx and patient-reported quality of life (QoL).

Current evidence suggests that improvement in oncologic outcomes for HNSCC has not only coincided with refinement of treatment techniques but also reflected a shift in the etiology and pathogenesis of oropharyngeal malignancies. ⁸ Converging clinical, molecular, and epidemiologic evidence now confirm that HPV status is the single most important determinant of prognosis in OPSCC. HPV is an epitheliotropic, double-stranded DNA virus with >100 characterized genotypes; HPV16 with its predilection for oropharyngeal mucosa is the most common genotype isolated from the oropharynx. ⁹ HPV initiation underlies the epidemiologic observation that both incidence and survival of OPSCC are increasing in contrast to cancers associated with tobacco and alcohol whose incidence is decreasing with survival essentially stable. ⁶ In the United States, population registry data confirm an epidemic rise in the proportion of oropharyngeal cancers infected with high-risk HPV between 1984 and 2004, from 16% to 72%. ⁴ Similar prevalence rates have been observed in western Europe and Australia, although large regional, racial, and ethnic variations exist as reflected by low reported rates in Central Europe, Latin America, and among U.S. blacks. ^10–13

The improved prognosis associated with HPV in oropharyngeal HNSCC is related to substantially different responsiveness to treatment. The carcinogenic process in HPV-related malignancies is primarily attributed to the viral oncoproteins, E6 and E7, which bind and inactivate tumor suppressors p53 and pRb, respectively. Deficiency of p53 and Rb results in loss of cell cycle checkpoints and appropriate apoptosis. HPV-infected cells demonstrate unbridled progression through the cell cycle, a pro-proliferative state which benefits the HPV life cycle in early infection. HPV-related oropharyngeal malignancies more frequently appear in young, male patients with a good performance status and are associated with an early T stage, yet advanced nodal stage, often with cystic nodes. When compared to patients with HPV-negative disease, HPV-positive tumors are consistently associated with a 50% reduction in risk of death. ¹⁴ This is exhibited in multiple secondary analyses of recent institutional as well as cooperative group prospective studies that examined RT alone or in combination with various chemotherapy regimens. ¹⁵

In the first prospective trial designed to investigate HPV-related cancers, ECOG investigators (in ECOG 2399) utilized an induction regimen of paclitaxel and carboplatin and reported a higher response rate in those who were HPV positive. ¹⁵ Additionally, after a median follow-up of 40 months, progression-free survival (PFS) and overall survival (OS) were superior in HPV-positive patients when compared to those who were HPV negative. ¹⁵ This significant response to induction therapy led to the first national cooperative group trial testing a deintensification strategy. In this recently completed trial (ECOG 1308), patients with resectable HPV-positive oropharyngeal cancers were treated with three cycles of induction chemotherapy including cisplatin, paclitaxel, and cetuximab. Complete clinical response at the primary site was used as a dynamic response biomarker; complete responders were treated with a 20% reduction in radiation dose (54.0 Gy vs. 69.3 Gy). For those receiving reduced dose intensity-modulated radiation therapy (IMRT), PFS at 23 months was 84%, primary site LC 94%, nodal control 95%, and distant control 92%. The Danish Head and Neck Cancer Group (DAHANCA) was among the first to report improved outcomes in those with HPV-related oropharyngeal malignancies. In the DAHANCA 5 trial, patients in which samples were analyzed for p16, an HPV surrogate demonstrated improved locoregional control (LRC) as well as disease-free survival (DFS) after adjustment for tumor and nodal stage. ¹⁶ Additionally, an unplanned subset analysis of RTOG 0129 identified an association between tumor HPV status and survival among patient with stage III and IV HNSCCs. Here, 64% of enrolled patients were HPV positive and showed improved 3-year survival (82.4%) versus that of HPV-negative tumors 57.1%. ⁷ Using a recursive-partitioning analysis (RPA) a significantly increased risk of death between HPV status and pack-years of smoking identified patients at low, intermediate, and high risk of death. ⁷ With improved patient risk stratification, future trials will aim at maintaining excellent survival in the HPV-positive nonsmoking cohort while reducing late toxicities associated with current CRT regimens. In contrast, high-risk cohorts will be the focus of intensification strategies as both local and distant failures continue to affect a significant portion of patients (see Table 56-1).

