AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Hypopharyngeal cancer is a term used for tumors of this subsite of the upper aerodigestive tract, and like most other subsite designations, this is an anatomic rather than pathophysiologic distinction within the group of head and neck malignancies. The hypopharynx is the region between the oropharynx above (at the level of the hyoid bone) and the esophageal inlet below (at the lower end of the cricoid cartilage). Embryologically, the larynx interjects into the hypopharynx anteriorly, and is therefore considered a separate structure.

Hypopharyngeal cancers are often named more specifically for their location, including pyriform sinus, lateral pharyngeal wall, posterior pharyngeal wall, or postcricoid pharynx (see Image 1). Most arise in the pyriform sinus.

Pathophysiology

As in other head and neck cancer sites, more than 95% of hypopharyngeal malignancies arise from the epithelium of the mucosa and, therefore, are squamous cell cancers. Premalignant mucosal lesions evolve into hyperproliferative lesions that develop the capacity to enlarge, invade local structures, invade lymphatics to spread to regional lymph nodes, and invade vascular channels to metastasize to other organs.

Frequency

United States

In 2006, 2,770 cases of hypopharyngeal cancer are projected to be diagnosed in the United States.

International

All pharyngeal subsites accounted for approximately 124,000 cancer cases worldwide in 2002.

Mortality/Morbidity

Early-stage hypopharyngeal cancers tend to be asymptomatic. Most patients, therefore, have no symptoms to bring them to medical attention until their disease is advanced, at which point the prognosis is poor.

• Prognosis varies with the stage. The 5-year survival with small (T1-T2) lesions is about 60%, but with T3-T4 lesions or multiple node involvement, survival falls to 17-32%. Five-year survival for all stages is approximately 30%.
• Morbidity and mortality are predominantly due to the primary tumor itself causing pain, bleeding, poor swallowing (with subsequent malnutrition), or aspiration. Very advanced tumors may cause airway obstruction as they grow into the larynx.
• Laryngectomy is often needed, leading to permanent loss of voice and permanent tracheostomy. Functional problems from surgical or radiation treatment can include swallowing dysfunction, recurrent aspiration pneumonias, neck fibrosis, facial edema, and pain.

Race

African Americans have had an increasing incidence of cancers of all pharyngeal subsites since the early 1970s.

Sex

US incidence shows an approximate male-to-female ratio of 3:1.

• Women have a higher incidence of postcricoid cancers related to nutritional deficiencies (Plummer-Vinson syndrome) than men.
• The prognosis for women generally is better than that for men.

Age

The incidence of hypopharyngeal cancer rises in people older than 40 years; it is rare in people younger than 30 years.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Neck mass: Cervical lymph node metastases occur as the presenting symptom in approximately 50% of cases (see Image 2).
• Sore throat
• • Typically, it is unilateral and well localized.
  • Often, pain radiates to the ears.
  • Patients commonly undergo one or more courses of empiric antibiotics without response.
• Hoarseness: This indicates either involvement of the recurrent laryngeal nerve, which runs deep to the anterior wall of the pyriform sinus, or direct invasion of the larynx (see Image 4).
• Dysphagia (Image 3)
• • Tumor invasion often causes a combination of painful swallowing (odynophagia) and neuromuscular dysfunction (dysphagia).
  • Aspiration occasionally is seen.
  • Weight loss and malnutrition are common at presentation.
• Otalgia: Referred pain to the ear is mediated by branches of the tenth cranial nerve (see Image 6). Invasion of the laryngeal nerve causes spread of neuropathic impulses to the auricular nerve (sensory to posterior external auditory canal and back of pinna).
• Hemoptysis
• Halitosis: Fetid breath is due to saprophytic bacterial overgrowth in fungating necrotic tumors.

