Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

5. Carcinomas of the Head and Neck

Barbara A. Murphy

Head and neck cancers (HNCs) are defined as those arising from the upper aerodigestive system. Although a variety of histopathologic subtypes have been associated with the anatomic region, the vast majority are squamous cell carcinoma (SCA); thus, the following chapter will focus specifically on this subtype.

I. ANATOMY

Understanding HNC begins with an understanding of aerodigestive anatomy. There are five sites within the head and neck region. These include the larynx, pharynx, oral cavity, paranasal sinuses, and the major salivary glands. Each site is composed of specific subsites (Table 5.1). A cross-sectional view of the anatomic regions and the relative frequency of cancer occurring in each area are shown in Figure 5.1. Identification of the primary site and extent of disease are critical for treatment planning, as will be discussed at length subsequently. Although thyroid cancers are frequently treated by otolaryngologists, they have unique pathologic and treatment issues and are covered in Chapter 13. Skin cancers, which are also common in the head and neck region, are discussed in Chapter 14.

II. EPIDEMIOLOGY

Approximately 40,000 cases of SCAs of the head and neck are diagnosed annually within the United States. Although SCAs of the head and neck are often considered together because of their anatomic proximity, it is important to recognize that HNC is comprised of a variety of distinct disease entities that may be distinguished based on etiology, histology, epidemiology, and natural history. These include the following: (1) SCA associated with traditional risk factors of smoking and drinking, (2) nasopharyngeal carcinomas (NPCs), and (3) human papillomavirus (HPV) associated oropharyngeal cancers. The distinction between these entities is critical in order to make appropriate treatment decisions.

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FIGURE 5.1 Anatomic divisions of the head and neck. Percentages indicate the relative frequencies of carcinoma in these regions.

A. SCA with traditional risk factors

Historically, HNCs have been associated with exposure to mucosal irritants such as tobacco and alcohol. Strong epidemiologic data demonstrates that there is a dose-response relationship between cigarette use and the incidence of HNC. Of note, alcohol use interacts synergistically with tobacco use, dramatically increasing the risk of cancer. Chewing tobacco is associated with oral cavity cancers. The median age at diagnosis for tobacco-associated HNC ranges from 55 to 67 years, depending on the site. There is a marked male predominance (3:1), which is felt to reflect the patterns of prior tobacco use within the general population. Of note, there has been a decreasing incidence of HNC associated with traditional risk factors.

B. NPC

NPCs have a highly variable rate of occurrence depending on geographic region. Areas with high rates of NPC include China, Southeast Asia, and North Africa. In low-risk areas, NPC is quite uncommon. Epidemiologic studies are ongoing to identify potential differences in the etiology and behavior of NPC in low- and high-risk regions. In low-risk areas, NPC has a bimodal age distribution with peak incidence occurring between the ages of 15 and 25 years, and again between the ages of 56 and 79 years. In high-risk areas, the initial peak is lacking, and incidence rates start to decline at an earlier age.

Risk factors for the development of NPC include infection with Epstein-Barr virus (EBV), environmental factors, and genetic predisposition. In the low-risk areas, the early peak in incidence is thought to be due to genetic susceptibility in conjunction with exposure to EBV and/or other environmental contacts. EBV appears to be associated with NPC in high-risk areas; however, in the low-risk population, more traditional risk factors such as tobacco and alcohol use may play a role. Of note, the incidence of EBV infection far exceeds the rate of cancer development, thus research is ongoing to try and identify determinates that favor the development of overt cancer.

NPC is usually classified histologically using one of two systems. The first is a World Health Organization classification that breaks NPC into three subtypes: type 1, keratinizing SCA; type 2, nonkeratinizing, well differentiated SCA; and type 3, nonkeratinizing, undifferentiated SCA. Alternatively, cancers may be categorized as (1) well differentiated keratinizing SCA and (2) undifferentiated SCA. Keratinizing SCA, is most common in the low-risk and older patients, whereas undifferentiated SCA is more common in the high-risk areas.

C. HPV-associated oropharyngeal carcinomas

Over the past decade, there has been a marked increase in the incidence of oropharyngeal carcinomas, specifically tumors arising from tonsillar tissue. Data now indicates that a substantial percentage of these tumors are related to infections with HPV. The vast majority of cases within the United States are associated with serotype 16. In general, HPV-associated tonsillar cancers have a better prognosis. It should be noted, however, that a heavy smoking history mitigates the favorable outcome to a significant degree. Histologically, HPV-associated tumors are frequently described as poorly differentiated due to the immature appearance of the cells. This is a misconception as tumors cells are similar in appearance to the specialized epithelial lining of the tonsillar crypts. In addition, tumor cells are frequently basaloid in appearance. It is important to distinguish tonsillar cancers with a basaloid appearance from “basaloid SCAs,” which are an aggressive subtype thought to have a poor outcome.

III. PRESENTING SYMPTOMS

The presenting symptoms of HNC vary based on the primary site; thus, a careful history may help guide the diagnostic work-up. For example, patients with hoarseness may have cancers of the larynx and should undergo endoscopic evaluation for a laryngeal mass. Common presenting complaints include pain, nonhealing ulcerative lesions, dysphagia, odynophagia, hemoptysis, epistaxis, sinus congestion, globus sensation, headaches, nonhealing dental infections, and a nonpainful neck mass. Presenting complaints of HNC are similar to symptoms associated with benign problems such as bacterial pharyngitis or sinusitis. This may lead to a protracted delay in diagnosis. Occasionally, patients may also present with complications secondary to local disease such as airway obstruction or aspiration pneumonia.

