What every physician needs to know:

The majority of head and neck carcinomas affect three major sites: oral cavity, pharynx, and larynx. Although less common pathologic variants may be seen, the common pathology is squamous cell carcinoma (SCC):

  • Oral cavity includes floor of mouth (FOM), hard palate, oral tongue, buccal mucosa, retromolar trigone, lower and upper alveolar ridge, anterior tonsillar pillar, and to the skin-vermilion junction.

  • Pharynx includes the subsites of nasopharynx, oropharynx (soft palate, posterior pharyngal wall, base of tongue [BOT], tonsil, and vallecula), and hypopharynx.

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  • Larynx includes the supraglottis, glottis, and subglottis.

While treatment strategies are individualized, several general treatment principals should be noted. In general, earlier stage disease (i.e. stage I/II) is treated with a single modality approach. Advanced stage disease (i.e. stage III/IV) is managed with combined modality therapy, utilizing a combination of surgery, radiation therapy and chemotherapy as primary therapy.

In some cases, all three modalities are warranted. Other times a non-operative approach using chemotherapy and radiation therapy for curative intent is used.

Are you sure your patient has head and neck cancer? What should you expect to find?

Patients with head and neck carcinomas manifest symptoms according to subsite of origination.

For oral cavity primaries; mouth pain, ill-fitting dentures, nonhealing ulcers, and erythroplakia or leukoplakia can be seen.

Oropharyngeal primaries often present with sore throat, otalgia and/or odynophagia.

For laryngeal primaries, hoarse voice is a common presenting feature. Any adult with hoarse voice for greater than two weeks should have an ear, nose and throat (ENT) evaluation.

Nasopharyngeal primaries may present with sinus “fullness”, cranial nerve palsies (including III, V, VI, and/or VII most commonly) or serous otitis media. Nasopharyngeal primaries are the most likely to have early nodal spread.

For all subsites, the primary may remain “clinically silent” and lymph node spread with palpable, non-resolving lymph nodes may appear in the neck. Non-resolving or enlarging lymphadenopathy should prompt further evaluation.

Unknown primary SCC of the head and neck are defined as metastatic squamous cell cancer in a neck lymph node with no identifiable primary tumor. This scenario occurs less than 5% of the time and is potentially curable.

Biopsy of the neck mass can usually be obtained via fine needle aspiration (FNA). If the sample obtained via FNA is not consistent with a head and neck primary (i.e. higher suspicion for lymphoma), then an excisional biopsy to analyze lymph node architecture and histology can be performed.

If squamous cell or undifferentiated on histology, then human papilloma virus (HPV) and Epstein-Barr virus (EBV) testing should be sent. If HPV-positive, then a base of tongue or tonsil primary is most likely, and treatment should be given accordingly. EBV-positivity would suggest nasopharyngeal primary and treatment guidelines for NPC should be followed.

In addition, all SCC of the head and neck should have ENT evaluation to evaluate for or verify the primary site. ENT evaluation also allows for identification of any concomitant primary malignancies since the entirety of the aerodigestive tract can be at risk.

Beware of other conditions that can mimic head and neck cancer:

The differential diagnosis of mucosal abnormalities in the head and neck region include dysplasia, carcinoma-in-situ, or invasive carcinoma. Lichen planus, erythroplakia or leukoplakia are considered pre-neoplastic conditions. Viral outbreaks with HSV-1 or 2, EBV, CMV, apthous ulcers, or yeast infections also cause mucosal changes.

If a cervical lymph node is present or enlarging for more than several weeks, FNA should be obtained. Cervical lymphadenopathy could represent a viral infection (e.g., mononucleosis from EBV infection), abscess, lymphoma, or nodal spread from other malignancies. Lung, esophageal, and thyroid primaries commonly metastasize to involve lymph nodes in the head and neck region and should be considered.

Which individuals are most at risk for developing head and neck cancer:

Alcohol and tobacco

Alcohol and tobacco remain major contributing factors for the development of head and neck squamous cell carcinoma (HNSCC) and seem to have an additive effect when used together. The definition and quantification for amount of exposure associated with the development of HNSCC varies between studies.

Each substance used is associated with increased risk and a dose-response relationship is noted for both smoking and alcohol. However, smoking is the more carcinogenic of the two and is the most powerful risk-factor for developing HNSCC.

The level of risk is affected both by the number of cigarettes smoked per day as well as the number of years of smoking. Regarding other forms of tobacco exposure, cigars and smokeless tobacco are still considered carcinogenic. Cigars are associated with lower rates of subsequent cancer compared to cigarettes, but the risk is still higher than that of non-smokers.

In addition, smokeless tobacco (snuff, chew) carries an increased risk for oral cavity cancer specifically given its absorption through the mucosal membranes of the mouth.

Human papilloma virus

HPV is the most common sexually transmitted virus in the United States. Recently, HPV was identified as a causative agent approximately 60% of the time for developing SCC of the oropharynx, specifically the base of tongue and tonsil.

High-risk or oncogenic strains of HPV include 16, 18, 31, 33 with HPV-16 identified in over 90% of HPV-associated head and neck carcinomas. Demographically, the patients who develop HPV-associated oropharyngeal tumors average approximately 5-10 years younger than HPV-negative patients.

In addition, patients with HPV-positive tumors have less exposure to alcohol and tobacco. They are, however, more likely to have multiple sexual partners with oral sex frequently reported.

Epstein-Barr virus

EBV is known to have a causal relationship in nasopharyngeal carcinoma (NPC). Asians and Mediterraneans are noted to have a higher incidence of EBV-related NPC compared to the US and Western European populations in which tobacco and alcohol still play a role.

NPC has three WHO classifications: keratinizing SCC (WHO, type I), nonkeratinizing carcinoma both differentiated (WHO, Type II) and undifferentiated (WHO, Type III), and basaloid SCC. Nonkeratinizing SCC is also known as lymphoepithelioma, and nonkeratinizing, undifferentiated NPC is most often noted with endemic cases of NPC and EBV-positivity.

Human papilloma virus

HPV-associated tumors are molecularly different from HPV-negative tumors, and mounting evidence suggests that these two entities are distinct in their response to therapy.

