This article focuses on squamous cell carcinoma of the head and neck (SCCHN), the most common malignancy of the head and neck area. Early detection limits morbidity of treatment and increases the chances of a cure. The treatment of SCCHN is often multidisciplinary in nature and provides a model for how multimodality therapy may be applied for optimal patient management. The role of surgery in SCCHN is continually undergoing evolution, and the surgeon’s role in the multidisciplinary treatment of head and neck cancers has changed as more cancers are being treated by chemoradiotherapy. Salvage surgery has become more common, and with it the increased challenges in managing metastatic disease to neck nodes as well as managing failure of organ preservation treatments. Surgeons continue to develop and refine reconstruction techniques to optimize cosmetic and functional outcomes.
Three major modalities are used in treating cancer: surgical resection, radiation therapy, and chemotherapy. Depending on the type of cancer and its stage, patients will be treated with one, two, or three modalities concurrently or consecutively. Surgery and radiation therapy are considered local/definitive therapies, but do not address the issue of distant metastasis, which can only be achieved with chemotherapy.
Patients who have different types of cancer require different types of treatment, and cancers can be divided into two major categories:
Solid tumors such as lung, breast, colorectal, head and neck, and prostate. These cancers are typically treated with a multidisciplinary approach combining surgery, radiation, and chemotherapy.
Hematological malignancies such as leukemia, multiple myeloma, and lymphoma. Treatment is primarily with chemotherapy; radiation therapy plays a limited role. The exception is Hodgkin lymphoma, where radiation plays a key role in tumor control.
This article focuses on squamous cell carcinoma of the head and neck (SCCHN), the most common malignancy of the head and neck area. These malignancies are quite important for the general dentist, who is in a unique position to detect these tumors early. Early detection limits morbidity of treatment and increases the chances of a cure. The treatment of SCCHN is often multidisciplinary in nature and provides a model for how multimodality therapy may be applied for optimal patient management.
General principles: head and neck cancer
SCCHN affects approximately 40,000 patients each year in the United States . Most of the cancers are related to cigarette smoking, although recent studies show that the human papillomavirus (HPV) is likely an important etiologic agent in squamous cell carcinomas of the oropharynx . Under the broad umbrella term of “head and neck cancer” are included cancers of the nasopharynx, oropharynx (tonsil and tongue base), oral cavity (tongue, floor of mouth, gingiva, palate, buccal mucosa, and lips), larynx, and hypopharynx. Management of these malignancies is complex, and a multidisciplinary approach is often required. Many vital structures in the head and neck area are affected by therapy, and organ preservation is a major focus when treating a patient with SCCHN to try to preserve structure and function. Negative sequelae such as difficulty speaking, swallowing, and breathing may be permanent and often result in significant physical and psychologic dysfunction in surviving patients. Therefore, multiple specialties are involved in managing these patients before, during, and after treatment. Those include care providers in the fields of dentistry, physical therapy, speech and swallowing therapy, nutrition, psychiatry, and social work.
Patients with SCCHN can present with a variety of symptoms depending on the site of primary tumor involvement. For example, hoarseness is common in a laryngeal cancer, whereas dysphagia, odynophagia, and a sore throat are more common in oropharyngeal cancer. Other symptoms include difficulty with chewing (primary tumor in the oral cavity) and unilateral or bilateral nasal symptoms (primary tumor in the nasopharynx). The history and symptoms help to locate the site of the primary cancer (especially if the tumor is not easily visualized—such as, base of tongue, pharyngeal or laryngeal lesions). Such symptoms should also raise the index of suspicion for cancer in a smoker. SCCHNs usually present as white or red plaques, ulcers, or masses. Unfortunately, most of the patients will have a neck mass on presentation, representing lymph node metastasis, and often this is the reason the patient sought medical attention in the first place.
Staging for SCCHN starts with an examination under anesthesia performed by a head and neck surgeon in the operating room. This is sometimes called a triple endoscopy as it involves assessment of the larynx, esophagus, and trachea. The goals are to establish a tissue diagnosis via a biopsy, stage the cancer, and rule out the presence of a second primary, a common occurrence in patients with SCCHNs.
