SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANATOMY, CLINICAL FEATURES, AND STAGING
  5. ETIOLOGY OF HEAD AND NECK CANCER
  6. GENERAL PRINCIPLES OF TREATMENT
  7. ADVANCES IN THERAPY
  8. CONCLUSION
  9. References

The multidisciplinary approach to treating squamous cell carcinoma of the head and neck is complex and evolving. This article aims to review some recent developments in squamous cell carcinoma of the head and neck, in particular the expanding role of chemotherapy in its management. Surgery and radiotherapy have remained the mainstay of therapy. Chemotherapy is increasingly being incorporated into the treatment of squamous cell carcinoma of the head and neck. Previously, radiotherapy following surgery was the standard approach to the treatment of locoregionally advanced resectable disease. Data from randomized trials have confirmed the benefits of concurrent chemoradiotherapy in the adjuvant setting. Chemoradiotherapy is also the recommended approach for unresectable disease. Induction chemotherapy has been useful in resectable disease where organ preservation is desirable, but this approach was inferior for the goal of larynx preservation, while leading to similar survival when compared with concomitant chemoradiotherapy. There is recent evidence that taxanes added to induction chemotherapy with cisplatin and fluorouracil result in improved survival outcomes. Novel targeted agents, such as epidermal growth factor receptor antagonists, are showing promise in the treatment of patients with both locoregionally advanced and recurrent/metastatic squamous cell carcinoma of the head and neck.1


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANATOMY, CLINICAL FEATURES, AND STAGING
  5. ETIOLOGY OF HEAD AND NECK CANCER
  6. GENERAL PRINCIPLES OF TREATMENT
  7. ADVANCES IN THERAPY
  8. CONCLUSION
  9. References

Head and neck cancer is the eighth most common cause of cancer death worldwide. Its incidence varies widely among different regions.1,2 In North America and the European Union, head and neck cancer accounts for 3% to 4% of all cancer diagnoses.3,4 Conversely, in Southeast Asia and Africa, head and neck cancer accounts for approximately 8% to 10% of all cancers.2 Although the incidence of head and neck cancers has decreased slightly from 1975 to 2002 in the United States,5 approximately 46,000 new cases are still expected in 2007 alone.4

Squamous cell carcinomas arise from organs lined by squamous epithelium. Squamous cell carcinoma of the head and neck (SCCHN), regardless of site within the head and neck, tends to share similar etiologies, pathogenesis, natural history, and response to therapy. In addition, there are lymphoid tissues, neuroendocrine cells, melanocytes, and minor salivary glands within the mucosal lining of these organs where neoplasms may arise. Such tumors are biologically distinct from SCCHN and have different natural histories. Similarly, tumors arising from the thyroid and major salivary glands behave differently than SCCHN. For the purposes of this review, we will limit our discussion to squamous cell carcinoma arising from aerodigestive organs within the head and neck.

Historically, the treatment of SCCHN has been in the realm of surgeons and radiation oncologists. Over the last 2 decades, there have been major developments in the field of surgery, radiation therapy, and chemotherapy. In radiation therapy, intensity-modulated radiation therapy and the development of various fractionation schemes have allowed improved delivery and tolerability of radiation. Advances in conservation surgical techniques with procedures such as hemilaryngectomy, laryngeal prosthesis, and laser surgery have allowed better preservation of organ function.

As more chemotherapeutic agents are identified and the activity of chemotherapy is improved, the treatment of SCCHN has evolved to incorporate chemotherapy as a key component in the multimodality treatment approach of advanced SCCHN. This increases the complexity of SCCHN therapy. Compounding this is the management of associated comorbidities from local effect of the tumor resulting in aspiration, dysphagia, malnutrition, and chronic illnesses such as alcoholism, nicotine dependence, liver cirrhosis, and chronic obstructive pulmonary disease. This review aims to highlight the increasing role of chemotherapy in the management of SCCHN.

ANATOMY, CLINICAL FEATURES, AND STAGING

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANATOMY, CLINICAL FEATURES, AND STAGING
  5. ETIOLOGY OF HEAD AND NECK CANCER
  6. GENERAL PRINCIPLES OF TREATMENT
  7. ADVANCES IN THERAPY
  8. CONCLUSION
  9. References

Anatomy

The head and neck are divided into several anatomically defined regions, namely the nasal cavity and paranasal sinuses, oral cavity, pharynx, and larynx (Figure 1). The pharynx comprises the nasopharynx, oropharynx, and hypopharynx, while the larynx is divided into the supraglottic, glottic, and subglottic regions.

thumbnail image

Figure FIGURE 1. Head and Neck Anatomy. Reprinted from Vokes EE, Weichselbaum RR, Lippman SM, Hong WK6 with permission from The New England Journal of Medicine.

Download figure to PowerPoint

Clinical Features

Presenting signs and symptoms vary with the location of the primary tumor.6 Patients with early-stage cancer frequently have vague symptoms with minimal physical findings. Nasal cavity and paranasal sinuses tumors present with unilateral epistaxis or nasal obstruction. Nasopharyngeal cancer frequently presents late with nodal neck metastasis. Local symptoms may be attributable to eustachian tube obstruction (serous otitis) or cranial nerve invasion. Oral cavity cancers present as nonhealing ulcers, pain, or poorly fitting dentures. Laryngeal tumors are often manifested by persistent hoarseness. Later symptoms include dysphagia, chronic cough, hemoptysis, stridor, and respiratory distress. Tumors of the oropharynx and supraglottic larynx usually present late with cervical adenopathy, pain, otalgia, dysphagia, or dysphonia.

Staging

The American Joint Committee on Cancer (AJCC) 2002 tumor-node-metastasis staging system7 divides tumors arising from the head and neck into several specific regions, namely lip-oral cavity, pharynx (nasopharynx, oropharynx, and hypopharynx), larynx, and nasal cavity-paranasal sinuses. The definitions for regional lymph node (N) involvement and spread to distant sites (M) are uniform for all regions. The N definition is based on the size and laterality of the involved nodes. One exception is the N definition in nasopharyngeal carcinoma (see section on nasopharyngeal carcinoma). The lifetime incidence of distant metastasis8,9 correlates with nodal stage: N1 10%, N2 15%, and N3 approximately 30% risk.8,9

The staging for the primary tumor (T) differs among tumor sites. For tumors in the lip-oral cavity and oropharynx, the T definition is based on size. In contrast, the T definition is based on subsite involvement and is specific to each subsite for the glottic larynx, supraglottic larynx, hypopharynx, and nasopharynx.

Staging evaluation is specific for each tumor site and involves physical examination, endoscopic examination, and radiologic imaging. Risk factors such as cigarette smoke and alcohol expose and precondition the mucosa of the aerodigestive tract to cancerous change-field cancerization and result in the occurrence of second metachronous and synchronous tumors.10 Therefore, imaging of the thorax is often included in the staging of SCCHN because of the potential of these tumors to metastasize to the lungs and to evaluate the presence of second primary tumors. Endoscopy, such as laryngopharyngoscopy, is often employed to enhance the evaluation of the primary tumor. Directed endoscopy of the lung and esophagus is performed if there are signs or symptoms relating to these organs. Positron emission tomography (PET) scans may be used to determine the benign or malignant nature of noncalcified lung nodules or to identify occult neck metastases.

ETIOLOGY OF HEAD AND NECK CANCER

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANATOMY, CLINICAL FEATURES, AND STAGING
  5. ETIOLOGY OF HEAD AND NECK CANCER
  6. GENERAL PRINCIPLES OF TREATMENT
  7. ADVANCES IN THERAPY
  8. CONCLUSION
  9. References

Tobacco and Alcohol Are Major Risk Factors

SCCHN is strongly associated with cigarette smoking11 and alcohol consumption.12,13 The risk of developing SCCHN is proportional to the number of cigarettes smoked and duration of smoking.14,15 Smoking cessation reduces the risk of developing SCCHN over time.14 Pipe and cigar smokers are at higher risk for developing oral cavity cancers compared with cigarette smokers.14 Other forms of tobacco products, such as betel quid, are associated with SCCHN in certain geographic regions.16,17 The risk of developing SCCHN increases with the frequency, duration, and concentration of alcohol consumed.18,19 The combined risk of alcohol and smoking in causing SCCHN is multiplicative rather than additive.13,14,17,20, [21], [22]23

The Role of Human Papillomavirus

A proportion of patients with SCCHN do not have the traditional risk factors for developing such malignancies.24 The nonsmoker, nondrinker SCCHN patients tend to be younger and have the primary tumor located within the lingual or palatine tonsils.25, [26]27 Human papillomavirus (HPV) has been identified in the pathogenesis of SCCHN in this group.24,28,29 The proposed mechanism of disease is that HPV oncoproteins E6 and E7 inactivate the tumor suppressor genes p5330, [31], [32]33 and pRb32,34 in the host cell, respectively, thereby increasing cell-cycle regulation and inhibiting apoptosis.

HPV DNA has been found in approximately 25% of SCCHN.35 HPV-associated tumors tend to arise in the oral cavity and pharynx,25,35,36 but not in the larynx.37 HPV-16 is found within 85% to 90% of HPV-positive SCCHN.35 It is unclear if there is an interaction between HPV and alcohol or tobacco.29,38, [39]40 HPV-positive SCCHN has been positively associated with sexual behavior parameters, such as multiple sexual partners, sexually transmitted diseases, oral sex, oral-anal contact, and human immunodeficiency virus infection.29,41, [42], [43], [44]45 Patients with Fanconi anemia have a 500-fold risk of developing SCCHN.46 Abnormal DNA repair and chromosomal instability characteristic of this disorder result in increased alteration of genes already implicated in the development of SCCHN and potentiate HPV-mediated tumorigenesis.47

The prognosis of HPV-positive SCCHN appears to be better than HPV-negative SCCHN.31,48, [49], [50]51 There is evidence to suggest that HPV-positive tumors are more radiosensitive.52,53 Other hypotheses to account for the improved outcome are the absence of field cancerization50 and the absence of comorbid conditions such as cirrhosis or chronic obstructive pulmonary disease that impact on overall prognosis of individual patients.

There are epidemiologic and therapeutic implications with the identification of HPV in SCCHN. Since patients with HPV-positive tumors are more radiosensitive, this parameter may be used in the selection of patients for organ-preservation strategies. The increasing use of the HPV vaccine for cervical cancer may also play a role in primary prevention of HPV-positive SCCHN.54

GENERAL PRINCIPLES OF TREATMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANATOMY, CLINICAL FEATURES, AND STAGING
  5. ETIOLOGY OF HEAD AND NECK CANCER
  6. GENERAL PRINCIPLES OF TREATMENT
  7. ADVANCES IN THERAPY
  8. CONCLUSION
  9. References

Once staging is completed, for treatment considerations, SCCHN can be divided into several general stages (Figure 2): early-stage disease (Stages I and II); nonmetastatic locoregionally advanced disease (LA-SCCHN) (Stages III and IVA/B [M0]); and metastatic (Stage IVC). Approximately 15% to 30% of patients present with early-stage disease, and 60% to 80% present with locoregionally advanced disease.4 Distant metastasis at the time of presentation is less common (2% to 17%),55, [56], [57]58 but a small percentage of patients may have a second primary tumor within the aerodigestive tract or lungs.

thumbnail image

Figure FIGURE 2. Staging of Squamous Cell Carcinoma of the Head and Neck and General Treatment Schema.

Download figure to PowerPoint

Treatment Modalities for SCCHN

Surgery and radiotherapy are the curative treatment modalities for SCCHN. Surgery has several advantages over radiotherapy: (1) limited amount of tissue is exposed to treatment; (2) treatment time is shorter; (3) acute and chronic radiation toxicities are avoided; and (4) tumor and nodal disease are assessed accurately. The advantages of radiotherapy include the following: (1) surgical complications are avoided; (2) appearance and, potentially, function of treated organ can be preserved; (3) irradiation of lymph nodes can be included with little added morbidity compared with the added morbidity of extensive neck dissection; and (4) medically unfit patients may tolerate radiotherapy better than surgery.

Chemotherapy itself is not a curative treatment modality. To this end, chemotherapy is used by itself as palliative therapy for patients with metastatic disease. When chemotherapy is administered at somewhat decreased doses simultaneously with radiotherapy, radiosensitization of the tumor occurs, resulting in increased tumor cell death. Chemotherapy at full doses can also be delivered together with radiotherapy to harness the radiosensitization and systemic cytotoxic properties of chemotherapy. In SCCHN, chemotherapy may be administered before definitive treatment (induction or neoadjuvant), simultaneously with radiotherapy (concomitant or concurrent), or after surgery (adjuvant) (Figure 3). The first 2 approaches are supported by results of randomized clinical trials (RCTs).

thumbnail image

Figure FIGURE 3. Treatment Schema for Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck.

