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. Stage III cancers are more than 4 centimeters in diameter or any size with spread to a single 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 cancers are those which have spread to adjacent tissues. The lymph nodes may or may not contain cancer or the cancer may be any size but 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) in diameter.

The following is a general overview of treatment for locally advanced cancer of the throat. Treatment may consist of surgery, radiation, chemotherapy, biological therapy, or a combination of these treatment techniques. Multi-modality treatment, which is treatment using two or more techniques, is increasingly recognized as an important approach for increasing a patient’s chance of cure or prolonging survival. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Circumstances unique to each patient’s situation may influence how these general treatment principles are applied and whether the patient decides to receive treatment. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.

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. For example, three large studies have shown that treatment with radiation plus chemotherapy lead to longer survival rates and a lower rate of recurrence than treatment with radiation alone. Currently, clinical trials are ongoing to determine the optimal chemotherapy combinations and sequencing of radiation.

Effects of treatment with radiation and chemotherapy vs radiation alone in three studies of patients with throat cancer

Neoadjuvant Chemotherapy

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. According to a recent clinical trial, the treatment regimen consisting of neoadjuvant paclitaxel , Ifex^® and Paraplatin^® appears to have anti-cancer activity and improve cancer-free survival in locally advanced head and neck cancers. Researchers from the M.D. Anderson Cancer Center recently reported the results of this chemotherapy regimen in 52 patients with locally advanced head and neck cancers. A complete disappearance of cancer, known as a complete response (CR), occurred at the site of cancer origin in 60% of patients. A CR in the local lymph nodes occurred in 40% of patients. Over 30% of patients achieved a CR in both the primary site and local lymph nodes.

This study also appears to show a low rate of cancer recurrence. Cancer recurred in only 12% of patients after one year, and 23% after two years. Overall, 82% of patients survived two years or more after treatment. In addition, sensitive tissues in the head and neck were preserved in 81% of patients. The majority of patients tolerated the treatment regimen relatively well.

Surgical Treatment of Locally Advanced Throat Cancer

Complete surgical removal of the cancer may sometimes be utilized as the only treatment for patients with stage III throat cancer, depending on the exact location and extent of the cancer. Surgery is also utilized for patients who have received chemotherapy. The role of surgery in patients who achieve a response to neoadjuvant chemotherapy has been evaluated in clinical trials.

Research conducted in Australia suggests that surgery is important in patients who achieve a response to chemotherapy, even when the response is complete. These researchers evaluated the outcomes of 314 patients with stage III and stage IV squamous cell cancer of the mouth and throat who were treated with chemotherapy before surgery. In order to evaluate the impact of surgery, patients that showed response to the treatment were divided into two groups: one group received chemotherapy, surgery, and radiation therapy, and the second group received chemotherapy and radiation therapy without surgery.

When analyzed by treatment group, 65% of patients receiving chemotherapy, surgery, and radiation therapy lived 5 years or more after treatment, compared to 56% of patients who did not undergo surgery. However, when complete response was assessed, 90% of patients receiving chemotherapy, surgery, and radiation therapy lived 5 years or more, compared to only 51% of patients who did not undergo surgery. Local cancer cancer recurrences were also less common in patients who were treated with surgery, chemotherapy, and radiation.

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 locally advanced cancer of the throat will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials 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

EGFRs are small proteins that are found on the surface of cells. EGFRs bind exclusively with small proteins circulating in the blood called growth factors. The binding action between EGFR and growth factors stimulates biological processes within the cell to promote controlled growth of the cell. However, in many cancer cells, EGFR is either abundantly overexpressed or the EGFR biological processes that normally stimulate cell growth are constantly active, leading to the uncontrolled and excessive growth of the cancer cell. Inhibition of EGFRs is believed to decrease cancer growth by facilitating apoptosis, or cell death. Research is ongoing to evaluate the effectiveness of EGFR inhibitors as single agents and in combination with chemotherapy. Three drugs that act on EGFRs, OSI 774, Iressa^®, and the monoclonal antibody IMC-225, have demonstrated anti-cancer effects in the treatment of head and neck cancers.