Although the bulk of patients present with symptoms related to local disease, it is important to assess systemic manifestations as well. Patients with more advanced disease may present with weight loss due to decreased oral intake and/or cancer cachexia. Other systemic manifestations of such as fatigue, neurocognitive changes, and debility should also be ascertained.

IV. STAGING AND WORK-UP

A. Initial work-up

Treatment is based on the extent of disease at presentation, so an accurate staging work-up is critical. A careful history may help point to the primary site and suggest involved structures. A thorough head and neck evaluation will include an assessment of the primary site and the extent of nodal disease. An endoscopic exam is usually performed on initial exam by an otolaryngologist to identify and/or confirm the primary site. Most patients with laryngeal or pharyngeal tumors will undergo direct laryngoscopy with biopsy to determine the extent of disease and to rule out a second primary tumor. Imaging studies are considered a standard component of the work-up in patients with locally advanced disease. The purpose of radiographic studies is to clearly define the extent of local disease, to identify nodal spread, and to rule out metastatic disease or a second primary tumor. Computed tomography scans, magnetic resonance imaging, and positron emission tomography scans may each contribute unique clinical information; it is therefore important to discuss the appropriate radiographic evaluation with the radiologist in order to optimize the staging work-up and to provide clinicians with the information needed for treatment planning.

B. TNM classification

The AmericanJoint Committee on Cancer TNM staging system integrates clinical and pathologic information regarding size of the primary tumor (T-stage); the size, number, and location of regional lymph nodes (N-stage); and the presence of distant metastases (M-stage). Each disease site within the head and neck region has a T-staging system. However, all sites, with the exception of NPCs, share a common nodal staging system. Because NPCs are associated with extensive nodal disease, a specific N-staging system has been developed that is applicable only to this cohort of patients.

Based on the T, N, and M stages, patients are grouped into overall stages I through IV (Tables 5.2 and 5.3). In general, stage I and II cancers are small and do not have evidence of nodal or distant spread. Stage III includes either larger primary tumors or tumors with early regional node involvement. Stage IV lesions may be either large tumors with significant local extension, extensive nodal disease, or distant metastatic disease. The stage grouping has been developed so that advancing stage is associated with worsening prognosis. With the recognition that patients with HPV-positive disease have an improved survival despite advanced disease, changes to the TNM classification may be anticipated.

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C. Assessment of comorbid disease and psychosocial issues

An initial evaluation is not complete without a detailed assessment of medical comorbidities, psychological issues, social supports, and financial status. Patients with SCA secondary to smoking and drinking frequently have comorbid diseases such as cerebrovascular disease, chronic obstructive pulmonary disease (COPD), and alcohol-related disorders. Risk stratification systems specific to HNC patients have been developed to assess long-term prognosis based on common comorbidities. Understanding the patient's long-term prognosis may help guide treatment decisions. A substance abuse history should be obtained from all patients, and patients with active abuse issues should be referred for appropriate counseling. Patients who are actively smoking should be advised to quit and should be referred to appropriate support services to aid in this effort. Depression and suicide are common in HNC patients, thus initial and ongoing screening for mood disorders is appropriate. Patients with the traditional risk factors of smoking and drinking may have poor support systems and lower socioeconomic status. Defining these issues at the time of initial diagnosis is important because treatment may need to be adjusted based on the patient's capacity to comply with therapy.

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In addition to general considerations in the work-up of HNC as noted above, there are also specific health-related issues that may impact on the decision to use specific chemotherapy agents. Specific issues are delineated below.

1. Bone marrow function. Chronic alcoholism, malnutrition, and tumor-related weight loss contribute to a significant incidence of folate deficiency and decreased bone marrow reserve in many patients.

2. Pulmonary function. Current or distant heavy smoking increases the likelihood of COPD and chronic bronchitis, leading to an increased risk of pulmonary infection during treatment. In addition to impaired pulmonary reserve, patients have a propensity to aspirate secondary to swallowing abnormalities and may have difficulty handling their secretions.

3. Renal function. Platinum compounds are used as first-line agents in HNC therapy. Adequate baseline renal function and continued monitoring of renal function is needed for administration. Methotrexate is renally excreted and may accumulate in patients with renal insufficiency, leading to increased toxicity.

4. Hepatic function. The presence of cirrhosis, whether related to alcoholism or viral hepatitis, can complicate management as it can impair the ability to accomplish forced hydration by leading to third space accumulations of ascites or edema. Routine use of diuretics may exacerbate treatment-related electrolyte abnormalities.

5. Neuropathy. Platinum compounds and taxanes may cause peripheral or autonomic neuropathy. Hearing loss may develop secondary to chemotherapy or radiation therapy. Patients should be screened for baseline neuropathy or hearing loss and have their therapies adjusted accordingly. Comorbidities that may be associated with baseline neuropathy include alcoholism and diabetes.

6. Fertility. All chemotherapy agents may impair fertility either temporarily or permanently. For male patients who wish to ensure their reproductive capacity, sperm donation should be accomplished promptly. For female patients, induced ovulation and harvesting and preservation of ova may be considered.

7. Concomitant drugs. Antihypertensives, diuretics, and drugs used for glycemic control all need careful assessment, monitoring, and adjustment during therapy as patients undergo treatment. Nausea, vomiting, anorexia, and limited oral intake often lead to dehydration and weight loss, making hypotension a common occurrence during therapy. Patients may need to be weaned off antihypertensives. The use of glucocorticoids as an adjunct to antiemetics and to prevent anaphylactic reactions, coupled with irregular feeding patterns, make glycemic control difficult. It is best to emphasize careful monitoring to avoid hypoglycemia rather than focus on hyperglycemia, which is not metabolically (homeostatically) significant.