Surgical Resection and Adjuvant Therapy

Prior to acceptance of definitive RT or CRT, surgical resection followed by adjuvant RT, if necessary, was the preferred treatment modality for HNSCC. For advanced, high-volume oropharyngeal carcinoma, surgical resection via an external approach was required for optimal oncologic control. The three main surgical routes consisted of transoral/transcervical, transpharyngeal, or transmandibular approaches, each of which could be extended with a maxillectomy and/or mandibulectomy if necessary. An accompanying flap reconstruction was often required. Each of these techniques has risks and sequelae including the potential to affect deglutition, respiration, and phonation. Resection was often followed by a 6- to 7-week course of external beam RT in order to diminish locoregional recurrence (LRR) at the expense of further reducing QoL. ¹⁷

Despite aggressive local therapy, approximately one-third of patients with advanced HNSCC treated by surgery and postoperative radiotherapy experienced LRR. ^18,19 Additionally, distant metastases (most commonly to the lungs) can also occur in advanced head and neck cancer patients, and the frequency is higher in patients who suffer LRR following definitive therapy.

In the postoperative setting, efforts to diminish both local and distant failure have focused primarily on the integration of chemotherapy. Two phase III cooperative group studies randomized postoperative HNSCC patients to radiation alone or radiation in combination with three cycles of cisplatin chemotherapy. These two randomized trials yielded positive results for their respective endpoints but differing results for OS. The EORTC trial enrolled 334 patients with pT3-4, TxN2-3, or T1-2N0-1 with adverse postoperative risk factors including extracapsular extension (ECE), positive margin, or perineural invasion (PNI). This trial demonstrated a clear benefit in LRC, DFS, as well as OS for those patients receiving cisplatin chemotherapy concurrent with radiation. ¹⁸ In contrast, the RTOG enrolled 459 stage III/IV HNSCC patients with greater than or equal to two lymph nodes, ECE, or positive margins. Here, the initial report identified a clear benefit in LRC, yet no evident increase in OS with the addition of cisplatin. ^19,20 With 10 years of follow-up, there was no difference in local-regional failure, DFS, or OS for the entire cohort; however, an unplanned subset analysis limited to those with microscopically involved margins and/or ECE demonsrtrated a significant improvement in all endpoints. ¹⁹ This supports a post hoc combined analysis suggesting that the combination of adjuvant CRT is best reserved for those with positive surgical margins and/or the presence of lymph nodes with ECE. ²¹ The OS benefit in those with microscopically involved margins and/or ECE outweigh the increase in toxicity exhibited by the addition of chemotherapy (Fig. 56-1).

Radiation and Cytotoxic Therapy

In an effort to avoid the cosmetic and functional impairment resulting from surgical resection and adjuvant CRT, several definitive RT regimens were developed that aimed to maximize tumor control while minimizing late side effects. ^22–24 The various radiotherapy regimens primarily rely on manipulating treatment time in order to exploit radiobiological principles such as reassortment of cells into the sensitive phase of the cell cycle (hours), repair of normal tissues (hours), reoxygenation (hours-days), and repopulation of tumor cells (weeks). In addition, the dose per treatment (fraction) is a critical variable in the design of a radiotherapy regimen as it drives dose-dependent late-occurring side effects such as fibrosis and stricture formation. These factors constitute the basis and radiobiological rationale for definitive, fractionated treatment courses.

Radiotherapy and Advanced Treatment Planning

In parallel with the advances in understanding the biology of HNSCC, transoral surgery, and integrating targeted systemic therapies, there have been technological improvements in RT. A widely used technique for improving the therapeutic ratio of RT is IMRT. ²⁵ IMRT employs fundamentally different means of radiation planning and delivery when compared to conventional head and neck RT. Conventional RT combines three or four large fields in which the RT dose to most normal structures (e.g., parotid glands, pharyngeal walls) is quite similar to the dosage to the target volumes of the tumor and regional lymphatics. IMRT combines numerous small and irregularly shaped radiation beams of variable intensities to achieve a radiation dose distribution that closely conforms to the target volumes. The planning process involves delineation of not only the tumor volume but also surrounding normal structures. Both the target as well as normal structures are assigned a priority and a desired dose to the volume of the structure (dose constraint). ^26,27 By assigning priorities and dose constraints, a computer algorithm assists in determining the optimal beam modulation in a process termed “inverse planning.”