Physical

• Oral examination
• • The hypopharynx is not visible directly, but other regional pathologies, including the synchronous oral cavity or oropharyngeal tumors, might be seen.
  • Asymmetry of tonsillar pillars can be a clue to a tumor invading the palatopharyngeus muscle at insertion to the inferior constrictor muscle.
• Larynx and pharynx examinations
• • The mirror examination is the quickest and simplest screening tool, but it cannot reveal lower pyriform sinus or postcricoid lesions.
  • Fiberoptic laryngoscopy is the examination of choice.
  • Findings include mass lesions, hyperkeratotic or erythematous mucosal lesions, ulcerations, and vocal cord paralysis.
• Neck examination
• • Examine and document the size, location, and number of palpable lymph nodes in all cervical and supraclavicular node-bearing areas.
  • Palpate and wiggle the larynx from side to side. Tenderness suggests invasion, while loss of normal tracheal crepitus suggests invasion of prevertebral tissue or a large postcricoid tumor.
• Head examination
• • Assess cranial nerve function.
  • Assess jaw mobility. Trismus suggests invasion of pterygoid muscles.
  • Areas of mass lesions or tenderness are suggestive of regional metastases.
• General examination for distant metastases and comorbidities
• • Examination of the lungs may reveal chronic obstructive pulmonary disease (COPD). Chest x-ray films may demonstrate metastases, synchronous lesions, or effusions suggesting metastases to pleura or lymphatic obstruction.
  • Examination of the heart may demonstrate congestive heart failure (CHF) or right-sided failure and pulmonary hypertension.
  • Examination of the extremities may reveal peripheral vascular disease or clubbing suggestive of advanced lung disease or synchronous lung cancer.
  • Hepatomegaly with a hard irregular contour suggests metastatic disease.
  • General neurologic examination may show toxic or metabolic encephalopathy or neuropathy. Focal neurologic findings suggest brain metastases or prior cerebrovascular accident (CVA).
  • Perform a peripheral lymph node examination to assess for possible distant lymph node metastases.

Causes

The etiology of squamous cell cancers is similar for most anatomic subsites. Tobacco and ethanol are the principle carcinogens responsible. Long-term exposure causes progressive cellular dysregulation by alteration of tumor suppressor genes such as TP53, amplification of proto-oncogenes such as cyclin D1, and damage to regulatory factors such as transforming growth factor–beta (TGFb) and retinoic acid receptors. The progression from normal mucosa to cancer correlates with accumulation of genetic abnormalities.

The role of human papilloma virus (HPV) in cancers of the hypopharynx is unclear, although it may play more of a role in cancers of the oropharynx and oral cavity. Nonsmokers with cancers of the head and neck are more likely to have detectable HPV, although this is less common than hypopharyngeal cancer in persons who smoke.

• Clinically, the mucosa first develops dysplastic lesions that may appear white (leukoplakia) or red (erythroplasia), and with time and continued carcinogen exposure, lesions can develop into frank malignancy.
• Nutritional and metabolic deficiencies are implicated in rare instances. Plummer-Vinson syndrome, mucosal webbing of the postcricoid area with iron deficiency, is associated with a higher incidence of cancer in that region. This is most common in women from northern Europe, including nonsmokers. The pathophysiology is not clear.
• Genetic factors are under investigation. Heritable polymorphisms of expression of enzymes that activate tobacco-related protocarcinogens (eg, aryl hydrocarbon hydroxylase) and detoxify carcinogens (eg, glutathione S-transferase) have been identified. Certain polymorphisms in the alcohol dehydrogenase genes may increase the risk of oral and pharyngeal cancers related to alcohol consumption. Racial differences in the metabolism of carcinogens may be a possible cause of the increasing incidence in African Americans.
• Clinical testing for peripheral, blood lymphocyte, chromosome fragility shows promise for identifying individuals at high risk of primary and secondary head and neck cancers, but it is still investigational.
• Deficient DNA repair mechanisms increase susceptibility to head, neck, and other cancers. Clinically recognized syndromes include xeroderma pigmentosum, Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia. Head and neck cancers are not constituents of the most common cancer family syndromes, which include nonpolyposis colorectal cancer, Li-Fraumeni, or BRCA1/BRCA2 mutation kindreds.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Complete blood count (CBC)
• • During general assessment of bone marrow function, check for the presence of anemia due to chronic disease, metabolic derangements, or occult blood loss. Macrocytic RBCs may hint at chronic alcohol abuse common in this population. Thrombocytopenia may suggest hypersplenism or nutritional deficiency.
  • A CBC helps assess the patient's ability to tolerate myelosuppressive chemotherapy and radiotherapy.
• Hepatic enzymes: Check for underlying liver disease or liver metastases.
• Serum creatinine
• • Assess renal function for general tolerance to therapy.
  • Measure 24-hour creatinine clearance if the serum creatinine concentration is elevated and cisplatin chemotherapy is under consideration.
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT): These are used to assess the safety of biopsy and other surgical procedures. Prolonged results may indicate hepatic insufficiency.
• Serum albumin: Assess the nutritional status.
• Serum calcium: Paraneoplastic hypercalcemia is common with head and neck cancer, even if it is not metastatic.
• Thyroid stimulating hormone (TSH): Check for underlying hypothyroidism. Radiation induces hypothyroidism in approximately 30-40% of patients. This may happen more quickly and more severely in those with hypothyroidism prior to treatment.