V. NATURAL HISTORY

The natural history of SCA of the head and neck can be quite variable. Tumor growth rates range from slow progression over years to rapidly expanding masses that progress measurably over days to weeks. There is a correlation between histologic grade and the rate of tumor growth, though this association is weak. The rapidity of growth may play a role in treatment decisions as surgeons may be reluctant to operate on large, rapidly expanding tumors.

Early stage cancers (stage I and II) are associated with a high cure rate. Unfortunately, the majority of patients present with locally advanced disease (T3, T4, or nodal disease). Of note, prominent nodal disease is common in patients with both NPC and HPV-associated oropharyngeal cancer. Metastatic disease at presentation is infrequent in all types of HNC, but it may develop following initial therapy. The most powerful predictor for development of metastatic disease is the extent of nodal disease at presentation. Patients who present with N0-N1 disease have a less than 5% chance of developing distant metastases, whereas patients with N2 or greater nodal disease have a 25% to 30% chance of subsequent distant spread. The most common sites of metastatic disease are lung, liver, and bone. Brain metastases are rare for patients with SCA of the head and neck.

Most recurrences appear within 18 months of primary treatment, and 90% appear within 2 years. Patients who are not cured usually die from the cancer within 3 to 4 years of diagnosis. Patients who succumb to the cancer generally experience local, regional, and distant failure in equal proportions. The manifestations of end-stage disease are typified by inanition, cachexia, aspiration, respiratory difficulty due to trouble with secretions or obstruction, fistulas, oral or neck ulceration, edema of the mucosal structures or face, and pain. Among survivors, the risk of second primary head and neck, lung, and esophagus tumors is a significant problem, thus long-term surveillance is indicated.

VI. TREATMENT: GENERAL CONSIDERATIONS

Treatment of HNC, regardless of histologic cell type or causal factors, requires a multidisciplinary approach with a team of experienced clinicians including head and neck surgeons, radiation and medical oncologists, nutritionists, speech and language pathologist, and oral health providers. Working with the patient, the treatment team must come to a consensus regarding (1) the goals of therapy, (2) treatment options that will adequately meet those goals, and (3) optimal methods for implementation and monitoring of treatment and treatment-related side effects. Although treatment paradigms are evolving rapidly, therapeutic principles for each of the major clinical entities are reviewed below.

A. SCA with traditional risk factors of tobacco and alcohol use

1. Early-stage disease. Small lesions without regional extension generally are treated with surgery or radiation. The choice is usually made based on the relative toxicity of therapeutic options. In addition, treatment may be determined by medical or social considerations. For example, surgery may be avoided in patients with significant comorbidities and radiation may not be an option for noncompliant patients with suboptimal social supports.

2. Locally advanced disease. Larger primary cancers and those with clinically detectable spread to lymph nodes (referred to as “locally advanced disease”) are usually treated with a combination therapy. Combination therapy may include surgery and radiation; chemotherapy and radiation; or surgery, radiation, and chemotherapy. Often, several different treatment approaches are reasonable for any given patient. The decision as to which treatment approach to take is based on (1) biopsychosocial status of the patient, (2) the patient's priorities and preferences regarding functionality and cosmesis, (3) the expertise and training of the treating physicians, and (4) the relative toxicities of therapy.

Locally advanced disease is usually categorized as either resectable or unresectable. Criteria for resectability are difficult to define because surgeons have differing levels of skill. Furthermore, individual surgeons differ in their opinions regarding the balance between providing patients with potentially curative surgery and the long-term morbidity of extensive resections. For those patients with locally advanced disease who undergo primary surgical resection, postoperative radiation or radiation with chemotherapy is frequently administered in order to eliminate residual disease.

In a subset of patients with resectable disease, surgery may entail loss of structures critical for speech and swallowing (e.g., larynx or base of tongue). In this cohort of patients, a radiation-based treatment approach may be preferable to surgery in order to minimize functional deficits. This is often referred to as a “function preservation” or “larynx preservation approach.” Patients undergoing function preservation therapy usually receive a combination of radiation therapy and chemotherapy. Unfortunately, the optimal sequence of radiation therapy and chemotherapy has yet to be determined.

A small but significant percentage of patients present with disease that is unresectable. These patients are usually treated with a combination of radiation therapy and chemotherapy. Despite the use of aggressive chemoradiation, this group of patients does poorly.

Combined modality treatment is utilized in order to improve outcome. Outcomes of interest may include the following: (1) decreased local, regional, or distant failure rates; (2) i mproved survival; (3) decreased rates of second primary tumor; or (4) decreased morbidity of therapy. Over the past three decades, investigators have conducted a number of clinical trials that have helped to define current practice. Key findings from these studies include the following:

bull When compared to preoperative radiation, postoperative radiation is associated with decreased complications and improved local disease control. There is no survival difference. Thus, patients undergoing surgery usually have radiation therapy postoperatively.

bull There are several ways in which chemotherapy may be incorporated into treatment: (1) it may be given as induction therapy—prior to surgery or radiation; (2) it may be given as adjuvant therapy—after surgery or radiation; (3) it may be given concurrent with radiation; or (4) it may be given sequentially— induction therapy followed by concurrent chemoradiation.

bull Neither induction chemotherapy followed by surgery nor adjuvant chemotherapy following surgery has improved survival.

bull Postoperative chemoradiation improves local control and survival in patients at high risk for recurrence when compared to postoperative radiation therapy only.

bull In patients with locally advanced disease, concurrent chemo-radiation improves survival compared to radiation alone.

bull In patients with laryngeal cancer, concurrent chemoradiation improves local disease control and laryngeal preservation but not survival. Improved local control is at the expense of increased late side effects.

