Overview of Throat Cancer

Overview of Throat Cancer: Symptoms, Diagnosis, & Treatment

Throat Cancer

Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 8/2018

The throat is a hollow tube about 5 inches long that starts behind the nose and roof of the mouth then merges into the windpipe and becomes the esophagus further down the neck.

The majority of throat cancers are related to tobacco and/or excessive alcohol exposure.(1) However, in 25% of cases, cancer of the throat is not associated with any known risk factor. Recent research has demonstrated a connection between viral infection by the human papilloma virus (HPV) and cancer of the mouth and throat.(2)

Treatment for patients with throat cancer is extremely variable and depends on the stage of disease. Surgery or radiation therapy is a highly effective treatment of most early stage cancers. However, the advanced stages of cancer that involve lymph nodes in the neck are more difficult to treat. More than 70% of patients with throat cancer have advanced cancers at the time of initial diagnosis. Recent advances in precision medicine and immunotherapy have led to new treatment options that improve cancer control and survival.(3,4)

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Signs and Symptoms of Throat Cancer

The signs and symptoms of throat cancer can be quite variable. The most common symptoms are a persistent sore throat, trouble swallowing, a lump in the neck, a change in voice, or ear pain. The clinical appearance of throat cancer ranges from symptomatic white patches to large wounds. Cancer of the throat may be preceded by visible lesions that appear as heaped up cells or reddish sores, and are not yet malignant.

Tests Used for Diagnosis of Throat Cancer

Proper diagnosis is important for assuring that the right treatment is selected for a certain cancer. Even when the primary cancer is obvious, a thorough examination is necessary because a second primary cancer is found in 10% to 15% of individuals.

How throat cancer is identified depends on where the cancer is located. Cancers in the upper part of the throat can easily be identified by looking into the mouth. Therefore, some throat cancers are initially detected by dentists. The lower part of the throat, however, is best observed using a thin-lighted tube called an endoscope.

If abnormal tissue is found with any of these diagnostic techniques, the doctor will examine the cells more closely to determine if they are cancerous by performing a biopsy. In this procedure, a small piece of tissue is cut out and examined under a microscope.

Once the primary throat cancer is identified, the margins of the cancer are tattooed using ink in order to facilitate later surgical procedures.

Other techniques may be used to determine the extent to which the cancer has spread to lymph nodes. These techniques include computed tomographic (CT) scans, magnetic resonance imaging (MRI) scans, ultrasound, and positron emission tomography (PET) scans. These tests can often be substituted for lymph node dissection of the neck for detecting spread of cancer.

Cellular Classification of Throat Cancer

Throat cancer is classified based on the type of cells involved. Most throat cancers begin in the squamous cells that line the throat, and are thus called squamous cell cancers. Biopsy specimens may show the cancer to be noninvasive, in which case the term “carcinoma-in-situ” is applied.

The term “leukoplakia” refers to an unusual looking white patch of tissue that can be observed during an examination and cannot be rubbed off. Cells from this unusual tissue are collected and examined under a microscope to determine their origin. Leukoplakia can be caused several factors: (1) a heaped up surface layer of normal cells (hyperkeratosis); (2) an actual early invasive carcinoma, or (3) may represent only a fungal infection, lichen planus, or other benign oral disease.

Staging of Throat Cancer

Staging is the process of identifying how extensive the cancer is. Accurately identifying the stage of a cancer helps determine what treatments will be most effective. Staging is particularly important for determining whether a cancer has spread from its original site to other parts of the body. The four general cancer stages are early, locally advanced, metastatic, and recurrent.

Early Stage Throat Cancer

Stage I, II, and some stage III cancers are referred to as early stage. At these stages, the cancer is small, localized and can typically be treated with surgery or radiation therapy.

Stage I The cancer is no more than 2 centimeters (about 1 inch) and has not spread to lymph nodes in the area.

Stage II The cancer is more than 2 centimeters, but less than 4 centimeters (less than 2 inches) and has not spread to lymph nodes in the area.

Stage III The cancer is considered “early” if it is small and the single involved node can be removed or irradiated with high probability of cure. Stage III cancers that are more extensive than this are considered locally advanced.

Locally Advanced Throat Cancer

Some stage III and all stage IV cancers are referred to as locally advanced. These are large and/or have spread to regional lymph nodes.

Stage III The cancer is more than 4 centimeters, or it is any size with spread to only one lymph node on the same side of the neck as the primary cancer. The lymph node containing the cancer can measure no more than 3 centimeters (just over 1 inch).

