Cancer of the Head and Neck

Initial Head and Neck Examination

An initial examination of the head and neck should be performed with the patient sitting upright in a chair. A standard and complete head and neck examination should then be conducted including inspection of the head and neck skin and the scalp. Cranial nerves II through XII should be assessed. Ear examination with otoscopy should be performed. Nasal examination may be performed with anterior rhinoscopy or nasal endoscopy as indicated. Examination of the oral cavity is performed with a headlight to allow bimanual examination of the lips, buccal mucosa, gingiva, floor of the mouth, and oral tongue. Palpation of the oral tongue and the base of the tongue is crucial for a thorough evaluation. The tongue base and larynx are examined with use of a mirror or, preferably, flexible fiberoptic laryngoscopy. While viewing the larynx fiberoptically, the physician should ask the patient to perform several maneuvers: vocalization to allow assessment of vocal cord motion; tongue protrusion to aid in viewing the vallecula; and filling the cheeks with air to help visualize the pyriform sinuses. After the subglottis has been evaluated, the laryngoscope can be removed and the examination completed with palpation of the parotid glands, the thyroid, and the cervical nodes. The size, mobility, and consistency of any mass should be carefully noted.

Staging Investigations

Radiography is a necessary component of the evaluation. It is standard practice to order a computed tomography (CT) scan of the head and neck, preferably with contrast material, for any patient with suspected cancer. This examination helps not only with evaluation of the size and location of the primary tumor, but also with assessment for any possible lymph node metastasis. A magnetic resonance imaging (MRI) scan can provide useful additional information in certain cases, such as nasopharyngeal lesions, skull base lesions, or soft tissue tumors, and for the assessment of parapharyngeal space lesions. Routine preoperative laboratory studies may be obtained if surgery is being considered, in addition to medical consultations as indicated.

If a suspicious mucosal lesion is anatomically accessible, a biopsy may be undertaken in the clinic after administration of a local anesthetic. In general, biopsies of oral cavity lesions and selected oropharyngeal lesions are performed in an outpatient setting. Biopsies of selected lesions of the tongue base, larynx, and hypopharynx may also be performed in the clinic with flexible laryngoscopes with biopsy ports, although most lesions require direct laryngoscopy and biopsy with the patient anesthetized. During this procedure, flexible esophagoscopy can be considered to rule out tumor involvement of the cervical esophagus. If lymphadenopathy is identified at palpation, the abnormal node may be assessed by means of fine-needle aspiration (FNA). Radiographically suspicious nodes that are not easily palpable can be assessed with ultrasound-guided or CT-guided FNA. An open biopsy of a neck node should be considered only if the findings of FNA are inconclusive.

Currently the American Joint Committee on Cancer (AJCC) staging system, which uses unidimensional tumor size and local anatomic invasion (T category), nodal involvement (N category), and presence of metastatic disease (M category), is the most widely accepted and applied prognostic system relating to cancer. In general, T1, T2, and T3 represent increasing tumor size, whereas T4 is defined by invasion of a surrounding structure (i.e., skin, nerve, vessel, and cartilage). The node (N) category is classified largely by size and location (ipsilateral versus contralateral) of involved lymph nodes. The absence or presence of distant metastases is defined as M0 if absent or M1 if present. The T, N, and M categories are combined into overall AJCC stages that are presented in Table 65.1 . Because the natural history of HNC varies somewhat according to specific anatomic location of the primary disease and because stages III and IV include a large number of individual T, N, and M stages, it is customary to refer to specific HNCs by their individual T, N, and M stage and the primary site. Recent work has shown that for HPV-positive oropharyngeal carcinoma, the current AJCC staging system may be suboptimally predictive; this is currently under review.