Download figure to PowerPoint

The choice of treatment modality for an individual patient needs to be carefully considered. It is good clinical practice that this decision-making process be deliberated at a multidisciplinary tumor board. Particular attention must be placed on choosing the most effective treatment approach while aiming to preserve organs and organ function and managing associated comorbid conditions. Functional outcomes such as speech and swallowing factor heavily in choosing the appropriate treatment modality. Several performance measures for good functional preservation include the ability to eat in public, understandability of speech, and normalcy of diet.59,60 Appropriate and expert use of modern surgical and radiation techniques can meet these goals, but the therapy must be carefully individualized.

Treatment for Early-stage SCCHN

For early-stage disease, curative therapy can be achieved with single-modality surgery or radiotherapy (Figure 2). The choice of modality depends on the specific site, stage, resectability, and functional outcome after therapy. Chemotherapy is not used in early-stage SCCHN. The 5-year overall survival rate for Stage I cancer is 80% to 90%, and Stage II is 65% to 80%.61, [62], [63]64

Treatment for LA-SCCHN

LA-SCCHN implies advanced T stage where tumor invasion into other structures has occurred or lymph node metastases without evidence of distant metastases. LA-SCCHN poses one of the most complex management challenges. This stage of disease is still potentially curable, but requires combined-modality therapy.

Implicit in choosing the primary treatment modality (radiotherapy and surgery) for LA-SCCHN is to determine resectability (Figure 4). There is no formal definition of “resectable,” and it varies significantly between disease site, disease extent, surgeons, and institutions. Ideally, the determination of resectability should be made for each individual patient during a multidisciplinary tumor board, taking into account the potential functional compromise and survival benefit conferred by each treatment modality. Of note, for some patients with resectable disease, an “organ-preserving” approach may be desired. These patients will usually be treated with concomitant chemoradiotherapy, with surgery reserved for patients with residual disease or recurrence after completion of chemoradiotherapy.

thumbnail image

Figure FIGURE 4. Various Treatment Schema Utilized in Squamous Cell Carcinoma of the Head and Neck Therapy.

Download figure to PowerPoint

Unresectable tumors should be treated with definitive concurrent chemoradiotherapy.65 This approach results in a 5-year overall survival of 30% to 50% in recent studies.66, [67]68 Patients with resectable tumors should undergo surgery. The locoregional recurrence rate is approximately 40% after successful surgical resection.69,70 Adjuvant radiotherapy for this stage of SCCHN has been effective in reducing the locoregional recurrence rates to approximately 30%.69,70 When adjuvant radiotherapy is combined concurrently with chemotherapy, the locoregional recurrence rates drop to approximately 20%.71,72

Pattern of Failure

An important aspect of SCCHN management is to understand the pattern of treatment failure. After definitive therapy, SCCHN patients may recur at the primary tumor site or regional lymph nodes (termed locoregional relapse) or at distant sites such as the lungs or liver (termed distant relapse). In general, LA-SCCHN patients treated with single-modality therapy (surgery or radiotherapy) tend to relapse locoregionally (50% to 60% at 2-year) rather than at distant sites (15% to 20% at 2-year).66, [67]68,73,74 The addition of chemotherapy impacts both locoregional and distant control rates. Paccagnella et al showed that induction chemotherapy reduced the 3-year distant relapse rate from 38% to 14%.75 This observation held true in a retrospective review of University of Chicago trials.76 Concurrent chemoradiotherapy, on the other hand, has been shown to improve locoregional relapse rates, but its impact on distant failure is inconsistent.67,68,77,78

Treatment for Recurrent and/or Metastatic SCCHN

Local recurrences without evidence of distant metastases may be salvaged surgically if the primary therapy was radiotherapy or with radiotherapy if the primary therapy was surgery. However, for unresectable recurrent and/or metastatic disease, the therapy is aimed at palliation since the cure rates at such an advanced stage are extremely low. Palliation is achieved with the use of chemotherapy and supportive care. The response rates to chemotherapy in this setting range from 10% to 40% depending on the agent(s) used.

ADVANCES IN THERAPY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANATOMY, CLINICAL FEATURES, AND STAGING
  5. ETIOLOGY OF HEAD AND NECK CANCER
  6. GENERAL PRINCIPLES OF TREATMENT
  7. ADVANCES IN THERAPY
  8. CONCLUSION
  9. References

Definitive Chemoradiotherapy for LA-SCCHN

Conventional, once-daily, fractionation radiotherapy in 2 Gy fractions up to a total of 66 to 70 Gy over 7 weeks has been used as definitive therapy in unresectable SCCHN and sometimes in resectable tumors instead of surgery.79 This results in high locoregional relapse rates (50% to 60% at 2-year) and overall survival of approximately 40% at 3-year.66, [67]68,73,74 Efforts to improve the locoregional control of SCCHN by altering the fractionation of radiotherapy have only been marginally successful. Hyperfractionation79,80 (multiple smaller fractions per day over the same time period) and accelerated fractionation79,81 (delivery of the total dose over a shorter time period) have been compared with conventional fractionation; altered fractionation regimens have led to a 10% to 20% improvement in local control rates, but effects on survival are less clear.79 Altered fractionation regimens consistently induce more severe acute mucositis than standard 7-week radiotherapy, but late toxicities are not appreciably increased.

In an attempt to improve local control and survival, chemotherapy has been investigated as an adjunct to locoregional treatment. Various schedules of chemotherapy and radiotherapy have been investigated: induction chemotherapy (chemotherapy given before radiotherapy), adjuvant or sequential chemotherapy (chemotherapy given after radiotherapy), and concurrent or concomitant chemotherapy (chemotherapy given at the same time as radiotherapy) (Figure 3). Theoretical benefits of delivering concurrent chemoradiotherapy are twofold: (1) local antitumor activity of radiotherapy is enhanced by the simultaneous use of chemotherapy as radiosensitizers and (2) the systemic activity of chemotherapy may eradicate possible micrometastases outside the irradiated field and improve survival.

Meta-analyses have shown that concurrent chemoradiotherapy is superior to other sequences of chemotherapy and radiotherapy.82,83 A systematic review by Browman et al pooled analyses of 18 RCTs and detected a reduction in mortality for concomitant chemoradiotherapy compared with radiotherapy alone (relative risk = 0.83).83 The MACH-NC group reviewed 63 randomized trials conducted between 1965 and 1993 comparing combinations of locoregional treatment and chemotherapy versus locoregional treatment alone.82,84 The magnitude of the survival benefit associated with the addition of concomitant chemoradiotherapy was 8% at 5 years. This survival benefit was mainly due to an improvement in the locoregional control and only had a marginal effect on distant metastases.

The use of concomitant chemoradiotherapy for locoregionally advanced unresectable SCCHN is further supported by several recent RCTs (Table 1). Adelstein et al, Olmi et al, and Calais et al reported randomized trials comparing conventional doses of radiotherapy with or without concomitant chemotherapy.74,85,86 Regardless of the specific chemotherapy regimens used, the trials demonstrated a significant and consistent benefit in local control rates, translating into improvement in disease-free survival by a magnitude of 15% to 20%. When hyperfractionated radiotherapy was tested with or without concomitant chemotherapy, investigators were able to show a further improvement in disease-free survival as a result of improved local control from hyperfractionated radiotherapy alone, but this was further improved with concomitant chemotherapy.68,87,88 To further support the role of concomitant chemotherapy, the trials by Brizel et al, Budach et al, and Dobrowsky et al are noteworthy.66,67,89 The radiotherapy dose delivered in the chemoradiotherapy arms was intentionally lower than in the radiotherapy-alone arms. Despite this apparent disadvantage, the chemoradiotherapy arms were still superior. These trials reinforce the concept that concurrent chemotherapy provides a synergistic enhancement of efficacy.

Table TABLE 1. Randomized Trials of Concomitant Chemoradiotherapy for Locoregionally Advanced Head and Neck Cancer
StudyRTCRTChemo-therapyPlatinum DoseLocal ControlDisease-free SurvivalOverall Survival
  1. * Three-arm study.

  2. † Statistically significant difference.

  3. Abbreviations: RT, radiation therapy; CRT, concurrent chemoradiotherapy; QD, daily; BID, twice daily; Cis, cisplatin; Carbo, carboplatin; 5-FU, 5-Fluorouracil; Mito, mitomycin-C; —, not reported.

Adelstein DJ, Li Y, Adams GL, et al,85 2003*70 Gy, QD, 7 wks70 Gy, QD, 7 wksCis100 mg/m2 wks 1, 3, and 63-y, 33% versus 51%3-y, 23% versus 37%
Olmi P, Crispino S, Fallai C, et al,86 2003*70 Gy, QD, 7 wks70 Gy, QD, 7 wksCarbo, 5-FU75 mg/m2 × 4d wks 1, 4, and 82-y, 23% versus 42%2-y, 40% versus 51%
Calais G, Alfonsi M, Bardet E, et al,74 199970 Gy, QD, 7 wks70 Gy, QD, 7 wksCarbo, 5-FU70 mg/m2 × 4d wks 1, 3, and 63-y, 42% versus 66%3-y, 20% versus 42%3-y, 31% versus 51%
Jeremic B, Shibamoto Y, Milicic B, et al,68 200077 Gy, BID, 7 wks77 Gy, BID, 7 wksCis6 mg/m2 /d5-y, 50% versus 36%5-y, 25% versus 46%5-y, 25% versus 46%
Huguenin P, Beer KT, Allal A, et al,87 200474 Gy, BID, 7 wks74 Gy, BID, 7 wksCis20 mg/m2 /d × 5d wks 1 and 55-y, 27% versus 59%5-y, 24% versus 27%5-y, 32% versus 46%
Bensadoun RJ, Dassonville O, Ramaioli A, et al,88 200680 Gy, BID, 7 wks80 Gy, BID, 7 wksCis, 5-FU100 mg/m2 wks 1, 3, and 62-y, 25% versus 48%2-y, 20% versus 38%
Brizel DM, Albers ME, Fisher SR, et al,66 199875 Gy, BID, 6 wks70 Gy, BID, 7 wksCis, 5-FU12 mg/m2 /d × 5d wks 1 and 53-y, 44% versus 70%3-y, 41% versus 61%3-y, 34% versus 55%
Budach V, Stuschke M, Budach W, et al,67 200578 Gy, BID, 6 wks70 Gy, BID, 6 wksMito, 5-FU5-y, 37% versus 50%5-y, 27% versus 29%5-y, 24% versus 29%
Dobrowsky W, Naude J,89 2000*70 Gy, QD, 7 wks55 Gy, BID, 17 dMito2-y, 31% versus 48%2-y, 24% versus 41%

Toxicities Associated with Chemoradiotherapy

Radiotherapy to the head and neck is commonly associated with acute and late toxicities. Commonly observed acute toxicities are mucositis, stomatitis, and dermatitis, while depending on the site of irradiation, late toxic effects may include chronic xerostomia, dysgeusia, dysphagia, skin fibrosis, trismus, feeding-tube dependence, aspiration, and thyroid dysfunction. In general, the acute toxicities of radiotherapy are increased with the addition of concurrent chemotherapy. Interobserver variability, differing toxicity assessment scales, and less-rigorous toxicity data collection during clinical trials may account for different rates of nonhematologic acute toxicities.90 For example, in the clinical trial by Calais et al, 35% of patients in the radiotherapy-alone arm experienced Grade 3/4 mucositis compared with 65% of patients in the chemoradiotherapy arm.74 On the other hand, Bensadoun et al reported that 69% of patients in the radiotherapy-alone arm experienced Grade 3/4 mucositis compared with 82% of patients in the chemoradiotherapy arm.88 Patients receiving chemoradiotherapy tend to experience more weight loss and more frequently require a feeding tube during therapy. Such rates could be double that of radiotherapy alone.74 The duration of acute toxicities also tends to be longer in patients receiving chemoradiotherapy.66 Furthermore, chemotherapy-specific toxicities such as nausea, vomiting, neuropathy, nephropathy, and ototoxicity occur with the use of systemic doses of chemotherapy.

Hematologic toxicities are seldom observed with radiotherapy alone. However, the addition of chemotherapy can cause significant anemia, leucopenia, and neutropenia in a proportion of patients. The rates of hematologic toxicities generally depend on the chemotherapy regimens used. In one study, single-agent cisplatin at 100 mg/m2 given every 3 weeks with radiotherapy was associated with Grade 3/4 anemia and leucopenia in 18% and 42% of patients, respectively, while the radiotherapy-alone arm had only a 1% leucopenia rate.85 Other regimens have rates of severe leucopenia varying between 9% and 40% with chemoradiotherapy.66,88

Acute hematologic and nonhematologic toxicity rates are consistently higher in the chemoradiotherapy arm across the clinical trials. Hospitalizations for toxicity related to concurrent chemoradiotherapy are increased, and dose reductions in chemotherapy are commonly needed.68 Toxic death rates are numerically higher with chemoradiotherapy.66,68,74,85,88 Forastiere et al reported a toxic death rate that is almost double in patients receiving concurrent chemoradiotherapy (4%) compared with radiotherapy alone (2%), but this difference was not statistically significant.65 Similarly, the toxic death rate reported by Calais et al was 1% in the concurrent chemoradiotherapy arm and none in the radiotherapy-alone arm.74 In a review of 324 patients with LA-SCCHN who were enrolled in 5 consecutive chemoradiotherapy trials at the University of Chicago, the toxic death rate was 9.3%.91 The most common causes of early- and late-treatment–related deaths were sepsis and surgical complications, respectively.