The HPV viral genome encodes multiple proteins, most notably E6 and E7 proteins. E6 and E7 functionally inactivate p53 protein and the retinoblastoma (Rb) tumor suppressor gene product, respectively. This activity proves important as both p53 and Rb help maintain the genomic integrity of the cell. Importantly, inactivation of the Rb protein has also become a key diagnostic feature for the presence of HPV in the tumor.

P16 is a cyclin-dependent functional kinase inhibitor that inhibits pRb phosphorylation and blocks cell cycle progression at the G1 to S check point. Loss of p16 expression is common in head and neck carcinomas. However, when HPV protein E7 inactivates pRb, overexpression of p16 results, making p16 expression analysis a good surrogate marker of HPV status in a particular tumor sample.

Available testing methods to assess for HPV positivity include qRT-PCR for HPV16 E6 mRNA detection, in situ hybridization (ISH) for HPV DNA, or p16 expression by immunohistochemistry. These have a concordance rate of 86-92%. Of the available testing options, immunohistochemistry for p16 expression or in situ hybridization for HPV DNA should be used to determine the HPV status of a tumor. P16 expression by IHC captures all high risk phenotypes and is technically easier to perform; thus, p16 expression by IHC is the preferred method of HPV detection.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, Ct/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Endoscopy

Endoscopy includes flexible laryngoscopy, nasopharyngoscopy, and esophagoscopy, and is the gold standard staging modality. In recent years, bronchoscopy is not typically included in this evaluation. Endoscopy allows for assessment of other potential concomitant primary tumors as well as T staging of existing tumor(s) and should be performed early in the evaluation of head and neck pathology.

Computed tomography (CT) of the neck

CT of the neck is the imaging modality of choice for initial staging evaluation of head and neck carcinoma. CT allows for excellent evaluation of both tumor volume and location as well as a non-invasive evaluation of lymph node involvement. CT is also good for evaluating bone involvement.

Magnetic resonance imaging (MRI)

MRI can address specific clinical concerns such as surgical planning and exact extent of tumor for lesions arising near the base of skull (e.g., as occurs with nasopharyngeal tumors).

PET/CT

PET/CT can be helpful in the assessment of nodal involvement in the neck or for metastatic disease but is not necessary for initial staging of most head and neck carcinomas. Exceptions would be nasopharyngeal cancer and occult primary where the PET/CT can assist in identifying more advanced disease or a primary tumor, respectively.

Fine needle aspiration of pathologic lymph nodes

FNA of pathologic lymph nodes (>1cm on imaging or with central necrosis or matting of multiple lymph nodes) should be performed to confirm neck involvement. However, if cervical node involvement is already documented, further biopsies are only warranted if this will change treatment planning. Initial excisional biopsy should be avoided as this procedure can interfere with surgical neck management that may be required at a later stage in therapy.

HPV testing

HPV testing should be included in the evaluation of oropharyngeal (especially tonsil or base of tongue) tumors or occult primary carcinomas which involve the head and neck. P16 expression analysis via immunohistochemistry is currently the preferred method of evaluating for HPV. See HPV section testing options for HPV.

Stage for stage, HPV-positive tumors respond better to both chemotherapy and radiation, and studies are ongoing to assess whether treatment modifications for this group of patients can be offered with comparable response rates to conventional therapies currently utilized.

Other molecular testing:

There is no established role for EGFR or KRAS testing in HNSCC.

Special considerations:

Nasopharyngeal (NPC)

NPC primaries are the most likely to have early nodal spread and distant disease at the time of presentation, and thus evaluation of NPC differs from other subsite primaries. MRI of the base of skull and nasopharynx is indicated to stage NPC as MRI is the superior imaging modality to assess for base of skull involvement. CT of the neck and chest should be obtained to assess for the presence of nodal and/or distant spread. Integrated PET/CT can be obtained at this step to more clearly define areas of involvement given NPC’s propensity for early spread. Bone marrow examination is performed if blood counts are abnormal.

Occult primary cancers

Occult primary cancers of the head and neck typically present with neck lymphadenopathy. Evaluation should include CT versus integrated PET/CT imaging of the head, neck and chest, as well as nasopharyngoscopy, oral cavity and oropharyngeal exams, laryngoscopy and esophagoscopy. Some studies indicate that up to 40% of initially unknown primary sites can be localized to the tonsils.

Based on this data, a unilateral or more often bilateral tonsillectomy is advocated if prior studies do not show a primary tumor in order to determine primary site. FNA sampling should be performed on the enlarged lymph node. HPV and EBV testing should be sent if squamous cell or undifferentiated carcinoma is found on histology.

Integrated PET/CT imaging is frequently utilized in the evaluation of occult primary cancers that involve lymph nodes in the head and neck region. Compared to PET alone, integrated PET/CT provides greater rates of tumor detection.

Staging

Table I. TNM staging of lip and oral cavity cancers.

Table II. TNM staging of nasopharyngeal, oropharyngeal and hypopharyngeal cancers.

Table III. TNM staging of laryngeal cancer.

What therapies should you initiate immediately i.e., emergently?

Airway obstruction can occur at diagnosis but may also occur later, including with the initiation of radiation therapy (RT) due to tissue swelling. If symptoms or signs suggest impending airway compromise (stridor, dyspnea – especially when supine, wheezing or hemoptysis) due to a bulky tumor or if narrowing is noted on initial laryngoscopy, a surgical procedure may be needed before proceeding with further therapy.

Palliative debulking by a qualified surgeon is considered if the airway is tight due to tumor, even if advanced stage disease or poor overall survival is expected. Alternatively, an urgent or emergent tracheostomy may be needed. Heliox helps make air flow less turbulent in larger airways, and thus, is felt to benefit patients with upper airway abnormalities, including tumors.

However, in practice, patients with increased work of breathing from impending airway obstruction will undergo an airway stabilizing procedure with tracheostomy. Heliox can be tried as a temporizing measure, but emergent evaluation for tracheostomy must be undertaken by a specialist (ENT or surgeon).

For the immediate management of impending airway compromise, prompt evaluation by a surgeon is essential.

What should the initial definitive therapy for the cancer be?