Once tissue diagnosis is established, imaging studies are helpful to further delineate the extent of the tumor and its relationship with adjacent structures, and to stage it. Imaging studies such as CT scans, MRI, and PET scans are all useful for staging. MRIs are more helpful for evaluating soft-tissue involvement; CT scans are more beneficial for evaluating bone involvement. PET scanning is a nuclear medicine imaging technique that produces a three-dimensional image or map of functional processes in the body. To conduct the scan, a short-lived radioactive tracer isotope is injected into the patient. This tracer becomes chemically incorporated into a metabolically active molecule and decays rapidly by emitting a positron. The molecule most commonly used for this purpose is fluorodeoxyglucose, a sugar molecule. Cancers may use more energy and glucose than surrounding tissues and therefore appear brighter on the PET scan.
The role of PET scanning in the diagnosis and staging of SCCHN is not well defined, and there is no agreement yet on when and how to use it. In the pretherapy setting, PET scanning is used as a whole-body imaging tool to complete the initial staging of the primary tumor and the neck and to rule out distant metastasis. In the post-therapy setting, however, it often results in a high false-positive rate because of inflammation that is present after surgery and chemoradiotherapy . In some institutions, PET scans are increasingly being used as part of radiation planning, but this is still considered investigational.
The staging system used in SCCHN is the standard T (tumor) N (nodes) M (distal metastasis) ( Table 1 ). The single most important determinant of 5-year survival is the stage of disease at presentation ( Table 2 ).
|– T1: Tumor 2 cm or less in greatest dimension|
|– T2: Tumor size between 2 and 4 cm in size|
|– T3: Tumor greater than 4 cm in size|
|– T4: Tumor invading adjacent structures such as bone, skin, deep muscle of tongue, pterygoid plates, skull base|
|Lymph node involvement|
|– N0: No lymph nodes metastasis|
|– N1: One lymph node involved; 3 cm or less in size|
|– N2a: One lymph node involved; more than 3 cm and less than 6 cm in size|
|– N2b: Multiple ipsilateral lymph nodes involved; none bigger than 6 cm in size|
|– N2c: Multiple bilateral or contralateral lymph nodes involved none more than 6 cm in size|
|– N3: At least one lymph node more than 6 cm in size|
|– M0: No distant metastasis|
|– M1: Distant metastasis present|
|Stage I: TIN0|
|Stage II: T2N0|
|Stage III: T3N0, T3N1, T2N1, T1N1|
|Stage IV: All others|
|Site||All stages (%)||Local: stage I and II (%)||Regional a : stage III and IV, no distant metastases (%)||Distant: stage IV distant metastasis (%)|
|Oral cavity and pharynx||58.8||81.3||51.7||26.4|
Patients who present with early stage disease (ie, stage I and II disease) are typically treated with a single modality approach such as radiation therapy or surgery and typically have a favorable prognosis (see Table 2 ). The choice of therapy depends on site of the primary tumor, the expected functional outcome, and the experience of the doctors at the treating center. On the other hand, most oral cancers are treated with surgery regardless of the stage of the disease.
Unfortunately, approximately 75% of patients with SCCHN present with locally advanced disease (ie, stage III and IV), and will require a multidisciplinary approach that incorporates chemotherapy, radiation, and surgery. This treatment, though still potentially curative, often has serious acute and long-term side effects (eg, mucositis, acute and chronic pain, swallowing dysfunction, shoulder pain and dysfunction, xerostomia and hyposalivation, dental problems, depression, and anxiety). With increasing numbers of survivors, quality of life has become a very important outcome measure (see related article elsewhere in this issue). Up to 40% of these patients with stage III and IV disease will have a recurrence, either locally or at distant sites, and often become noncurable. Management of these patients includes salvage surgery if feasible, re-irradiation, and/or palliative chemotherapy. In general, patients with laryngeal cancer have more potential for curative salvage surgery after chemoradiotherapy failures than patients with cancers at other head and neck sites .