Follow-up Program

After completion of initial treatment, patients are carefully assessed for response to treatment. For advanced-stage cancers treated with chemoradiation therapy (CRT), CT, positron emission tomography (PET), and/or MRI is performed in order to assess radiographic disease response approximately 12 weeks after completion of treatment. Thereafter, patients are seen at gradually increasing intervals for surveillance examinations. Chest radiographs may be obtained intermittently as indicated for surveillance for metastatic disease or secondary primary malignancies, particularly for patients with a smoking history. Thyroid-stimulating hormone (TSH) levels should be checked every 12 months because 20% to 25% of patients who have had neck irradiation experience hypothyroidism necessitating thyroid hormone supplementation. After 5 years, patients may be examined yearly.

Defining Treatment Algorithms: Primary Site

The single-modality principle for treatment of early-stage disease attempts to minimize toxicity and emphasizes the importance of patient and tumor selection. When postoperative radiation therapy (PORT) appears likely, definitive RT may be more appropriate, particularly for small-volume disease, because it is unclear that combined-modality therapy is superior to RT alone. This consideration is particularly relevant when initial definitive en bloc resection may, in combination with PORT, increase treatment toxicity and organ dysfunction. Not uncommonly, these issues arise with more extensive early-stage HNSCC or in cases in which the anatomic location limits achievement of adequate surgical margins. For unresectable locally advanced disease, conventionally fractionated RT has been traditionally recommended. Suboptimal locoregional disease control in the absence of surgical options has forced investigation into various modalities of treatment intensification including neoadjuvant chemotherapy, concurrent CRT, and altered fractionated RT.

Although the AJCC staging system is the most widely accepted and applied prognostic system in persons with cancer, much attention has been given to its inability to enable identification of patients with HNC who are at high risk of treatment failure. Accordingly, various radiographic biomarkers have been studied to help improve our ability to prognosticate outcomes for individual patients.

During the past decade, interest has expanded in the use of PET-CT, specifically given its ability to be an accurate and sensitive imaging modality for the pretreatment and posttreatment evaluation of patients with HNC compared with clinical examination and CT alone. Controversy has plagued studies evaluating the prognostic and predictive usefulness of the standardized uptake value (SUV), essentially the metabolic tumor activity. The success of metabolic-based radiographic biomarkers rests on the ability to standardize protocols to enable interinstitutional comparisons.

Similarly, some volumetric indices have been explored as potential prognostic and predictive indices. Multiple studies have demonstrated that the gross tumor volume correlates with locoregional control and survival in patients with HNSCC undergoing surgery, radiation, or CRT treatments in various HNC sites. Further incorporation of metabolic volumetric parameters in defining tumor volume, such as the metabolic tumor volume, has defined yet another prognostic radiologic biomarker. Unfortunately, no volumetric cut points have been prospectively validated.

Defining Treatment Algorithms: Management of the Neck

Traditionally, the management of the primary tumor site dictated the treatment modality for the neck as a strategy to facilitate efficient management of HNSCC. Treatment decision making for the neck has adopted a similar therapeutic paradigm of risk stratification to optimize the therapeutic ratio, but the algorithm becomes more complex as a result of the primary treatment considerations. Conceptually, the issue of functional organ preservation also may be extended to the neck, because neck dissection may result in cosmetic changes and compromised neck and shoulder function. Similarly, RT-induced edema and fibrosis may compromise the goal of functional neck preservation and may be exacerbated by a neck dissection.

Typically, combined-modality strategies are used for the treatment of neck disease. In a neck with negative clinical findings, when surgical resection has been elected for the primary site management, elective neck dissection may be omitted for most subsites if preoperative evaluation determines a high risk of requiring PORT and if the risk of occult nodal metastasis is sufficiently high to warrant elective management. When RT has been selected for management of the primary site, neck dissection in a neck with negative clinical findings is not indicated. In fact, pre-RT neck dissection may alter the lymphatic flow of the neck, necessitating that larger volumes of the neck be irradiated. Pre-RT neck dissection also may contribute to delays in the delivery of RT, which have been reported in a retrospective analysis to contribute to an adverse overall survival when compared with post-RT neck dissection.