The role of induction chemotherapy prior to concurrent chemoradiation (sequential therapy) has yet to be clearly established. Meta-analysis demonstrates a small improved survival with three cycles of aggressive induction therapy. The results of randomized phase III trials comparing concurrent chemoradiation to sequential therapy are pending.

It must be noted that the use of combined modality therapy substantially increases both the acute and late effects of treatment. Aggressive treatments push patients to their physiologic tolerance and, in some cases, well beyond. Thus, we must recognize that patients with a poor performance status and multiple comorbidities may not tolerate aggressive combined modality therapy well; it is important to tailor treatment to the patient.

3. Metastatic disease. Only a small percentage of patients present with metastatic disease. In this cohort of patients, treatment is directed at palliation.

B. NPCs

NPCs are exquisitely sensitive to radiation with or without chemotherapy. Thus, radiation-based treatment is the cornerstone of therapy for NPC. Furthermore, NPCs are anatomically located adjacent to the bony structures of the base of skull, making surgical excision difficult if not impossible. Patients who present with stage I or II disease are usually treated with radiation therapy alone, although there are those who would advocate for the addition of chemotherapy to the treatment of all stages of NPC. Patients with locally advanced stage III or IV disease should be treated with combined modality therapy. Data support an improvement in local control, disease-free survival, overall survival, and metastatic disease–free survival in patients treated with concurrent chemotherapy. The role of induction or adjuvant chemotherapy has yet to be clarified; however, a recent meta-analysis has confirmed a modest survival advantage for patients receiving induction therapy followed by concurrent chemoradiation.

C. HPV-associated oropharyngeal carcinomas

The optimal treatment for HPV-associated oropharyngeal carcinomas has yet to be determined. It is clear that HPV-associated tumors have an improved survival compared to non-HPV–associated tumors regardless of the type of therapy. However, smoking may mitigate the improved outcomes seen in HPV-associated tonsil cancers. Risk stratification systems that incorporate HPV and smoking status are being developed. Low-risk patients are currently being defined as those with HPV-associated tonsil cancers in nonsmokers (a history of fewer than 10 packs per year). In this population, long-term survival is over 90%; thus, in this cohort of patients, investigators are conducting and/or planning treatment trials that dees-calate therapy and minimize late effects. The general consensus of the head and neck community is that a radiation-based treatment approach is preferable to a surgical approach. That being said, small tumors may be excised as a part of the initial diagnostic work-up, thus obviating the need for high doses of radiation to the pharynx.

VII. TREATMENT: CHEMOTHERAPY

The expected response of SCA to chemotherapy will vary based on well-established predictive factors. The most powerful predictive factors for antitumor response include stage, performance status, and prior treatment. Patients who present with localized disease have a substantially higher response rate than patients with metastatic disease. Patients with a good performance status are more likely to respond than those with a poor performance status. In addition, patients with a poor performance status are more likely to develop treatment-related toxicity. The more extensively treated a cancer becomes, the less likely it will respond to subsequent chemotherapy. Primarily radiation-resistant tumors or tumors that recur rapidly after radiation have also been shown to have a particularly poor outcome.

A. Single agent activity

SCA of the head and neck is modestly responsive to a number of chemotherapy agents. The phase II studies listed in Table 5.4 were largely conducted in patients with recurrent or metastatic disease. These patients tend to have been heavily pretreated and their disease is more chemoresistant than patients with previously untreated, locally advanced disease.

1. Cisplatin. Cisplatin is one of the most commonly used agents in HNC therapy. Response rates are similar to other single agents; however, cisplatin is associated with significant toxicity and requires aggressive supportive measures. Therefore, it is seldom used as a single agent. More commonly, it is used in combination with other agents in patients with a good performance status for whom an aggressive treatment regimen is feasible. Acute and delayed nausea and vomiting require aggressive antiemetics including 5-HT3 receptor antagonists and neurokinin-1 receptor antagonists (aprepitant) for optimum control. A standard regimen to maintain urine output is as follows: cisplatin 60 to 100 mg/m2 given intravenously (IV) once every 3 weeks preceded by 1 to 2 L of hydration, 12.5 to 25 g of mannitol, and 1 to 2 L of post cisplatin hydration with mannitol and/or 10 to 20 mg of furosemide. Adequate replacement of potassium, magnesium, and sodium losses is requisite, as is monitoring hydration.

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2. Carboplatin. Carboplatin, given at an area under the curve (AUC) of 5 to 6, is easier to administer than cisplatin because there is no requirement for forced hydration and less nausea and vomiting, renal toxicity, ototoxicity, and neuropathy. Response rates comparable to single-agent cisplatin are reported but myelosuppression, in particular thrombocytopenia, can be dose-limiting. Allergic reactions may occur in patients, particularly after multiple cycles.

3. Paclitaxel. Paclitaxel may be given at high doses every three weeks (175–250 mg/m2 over 3 hours) or at low doses weekly (60–120 mg/m2). A response rate of 15% to 40% has been reported. The high-dose regimen is associated with a significant risk of neutropenia, neuropathy, and allergic reactions.

4. Docetaxel. Docetaxel is usually given as doses of 75 to 100 mg/ m2 IV over 1 hour every 3 weeks or as 30 to 40 mg/m2 IV over 1 hour weekly. Neuropathy may be lower than with paclitaxel, but asthenia may be greater with the high-dose regimen. Tissue edema may occur with higher doses; thus, steroid prophylaxis is indicated.