OSI-774: The novel agent OSI-774 (Tarceva) has been shown to produce an anti-cancer response and slow the growth of head and neck cancer cells that overexpress EGFRs. OSI-774 halts excessive cellular growth by inhibiting the EGFR process within a cell. Researchers recently reported the results of a clinical trial evaluating OSI-774 in 124 patients with advanced head and neck cancer. Overall, 45% of patients experienced an anti-cancer response following treatment. Disease was stabilized for 3 or more months in approximately 50 patients. Patients survived 174 days, on average, with 14 patients surviving over 300 days. Only 2 patients discontinued treatment due to side effects, the most common of which was rash.

Iressa^®: Another EGFR-inhibitor, Iressa^®, has demonstrated anti-cancer effect in patients with head and neck cancer. Of 52 patients with recurrent or metastatic head and neck cancer treated with Iressa^®, approximately 10% of patients had an anti-cancer response. Disease was controlled in 53% of patients, resulting in stable disease in approximately 42% of patients. Control of the disease lasted from 1.2 to 11 months. The median time to disease progression was 3.4 months. The median duration that patients survived was approximately 8 months. The most common side effects observed were skin rash and diarrhea. Only one patient discontinued treatment by choice because of a severe skin rash. Future trials will evaluate the effective of Iressa^® on locally advanced head and neck cancers.

Monoclonal Antibody Treatment: Small proteins that can locate cancer cells in the body are called monoclonal antibodies. These proteins 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. Monoclonal antibodies may also block EGFRs, as is the case with the new agent, IMC-225 (Erbitux).

Results of a recent study indicate that the use of IMC-225 in combination with radiation therapy appears to prolong survival time for persons with locally advanced cancer of the tongue, tonsils, throat, or larynx. Researchers treated 15 patients with locally advanced cancers of the tongue, tonsils, throat or larynx with a combination of radiation therapy and IMC-225. The overall complete response rate was 87%, which favorably compared to the 30% commonly achieved with radiation therapy alone. The average duration of the response was 14 months. At the last reported follow-up, 67% of the patients were alive and had not experienced cancer progression; some had been in complete remission for more than 27 months. Previous studies indicate that less than half of these patients would live past 18 months using radiation therapy alone.

New Chemotherapy and Radiation Combinations

The combination of Platinol^® and 5-FU chemotherapy is considered a standard treatment for locally advanced squamous cell cancer of the head and neck. The taxanes, Taxotere^® and paclitaxel, are active chemotherapy agents in many cancers and appear to be active for the treatment of head and neck cancer. Adding taxanes into a treatment program utilizing Platinol^® and/or 5-FU is a logical step in the development of effective combination chemotherapy.

Taxotere^®: Researchers from the Dana Farber Cancer Center recently conducted a clinical trial to evaluate the addition of Taxotere^® to Platinol^® and 5-FU in the treatment of locally advanced head and neck cancer. This trial involved 101 patients who also received radiation therapy following chemotherapy. Approximately 4 years following therapy, 64% of patients were alive with no evidence of cancer and overall survival was 67%. Of the 36 patients who experienced a cancer recurrence following therapy, 26 had a local (near the site of origin) recurrence, 5 had a local and distant recurrence and 5 had a distant recurrence only.

Taxotere^® has also been evaluated in combination with radiation therapy for the treatment of cancer of the head and neck. In one clinical study, 30 previously untreated patients with head and neck cancer were treated with a 4-day regimen consisting of Taxotere^®, Platinol^®, 5-FU, and leucovorin chemotherapy for an average of 3 treatment cycles. Over 90% of patients responded to the treatment: 63% achieved a complete response and 30% a partial response. All responding patients also received radiation therapy. Approximately 60% of patients survived without cancer recurrence 1 year from treatment. The researchers also concluded that the addition of Taxotere^® to Platinol^® and 5-FU chemotherapy appeared promising and should be compared to commonly used regimens to determine if it improves outcomes for patients with head and neck cancer.

Paclitaxel: Another more recently used therapeutic regimen for treatment of head and neck cancer consists of the chemotherapy agents paclitaxel, 5-FU, and hydroxyurea with twice-daily radiation treatments and is referred to as THFX. In patients with cancer that has spread regionally but not to distant sites in the body, the local recurrence rate following THFX is approximately 13% and the distant recurrence rate is approximately 23%. Approximately 60% of patients receiving THFX will survive 3 years or more.