Imaging Studies

• Chest x-ray films
• • Check for lung metastases, synchronous lung cancer, and comorbid heart or lung disease.
  • If hypopharynx cancer is aggressive (T4, N2-N3, or poorly differentiated histology), consider chest CT scan or positron emission tomography (PET) scan for most sensitive detection of metastases.
• CT scan or MRI of oral cavity and neck
• • Evaluate local extent of tumor and cervical nodes.
  • MRI provides no clear superiority to CT scan in all cases. MRI (with gadolinium) is better for delineating soft tissue extension, while CT scan (with bone windows) is better for delineating bone invasion.
• PET scan: The role of PET scanning is emerging in initial assessment of patients with head and neck cancer, especially those with locally advanced disease, nodal involvement (particularly when MRI or CT scan findings are equivocal), suspicion of metastatic disease, or for evaluation of an unknown primary site.
• Abdominal CT scan: If alkaline phosphatase and gamma-glutamyltransferase (GGT) levels are elevated, consider an abdominal CT scan to rule out liver metastases.
• Bone scan: If alkaline phosphatase levels are elevated and GGT levels are normal, consider a bone scan to rule out bone metastases.

Other Tests

• ECG: Perform this test because a high incidence of cardiovascular disease exists in this patient population.

Procedures

• Biopsy
• • It is the first step and is necessary to establish a diagnosis.
  • It usually is performed during a triple endoscopy.
• Triple endoscopy
• • This operating room procedure, performed by an otolaryngologist (head and neck) surgeon, is an essential step in planning the definitive treatment for all head and neck subsites.
  • With under mask general anesthesia, the entire oral cavity and throat are palpated and visually inspected, including direct-vision laryngoscopy. The extent of the tumor can most accurately be ascertained in this manner.
  • Biopsies of all suspicious lesions are taken. Bronchoscopy and esophagoscopy are performed to rule out synchronous cancers.
  • Multiple synchronous pharyngeal tumors can be found in approximately 15% of cases.
  • Synchronous lung or esophageal tumors can be found in approximately 5-10% of cases.

Histologic Findings

Most hypopharyngeal cancers are squamous cell neoplasms. Nearly 100% of head and neck cancers overexpress epidermal growth factor receptor (EGFR), although the clinical significance is still unclear. Sarcomas, plasmacytomas, non-Hodgkin lymphomas, and metastatic lesions can be encountered in rare instances.

Histologic factors that denote a higher risk tumor include lymphovascular invasion, perineural invasion, or poorly differentiated cell morphology.

Staging

Summation of examination and radiographic findings into prognostic categories, using tumor (T), nodal (N), and metastatic (M) categories, assists in treatment selection and planning.

• Tumor category
• • T1 - Tumor in 1 subsite of hypopharynx and less than 2 cm
  • T2 - Tumor in 1 subsite of hypopharynx and greater than 2 cm but less than 4 cm, or tumor invades more than 1 subsite of hypopharynx or an adjacent site, and without fixation of larynx
  • T3 - Tumor greater than 4 cm or with fixation of larynx
  • T4a - Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophagus, or central compartment soft tissue

    T4b - Tumor invades prevertebral fascia, encases carotid arteries, or involves mediastinal structures