5. Methotrexate. Intravenous methotrexate doses of 40 to 60 mg/m2IV weekly given over 15 minutes is a convenient standard single-agent treatment. Dose escalation can increase response rates but is accompanied by increased toxicity and does not improve survival. Minimal to moderate nausea and few significant acute side effects make this a well-tolerated and easily monitored treatment. Responses may occur after 1 or 2 weeks of treatment but usually require 4 to 8 weeks of treatment, so patience is needed before abandoning this regimen.

6. Cetuximab. Epidermal growth factor receptors are over-expressed in 90% of HNCs. Cetuximab is a monoclonal antibody that binds to epidermal growth factor receptors, thus blocking the proliferative signal. Cetuximab has been approved by the U.S. Food and Drug Administration for the treatment of metastatic disease and unresectable disease that failed prior platinum-based therapy and as a radiation-sensitizing agent. The standard regimen begins with a loading dose of cetuximab 400 mg/m2 IV given over 2 hours followed by weekly doses of 250 mg/m2 IV over 1 hour. Responses of up to 10% have been observed among patients with metastatic or recurrent disease. Skin rash, hypomagnesemia, and diarrhea are the common side effects. Anaphylactic reactions, although uncommon, may be severe. Of note, anaphylactic reactions are more common in areas of the southeastern United States, where rates are as high as 20%.

7. Fluorouracil. Fluorouracil is well tolerated and has comparable activity to cisplatin and other single agents. It is most often given as a 4- or 5-day continuous infusion. The drug is a vascular irritant at high concentrations and therefore, for prolonged infusions, a central venous catheter or access device is customary. Although suitable for use as a single agent, it is most often used in combination with other drugs.

8. Ifosfamide. Ifosfamide is given at doses of 1000 mg/m2/day IV over 2 hours for 4 days every 3 to 4 weeks and yields response rates of 20% to 40%. The need for uroprotection with mesna 200 mg/m2before and 400 mg/m2 after ifosfamide makes this a cumbersome single-agent regimen to administer.

9. Bleomycin. Bleomycin has comparable activity to other agents without associated myelosuppression or nausea. Bleomycin is dosed as 10 to 20 units/m2 intramuscularly or IV and can be given weekly, every 2 weeks, or 5 days a month. Pulmonary tox-icity is commonly seen. Responses are often very brief.

10. Gemcitabine. Gemcitabine, dosed at 1000 mg/m2 weekly, has activity in NPC and is well tolerated.

11. Anthracyclines. Doxorubicin and mitoxantrone are useful in NPC, which is very responsive to multiple agents; many patients are younger with good performance status so that they often tolerate and respond to multiple sequential treatment regimens. These agents have utility in that setting.

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B. Combination chemotherapy—metastatic disease (Table 5.5)

Similar to single agents, most novel chemotherapy regimens were initially developed in patients with metastatic or recurrent disease. Theoretically, the use of multiple agents with additive or synergistic activity and nonoverlapping toxicity should improve outcome. However, in the population of patients with HNC, confirmation of this theory proved elusive for many decades. Studies conducted in the 1980s and 1990s demonstrated that combination chemotherapy increased response rates but failed to improve survival when compared to single-agent therapy. Median survival was short (6–9 months) and was similar across treatment regimens. Only with the addition of the targeted agent cetuximab were investigators able to identify a multidrug regimen that clearly improved survival. The EXTREME trial compared cisplatin and fluorouracil to cisplatin, fluorouracil, and cetuximab. The three-drug combination was associated with a marked increase in survival. This study clearly established the critical role of cetuximab in the treatment of patients with metastatic/recurrent HNC. Other less toxic combination therapies incorporating cetuximab have been reported; however, randomized comparative trials are lacking. Several other targeted agents have been under investigation. We await the results of phase III trials to establish clinical efficacy. Because toxicity is usually greater with combination therapy, the general consensus is that these regimens are most appropriate for patients with an Eastern Cooperative Oncology Group performance status of 0 or 1. The most commonly used combination regimens used are listed below.

1. Cisplatin and fluorouracil. Cisplatin dosed at 75 to 100 mg/m2 is given IV over 1 to 4 hours on day 1, and fluorouracil dosed at 600 to 1000 mg/m2/day is given as a 96- to 120-hour continuous infusion. Forced hydration, aggressive antiemetics, and close monitoring for electrolyte abnormalities, mucositis, dehydration, and cytopenias are needed. Recently, it has been appreciated that significant rates of neutropenia accompany this regimen and that these patients may benefit from filgrastim and prophylactic antibiotics. When this regimen is used during or after prior radiotherapy, only four days (96 hours of continuous infusion) of fluorouracil are used because of enhanced mucosal and skin toxicity in that setting.

2. Cisplatin, fluorouracil, and cetuximab. Cetuximab, at an initial dose of 400 mg/m2 then 250 mg/m2 weekly, is given with a maximum of six every 3-weeks cycles of cisplatin dosed at 100 mg/m2 IV on day 1 and fluorouracil dosed at 1000 mg/m2/day continuous infusion for the first 4 days of each cycle. Cetuximab is administrated until progression or unacceptable toxicity.

