Patients with recurrent cancer of the throat have residual cancer after initial treatment or a recurrence after an initial complete response. These patients fall into one of two broad categories: 1) those with cancer that returns locally or regionally and 2) those that have metastatic recurrence, or a recurrence at a distant site. Due to both a lack of local disease control and the spread of the cancer, patients with metastatic disease tend to have a poor long-term survival rate.
The following is a general overview of treatment for recurrent 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.
Approaches to Treatment
Local or Regional Recurrence: Treatment for local or regional recurrence will generally consist of surgery and/or radiation therapy, but will be dictated 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. For more information on radiation and surgery for throat cancer, go to Radiation Therapy for Head and Neck Cancers and Surgery for Head and Neck Cancers.
Metastatic Recurrence: Chemotherapy figures prominently in the treatment of metastatic recurrent cancer of the throat. Most patients with recurrent metastatic throat cancer have not responded to radiation therapy, and are treated with chemotherapy. Patients with recurrent metastatic disease who have not received radiation therapy may be treated with combinations of radiation and chemotherapy.
The goal of administering chemotherapy to patients with metastatic recurrent throat cancer is mainly to relieve symptoms. Chemotherapy may include one or a combination of drugs. Combination chemotherapy is more commonly utilized due to improved response rates over single drugs. Clinical trials aimed at identifying the optimal chemotherapy regimen and evaluating novel anti-cancer therapies for recurrent throat cancer are ongoing.
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. 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 metastatic cancer of the throat include the following:
Epidermal Growth Factor Receptor Inhibitors
Epidermal Growth Factor Receptors (EGFRs) are small proteins that are found on the surface of all 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, EGFRs are 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.
Iressa®: The 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 toxicities observed were skin rash and diarrhea. Only one patient discontinued treatment by choice because of a severe skin rash.
Monoclonal Antibodies: Monoclonal antibodies are proteins that can locate cancer cells. 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 had survived without 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 Combination Treatment and Chemotherapy Approaches
Taxotere® and Radiation: Taxotere® has demonstrated promising results in the treatment of head and neck cancer when used in combination with radiation therapy. In a clinical trial, 30 previously untreated patients with stage III and IV 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. All chemotherapy treatments were supported with Neupogen®. 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. Mucositis and nausea were frequent side effects of the treatment.
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.
New Chemotherapy Drugs
Doxil®: The results from two recent clinical trials indicate that Doxil® produces anti-cancer responses in patients with metastatic head and neck cancer. Doxil® is an encapsulated form of the commonly used chemotherapy agent, doxorubicin. Encapsulation prevents the active form of the drug from being broken down as quickly, providing more anti-cancer activity to in the cancer cells. In the first trial, 8 of 21 patients with locally recurrent head or metastatic head and neck cancer had their cancer stabilized following treatment with Doxil®. In a second clinical trial, patients with recurrent head and neck cancer treated with Doxil® demonstrated a greater response rate, lived longer, and had a longer time to cancer progression than patients treated with doxorubicin plus the chemotherapy agent trofosfamide.
Anti-Cancer Effect of Doxil® vs. doxorubicin/trofosfamide
||Time to Cancer Progression
One important effect of Doxil® is that it spares healthy tissue, thereby reducing side effects and improving patient quality of life. Some clinical studies have demonstrated that patients treated with Doxil® have a reduced risk of developing hair loss compared to patients treated with doxorubicin. In addition, short-term results of some clinical trials have demonstrated that Doxil® appears to be less damaging to the heart than doxorubicin; however, longer follow-up is necessary in order to confirm this finding. Furthermore, fewer side effects of treatment tend to result in fewer dose delays and reductions, increasing a patient’s chances for an optimal outcome.
Paclitaxel: The addition of paclitaxel to Platinol® and 5-FU appears to be an effective combination chemotherapy treatment for metastatic cancer of the throat. The safe dose and schedule of the regimen including Platinol®, 5-FU, paclitaxel, and Neupogen® was established in 25 patients with advanced head and neck cancer, including 19 who had recurrent cancer or metastatic cancer and 6 with untreated locally advanced disease. Of the patients with metastatic or recurrent cancer, 58% responded to treatment. Complete remission occurred in 2 patients and 37% of patients survived for more than a year. The major side effects following treatment were mucositis, or mouth sores, and toxicity to the bone marrow resulting in low blood counts.
Taxotere®: The relatively new chemotherapy drug Taxotere® has demonstrated anti-cancer activity in patients with recurrent head and neck cancer when combined with Platinol®. There were 36 patients in this clinical trial: 6 patients had loco-regional cancers that were considered incurable, 14 patients had recurrent cancer, and 16 with metastatic cancer. Following treatment with Taxotere® and Platinol®, 40% of patients experienced an anti-cancer response, and 6% had a complete disappearance of their cancer. The anti-cancer response lasted an average of approximately 5 months. Nearly one third of patients survived one year or more after treatment.
Other Novel Treatments
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.
Two gene therapies currently in development, ONYX-015 and Advexin®, are viruses that cause the common cold, called adenoviruses, which have been genetically engineered 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 with ONYX-015 indicate that injection 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.
Patients who were treated with Advexin® have been shown to live longer with minimal side effects, particularly at the higher doses. Within the first five months of treatment, patients treated with the higher doses were 50% more likely to live than patients treated with lower doses. On average, patients lived over six months after treatment in the high-dose group, compared to less than five months in the low-dose group. The most common side effects were fever, chills, and pain/hemorrhage at the site of injection. Patients treated with higher doses reported more fever and chills. Since patients with inoperable head and neck cancer have few treatment options, researchers believe that the survival achieved with Advexin® is significant.
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. In this study, patients with smaller tumors had a better response than patients with larger tumors. A complete disappearance of cancer occurred in 4 of the injected areas. There was a partial disappearance in 6, and a minor response in 2. The cancer was stable in 18 of the patients for a period of 3-7+ months. There were no treatment-related deaths and side effects were minimal. 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 completely cleared cancers at 12 weeks in 83% of 115 patients with primary head and neck cancers. Of these patients, 87% survived one year or more. This approach was also successful for 50% of 96 patients with recurrent or second primary cancers. In these patients, 65% of patients lived one year or more. These rates of survival are comparable to those published for surgery and/or radiotherapy in 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 reddness. There is also significant post-treatment pain, which may require opiate pain medication.
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.
Radiation Protection Drugs: Radio-protectantion drugs selectively protect normal tissues from radiation treatment, while exposing cancer cells. Over the past 50 years, many drugs called radiation protectors have been tested in the laboratory for prevention of radiation damage to normal cells and tissues. Ethyol® is a radiation protector and the only drug that has been approved by the US Food and Drug Administration (FDA) for use in patients receiving radiation therapy for cancers of the head and neck. Clinical trials have demonstrated that Ethyol® can reduce both acute and late radiation-induced toxicities. The development of Ethyol® has thus resulted in greater cancer control without sacrificing patient well-being.
Treatment with Ethyol® resulted in fewer and less severe cases of xerostomia. Xerostomia can greatly impair a patient’s ability to speak, chew, swallow, and taste and therefore, has a negative effect on a patient’s quality of life. In a large multi-center clinical trial, 300 patients with cancer of the head and neck received either radiation therapy combined with Ethyol® or radiation therapy alone. Xerostomia occurred in 51% of patients receiving Ethyol®, compared to 78% for patients receiving radiation therapy without Ethyol®. One year following completion of radiation therapy, only 35% of patients who had received Ethyol® were still experiencing symptoms of xerostomia, whereas 57% of patients who had received radiation therapy alone were still experiencing symptoms.