Patient selection for chemoradiotherapy and adequate supportive care during therapy are crucial. Comorbidities play an important role in determination of therapy. Comorbidities in younger patients may not impact on overall survival, but complication rates are increased with more advanced intercurrent conditions.92 In elderly patients, the presence of comorbidities has a definite impact on survival.93 In line with this observation, the benefit of concomitant chemoradiotherapy decreases with increasing age.94 The increasing risk of death with increasing age may result from a combination of death from therapy-related complications or existing intercurrent illnesses. The medical oncologist must weigh the risk of chemoradiotherapy with its potential benefit while taking into account the patient's comorbidities, performance status, and function of involved organ.

Since approximately 50% of patients with LA-SCCHN receiving concurrent chemoradiotherapy are expected to be alive at 3 years or longer, particular attention must be paid to possible long-term chronic toxicities of chemoradiotherapy. Most clinical trials have reported equivalent rates of long-term toxicities between radiotherapy alone and concurrent chemoradiotherapy. Rates of osteoradionecrosis are not increased with concurrent chemoradiotherapy.67,74,88 One important long-term quality-of-life outcome after chemoradiotherapy to the head and neck is swallowing function. The reader is referred to a detailed review on this topic.95

Biologic Agents in Frontline Therapy

An important step forward in the field of concomitant chemoradiotherapy was made with the advent of molecularly targeted therapies. It has been observed that the epidermal growth factor receptor (EGFR) is overexpressed in almost all SCCHN tumors, and overexpression of EGFR is associated with higher disease stage, lymph node metastasis, and poorer survival.96,97 EGFR expression increases progressively with increasing degrees of dysplasia and becomes markedly elevated in carcinomas, suggesting that EGFR upregulation is an early event in SCCHN oncogenesis.98 Since EGFR plays a significant role in SCCHN, a randomized trial comparing radiotherapy with or without cetuximab (anti-EGFR monoclonal antibody) was performed in patients with LA-SCCHN.73,99 The 2-year locoregional control rates increased from 48% to 56% with concurrent cetuximab-radiotherapy (Table 2). Major toxicities were dermatitis, mucositis, dysphagia, and acneiform rash (in the cetuximab arm). The toxicity rates in both arms were similar, except for rash in the cetuximab arm. This trial provides an important proof of principle that modulating the biology of SCCHN in combination with a physically targeted agent can impact on therapeutic outcome. This increases the armamentarium of drugs that are active with radiotherapy. The favorable toxicity profile of cetuximab allows this drug to be combined with existing chemoradiotherapy regimens in future trials.

Table TABLE 2. Selected Novel Targeted Therapeutics Trials in Squamous Cell Carcinoma of the Head and Neck
 DrugPhasePrimary Endpoints and Results
  1. * Statistically significant difference.

  2. Abbreviations: SCCHN, squamous cell carcinoma of the head and neck; RR, response rate; med surv, median survival; BID, twice daily; NR, not reported; med dur local control, median duration of local control; NPC, nasopharyngeal carcinoma; RT, radiation therapy.

Recurrent and/or metastatic SCCHN
   Cohen EE, Rosen F, Stadler WM, et al,100 2003Gefitinib 500 mgIIRR 11%, med surv 8 mo
   Wheeler RH, Jones D, Sharma P, et al,101 2005Gefitinib 500 mgII1st line RR 15%, 2nd line RR 0%
   Kirby AM, A'Hern RP, D'Ambrosio C, et al,102 2006Gefitinib 500 mgIIRR 8%, med surv 4 mo
   Cohen EE, Kane MA, List MA, et al,103 2005Gefitinib 250 mgIIRR 1%, med surv 6 mo
   Soulieres D, Senzer NN, Vokes EE, et al,104 2004Erlotinib 150 mgIIRR 4%, med surv 6 mo
   Williamson SK, Moon J, Huang CH, et al,105 2006Sorafenib 400 mg BIDIIRR 3%, med surv 7 mo
   Belón J, Irigoyen A, Rodríguez I, et al,106 2005Gefitinib 250 mg, cisplatin and docetaxelIIRR 62%, med surv NR
   Kim ES, Kies MS, Glisson BS, et al,107 2006Erlotinib 150 mg, cisplatin and docetaxelIIRR 88%, med surv NR
   Vokes EE, Cohen EE, Mauer AM, et al,108 2005Erlotinib and bevacizumabI/IIRR 15%, med surv 7 mo
   Burtness B, Goldwasser MA, Flood W, et al,109 2005A: Cetuximab + cisplatin, B: CetuximabIIIA: RR 26%*, med surv 9 mo, B: RR 10%, med surv 8 mo
   Chan AT, Hsu MM, Goh BC, et al,110 2005Cetuximab and carboplatin in NPCIIRR 12%, med surv 8 mo
Locoregionally advanced SCCHN
   Bonner JA, Harari PM, Giralt J, et al,73 2006A: RT + cetuximab, B: RTIIIMed dur local control,    A: 24 mo*,    B: 15 mo, Med surv,    A: 49 mo*,    B: 29 mo

It is important to note the trial described above did not compare cetuximab-radiotherapy with concurrent chemoradiotherapy, which is the standard of care today for LA-SCCHN. Therefore, concurrent chemoradiotherapy must not be equated with cetuximab-radiotherapy. Secondly, since the toxicities associated with standard chemoradiotherapy may be poorly tolerated in elderly or frail patients, cetuximab-radiotherapy has often been considered in this setting. However, the median age in the trial was 56 years (34 to 81 years), and the trial did not specifically evaluate elderly patients or patients with poor performance status.

Current Questions and Future Challenges

There remain many unanswered questions. First, the importance of radiotherapy dose fractionation during concomitant chemoradiotherapy is unknown. Meta-analysis evidence points toward improved locoregional control and survival with altered fractionation radiotherapy.111 This needs to be addressed in chemoradiotherapy trials comparing conventional radiotherapy with altered fractionation regimens (RTOG 0129). Second, there has been much variability in the delivery and choice of chemotherapy. Most investigators have used platinum-based regimens, frequently with 5-Fluorouracil (5-FU). However, numerous other chemoradiotherapy regimens have been studied. For example, the TFHX regimen pioneered at the University of Chicago utilizing paclitaxel, 5-FU, and hydroxyurea with concurrent radiotherapy has demonstrated high local control and survival rates.112,113 Many different schedules of cisplatin administration have been used, ranging from daily cisplatin at 6 mg/m2 /day continuously68 to boluses of cisplatin at 100 mg/m2 every 3 weeks.85 To add to this complexity, investigators have combined other chemotherapies to cisplatin, such as 5-FU or mitomycin. With the multitude of possible permutations, we may never come to a definitive dose or schedule for the chemotherapy. It is sufficient to state that concurrent chemoradiotherapy with a platinum agent is the current standard of care when a chemoradiation regimen is selected for therapy of LA-SCCHN; however, this remains a moving target as more effective chemotherapies and biologics are investigated.

As the use of concurrent chemoradiotherapy increases in SCCHN, patient selection for primary surgery or definitive concurrent chemoradiotherapy becomes more complex. There has been no prospective randomized trial comparing outcomes of primary surgery versus definitive concurrent chemoradiotherapy to guide us. Therefore, a multidisciplinary approach coupled with close communication among the medical oncologist, radiation oncologist, radiologist, and surgeon is crucial to develop the best treatment plan for a particular patient.

Postoperative Chemoradiotherapy for LA-SCCHN

Although surgery alone may be adequate treatment for early-stage SCCHN, additional therapy is required to prevent disease recurrence, even after an apparently complete resection for LA-SCCHN. A number of pathologic poor-risk factors have been associated with higher recurrence rates after surgery, including positive margins of resection,114, [115]116 extracapsular extension of disease from a lymph node,115, [116], [117], [118], [119]120 oral cavity primary,118 involvement of lymph nodes at levels 4 or 5 from carcinomas arising in the oral cavity or oropharynx,121 perineural extension,118,121 and vascular tumor emboli.121 Data from 2 large randomized trials have substantiated that microscopically involved resection margins and/or extracapsular spread of tumor from lymph nodes are the most significant adverse prognostic factors.121

Retrospective studies have shown that adjuvant radiotherapy significantly reduces the recurrence rate of LA-SCCHN, especially for poor-risk patients.122,123 Despite adjuvant radiotherapy achieving good local control rates, distant metastasis occurred in almost one-third of patients with poor-risk factors.117 Therefore, investigators have combined radiotherapy with radiosensitizing doses of chemotherapy. This strategy utilizing cisplatin weekly with radiotherapy resulted in improvement in overall and disease-free survivals over radiotherapy alone (5-year overall survival 36% versus 13%).119 However, distant disease control rates were similar. This implies that although good local control is achievable with radiosensitizing chemoradiotherapy, distant micrometastases are not obliterated with low doses of chemotherapy.

To further improve local failure, distant failure, and overall survival rates, full-dose chemotherapy has been utilized with radiotherapy. This strategy harnesses the radiosensitizing and systemic cytotoxic properties of chemotherapy. Furthermore, this strategy has been proven superior to radiotherapy alone for definitive therapy of LA-SCCHN, as described above. Three such trials have been reported to date (Table 3): the European Organization for Research and Treatment of Cancer (EORTC) 22931,71 the Radiation Therapy Oncology Group (RTOG) 9501,72 and the German ARO 96–3 trial.124

Table TABLE 3. Randomized Trials of Adjuvant Concomitant Chemoradiotherapy for Locoregionally Advanced Nonmetastatic Head and Neck Cancer
 RTOG 9501*72EORTC 2293171German ARO 96–3124
  1. * Three-year endpoint.

  2. † Five-year endpoint.

  3. ‡ Statistically significant difference.

  4. Abbreviations: CRT, concurrent chemoradiotherapy; RT, radiation therapy; 5-FU, 5-Fluorouracil; ECS, extracapsular spread; LN, lymph node.

Number of patients459334440
ChemotherapyCisplatin 100mg/m2, d 1, 22, and 43Cisplatin 100mg/m2, d 1, 22, and 43Cisplatin 20mg/m2, 5-FU 600mg/m2, d 1 to 5 and 29 to 33
Radiotherapy60 to 66 Gy/6 wks66 Gy/6.5 wksNegative LN—50 Gy, positive LN—56 Gy, ECS—64 Gy/6.6 wks
Endpoints (CRT versus RT)
Locoregional failure rate19% versus 30%18% versus 31%17% versus 38%
Distant failure rate21% versus 25%20% versus 23%30% versus 32%
Disease-free survival47% versus 36%47% versus 36%62% versus 50%
Overall survival56% versus 47%53% versus 40%58% versus 49%

Both the EORTC71 and RTOG72 trials had similar designs and administered adjuvant cisplatin at high doses (100 mg/m2 ) on days 1, 22, and 43 of radiotherapy to patients with completely resected SCCHN. The EORTC trial reported a beneficial effect on overall survival and local control with adjuvant chemoradiotherapy. In the RTOG trial, despite having an improvement in disease-free survival in the adjuvant chemoradiotherapy arm, there was only a trend toward improved local control and overall survival rates. Combined analysis of the 2 trials showed an advantage in locoregional control and survival for patients receiving adjuvant chemoradiotherapy in the setting of poor-risk features, ie, extracapsular invasion and/or positive resection margins.121 The German ARO 96–3 trial124 differed from the above trials in that patients were given different doses of radiotherapy based on their risk factors and used a doublet chemotherapy regimen of cisplatin and 5-FU. The locoregional control rate and disease-free survival in the adjuvant chemoradiotherapy arm were significantly better than radiation alone. Taken together, these trials provide new evidence that adjuvant chemoradiotherapy with a cisplatin-based regimen improves locoregional control rates and disease-free survival, and improvement in overall survival appears very likely.

Adjuvant concurrent chemoradiotherapy is associated with higher incidences of severe acute toxicities. For example, in the EORTC and RTOG trials, the rates of severe mucositis in the concurrent chemoradiotherapy arms were approximately double that in the radiotherapy-alone arms. Late toxicities were similar between both arms.71,72 Chemotherapy completion rates were only 49%, 61%, and 73% in the EORTC, RTOG, and ARO 96–3 studies, respectively. Careful patient selection for chemoradiotherapy and intensive supportive care during therapy is crucial to ensure successful completion of the treatment regimen. Certain subgroups, such as elderly patients, patients with advanced T stage, and patients with larynx/hypopharynx primaries, tend to experience more severe late toxicities, feeding-tube dependence, and laryngopharyngeal dysfunction after adjuvant chemoradiotherapy.94,125 Moreover, the benefit of chemoradiotherapy is less clear in the elderly.94 Alternative strategies utilizing biological agents126 or cytotoxic agents with more tolerable toxicity profiles127 should be investigated for adjuvant therapy in the elderly or the medically unfit.