Stage IV The cancer has spread to tissues around the lip and mouth. The lymph nodes may or may not contain cancer or the cancer is any size and has spread to more than one lymph node on the same side of the neck as the cancer, to lymph nodes on one or both sides of the neck or to any lymph node that measures more than 6 centimeters (over 2 inches).

Metastatic Cancer has spread to distant sites.

Recurrent Cancer has failed to respond completely to primary treatment or has recurred after a complete response.

Treatment of Throat Cancer

Early stage cancer of the throat is treated with surgery or radiation. More advanced stages and recurrent cancers often require a combination of surgery, radiation and systemic treatment with chemotherapy or precision cancer medicines.

Patients with throat cancer should be evaluated in a medical center that treats many patients with these cancers because effective treatment typically require a multidisciplinary team approach comprised of a head and neck surgeon, a radiation oncologist, a medical oncologist, a pathologist, a dentist, and social services personnel. Evaluation and treatment by an experienced team is essential for optimal treatment and support.

Treatment of Early Stage Cancer of the Throat

Early stage cancers of the throat are small, localized, and highly curable when treated with surgery and/or radiation therapy. Early stage disease includes stage I, II, and some stage III cancers. Stage III cancer can be considered “early” if it is small and involves only a single lymph node, which can be surgically removed or treated with radiation with a high probability of cure.

Patients with throat cancers should consider being evaluated in a medical center that treats many patients with these cancers because cancers of the head and neck often require a multidisciplinary team approach comprised of a head and neck surgeon, a radiation oncologist, a medical oncologist, a plastic surgeon, a dentist, and social services personnel. Evaluation and treatment by an experienced team is essential for determining optimal treatment and support.

Treatment of throat cancer is multi-modality in nature. Because the throat is involved in talking, swallowing, and breathing, the type of treatment is selected to minimized impact on these important functions. Furthermore, treatment may be dictated by how it affects a patient’s appearance, and thus, quality of life.

Surgery: The most common treatment of early stage cancer of the throat is surgery, which results in cure for the majority of patients. In some cases, patients are unable to tolerate surgery or surgery results in significant functional defects, including difficulty in talking or swallowing.(1) In these situations radiation treatment may be a viable alternative to surgery.

Radiation therapy: Radiation therapy has been shown to produce similar results to that of surgery for the treatment of early stage cancers of the throat. Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. Radiation therapy works by damaging the DNA in the cancer cell, thereby disabling the cancer cells from reproducing and growing. The National Cancer Institute recommends that patients undergoing radiation therapy be seen by a radiation oncologist experienced in managing head and neck cancer. The choice of treatment is dictated by the anticipated functional and cosmetic outcome of the treatment options and by the available expertise of the surgeon or radiation therapist. Treatment is individualized for each patient and will take advantage of the latest advances in the delivery of radiation therapy.(1)

Radiation and Surgery: Combined radiation and surgery is standard treatment for stage III throat cancer although not always necessary for stage I, or II disease because it produces superior outcomes to treatment with surgery or radiation alone. Combined therapy is usually reserved for larger cancers of the throat. However, this approach may also be used to treat patients who have cancer detected in the margins of the removed tissue or who have only a narrow margin of normal tissue remaining after surgical removal of the cancer.(2)

Treatment of the Lymph Nodes in the Neck

One of the controversies in treatment of early stage cancers of the throat has been whether or not to routinely treat the lymph nodes in the neck with surgery and radiation therapy. If left untreated, cancers of the throat can ultimately spread throughout the lymph system in the neck. Untreated cancer that has spread to lymph nodes is responsible for cancer recurrence. Thus, identifying whether cancer is present in the lymph nodes in the neck is important for preventing recurrence.

Currently, surgical removal of the lymph nodes in the neck by performing a “lymph node dissection” is the best way to determine whether cancer is present, and may represent effective treatment.3 Experts have debated the benefit of neck dissection in early stage squamous cancers before the disease spreads to the lymph nodes. Neck dissection performed in these circumstances is known as elective neck dissection. The alternative is an approach called therapeutic neck dissection, which involves waiting until cancer in the lymph nodes is detected by biopsy and removing them at that time.

To determine which approach might have the best outcomes, researchers compared survival between 596 patients with early stage cancer who had undergone elective neck dissection and those who had undergone therapeutic neck dissection. Patients in the elective surgery group appear to have better outcomes. These patients experienced improved survival and a delay until cancer recurrence. Patients with early-stage squamous-cell cancer may have better outcomes if they undergo elective surgery to remove lymph nodes in the neck than if they wait for disease to spread to the lymph nodes before removing them.