• Nodal category
• • N0 - No regional nodes involved
  • N1 - Single ipsilateral node involved, not greater than 3 cm
  • N2a - Single ipsilateral node, greater than 3 but less than 6 cm
  • N2b - Multiple ipsilateral nodes, none larger than 6 cm
  • N2c - Multiple bilateral or contralateral nodes, none larger than 6 cm
  • N3 - Any node larger than 6 cm
• Metastatic category
• • M0 - No distant metastases
  • M1 - Distant metastases present
• Stage grouping
• • Stage I - T1 N0 M0
  • Stage II - T2 N0 M0
  • Stage III - T3 N0 M0; T1-3 N1 M0
  • Stage IVA - T4a N0-1 M0; T1-4a N2 M0
  • Stage IVB - T any N3 M0, T4a N any M0
  • Stage IVC - T any N any M1

TREATMENT

Section 6 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• General medical care for comorbid conditions is essential to see the patient through cancer therapy.
• The head and neck cancer patient population has a high prevalence of tobacco-related and alcohol-related comorbid diseases, including cardiovascular disease, chronic obstructive pulmonary disease (COPD), liver dysfunction, malnutrition, alcohol abuse, and tobacco addiction.
• If cancer surgery is planned, obtain preoperative medical consultation and perioperative or postoperative care.
• If radiation is used in therapy, radiation-induced mucositis pain requires therapy, including narcotic analgesics via oral, feeding tube, transdermal, or parenteral routes.

Surgical Care

• An experienced otolaryngologist (head and neck) surgeon working with radiation and medical oncologists in a team approach should direct surgical care of the patient. T1-T2 tumors show similar outcomes with radiation or surgery. The timing of surgery, chemotherapy, and radiation should be determined by the treating physicians based on the staging and clinical features of the tumor.
• Medical and technical operability needs to be determined by addressing the following questions:
• • Can the whole patient tolerate curative surgery?
  • Can the cancer be resected with clear margins and acceptable morbidity?
• The extent of surgery for primary tumors depends on the local size and location.
• • Well-localized T1-T2 lesions can be amenable to partial pharyngectomy or laryngopharyngectomy.
  • Laryngopharyngectomy is more commonly required for T3-T4 tumors.
  • Reconstruction of the pharynx can involve a gastric pull-up, jejunal transposition, skin graft, myocutaneous flap, or a combination of these.
• Neck dissection is generally performed if there is a N1-N3 palpable adenopathy or clinical N0 neck but a T3-T4 primary tumor.

Consultations

• Radiation oncology
• • Radiotherapy should be considered as an alternative to surgery in T1-T2 lesions for organ preservation.
  • Chemoradiotherapy can be used as definitive therapy in higher stage cancers.
  • Postoperative adjuvant radiation therapy (PORT) should be used after complete resection of hypopharyngeal tumors in most patients, while adjuvant chemoradiation should be used when the surgical pathology shows high-risk features (more than 2 lymph nodes positive, extracapsular invasion, positive margins, and possibly T4 tumors or lymphovascular invasion). The addition of chemotherapy to PORT was controversial for years until two large, randomized trials published in 2004 clearly demonstrated the benefit of adding cisplatin to standard radiation.
  • Chemotherapy with radiotherapy is the preferred treatment for unresectable tumors.
• Medical oncology
• • Chemotherapy is never curative as a single modality, but its role in multidisciplinary treatment is growing, especially in more advanced disease (see Image 5).
  • As an alternative to surgery, concomitant chemoradiotherapy has demonstrated disease control approximating surgical results, with 30-50% of patients retaining the larynx. Several single- or multiple-drug regimens are commonly used, and there have been no phase III studies to define which, if any, is superior. Cisplatin has been the most widely used. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, has been shown to improve outcomes when given concurrently with definitive radiotherapy, with less toxicity than conventional cytotoxic chemotherapy drugs.
  • More successful chemotherapy combinations have allowed the re-emergence of induction chemotherapy to shrink the tumor and decrease morbidity from subsequent chemoradiation. The drugs, doses, schedules, and sequencing of chemotherapy and radiation remain areas of investigation.
  • Chemotherapy can reduce the incidence of distant metastases when used in primary or postoperative therapy. Since locoregional relapse remains the primary cause of cancer-related mortality, reduction in metastases has not translated into improved survival.
  • In metastatic disease, chemotherapy may be useful in palliating symptoms and slowing disease progression, but survival prolongation cannot be guaranteed. Combination regimens show higher response rates than single agents.
  • Novel agents include epidermal growth factor receptor blockers and small molecule tyrosine kinase inhibitors. Gene therapy to deliver wild-type p53 through viral vectors is under investigation.
• Dental: Repair or extract damaged teeth prior to radiation therapy. The risk of osteoradionecrosis of bone is increased with poor dental hygiene or extractions performed after high-dose radiation. Dental prophylaxis with fluoride is important during and after radiation due to loss of saliva. Bisphosphonates should be used with caution in this population due to the risk of mandibular osteonecrosis.
• Nutrition: Malnutrition is common at presentation and worsens following surgery, radiation, or both. At diagnosis, obtain nutritional evaluation and recommendations for ongoing nutrition support and follow-up.
• Speech/swallowing therapy: Specialists in this field should direct rehabilitation for speech and swallowing function. This can include training in electrolarynx use following laryngectomy, evaluation of posttreatment function (and risk of aspiration) by observation and barium swallow, and mouth and throat exercises to regain coordination of swallowing and phonation.