In order to improve overall survival, the gain in locoregional control from the radiosensitizing effect of the chemotherapy needs to be integrated with therapy that decreases the risk of distant metastases. Adequate control of distant failure still has not been achieved, with approximately 20% to 30% of patients failing as a result of metastatic disease.71,72,124 One possible hypothesis is the chemotherapy used in these trials is ineffective in eradicating micrometastasis. Therefore, the incorporation of additional effective drugs should be investigated in the adjuvant setting.128 One such trial is the RTOG 0234 trial, which is a randomized Phase II trial combining postoperative radiation with cetuximab and either docetaxel or cisplatin.

Revisiting Induction Chemotherapy

Chemotherapy results in remarkably high response rates in treatment-naïve LA-SCCHN patients. The response rates to induction chemotherapy approach 50% to 70%, including a 10% to 15% complete response rate. Despite achieving complete responses, the response to chemotherapy is transient, and definitive therapy with surgery and/or radiotherapy is required. However, the sensitivity of SCCHN to induction chemotherapy can be capitalized on to improve locoregional and distant control.

Organ preservation with induction chemotherapy followed by radiotherapy was first reported by Jacobs et al to be a feasible approach to eliminate the need for surgery without compromising survival.129 This led to the Veterans Affairs Cooperative Study demonstrating equivalent survival rates between patients who received induction chemotherapy followed by radiotherapy and those who had laryngectomy.130 Lefebvre et al reported similar results several years later.131 With the use of induction chemotherapy followed by radiotherapy, patients were able to retain a functional larynx and only require a laryngectomy as salvage therapy (Table 4).

Table TABLE 4. Selected Induction Chemoradiotherapy Trials for Locoregionally Advanced Nonmetastatic Head and Neck Cancer with Organ Preservation and Survival Endpoints
StudyRegimen/Treatment ArmPrimary EndpointComments
  1. * Statistically significant difference.

  2. Abbreviations: RT, radiation therapy; Cis, cisplatin; 5-FU, 5-Fluorouracil; Sx, surgery; Doc, docetaxel; Pac, paclitaxel; Carbo, carboplatin; NS, not significant; CR, complete response; PFS, progression-free survival.

Endpoint: laryngeal preservation
   VA Study Group,130 1991A: RTLarynx preservation2-y survival
 B: Cis, 5-FU × 3 [RIGHTWARDS ARROW] RT +/− Sx2 y 64%A: 68%
   B: 68%
   P = NS
   Lefebvre JL, Chevalier D, Luboinski B, et al,131 1996A: RTLarynx preservation3-y survival
 B: Cis, 5-FU × 3 [RIGHTWARDS ARROW] RT +/− Sx5 y 35%A: 43%
   B: 57%
   P = NS
 
   Forastiere AA, Maor M, Weber RS, et al,132 Intergroup 91-11, 2003A: RTLarynx preservation5-y survival
 B: Cis, 5-FU × 4 [RIGHTWARDS ARROW] RT +/− Sx2 yA: 56%
 C: Cis + RTA: 70%B: 55%
  B: 75%*C: 54%
  C: 88%*P = NS
Endpoint: survival
   Paccagnella A, Orlando A, Marchiori C, et al,75 GSTTC, 1994, 2004A: RT +/− Sx10-y survivalPatients with unresectable tumors
 B: Cis, 5-FU × 4 [RIGHTWARDS ARROW] RT +/− SxA: 9%10-y survival
  B: 19%A: 6%
  P = NSB: 8%*
   Domenge C, Hill C, Lefebvre JL, et al,133 GETTEC, 2000A: RT +/− SxMedian survivalCR after chemotherapy: 20%
 B: Cis, 5-FU × 3 [RIGHTWARDS ARROW] RT +/− SxA: 3.3 y 
  B: 5.1 y* 
   Remenar E, Van Herpen C, Germa Lluch J, et al,134 EORTC 24971, 2006A: Cis, 5-FU × 4 [RIGHTWARDS ARROW] RT +/− SxMedian PFSMedian survival
 B: Doc, Cis, 5-FU × 4 [RIGHTWARDS ARROW] RT +/− SxA: 8 moA: 15 mo
  B: 13 mo*B: 19 mo*
   Hitt R, López-Pousa A, Martínez-Trufero J, et al,135 Madrid, 2005A: Cis, 5-FU × 3 [RIGHTWARDS ARROW] Cis + RTCR after inductionMedian time to treatment failure
 B: Pac, Cis, 5-FU × 3 [RIGHTWARDS ARROW] Cis + RTA: 14% 
  B: 33%A: 12 mo
   B: 20 mo*
   Posner MR, Herchock D, Le Lann L, et al,136 TAX324, 2006A: Cis, 5-FU × 3 [RIGHTWARDS ARROW] Carbo + RT3-y survival 
 B: Doc, Cis, 5-FU × 3 [RIGHTWARDS ARROW] Carbo + RTA: 48% 
  B: 62%* 

Developing in parallel with the induction chemotherapy approach was concomitant chemoradiotherapy, which in itself is able to achieve high locoregional control rates. The 2 approaches were compared in the InterGroup 91–11 trial.65,132 The trial had 3 arms: (1) induction chemotherapy followed by radiation therapy (RT), (2) concurrent chemoradiotherapy, and (3) daily single-fraction RT (Table 4). The concurrent chemoradiotherapy arm showed the best laryngectomy-free survival and local control rate. Acute toxicities were higher in both chemotherapy arms, but late toxicities and swallowing function at 2 years were equivalent among all arms. With the reporting of this trial, the induction chemotherapy approach fell out of favor.

Numerous other clinical trials have evaluated the role of induction chemotherapy followed by radiotherapy for a survival endpoint. These trials have largely been negative, except for 2 trials from the 1990s—the Groupe d'Etude des Tumeurs de la Tete et du Cou (GETTEC)133 and Gruppo di Studio sui Tumori della Testa e del Collo (GSTTC)75 studies (Table 4). There are several reasons that induction chemotherapy trials have been negative for their survival endpoints. Firstly, the definitive therapy delivered in the trials used radiotherapy alone, which is inadequate to achieve the locoregional control rates of concurrent chemoradiotherapy. Secondly, the induction regimens used have been variable, and many trials used suboptimal chemotherapy. Thirdly, many trials were underpowered to address the survival endpoint. Using pooled data from various heterogenous randomized induction chemotherapy trials, several meta-analyses have postulated that induction may provide minimal survival benefit.84,137, [138]139 The MACH-NC meta-analysis provided important information to further research in this area. After analyzing approximately 60 induction chemotherapy trials, only 15 trials utilized effective drugs such as cisplatin-5-FU. Pooled data from these trials showed a significant survival improvement of 5% with the use of effective induction chemotherapy.84,138

More Potent Chemotherapy

Both paclitaxel140.141 and docetaxel142,143 induction combinations resulted in high response rates. Induction chemotherapy with carboplatin-paclitaxel was reported by the University of Chicago to achieve complete and partial response rates of 33% and 57%, respectively.144 The EORTC 24971 trial compared 2 induction regimens, cisplatin/5-FU with docetaxel/cisplatin/5-FU, followed by radiotherapy.134 Complete response rates to cisplatin/5-FU and docetaxel/cisplatin/5-FU were 7% and 9%, respectively. The triple induction-regimen arm showed significantly improved progression-free and overall survival rates, but higher toxic death rates and hemotologic toxicities. Estimated 3-year survival rates were 24% for the cisplatin/5-FU arm and 37% for the docetaxel/cisplatin/5-FU arm.

With the taxanes proving efficacious as part of an induction regimen before definitive radiotherapy, the taxane-containing induction regimens were then evaluated with concurrent chemoradiotherapy. Hitt et al performed a randomized Phase II trial to compare the antitumor activity of 2 induction chemotherapy treatments of paclitaxel/cisplatin/5-FU versus cisplatin/5-FU, both followed by chemoradiotherapy with cisplatin.135 Induction with paclitaxel/cisplatin/5-FU resulted in significantly higher complete response rates compared with cisplatin/5-FU (33% versus 14%). Median time-to-treatment failure was 20 months in the paclitaxel/cisplatin/5-FU arm compared with 12 months in the cisplatin/5-FU arm.

Similarly, the docetaxel/cisplatin/5-FU induction regimen was tested in a randomized study by Posner et al.136 The study compared 2 induction chemotherapy regimens: docetaxel/cisplatin/5-FU versus cisplatin/5-FU for 3 cycles. After induction chemotherapy, patients in both arms received concurrent chemoradiotherapy with carboplatin (AUC 1.5, weekly). The complete response rates to induction chemotherapy with the cisplatin/5-FU arm and the docetaxel/cisplatin/5-FU arm were 15% and 17%, respectively. Severe neutropenic rates (84%) were higher in the docetaxel/cisplatin/5-FU arm. The 3-year survival rates were 48% for the cisplatin/5-FU arm and 62% for the docetaxel/cisplatin/5-FU arm (P = .0058). This trial is noteworthy for its concurrent chemoradiotherapy regimen utilizing carboplatin. The contribution of carboplatin to this regimen is unknown.145 Together, these 3 trials prove that taxanes, when added to a standard induction regimen (cisplatin/5-FU), result in a superior induction regimen, but are associated with increased toxicities.135,136,146

Future Investigations

With the development of more effective induction chemotherapy regimens as described above, we are now poised to answer the question on whether induction chemotherapy confers a survival benefit over concurrent chemoradiotherapy. Early evidence from a randomized Phase II study by Paccagnella et al showed that the complete response rates after chemoradiotherapy were 47% in the induction chemotherapy followed by concurrent chemoradiotherapy arm versus 20% in the immediate concurrent chemoradiotherapy arm.146 This trial lends support to the premise that an effective induction chemotherapy regimen is needed to have a stronger impact on outcome.

There are several ongoing induction chemotherapy randomized trials targeting different SCCHN patient populations. The University of Chicago “DeCIDE” trial (Docetaxel based Chemotherapy plus or minus Induction Chemotherapy to Decrease Events) is comparing chemoradiotherapy using the DFHX platform (docetaxel/5-FU/hydroxyurea/RT) with or without induction chemotherapy comprising docetaxel/cisplatin/5-FU (TPF) for 2 cycles. A completed Southwest Oncology Group/Eastern Cooperative Oncology Group Phase III trial is investigating the role of TPF induction chemotherapy followed by concurrent cisplatin and radiotherapy in patients with locally advanced but resectable oropharyngeal cancer. Nonresponders to induction therapy will undergo surgical resection. A third trial led by the Dana-Farber Cancer Institute randomizes patients to receive TPF induction chemotherapy or immediate concurrent cisplatin and accelerated fractionation/concomitant boost radiotherapy. For patients in the induction chemotherapy arm, partial responders will receive concurrent docetaxel and accelerated fractionation radiotherapy, while complete responders will receive concurrent carboplatin and conventionally fractionated radiotherapy.

Since the induction chemotherapy approach was tested 3 decades ago, one key observation was made: complete responders following induction chemotherapy have a significant survival benefit over partial or nonresponders.147, [148]149 Among complete responders, patients with complete pathological tumor response to induction chemotherapy have significantly better outcomes than patients with microscopic residual disease.150 In addition, it was noted that initial response to chemotherapy correlates with subsequent response to radiotherapy and, ultimately, survival.147 These observations are crucial in launching a new concept for selection of therapy for patients based on their initial response to therapy. Urba et al administered 1 cycle of neoadjuvant cisplatin and 5-FU.151 Patients who achieved less than 50% response had immediate laryngectomy, while those who achieved more than 50% response went on to concurrent chemoradiotherapy. The overall survival rate at 3 years is 85%, and larynx preservation was achieved in 70% of patients. Trials like this allow individualization of therapy based on the nature of specific tumors.

