The term head and neck cancer refers to a group of biologically similar cancers originating from the upper aerodigestive tract, including the lip, oral cavity (mouth), nasal cavity, paranasal sinuses, pharynx, and larynx. Most head and neck cancers are squamous cell carcinomas, originating from the mucosal lining (epithelium) of these regions.[1] Head and neck cancers often spread to the lymph nodes of the neck, and this is often the first (and sometimes only) manifestation of the disease at the time of diagnosis. Head and neck cancer is strongly associated with certain environmental and lifestyle risk factors, including tobacco smoking, alcohol consumption, UV light and occupational exposures, and certain strains of viruses, such as the sexually transmitted human papillomavirus.[2] These cancers are frequently aggressive in their biologic behavior; patients with these types of cancer often develop a second primary tumor.[2] Head and neck cancer is highly curable if detected early, usually with some form of surgery although chemotherapy and radiation therapy may also play an important role.
Classification
Head and neck squamous cell carcinomas (HNSCC's) make up the vast majority of head and neck cancers, and arise from mucosal surfaces throughout this anatomic region. These include tumors of the nasal cavities, paranasal sinuses, oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx.
Oral cavity
Main article:
Oral cancerSquamous cell cancers are common in the oral cavity, including the inner lip, tongue, floor of mouth, gingivae, and hard palate. Cancers of the oral cavity are strongly associated with tobacco use, especially use of chewing tobacco or "dip", as well as heavy alcohol use. Cancers of this region, particularly the tongue, are more frequently treated with surgery than are other head and neck cancers.
Surgeries for oral cancers include
- Maxillectomy (can be done with or without Orbital exenteration)
- Mandibulectomy (removal of the mandible or lower jaw or part of it)
- Glossectomy (tongue removal, can be total, hemi or partial)
- Radical neck dissection
- Moh's procedure
- Combinational e.g. glossectomy and laryngectomy done together.
The defect is covered/improved by using another part of the body and/or skin grafts and/or wearing a prosthesis.
Nasopharynx
Nasopharyngeal cancer arises in the nasopharynx, the region in which the nasal cavities and the Eustachian tubes connect with the upper part of the throat. While some nasopharyngeal cancers are biologically similar to the common HNSCC, "poorly differentiated" nasopharyngeal carcinoma is distinct in its epidemiology, biology, clinical behavior, and treatment, and is treated as a separate disease by many experts.
Oropharynx
Oropharyngeal cancer begins in the oropharynx, the middle part of the throat that includes the soft palate, the base of the tongue, and the tonsils. Squamous cell cancers of the tonsils are more strongly associated with human papillomavirus infection than are cancers of other regions of the head and neck.
Hypopharynx
The hypopharynx includes the pyriform sinuses, the posterior pharyngeal wall, and the postcricoid area. Tumors of the hypopharynx frequently have an advanced stage at diagnosis, and have the most adverse prognoses of pharyngeal tumors. They tend to metastasize early due to the extensive lymphatic network around the larynx.
Larynx
Laryngeal cancer begins in the larynx or "voice box." Cancer may occur on the vocal folds themselves ("glottic" cancer), or on tissues above and below the true cords ("supraglottic" and "subglottic" cancers respectively). Laryngeal cancer is strongly associated with tobacco smoking.
Surgeries can include partial laryngectomy (removal of part of the larynx) and total laryngectomy (removal of the whole larynx). If the whole larynx has been removed the person is left with a permanent tracheostomy opening and learns to speak again in a new way with the help of intensive teaching and speech therapy and/or an electronic device.
Also anyone who has had a glossectomy (tongue removal) will be taught to speak again in a new way and have intensive speech therapy.
Trachea
Cancer of the trachea is a rare malignancy which can be biologically similar in many ways to head and neck cancer, and is sometimes classified as such.
Most tumors of the salivary glands differ from the common carcinomas of the head and neck in etiology, histopathology, clinical presentation, and therapy, Other uncommon tumors arising in the head and neck include teratomas, adenocarcinomas, adenoid cystic carcinomas, and mucoepidermoid carcinomas.[2] Rarer still are melanomas and lymphomas of the upper aerodigestive tract.