In general, earlier stage HNSCC (i.e. stage I/II) is treated with a single modality approach. Advanced stage disease (i.e. stage III/IV) is managed with combined modality therapy utilizing radiation and/or concurrent chemotherapy and/or surgery.

For all head and neck cancer patients, a multidisciplinary team should be involved in treatment planning and execution. A multidisciplinary team must include medical, surgical and radiation oncologists. Ideally, a pathologist and a radiologist should be present for case review.

The patient should also have evaluation and/or co-management by a dentist as dental extraction may be required before starting radiotherapy, as well as a nutritionist, speech therapist, and physical therapist. In addition, ancillary services such as social work and psychiatrists/psychologists are beneficial for total patient care.

Continued tobacco and alcohol consumption can interfere with treatment and general health, and cessation of use should be discussed with the patient. Enteral feeding tubes are considered once a person has lost more than 10% of his/her bodyweight prior to or during treatment. This guideline can be modified as indicated.

PEG tubes can be placed during therapy and treatment does not need to be withheld to place a PEG tube. It is best to schedule tube placement as far from the next scheduled chemotherapy as possible to ensure count recovery. PEG tubes can be placed in a prophylactic fashion if induction therapy or resection has resulted in significant decrease in the patient’s ability to eat or if nutritionally unstable prior to therapy. Significant aspiration is another absolute indication for PEG tube placement (see acute toxicities section).

Surgery

Resectability

Resectability is determined by the extent of the tumor and experience of the surgeon as well as by the resources of the institution, such as oromaxillofacial surgeons or plastic surgeons for reconstruction options. A tumor is generally felt to be unresectable if all gross tumor is not expected to be fully removed or if local control is not possible, even with adjuvant RT. Primary tumors are not usually removed if distant metastases are found on staging.

Neck dissection

The decision of whether or not to perform a neck dissection is individualized to each case. Tumor extent as assessed pre-operatively influences whether a selective or comprehensive neck dissection is performed. Neck dissection can improve local control of disease. Additionally, the information obtained by a thorough pathological evaluation of lymph nodes guides adjuvant therapy decisions and provides important prognostic information.

In general, surgical removal of lymphatics is dictated by extent of the primary tumor and is typically performed on the ipsilateral neck to the primary tumor. However, some tumor sites tend to drain to bilateral lymphatics, typically midline positioned tumors such as base of tongue, palate, supraglottic larynx or deep space pre-epiglottic locations, and thus a bilateral neck dissection may be necessary. Anterior oral tongue or floor of mouth lesions should have a contralateral submental dissection if the primary tumor approaches the midline.

Radiation therapy

RT total dose depends on primary tumor size, lymph nodes involved, and whether concurrent chemotherapy will be given. Usually a total dose of 66-70 Gy is given to the primary site at 2 Gy per day for 35 fractions. Gross neck involvement also receives 70 Gy, and subclinical neck disease should receive 50 Gy in 25 fractions.

Chemotherapy

The administration of chemotherapy in HNSCC depends both on tumor stage as well as subsite of the primary. Single modality therapy with chemotherapy alone is reserved for the metastatic, noncurative setting. Otherwise, the role of chemotherapy in head and neck carcinomas is either as induction therapy or concurrent with radiation therapy.

Induction chemotherapy

Induction chemotherapy can be followed by surgical resection, definitive RT, or definitive concurrent chemoradiotherapy. The role of induction chemotherapy gained favor with early studies attempting an “organ-preservation approach” with laryngeal primaries which otherwise would necessitate total laryngectomy.

However, definitive trials comparing induction chemotherapy followed by concurrent chemoradiotherapy (CCR) versus initial treatment with concurrent chemoradiotherapy have not been reported. Induction chemotherapy is most often considered in cases with bulky primary lesions to attempt improved resectability at the time of surgery and is also felt to potentially control micrometastatic disease quickly, thus diminishing the rate of distant recurrence.

Randomized phase III trials evaluating induction chemotherapy in HNSCC sites which include the oral cavity, oropharynx, hypopharynx, and larynx demonstrated the following:

  • With inoperable disease, a significant increase in disease-free and overall survival as well as a decrease in distant disease.

  • A three-drug regimen including docetaxel, cisplatin, and 5-fluorouracil compared to the standard two-drug regimen of cisplatin and 5-fluorouracil demonstrated an additional significant increase in overall survival in patients with unresectable disease.

Induction regimens:

  • Docetaxel 75mg/m2; day 1, cisplatin 75mg/m2; day 1, 5-fluorouracil 750mg/m2;/day 96-hour continuous infusion every 21 days for three cycles.

(Given to patients with an excellent performance status and no limiting comorbidities. A gold standard induction regimen.)

  • Carboplatin (AUC 2) and paclitaxel 60mg/m2; weekly x 9 weeks

(Chosen when the patient has multiple comorbidities or a lower performance status which limit the ability to give a three-drug regimen.)

Concurrent chemoradiotherapy

CCR is supported by randomized, prospective data as primary therapy for locally advanced disease as well as adjuvant therapy for patients with completely resected high-risk disease (see below). When compared to RT alone, CCR demonstrates superior locoregional control, overall survival and disease-free survival.

When CCR is pursued first-line, surgical resection is reserved for residual or recurrent disease management. Platinum chemotherapy agents remain the standard of care for concurrent chemoradiotherapy with cisplatin being the best studied agent.

The Intergroup trial of laryngeal preservation set the gold standard of CCR, adopted to other sites as well:

  • Cisplatin 100 mg/m2; every 3 weeks concurrent with RT.

  • Typically this will equal 3 doses of cisplatin during CCR (days 1, 22, 43).

(Importantly, recent data has suggested that the day 43 cisplatin may possibly be able to be dropped without compromise on OS, depending on toxicities occurring at that point during CCR.)

Other CCR regimens (equivalency data for these regimens is lacking):

  • Carboplatin (AUC 1) and paclitaxel 30mg/m2; weekly.

(For lower performance status patients or comorbid conditions prohibiting cisplatin use.)

  • Cetuximab 400 mg/m2; (initial dose), followed by 250 mg/m2; x 7 weekly doses.

  • Cetuximab + RT has been shown to improve survival when compared to RT alone.

  • Cetuximab plus RT has never been compared to other standard chemotherapeutic agents known to be effective in the CCR setting.