When conventionally fractionated RT alone has been used for locally advanced HNSCC, suboptimal regional control rates coupled with the morbidity and the limited success of subsequent salvage neck dissection have prompted the incorporation and general acceptance of a planned neck dissection. This approach, in the presence of residual adenopathy after RT, also has been selectively applied to patients with adverse risk factors such as large nodal size (typically ≥3 cm). This risk stratification is based on RT series demonstrating an inverse relationship between nodal size and control rate. In a study of RT alone for treatment of HNSCC in 1251 patients, Dubray and colleagues noted 3-year neck control rates, by maximum nodal size, of 77% for 0.5 cm, 67% for 2 cm; 60% for 4 cm, 52% for 6 cm, 37% for 8 cm, and 7% for 10 cm. Multivariate analysis revealed that regional relapses independently increased with increased nodal size ( P = .0001), decreased radiation dose ( P = .0001), T4 primary disease ( P = .0001), node fixation ( P = .02), bilateral neck disease ( P = .03), and geographic miss ( P = .0001).

Controversy continues, however, regarding the benefit of a planned neck dissection in the setting of a complete clinical response in the neck, particularly in large pretreatment lymph nodes, after completion of RT. Treatment with conventionally fractionated RT has demonstrated that the prognosis for patients with large neck nodes with a complete response (CR) is a comparable with that of patients with smaller nodal metastases, and that the risk of relapse is low. This finding suggests that perhaps the subgroup of patients with a CR in the neck may have more radiosensitive disease and may not require a neck dissection. For patients with oropharyngeal carcinoma, Level I evidence has demonstrated that follow-up with PET-CT surveillance is noninferior to planned neck dissection and results in fewer operations and cost savings. A neck dissection continues to be sometimes favored for persons with advanced neck disease (especially stage N3), because the likelihood of achieving a CR with RT alone is limited. Assessment of disease response by PET-CT allows a more objective evaluation of patients who would likely benefit most from a neck dissection.

Second Primary Tumors

Management of patients with HNSCC is further complicated by the risk for the development of second primary carcinomas and relapses within the aerodigestive tract that may have been extensively exposed to prior treatment. An irradiated aerodigestive tract not only limits reirradiation but also may preclude effective surgical salvage, because concerns of residual microscopic disease often exist in cases that would otherwise warrant use of PORT. When a second primary or relapse occurs within a previously irradiated field, surgical resection should be the primary treatment option. Experiences with various repeat external beam radiotherapy (EBRT) strategies, including the integration of chemotherapy, have unfortunately demonstrated limited success, although advances in proton beam therapy may mitigate reirradiation toxicity to some extent. The exception appears to be nasopharyngeal carcinomas (NPCs) that are more radiosensitive. Even then, significant late complications may arise but may need to be considered in view of the limited surgical options.

Surgery

The decision to treat HNSCC with surgical therapy must be undertaken carefully. To assess whether a patient is a surgical candidate, the input of a multidisciplinary team is invaluable. Of the many issues to be considered is the medical condition of the patient. Severe cardiac or pulmonary disease, profound malnutrition, and generalized debilitation are relative contraindications to immediate surgical intervention, and therefore a detailed assessment by an experienced internist or cardiologist is mandatory when a major resection is planned.

The next important consideration is whether the lesion can be removed safely with adequate margins. The resectability of a tumor is assessed via physical examination and radiographic studies. In general, tumor involvement of certain anatomic landmarks, including skull base involvement, intracranial extension, invasion of the prevertebral fascia, or carotid encasement, renders the lesion unresectable. This is due to the inability to achieve adequate normal tissue margins in these areas. In addition to tumor location, massive tumor size also can preclude total extirpation because tumor-free margins may be impossible to obtain. In some cases, adequate reconstruction may be difficult, and other forms of therapy should be considered.

Postoperative function is a primary concern in considering surgical therapy. Speech articulation, voice quality, swallowing, airway stability and protection, cosmetic appearance, facial motion, shoulder and neck function, facial and neck sensation, and many other functional outcomes may be affected by surgery in the head and neck region. Although complete resection of the malignancy is of paramount importance, reconstruction of the surgical defect must be designed so that the patient has an opportunity to regain as much speech and swallowing function as possible. Site-specific considerations are discussed in the following sections.