Etiology
Alcohol[3] and tobacco use are the most common risk factors for head and neck cancer in the United States. Alcohol and tobacco are likely synergistic in causing cancer of the head and neck.[4] Smokeless tobacco is an etiologic agent for oral and pharyngeal cancers.[5] Cigar smoking is an important risk factor for oral cancers as well.[6] Other potential environmental carcinogens include marijuana and occupational exposures such as nickel refining, exposure to textile fibers, and woodworking. Cigarette smokers have a lifetime increased risk for head and neck cancers that is 5- to 25-fold increased over the general population.[7] The ex-smoker's risk for squamous cell cancer of the head and neck begins to approach the risk in the general population twenty years after smoking cessation. The high prevalence of tobacco and alcohol use worldwide and the high association of these cancers with these substances makes them ideal targets for enhanced cancer prevention.
Dietary factors may contribute. Excessive consumption of processed meats and red meat were associated with increased rates of cancer of the head and neck in one study, while consumption of raw and cooked vegetables seemed to be protective.[8] Vitamin E was not found to prevent the development of leukoplakia, the white plaques that are the precursor for carcinomas of the mucosal surfaces, in adult smokers.[9] Another study examined a combination of Vitamin E and beta carotene in smokers with early-stage cancer of the oropharynx, and found a worse prognosis in the vitamin users.[10]
Betel-nut chewing is associated with an increased risk of squamous cell cancer of the head and neck.[11]
Recent evidence is accumulating pointing to a viral etiology for some head and neck cancers. [12] Although the DNA of human papillomavirus (HPV) has been detected in the tissue of cancers throughout the head and neck, the most common site for HPV to be associated with head and neck cancer is in the oropharynx (the tonsils and base of the tongue). Some experts estimate that while up to 50% of cancers of the tonsil may be infected with HPV, only 50% of these are likely to be caused by HPV (as opposed to the usual tobacco and alcohol causes). The role of HPV in the remaining 25-30% is not yet clear.[2]
Epstein-Barr virus (EBV) infection is associated with nasopharyngeal cancer.[12] Nasopharyngeal cancer occurs endemically in some countries of the Mediterranean and Asia, where EBV antibody titers can be measured to screen high-risk populations.[12] Nasopharyngeal cancer has also been associated with consumption of salted fish, which may contain high levels of nitrites.
There are a wide variety of factors which can put someone at a heightened risk for throat cancer. Such factors include smoking or chewing tobacco or other things, such as betel, gutkha, marijuana or paan, heavy alcohol consumption, poor diet resulting in vitamin deficiencies (worse if this is caused by heavy alcohol intake), weakened immune system, asbestos exposure, prolonged exposure to wood dust or paint fumes, exposure to petroleum industry chemicals, and being over the age of 55 years. Another risk factor includes the appearance of white patches or spots in the mouth, known as leukoplakia;[2] in about ⅓ of the cases this develops into cancer.
The presence of acid reflux disease (GERD - gastroesphogeal reflux disease) or larynx reflux disease can also be a major factor. In the case of acid reflux disease, stomach acids flow up into the esophagus and damage its lining, making it more susceptible to throat cancer.
Ethnicity may also play a part, with African American men in the U.S. being found to be at a 50% higher risk of throat cancer than caucasian men.
Diagnosis
Symptoms
Throat Cancer usually begins with symptoms that seem harmless enough, like an enlarged lymph node on the outside of the neck, a sore throat or a hoarse sounding voice. However, in the case of throat cancer, these conditions may persist and become chronic. There may be a lump or a sore in the throat or neck that does not heal or go away. There may be difficult or painful swallowing. Speaking may become difficult. There may be a persistent earache. Other possible but less common symptoms include some numbness or paralysis of the face muscles.
Presenting symptoms include
- Mass in the neck
- Neck pain
- Bleeding from the mouth
- Sinus congestion, especially with nasopharyngeal carcinoma
- Bad breath
- Sometimes a sore tongue
- Painless ulcer or sores in the mouth that do not heal.
- White, red or dark patches in the mouth that will not go away.
- Ear-ache.
- Unusual bleeding or numbness in the mouth.
- A lump in your lip, mouth or gums.
- Enlarged lymph glands in the neck.
- If the cancer affects the tongue it may cause some slurring of speech.
- A hoarse voice, which persists for more than six weeks.
- A sore throat which persists for more than six weeks
- difficulty swallowing food,
- change in diet or weight loss,
- any neck lumps which persists for more than three weeks.
- A mouth ulcer that does not heal
Diagnostic approach
A patient usually presents to the physician complaining of one or more of the above symptoms The patient will typically undergo a needle biopsy of this lesion, and a histopathologic information is available, a multidisciplinary discussion of the optimal treatment strategy will be undertaken between the radiation oncologist, surgical oncologist, and medical oncologist.
