Head and Neck Cancer
by I. Athanasiadis, M.D., Medical Oncologist

Introduction

Head and neck cancer is a term used collectively for malignant tumors arising in the area of head and neck. It includes tumors related to distinct primary sites, usually with a variety of presenting symptoms and challenges in treating them. The head and neck cancers though, share common biology and natural course, with notable exceptions, such as nasopharyngeal carcinoma.

Usually, such tumors are closely related to tobacco and alcohol use, but viruses have a striking role in some forms of head and neck cancer. Restricting the tumor within its region is critical for cancers arising in the area of head and neck, so surgery and radiation therapy are fundamental in successful treatment of the primary disease.

 

Epidemiology-biology

Traditionally, head and neck cancers present in heavy smokers, usually with poor oral hygiene and in most cases carrying a long history of alcohol abuse. Other health conditions affecting the patient are usually an important factor, and the head and neck cancer patient is facing a complex pattern of competing risks, cardiovascular disease, peripheral arterial disease and other primary cancers, characteristically lung cancer and bladder cancer. A long term successful course for these patients requires meticulous balance of the competing risks; delayed consequences of therapies along with evolution of the comorbid conditions carry a heavy burden in the long term management of the survivors of head and neck cancer.

Over the years viruses have come to represent a significant cause of cancer in head and neck. The Ebstein Barr Virus (known as EBV) is a proven cause of nasopharyngeal cancer in endemic areas. It has been closely connected to the epidemic of nasopharyngeal carcinoma in Southeastern China and Taiwan, where it represents a major source of cancer morbidity, not resulting though in major mortality figures because of effective therapy resulting in eradication of the disease and cure for most of the patients. The Mediterranean basin is also characterized by increased prevalence of nasopharyngeal cancer.

Recently, a major shift in head and neck cancer epidemiology has been documented, involving the Western countries and almost exclusively for males. The stereotype of the head and neck cancer patient described above is shifting, mostly because of successful anti-tobacco campaign for many countries.

Over the last 20 years, a sharp increase in the number of cases of oropharynxeal cancer has been noted. The surge is most striking for younger patients who do not smoke and do not have a history of alcohol abuse. Disease control and survival outcome was definitely improved compared to historical controls and it was evident that we are facing a new disease entity.

The role of HPV in the pathogenesis of these tumors was unequivocally proven and currently there is a strong recommendation that HPV status for all cases of oropharyngeal cancer should be part of the initial evaluation, even though treatment decisions, at least for the time, should not be influenced by the HPV status.

 

Symptoms

Usually patients either have symptoms related to the primary disease or with a mass in the neck. Symptoms which should not be ignored include hoarseness, oral ulceration, painful swallowing ("odynophagia"), nasal bleeding ("epistaxis"), unusual recurring headache and earache. Evaluation of persisting symptoms should be undertaken by an experienced head and neck surgeon.

 

Diagnostic and Staging procedures

A neck mass should be evaluated with high suspicion and any diagnostic intervention should be performed by a specialist since inappropriate maneuvers in the neck could possibly harm the subsequent surgical treatment. Also, a complete endoscopy of pharynx, larynx and the esophagus should be considered for patients carrying the risk of coexisting second primary cancers. Finally, confirmation of the diagnosis is always required with an appropriately performed biopsy.

Advanced cases should undergo Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scanning of the head and neck. The therapeutic strategy should be decided by a tumor board where all the involved specialties, most notably the ear-nose-throat (ENT) surgeon, a radiation oncologist and a medical oncologist should discuss and decide the primary therapy. Also, a dental evaluation and the appropriate therapeutic intervention should be completed before application of therapy.

Delivering a state of the art treatment for head and neck cancer requires a coordinated team of medical and non medical disciplines and should be undertaken only by centers with documented experience in the field.

 

Surgical therapy

Appropriate treatment of a primary head and neck cancer should be decided by a team including all the involved specialties and should be undertaken by a team with documented experience in the field. Ancillary services including plastic surgery and reconstruction, dental prosthetics and speech pathology are essential part of a quality team. Organ and function preservation are essential and should always be a goal, as long as the primary goal of cancer control is not compromised.