(Cetuximab with RT is typically reserved for patients who cannot tolerate platinum therapy.)

  • Cisplatin 30-40 mg/m2; weekly.

Less commonly used combinations include:

  • Cisplatin/infusional 5-fluorouracil.

  • Cisplatin/paclitaxel.

  • 5-fluorouracil/hydroxyurea.

High-risk features

Importantly, some cases of HNSCC with a primary surgical approach demonstrate high-risk features on final pathology. These high-risk features for cancers of the oral cavity, oropharynx, larynx, or hypopharynx include:

  • Two or more positive lymph nodes.

  • Extracapsular extension.

  • Positive surgical margins.

  • Lymphovascular or perineural involvement.

  • OC or OP primaries with level IV or V lymph node involvement.

High-risk pathologic features, T3/T4 (except laryngeal T3N0), or N2/N3 disease should prompt adjuvant CCR, but trials examining this issue have differed a bit in their inclusion criteria. Positive margins and/or extracapsular lymph node extension are considered the most high-risk features. Positive surgical margins would also prompt either re-excision or adjuvant radiation therapy to reduce relapse risk.

Metastatic disease

The lung is the common site of distant spread with an incidence of 80%, followed by mediastinal nodes, liver and bone with approximately 30% incidence each. Therapy for metastatic disease is palliative chemotherapy or immunotherapy, with RT utilized for sites of focal problems, such as pain or impending fracture.

Taxanes and platinum agents seem to have the most consistent response rates of around 20-30%. Response rates are low for targeted agents, in the 5-10% range, with cetuximab having the most mature data and the only agent that has been shown to have a survival advantage in the metastatic setting.

Approved immune checkpoint inhibitors target the anti-programmed death 1 (PD-1) protein on T-lymphocytes increasing anti-tumor cellular cytotoxicity. The humanized monoclonal PD-1 antibody pembrolizumab and the fully-human monoclonal PD-1 antibody nivolumab are both approved for recurrent and unresectable or metastatic HNSCC that has progressed on prior platinum-based chemotherapy regimens. At this time, testing for tumor PD ligand 1 (PDL-1) expression is not required for the selection of either drug. However, it does appear response rates are superior for PDL-1 positive tumors. Responses appear to be similar regardless of p16 status, a marker of human papilloma virus (HPV) infection.

Combination regimens, usually with a platinum and taxane, have been evaluated, but data demonstrating a survival advantage is lacking.

The following are possible treatment regimens for metastatic disease:

  • Cisplatin 100 mg/m2; day 1 or carboplatin (AUC 5) day 1 + 5-fluorouracil 1000 mg/m2;/day x 4-day continuous infusion every 21 days + cetuximab 400 mg/m2; initial dose as a 2-hour infusion followed by 250 mg/m2; over 1-hour given weekly. Six cycles given followed by maintenance weekly cetuximab until disease progression or unacceptable toxicity (EXTREME trial).

  • Docetaxel 75 mg/m2; + carboplatin (AUC 6) every 21 days.

  • Cisplatin 100 mg/m2; day 1 + 5-fluorouracil 1000 mg/m2;/day 4-day continuous infusion every 21 days for maximum of 6 cycles.

  • Cisplatin 75 mg/m2; day 1 + paclitaxel 175 mg/m2; over 3 hours day 1 every 21 days for maximum of 6 cycles.

  • Single-agent cetuximab at 400 mg/m2; initial dose over 2 hours followed by 250 mg/m2; over 1-hour weekly for maximum of 6 weeks

  • Pembrolizumab 200 mg IV every 3 weeks (KEYNOTE 012 trial)

  • Nivolumab 3 mg/kg IV every 2 weeks (CheckMate 141 trial)

Therapy by subsite

1. Oral cavity Carcinoma (OCC)

Floor of mouth (FOM), hard palate, oral tongue, buccal mucosa, retromolar trigone, lower and upper alveolar ridge, anterior tonsillar pillar, and to the skin-vermilion junction. See Table I.

For primaries involving the oral cavity, surgical resection is preferred if possible.

Stage I/II OCC, defined as T1 or 2, N0, is typically managed by surgical resection. Primary radiotherapy (RT) can be used and both surgery or primary RT have similar overall survival numbers. However, surgery is preferred due to the high morbidity associated with RT.

For floor of mouth cancers, surgery is typically preferred due to risks of significant complications from RT, including osteoradionecrosis. However, primary RT is a treatment option with comparable overall results in this subsite as well.

Selective neck dissection is often performed when tumors are suspected to be more than superficial in depth, given a higher incidence of occult nodal metastasis with thicker tumors. If the primary tumor involves the midline, then bilateral neck dissection is recommended.

For stage III/IV OCC, defined as T3N0 or any T/N1 disease, assessment must include evaluation for metastatic disease with high quality chest imaging. Surgical resection followed by adjuvant therapy is still the preferred method of treatment for advanced stage OCC.

However, if the tumor is unresectable or surgery is unacceptable to either the patient or surgeon at the time of diagnosis, then induction chemotherapy followed by CCR or primary CCR can be given. Given the high rates for locoregional recurrence with advanced OCC, adjuvant CCR should be administered for improved locoregional control over RT alone. See discussion of CCR principles.

2. Oropharyngeal (OP)

Soft palate, posterior pharyngeal wall, base of tongue (BOT), tonsil, and vallecula. See Table II.

Early stage OP carcinoma, defined as T1-2, N0-1, can be managed either by surgical resection and neck dissection as indicated or definitive RT alone. If high-risk features (see discussion above on high-risk features) are found after resection, then adjuvant CCR is superior to RT alone.

For more locally advanced tumors, T3-4a, N0-1 or any T/N2-3, three treatment options are considered:

  • Concurrent Chemoradiation -generally, the preferred treatment is CCR with cisplatin (100 mg/m2; day 1, 22, 43). Surgical resection is then reserved for recurrent or residual disease.

  • Induction Chemotherapy – many would use induction chemotherapy prior to CCR, but the data is not clear on which population benefits most from this more aggressive approach. This issue becomes especially meaningful in the relatively “good risk” HPV-positive population.