Results of a recent clinical trial indicate that induction therapy with paclitaxel and 5-FU prior to THFX for advanced head and neck cancer appears to produce promising long-term survival. This trial involved 61 patients with advanced cancer that had not spread to distant sites in the body who were treated with Paraplatin^® plus paclitaxel weekly for 6 weeks followed by standard THFX. At 28 months following therapy, 10 patients experienced cancer progression. Survival rates at 2 and 3 years following therapy were 77% and 70%, respectively. Side effects included inflammation and pain of the mouth and throat and low white blood cell levels.

Gemzar^®: Results from a small study suggest that Gemzar^® plus Platinol^® also produces anti-cancer responses in patients with advanced head and neck cancer. In this study, the combination of Gemzar^® plus Platinol^® was evaluated in 18 patients with advanced squamous cell head and neck cancer. Following treatment, one patient had a complete disappearance of cancer, 8 patients achieved a partial disappearance of cancer, 7 patients had their disease stabilized, and 2 patients did not respond to treatment. Future clinical trials evaluating this chemotherapy combination with other treatment modalities are warranted in an attempt to further improve outcomes for patients with this disease.

Selective Intraarterial Infusion of Chemotherapy: The administration of chemotherapy into a selected artery that delivers blood directly to the cancer has been evaluated as a treatment option for patients with different types of cancer, particularly abdominal cancers. This technique is now being refined and evaluated as a possible new treatment option for patients with head and neck cancer. This treatment strategy augments anti-cancer effects of chemotherapy compared with systemic (full body) delivery through several mechanisms:

• The chemotherapy agent does not become diluted by mixing with the rest of the blood from the body prior to reaching the cancer.
• The chemotherapy agent is not broken down in the body through biochemical processes prior to reaching the cancer.
• Larger amounts of the chemotherapy agent can reach the cancer with fewer associated systemic side effects.

The results of a recent trial using intraarterial infusion of chemotherapy are encouraging, indicating effectiveness and tolerability in the treatment of head and neck cancer. In this clinical trial, researchers from Japan delivered selective intraarterial chemotherapy in 32 patients with locally advanced head and neck cancer. In each patient, a catheter (very small hollow tube) was surgically placed in a specific artery that directly delivered blood to the area involving the cancer. The chemotherapy agent Paraplatin^® was continuously administered though the catheter by an electric pump for a time period of a couple weeks to over a month, depending on the dose administered. These patients also received radiation therapy as a component of their treatment. All but one patient receiving this treatment experienced a complete or partial disappearance of their cancer. Five years following treatment, nearly 60% of patients were still cancer free. This treatment was generally very well-tolerated in these patients.

Once these results are confirmed by additional clinical trials, intraarterial chemotherapy infusion may potentially emerge as a standard alternative treatment to surgery or may be used in combination with other treatments for patients with this disease.

Other Novel Treatments

Proleukin^®: Proleukin^® is interleukin-2 (IL-2), a substance normally produced by the body that stimulates the immune system to attack “foreign” material such as viruses and cancer cells. Recent research indicates that the addition of Proleukin^® injections into local lymph nodes appears to reduce cancer recurrences and improve survival in patients with locally advanced oral and pharyngeal cancers.

Researchers in Italy recently evaluated the use of Proleukin^® as part of a treatment regimen for patients with locally advanced cancers of the mouth and pharynx. This trial involved 22 patients who were treated with surgery and radiation plus Proleukin^® injections or just surgery and radiation (control group). Proleukin^® was administered by way of injections directly into local lymph nodes surrounding the cancer prior to surgery and for one year following surgery. In the first 3 years following surgery, cancer recurrences occurred in only 31% of patients who were treated with Proleukin^®, compared to 48% of patients in the control group. Cancer-free survival at 5 years was 64% for patients treated with Proleukin^®, compared to only 51% for patients in the control group. The overall survival at 5 years was 73% for patients treated with Proleukin^®, compared to only 55% for patients in the control group. Proleukin^® injections were extremely well tolerated.