Treatment of locally advanced SCCHN is currently undergoing a fundamental change. In the past, most patients with SCCHN of any stage were treated primarily with surgery. Today, the standard of care for patients with previously untreated, newly diagnosed, stage III and IV disease has been concurrent chemotherapy and radiation therapy. This is based on multiple phase III studies that established chemoradiotherapy as the best therapy in patients who have unresectable disease , laryngeal cancer , and nasopharyngeal cancer and in patients treated postoperatively . However, oral cavity cancer continues to be managed primarily with surgery, regardless of stage. The chemotherapy agent most commonly studied and used is bolus cisplatin. The toxicity of cisplatin is significant, and many patients are not able to tolerate the prescribed high-dose therapy during radiation. Fortunately, identification of molecular targets within cancer cells has led to the introduction of novel biologic agents for treating SCHNN. Indeed, cetuximab (Erbitux, ImClone Systems Inc., Branchburg, NJ), an epidermal growth factor receptor (EGFR) inhibitor, was recently approved by the US Food and Drug Administration (FDA) for the treatment of locally advanced and recurrent head and neck cancer, including oral cavity tumors . Another new approach that is being increasingly used in the clinic is sequential chemoradiotherapy (see below), with encouraging results from recently reported phase III studies . An area of active research in head and neck cancer is the development of cytoprotective agents and techniques that mitigate some of the effects of chemotherapy and radiation (see the articles by Lalla and colleagues and Fischer and Epstein elsewhere in this issue).
Chemotherapy in squamous cell carcinoma of the head and neck
Chemotherapy can be used in the following three settings:
Induction chemotherapy (also known as neoadjuvant chemotherapy or sequential chemotherapy ). This refers to using chemotherapy before definitive therapy (radiation therapy, chemoradiotherapy, or surgery). This is often used in patients with locally advanced disease and in patients with advanced nodal disease (ie, N2 and N3). These patients have a high rate of distant metastases on follow-up.
Concurrent chemoradiotherapy . In this model, chemotherapy is given during radiation therapy usually in an effort to achieve radiosensitization. This is a very common modality of treatment for cancers of the head and neck, esophagus, lung, rectum, and cervix.
Adjuvant chemotherapy , where chemotherapy is given after definitive therapy (surgery and/or radiation). This is done in an effort to eradicate micrometastasis. Adjuvant chemotherapy offers a survival advantage in patients with breast and colorectal cancer. The only setting where adjuvant chemotherapy is given in SCCHN is a primary tumor in the nasopharynx.
All of these delivery methods are used in SCCHN, and treatment is usually dependent on the site and stage of the tumor. Early stage I and II disease is treated with a single modality—either surgery or radiation therapy—whereas more advanced disease is treated with chemotherapy, radiation, and surgery. Concurrent chemoradiotherapy had been the cornerstone in treating locally advanced disease . Recent data support the use of induction chemotherapy, followed by concurrent chemoradiotherapy. Clinical trials have established the superiority of TPF (Taxotere [docetaxel; Sanofi-aventis, Bridgewater, NJ], cisplatin, and 5-fluorouracil) as the best induction regimen. Current trials are under way to compare TPF-based induction regimens with concurrent chemoradiotherapy .
Table 3 provides a summary of the agents typically used in head and neck cancer and the circumstances in which they are used. In general, the classes of drugs most efficacious in treating SCCHN are alkylating agents and antimetabolites. The agent most commonly used is bolus cisplatin every 3 weeks during radiation, and this drug is considered to be the reference drug in SCCHN . The toxicity of cisplatin is significant, and many patients are not able to tolerate the prescribed high-dose therapy during radiation. Toxicities include neuropathy, hearing loss, kidney failure, and bone marrow suppression. Other drugs commonly used are carboplatin, methotrexate, and 5-fluorouracil.