Histopathology
Throat cancers are classified according to their histology or cell structure, and are commonly referred to by their location in the oral cavity and neck. This is because where the cancer appears in the throat affects the prognosis - some throat cancers are more aggressive than others depending upon their location. The stage at which the cancer is diagnosed is also a critical factor in the prognosis of throat cancer.
Squamous Cell Carcinoma
Squamous cells are the epithelium (tissue layer) that is the surface cells of much of the body. Skin and mucous membranes are squamous cells. This is the most common form of larynx cancer, accounting for over 90% of throat cancer.[2] Squamous Cell Carcinoma is most likely to appear in males over 40 years of age with a history of heavy alcohol use coupled with smoking.
Adenocarcinoma
Adenocarcinoma is a cancer of the columnar epithelium typical of the lower esophagus. It is typical of Barrett's Esophagus but may be at another location. Adenocarcinoma is thought of as a product of Barrett's Oesophagus.
Treatment
General considerations
Improvements in diagnosis and local management, as well as targeted therapy, have led to improvements in quality of life and survival for head and neck cancer patients since 1992[13]
After a histologic diagnosis has been established and tumor extent determined, the selection of appropriate treatment for a specific cancer depends on a complex array of variables, including tumor site, relative morbidity of various treatment options, patient performance and nutritional status, concomitant health problems, social and logistic factors, previous primary tumors, and patient preference. Treatment planning generally requires a multidisciplinary approach involving specialist surgeons and medical and radiation oncologists.
Several generalizations are useful in therapeutic decision making, but variations on these themes are numerous. Surgical resection and radiation therapy are the mainstays of treatment for most head and neck cancers and remain the standard of care in most cases. For small primary cancers without regional metastases (stage I or II), wide surgical excision alone or curative radiation therapy alone is used. More extensive primary tumors, or those with regional metastases (stage III or IV), planned combinations of pre- or postoperative radiation and complete surgical excision are generally used. Survival and recurrence risk has been roughly equivalent between surgical and radiation-based approaches, with a head-to-head comparison in only one randomized study[citation needed]. More recently, as historical survival and control rates are recognized as less than satisfactory, there has been an emphasis on the use of various induction or concomitant chemotherapy regimens.
Patients with head and neck cancer can be categorized into three clinical groups: those with localized disease, those with locally or regionally advanced disease, and those with recurrent and/or metastatic disease. Comorbidities (medical problems in addition to the diagnosed cancer) associated with tobacco and alcohol abuse can affect treatment outcome and the tolerability of aggressive treatment in a given patient.
Many different treatments and therapies are used in the treatment of throat cancer. The type of treatment and therapies used are largely determined by the location of the cancer in the throat area and also the extent to which the cancer has spread at time of diagnosis. Patients’ also have the right to decide whether or not they wish to consent to a particular treatment. For example, some may decide to not undergo radiation therapy which has serious side effects if it means they will be extending their lives by only a few months or so. Others may feel that the extra time is worth it and wish to pursue the treatments.
Surgery
Surgery as a treatment is sometimes used in cases of throat cancer. In such cases an attempt is made to remove the cancerous cells. This can be particularly tricky if the cancer is near the larynx and can result in the patient being unable to speak. Surgery is more commonly used to resection (remove) some of the lymph nodes to prevent further spread of the disease.
Radiation therapy
Radiation therapy is the most common form of treatment. There are different forms of radiation therapy. One of newer treatments is Intensity-modulated radiotherapy or IMRT which is able to focus more precisely so that fewer healthy cells are destroyed than was the case with some of the older radiation therapies. IMRT reduces incidental damage to the many important structures of the throat and mouth that may not be involved. However, if the cancer has metastisized or is widespread, the older form of treatment may be the most effective at slowing the progression of the disease. Radiation will generally cause the patient to feel sicker and weaker for several weeks following the treatment, but is a very effective treatment in stopping the disease.
Radiation mask used in treatment of throat cancer
Chemotherapy
Chemotherapy in throat cancer is not generally used to cure the cancer as such. Instead, it is used to provide an inhospitable environment for metastases so that they will not establish in other parts of the body. Typical chemotherapy agents are a combination of Taxol and Carboplatin. Erbitux is also used in the treatment of throat cancer. While not specifically a chemotherapy, Amifostine is often administered intravenously by a chemotherapy clinic prior to a patient's radiotherapy sessions. Amifostine protects the patient's gums and salivary glands from the effects of radiation.