While IMRT improves the dosimetry of RT, its effects on clinical outcomes are still being investigated. Small randomized trials of IMRT versus standard RT for nasopharynx cancer did not show a significant QoL benefit (despite showing significantly increased parotid gland flow with IMRT). ²⁸ In the United Kingdom, PARSPORT trial conventional RT was compared prospectively with IMRT in regard to parotid sparing and subsequent reduction of xerostomia in patients with pharyngeal carcinoma. ²⁹ The findings from this study at 12 and 24 months revealed that grade 2 or worse xerostomia was significantly lower in the IMRT group than in the conventional RT group. These findings were attributed to benefits in recovery of saliva secretion with IMRT compared to conventional treatment.

In addition to reducing dose to the parotid and other salivary structures with IMRT, it seems possible to improve dysphagia by limiting the incidental dose to the pharyngeal constrictors (PCs). Increased dose to the PCs contributes to prolonged feeding tube dependence. In a multivariate analysis, the volume of PCs receiving 70 Gy was associated with prolonged tube dependence along with advanced T-stage. Here, the proportion of patients requiring a feeding tube longer than 6 months were 8% and 28% for treatment plans with PC volume receiving higher doses. This suggests an opportunity to restrict the dose to the PCs during the planning process and potentially improve functional outcomes.

In general, conventional dose and fractionation consist of 2.0 Gy/d to a total dose of 70.0 Gy. Pure hyperfractionation is delivery of the same total dose in the same overall treatment time but with more fractions (i.e., two fractions per day). This strategy is not satisfactory since the total dose must be increased to account for the lower dose per fraction to achieve equivalent local control. Instead, when hyperfractionation is applied clinically, typically two fractions are delivered per day (with a 6-hour interfraction interval to allow for normal tissue repair). A common hyperfractionation schedule is 81.6 Gy delivered in 1.2-Gy fractions over about 7 weeks. This allows for a higher total dose with a minimal increase in late toxicity due to the lower dose per fraction. Another approach, acceleration with concomitant boost, delivers conventional fractionation during the first portion of treatment while the final 12 treatments are delivered twice per day. This effectively shortens the overall time to deliver a curative dose and is a treatment strategy designed to specifically address tumor repopulation. Multiple other approaches have been developed to accelerate the treatment course and address repopulation including a six-fraction per week strategy employed in DAHANCA 7 trial. ²⁴ Clinical trials have revealed that hyperfractionation and accelerated fractionation regimens have improved LRC and, in some trials, also survival. In a meta-analysis of 15 phase III trials with more than 6000 patients, altered fraction RT was associated with a 3.4% absolute benefit in 5-year OS when compared to conventional fractionation. ²²

An alternative approach, combining chemotherapy and radiation therapy, was also investigated. Results of phase III trials show that cisplatin chemotherapy given concurrently with radiation yields better LRC and survival rates than radiation alone in patients with locally advanced HNSCC. ^30,31 Cisplatin–radiotherapy significantly improved OS, PFS, and LRC compared with radiotherapy alone or the sequential administration of chemotherapy and RT in the sentinel Intergroup trial 0126. ^31,32 Although LRC and OS are improved with concurrent platinum-based CRT, a meta-analysis including 93 randomized trials with more than 17,000 patients revealed disappointing local and distant failure rates of 50% and 15%, respectively, coupled with an absolute 5-year OS benefit of only 6.5% compared to radiotherapy alone. ²

Platinum chemotherapy drugs are the best studied cytotoxic agents administered in combination with RT, either as monotherapy or in combination with 5-fluorouracil or a taxane. ² Concurrent cisplatin has been associated with the greatest benefit in LRC and OS. Doublet chemotherapy increases toxicity; no added oncologic benefit is observed over cisplatin monotherapy. ² Four large trials evaluating concurrent cisplatin in the definitive or adjuvant setting have defined a common dose and schedule: 100 mg/m², administered during weeks 1, 4, and 7 of RT. However, approximately one-third of patients are unable to tolerate the last dose; the hematologic, gastrointestinal, renal, otologic, and mucosal toxicities of this high-dose bolus cisplatin regimen can be significant. ^33–36 Recognition of the importance of the cumulative dose of cisplatin (greater than or equal to 200 mg/m²), rather than the dosing schedule per se, has resulted in increasing preference for less toxic weekly dosing schedules. ^32,34–37

The benefits achieved by altered fractionation appear to be limited when RT is delivered concurrently with high-dose cisplatin. The RTOG 0129 phase III study compared the efficacy of the combination of accelerated radiotherapy by concomitant boost with cisplatin to that of standard fraction with cisplatin. This trial demonstrated no significant difference in OS between accelerated and standard fractionation with 3-year OS of 70.3% and 64.3%, respectively. ^7,38 Additionally, there was no difference in PFS or patterns of failure. ^7,38 Combination therapy continued to exhibit a significant degree of acute grade 3 or greater toxicity, occurring in approximately 80% of patients in both arms of the study; therefore, CRT is best utilized in those with locally advanced disease.