Metastatic Disease

The prevalence of distant metastasis at presentation commonly involving the lung, bones, and liver varies from 2% to 17%.55, [56], [57]58,152 The incidence of distant metastasis is correlated with presence of neck lymph node involvement at the time of diagnosis, in particular bilateral nodal metastasis.56,153, [154]155 Due to the propensity for SCCHN to metastasize to the lungs and the presence of second primary tumors within the aerodigestive tract, the thorax should be imaged. The role of PET is increasing in clinical practice. PET has a higher sensitivity than computed tomography (CT) to detect occult metastasis, which may significantly alter the treatment plan.156, [157], [158]159 One important use of PET is in evaluating for occult neck metastasis in clinically node-negative SCCHN. Occult neck metastases identified on PET with CT correlation were found in 3% of T1 tumors, 9% of T2 tumors, 13% of T3 tumors, and 25% of T4 tumors.158 Furthermore, PET has been used to evaluate for distant metastasis and to determine the nature of pulmonary nodules found by other imaging tests.159,160

Autopsy series report the prevalence of distant metastases in SCCHN patients ranges from 10% to 60%.152 The most common sites of distant metastases are lungs, mediastinal lymph nodes, bone, and liver.152 Skin metastases are uncommon in SCCHN (1%) and confer poor outcome.161 Therapy at this stage of disease is directed toward palliation. Data supporting a positive impact of chemotherapy on quality of life have not been generated. There has only been one study evaluating the benefit of chemotherapy for recurrent and/or metastatic SCCHN in terms of survival, which showed that cisplatin significantly prolonged median survival by 10 weeks over best supportive care.162

Active Chemotherapy in Metastatic SCCHN

The platinum analogs have been one of the most active agents in metastatic SCCHN. Single-agent response rates of cisplatin are 15% to 40%163, [164]165 and carboplatin is around 25%.166 Platinum agents are key in combination chemotherapy for recurrent and/or metastatic SCCHN.167 This was shown in a large randomized trial comparing methotrexate-bleomycin-vincristine with or without cisplatin. The arm that received cisplatin attained a 50% response rate compared with 28% in the group that did not receive cisplatin. Median survival was slightly longer in the cisplatin arm (18 weeks), but this was not significantly different from the other arm. The closest comparison of efficacy between cisplatin and carboplatin comes from a trial comparing the 2 agents in combination with 5-FU.168 The cisplatin/5-FU arm had a response rate of 32% compared with 21% in the carboplatin/5-FU arm, but there was no significant difference in overall survival.

The platinum analogs have been combined with other chemotherapy agents, most commonly with 5-FU. Although 5-FU has only a modest single-agent response rate (13%), when combined with cisplatin the response rate of the combination (32%) is significantly augmented.164 In the 1990s, taxanes were evaluated in SCCHN and their single-agent activity was found to be among the highest of any chemotherapy drug class. Response rates of up to 40% were observed with paclitaxel169 and docetaxel.170 Various combinations of the most active chemotherapies in SCCHN—platinums, taxanes, and 5-FU—have been evaluated.128 To date, no randomized trial has demonstrated improvement in overall survival, even though high response rates have been achieved. The response rates appear greater with platinum-taxane combinations, but the greater toxicity associated with these regimens may preclude their ability to offer palliation.128 The inability of combination chemotherapy to significantly impact overall survival indicates that a therapeutic plateau has been reached for cytotoxic therapy.

Targeted Agents in Metastatic SCCHN

In recent years, several promising agents have emerged. EGFR signaling, which plays an important role in SCCHN, can be inhibited by small-molecule inhibitors (erlotinib, gefitinib) binding to the tyrosine kinase adenosine triphosphate-binding site or by using monoclonal antibodies (cetuximab) to block the ligand-binding site of EGFR.

Gefitinib and erlotinib have demonstrated activity in metastatic SCCHN. Gefitinib administered orally at 500 mg daily resulted in a response rate of 8% to 11%, and median survival was 6 to 8 months.100,102 Similarly, erlotinib 150 mg orally daily resulted in a 4% response rate with a median survival of 6 months.104 Both drugs were well tolerated, and adverse effects are mainly mild rash and diarrhea. A strong correlation between skin toxicity and clinical outcome was observed with gefitinib and erlotinib. Erlotinib has since been combined with docetaxel and cisplatin, achieving a 66% response rate without significantly increasing the toxicity profile of the regimen in a single-arm uncontrolled trial.107

In platinum-refractory patients, cetuximab monotherapy resulted in a response rate of 13% and 6 months median survival.171 Addition of cetuximab to cisplatin in a randomized trial resulted in higher response rates in the cisplatin/cetuximab arm (26%) compared with the cisplatin-alone arm (10%).109 Development of rash was highly correlated with response. However, despite the higher response rate and improved progression-free survival, both arms had similar median overall survivals (9 versus 8 months). A second trial (EXTREME) evaluating cetuximab in combination with cisplatin/carboplatin and 5-FU as first-line treatment of recurrent and/or metastatic SCCHN shows a significant survival impact.172 This 442-patient randomized study found that the addition of cetuximab to chemotherapy improved median survival from 7.4 months to 10.1 months (P = .03), and the toxicity profile of the regimen was not increased. This is the first systemic therapy in the last 3 decades to show a survival benefit over platinum-based chemotherapy in recurrent and/or metastatic SCCHN.

With the mild toxicity profile of novel agents, there is heightened interest in investigating inhibitors of 2 or more targets involved in the pathogenesis of SCCHN. Sorafenib, a multikinase inhibitor of C-Raf, B-Raf, vascular endothelial growth factor (VEGF) receptor, and platelet-derived growth factor receptor, resulted in a 3% response rate in chemotherapy-naïve patients, but the median and progression-free survival were 7 months and 4 months, respectively.105 In spite of the scientific rationale behind targeted therapies, not all such therapies are effective. Lapatinib, an inhibitor of EGFR and HER2/neu, was ineffective in metastatic SCCHN.173 In the recent years, several mechanisms of resistance toward upstream signaling inhibition have been identified, such as the presence of independently activated downstream proteins and the upregulation of other cell-surface receptors. There are currently clinical trials underway to target downstream activators such as mTOR (mammalian target of rapamycin). It is known that VEGF upregulation may result in anti-EGFR therapy resistance. By inhibiting both EGFR and VEGF receptor activation with erlotinib and bevacizumab, significantly improved responses have been observed.108 These trials represent the first steps toward rational targeting of SCCHN through comprehension of the disease's biology and hold significant promise for the outcome of SCCHN.

Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is a unique type of head and neck cancer with a distinct natural history, etiology, histopathology, and epidemiology. The World Health Organization histological classification of NPC categorized the tumors into 3 histologic groups: type I (keratinizing squamous cell carcinomas, similar to those found in the rest of the upper aerodigestive tract); type II (nonkeratinizing squamous cell carcinomas); and type III (nonkeratinizing undifferentiated carcinomas). Compared with the keratinizing type of NPC, nonkeratinizing NPC tends to be associated with Epstein-Barr virus (EBV) and is commonly seen in endemic areas such as East Asia, North Africa, and the far Northern Hemisphere. The average age at diagnosis of NPC is in the sixth decade of life, but a significant proportion of patients are diagnosed in their 20s and 30s.174 NPC tends to metastasize early during the course of the disease; cervical lymph node metastases are observed in almost 90% of patients at presentation175 and distant metastases are found in 5% to 10% at diagnosis.175,176 The most frequent sites of distant metastases are bone, noncervical lymph nodes, and liver.177

NPC is staged by the tumor-node-metastasis staging system or the Ho staging. Two major differences distinguish the systems: (1) the Ho system compresses the 4 current AJCC T categories into 3, and (2) the Ho system categorizes lymph node disease by its anatomic position.178 The nodal definition of the Ho system provides important prognostic information.179 In recognition of this important aspect of the Ho system, the AJCC staging system was revised in 1997. For cervical nodal staging, N1 under the revised system referred to unilateral nodal involvement; N2 to bilateral nodal disease that had not reached N3 designation, irrespective of the size, number, or location of nodes; and N3 to lymph nodes larger than 6 cm (N3a) or nodes that had extended to the supraclavicular fossa (N3b).The new staging system improved the accuracy of predicting prognosis.180,181

A close association between EBV and nasopharyngeal carcinoma182,183 has been established on the basis of the presence of EBV DNA and proteins in NPC cells182,183 and premalignant lesions,184 and the presence of high concentrations of antibodies against EBV proteins in healthy people who later develop NPC.185,186 High pretreatment EBV-DNA levels correlate with higher disease stage, poorer tumor response, greater likelihood of distant relapse, and survival.187,188 Therapeutic monitoring of plasma EBV DNA provides a noninvasive method to monitor tumor response.188 Furthermore, this test may allow early detection of recurrences after treatment. Current research efforts are focused on the management of patients with persistent or increasing plasma EBV DNA after definitive therapy, but without any clinical evidence of disease, and risk stratification of patients for treatment.

The Intergroup-0099 study forms the basis for the standard of care for locoregionally advanced NPC in the United States. The Intergroup regimen utilized concurrent chemoradiotherapy with cisplatin 100 mg/m2 every 3 weeks followed by adjuvant cisplatin and 5-FU for 3 cycles.189,190 The 5-year survival was 67% in the chemotherapy arm compared with 37% in the RT-alone arm. A quarter of the 147 patients accrued had World Health Organization type I NPC, which has a different natural history from nonkeratinizing NPC. This led to 2 studies that limited enrollment to endemic nonkeratinizing NPC and have recently confirmed the efficacy of concurrent chemoradiotherapy and adjuvant chemotherapy.191,192 Both studies compared chemoradiotherapy with cisplatin followed by adjuvant chemotherapy with cisplatin-5-FU with radiotherapy alone. The 3-year survivals in both trials were approximately 80% in the chemoradiotherapy arm compared with 65% in the radiotherapy arm. Local control rates were similar in the chemoradiotherapy arms, but distant metastases were significantly less in the chemoradiotherapy arm of one trial,192 but not another.191 With these confirmatory trials, concurrent cisplatin chemoradiotherapy followed by adjuvant cisplatin-based chemotherapy is the current standard of care for locoregionally advanced NPC.

Locoregional Nonmetastatic Recurrence of Head and Neck Cancer

Locoregional recurrence of SCCHN in a previously irradiated field is a therapeutic challenge. Salvage surgical procedure provides the best chance of long-term disease control and possible cure for operable patients with resectable, recurrent cancers. Extensive surgery is often required and may be associated with surgical complications, permanent loss of function, visible deformity, high cost, and even death. Furthermore, surgical salvage is not always feasible. Eligible patients must be free of metastatic disease, have a resectable tumor, and be medically fit to undergo the surgery. Long-term survival is possible from surgery in well-selected patients with 5-year survival rates ranging from 15% to 40%.193, [194], [195], [196], [197], [198], [199]200 However, if surgery is not feasible, systemic chemotherapy with palliative intent is an alternative, but offers limited therapeutic benefit.

While palliative chemotherapy may be an acceptable option for some patients with widespread metastatic disease, it may not be the best approach for patients with only locoregionally recurrent disease. In carefully selected cases, reirradiation may be delivered with curative intent. However, since the majority of tumors that recur after primary radiotherapy arose from radiation-resistant tumor cells, reirradiation alone may be ineffective. Hence, reirradiation with concurrent chemotherapy may be more effective since both the radiosensitization and direct cytotoxic properties of chemotherapy are utilized. This toxic approach remains investigational and should only be performed at institutions with such experience. There are risks of unacceptable normal-tissue toxicity in reirradiated patients where cumulative radiation doses may reach twice the expected tolerance of normal tissues.

Two concurrent chemoradiotherapy regimens for reirradiation of recurrent head and neck cancer are commonly utilized—cisplatin-paclitaxel-reirradiation and hydroxyurea-5-FU-reirradiation (FHX). A review of the University of Chicago reirradiation experience with the FHX platform found that patients tolerated a median lifetime radiation dose of 131 Gy and achieved a 3-year overall survival, progression-free survival, locoregional control, and freedom from distant metastasis rate of 22%, 33%, 51%, and 61%, respectively.201 The treatment-related death rate was 17%. The RTOG 96–10 and Institut Gustave-Roussy trials have also assessed the FHX platform.202,203 The results of these trials consistently show that about 20% of patients attain long-term survival. Similarly, the cisplatin-paclitaxel-reirradiation platform has been demonstrated to be effective in patients with recurrent SCCHN.204,205

Although reirradiation is a potentially curative therapy, this modality carries an increased risk of treatment-related mortality.201 Mucositis, stomatitis, and dermatitis occur in almost all reirradiated patients. Furthermore, complications such as osteoradionecrosis, severe fibrosis, soft tissue necrosis, vascular necrosis, and mucosal necrosis have been reported. Late complications of reirradiation, such as vascular stenosis and impairment of swallowing or speech, may compromise quality of life. Reirradiation remains investigational, and the benefits of such an aggressive therapy need to be assessed further in randomized trials comparing it with the current standard therapy, chemotherapy.206

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANATOMY, CLINICAL FEATURES, AND STAGING
  5. ETIOLOGY OF HEAD AND NECK CANCER
  6. GENERAL PRINCIPLES OF TREATMENT
  7. ADVANCES IN THERAPY
  8. CONCLUSION
  9. References