Treatment of Locally Advanced Cancer of the Throat

Stage III and IV cancers of the throat are referred to as locally advanced. These cancers are large and/or have spread to regional lymph nodes. Treatment of locally advanced throat cancer may consist of surgery, radiation, chemotherapy, immunotherapy, or a combination of these treatment techniques. Precision medicine is the ability to test patients’ cancers for individual differences, mainly at the genetic level, and to make treatment decisions based on those differences. The development of new targeted precision medicines is ongoing and they are increasingly being incorporated into the management of throat cancer.(1,2)

Patients with throat cancer should consider being evaluated in a medical center that treats many patients with these cancers because cancers of the throat often require a multidisciplinary team approach comprised of a head and neck surgeon, a radiation oncologist, a medical oncologist, a plastic surgeon, a dentist, and social services personnel. Evaluation and treatment by an experienced team is essential for determining optimal treatment and support. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment.

It is very important to understand that cancer may spread from where it began in the throat to other parts of the body. When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away and travel through the lymph system or blood. These unseen “micro-metastasis” are responsible for the majority of local and distant cancer recurrences and treatment effective at eradicating these cancer cells is essential for long term survival.

Currently a combination of surgery and post surgical radiation has become the standard treatment for the majority of locally advanced cancers of the throat because the combination of surgery and radiation reduces cancer recurrences and improves survival.(3,4,5) In addition, both preoperative or neoadjuvant, and postoperative adjuvant therapy with chemotherapy,(4) immunotherapy or newer precision drugs appear to improve patient outcomes and should be considered.

Neoadjuvant Therapy

Neoadjuvant therapy refers to treatment that is used prior to surgery in an attempt to reduce the cancer size thereby allowing for more complete surgical removal. The results of current research are conflicting because some but not all studies suggest that neoadjuvant chemotherapy can improve cancer-free survival in locally advanced throat cancers.(6,7,8) Additional clinical studies are ongoing to evaluate various drug regimens in the neoadjuvant setting and patients should request the most recently available information regarding the role of neoadjuvant therapy from their treatment team to understand the potential benefit of using neoadjuvant therapy in their specific situation.

Combined Chemotherapy and Radiation Therapy

Combined modality therapy plays a central role in the management of locally advanced cancer of the throat. Clinical studies have suggested that combining chemotherapy with radiation is better than using either treatment alone for the treatment of locally advanced cancer. Currently, clinical trials are ongoing to determine the optimal chemotherapy combinations and sequencing of radiation.

Patients with locally advanced throat cancer should also consider treatment with combined postoperative, adjuvant radiation therapy and chemotherapy because clinical studies directly comparing post operative radiation with or without concurrent chemotherapy suggest that the addition of chemotherapy delays the time to cancer recurrence and improves overall survival.(9,10,11)

Strategies to Improve Treatment

The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of throat cancer. Patients should discuss the risks and benefits of clinical trials participation with their physician. Areas of active exploration to improve the treatment of locally advanced cancer of the throat include the following:

Epidermal Growth Factor Receptor (EGFR) Inhibitors

EGFR The epidermal growth factor receptor (EGFR) pathway is a normal biologic pathway found in healthy cells. It is involved in regular cellular division and growth. However, certain mutations within the EGFR gene can lead to an overactive EGFR pathway, leading to the development and/or spread of cancer. These cancers are referred to as EGFR-positive. There are several FDA-approved drugs to block the activity of EGFR and slow cancer growth for EGFR-positive cancers. Drugs that act on EGFRs have demonstrated anti-cancer effects in the treatment of throat cancer, and others are in development.

Erbitux® (cetuximab): Monoclonal antibodies are small proteins that are produced in a laboratory to either kill cancer cells directly, activate the immune system to kill cancer cells, or serve as a delivery system for a radioactive isotope or a toxin which kills the cancer cells. Erbitux is a monoclonal antibody that can block EGFRs. In a comparative trial of locally advanced head and neck cancer patients, curative-intent radiation therapy alone was compared with radiation therapy plus weekly Erbitux.(12) patients treated with Erbitux and radiation therapy demonstrated significantly improved progression-free survival.(12,13)

PD-1 Inhibitors: Opdivo® (nivolumab) and Keytruda® (pembrolizumab) belong to a new class of medicines called PD-1 inhibitors that have generated great excitement for their ability to help the immune system recognize and attack cancer. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 enhance the ability of the immune system to fight cancer. Both Opdivo and Keytruda work by blocking PD-1 and have demonstrated impressive activity in the treatment of head and neck cancer.(1,2)

Treatment of Metastatic Cancer of the Throat

Patients with metastatic cancer of the throat have cancer that has spread to distant sites beyond the throat and neck region. Patients with metastatic cancer are usually treated with systemic combination chemotherapy. However, control of the primary cancer and regional lymph node spread through surgery or radiation is as important as controlling the metastases.