  • Surgery with post-operative RT or chemoradiation (depending on high-risk features): prospective trials are ongoing to determine if treatment can be de-escalated based on whether the tumor is HPV-positive given the improvement in treatment response and prognosis with HPV-positive tumors in early studies. Presently, treatment is the same even with HPV-positive tumors of the OP unless part of a clinical trial.

3. Hypopharynx (HP)

Early stage disease is typically T1N0 but some T2 tumors can be considered in this group if total laryngectomy is not required. For early stage disease, organ preservation is emphasized and either primary RT versus organ sparing surgery with neck dissection as indicated can be pursued.

If definitive RT is chosen, then surgical resection is utilized for residual or recurrent disease. If complete clinical response with RT, then close follow-up is acceptable without further adjuvant therapy. If primary resection is chosen, then adjuvant therapy is appropriate if high-risk features are found on the surgical specimen (see discussion above on high-risk features).

Adjuvant therapy options include:

  • CCR if extracapsular spread and/or a positive margin is found.

  • Radiation alone versus re-resection can be considered if a positive margin is the only high-risk feature present.

  • Lastly, if high-risk features are found other than extracapsular spread or a positive margin, then CCR versus RT alone can be considered for adjuvant therapy

Later stage disease is classified by those patients who would require a total laryngectomy and have T2-4a primary tumors or any stage nodal involvement. Several treatment algorithms are considered for advanced disease:

Induction chemotherapy followed by radiation therapy if a complete clinical response is achieved. However, standard of care now includes CCR after induction.

  • If a partial response is obtained after induction chemotherapy (generally defined as >50% response in the primary tumor), then CCR is indicated with surgery reserved for residual disease.

  • If less than a partial response is obtained after induction chemotherapy for advanced disease, then surgical resection is indicated.

  • Adjuvant RT versus CCR after resection is determined based on the presence or absence of pathologic high risk features as discussed previously with early stage disease.

Another acceptable option is definitive, cisplatin-based CCR for advanced stage disease (M0):

  • If neck disease is persistent or found in follow-up, then neck dissection is indicated to surgically manage the neck.

  • If residual disease is found at the primary site after initial CCR, then surgical resection is indicated at that time with management of the neck as indicated by surgical findings.

For very advanced local disease with T4b (invasion of prevertebral fascia, encasement of the carotid artery, or involvement of mediastinal structures), any unresectable N status, clinical trial or combination chemoradiotherapy or RT alone is recommended, depending on functional status and other comorbidities.

4. Larynx

Early stage supraglottic tumors are typically T1-2, N0 and can be managed without laryngectomy. Partial resections without total laryngectomy or RT alone have similar results.

Initial treatment involves endoscopic removal or partial supraglottic laryngectomy with neck management as indicated for either approach. If a single lymph node on neck dissection is positive with either of these approaches, then adjuvant radiation therapy alone is appropriate.

If other high-risk features on pathology are present (see high-risk features discussion above), then treatment varies depending on which risk factor is present. With a positive margin AND a positive lymph node, then re-resection, CCR, or RT alone can be considered. If a positive lymph node AND extracapsular extension (ECS) are present, then CCR for most and RT alone for some would be the next step in therapy. If other high risk features are found on pathology (as described above), many people would give CCR but RT alone may be acceptable in some cases in which the high risk features are not ECS or positive margin.

For locally advanced disease, an organ-sparing approach is often preferred by patients, and thus definitive CCR +/- induction chemotherapy is recommended with resection reserved for residual or recurrent disease. If the larynx is nonfunctional or not salvagable due to advanced T stage of the primary, then laryngectomy is required. For the potentially salvagable larynx, CCR with cisplatin is preferred upfront.

Induction chemotherapy followed by radiation therapy if a complete clinical response is achieved. However, standard of care now includes CCR after induction:

  • If a partial response is obtained after induction chemotherapy (generally defined as >50% response in the primary tumor), then CCR is indicated with surgery reserved for residual disease.

  • If less than a partial response is obtained after induction chemotherapy for advanced disease, then surgical resection is indicated.

  • Adjuvant RT versus CCR after resection is determined based on the presence or absence of pathologic high risk features as discussed previously with early stage disease

Another acceptable option is definitive, cisplatin-based CCR for advanced stage disease (M0):

  • If neck disease is persistent or found in follow-up, then neck dissection is indicated to surgically manage the neck.

  • If residual disease is found at the primary site after initial CCR, then surgical resection is indicated at that time with management of the neck as indicated by surgical findings.

Other options for advanced disease other than laryngectomy and neck dissection as indicated include:

  • Single modality RT if the patient is not a candidate for CCR or Induction chemotherapy with reassessment after induction (adequate response generally 50% shrinkage at primary tumor site).

  • After induction chemotherapy, definitive RT or CCR should be given if an adequate clinical response was achieved after induction therapy.

  • Surgical resection is utilized for any residual or recurrent disease after either CCR or RT.

Laryngectomy upfront can be performed for locally advanced disease. If resection is done first, then adjuvant therapy depends on the surgical pathology findings, as above. If none or only one lymph node positive that is without adverse features, then single modality RT can be considered. However, if adverse features are present, CCR or RT should be given adjuvantly. CCR is preferred based on randomized data when ECS or a positive margin is found.

5. Nasopharyngeal (NPC):

Early stage NPC (see Table II), defined as T1N0 disease, can be treated with definitive RT alone to the primary tumor and with lower doses to the neck, even though clinically uninvolved.

For intermediate stage disease, including T1N1-3 or T2-4, combination therapy with chemotherapy and radiation has superior survival rates. Intergroup trial 0099 demonstrated the improved survival rates with combination therapy in higher stage disease. However, patients’ ability to receive the additional chemotherapy after completing CCR was diminished due to the significant morbidity associated with combined therapy.

Thus, giving the chemotherapy alone as induction therapy followed by CCR can be done to increase delivery rates of the entire treatment schedule. CCR using cisplatin is preferred in this setting, but carboplatin can be utilized if necessary due to patient factors. If residual neck disease is found after CCR, then neck dissection is indicated.

  • Induction: cisplatin 80 mg/m2; day 1 and 5-fluorouracil 1000 mg/m2;/day 96-hour continuous infusion every 28 days x 3 cycles.