The ability of the patient to participate in postoperative rehabilitation should also be reviewed. Patients who are emotionally or socially unable to participate should be identified early in the decision-making process. They may be better served with different forms of therapy.

In general, primary surgical therapy is selected for patients with tumors of the oral cavity, skin, salivary gland, paranasal sinus, thyroid, selected early-stage or advanced-stage larynx cancer, and carefully selected lesions of the oropharynx. Patients with very advanced tumors invading bone, destroying cartilage, or extending into the soft tissues of the neck are considered for primary surgical therapy. When patients have severe organ dysfunction as a consequence of cancer infiltration, surgery should be considered because functional restoration with nonsurgical therapy is unlikely.

Neck Dissection

A variety of different types of neck dissection may be performed ( Fig. 65.1 ). The radical neck dissection is a procedure wherein the lymph nodes from all five levels of the neck, the sternocleidomastoid muscle, the internal jugular vein, and the spinal accessory nerve are all removed en bloc. This procedure is indicated in the setting of high-volume neck metastases involving these nonlymphatic structures.

A modified radical neck dissection removes lymph nodes from all five levels of the neck but spares one or more of the nonlymphatic structures. Three types of modified radical neck dissection are type I (which spares one structure, most commonly the spinal accessory nerve), type II (which spares two structures, most commonly the spinal accessory nerve and the internal jugular vein), and type III (spares all three structures—the spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscle). A type III dissection also is termed a functional or Bocca neck dissection. Of these three structures, removal of the accessory nerve is generally considered to result in the most clinically significant functional deficit from shoulder dysfunction. Selective neck dissections involve the resection of fewer than all five levels of lymph nodes, usually involving three or four levels according to the site of the primary cancer.

Radiation Therapy

RT has a long and successful history in the treatment of primary head and neck malignancies. Current RT practices have evolved to include a fractionated RT prescription delivered with modern linear accelerators that can produce a spectrum of beam energies. With fractionation, issues of patient immobilization and treatment setup reproducibility become important considerations. For the head and neck, critical normal tissue structures such as the spinal cord, brainstem, and optic chiasm often are in close proximity to the irradiated target. For these reasons, a prerequisite for treatment simulation is that patients be immobilized with various devices such as a custom made facemask and frame, with the setup referenced to a laser light coordinate system in the treatment rooms ( Figs. 65.2 and 65.3 ).

Immobilization addresses the issue of the precision of the treatment delivery as a strategy to optimize the therapeutic ratio. Historically, patients were treated with two-dimensional (2D) RT or three-dimensional (3D) conformal RT, which did not permit significant sparing of normal tissues and resulted in significant toxicity. In these cases, the oncologist would outline the areas to irradiate on a radiograph of the head and neck. Modern treatment with intensity-modulated radiation therapy (IMRT) involves obtaining axial CT images and delineating the tumor and normal tissue on each CT slice. IMRT uses multiple beam angles and allows the beam modulation to achieve exquisite dose conformality, which means that the tumor receives the full dose of RT while the dose delivered to critical normal structure is minimized. Multiple randomized trials have now demonstrated significantly reduced toxicity with IMRT compared with 2D RT and 3D conformal RT.

Given the improved conformality, the success of IMRT is dependent on the ability to identify anatomic sites that harbor subclinical disease. Currently, the basis for this determination is derived from surgical and clinical documentation of disease extension that is often unique to each head and neck subsite. Over the past decade, interest has been expanding in PET-CT, specifically given its ability to be an accurate and sensitive imaging modality for the pretreatment and posttreatment evaluation of patients with HNC compared with clinical examination and CT alone. Currently, the radiation oncologist must incorporate data from the clinical examination, CT, PET-CT, and often MRI when designing the radiation plan.