3. Carboplatin and fluorouracil. Carboplatin dosed at 300 mg/m2 IV day 1 and fluorouracil dosed at 1000 mg/m2/day by continuous infusion for 4 days are used for recurrent disease with responses and survival comparable to cisplatin and fluorouracil. For simultaneous chemoradiation in oropharynx cancer, carboplatin dosed at 70 mg/m2 IV daily for 4 days and fluorouracil dosed at 600 mg/m2 daily by continuous infusion (96 hours) for 4 days is a standard regimen. These carboplatin regimens predate the use of the Calvert formula but roughly correspond to an AUC of 5 and AUC 1.25, respectively.

4. Cisplatin and paclitaxel. Cisplatin dosedat60 mg/m2 IV and paclitaxel dosed at 135 to 175 mg/m2 IV every 3 weeks were found to be equivalent to fluorouracil regimens in patients with recurrent disease. The lower dose of paclitaxel was better tolerated. Careful monitoring for neuropathy is needed.

5. Carboplatin and paclitaxel—every 3 weeks. Carboplatin AUC 6 IV and paclitaxel dosed to 175 mg/m2 IV given every 3 weeks is a widely utilized combination regimen with similar results.

6. Carboplatin and paclitaxel—weekly. Carboplatin at AUC 2 IV day 1 and paclitaxel at 135 mg/m2 IV day 1 weekly for 6 weeks or 60 mg/m2 for 9 weeks is a simple outpatient regimen with acceptable response rate and minimal toxicity. Neutropenia is seen in 18% of patients, but febrile neutropenia is uncommon.

7. Cisplatin and docetaxel. Cisplatin dosed at 75 mg/m2 IV and docetaxel dosed at 75 mg/m2 IV each on day 1 every 3 weeks. Neutropenia is frequently seen in this regimen.

8. Docetaxel, cisplatin, and fluorouracil. Docetaxel dosed at 75 mg/m2IV on day 1, cisplatin dosed at 100 mg/m2 IV on day 1, fluorouracil dosed at 1000 mg/m2 IV daily on days 1 to 4 (96-hour continuous infusion) every 3 weeks for three cycles is administered. Based on the results of TAX 324, this regimen has become a widely used treatment for patients with advanced disease and a good performance status. This regimen requires prophylactic fluoroquinolone antibiotics.

9. Paclitaxel, ifosfamide, and cisplatin or carboplatin is a three-drug regimen with high activity that is well tolerated but requires good performance status patients and filgrastim support.

C. Chemotherapy as a radiation sensitizer

The concurrent administration of chemotherapy and radiation has improved outcomes in a variety of clinical scenarios. These include locally advanced NPCs, advanced unresectable cancers, organ preservation in locally advanced larynx and base of tongue cancers, and in high-risk postoperative patients. Thus, concurrent chemoradiation is accepted as a standard option for these patients. Meta-analysis demonstrates that the addition of chemotherapy concurrently to radiation therapy results in up to a 4% to 8% absolute improvement in survival, which amounts to a 12% to 19% reduction in the risk of death, whether in definitive or postoperative adjuvant settings. While many regimens have been tested in these settings, high-dose cisplatin has been the most commonly studied agent. A variety of alternative single-agent and multiagent chemo-radiotherapy regimens have been tested and found to be superior to radiation alone. Unfortunately, there is no comparative data to delineate the relative efficacy and toxicity of these regimens. It should be noted that the addition of chemotherapy concurrent with radiation is associated with a marked increase in both acute and late treatment effects. The dose-limiting toxicity is usually severe oral mucositis. The increased toxicity must be carefully weighed against the improved outcomes on a patient-by-patient basis. Commonly used concurrent regimens are noted below.

1. Cisplatin dosed at 100 mg/m2 IV over 1 to 4 hours every 21 days during radiation.

2. Cetuximab dosed at 400 mg/m2 IV on day lasa loading dose followed by 250 mg/m2 IV weekly during radiation.

3. Cisplatin and fluorouracil. Cisplatin dosed at 60 to 75 mg/m2 IV on day 1 and fluorouracil dosed at 600 to 1000 mg/m2 daily for4 days by continuous 96-hour infusion on days 1 and 29.

4. Carboplatin and fluorouracil. Carboplatin dosed at 70 mg/m2 IV daily for 4 days and fluorouracil at 600 mg/m2 daily for 4 days by continuous infusion (96 hours) is a standard regimen on days 1 and 29.

5. Hydroxyurea and fluorouracil. Hydroxyureaat 1000mg orally every 12 hours for 11 doses and fluorouracil at 800 mg/m2 daily for 5 days given as a 120-hour intravenous infusion repeated every 14 days for five cycles concomitantly with radiotherapy for 5 days every 14 days.

6. Cisplatin and paclitaxel. Cisplatinat20mg/m2 weeklyandpaclitaxel at 30 mg/m2 weekly during standard fractionated radiation.

7. Paclitaxel dosed at 20 to 40 mg/m2 given over 1 hour weeklyduring radiotherapy.

8. Paclitaxel, hydroxyurea, and fluorouracil may be given on alternating weeks during simultaneous chemoradiation.

D. Combination chemotherapy—adjuvant therapy

Combination chemotherapy has also been investigated in the adjuvant setting. In patients with locally advanced NPC, a sentinel study compared radiation therapy alone to radiation with concurrent chemotherapy using cisplatin dosed at 100 mg/m2 on days 1, 22, and 43 followed by three cycles of cisplatin and fluorouracil. The results demonstrated a marked improvement in outcome for patients treated with combined modality therapy. Critics of this trial argue that it is impossible to determine the relative contribution of the concurrent and adjuvant components of the combined treatment regimens. Furthermore, a high percentage of patients were unable to complete all three planned cycles of adjuvant therapy due to excessive toxicity. Nonetheless, this regimen remains a standard treatment option for patients undergoing therapy for locally advanced NPC. In the postoperative setting, studies have failed to demonstrate a benefit for adjuvant chemotherapy. Studies of adjuvant chemotherapy after definitive radiation therapy are limited.