Collectively, the CRT regimen most extensively tested for the management of locally advanced HNSCC is the combination of conventionally fractionated radiotherapy (70 Gy in 35 fractions over 7 weeks) with cisplatin, 100 mg/m², every 3 weeks or equivalent dosing regimen. Consequently, the majority of head and neck oncologists consider concurrent radiation and cisplatin the current standard-of-care for patients with locally advanced HNSCC seeking nonsurgical therapy.

Radiation and Biological Therapy

The epidermal growth factor receptor (EGFR), HER-1, is a member of the ErbB family of transmembrane receptor tyrosine kinases which is overexpressed and aberrantly activated in the majority of HNSCCs. ³⁹ EGFR activation in response to its ligand results in phosphorylation of its intracytoplasmic tyrosine kinase domain, leading to a cascade of signal transduction within the cell and ultimately alterations in DNA synthesis, cell proliferation, anti-apoptosis, and transcription of growth factors such as pro-angiogenic molecules. EGFR overexpression is associated with reduced survival and radiation resistance in HNSCC, supporting the clinical development of EGFR-targeting drugs as an effective antineoplastic or radiosensitization strategy. ⁴⁰

Cetuximab, a murine-human chimeric monoclonal antibody against EGFR, was evaluated and first approved in HNSCC in the context of radiosensitization. In a phase III trial, patients with locally advanced nonoperative HNSCC were randomized to RT alone or RT with weekly cetuximab. ⁴⁰ Both LRC and OS were significantly improved with cetuximab. The 3-year rate for freedom from local-regional progression and OS were 47% and 55% for RT plus cetuximab, compared to 34% and 45% for RT alone. ⁴⁰ The relative reduction in the risks of local-regional progression and death were 32% (p = 0.005) and 26% (p = 0.03), respectively. ⁴⁰ Important here, post hoc subgroup analysis noted that the survival benefit is most evident in the oropharyngeal subgroup.

Additionally, cetuximab appears to have a different toxicity profile than that of cisplatin. In the phase III study of cetuximab and RT for locally advanced nonoperated HNSCC, 93% of patients received the prescribed cetuximab dose, which compares very favorably to the compliance rate of high-dose cisplatin in RTOG 0129 (58%). ^38,40 Furthermore, the study showed no evidence that cetuximab increased the rate of grade 3 or greater mucositis or dysphagia, no evidence of an increased rate of late effects, and no evidence of a worsening of QoL relative to RT alone. ^40,41 This contrasts to the literature with concurrent platinum-based CRT, which suggests that certain long-term side effects such as feeding tube dependence are greatly increased relative to RT alone.

Because concurrent cisplatin or concurrent cetuximab improved survival compared to RT alone in separate phase III randomized trials, the natural and subsequent question was whether the addition of cetuximab to cisplatin–RT would confer a further survival benefit. RTOG 0522 randomized patients with stage III and IV HNSCC to CRT with cisplatin delivered every 3 weeks, with or without cetuximab. The patients were treated with accelerated fractionation as performed in both RTOG 9003 and RTOG 0129. Between 2005 and 2009, 940 patients were enrolled, of which 895 were evaluable. In the initial report of this study there were no differences in PFS or in OS; however, the addition of cetuximab led to an increased rate of grade 3 and 4 mucositis (45% vs. 35%, p = 0.003) and skin reactions (40% vs. 17%, p < 0.0001). While concurrent cisplatin–RT remains the standard of care for nonoperative management of HNSCC, concurrent cetuximab is an accepted alternative in patients who are cisplatin-ineligible. In addition, a direct comparison of cisplatin-based CRT to that radiotherapy combined with eight doses of cetuximab is being examined in RTOG 1016, a randomized phase III for HPV-positive stage III/IV patients.