The identification of nodal groups typically at risk for harboring subclinical nodal metastases has proven more difficult. To aid in this identification, several reports have defined axial anatomic structures that may be used to delineate the various nodal groups ( Table 65.2 ). The incidence of nodal metastases has been summarized by site and can aid the radiation oncologist ( Table 65.3 ). Of note, however, when prior treatment to the neck has occurred, altered flow of lymphatics is a concern. As with head and neck surgery, judgment must be exercised with these precise treatment techniques.

Conventional or daily RT fractionation (typically, daily 1.8- to 2-Gy fractions to a total dose of 70 Gy) has permitted the delivery of high RT doses, which is currently limited by normal tissue radiation dose tolerance levels, such as in the mandible, parotid glands, brainstem, and lens. Conceptually, RT failures may result from insufficient doses of RT relative to the number of tumor clonogens or may be due to intrinsic tumor radioresistance. The former has proven to be more amenable to therapeutic manipulation with the use of altered fractionation schedules, which may be generalized into two groups: hyperfractionation and accelerated fractionation.

A hyperfractionation schedule, or the use of lower doses per treatment fraction, has been hypothesized to reduce the risk of late RT-induced complications associated with an increase in the total RT dose. Typically, the dose per fraction is reduced to 1.2 to 1.5 Gy and exploits a differential radiosensitivity between normal late-responding tissues and most HNSCC. To ensure that the overall treatment time is not adversely protracted, fractions often are delivered twice a day, with an interfraction period of 6 hours. European Organisation for Research and Treatment of Cancer (EORTC) trial 22791 compared hyperfractionation (1.5 Gy twice daily to a total dose of 80.5 Gy) with conventional fractionation (2 Gy once daily to a total dose of 70 Gy) in patients with T2–3N0–1 oropharyngeal cancer (excluding the base of the tongue). This trial demonstrated a statistically significant improvement in local control of the hyperfractionation arm (38% versus 56%; P = .01) at 5 years with no increase in late complications.

Alternatively, an accelerated fractionation RT schedule attempts to deliver the prescribed total dose over a shorter treatment duration. This strategy was founded on observations of adverse locoregional control rates with protracted treatment durations (with conventional fractionated schedules) such that higher total doses are required to maintain the same probability of tumor control. These results have been interpreted to be consistent with a model whereby tumor clonogens surviving each daily RT fraction undergo an accelerated rate of repopulation. As a consequence, a larger tumor burden would be expected with increasing duration of treatment interruptions. It has been rationalized that when the overall treatment time is reduced, the opportunity and impact of accelerated tumor repopulation would be minimized. As the severity of acute toxicities is increased, some accelerated schedule studies have attempted to modify the risk of unacceptable acute toxicities by modifying either the dose per fraction or the total dose as a strategy to achieve an acceptable therapeutic ratio. EORTC 22851 compared accelerated fractionation (1.6 Gy three times daily to a total dose of 72 Gy) with conventional fractionation (1.8 to 2 Gy once daily to a total dose of 70 Gy) in patients with intermediate to advanced HNCs, excluding the hypopharynx. A significantly improved 5-year locoregional control rate ( P = .02) was noted, but acute and late toxicities were increased in the accelerated fractionation arm.

To date no single fractionation schedule has proven optimal. Radiation Therapy Oncology Group (RTOG) 90-03, a phase III randomized study comparing hyperfractionation, two variants of accelerated fractionation, and standard fractionation, found that both accelerated fractionation with a concomitant boost and hyperfractionation were associated with improved locoregional control and disease-free survival as compared with standard fractionation, but acute toxicity was increased.

The Meta-Analysis of Radiotherapy in Carcinomas of the Head and Neck (MARCH) Collaborative Group pooled 15 HNSCC randomized trials for a total of 6515 patients and reported that altered fraction schedules, hyperfractionated or accelerated RT, had a 5-year absolute survival benefit of 3.4% (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.86–0.97; P = .003) and an absolute local control benefit of 6.4% (P < .0001) when compared with standard fractionation ( Fig. 65.4 ). It is important to note that the benefit was significantly higher for younger patients (aged <50 years). Because RTOG 01-29 and GORTEC 99-02 both demonstrated no significant improvement in concurrent conventionally fractionated CRT versus altered fractionated CRT, altered fractionated therapy is typically reserved for patients who are not candidates for systemic therapy.