After years of minimal progress in improving disease control and survival rates, the field of head and neck cancer therapy is rapidly advancing. Although such progress is good for patient care, this adds to the complexity of its management. It must be emphasized that the management of SCCHN today crosses multiple disciplines of medicine, and this will be the case for years to come. In this article, we have highlighted the increasing role of chemotherapy in the management of various stages of SCCHN. The cure rates achievable today, even in advanced disease, are a testament to the years of research that have been invested in this disease. There remains much to be learned; with the number of new targeted therapies that are produced presently, the permutations for combination multimodality therapies are infinite, and with the identification of various pathogenetic pathways in SCCHN, we are hopeful that this disease may one day be history.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANATOMY, CLINICAL FEATURES, AND STAGING
  5. ETIOLOGY OF HEAD AND NECK CANCER
  6. GENERAL PRINCIPLES OF TREATMENT
  7. ADVANCES IN THERAPY
  8. CONCLUSION
  9. References
  • 1
    Shibuya K, Mathers CD, Boschi-Pinto C, et al. Global and regional estimates of cancer mortality and incidence by site: II. Results for the global burden of disease 2000. BMC Cancer 2002; 2: 37.
  • 2
    Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006; 24: 21372150.
  • 3
    Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007; 18: 581592.
  • 4
    Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin 2007; 57: 4366.
  • 5
    Edwards BK, Brown ML, Wingo PA, et al. Annual report to the nation on the status of cancer, 1975–2002, featuring population-based trends in cancer treatment. J Natl Cancer Inst 2005; 97: 14071427.
  • 6
    Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J Med 1993; 328: 184194.
  • 7
    Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer-Verlag; 2002.
  • 8
    Leon X, Quer M, Orus C, et al. Distant metastases in head and neck cancer patients who achieved loco-regional control. Head Neck 2000; 22: 680686.
  • 9
    Ellis ER, Mendenhall WM, Rao PV, et al. Does node location affect the incidence of distant metastases in head and neck squamous cell carcinoma? Int J Radiat Oncol Biol Phys 1989; 17: 293297.
  • 10
    Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953; 6: 963968.
  • 11
    Tobacco smoking. IARC Monogr Eval Carcinog Risk Chem Hum 1986; 38: 35394.
  • 12
    Kato I, Nomura AM. Alcohol in the aetiology of upper aerodigestive tract cancer. Eur J Cancer B Oral Oncol 1994; 30B: 7581.
  • 13
    Kato I, Nomura AM, Stemmermann GN, Chyou PH. Prospective study of the association of alcohol with cancer of the upper aerodigestive tract and other sites. Cancer Causes Control 1992; 3: 145151.
  • 14
    Franceschi S, Talamini R, Barra S, et al. Smoking and drinking in relation to cancers of the oral cavity, pharynx, larynx, and esophagus in northern Italy. Cancer Res 1990; 50: 65026507.
  • 15
    Talamini R, Franceschi S, Barra S, La Vecchia C. The role of alcohol in oral and pharyngeal cancer in non-smokers, and of tobacco in non-drinkers. Int J Cancer 1990; 46: 391393.
  • 16
    Znaor A, Brennan P, Gajalakshmi V, et al. Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. Int J Cancer 2003; 105: 681686.
  • 17
    Lee KW, Kuo WR, Tsai SM, et al. Different impact from betel quid, alcohol and cigarette: risk factors for pharyngeal and laryngeal cancer. Int J Cancer 2005; 117: 831836.
  • 18
    Dal Maso L, La Vecchia C, Polesel J, et al. Alcohol drinking outside meals and cancers of the upper aero-digestive tract. Int J Cancer 2002; 102: 435437.
  • 19
    Huang WY, Winn DM, Brown LM, et al. Alcohol concentration and risk of oral cancer in Puerto Rico. Am J Epidemiol 2003; 157: 881887.
  • 20
    Baron AE, Franceschi S, Barra S, et al. A comparison of the joint effects of alcohol and smoking on the risk of cancer across sites in the upper aerodigestive tract. Cancer Epidemiol Biomarkers Prev 1993; 2: 519523.
  • 21
    Franceschi S, Levi F, La Vecchia C, et al. Comparison of the effect of smoking and alcohol drinking between oral and pharyngeal cancer. Int J Cancer 1999; 83: 14.
  • 22
    Mashberg A, Boffetta P, Winkelman R, Garfinkel L. Tobacco smoking, alcohol drinking, and cancer of the oral cavity and oropharynx among U.S. veterans. Cancer 1993; 72: 13691375.
  • 23
    Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 1988; 48: 32823287.
  • 24
    Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000; 92: 709720.
  • 25
    Mellin H, Friesland S, Lewensohn R, et al. Human papillomavirus (HPV) DNA in tonsillar cancer: clinical correlates, risk of relapse, and survival. Int J Cancer 2000; 89: 300304.
  • 26
    Hammarstedt L, Lindquist D, Dahlstrand H, et al. Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer. Int J Cancer 2006; 119: 26202623.
  • 27
    Hansson BG, Rosenquist K, Antonsson A, et al. Strong association between infection with human papillomavirus and oral and oropharyngeal squamous cell carcinoma: a population-based case-control study in southern Sweden. Acta Otolaryngol 2005; 125: 13371344.
  • 28
    Mork J, Lie AK, Glattre E, et al. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 2001; 344: 11251131.
  • 29
    D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007; 356: 19441956.
  • 30
    Brachman DG, Graves D, Vokes E, et al. Occurrence of p53 gene deletions and human papilloma virus infection in human head and neck cancer. Cancer Res 1992; 52: 48324836.
  • 31
    Chiba I, Shindoh M, Yasuda M, et al. Mutations in the p53 gene and human papillomavirus infection as significant prognostic factors in squamous cell carcinomas of the oral cavity. Oncogene 1996; 12: 16631668.
  • 32
    Wiest T, Schwarz E, Enders C, et al. Involvement of intact HPV16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and perturbed pRb cell cycle control. Oncogene 2002; 21: 15101517.
  • 33
    Hafkamp HC, Speel EJ, Haesevoets A, et al. A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 DNA and overexpression of p16INK4A and p53 in the absence of mutations in p53 exons 5–8. Int J Cancer 2003; 107: 394400.
  • 34
    Andl T, Kahn T, Pfuhl A, et al. Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control. Cancer Res 1998; 58: 513.
  • 35
    Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005; 14: 467475.
  • 36
    Paz IB, Cook N, Odom-Maryon T, et al. Human papillomavirus (HPV) in head and neck cancer. An association of HPV 16 with squamous cell carcinoma of Waldeyer's tonsillar ring. Cancer 1997; 79: 595604.
  • 37
    Smith EM, Summersgill KF, Allen J, et al. Human papillomavirus and risk of laryngeal cancer. Ann Otol Rhinol Laryngol 2000; 109: 10691076.
  • 38
    Schwartz SM, Daling JR, Doody DR, et al. Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. J Natl Cancer Inst 1998; 90: 16261636.
  • 39
    Smith EM, Hoffman HT, Summersgill KS, et al. Human papillomavirus and risk of oral cancer. Laryngoscope 1998; 108: 10981103.
  • 40
    Herrero R, Castellsague X, Pawlita M, et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003; 95: 17721783.
  • 41
    Rosenquist K, Wennerberg J, Schildt EB, et al. Oral status, oral infections and some lifestyle factors as risk factors for oral and oropharyngeal squamous cell carcinoma. A population-based case-control study in southern Sweden. Acta Otolaryngol 2005; 125: 13271336.
  • 42
    Kreimer AR, Alberg AJ, Daniel R, et al. Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis 2004; 189: 686698.
  • 43
    Hemminki K, Jiang Y, Dong C. Second primary cancers after anogenital, skin, oral, esophageal and rectal cancers: etiological links? Int J Cancer 2001; 93: 294298.
  • 44
    Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 2000; 92: 15001510.
  • 45
    Smith EM, Ritchie JM, Summersgill KF, et al. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer 2004; 108: 766772.
  • 46
    Kutler DI, Auerbach AD, Satagopan J, et al. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch Otolaryngol Head Neck Surg 2003; 129: 106112.
  • 47
    Kutler DI, Wreesmann VB, Goberdhan A, et al. Human papillomavirus DNA and p53 polymorphisms in squamous cell carcinomas from Fanconi anemia patients. J Natl Cancer Inst 2003; 95: 17181721.
  • 48
    Schwartz SR, Yueh B, McDougall JK, et al. Human papillomavirus infection and survival in oral squamous cell cancer: a population-based study. Otolaryngol Head Neck Surg 2001; 125: 19.
  • 49
    Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus-associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 2006; 24: 736747.
  • 50
    Licitra L, Perrone F, Bossi P, et al. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 2006; 24: 56305636.
  • 51
    Ritchie JM, Smith EM, Summersgill KF, et al. Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. Int J Cancer 2003; 104: 336344.
  • 52
    Mellin Dahlstrand H, Lindquist D, Björnestål L, et al. P16(INK4a) correlates to human papillomavirus presence, response to radiotherapy and clinical outcome in tonsillar carcinoma. Anticancer Res 2005; 25: 43754383.
  • 53
    Lindel K, Beer KT, Laissue J, et al. Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma. Cancer 2001; 92: 805813.
  • 54
    Harputluoglu H, Dizdar O, Altundag K. Prophylactic human papilloma virus vaccines for cervical cancer may also prevent development of breast and oropharyngeal cancers in women. Med Hypotheses 2006; 67: 431432.
  • 55
    Black RJ, Gluckman JL, Shumrick DA. Screening for distant metastases in head and neck cancer patients. Aust N Z J Surg 1984; 54: 527530.
  • 56
    de Bree R, Deurloo EE, Snow GB, Leemans CR. Screening for distant metastases in patients with head and neck cancer. Laryngoscope 2000; 110: 397401.
  • 57
    Dennington ML, Carter DR, Meyers AD. Distant metastases in head and neck epidermoid carcinoma. Laryngoscope 1980; 90: 196201.
  • 58
    Jackel MC, Rausch H. Distant metastasis of squamous epithelial carcinomas of the upper aerodigestive tract. The effect of clinical tumor parameters and course of illness [in German]. HNO 1999; 47: 3844.
  • 59
    List MA, Ritter-Sterr C, Lansky SB. A performance status scale for head and neck cancer patients. Cancer 1990; 66: 564569.
  • 60
    Mendenhall WM, Stringer SP, Amdur RJ, et al. Is radiation therapy a preferred alternative to surgery for squamous cell carcinoma of the base of tongue? J Clin Oncol 2000; 18: 3542.
  • 61
    Spector JG, Sessions DG, Chao KS, et al. Management of stage II (T2N0M0) glottic carcinoma by radiotherapy and conservation surgery. Head Neck 1999; 21: 116123.
  • 62
    Spector JG, Sessions DG, Chao KS, et al. Stage I (T1 N0 M0) squamous cell carcinoma of the laryngeal glottis: therapeutic results and voice preservation. Head Neck 1999; 21: 707717.
  • 63
    Sessions DG, Lenox J, Spector GJ. Supraglottic laryngeal cancer: analysis of treatment results. Laryngoscope 2005; 115: 14021410.
  • 64
    Sessions DG, Lenox J, Spector GJ, et al. Analysis of treatment results for base of tongue cancer. Laryngoscope 2003; 113: 12521261.
  • 65
    Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003; 349: 20912098.
  • 66
    Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 1998; 338: 17981804.
  • 67
    Budach V, Stuschke M, Budach W, et al. Hyperfractionated accelerated chemoradiation with concurrent fluorouracil-mitomycin is more effective than dose-escalated hyperfractionated accelerated radiation therapy alone in locally advanced head and neck cancer: final results of the radiotherapy cooperative clinical trials group of the German Cancer Society 95-06 Prospective Randomized Trial. J Clin Oncol 2005; 23: 11251135.
  • 68
    Jeremic B, Shibamoto Y, Milicic B, et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 2000; 18: 14581464.
  • 69
    Vikram B, Strong EW, Shah JP, Spiro R. Failure at the primary site following multimodality treatment in advanced head and neck cancer. Head Neck Surg 1984; 6: 720723.
  • 70
    Vikram B, Strong EW, Shah JP, Spiro R. Failure in the neck following multimodality treatment for advanced head and neck cancer. Head Neck Surg 1984; 6: 724729.
  • 71
    Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004; 350: 19451952.
  • 72
    Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004; 350: 19371944.
  • 73
    Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567578.
  • 74
    Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 1999; 91: 20812086.
  • 75
    Paccagnella A, Orlando A, Marchiori C, et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 1994; 86: 265272.