Treatment for each primary site and each patient should be individualized. Elective neck dissection of the non involved neck is decided depending on the risk of involvement.

Early cancers with minimal invasion could be treated with surgery only, while more advanced cases or cancers associated with lymph node involvement are treated after the operation with radiation therapy.

In case of positive surgical margins of resection (i.e. where cancerous tissue reaches up to and including the marging of the removed tissue) or involvement of lymph nodes beyond the wall of the node (extracapsular involvement), radiation therapy is delivered after the operation. For some patients, this is combined with Cisplatin chemotherapy, to make tumor cells respond better to radiation.

 

Radiation therapy

Radiation therapy is a curative local therapy as a single therapy for early head and neck cancers. It is more applicable for early tumors of the vocal cords where cure is achieved for most patients with larynx and voice preservation.

It is less attractive for lesions in the bottom of the mouth where the impact to the normal bone structures is prohibitive, since bone necrosis is a risk for higher doses of radiation therapy.

Traditionally, before the introduction of chemotherapy, advanced tumors were treated with a combination of surgery and radiation therapy. Currently, with the exception of early cancers, a combined strategy including organ preserving surgery, radiation therapy and chemotherapy along with novel targeted agents is applied to medically fit patients with advanced disease. The appropriate sequence is individualized and ideally it should be discussed and decided by a combined modality team at the time of diagnosis. Integrity and precision of the primary therapies is crucially essential, which is translated to the fact that the main opportunity for cure is offered at the initial presentation and not at the time of recurrence.

Quality of the applied therapy also depends on the precision and intensity of the delivered radiation dose. All the involved specialties exhibit a striking progress, but the Radiation Oncology field has undergone breathtaking transformation over the last two decades. The application of cutting edge technology and precision targeting in radiation therapy has vastly transformed the field. Especially for head and neck cancer, identification of the most appropriate establishment for quality care is crucial. As of 2013, it is extremely important that radiation therapy for head and neck cancer is applied using advanced machinery and precision targeting. Simulation of the radiation therapy to be delivered is prepared on Computed Tomograph (CT) images of the targeted area. The experience of the radiation oncologist in the application of novel technology is an important issue; otherwise novelties in therapy could have the opposite effect.

Also, the delivery of concurrent sensitizing chemotherapy or targeted therapy with radiation therapy is improving cancer control and survival. This makes tumor cells more sensitive to radiation therapy. The requirement for appropriate and timely supportive care is fundamental in the treatment of the primary disease and the active involvement of a medical oncology team with expertise in head and neck cancer is coordinating the therapeutic effort and consolidating efficacy and safety.

 

Chemotherapy

Chemotherapy has been moderately active for recurrent or metastatic head and neck cancer and symptom control along with prolongation of survival has been documented.

The most active combination, representing the backbone of any further development, has been the combination of Cisplatin and infusional 5-Fluorouracil, known as the PF regimen. A classic agent with documented activity has been single-agent methotrexate, still applicable today. The taxanes Paclitaxel and Docetaxel have offered striking responses and represent a real progress, especially for weekly Paclitaxel in combination with Carboplatin.

The effect of chemotherapy in previously untreated patients has been spectacular, demonstrating objective responses for most of the treated patients and even complete responses in 20-30% of the treated patients. This observation instigated studies of chemotherapy administered before the local therapy for advanced cases, a principle described with the term neoadjuvant or induction chemotherapy.

As of today, chemotherapy before the main treatment (called neoadjuvant therapy) does not represent a standard approach for squamous cell carcinoma of the head and neck. It is selectively administered for locally advanced cases with bulky disease. Studies with neoadjuvant chemotherapy are underway aiming individualization of local therapy in an attempt to de-escalate therapy for favorable patients, but this is still an experimental approach. In the selected cases where neoadjuvant chemotherapy is applied, the combination of Docetaxel, Cisplatin and infusional 5-Fluorouracil, known as TPF is the accepted standard. It has demonstrated survival benefit in treated patients, along with an improved toxicity profile, compared to Cisplatin and infusional 5-Fluorouracil (PF).