Surgery: Surgery is often performed after chemotherapy and radiation therapy to assist in control of local and regional cancer.

Radiation therapy: Sometimes, radiation therapy is used to control both the primary cancer and lymph node spread in patients with metastatic disease. In most instances, chemotherapy is combined with radiation therapy.

Systemic therapy figures prominently in the treatment of metastatic cancer of the throat. Systemic therapy is treatment directed at destroying cancer cells throughout the body, and may include chemotherapy, targeted therapy, or immunotherapy. Most patients with metastatic throat cancer will be treated with systemic chemotherapy or immunotherapy. The goal of administering systemic therapy is to relieve symptoms, delay cancer progression and prolong survival.(1)

Systemic therapy may include one or a combination of drugs. Combination therapy is more commonly utilized due to improved response rates over single drugs.(2) Historically, the most frequently used combination was cisplatin and 5-FU chemotherapy.(1)

PD-1 Inhibitors: Keytruda® (pembrolizumab) is a systemic immunotherapy that belong to a new class of drugs called PD-1 inhibitors that work by helping the immune system recognize and attack cancer cells. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 enhance the ability of the immune system to fight cancer. Keytruda works by blocking PD-1.(3,4)

Results from the KEYNOTE-012 clinical trial led to the FDA granting accelerated approval of Keytruda in some head and neck cancers.(50 The trial evaluated Keytruda in the treatment of 192 patients with metastatic or recurrent head and neck cancers. Overall ~20% of individuals responded to treatment and over 70% of individual responses lasted longer than one year. Keytruda is approved for patients with recurrent or metastatic head and neck squamous cell carcinoma who have experienced disease preogression on or after platinum-containing chemotherapy.

EGFR Inhibitors: The epidermal growth factor receptor (EGFR) pathway is a normal biologic pathway found in healthy cells. It is involved in regular cellular division and growth. However, certain mutations within the EGFR gene can lead to an overactive EGFR pathway, leading to the development and/or spread of cancer. These cancers are referred to as EGFR-positive. There are several FDA-approved drugs that target or block the activity of EGFR and slow cancer growth for EGFR-positive cancers.

Erbitux® (cetuximab): Monoclonal antibodies are small proteins that can locate and target cancer cells in the body that are produced in a laboratory to either kill cancer cells directly, activate the immune system to kill cancer cells, or serve as a delivery system for a radioactive isotope or a toxin which kills the cancer cells. Erbitux is a monoclonal antibody that can block EGFRs. In a comparative trial of locally advanced head and neck cancer patients, curative-intent radiation therapy alone was compared with radiation therapy plus weekly Erbitux.[1] patients treated with Erbitux and radiation therapy demonstrated significantly improved progression-free survival.(6,7)

A study known as EXTREME (ErbituX in first-line Treatment of REcurrent or MEtastatic head and neck cancer) contributed to the FDA approval of Erbitux. The study enrolled patients with metastatic or locally recurrent head and neck cancer who were not candidates for potentially curative treatment with surgery or radiation. Patients were treated with chemotherapy alone or in combination with Erbitux. The combination of chemotherapy and Erbitux improved overall survival and delayed cancer progression.(8)

Combined Chemotherapy and Radiation Therapy: Combined modality therapy can play a central role in the management of metastatic cancer of the throat. A German study involving 226 patients with stage III and IV cancer of the head and neck demonstrated that combining chemotherapy with radiation is more effective than treatment with radiation alone. In this study, 51% of patients who received the combination therapy lived 5 years or more after treatment, compared to 31% with radiation alone. Control of the local cancer was achieved in 66% of the patients on combination therapy, compared to 42% with radiation alone. Also, the rate of cancer recurrence was lower for the patients receiving combination therapy, 58% versus 80% with radiation alone.(2)

Treatment of Recurrent Cancer of the Throat

Patients with recurrent cancer of the throat have residual cancer after initial treatment or a recurrence after an initial complete response. Recurrent throat cancer falls into one of two broad categories: 1) a cancer that returns locally or regionally and 2) metastatic recurrence, or a recurrence at a distant site. Historically, due to the lack of local disease control and the spread of the cancer, patients with metastatic disease tended to have a poor long-term survival rate, however advances in targeted precision medicines and immunotherapies are increasing disease control and providing new treatment options.