Neoadjuvant and Induction Chemotherapy

Induction chemotherapy, which has been studied for more than four decades, has been repeatedly associated with significant tumor shrinkage and possibly with a decrease in the risk of distant metastases. Unfortunately, an improvement in overall survival for induction chemotherapy over standard treatment approaches has not been definitively demonstrated.

The concept of induction chemotherapy arose from several principles. It was postulated that chemotherapy could promote tumor regression, enhance locoregional therapy through sensitization, and identify potential candidates for a more conservative surgical approach as the need for improved quality of life through functional preservation arose. Thus organ preservation, rather than extensive, potentially morbid surgical procedures, came into vogue as a philosophical consideration in the management of advanced-stage disease. An additional attractive feature with this approach was the conceptual ability to treat micrometastatic disease in hopes of reducing distant failure rates.

Nonrandomized phase II trials in the 1970s used single-agent chemotherapy based on strategies used in the recurrent and metastatic setting. In these single-agent trials, 30% to 40% response rates were reported. Induction strategies subsequently evolved to include multiple chemotherapy regimens. The first reported trials by Wittes and colleagues demonstrated a 71% response rate, with CRs noted in 21% of patients with use of cisplatin and continuous infusion bleomycin in 21 patients. Other studies followed using cisplatin-bleomycin with other drugs such as hydroxyurea, and revealed increased toxicity with no improvement in response rates or survival. Investigators from Wayne State University reported the first trial using neoadjuvant cisplatin with infusional 5-fluorouracil (5-FU), with an overall response rate of 88% and a CR rate of 54%. Trials using carboplatin with 5-FU have also produced good rates of response.

In 1985, the increasing interest in laryngeal preservation coupled with disappointing experiences with up-front RT for advanced disease laid the foundation for the Veterans Affairs Cooperative Studies Program to initiate a multiinstitutional randomized trial of neoadjuvant chemotherapy as an organ preservation strategy. Patients with previously untreated, locally advanced but potentially resectable stage III (T2–3N1 or T3N0) or stage IV (T1–3N2–3 or T4N0–1) disease of the supraglottic or glottic larynx were randomized either to receive neoadjuvant chemotherapy or to undergo surgical resection. The chemotherapy regimen was cisplatin (100 m/m ² ) with continuous infusion 5-FU (1000 mg/m ² ) for 5 days every 21 days, with response after two cycles used to stratify patients to either continue with an additional cycle of chemotherapy followed by RT or, for nonresponders, salvage surgery followed by PORT. In total, 332 patients were enrolled: 216 patients with T3 disease, 85 with T4 disease, and 240 patients with N0–1 disease. Laryngeal preservation was achieved in 64% of patients enrolled in the chemotherapy arm. The local failure rate was significantly higher in the chemotherapy plus irradiation arm, but the distant failure rate was significantly lower in this arm. The estimated 2-year overall survival rate was 68% in each arm. This trial demonstrated that laryngeal conservation was achievable in a significant proportion of patients with advanced laryngeal carcinoma without sacrificing overall survival. However, the incremental value of neoadjuvant chemotherapy over RT alone was not answered in this trial.

These findings led to the RTOG 91-11 trial, which was conducted in patients with stage III or IV resectable disease of the larynx. Patients were randomized to three treatment groups: chemotherapy (cisplatin plus 5-FU) followed by RT, concurrent CRT with high-dose cisplatin as the radiosensitizer, or standard fractionated EBRT. The rate of laryngeal preservation at a median follow-up of 3.8 years was significantly higher among patients who received RT with concurrent cisplatin (84%) than in those who received induction chemotherapy followed by RT (72%; P = .005) or RT alone (67%, P < .001). Both chemotherapy regimens suppressed distant metastases and resulted in better disease-free survival than did RT alone. Despite these differences, the overall survival rates were similar in all three groups. As expected, the rate of high-grade toxic effects was greater with the chemotherapy-based regimens as compared with RT alone. This study demonstrated that concurrent CRT was the preferred approach for laryngeal preservation.