  • 76
    Brockstein B, Haraf DJ, Rademaker AW, et al. Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience. Ann Oncol 2004; 15: 11791186.
  • 77
    Adelstein DJ, Saxton JP, Lavertu P, et al. Maximizing local control and organ preservation in stage IV squamous cell head and neck cancer with hyperfractionated radiation and concurrent chemotherapy. J Clin Oncol 2002; 20: 14051410.
  • 78
    Adelstein DJ, Saxton JP, Lavertu P, et al. A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck 1997; 19: 567575.
  • 79
    Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 2000; 48: 716.
  • 80
    Horiot JC, Le Fur R, N'Guyen T, et al. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 1992; 25: 231241.
  • 81
    Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003; 362: 933940.
  • 82
    Bourhis J, Amand C, Pignon J-P. Update of MACH-NC (Meta-Analysis of Chemotherapy in Head & Neck Cancer) database focused on concomitant chemoradiotherapy [abstract]. Proc Am Soc Clin Oncol 2004; 22: 14s. Abstract 5505.
  • 83
    Browman GP, Hodson DI, Mackenzie RJ, et al. Choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer: a systematic review of the published literature with subgroup analysis. Head Neck 2001; 23: 579589.
  • 84
    Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000; 355: 949955.
  • 85
    Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003; 21: 9298.
  • 86
    Olmi P, Crispino S, Fallai C, et al. Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy—a multicenter randomized trial. Int J Radiat Oncol Biol Phys 2003; 55: 7892.
  • 87
    Huguenin P, Beer KT, Allal A, et al. Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy. J Clin Oncol 2004; 22: 46654673.
  • 88
    Bensadoun RJ, Dassonville O, Ramaioli A, et al. Phase III multicenter randomized study of concurrent twice-a-day radiotherapy with and without cisplatin-5FU (BiRCF) in unresectable pharyngeal carcinoma. Results at 18 months (FNCLCC-GORTEC) [abstract]. Proc Am Soc Clin Oncol 2004; 22: 14s. Abstract 5504.
  • 89
    Dobrowsky W, Naude J. Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancers. Radiother Oncol 2000; 57: 119124.
  • 90
    Bentzen SM, Trotti A. Evaluation of early and late toxicities in chemoradiation trials. J Clin Oncol 2007; 25: 40964103.
  • 91
    Argiris A, Brockstein BE, Haraf DJ, et al. Competing causes of death and second primary tumors in patients with locoregionally advanced head and neck cancer treated with chemoradiotherapy. Clin Cancer Res 2004; 10: 19561962.
  • 92
    Singh B, Bhaya M, Zimbler M, et al. Impact of comorbidity on outcome of young patients with head and neck squamous cell carcinoma. Head Neck 1998; 20: 17.
  • 93
    Sanabria A, Carvalho AL, Vartanian JG, et al. Comorbidity is a prognostic factor in elderly patients with head and neck cancer. Ann Surg Oncol 2007; 14: 14491457.
  • 94
    Bourhis J, Le Maître A, Pignon J, et al. Impact of age on treatment effect in locally advanced head and neck cancer (HNC): two individual patient data meta-analyses [abstract]. Proc Am Soc Clin Oncol 2006; 24: 18s. Abstract 5501.
  • 95
    Rosenthal DI, Lewin JS, Eisbruch A. Prevention and treatment of dysphagia and aspiration after chemoradiation for head and neck cancer. J Clin Oncol 2006; 24: 26362643.
  • 96
    Dassonville O, Formento JL, Francoual M, et al. Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol 1993; 11: 18731878.
  • 97
    Xia W, Lau YK, Zhang HZ, et al. Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members. Clin Cancer Res 1999; 5: 41644174.
  • 98
    Shin DM, Ro JY, Hong WK, Hittelman WN. Dysregulation of epidermal growth factor receptor expression in premalignant lesions during head and neck tumorigenesis. Cancer Res 1994; 54: 31533159.
  • 99
    Bonner JA, Giralt J, Harari PM, et al. Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: a phase III study of high dose radiation therapy with or without cetuximab [abstract]. J Clin Oncol 2004; 22: 14s. Abstract 5507.
  • 100
    Cohen EE, Rosen F, Stadler WM, et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003; 21: 19801987.
  • 101
    Wheeler RH, Jones D, Sharma P, et al. Clinical and molecular phase II study of gefitinib in patients (pts) with recurrent squamous cell cancer of the head and neck (H&N Ca) [abstract]. Proc Am Soc Clin Oncol 2005; 23: 16s. Abstract 5531.
  • 102
    Kirby AM, A'Hern RP, D'Ambrosio C, et al. Gefitinib (ZD1839, Iressa) as palliative treatment in recurrent or metastatic head and neck cancer. Br J Cancer 2006; 94: 631636.
  • 103
    Cohen EE, Kane MA, List MA, et al. Phase II trial of gefitinib 250 mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 2005; 11: 84188424.
  • 104
    Soulieres D, Senzer NN, Vokes EE, et al. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 2004; 22: 7785.
  • 105
    Williamson SK, Moon J, Huang CH, et al. A phase II trial of BAY 43-9006 in patients with recurrent and/or metastatic head and neck squamous cell carcinoma: a Southwest Oncology Group (SWOG) trial [abstract]. Proc Am Soc Clin Oncol 2006; 24: 18s. Abstract 5550.
  • 106
    Belón J, Irigoyen A, Rodríguez I, et al. Preliminary results of a Phase II study to evaluate gefitinib combined with docetaxel and cisplatin in patients with recurrent and/or metastatic squamous-cell carcinoma of the head and neck [abstract]. Proc Am Soc Clin Oncol 2005; 23: 16s. Abstract 5563.
  • 107
    Kim ES, Kies MS, Glisson BS, et al. Phase II study of combination cisplatin, docetaxel and erlotinib in patients with metastatic/recurrent head and neck squamous cell carcinoma [abstract]. Proc Am Soc Clin Oncol 2006; 24: 18s. Abstract 5521.
  • 108
    Vokes EE, Cohen EE, Mauer AM, et al. A phase I study of erlotinib and bevacizumab for recurrent or metastatic squamous cell carcinoma of the head and neck (HNC) [abstract]. Proc Am Soc Clin Oncol 2005: 23: 16s. Abstract 5504.
  • 109
    Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005; 23: 86468654.
  • 110
    Chan AT, Hsu MM, Goh BC, et al. Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. J Clin Oncol 2005; 23: 35683576.
  • 111
    Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006; 368: 843854.
  • 112
    Kies MS, Haraf DJ, Rosen F, et al. Concomitant infusional paclitaxel and fluorouracil, oral hydroxyurea, and hyperfractionated radiation for locally advanced squamous head and neck cancer. J Clin Oncol 2001; 19: 19611969.
  • 113
    Rosen FR, Haraf DJ, Kies MS, et al. Multicenter randomized Phase II study of paclitaxel (1-hour infusion), fluorouracil, hydroxyurea, and concomitant twice daily radiation with or without erythropoietin for advanced head and neck cancer. Clin Cancer Res 2003; 9: 16891697.
  • 114
    Cooper JS, Pajak TF, Forastiere A, et al. Precisely defining high-risk operable head and neck tumors based on RTOG #85-03 and #88-24: targets for postoperative radiochemotherapy? Head Neck 1998; 20: 588594.
  • 115
    Langendijk JA, de Jong MA, Leemans CR, et al. Postoperative radiotherapy in squamous cell carcinoma of the oral cavity: the importance of the overall treatment time. Int J Radiat Oncol Biol Phys 2003; 57: 693700.
  • 116
    Rosenthal DI, Liu L, Lee JH, et al. Importance of the treatment package time in surgery and postoperative radiation therapy for squamous carcinoma of the head and neck. Head Neck 2002; 24: 115126.
  • 117
    Ang KK, Trotti A, Brown BW, et al. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001; 51: 571578.
  • 118
    Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial. Int J Radiat Oncol Biol Phys 1993; 26: 311.
  • 119
    Bachaud JM, Cohen-Jonathan E, Alzieu C, et al. Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys 1996; 36: 9991004.
  • 120
    Johnson JT, Barnes EL, Myers EN, et al. The extracapsular spread of tumors in cervical node metastasis. Arch Otolaryngol 1981; 107: 725729.
  • 121
    Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005; 27: 843850.
  • 122
    Huang DT, Johnson CR, Schmidt-Ullrich R, Grimes M. Postoperative radiotherapy in head and neck carcinoma with extracapsular lymph node extension and/or positive resection margins: a comparative study. Int J Radiat Oncol Biol Phys 1992; 23: 737742.
  • 123
    Lundahl RE, Foote RL, Bonner JA, et al. Combined neck dissection and postoperative radiation therapy in the management of the high-risk neck: a matched-pair analysis. Int J Radiat Oncol Biol Phys 1998; 40: 529534.
  • 124
    Fietkau R, Lautenschläger C, Sauer R, et al. Postoperative concurrent radiochemotherapy versus radiotherapy in high-risk SCCA of the head and neck: results of the German phase III trial ARO 96–3 [abstract]. Proc Am Soc Clin Oncol 2006; 24: 18s. Abstract 5507.
  • 125
    Machtay M, Moughan J, Trotti A, et al. Pre-treatment and treatment related risk factors for severe late toxicity after chemo-RT for head and neck cancer: an RTOG analysis [abstract]. Proc Am Soc Clin Oncol 2006; 24: 18s. Abstract 5500.
  • 126
    Pfister DG, Su YB, Kraus DH, et al. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. J Clin Oncol 2006; 24: 10721078.
  • 127
    Airoldi M, Cortesina G, Giordano C, et al. Postoperative adjuvant chemoradiotherapy in older patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 2004; 130: 161166.
  • 128
    Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2006; 24: 26442652.
  • 129
    Jacobs C, Goffinet DR, Goffinet L, et al. Chemotherapy as a substitute for surgery in the treatment advanced resectable head and neck cancer. A report from the Northern California Oncology Group. Cancer 1987; 60: 11781183.
  • 130
    Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991; 324: 16851690.
  • 131
    Lefebvre JL, Chevalier D, Luboinski B, et al. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 1996; 88: 890899.
  • 132
    Forastiere AA, Maor M, Weber RS, et al. Long-term results of Intergroup RTOG 91–11: a phase III trial to preserve the larynx-induction cisplatin/5-FU and radiation therapy versus concurrent cisplatin and radiation therapy versus radiation therapy [abstract]. Proc Am Soc Clin Oncol 2006; 24: 18s. Abstract 5517.
  • 133
    Domenge C, Hill C, Lefebvre JL, et al. Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. French Groupe d'Etude des Tumeurs de la Tête et du Cou (GETTEC). Br J Cancer 2000; 83: 15941598.
  • 134
    Remenar E, Van Herpen C, Germa Lluch J, et al. A randomized phase III multicenter trial of neoadjuvant docetaxel plus cisplatin and 5-fluorouracil (TPF) versus neoadjuvant PF in patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN). Final analysis of EORTC 24971 [abstract]. Proc Am Soc Clin Oncol 2006; 24: 18s. Abstract 5516.
  • 135
    Hitt R, López-Pousa A, Martínez-Trufero J, et al. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 2005; 23: 86368645.
  • 136
    Posner MR, Herchock D, Le Lann L, et al. TAX 324: a phase III trial of TPF vs PF induction chemotherapy followed by chemoradiotherapy in locally advanced SCCHN. Presented at: 42nd Annual Meeting of the American Society of Clinical Oncology; June 2006; Atlanta, GA. Special session.
  • 137
    El-Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region. A meta-analysis of prospective and randomized trials. J Clin Oncol 1996; 14: 838847.
  • 138
    Monnerat C, Faivre S, Temam S, et al. End points for new agents in induction chemotherapy for locally advanced head and neck cancers. Ann Oncol 2002; 13: 9951006.
  • 139
    Munro AJ. An overview of randomised controlled trials of adjuvant chemotherapy in head and neck cancer. Br J Cancer 1995; 71: 8391.
  • 140
    Hainsworth JD, Meluch AA, McClurkan S, et al. Induction paclitaxel, carboplatin, and infusional 5-FU followed by concurrent radiation therapy and weekly paclitaxel/carboplatin in the treatment of locally advanced head and neck cancer: a phase II trial of the Minnie Pearl Cancer Research Network. Cancer J 2002; 8: 311321.
  • 141
    Machtay M, Rosenthal DI, Hershock D, et al. Organ preservation therapy using induction plus concurrent chemoradiation for advanced resectable oropharyngeal carcinoma: a University of Pennsylvania Phase II Trial. J Clin Oncol 2002; 20: 39643971.
  • 142
    Posner MR, Glisson B, Frenette G, et al. Multicenter phase I-II trial of docetaxel, cisplatin, and fluorouracil induction chemotherapy for patients with locally advanced squamous cell cancer of the head and neck. J Clin Oncol 2001; 19: 10961104.
  • 143
    Tishler RB, Norris CM, Jr, Colevas AD, et al. A Phase I/II trial of concurrent docetaxel and radiation after induction chemotherapy in patients with poor prognosis squamous cell carcinoma of the head and neck. Cancer 2002; 95: 14721481.