Diet

Consider feeding tube placement if oral feeding is likely to be disrupted by therapy. At least 75% of patients undergoing chemoradiotherapy require a feeding tube. A nutritionist should direct the choice and amount of tube feedings and supplements.

MEDICATION

Section 7 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Chemotherapeutic agents are used in conjunction with surgery, radiotherapy, or both. Various chemotherapy agents demonstrate single-agent response rates of 15-38%. The platinum compounds, 5-fluorouracil, taxanes, and cetuximab demonstrate radiosensitizing properties, making them logical choices for combination chemoradiotherapy. The optimal combination is not established. The following tables are not in order of preference but include some of the frequently used agents.

Drug Category: Antineoplastic agents

Inhibit cell growth and differentiation.

Drug Name	5-fluorouracil (Efudex, Adrucil, Fluoroplex)
Description	Commonly used for radiosensitization. Single-agent response rate is 15%.
Adult Dose	Varies with setting and schedule
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; myelosuppression; acute active infection
Interactions	None reported
Pregnancy	D - Unsafe in pregnancy
Precautions	Incidence of inflammatory reactions can occur with occlusive dressings; porous gauze dressing can be applied for cosmetic reasons without increase in reaction

Drug Name	Leucovorin (Folinic Acid, Wellcovorin)
Description	Reduced form of folic acid that does not require enzymatic reduction reaction for activation. Allows for purine and pyrimidine synthesis, both of which are needed for normal erythropoiesis. Derivative of folic acid, used only as an adjunct to 5-fluorouracil.
Adult Dose	Variable dose and schedule
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; pernicious anemia; vitamin-deficient megaloblastic anemias
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not administer intrathecally or intraventricularly

Drug Name	Paclitaxel (Taxol)
Description	Mechanisms of actions are tubulin polymerization and microtubule stabilization. In vitro data suggest use as radiosensitizer; 38% response rate as single agent.
Adult Dose	Varies with setting and schedule
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; documented hypersensitivity to polyoxyethylated castor oil; peripheral neuropathy; bone marrow suppression; liver failure; severe cardiac disease
Interactions	Cisplatin administered before paclitaxel 24-h infusion reduces paclitaxel clearance; coadministration with cisplatin can further increase myelosuppression
Pregnancy	D - Unsafe in pregnancy
Precautions	Premedicate with steroids, H1-blockers, and H2-blockers to decrease risk of hypersensitivity reactions; myelosuppression, alopecia, arthralgia/myalgias, and cardiac arrhythmia can occur

Drug Name	Methotrexate (Folex, Rheumatrex)
Description	Antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells; can suppress immune system. Satisfactory response seen in 3-6 wk following administration. Often used in low weekly doses for palliation; single-agent response rate is 31%.
Adult Dose	Varies with setting and schedule
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; alcoholism; hepatic insufficiency; renal insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); presence of pleural effusions or ascites significantly prolongs clearance
Interactions	Oral aminoglycosides can decrease absorption and blood levels of concurrent oral MTX; charcoal lowers levels; coadministration with etretinate can increase hepatotoxicity; folic acid or its derivatives contained in some vitamins can decrease response; coadministration with NSAIDs can be fatal; indomethacin and phenylbutazone can increase MTX plasma levels; can decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, can increase effects and toxicity; can increase plasma levels of thiopurines
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor CBCs monthly and liver and renal function q1-3mo during therapy, and monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels (eg, dehydration); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts; aspirin, NSAIDs, or low-dose steroids can be administered concomitantly (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested)