Efforts to improve the clinical efficacy of neoadjuvant chemotherapy continue, in hopes of achieving significant activity to yield consistent survival benefits. Largely based on evidence from two European studies (TAX 323 and TAX 324) the Food and Drug Administration (FDA) approved induction chemotherapy with docetaxel (Taxotere), cisplatin (Platin), and 5-FU (TPF) in patients with inoperable and operable HNSCC. The TAX 323 trial was a multicenter, randomized, phase III trial of 358 patients with previously untreated, unresectable, locally advanced stage III and IV tumors who were randomized to cisplatin and 5-FU with or without docetaxel (TPF and PF regimens, respectively). Four to 7 weeks after chemotherapy, patients who did not have progressive disease underwent RT. Patients treated with TPF had a reduction in their risk of death (27%; P = .02) and improved progression-free survival (HR, 0.72; P = .007). In the TAX 324 trial, 501 patients with stage III or IV HNSCC were randomly assigned to receive either PF or TPF as induction chemotherapy, followed by CRT with concurrent carboplatin (sequential therapy) in patients who did not have progressive disease. In this trial, patients who received TPF had improved overall survival (HR, 0.70; P = .006) and locoregional control ( P = .004). Benefits with TPF did come at the cost of higher rates of toxicity. Notably, neither of these trials had a control arm with standard CRT alone.

The meta-analysis of chemotherapy for HNC (MACH-NC) from Pignon and colleagues included 31 induction chemotherapy trials for a total of 5311 patients over a median follow-up of 6.1 years. Overall, induction chemotherapy had a nonsignificant absolute survival benefit of 2.4% at 5 years (HR, 0.96 [95% CI, 0.90 to 1.02]; P = .18; Fig. 65.5 ). No significant variation ( P = .23) of the effect according to the type of chemotherapy was found. These investigators concluded that no clear evidence existed of a differential effect of induction chemotherapy on survival according to age, sex, performance status, stage, or tumor site. In the DeCIDE trial, 285 patients from 20 sites in five countries with N2 or N3 disease were randomized to two cycles of induction chemotherapy with TPF followed by concurrent CRT with docetaxel, 5-FU, and hydroxyurea versus CRT alone. No significant difference in overall survival, recurrence-free survival, or distant failure-free survival was observed, and severe adverse events were more common in the induction arm. A modest benefit was seen in cumulative incidence of distant metastasis without prior locoregional recurrence ( P = .043). The study, however, did not meet planned accrual and so was underpowered.

Similarly, the PARADIGM trial enrolled 145 patients across 16 sites for randomization between induction TPF followed by docetaxel- or carboplatin-based CRT versus cisplatin-based CRT alone. No difference was seen in progression-free survival or overall survival, although the trial was terminated early. The lack of observed benefit may partly have been due to unexpectedly good survival in the CRT arm and lack of stratification for HPV-related disease. Nevertheless, without randomized data demonstrating the benefit of induction chemotherapy compared with CRT alone, the use of induction chemotherapy remains an investigational approach and reserved for select cases.