  • 144
    Vokes EE, Rosen FR, Kies MS, et al. Weekly carboplatin and paclitaxel followed by concomitant T-FHX chemoradiotherapy for advanced head and neck cancer: a potentially successful strategy [abstract]. Proc Am Soc Clin Oncol 2002; 21: 230a. Abstract 916.
  • 145
    Fountzilas G, Ciuleanu E, Dafni U, et al. Concomitant radiochemotherapy vs radiotherapy alone in patients with head and neck cancer: a Hellenic Cooperative Oncology Group Phase III Study. Med Oncol 2004; 21: 95107.
  • 146
    Paccagnella A, Buffoli A, Koussis H, et al. Randomized phase II trial of concomitant CT/RT versus TPF followed by concomitant CT/RT in locally advanced squamous cell carcinoma of the head and neck [abstract]. Proc Am Soc Clin Oncol 2006; 24: 18s. Abstract 5518.
  • 147
    Ervin TJ, Clark JR, Weichselbaum RR, et al. An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck. J Clin Oncol 1987; 5: 1020.
  • 148
    Kies MS, Gordon LI, Hauck WW, et al. Analysis of complete responders after initial treatment with chemotherapy in head and neck cancer. Otolaryngol Head Neck Surg 1985; 93: 199205.
  • 149
    Rooney M, Kish J, Jacobs J, et al. Improved complete response rate and survival in advanced head and neck cancer after three-course induction therapy with 120-hour 5-FU infusion and cisplatin. Cancer 1985; 55: 11231128.
  • 150
    Al-Kourainy K, Kish J, Ensley J, et al. Achievement of superior survival for histologically negative versus histologically positive clinically complete responders to cisplatin combination in patients with locally advanced head and neck cancer. Cancer 1987; 59: 233238.
  • 151
    Urba S, Wolf G, Eisbruch A, et al. Single-cycle induction chemotherapy selects patients with advanced laryngeal cancer for combined chemoradiation: a new treatment paradigm. J Clin Oncol 2006; 24: 593598.
  • 152
    Ferlito A, Shaha AR, Silver CE, et al. Incidence and sites of distant metastases from head and neck cancer. ORL J Otorhinolaryngol Relat Spec 2001; 63: 202207.
  • 153
    Houghton DJ, Hughes ML, Garvey C, et al. Role of chest CT scanning in the management of patients presenting with head and neck cancer. Head Neck 1998; 20: 614618.
  • 154
    Ferlito A, Buckley JG, Rinaldo A, Mondin V. Screening tests to evaluate distant metastases in head and neck cancer. ORL J Otorhinolaryngol Relat Spec 2001; 63: 208211.
  • 155
    Loh KS, Brown DH, Baker JT, et al. A rational approach to pulmonary screening in newly diagnosed head and neck cancer. Head Neck 2005; 27: 990994.
  • 156
    Schmid DT, Stoeckli SJ, Bandhauer F, et al. Impact of positron emission tomography on the initial staging and therapy in locoregional advanced squamous cell carcinoma of the head and neck. Laryngoscope 2003; 113: 888891.
  • 157
    Ng SH, Yen TC, Liao CT, et al. 18F-FDG PET and CT/MRI in oral cavity squamous cell carcinoma: a prospective study of 124 patients with histologic correlation. J Nucl Med 2005; 46: 11361143.
  • 158
    Ng SH, Yen TC, Chang JT, et al. Prospective study of [18F]fluorodeoxyglucose positron emission tomography and computed tomography and magnetic resonance imaging in oral cavity squamous cell carcinoma with palpably negative neck. J Clin Oncol 2006; 24: 43714376.
  • 159
    Teknos TN, Rosenthal EL, Lee D, et al. Positron emission tomography in the evaluation of stage III and IV head and neck cancer. Head Neck 2001; 23: 10561060.
  • 160
    Schwartz DL, Rajendran J, Yueh B, et al. Staging of head and neck squamous cell cancer with extended-field FDG-PET. Arch Otolaryngol Head Neck Surg 2003; 129: 11731178.
  • 161
    Pitman KT, Johnson JT. Skin metastases from head and neck squamous cell carcinoma: incidence and impact. Head Neck 1999; 21: 560565.
  • 162
    Morton RP, Rugman F, Dorman EB, et al. Cisplatinum and bleomycin for advanced or recurrent squamous cell carcinoma of the head and neck: a randomised factorial phase III controlled trial. Cancer Chemother Pharmacol 1985; 15: 283289.
  • 163
    Clavel M, Vermorken JB, Cognetti F, et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol 1994; 5: 521526.
  • 164
    Jacobs C, Lyman G, Velez-García E, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992; 10: 257263.
  • 165
    Wittes RE, Cvitkovic E, Shah J, et al. CIS-Dichlorodiammineplatinum(II) in the treatment of epidermoid carcinoma of the head and neck. Cancer Treat Rep 1977; 61: 359366.
  • 166
    Eisenberger M, Hornedo J, Silva H, et al. Carboplatin (NSC-241-240): an active platinum analog for the treatment of squamous-cell carcinoma of the head and neck. J Clin Oncol 1986; 4: 15061509.
  • 167
    Clavel M, Cognetti F, Dodion P, et al. Combination chemotherapy with methotrexate, bleomycin, and vincristine with or without cisplatin in advanced squamous cell carcinoma of the head and neck. Cancer 1987; 60: 11731177.
  • 168
    Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992; 10: 12451251.
  • 169
    Forastiere AA, Shank D, Neuberg D, et al. Final report of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck: an Eastern Cooperative Oncology Group trial (PA390). Cancer 1998; 82: 22702274.
  • 170
    Dreyfuss AI, Clark JR, Norris CM, et al. Docetaxel: an active drug for squamous cell carcinoma of the head and neck. J Clin Oncol 1996; 14: 16721678.
  • 171
    Trigo J, Hitt R, Koralewski P, et al. Cetuximab monotherapy is active in patients (pts) with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN): results of a phase II study [abstract]. J Clin Oncol 2004; 22: 14s. Abstract 5502.
  • 172
    Vermorken JB, Mesia R, Vega V, et al. Cetuximab extends survival of patients with recurrent or metastatic SCCHN when added to first line platinum based therapy—results of a randomized phase III study [abstract]. Proc Am Soc Clin Oncol 2007; 25: 18s. Abstract 6091.
  • 173
    Abidoye OO, Cohen EE, Wong SJ, et al. A phase II study of lapatinib (GW572016) in recurrent/metastatic squamous cell carcinoma of the head and neck [abstract]. Proc Am Soc Clin Oncol 2006; 24: 18s. Abstract 5568.
  • 174
    Lee AW, Foo W, Mang O, et al. Changing epidemiology of nasopharyngeal carcinoma in Hong Kong over a 20-year period (1980–99): an encouraging reduction in both incidence and mortality. Int J Cancer 2003; 103: 680685.
  • 175
    Lee AW, Poon YF, Foo W, et al. Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976–1985: overall survival and patterns of failure. Int J Radiat Oncol Biol Phys 1992; 23: 261270.
  • 176
    Tang SG, Lin FJ, Chen MS, et al. Prognostic factors of nasopharyngeal carcinoma: a multivariate analysis. Int J Radiat Oncol Biol Phys 1990; 19: 11431149.
  • 177
    Ahmad A, Stefani S. Distant metastases of nasopharyngeal carcinoma: a study of 256 male patients. J Surg Oncol 1986; 33: 194197.
  • 178
    Cooper JS, Cohen R, Stevens RE. A comparison of staging systems for nasopharyngeal carcinoma. Cancer 1998; 83: 213219.
  • 179
    Lee AW, Foo W, Poon YF, et al. Staging of nasopharyngeal carcinoma: evaluation of N-staging by Ho and UICC/AJCC systems. Union Internationale Contre le Cancer. American Joint Committee for Cancer. Clin Oncol (R Coll Radiol) 1996; 8: 146154.
  • 180
    Chien CR, Chen SW, Hsieh CY, et al. Retrospective comparison of the AJCC 5th edition classification for nasopharyngeal carcinoma with the AJCC 4th edition: an experience in Taiwan. Jpn J Clin Oncol 2001; 31: 363369.
  • 181
    Ozyar E, Yildiz F, Akyol FH, Atahan IL. Comparison of AJCC 1988 and 1997 classifications for nasopharyngeal carcinoma. American Joint Committee on Cancer. Int J Radiat Oncol Biol Phys 1999; 44: 10791087.
  • 182
    Chang YS, Tyan YS, Liu ST, et al. Detection of Epstein-Barr virus DNA sequences in nasopharyngeal carcinoma cells by enzymatic DNA amplification. J Clin Microbiol 1990; 28: 23982402.
  • 183
    Tsai ST, Jin YT, Su IJ. Expression of EBER1 in primary and metastatic nasopharyngeal carcinoma tissues using in situ hybridization. A correlation with WHO histologic subtypes. Cancer 1996; 77: 231236.
  • 184
    Pathmanathan R, Prasad U, Sadler R, et al. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med 1995; 333: 693698.
  • 185
    Chien YC, Chen JY, Liu MY, et al. Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. N Engl J Med 2001; 345: 18771882.
  • 186
    Ji MF, Wang DK, Yu YL, et al. Sustained elevation of Epstein-Barr virus antibody levels preceding clinical onset of nasopharyngeal carcinoma. Br J Cancer 2007; 96: 623630.
  • 187
    Lin JC, Wang WY, Chen KY, et al. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med 2004; 350: 24612470.
  • 188
    Chan AT, Ma BB, Lo YM, et al. Phase II study of neoadjuvant carboplatin and paclitaxel followed by radiotherapy and concurrent cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma: therapeutic monitoring with plasma Epstein-Barr virus DNA. J Clin Oncol 2004; 22: 30533060.
  • 189
    Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998; 16: 13101317.
  • 190
    Al-Sarraf M, LeBlanc M, Giri PG, et al. Superiority of five year survival with chemo-radiotherapy (CT-RT) vs radiotherapy in patients (Pts) with locally advanced nasopharyngeal cancer (NPC). Intergroup (0099) (SWOG 8892, RTOG 8817, ECOG 2388) phase III study: final report [abstract]. Proc Am Soc Clin Oncol 2001; 20: 227a. Abstract 905.
  • 191
    Lee AW, Lau WH, Tung SY, et al. Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group. J Clin Oncol 2005; 23: 69666975.
  • 192
    Wee J, Tan EH, Tai BC, et al. Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 2005; 23: 67306738.
  • 193
    Farrag TY, Lin FR, Cummings CW, et al. Neck management in patients undergoing postradiotherapy salvage laryngeal surgery for recurrent/persistent laryngeal cancer. Laryngoscope 2006; 116: 18641866.
  • 194
    Ganly I, Patel SG, Matsuo J, et al. Results of surgical salvage after failure of definitive radiation therapy for early-stage squamous cell carcinoma of the glottic larynx. Arch Otolaryngol Head Neck Surg 2006; 132: 5966.
  • 195
    Goodwin WJ Jr. Salvage surgery for patients with recurrent squamous cell carcinoma of the upper aerodigestive tract: when do the ends justify the means? Laryngoscope 2000; 110(suppl): 118.
  • 196
    Jones AS, Bin Hanafi Z, Nadapalan V, et al. Do positive resection margins after ablative surgery for head and neck cancer adversely affect prognosis? A study of 352 patients with recurrent carcinoma following radiotherapy treated by salvage surgery. Br J Cancer 1996; 74: 128132.
  • 197
    Pacheco-Ojeda L, Marandas P, Julieron M, et al. Salvage surgery by composite resection for epidermoid carcinoma of the tonsillar region. Arch Otolaryngol Head Neck Surg 1992; 118: 181184.
  • 198
    Pradhan SA, Rajpal RM, Kothary PM. Surgical management of postradiation residual/recurrent cancer of the base of the tongue. J Surg Oncol 1980; 14: 201206.
  • 199
    Stoeckli SJ, Pawlik AB, Lipp M, et al. Salvage surgery after failure of nonsurgical therapy for carcinoma of the larynx and hypopharynx. Arch Otolaryngol Head Neck Surg 2000; 126: 14731477.
  • 200
    Yuen AP, Wei WI, Ho CM. Results of surgical salvage for radiation failures of laryngeal carcinoma. Otolaryngol Head Neck Surg 1995; 112: 405409.
  • 201
    Salama JK, Vokes EE, Chmura SJ, et al. Long-term outcome of concurrent chemotherapy and reirradiation for recurrent and second primary head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2006; 64: 382391.
  • 202
    De Crevoisier R, Bourhis J, Domenge C, et al. Full-dose reirradiation for unresectable head and neck carcinoma: experience at the Gustave-Roussy Institute in a series of 169 patients. J Clin Oncol 1998; 16: 35563562.
  • 203
    Spencer SA, Harris J, Wheeler RH, et al. RTOG 96-10: reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck. Int J Radiat Oncol Biol Phys 2001; 51: 12991304.
  • 204
    Horwitz EM, Harris J, Langer CJ, et al. Concurrent split course hyperfractionated radiotherapy (Hfx RT), cisplatin (DDP) and paclitaxel (P) in patients with recurrent, previously irradiated squamous cell carcinoma of the head and neck (SCCHN): update of RTOG 9911 [abstract]. Proc Am Soc Clin Oncol 2005; 23: 16s. Abstract 5577.
  • 205
    Kramer NM, Horwitz EM, Cheng J, et al. Toxicity and outcome analysis of patients with recurrent head and neck cancer treated with hyperfractionated split-course reirradiation and concurrent cisplatin and paclitaxel chemotherapy from two prospective phase I and II studies. Head Neck 2005; 27: 406414.
  • 206
    Wong SJ, Machtay M, Li Y. Locally recurrent, previously irradiated head and neck cancer: concurrent re-irradiation and chemotherapy, or chemotherapy alone? J Clin Oncol 2006; 24: 26532658.