Drug Name	Docetaxel (Taxotere)
Description	Semisynthetic taxane, a class of drugs that inhibits cancer cell growth by promoting assembly and blocking the disassembly of microtubules, thereby preventing cancer cell division, leading to cell death.
Adult Dose	Varies with setting and schedule
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to docetaxel or polysorbate 80
Interactions	Toxicity may increase when administered concurrently with ketoconazole, erythromycin, or cyclosporine
Pregnancy	D - Unsafe in pregnancy
Precautions	Premedicate with oral corticosteroids (eg, dexamethasone 8 mg bid for 3 d), starting 1 d before docetaxel administration to reduce incidence of hypersensitivity reactions and fluid retention; patients with preexisting effusions should be closely monitored during first dose of docetaxel for the possibility of exacerbation of the effusion; caution when administering docetaxel to subjects with abnormal liver function; blood counts should be monitored and if neutrophil count is below 1,500/mm3 refer to specific dose reduction recommendations

Drug Name	Cetuximab (Erbitux)
Description	Indicated for use in combination with radiation therapy to treat patients with squamous cell cancer of the head and neck (SCCHN) that can not be removed by surgery. Approved for monotherapy to treat patients whose head and neck cancer has metastasized despite the use of standard chemotherapy. Recombinant, human/mouse chimeric monoclonal antibody that specifically binds to the extracellular domain of human epidermal growth factor receptors (EGFR, HER1, c-ErbB-1). Cetuximab-bound EGF receptor inhibits activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased production of matrix metalloproteinase and vascular endothelial growth factor.
Adult Dose	First dose: 400 mg/m2 IV infused over 2 h; if combined with radiation, administer 1 wk before radiation Weekly maintenance doses: 250 mg/m2 IV infused over 1 h; if combined with radiation, administer 1 h before Not to exceed infusion rate of 10 mg/min (ie, 5 mL/min); must administer with low-protein–binding 0.22 mm in-line filter; premedication with an H1 antagonist (eg, diphenhydramine 50 mg IV) recommended
Pediatric Dose	Not established
Contraindications	None for metastatic colorectal carcinoma
Interactions	Limited data exist; none reported
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution with documented hypersensitivity, including allergy to murine proteins; may cause infusion-related hypotension and airway distress (eg, bronchospasm, stridor, hoarseness), particularly with the first infusion (90%); premedicate with diphenhydramine 50 mg IV; decrease dose with mild or moderate (grade 1 or 2) infusion reaction and immediately and permanently discontinue with severe (grade 3 or 4) infusion reactions; common adverse effects include acnelike rash, dry skin, tiredness or weakness, fever, constipation, and abdominal pain; may rarely cause interstitial lung disease; do not shake or dilute solution; sunlight can exacerbate any skin reactions

FOLLOW-UP

Section 8 of 11  

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Further Outpatient Care

• Close monitoring is required during radiation, chemotherapy, or both for evaluating tumor response, management of adverse effects, nutritional support, pain medications, and psychosocial support.
• Reevaluate the disease status periodically due to high risk of recurrence. Perform a neck examination and fiberoptic laryngoscopy every 1-3 months for 1-2 years after the initial treatment and 2-4 times per year thereafter. If PET scan was informative at initial diagnosis, consider repeating not sooner than 4 months after radiation or surgery; prior to this time, the inflammation from treatment may give a false-positive reading.
• Monitor for second primary cancers (incidence of approximately 3% per y) once or twice per year.
• • Chest x-ray films for detection of lung cancer or metastases
  • Hepatic panel to check for liver metastases
  • Oral examination, neck examination, and fiberoptic laryngoscopy checking for new oral or throat lesions
  • TSH levels once or twice per year if neck was radiated
• Dental monitoring is important following radiation to the neck, due to xerostomia and increased risk of tooth decay. Careful attention to cleaning, scaling, periodontal health, and lifelong topical fluoride treatment can reduce the risk of tooth loss.

