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From OncoLog, January 2012, Vol. 57, No. 1

Graphic: Compass: Quarterly discussion of cancer types for which there is no standard treatment or more than one standard treatment

Locally Advanced Squamous Cell Carcinoma of the Tonsil
Advances in surgical techniques may broaden treatment options for some patients

By Sunni Hosemann

Introduction

The treatment paradigm for squamous cell carcinomas of the palatine tonsil is evolving as a result of new radiation therapy and surgical techniques and, to a lesser extent, a shift in epidemiology.

This discussion is confined to tonsil cancers that are considered locally advanced—all but very small, confined lesions that would be considered stage I and very large or metastatic lesions that would be considered stage IVb or greater. Most patients with tonsil cancer present with these locally advanced, intermediate-stage cancers (stage II–IVa), and these patients’ treatment options are affected by anatomic considerations and complexities in staging that are unique to this disease. As with any type of cancer, individual patient characteristics are an important factor in treatment decisions, and the typical patient profile has changed in recent years.

Changing epidemiology: HPV

In the past three decades, a shift in epidemiology has occurred that can affect treatment considerations for oropharyngeal cancers, and those of the tonsil in particular. At one time, the classic patient presenting with tonsil cancer was an older patient who was a heavy user of alcohol or tobacco and often had comorbidities such as cardiopulmonary disease that could affect treatment decisions. But clinicians are now seeing younger, otherwise healthy patients with tonsil cancer without risk factors related to tobacco or alcohol use; in these cases, human papillomavirus (HPV) infection is the cause.

HPV has now replaced tobacco use as the leading cause of tonsil cancers. Chris Holsinger, M.D., an associate professor in the Department of Head and Neck Surgery at The University of Texas MD Anderson Cancer Center, estimates that 80% of the current population has been exposed to HPV. Of these people, only a minority will develop chronic infections, and some of these will develop a cancer. The latency period between time of infection with HPV and the emergence of a related cancer is unknown, and most experts anticipate a continued increase in the incidence of HPV-related cancers.

Fortunately, it appears that HPV-related tonsil cancers respond more favorably to treatment than do tobacco- or alcohol-related tonsil cancers. According to David Rosenthal, M.D., a professor in the Department of Radiation Oncology, studies have shown that patients whose oropharyngeal tumors tested positive for HPV had a longer overall survival than those whose tumors tested negative for the virus. While he noted that HPV status has not yet changed standard treatment recommendations, Dr. Rosenthal believes it will drive much of the research in this area.

Graphic: Squamous cell carcinoma of the tonsil: treatment options

Although HPV status does not necessarily affect treatment decisions, Dr. Holsinger said the younger age of patients with HPV-related cancers should be considered. “Chemoradiation therapy is effective, but it is associated with significant longterm toxicities,” he said. “Long-term toxicities were a lesser concern in the prototypical patient of the past who presented with this cancer at an advanced age but are a greater concern as we consider the younger population of patients presenting with this cancer.”

Anatomic factors

If tonsil cancer spreads locally, it often does so to the tongue, soft palate, or nasopharynx. Because of the tonsils’ proximity to lymphatics, tonsillar neoplasms often spread to lymph nodes in the neck and manifest as cystic masses.

The anatomic location of the tonsils is additionally important because of the delicate nature of the area. Vital functions such as swallowing and breathing as well as quality-of-life considerations such as speech and appearance may be threatened by the cancer itself and by its treatment.

Treatment strategies for tonsil cancers have evolved over time, in large part owing to a quest for treatment that is less disruptive to these functions. Until the 1990s, the standard treatment for these cancers was open dissection, often involving the mandible and often requiring at least a temporary tracheostomy tube and perhaps a gastrostomy tube as well. When radiation therapy was shown to achieve similar outcomes with less morbidity and less functional disruption, it became the preferred treatment. However, radiation therapy is not without side effects and may permanently affect swallowing function.

Staging

Stage II–IVa tonsil cancers are those classified as T1 N1–2 M0 or T2–4a N0–2 M0 using the American Joint Committee on Cancer staging system. About 80% of patients with locally advanced tonsil cancer present with T1–2 disease and 20% with T3–4a disease.

According to Dr. Holsinger, it is important to understand some of the nuances of the American Joint Committee on Cancer staging system for tonsil cancers when considering treatment options. Within a given stage, the clinical presentation of tonsil cancers varies widely, and thus appropriate treatment choices vary also. Therefore, stage is not a very helpful determinant of treatment choice.

As an example, Dr. Holsinger cited stage IVa disease, which includes large tumors with little or no lymph node involvement (T4a N0 and T3 N1) as well as smaller tumors with significant nodal involvement (T1 N2b and T2 N2a). At least some patients presenting with the smaller stage IVa tumors might be candidates for endoscopic surgery, as described below, while larger stage IVa tumors would preferentially be treated with radiation therapy and chemotherapy. The sequence in which these treatments are given varies and is determined on an individual basis.

Treatment options

According to Merrill Kies, M.D., a professor in the Department of Thoracic/Head and Neck Medical Oncology, the optimal treatment sequence for a given patient with tonsil cancer should be determined by a very thorough pretreatment evaluation and a multidisciplinary consultation that includes medical, radiation, and surgical oncologists whose goal is to achieve cancer control with optimal functional outcomes. The decisions weighed for a given patient are whether transoral surgery is feasible and, if not, whether chemotherapy and radiation will be given concurrently or as induction chemotherapy followed by radiation therapy. The factors that determine the best approach include the size and location of the primary tumor, the patient’s performance status, and the extent of the disease.