E. Combination chemotherapy—induction therapy

Combination chemotherapy regimens have been extensively studied as induction therapy prior to definite treatment with either radiation or surgery. The role of induction chemotherapy is one of the most debated issues in HNC therapy and has polarized the head and neck community. It is beyond the scope of this review to provide a detailed discussion of the current status of induction chemotherapy in the treatment of HNC; however, the following is a review of critical concepts and current directions for research.

The interest in multidrug induction therapy stemmed from the observation that response rates in treatment-naive patients is extremely high. It is clear and generally agreed on that there is no benefit to induction chemotherapy prior to surgical resection. However, the data pertaining to induction therapy prior to radiation therapy has yet to be clarified.

Induction therapy followed by radiation has been assessed in two separate populations: locally advanced disease (which can be further divided into resectable and unresectable) and larynx preservation. For patients with locally advanced disease, the primary outcome of interest is overall survival. For patients with laryngeal and hypopharyngeal tumors, the primary outcome of interest is function preservation. Unfortunately, our methods for assessing function preservation in large randomized trials are limited. Usually, function loss is defined as laryngectomy or feeding tube dependence. These are coarse and insensitive measures of functionality that fail to take into account clinically significant but less overt deficits.

I nterpretation of induction trials has been complicated by three important advances in our understanding of HNC therapy: (1) the recent acceptance of concurrent chemoradiation as a standard treatment approach for improving outcomes in a variety of clinical settings; (2) the recognition that concurrent chemo-radiation is associated with increased late toxicities and substantial functional deficits; and (3) the recognition that locally advanced HPV-associated oropharyngeal cancers have an excellent outcome.

VIII. SUPPORTIVE CARE

A. Support systems

Treatment of HNC is time-intensive, complex, and fraught with complications. It requires a compliant and willing patient as well as a dedicated support system. The support system is composed of the patient's caregivers, usually defined as a network of family and friends, and the healthcare team. Prior to initiating therapy, it is important to inform the patient and caregivers about anticipated treatment toxicities and their potential impact on the patient's ability to conduct routine actives of daily living. Working with the healthcare team, the patient must identify the individuals who will provide support if and when it becomes necessary. Specific issues that should be discussed include the following: (1) insurance coverage (including dental and pharmacy); (2) living situation (homeless, living alone, or living with others); (3) social supports (ability and willingness of caregivers to provided physical and emotional support); (4) financial issues (with specific discussion of ability to pay for household expenses during treatment); and (5) work issues (impact of cancer on work status of patient and caregivers). It is important to identify patients with critically limited resources in order to plan adequately for their ongoing care and to guide treatment decisions.

The healthcare team should be composed of physicians, nursing staff, nutritionists, speech and swallowing therapists, physical therapists, and social workers who are trained to deal with the unique challenges faced by HNC patients and their caregivers. Because patient support needs change dramatically over time, frequent and ongoing assessment is required.

B. Nutrition

Due to the anatomic proximity to structures critical for normal alimentation, HNC and its treatment may have a dramatic impact on oral intake. Malnutrition is associated with impaired healing, increased toxicity of treatment, and decreased survival. Therefore, it is important to identify and treat nutritional deficiencies in a proactive and aggressive manner. Factors contributing to decreased oral intake and weight loss are shown in Table 5.6. At the time of diagnosis and periodically thereafter, patients should undergo a nutritional assessment by a dietician who is familiar with the issues facing HNC patients. A nutritional assessment should include a weight loss history, assessment of nutrient intake, and identification of barriers to adequate nutritional intake. Treatable causes of decreased caloric intake should be identified and appropriate interventions instituted.

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Ongoing monitoring and education is critical and should include routine measurement of weight, assessment of hydration, and counseling by a certified dietician. Dieticians also ensure adequate nutrition as patients transition from an enteral to oral diet.

It should also be noted that the sequelae of HNC therapy may lead to dietary adaptations that are permanent For example, many patients experience xerostomia, which alters their ability to take in dry foods such as breads. Patients who are edentulous may have difficulty with intake of adequate protein. Dietary adaptations may predispose to long-term nutrient deficiencies that may impair overall health. Periodic dietary assessment and ongoing counseling of HNC survivors is a necessary part of health maintenance.

C. Mucositis

Radiation therapy and select chemotherapy agents cause mucositis. Mucositis is a pan-tissue inflammation of the mucosa and underlying soft tissue. The classic mucosal manifestations are erythema, ulcer, and pseudomembrane formation. Mucositis associated with systemic chemotherapy is cyclic in nature. The Common Terminology Criteria for Adverse Events v4.0 grading system for mucositis is available on the Internet at http://ctep.cancer.gov/protocolDevelopment/electronicapplications/ctc.htm. The pattern of mucositis development and resolution depends on the treatment. With chemotherapy regimens administered on a 3-week cycle, mucositis usually develops 7 to 10 days after administration and resolves 5 to 7 days later. Chemotherapy regimens administered weekly tend to have a slow escalation of mucosal symptoms over time, with resolution when chemotherapy is dose-reduced or held. Radiation-associated mucositis begins to develop 2 to 4 weeks after the initiation of therapy. Symptoms usually peak at 5 to 7 weeks, although occasionally patients will note worsening mucositis after the completion of therapy. Radiation-induced mucositis may take 4 to 12 weeks to resolve. Some patients have persistent symptomatic ulceration for protracted periods of time. It should be noted that the incidence of grade 3 to 4 mucositis increases from 25% to 35% with radiation alone to 40% to 100% with concurrent chemotherapy. Treatment of mucositis is discussed in Chapter 26.