  • CCR using cisplatin 100 mg/m2; day 1 every 21 days during concomitant radiotherapy.

  • Supportive care includes forced hydration, mannitol 12.5g IV on cisplatin days, aggressive electrolyte repletion.

If M1 disease at presentation, then combination chemotherapy incorporating a platinum agent is recommended. If limited metastatic disease and/or low tumor burden, then CCR can be considered. In addition, CCR can be given if radiation to a symptomatic site is indicated. The take home message from NPC is that this is largely a non-surgically managed cancer. Moreover, due to early propensity for distant metastatic disease, chemotherapy plays a significant role.

6. Occult primary

Multiple treatment options exist, including surgical resection, definitive CCR versus single modality RT, or induction chemotherapy followed by CCR, or RT alone. If non-surgical management is chosen initially, neck dissection may be necessary based on clinical response to primary therapy. Depending on findings after neck dissection, further therapy versus observation is indicated.

  • For N1 disease without ECS, RT alone to potential primary sites based on pattern of lymph node spread or observation is appropriate.

  • If N2-3 disease on neck dissection without ECS, then RT to potential primary sites and neck versus CCR versus RT to the neck only can be considered but limited data exists to show any survival benefit to radiating every possible primary site.

  • If ECS is noted, then CCR is recommended with radiation to likely primary sites based on pattern of nodal spread as well as to the bilateral neck.

What other therapies are helpful for reducing complications?

Treatment for head and neck cancer involves multimodality therapy which includes RT, surgery, and/or chemotherapy. Each modality has acute and late side effects which are graded according to the CTCAE grading system. Due to the risk for significant treatment morbidity, we recommend that these patients be seen weekly by a physician or physician-extender until CCR is over and/or acute symptoms resolve. Regular follow-up to assess for late toxicities is also necessary.

Pretreatment, head and neck cancer patients should undergo a complete evaluation which includes oral care instruction, nutritional assessment, swallowing assessment and instruction on swallowing and neck exercises, and psychosocial evaluation.

Pretreatment oral care includes dental assessment with restorative work and periodontal treatment as indicated. Diseased teeth should be removed. Oral hygiene should be taught and continued during therapy. Oral hygiene includes:

Salt and soda rinses 8-10 times per day with salt and bicarbonate warm water solution.

Soft bristle tooth brushing and flossing until pain from therapy prevents.

Infrequent denture wearing.

Topical fluoride with 1% sodium fluoride gel application every other day.

Acute side effects

Chemotherapy supportive care

Chemotherapy-induced nausea and/or vomiting, diarrhea, electrolyte imbalances, and possibly even nephrotoxicity with use of cisplatin can occur. Supportive care templates should exist for these side effects. Cisplatin is regarded as a highly emetogenic chemotherapy agent, and thus, standard antiemetic prescriptions should be given when high doses such as 100 mg/m2 are used. With highly emetogenic chemotherapy, the following antiemetic regimen is recommended:

  • Aprepitant 125 mg PO day 1, 80 mg po days 2 and 3.

  • 5-HT3 antagonist before chemotherapy (doses vary depending on which agent is chosen) and PO on days 2 and 3.

  • Dexamethasone 12 mg IV pre-chemotherapy on day 1 and 8 mg PO on days 2 and 3.

As needed antiemetic scripts should be given to the patient for prochlorperazine, promethazine, or similar agent commonly used for chemotherapy-induced nausea and vomiting. The same regimen for nausea and vomiting prophylaxis should be used with TPF chemotherapy as it is considered highly emetogenic, both because three agents are being used as well as a relatively high dose of cisplatin at 75 mg/m2.

With cisplatin chemotherapy, intravenous fluid administration should be given to reduce the likelihood of nephrotoxicity. A one liter bolus of normal saline (plus or minus 12.5 grams intravenous mannitol) is recommended before and after high-dose cisplatin administration (75 mg/m2 or higher).

With TPF (docetaxel, cisplatin, 5-fluorouracil) induction chemotherapy, myelosuppression rates exceed 20%, and thus, growth factor support should be given. Antibiotic prophylaxis is commonly given, though typically head and neck patients receiving induction chemotherapy fall into an intermediate risk group secondary to anticipated neutropenia lasting 7-10 days.

Cetuximab is a monoclonal antibody against the EGFR receptor and is known to cause anaphylaxis in some patients with rates as high as 20% in some regions. Because of this life-threatening reaction, a test dose is recommended.

Typically the severe reaction will occur within the first 3-5 minutes of giving cetuximab, even with the first dose, due to pre-existing IgE antibodies in patients’ serum. Also recommended is a standard operating procedures protocol for the chemotherapy nurses administering cetuximab. An anaphylaxis kit should be at the bedside and staff should watch closely for signs and symptoms of a drug-reaction, including flushing, urticaria, shortness of breath, hypotension, and anaphylaxis.

Classic side effects of cetuximab therapy are listed below with suggested management options:

Rash

Begin prophylactic tetracycline antibiotics using either minocycline 100 mg by mouth daily or doxycycline 100 mg by mouth twice daily at the start of cetuximab therapy; avoidance of full sun exposure and wearing broad spectrum SPF sunscreen; 1% hydrocortisone cream to the face. Any or all of these methods can be used in combination.

Hypokalemia/hypomagnesemia: aggressive repletion with IV and oral formulations; many patients will require maintenance doses daily.

Infusion reactions

Infusion reactions must premedicate with benadryl IV 30-60 minutes prior to infusion. Exact dose is at the prescriber’s discretion. Non-serious infusion reactions can be restarted at 50% rate reduction and with retreatment with antihistamines. Severe infusion reactions necessitate permanent discontinuation of cetuximab.

Toxicities of immune checkpoint inhibitors

The most common adverse events of immune checkpoint inhibitors are fatigue, low-grade nausea, and anorexia. No standard premedication is given.

In a minority of cases, patients may develop autoimmune toxicities affecting specific organs. Clinical syndromes include pneumonitis, thyroiditis, colitis, hepatitis, dermatitis, nephritis, hypophysitis, endophthalmitis, and others.