Photodynamic therapy
Photodynamic therapy may have promis in treating mucosal dysplasia and small head and neck tumors.[2]
Targeted therapy
Targeted therapy, according to the National Cancer Institute, is "a type of treatment that uses drugs or other substances, such as monoclonal antibodies, to identify and attack specific cancer cells without harming normal cells." Some targeted therapy used in squamous cell cancers of the head and neck include cetuximab, bevacizumab, erlotinib, and reovirus.
The best quality data are available for cetuximab since the 2006 publication of a randomized clinical trial comparing radiation treatment plus cetuximab versus radiation treatment alone.[14] This study found that concurrent cetuximab and radiotherapy improves survival and locoregional disease control compared to radiotherapy alone, without a substantial increase in side effects, as would be expected with the concurrent chemoradiotherapy, which is the current gold standard treatment for advanced head and neck cancer. Whilst this study is of pivotal significance, interpretation is difficult since cetuximab-radiotherapy was not directly compared to chemoradiotherapy. The results of ongoing studies to clarify the role of cetuximab in this disease are awaited with interest.
Another study evaluated the impact of adding cetuximab to conventional chemotherapy (cisplatin) versus cisplatin alone. This study found no improvement in survival or disease-free survival with the addition of cetuximab to the conventional chemotherapy.[15]
However, another study which completed in March 2007 found that there was an improvement in survival.
The EXTREME (Erbitux in First-Line Treatment of Recurrent or Metastatic Head & Neck Cancer) study is a European multicenter phase III trial to determine whether adding cetuximab improves the impact of platinum-based chemotherapy.
Between December 2004 and March 2007, researchers enrolled 442 patients in 17 countries who had stage III or IV recurrent and/or metastatic SCCHN, and who were not candidates for further surgery or radiation. About half of the patients had cancer in their pharynx (throat), and a quarter in their larynx (voice box), but none in the nasopharynx (upper part of the throat). The patients averaged 57 years of age. Only about 10 percent were women.
Patients were randomly assigned to receive either chemotherapy (222 patients) or the same chemotherapy with cetuximab (220 patients). Chemotherapy consisted of 5-fluorouracil plus either carboplatin or cisplatin.
The trial was led by Jan Vermorken, M.D., Ph.D., of the University of Antwerp in Belgium. Vermmorken as well as other researchers involved in the trial have various relationships with Merck KGaA, Amgen, Oxygene, and sanofi-aventis. Merck KGaA provided funding for the study. (See the protocol summary.)
Results Patients treated with cetuximab reduced their risk of dying by 20 percent, surviving a median of 10.1 months compared to 7.4 months for those receiving chemotherapy alone.
Head and neck cancer clinical trials employing bevacizumab, an inhibitor of the angiogenesis receptor VEGF, are recruiting patients as of March, 2007. No published clinical trial information is available as of that date.
Erlotinib is an oral EGFR inhibitor, and was found in one Phase II clinical trial to retard disease progression.[16] Scientific evidence for the effectiveness of erlotinib is otherwise lacking to this point. A clinical trial evaluating the use of erlotinib in metastatic head and neck cancer is recruiting patients as of March, 2007.
Reovirus is an oncolytic virus that targets RAS activated cancer cells. Trial update on November 2008 showed stable disease or better in the first eight of nine patients with refractory head and neck cancer [3]. Phase II trials are ongoing in England and the USA with phase III trials planned.
Symptoms and Side Effects
Patients with head and neck cancer may experience the following symptoms and treatment side effects[2]
Prognosis
Although early-stage head and neck cancers (especially laryngeal and oral cavity) have high cure rates, up to 50% of head and neck cancer patients present with advanced disease.[17] Cure rates decrease in locally advanced cases, whose probability of cure is inversely related to tumor size and even more so to the extent of regional node involvement. Consensus panels in America (AJCC) and Europe (UICC) have established staging systems for head and neck squamous cancers. These staging systems attempt to standardize clinical trial criteria for research studies, and attempt to define prognostic categories of disease. Squamous cell cancers of the head and neck are staged according to the TNM classification system, where T is the size and configuration of the tumor, N is the presence or absence of lymph node metastases, and M is the presence or absence of distant metastases. The T, N, and M characteristics are combined to produce a “stage” of the cancer, from I to IVB.[18]
Residual deficits
Even after successful definitive therapy, head and neck cancer patients face tremendous impacts on quality of life. Despite marked advances in reconstructive surgery and rehabilitation, intensity-modulated radiotherapy (IMRT) and conservation approaches to certain malignancies, some patients continue to have significant functional deficits.