Deterrence/Prevention

• Smoking cessation is associated with improved response to radiation, improved survival, and lower risk of second primary cancers.
• Initial studies suggested that secondary chemoprevention with 13-cis-retinoic acid (Accutane) showed promise in reducing the risk of second primary cancers; however, more recent long-term follow up of a randomized trial showed no benefit.

Complications

• Surgical complications include infection, nerve damage, and pharyngocutaneous fistula.
• Radiotherapy complications include mucositis, skin breakdown, fibrosis, edema due to lymphatic scarring, chronic aspiration, and osteoradionecrosis, particularly of the mandible.
• Chemotherapy complications include infection due to myelosuppression, alopecia, nausea and vomiting, peripheral neuropathy (taxanes, platinum drugs), and increased skin and mucous membrane damage from radiation.

Prognosis

• Hypopharyngeal cancers generally have a poorer prognosis than other head and neck subsites, partly due to frequent late-stage presentation.
• • Prognosis varies with stage. With small (T1-T2) lesions, the 5-year survival rate is about 60%, but with T3-T4 lesions or multiple node involvement, this rate falls to 15-30%.
  • Distant metastatic disease develops in approximately 25% of patients. The lungs, liver, and bones are the principle organs affected.
  • The principle cause of death is local tumor recurrence. Distant metastases, second primary cancers, and comorbid diseases are secondary causes.

Patient Education

• Refer the patient to speech therapy for ongoing voice and swallowing rehabilitation.

MISCELLANEOUS

Section 9 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• In a patient with throat symptoms, inadequate examination (flashlight and tongue blade or mirror examination) may provide false reassurance.
• Protracted empiric antibiotic therapy for nonresponding earaches, sore throat, or cervical lymphadenopathy can delay diagnosis.
• Negative office biopsy of suspicious mucosal lesions or fine-needle aspiration of cervical lymph nodes does not rule out malignancy.
• • Necrotic debris can interfere with pathologic interpretation.
  • If clinical setting is suspicious, obtain further biopsies.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Patient with left-sided sore throat and neck mass. CT scan demonstrates left pyriform sinus mass (white arrows) and large neck node (black arrow).
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Media type:  CT

Media file 2:  Patient with left-sided sore throat and neck mass. CT scan demonstrated left pyriform sinus mass and large neck node. Two years after chemoradiotherapy, no evidence of tumor exists.
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Media type:  CT

Media file 3:  Patient presenting with hoarseness and dysphagia. CT scan demonstrates bulky right pyriform sinus tumor (white arrows) eroding through thyroid cartilage, with displacement of supraglottic airway. A total laryngectomy would have been required, because the patient placed a high value on retaining the ability to talk, chemoradiotherapy was chosen.
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Media type:  CT

Media file 4:  Patient presenting with hoarseness and dysphagia. CT scan demonstrated bulky right pyriform sinus tumor eroding through thyroid cartilage, with displacement of supraglottic airway. Total laryngectomy would have been required, because the patient placed a high value on retaining the ability to talk, chemoradiotherapy was chosen. Following chemoradiotherapy, note persistent fullness in tumor bed. Endoscopy revealed edema and scarring, but the biopsy was negative for tumor. Continued vigilance is needed in this situation.
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Media type:  CT

Media file 5:  Patient presented with hoarseness and otalgia. Note the bulky left pyriform sinus tumor (black arrow) with an area of gadolinium enhancement extending to the carotid sheath (white arrows). This T4 tumor was unresectable, and the patient was treated with chemoradiation.
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Media type:  MRI

Media file 6:  Patient presented with hoarseness and otalgia. On MRI, there was a bulky left pyriform sinus tumor with an area of gadolinium enhancement extending to the carotid sheath. This T4 tumor was unresectable, and the patient was treated with chemoradiation. Despite a good response to chemoradiotherapy, the evaluation for progressive neck pain 4 months later revealed a bulky recurrence in the left neck. Note tumor (white arrows) surrounding the carotid artery (black arrow).
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Media type:  CT

REFERENCES

Section 11 of 11

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• Introduction
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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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Article Last Updated: Sep 28, 2004