Gene Therapy: Gene therapy involves the manipulation of genes in order to correct or override the abnormal alterations that cause cancer. This can be accomplished by replacing or inactivating a dysfunctional gene or replacing or inserting a functional gene.

Many different types of cancers develop due to a mutation (alteration) in a certain gene called the p53 gene. An estimated 70% of persons with head and neck cancers carry a mutation in this gene. This gene, sometimes called the “cell suicide” gene, keeps normal cell replication under strict control. If there is a mutation in a cell’s DNA, or if a cell is infected with a virus, the action of the p53 gene is to stop further replication of this damaged cell, inhibiting further progression of the mutation. In cells that have a mutation within their p53 gene, there is no restraint on replication, leading to uncontrolled, rapid growth of the cell – the hallmark trait of cancer.

ONYX-015 is a genetically engineered, or altered, adenovirus (a virus that causes a common cold) that was developed to specifically target and infect cells with a destroyed or mutated p53 gene. This virus has been altered in such a way that it will infect cancer cells, ultimately killing them, but will not infect normal healthy cells. Early trials indicate that the injection of ONYX-015 directly into the cancer along with the use of systemic (full body) chemotherapeutic agents, Platinol^® and 5-FU, is more effective than chemotherapy alone in patients with recurrent head and neck cancers.

Another gene therapy agent, Ad5CMV-p53, has demonstrated clinically beneficial anti-cancer activity in patients with recurrent/refractory head and neck cancer. In one clinical trial Ad5CMV-p53 was injected daily into recurrent head and neck cancers. Four injected areas achieved a complete response, 6 a partial response and 2 a minor response. Eighteen remained stable for a period of 3-7+ months. There were no treatment-related deaths and side effects were minimal. In this study, patients with smaller tumors had a better response than patients with larger tumors. The treatment was well tolerated.

Photodynamic Therapy: The concept behind photodynamic therapy is that light from a laser, enhanced by photosensitizing agents, can kill cancer cells without damaging normal cells. The basic technique is over 50 years old but the past 5 years have seen the development of reliable, portable lasers and better photosensitizing agents, making the technique quick, effective, and relatively free from side-effects. For patients with head and neck cancer, functional outcomes with photodynamic therapy are probably better than surgery and radiation therapy but there is inadequate long-term survival data.

In two clinical studies, photodynamic therapy with temoporfin (Foscan) completely cleared cancers at 12 weeks in 83% of 115 patients with primary head and neck cancers with a one-year survival of 87%. This approach was also successful for 50% of 96 patients with recurrent or second primary cancers. In these patients, the one-year survival rate was 65%. These findings may compare favorably with published survival rates for surgery and/or radiotherapy for similar patients but no comparative studies have been performed.

An advantage to photodynamic therapy is that it can usually be given to outpatients under local anaesthetic. Patients receive intravenous temoporfin, followed 4 days later by brief laser illumination of the cancer site. Photosensitivity is one side effect that takes 2–3 weeks to resolve, during which time patients must avoid bright light. Approximately 10% of some 1000 patients treated worldwide had photosensitivity reactions – mostly only mild erythema. There is also significant post-treatment pain, which may require opiate analgesia.

Photodynamic treatment may also be of palliative benefit in more than 50% of patients with incurable head and neck cancers and may offer complete local cancer control in 17% of patients.

Immune System Support

One approach to improving cure rates in patients with locally advanced cancer is to strengthen their immune system so that the body’s natural anti-cancer response can effectively prevent cancer recurrence. Recently, researchers from the M.D. Anderson Cancer Center, Vanderbilt University, and the University of Pittsburgh Cancer Institute administered a combination of natural substances that support immune function to 42 patients with locally advanced head and neck cancer. The 12 month treatment regimen consisted of:

• Interferon-alpha, a natural substance produced by the body to stimulate the immune system
• 13 cis-retinoic acid, a vitamin A derivative that has demonstrated an anti-cancer effect
• Alpha-tocopherol, a vitamin E derivative that protects cells from free-radical damage

All patients received prior surgery and/or radiation and had a complete disappearance of their cancer upon initiation of this treatment combination. Overall, 98% of patients survived one year or more following treatment and 91% of were cancer-free. Two years following treatment, 91% had survived and 84% were cancer free.

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