D. Dysphasia and aspiration

Swallowing is a complex function that requires intact musculature, dentition, vasculature, and nervous system. Damage to any of these components may result in altered swallowing function. Thus, swallowing dysfunction is one of the common and devastating acute and late effects of therapy. Surgery-induced dysphagia is secondary to structural changes due to tissue extirpation and altered sensation from transected nerves. Acutely, radiation therapy-induced dysphagia is secondary to edema and painful mucositis. Over the long term, radiation therapy results in noncompliant fibrotic or contracted tissues that are unable to function normally. Of particular note, radiation may cause upper esophageal stricture formation. Stricture-induced dysphagia may be successfully treated with balloon dilation procedures.

In order to maximize swallow function, it is important to involve speech and language pathologists (SLPs) at an early point in a patient's treatment course. Healthcare providers should also be aware of signs and symptoms that may indicate aspiration, which requires rapid referral and evaluation. These include coughing or throat clearing during or after swallow. Other indications for an SLP evaluation include nasal regurgitation, drooling, pocketing food in the cheek, and food sticking in the throat. The role of the SLP includes (1) identifying swallowing abnormalities; (2) recommending further testing; (3) developing a treatment plan (including education and swallow therapy); (4) helping dieticians develop an adequate yet safe diet; and (5) ruling out significant aspiration. Common instrumental methods to assess swallow function include the modified barium swallow and the flexible endoscopic evaluation of swallowing safety.

As noted above, dysphagia may result in dietary adaptations and/or weight loss due to inadequate caloric intake. In addition, dysphagia may result in aspiration. Aspiration puts patients at risk for acute and long-term pulmonary toxicity. Acutely, aspiration may lead to pneumonia; in patients actively undergoing myelosuppressive chemotherapy, aspiration pneumonia is associated with a high rate of morbidity and mortality. Over the long term, aspiration may lead to pulmonary fibrosis and respiratory compromise. Of note, microaspiration can simulate pulmonary metastasis.

E. Xerostomia and oral care

Poor oral health outcomes are one of the major late effects of HNC therapy. This is largely related to radiation-induced xerostomia.

Initial dental evaluation is important for all patients undergoing therapy for HNC, particularly for those who will receive radiation therapy. Patients require extensive education regarding oral hygiene and preventive strategies to avoid radiation-induced dental caries. Oral hygiene should include the use of prescription strength fluoride treatments because this agent has consistently demonstrated the ability to significantly reduce adverse late dental effects. In addition, patients undergoing radiation therapy should have extraction of nonviable teeth at least 10 to 14 days prior to initiation of therapy. This will allow adequate time for healing. As healthcare providers, our role is to assess compliance with dental hygiene regimens and to refer to oral health specialists if problems are identified.

F. Lymphedema and fibrosis

Surgery and radiation therapy can damage the soft tissues within the head and neck region with resulting lymphedema (swelling with lymphatic fluid) and fibrosis. In contemporary grading systems, lymphedema and fibrosis exist on a continuum with fibrosis, considered the end stage of tissue damage. Chronic inflammation may accompany lymphedema and fibrosis; damage may be ongoing and self-perpetuating, thus resulting in late toxicity. Generally, lymphedema and fibrosis may be characterized as involving external (neck and shoulders) or internal (pharynx and tongue) structures. Associated function loss may be severe. Early identification and treatment by certified physical therapists experienced in lymphedema and scar management is critical.

Trismus is one of the most common and problematic manifestations of fibrosis. It is caused by surgery or radiation therapy involving the mandibular joint and muscles of mastication. It is characterized by a decrease in the movement of the jaw, thus limiting the opening of the oral cavity. When trismus is severe, patients have difficulty with eating solid foods, dental hygiene, and procedures such as intubation. Trismus usually begins to develop within 1 year of the completion of therapy and is progressive in nature. Aggressive physical therapy may halt progression of symptoms; however, reversal of existing symptoms is limited.

G. Metabolic abnormalities

HNC patients are subject to a number of metabolic abnormalities. First, radiation therapy to the thyroid gland can result in gradual loss of function. Estimated to occur in 25% to 50% of patients who receive doses above 6000 cGy to the thyroid gland, hypothyroidism may develop years after the completion of therapy. Routine testing of thyroid function is recommended, particularly in patients with symptoms indicative of hypothyroidism.

Patients with late-stage HNC may develop humoral hypercalcemia of malignancy. Although estimates vary widely, up to 23% of patients with advanced recurrent HNCs will manifest hypercalcemia before death. Standard treatment with hydration, saline diuresis, and bisphosphonate therapy are used.

IX. SECONDARY CANCER PREVENTION

HNC survivors with the traditional risk factors of smoking and drinking are at risk for the development of second primary cancers. The majority of second primary tumors involve the upper aerodigestive tact. It is hypothesized that this is related in part to a field cancerization effect of tobacco and alcohol exposure. Thus, smoking cessation and abstinence from alcohol are important adjuncts to the care of these patients. Chemopreventive agents have been assessed to determine their ability to prevent second cancers from developing. Although isotretinoin (13-cis-retinoic acid) 1 to 2 mg/kg was shown to prevent second primary cancers in HNC patients, there was no improvement in survival, and the effect was lost when treatment was discontinued. Although data is lacking, the widespread use of vaccination against HPV infections may lead to decreases in tumors associated with this virus.

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