Local or Regional Recurrence: The cornerstone of treatment for local or regional recurrence is surgery and/or radiation therapy, and may include systemic therapy. The use of radiation/surgery is influenced by the location and size of the recurrent cancer and prior treatment. If the patient initially received radiation therapy, surgery can sometimes be utilized to control a local or regional recurrence of the cancer. If a patient was initially treated with surgery, radiation therapy or a combination of these modalities may be effective for controlling the cancer recurrence.

  • Surgical resection is used if radiation therapy fails and if technically feasible.(1)
  • Radiation therapy is used, if not previously used in curative doses that preclude further treatment, if surgery fails.
  • Surgical salvage if technically feasible, when surgery fails.
  • Systemic therapy with chemotherapy or other drugs is used for metastatic disease.(2)

Strategies to Improve Treatment

The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of metastatic cancer of the throat will result from the continued evaluation of new treatments in clinical trials.

PD-1 Inhibitors: Keytruda® (pembrolizumab) and Opdivo® (nivolumab) belong to a new class of drugs called PD-1 inhibitors that have generated great excitement for their ability to help the immune system recognize and attack cancer. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 enhance the ability of the immune system to fight cancer. Both Opdivo and Keytruda are immunotherapies that work by blocking PD-1 and have demonstrated impressive activity in the treatment of head and neck cancer.(3,4) Clinical studies are ongoing that combine PD-1 inhibitors with other drugs in order to determine their optimal use in the management of throat cancer.

EGFR Inhibitors: Vectibix® (panitumumab) inhibits cancer cell growth and survival by targeting the EGFR. Although a clinical study indicated that Vectibix did not improve overall survival compared to chemotherapy alone, a subset analysis of this study indicated that patients with HPV-negative head and neck cancer did experience an ijmprovement in survival with the addition of Vectibix to chemotherapy.(9)

References:

  1. Blot WJ, McLaughlin JK, Winn DM, et al.: Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 48 (11): 3282-7, 1988.
  2. D’Souza G, Kreimer AR, Viscidi R, et al.: Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356 (19): 1944-56, 2007.
  3. Seiwert TY, Haddad RI, Gupta S, et al. Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort. Journal of Clinical Oncology. 33, 2015 (supplement; abstract LBA6008).
  4. Bristol-Myers Squibb. First Presentation of Overall Survival Data for Opdivo® (nivolumab) Shows Significant Survival Benefit at One-Year Versus Investigator’s Choice in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck. Available at: http://news.bms.com/press-release/aacr/first-presentation-overall-survival-data-opdivo-nivolumab-shows-significant-survi. Accessed May 1, 2016.
  5. Adelstein DJ, Tan EH, Lavertu P: Treatment of head and neck cancer: the role of chemotherapy. Crit Rev Oncol Hematol 24 (2): 97-116, 1996.
  6. Jacobs C, Lyman G, Velez-García E, et al.: A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10 (2): 257-63, 1992.
  7. Seiwert TY, Haddad RI, Gupta S, et al. Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort. Journal of Clinical Oncology. 33, 2015 (supplement; abstract LBA6008).
  8. Bristol-Myers Squibb. First Presentation of Overall Survival Data for Opdivo® (nivolumab) Shows Significant Survival Benefit at One-Year Versus Investigator’s Choice in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck. Available at: http://news.bms.com/press-release/aacr/first-presentation-overall-survival-data-opdivo-nivolumab-shows-significant-survi. Accessed May 1, 2016.
  9. Mehra R, Seiwert T, Mahipal A, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): Pooled analyses after long-term follow-up in KEYNOTE-012. Proceedings from the 201 annual ASCO meeting. Abstract #6012. Available at: . Accessed June 7, 2016.
  10. Vermorken JB, Stohlmacher-Williams J, Davidenko I, et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. The Lancet Oncology. 2013; 14(8): 697-710.
  11. Curran D, Giralt J, Harari PM, et al.: Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol 25 (16): 2191-7, 2007.
  12. US Food and Drug Administration. Cetuximab (Erbitux). November 7, 2011.
  13. Vermorken J, Stöhlmacher J, Oliner K, et al: Safety and efficacy of panitumumab in HPV positive and HPV negative recurrent/metastatic squamous cell carcinoma of the head and neck: Analysis of the phase 3 SPECTRUM trial. 2011 European Multidisciplinary Cancer Congress. Abstract 25LBA. Presented September 24, 2011.
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