|Agent/regimens||Mechanism of action||Dosage||Benefits||Side effects||Notes|
|Cisplatin||Alkylating agent||75 or 100 mg/m 2 every 3 wk||Survival benefit when combined with radiation||Nausea, vomiting, neuropathy, ototoxicity, renal failure||Could be used both in a curative setting with radiation or for palliation as a single agent for recurrent/metastatic disease|
|Cisplatin (P)||Alkylating agent||Cisplatin: 75 or 100 mg/m 2||Survival advantage when combined with radiation therapy||Nausea, vomiting, neuropathy, ototoxicity, renal failure, mucositis, diarrhea||Could be used in an induction setting, during radiotherapy, or for palliative therapy in recurrent disease|
|5-Fluorouracil (5-FU)||Antimetabolite||5-Fu: 1000 mg/m 2 /qd continuous infusion for 5 d|
|Cisplatin (P)||Alkylating agent||Cisplatin: 75–100 mg/m 2||Survival advantage compared with PF when used in an induction setting||Nausea, vomiting, neuropathy, ototoxicity, renal failure, mucositis, diarrhea, hair loss, bone marrow suppression||Induction chemotherapy regimen in curative settings; FDA approved for unresectable disease|
|Docetaxel (D)||D: microtubule targeting||Docetaxel: 75 mg/m 2|
|5-FU||5-Fu: antimetabolite||5-Fu: 1000 mg/m 2 /d continuous infusion for 4 d|
|Carboplatin (C)||Alkylating agent||Carboplatin: AUC 1.5 weekly||Alternative to cisplatin regimens; very well tolerated||Neuropathy, bone marrow suppression||Used in combination with radiotherapy|
|Paclitaxel (P)||Microtubule targeting||Paclitaxel: 45 mg/m 2 weekly|
|Carboplatin (C)||Alkylating agent||Carboplatin: AUC 6 every 3 wk||Alternative to cisplatin regimens||Neuropathy, bone marrow suppression, hair loss||Used in induction setting with radiation for cure or in palliative setting for recurrent disease|
|Paclitaxel (P)||Microtubule targeting||Paclitaxel: 200 mg/m 2 every 3 wk|
|Methotrexate||Antimetabolite||40 mg/m 2 weekly||Well tolerated, palliative||Mucositis, hepatitis||Used for palliation|
|Docetaxel||Microtubule targeting||30–35 mg/m 2 weekly or 75–100 mg/m 2 every 3 wk||Palliative||Fatigue, fluid retention, bone marrow suppression||Used for palliation|
|Cetuximab||EGFR inhibitor||250 mg/m 2 weekly||Survival advantage in curative setting and can be used for palliation||Skin rash, hypomagnesemia, infusion reaction||Survival advantage in curative setting when combined with radiation. For palliation in patients with platinum-refractory head and neck cancer with a 10% response rate.|
Among the newer chemotherapy agents, taxanes such as docetaxel and paclitaxel appear to have significant activity against SCCHN . Cetuximab, an EGFR inhibitor, was recently approved by the FDA in combination with radiation in the treatment of curable patients with locally advanced disease and as a single agent for patients with cisplatin-refractory disease . Cetuximab is a monoclonal antibody that specifically targets EGFR, which is overexpressed in the majority of squamous cell carcinoma cell lines . There is a clear synergistic activity between these new agents and radiation and chemotherapy.
The trend in chemotherapy in SCCHN is following the advances that have occurred in the treatment of other solid tumors such as lung, breast, and, most notably, colorectal cancer. Results of trials performed in patients with these cancers show that combination therapy with chemotherapy and targeted biological therapy instead of radiation improves outcomes. Bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA), an anti-angiogenesis drug that targets vascular endothelial growth factor (VEGF), for example, is becoming a standard agent used in combination with chemotherapy in lung and colorectal cancer. There is synergistic activity when these biologic agents are combined with standard chemotherapy. In recurrent, refractory, and metastatic SCCHN, current studies are investigating these new targeted agents—especially VEGF inhibitors—used both as single agents and in combination with standard chemotherapy. No VEGF inhibitors are currently approved for treatment of head and neck cancer.