Depending on the severity of the toxicity, treatment is either withheld or permanently discontinued. There are no dose reductions. The mainstay of management is corticosteroids. A typical approach might be prednisone 1 mg/kg equivalent daily. Once toxicity has improved to grade 1 in severity, a 4-6 week taper is initiated. Only if symptoms remain improved after taper completion is the immunotherapeutic agent re-initiated. In some instances, other immune-modulating agents such as TNF inhibitors may be warranted. Consultation with appropriate medical services (endocrinology, pulmonary medicine, gastroenterology, nephrology) for assistance with diagnosis and treatment may be considered. For patients with treatment-related hypothyroidism and adrenal insufficiency, replacement with levothyroxine and hydrocortisone is given.

Mucositis

Both chemotherapy and/or radiation therapy can cause mucositis acutely with an incidence of 80% during therapy. Mucositis occurs secondary to mucosal damage and sloughing. Mucositis should be aggressively managed to prevent significant weight loss and dehydration with further complications.

  • Management of mucositis includes adequate pain control with pain medications as necessary, which will often include narcotics or transdermal pain patches.

  • Liquid formulations are often required for PEG tube administration or increased ease of swallowing.

Ketoprofen paste for topical application can be given. Mouth rinses can be gargled or swallowed and contain local anesthetics such as lidocaine, benzocaine, or tetrocaine to help ease discomfort. In addition, these mouth rinses can also be formulated to contain antifungal agents if oral candidiasis develops.

Hot temperature or spicy foods, acidic foods, alcohol and tobacco should be avoided as these worsen the discomfort of mucositis. Caphasol type medications help mucositis discomfort. Ice chips should be eaten during 5-fluorouracil bolus administration to decrease the severity of mucositis.

Phlegm

Secretions may become thick and difficult to manage due to irritation of the mucosa from therapy. This irritation causes overproduction of secretions. Sleeping with the head of the bed elevated may be required to avoid pooling of secretions at night. A suction catheter for home use can be obtained. Warm, moist showers and a room humidifier can help loosen secretions. Avoid sugar and milk as these substances worsen thick mucous production.

A scopolamine patch, atropine drops, or hyoscyamine tablets for their anticholinergic properties can be prescribed but may be too drying for some patients. Alternatively, antihistamines for their drying side effect can be used. Mucolytics with guaifenesin help thin the secretions to make them more manageable. Cough suppressants can be prescribed for throat irritation and intravenous fluids may even be necessary for support.

Dermatitis

Radiation can induced a localized dermatitis ranging from erythema or dry peeling skin to moist desquamation, or ulceration and/or necrosis. If severe dermatitis develops, RT should be held. For moist areas, a drying paste can be used. Gel formulations are more appropriate for seborrheic areas and creams for affected skin outside of skin folds.

For superinfection of areas of desquamation, antibiotic cream can be applied and systemic antibiotics may be necessary, depending upon severity of the infection. Antiseptic creams with a chlorhexidine base, hydrophilic dressings, and anti-inflammatory emulsions formulated with trolamine or hyaluronic acid cream are all available. Consult with the radiation oncologist regarding the need to hold treatments.

Anemia

Treatment-related anemia can occur frequently. Transfusion of red blood cells is advised if hematocrits drop to the point of causing significant fatigue, decreased performance status, or other significant symptoms. Erythropoiesis-stimulating agents (ESAs) should not be given to this patient population as multiple randomized control trials in the HNSCC patient population have demonstrated a significantly worse overall survival in HNSCC patients treated with ESAs.

Dysphagia

Swallow assessment should be documented prior to therapy. Ongoing evaluation for early signs of aspiration is warranted during therapy by a speech pathologist. After a pre-treatment swallow evaluation, swallow exercises should be continued daily to maintain the functional level. Continued swallowing is preferred throughout therapy. Significant aspiration requires PEG tube insertion.

Xerostomia may contribute dysphagia, particularly once RT finishes. See xerostomia section below for treatment options. Physical therapy should be consulted when treatment finishes so that a rehabilitation program can be prescribed.

Neck exercises will be taught for ongoing prevention of late RT side effects which include fibrosis, trismus, lymphedema and cervical dystonia. Those patients with soft tissue swelling during treatment are at highest risk for radiation fibrosis later. In addition, these patients are at risk of esophageal strictures that can require dilation depending on severity.

Weight loss

Weight loss typically occurs due to a significant decrease in oral nutrition secondary to mucositis and at times, uncontrolled chemotherapy-induced nausea and vomiting or diarrhea.

Generally, a PEG tube should be placed if the patient loses more than 10% of his or her bodyweight during treatment. This can be modified as indicated. PEG tubes can be placed during therapy and treatment does not need to be withheld to place a PEG tube. It is best to schedule tube placement as far from the next scheduled chemotherapy as possible to ensure count recovery.

PEG tubes can be placed in a prophylactic fashion if induction therapy or resection has resulted in significant decrease in the patient’s ability to eat. Studies of prophylactic PEG tube placement show increased rates of long-term PEG-tube dependence but less weight loss during the remaining therapy and fewer hospital admissions for dehydration.

Late side effects

Xerostomia

Xerostomia results from damage to salivary glands during RT. Incidence is around 60% for some degree of lasting xerostomia in patients treated with conventional RT and can lead to other oral complications such as pain, altered taste, increased dental caries and oral infections, as well as reduced quality of life. IMRT is utilized frequently when RT needs to be given to primary tumors near critical structures, such as salivary glands.

Amifostine administration can be considered in patients receiving single-modality RT as an acute and late-preventative xerostomia agent:

  • Amifostine: 200 mg/m2 over 3 minutes once daily 15-30 minutes prior to radiation therapy.

Practical treatments include humidified air, and topical products such as artificial saliva improve comfort. These therapies should be started early to lessen the severity of the xerostomia:

  • Options include Numoisyn™, Oasis® mouthwash or spray, Oral Balance®.

Pilocarpine or cevimeline stimulate cholinergic receptors to increase saliva production and can be prescribed:

  • pilocarpine: 5 mg 3 times/day, up to 10 mg 3 times/day as needed; max 2 tablets/dose.

  • cevilemine: 30 mg 3 times/day.

Avoidance of products which contain sugar should be advised to reduce the incidence of dental caries.