Concurrent and Concomitant Chemoradiotherapy

A significant body of literature exists, including numerous randomized trials of concurrent chemotherapy, systematically analyzed by several investigators. These independent reviews have consistently favored the concurrent integration of chemotherapy with RT. Pignon and colleagues from the MACH-NC have reported the largest and most recently updated of these meta-analyses. A patient-based meta-analysis of 9605 patients who underwent concomitant CRT was derived from 50 randomized trials and confirmed an absolute 5-year survival benefit of 6.5% (HR, 0.81 [95% CI, 0.78 to 0.86]; see Fig. 65.5 ). The benefit of chemotherapy was due to its effect on deaths related to HNC (HR, 0.78 [95% CI, 0.73 to 0.84]), because no benefit was seen for noncancer deaths (HR, 0.96 [95% CI, 0.82 to 1.12]). Similarly, an absolute benefit of 6.2% was seen in event-free survival (HR, 0.79 [95% CI, 0.76 to 0.83]). This benefit was largely restricted to patients 70 years of age and younger because a statistically significant decreasing effect of chemotherapy on survival with increasing age was found ( P = .003). Important to note, no significant difference was seen between monochemotherapy and polychemotherapy regimens ( P = .19), and no difference was noted among different polychemotherapy subgroups ( Fig. 65.6 ). In patients receiving monochemotherapy, the effect was significantly higher with platin agents than with other types of monochemotherapies (see Fig. 65.6 ).

In its most recent update the MACH-NC collaborative group published a comprehensive analysis by tumor site. This analysis included 4331 patients with cancer of the oral cavity, 5878 patients with oropharyngeal cancer, 3216 patients with laryngeal cancer, and 2767 patients with hypopharyngeal cancer. Overall, the addition of chemotherapy resulted in a reduction of the risk of death by 13% ( Fig. 65.7 ), with greater benefit for tumor sites associated with concomitant administration. The 5-year absolute overall survival benefits associated with concomitant chemotherapy were 8.9%, 8.1%, 5.4%, and 4% for oral cavity, oropharynx, larynx, and hypopharynx tumors, respectively ( Table 65.4 ). Similarly, the 5-year absolute event-free survival benefits associated with concomitant chemotherapy were 6.9%, 8.4%, 5.4%, and 3.2% for oral cavity, oropharynx, larynx, and hypopharynx tumors, respectively. In a direct comparison of concomitant versus induction chemotherapy, MACH-NC analyzed six trials with a total of 861 patients over a median follow-up of 10.9 years. Patients who underwent concomitant CRT had a nonsignificant improvement in overall survival with an absolute benefit of 3.5%, significantly decreased locoregional failure, and significantly improved event-free survival compared with patients who were treated with induction chemotherapy patients ( Fig. 65.8 ).

Cetuximab, a monoclonal immunoglobulin G1 (IgG1) antibody against the ligand binding domain of the epidermal growth factor receptor (EGFR), has been studied as a single agent or in combination with cisplatin in patients with HNC with promising results. Bonner and colleagues randomized 424 patients with stage III or IV HNC to treatment with high-dose RT alone ( n = 213) or high-dose RT plus weekly cetuximab ( n = 211) at an initial dose of 400 mg/m ² followed by weekly 250 mg/m ² doses for the duration of RT. RT with concurrent cetuximab resulted in a significant 32% reduction in the risk of locoregional progression, increased overall survival (HR for death, 0.74; P = .03), and prolonged progression-free survival (HR for disease progression or death, 0.70; P = .006). This overall survival advantage was maintained in a subsequent report on the updated 5-year analysis (HR, 0.73; P = .018). Unfortunately, in the MACH-NC meta-analysis, concurrent CRT trials with cetuximab were limited, preventing definitive conclusions.

Sequential Therapy

In patients with locally advanced unresectable HNSCC, interest has been increasing in the use of sequential therapy (induction chemotherapy followed by concurrent CRT). As described previously, the MACH-NC chemotherapy meta-analysis demonstrated the significant superiority of concurrent CRT (absolute benefit 6.5%) and a nonsignificant benefit from induction chemotherapy (absolute benefit 2.4%). Subsequently, the TAX 323 and TAX 324 trials demonstrated additional benefit with the addition of a taxane to cisplatin and 5-FU induction (TPF regimen). Although the TAX 324 trial demonstrated the principle of sequential therapy (induction TPF with subsequent CRT), it did not include a CRT-alone arm to allow formulation of conclusions regarding the comparative efficacy of these two approaches. Randomized trials comparing sequential therapy and CRT are ongoing.

Nasopharyngeal Carcinoma