Problem of second primaries
Survival advantages provided by new treatment modalities have been undermined by the significant percentage of patients cured of head and neck squamous cell carcinoma (HNSCC) who subsequently develop second primary tumors. The incidence of second primary tumors ranges in studies from 9.1%[19] to 23%[20] at 20 years. Second primary tumors are the major threat to long-term survival after successful therapy of early-stage HNSCC. Their high incidence results from the same carcinogenic exposure responsible for the initial primary process, called field cancerization.
Throat cancer has numerous negative effects on the body systems.
Digestive system
As it can impair a person’s ability to swallow and eat, throat cancer affects the digestive system. The difficulty in swallowing can lead to a person to choke on their food in the early stages of digestion and interfere with the food’s smooth travels down into the esophagus and beyond.
The treatments for throat cancer can also be harmful to the digestive system as well as other body systems. Radiation therapy can lead to nausea and vomiting, which can deprive a body of vital fluids (although these may be obtained through intravenous fluids if necessary). Frequent vomiting can lead to an electrolyte imbalance which has serious consequences for the proper functioning of the heart. Frequent vomiting can also upset the balance of stomach acids which has a negative impact on the digestive system, especially the lining of the stomach and esophagus.
Respiratory system
In the cases of some throat cancers, the air passages in the mouth and behind the nose may become blocked from lumps or the swelling from the open sores. If the throat cancer is near the bottom of the throat it has a high likelihood of spreading to the lungs and interfering with the person’s ability to breathe; this is even more likely if the patient is a smoker, because they are highly susceptible to lung cancer. If the respiratory system is unable to bring oxygen into the body, the oxygen deprivation will cause the body's cells to wither and die, causing one to become weaker and sicker.
Others
Like any cancer, metastasization affects many areas of the body, as the cancer spreads from cell to cell and organ to organ. For example, if it spreads to the bone marrow, it will prevent the body from producing enough red blood cells and affects the proper functioning of the white blood cells and the body's immune system; spreading to the circulatory system will prevent oxygen from being transported to all the cells of the body; and throat cancer can throw the nervous system into chaos, making it unable to properly regulate and control the body.
Prevention
Avoidance of recognised risk factors (as described above) is the single most effective form of prevention. Regular dental examinations may identify pre-cancerous lesions in the oral cavity.
When diagnosed early, oral, head and neck cancers can be treated more easily and the chances of survival increase tremendously.
Epidemiology
The number of new cases of head and neck cancers in the United States was 40,490 in 2006, accounting for about 3% of adult malignancies. 11,170 patients died of their disease in 2006.[21] The worldwide incidence exceeds half a million cases annually. In North America and Europe, the tumors usually arise from the oral cavity, oropharynx, or larynx, whereas nasopharyngeal cancer is more common in the Mediterranean countries and in the Far East. In Southeast China and Taiwan, head and neck cancer, specifically nasopharyngeal cancer is the most common cause of death in young men.[22] African Americans are disproportionately affected by head and neck cancer, with younger ages of incidence, increased mortality, and more advanced disease at presentation.[23]
- In 2008, there were 22,900 cases of oral cavity cancer, 12,250 cases of laryngeal cancer, and 12,410 cases of pharyngeal cancer in the United States.[2]
- Seventy-four hundred Americans are projected to die of these cancers.[24]
- More than 70% of throat cancers are at an advanced stage when discovered.[25]
- Men are 89% more likely than women to be diagnosed with, and are almost twice as likely to die of, these cancers.[24]
- Laryngeal cancer incidence is higher in African Americans relative to white, Asian and Hispanic populations. There is a lower survival rate for similar tumor states in African Americans with head and neck cancer.[2]
- Smoking and tobacco use are directly related to Oro-pharangeal (throat) cancer deaths.[26]
- Head and neck cancer increases with age, especially after 50 years. Most patients are between 50 and 70 years old.[2]
References
- ^ NCI factsheet on head and neck cancer
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- ^ Andre K, Schraub S, Mercier M, Bontemps P (1995). "Role of alcohol and tobacco in the aetiology of head and neck cancer: a case-control study in the Doubs region of France". Eur J Cancer B Oral Oncol 31B (5): 301–9. doi:10.1016/0964-1955(95)00041-0. PMID 8704646.