Dysphagia

Dysphagia can occur as a late RT side effect due to the potential development of fibrosis or stricturing. Xerostomia can also contribute to dysphagia. Swallow exercises should be continued daily and early reinstitution of oral intake should be pursued if tube feeds were necessary during therapy.

Physical therapy should be consulted at the start of therapy and again when treatment finishes so that a rehabilitation program can be prescribed. Neck exercises will be taught for ongoing prevention of late RT side effects which include fibrosis, trismus, lymphedema and cervical dystonia. Those with soft tissue swelling during treatment are at highest risk for radiation fibrosis later.

Trismus

Trismus occurs due to radiation-induced damage to tissues and must be treated with physical therapy as it can worsen over time. Stretching of the affected jaw muscles must be performed daily and effective maneuvers include simple neck stretching, maintenance of good posture, and ongoing evaluation with a speech and language therapist. A therabite or dynasplint may ultimately be required.

Lymphedema

Swelling of the face and neck after therapy is caused by radiation damage to tissues and lymphatics. It can occur months to years after therapy and can affect swallowing, phonation, range of motion, and even breathing. Physical therapy with a specialist in lymphedema management is paramount in treating lymphedema to prevent fibrosis and permanent deficits.

Radiation fibrosis with stricturing or stenosis

If full fibrosis occurs, reversal of symptoms is not possible. The best treatment is prevention with daily jaw and neck exercises as directed by a speech and language therapist or with a physical therapist familiar with this patient population. Aggressive lymphedema management is also needed to reduce the development of fibrosis.

Dental complications

Long-term radiation consequences to the oral cavity include dental caries, decay, or even osteoradionecrosis. Regular dental examination should be performed and a daily oral care regimen should be continued. See above for the suggested daily oral hygiene regimen.

Thyroid dysfunction

Hypothyroidism occurs anywhere from 20-50% of the time after undergoing radiation therapy to the neck due to toxic effects received by the thyroid tissue. No threshold dose has been defined that correlates with a higher chance of post-irradiation hypothyroidism. Mean time to onset is between 1-2 years but can be seen at any time after radiation therapy. Efforts center on diagnosis and treatment rather than prevention. Thyroid stimulating level (TSH) should be checked every 6-12 months after treatment that includes neck irradiation.

Osteoradionecrosis of the jaw

Osteoradionecrosis usually occurs in the mandible, though it can occur in the maxilla. Incidence is approximately 5-10%. Symptoms can include bad breath, difficulty chewing, local or systemic infection, pathologic fracture, or trismus. Severity ranges from asymptomatic exposed bone managed conservatively with local care and possibly antibiotics to severe necrosis necessitating bone resection with reconstruction.

Studies demonstrate the highest risk group for developing osteoradionecrosis are those who undergo post-radiotherapy dental extraction. However, the risk for osteoradionecrosis is not eliminated with pre-radiotherapy dental extraction. Patients treated for nasopharyngeal carcinoma have the highest rates of RT-related osteoradionecrosis due to the jaw bones being included in the RT field.

What should you tell the patient and the family about prognosis?

In general, locally advanced, tobacco-related HNSCC have cure rates just under 50%. In HPV-positive tumors in non-smokers, even with locally advanced disease, the cure rate approaches 90%. If HPV-positive, but the patient is still smoking, then the cure rate drops to approximately 70%.

What if scenarios.

Dental evaluations are part of follow-up as radiation can cause dental injury and osteoradionecrosis. In addition, individuals who have had one HNSCC are at risk for second primaries. Thus, heightened surveillance in these individuals is indicated.

Regarding therapy, adjuvant chemotherapy may be difficult to deliver if the patient has already undergone CCR. Thus, it may be appropriate to give this chemotherapy as induction therapy followed by CCR. See discussion of nasopharyngeal carcinoma in above “initial treatment” section as an example.

Follow-up surveillance and therapy/management of recurrences.

Treated patients should have regular follow-up to allow early detection of persistent or recurrent disease. Unless metastatic disease is present, the goal at re-resection should be curative intent. Please also see initial management section. Follow-up after treatment consists of:

General (at any point)

  • Physical, speech and swallow therapy with a THS check every 6-12 months if neck irradiation received.

  • Hearing evaluations as clinically indicated.

  • Alcohol and tobacco cessation counseling.

  • Regular dental evaluations, particularly if oral cavity primary or mouth irradiation was received.

  • Some recommend following EBV titers post-therapy for nasopharyngeal carcinoma, but the need for this step is controversial.

Year 1

  • Clinical exam every 1-3 months, baseline imaging within 6 months of therapy.

  • TSH check every 6-12 months if neck irradiation received.

  • Of note, for oropharyngeal, hypopharyngeal, glottic larynx, supraglottic larynx, and nasopharyngeal primaries, follow-up imaging only needs to be obtained if the original stage was T3/4 or N2/3. Imaging should include a neck CT 3 months after completing concomitant chemoradiotherapy and then every 6 months for 3 years. Chest imaging is only as indicated. If a PET/CT scan is obtained, it should not be obtained before 10 weeks after therapy to lower the chance for a false-positive result.

Year 2

  • Clinical exams every 2-4 months.

  • Neck CT every 6 months for 3 years.

Years 3-5

  • Clinical exams every 4-6 months during years 3-5.

  • Neck CT every 6 months for first 3 years.

After 5 years

  • Follow-up exams every 6-12 months, with imaging obtained as suggested by symptoms.

PET/CT has been shown to be a reliable method for evaluating disease status after treatment when clinical exam suggests a complete response to therapy. However, integrated PET/CT should not be obtained before 10 weeks after completing therapy, as PET/CT after 10 weeks is both sensitive and specific. Older literature may report lower than acceptable results but likely utilized PET alone, rather than integrated PET/CT.

Any patient with residual disease or imaging that suggests progression of disease after initial therapy should undergo further evaluation with either FNA or neck dissection. Lymph nodes larger than 1cm and/or PET positivity and/or necrotic lymph nodes are suspicious for recurrence or persistent disease. It should be noted that salvage surgery after prior operations or CCR has a much higher risk of both early and late complications, such as delayed wound healing, skin necrosis, fistula formation, or more extensive operations with higher morbidity.

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