Induction chemotherapy is also an established therapy for laryngeal cancer, with a proven benefit in larynx preservation. Even though the original publication of the "larynx preservation trial" (under the name RTOG-9111) claimed higher rates of larynx preservation for concurrent Cisplatin and radiotherapy, mature results of the study have demonstrated higher survival rates for patients undergoing induction compared to concurrent chemotherapy, keeping induction TPF as a validated option for advanced laryngeal cancer.

Chemotherapy administered concurrently with radiation therapy has demonstrated a radiosensitizing effect (increase tumor cells response to radiation), which has been translated to improved local tumor control and survival in a series of randomized trials. Currently, radiation therapy for advanced squamous cell carcinoma of the head and neck administered as the primary therapy, and should always be combined with chemotherapy in medically fit patients. Combination of radiotherapy with Cisplatin, either every 3 weeks or in a weekly regimen is the preferred and strongly validated combination. Concurrent chemoradiotherapy is a toxic therapy and should be delivered only by a coordinated team in a center with documented experience in head and neck cancer.

 

Targeted therapies

Targeting a pathway called EGFR (Epidermal Growth Factor Receptor) has been extremely successful in squamous cell carcinoma of the head and neck.

Excluding nasopharyngeal carcinoma, the monoclonal antibody Cetuximab is the accepted standard of care for metastatic disease combined with the chemotherapy combination PF, described above. Also, Cetuximab is a proven radiosensitizer for patients not fit for platinum chemotherapy. Combined with radiotherapy it improves local control and survival, representing an acceptable alternative for radiosensitization.

 

Specific primary sites

Cancer of the larynx

Cancer developing in the vocal cords, described by the term cancer of the glottis is usually presented in early stage and either radiation therapy or limited surgical resection are curative for most of the cases. Early diagnosis and identification of the patients at high risk is crucially important.

More advanced cancers of the larynx are treated with a combined modality, always aiming an organ and function preserving surgery. Initial staging requires a meticulous video endoscopy and appropriate strategies include:

  • Chemoradiotherapy with laryngectomy as a salvage treatment for refractory disease
  • Sequential chemotherapy and radiotherapy with laryngectomy as a salvage in refractory disease
  • Organ and voice preserving surgery with postoperative therapy determined by pathology

 

Cancer of the oropharynx, tonsil and base of tongue

As detailed above, there is increased incidence for these sites because of the epidemy of HPV related cancers. Testing for HPV (either with p16 immunohistochemistry or PCR for HPV) is strongly recommended.

Concurrent chemotherapy with Cisplatin and radiotherapy is usually the most applicable strategy, but organ preserving surgical resection followed by chemoradiotherapy is an equal alternative especially for tonsillar cancer.

 

Cancer of the oral cavity and mobile tongue

Surgical resection is usually the most applicable curative therapy and post-operative radiotherapy or chemoradiotherapy have specific indications

 

Cancer of the nasopharynx

Radiotherapy is extremely effective and is a single modality therapy for early cases. Chemotherapy concurrently with radiotherapy is effective and curative even in advanced cases. Surgery is applied only as a neck dissection for residual disease in the neck for a minority of patients.

Delayed diagnosis and invasion of the base of skull are challenging issues. Timely diagnosis is based on physician awareness, especially in endemic areas. Very advanced cases with large cervical lymph nodes could be selectively treated with induction (neoadjuvant) chemotherapy followed by chemoradiotherapy, although this strategy has not been firmly validated in a randomized phase 3 trial. Recurrences in the base of skull are treated with reirradiation, augmented with Intensity Modulated Radiation Therapy (IMRT) technique or stereotactic radiation.

 

Cancer of the parotid and minor salivary glands

Cancers of the parotid and minor salivary glands present with local disease and histologic picture of adenocarcinoma or other non squamous varieties, different from the squamous cell carcinoma presentation of the other primary sites, discussed so far.

Surgical resection is the foundation of therapy, and radiation therapy is applied after the operation in cases considered to carry a high risk of recurrence. Recurrences are usually local and treated with surgical resection followed by radiotherapy, when applicable. Chemotherapy has limited activity and is used only selectively for distal metastatic disease with occasional responses. Metastatic lung disease in the form of multiple peripheral nodules has a prolonged course and systemic chemotherapy is not mandatory and should be applied with caution.

 

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