Definitive chemoradiation

Radiation therapy with concurrent cisplatin-based chemotherapy is the standard initial treatment for patients with locoregionally advanced, nonmetastatic tonsil cancer who have larger primary tumors (T3-4). At MD Anderson, intensity-modulated radiation therapy or proton therapy is used.

Because chemotherapy acts as a sensitizer for radiation, their concurrent use optimizes local disease control.

Surgery

Radiation with concurrent chemotherapy is the preferred definitive treatment for most patients with tonsil cancer because radiation therapy is associated with less morbidity, disfigurement, and loss of function than the older standard surgery—a transcervical partial pharyngectomy often including a partial mandibulectomy as well as a tracheostomy. For most patients with tonsil cancer, the role of surgery is an adjuvant one for remaining or recurrent tumor when needed.

However, a new, minimally invasive surgery, transoral lateral oropharyngectomy (TLO), is now a primary treatment option for select patients. According to Dr. Holsinger, who is one of the pioneers of this approach, TLO has been shown to achieve rates of local control equivalent to those of radiation therapy for unilateral anterior T1–2 squamous cell carcinomas of the tonsil without posterior spread.

A related surgical advance has also made surgery possible for some patients in whom it was previously precluded by the proximity of the deep margin of the tonsil to the carotid artery. Dr. Holsinger described the technique, which is performed during TLO, as a maneuver that uses continual strong medial retraction of the specimen away from the parapharyngeal space to ensure the visualization and safety of the carotid artery. “Now we can get a wider and deeper mucosal margin without vascular injury,” he said.

These advances mean that more patients may now benefit from surgery than was previously possible. This is an important development because the younger population of patients with tonsil cancer has led to increased concern about longterm radiation sequelae.

Chemotherapy or radiation therapy may be given as adjuvants to TLO.

Induction chemotherapy

Although induction chemotherapy followed by radiation therapy or surgery is considered a treatment option for intermediate-stage tonsil cancer, its use is controversial.

A main goal of induction chemotherapy is to eradicate distant microscopic disease that would ultimately undermine the strategy of pursuing local treatments (surgery or radiation) with curative intent. For this reason, induction chemotherapy is often used to treat cancer types that are typically discovered at advanced stages, in which there is a greater risk for distant micrometastatic disease.

Tonsil cancer, however, produces noticeable symptoms that prompt most patients to seek medical attention before distant spread occurs. Despite the fact that its proximity to rich lymphatics often leads to tonsil cancer’s being detected after it has spread to lymph nodes in the neck, the immediate danger posed by tonsil cancer is more local and regional than distant.

Therefore, local control is a major driver of treatment decisions. “The natural history of the cancer is important,” Dr. Kies said. “For breast or lung cancers, the problem is distant disease, but for head and neck cancers it is more likely to be an uncontrolled primary tumor.” Further, he said that a decision to give systemic treatment first will delay local treatment and should be undertaken only with due consideration of the risk a growing tumor might pose to vital adjacent areas of the neck and their associated functions.

Another consideration related to this option is increased toxicity. Higher doses of drugs are used for induction chemotherapy than for chemoradiation therapy. “The resulting toxicity can be debilitating,” Dr. Kies said. He recommended that induction chemotherapy be reserved for patients with more advanced neck disease—involvement of multiple lymph nodes, retropharyngeal lymph nodes, or nodes lower in the neck—that might herald a risk for distant metastasis. He said that most studies currently investigating induction chemotherapy for tonsil cancers require that patients have N2b or N3 disease to enroll.

Future directions

According to Dr. Rosenthal, HPV is an independent prognostic factor whose value overrides other factors such as tumor size and lymph node status. “Since patients with HPV-related tumors have a better prognosis than those with tobacco-related tumors, we are now looking at ways to deintensify treatment in these patients in order to address survivorship issues,” he said. “The question is: how can we get the same survival outcomes with better long-term function and fewer long-term side effects?”

According to Dr. Kies, the more favorable outcomes are not due just to the relatively better health of patients with HPV-related disease. “These cancers are generally more responsive to treatment, regardless of the modality used,” he said. “This may mean that less intensive treatments—with less risk of long-term effects—might be required, which would be particularly advantageous for patients in the 30–50-year age range.”

To those ends, studies are under way to identify the best initial treatments for patients presenting with this disease. One is a protocol headed by Dr. Kies in which patients are assigned to either chemoradiation therapy or induction chemotherapy based on likely patterns of failure—patients at high risk for distant disease are assigned to the latter arm. Studies such as this could further enable clinicians to identify which treatment strategy is best suited for each individual patient.

Contributing Faculty
The University of Texas MD Anderson Cancer Center

Photo: Dr. F. Christopher Holsinger

F. Christopher Holsinger, M.D.
Associate Professor, Head and Neck Surgery

Photo: Dr. Merrill S. Kies

Merrill S. Kies, M.D.
Professor, Thoracic/Head and Neck Medical Oncology

Photo: Dr. David Rosenthal

David Rosenthal, M.D.
Professor, Radiation Oncology

References
Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011;29:4294–4301.
Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol 2006;24: 2606–2611.
Greene FL, Trotti A III, Fritz AG, et al., eds. AJCC Cancer Staging Handbook. 7th ed. Chicago, IL. American Joint Committee on Cancer; 2010.
Laccourreye O, Hans S, Ménard M, et al. Transoral lateral oropharyngectomy for squamous cell carcinoma of the tonsillar region: II. An analysis of the incidence, related variables, and consequences of local recurrence. Arch Otolaryngol Head Neck Surg 2005;131:592-599.
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology, Head and Neck Cancer, V.2.2011. [Subscription required]

Other articles in OncoLog, January 2012 issue:

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