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- ^ Liede K, Hietanen J, Saxen L, Haukka J, Timonen T, Häyrinen-Immonen R, Heinonen O (1998). "Long-term supplementation with alpha-tocopherol and beta-carotene and prevalence of oral mucosal lesions in smokers". Oral Dis 4 (2): 78–83. PMID 9680894.
- ^ Bairati I, Meyer F, Gélinas M, Fortin A, Nabid A, Brochet F, Mercier J, Têtu B, Harel F, Mâsse B, Vigneault E, Vass S, del Vecchio P, Roy J (2005). "A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients". J Natl Cancer Inst 97 (7): 481–8. PMID 15812073.
- ^ Jeng J, Chang M, Hahn L (2001). "Role of areca nut in betel quid-associated chemical carcinogenesis: current awareness and future perspectives". Oral Oncol 37 (6): 477–92. doi:10.1016/S1368-8375(01)00003-3. PMID 11435174.
- ^ a b c Everett E. Vokes (June 28 2006). "Head and Neck Cancer". Head and Neck Cancer. Armenian Health Network, Health.am. http://www.health.am/cr/head-and-neck-cancer/. Retrieved on 2007-09-25.
- ^ Al-Sarraf M. "Treatment of locally advanced head and neck cancer: historical and critical review". Cancer Control 9 (5): 387–99. PMID 12410178.
- ^ Bonner J, Harari P, Giralt J, Azarnia N, Shin D, Cohen R, Jones C, Sur R, Raben D, Jassem J, Ove R, Kies M, Baselga J, Youssoufian H, Amellal N, Rowinsky E, Ang K (2006). "Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck". N Engl J Med 354 (6): 567–78. doi:10.1056/NEJMoa053422. PMID 16467544.
- ^ Burtness B, Goldwasser M, Flood W, Mattar B, Forastiere A (2005). "Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study". J Clin Oncol 23 (34): 8646–54. doi:10.1200/JCO.2005.02.4646. PMID 16314626.
- ^ Soulieres D, Senzer N, Vokes E, Hidalgo M, Agarwala S, Siu L (2004). "Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck". J Clin Oncol 22 (1): 77–85. doi:10.1200/JCO.2004.06.075. PMID 14701768.
- ^ Gourin C, Podolsky R (2006). "Racial disparities in patients with head and neck squamous cell carcinoma". Laryngoscope 116 (7): 1093–106. doi:10.1097/01.mlg.0000224939.61503.83. PMID 16826042.
- ^ Iro H, Waldfahrer F (1998). "Evaluation of the newly updated TNM classification of head and neck carcinoma with data from 3247 patients". Cancer 83 (10): 2201–7. doi:10.1002/(SICI)1097-0142(19981115)83:10<2201::AID-CNCR20>3.0.CO;2-7. PMID 9827726.
- ^ Jones A, Morar P, Phillips D, Field J, Husband D, Helliwell T (1995). "Second primary tumors in patients with head and neck squamous cell carcinoma". Cancer 75 (6): 1343–53. doi:10.1002/1097-0142(19950315)75:6<1343::AID-CNCR2820750617>3.0.CO;2-T. PMID 7882285.
- ^ Cooper J, Pajak T, Rubin P, Tupchong L, Brady L, Leibel S, Laramore G, Marcial V, Davis L, Cox J (1989). "Second malignancies in patients who have head and neck cancer: incidence, effect on survival and implications based on the RTOG experience". Int J Radiat Oncol Biol Phys 17 (3): 449–56. PMID 2674073.
- ^ Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun M (2006). "Cancer statistics, 2006". CA Cancer J Clin 56 (2): 106–30. doi:10.3322/canjclin.56.2.106. PMID 16514137.
- ^ Titcomb C (2001). "High incidence of nasopharyngeal carcinoma in Asia". J Insur Med 33 (3): 235–8. PMID 11558403.
- ^ Gourin C, Podolsky R (2006). "Racial disparities in patients with head and neck squamous cell carcinoma". Laryngoscope 116 (7): 1093–106. doi:10.1097/01.mlg.0000224939.61503.83. PMID 16826042.
- ^ a b Cancer Facts and Figures, [1], American Cancer Society 2002.
- ^ Throat Cancer patient information web page, http://cancer.nchmd.org/treatment.aspx?id=741, NCH Healthcare Systems, 1999
- ^ Reducing the Health Consequences of Smoking: 25 Years of Progress. A Report of the Surgeon General, U. S. Department of Health and Human Services, Public Health Service,Centers for Disease Control and Prevention, 1989.sad
See also
External links
