15 Apr Recurrent and Metastatic Head and Neck Cancer
Written by Geoffrey Neuner, MD
It is an understatement to say head and neck cancer is a challenging disease for patients, caregivers and clinicians. Curative treatment consists of either surgery, radiation or both, often combined with cytotoxic chemotherapy. The individual treatments for head and neck cancer have improved somewhat over the past 30 years with the development of minimally invasive surgical techniques, organ sparing radiation techniques, better side effect control for chemotherapy, and newer systemic agents such as immunotherapy. However, the overall backbone of curative treatment has changed little in that time period and is associated with significant toxicity. As survivors of head and neck cancer understand, once diagnosed there can be a permanency of the disease or its sequelae in the lives of patients and their caregivers. Although improvements in outcomes are occurring in the oropharyngeal subgroup of patients, this improvement is mainly related to the distinct biological differences in the origin of this disease as well as the generally better health of these patients. Even still, there is a significant risk of recurrence in both oropharyngeal patients with advanced disease and in patients with oral, laryngeal, sinus, hypopharyngeal, or nasopharyngeal cancer. This can consist of recurrence of disease in the site of origin (local), the neck (regional recurrence), as well as in organs distant from the original cancer (distant metastases), or any and all of these areas. A lack of studies guiding treatment in these situations, called “salvage treatment,” requires patients and clinicians to be astute in the nature of the recurrence, probable outcomes, and risks of further treatment toxicity. This article will discuss some of the most common recurrence scenarios encountered in head and neck cancer patients.
Local and Regional Recurrence of Disease
Unfortunately, there is no subsite in the head and neck that is associated with a 100% cure rate after local therapy. After surgery, radiation, or chemotherapy combined with radiation (chemoradiation) are well established treatment regimens used to reduce the risk of recurrence, but up to 30% of patients recur nonetheless. The need for salvage treatment is not just limited to patients treated primarily by surgery. In trials and retrospective reports, 10-15% of patients undergoing curative radiation for very small larynx cancers will require removal of the larynx afterward, either for return of the cancer or for a second tumor that arises years later. Salvage treatment after initial curative treatment can be challenging, as anatomy may have already been altered by initial surgery, radiation, or both, and further treatment may severely limit functional outcomes.
Salvage treatment of head neck cancer is a very specialized field and requires input from experienced clinicians, including head and neck surgeons, radiation oncologists and medical oncologists who specialize in head and neck cancer. As head and neck cancer is actually a rare disease, specialization in the treatment of recurrence is something that is best undertaken at large referral centers that possess the expertise to advise patients accurately and manage both the salvage treatment and potential sequelae thereof.
Treatment is often tailored to very individualized situations, and the salvage treatment recommended depends on the initial therapy that was delivered, site of disease, patient health, and even the location within the organ. For example, a well lateralized recurrent oral tongue cancer may be excised, but another recurrent oral tongue cancer of the same size in the middle of the tongue may require complete removal of the tongue. In retrospective reports, patients who are able to undergo surgery as a salvage local treatment tend to fare better. Although this may point to the biology of the recurrent cancer itself, if patients are able to undergo surgery, it is generally preferred because of this data. Recurrent cancer, in general, is a reason to receive radiation. In patients with a previous history of radiation treated with salvage surgery, there is very little data to guide treatment immediate post-operative chemo reirradiation to observation. Although local control of the cancer was improved with post-operative therapy, life span was no different and severe adverse events were higher in the group that received immediate therapy. This is thought to be due to many reasons, including the multiple medical problems these patients have at this point in their lives as well as the high risk of the cancer to have spread to other organs after the application of salvage surgery.
Regional recurrence of disease describes regrowth of cancer in the lymph nodes of the neck, one of the primary routes of spread of head and neck cancer. In the event that a patient hasn’t had radiation, regional recurrence can be managed with chemoradiation or surgery. However, if radiation was given before, regional recurrences are best managed with surgery, when possible. Reirradiation or chemo reirradiation can be given after surgery, but again there are risks given the neck muscles, skin, blood vessels, nerves, and spinal cord have all been radiated, and could sustain potential injury from the second dose of radiation. One radiation option performed in very specialized centers with experience in this area is brachytherapy. Meaning “near-therapy,” it consists of the placement of radioactive sources right next to the area at risk for recurrence. This potentially limits the amount of radiation given to the already treated neck, while delivering a substantial dose of radiation right to the tissues at risk.
For patients who are unable to undergo salvage surgery, re-irradiation or chemo re-irradiation are potential options. Unfortunately, long term control of the recurrent cancer as well as survival of these patients are poor, for the same reasons listed above; poor patient health, further local/regional recurrence, and a high risk of spread to other organs. In addition, re-irradiation as a treatment modality is often limited because it is considered unsafe to deliver another full dose of radiation, and the therapeutic benefit doesn’t justify further treatment of sites that may have be at risk for spread. In addition, if the patient has received radiation before, the blood supply to the tissue will often be poorer than it was before receiving radiation, and this can cause radiation to be less effective, as radiation at low doses requires oxygen in the tissue to help facilitate the destruction of tumor DNA.
Radiation is typically given in small daily doses for 6 weeks in the recurrent setting. Radiation oncologists can lower the dose per treatment and give two treatments per day, which should biologically make the radiation easier on the normal tissues surrounding the tumor. This is important, because patients who receive radiation for a second time have a small risk of severe life threatening tissue damage. A newer form of treatment called stereotactic body radiotherapy is delivered with high doses per treatment over 1 to 2 weeks, which biologically may overcome some of the issues with tissue oxygenation. These radiation regimens have not been compared and any one of them may be more appropriate based on the tumor location, patient prognosis, patient health, and patient desires. Finally, there are situations where proton therapy may have a therapeutic advantage, given its ability to deposit less dose in the surrounding normal tissues.
The poor outcomes with reirradiation are reflected in the National Comprehensive Cancer Network Guidelines (www.nccn.org) for recurrent/persistent/advanced head and neck cancer, as clinical trial enrollment is preferred for these patients. If not amenable to clinical trial and/or not eligible for reirradiation, systemic therapy such as chemotherapy or immunotherapy are possible treatments. For many years, this consisted of platinum based chemotherapy, the same sorts of agents used in combination with radiation for definitive treatment, combined with other cytotoxic chemotherapy. More recently, cetuximab, an antibody to a growth factor receptor often found on head and neck cancer cells, was found to improve outcomes in patients with recurrent or metastatic head and neck cancer when combined with cytotoxic chemotherapies Cisplatin and 5-FU.
More recently, excitement has been generated by results seen in clinical trials comparing immunotherapy to chemotherapy in patients who have suffered a recurrence of their cancer. Considered second line treatment, to be given after the failure of platinum based regimens, these therapies work differently by “waking up” the immune system when it had been turned off by the cancer. Although long term control rates are modest with immunotherapy as a whole, there have been patients, albeit a small minority, who have experienced complete disappearance of their recurrent cancer for several years. The two agents currently approved for use in recurrent head and neck cancer are nivolumab and pembrolizumab. These agents have been described in great detail in the April 2018 issue of SPOHNC. In a large clinical trial, nivolumab was found to have less side effects and better improvement in patient quality of life than chemotherapy in this setting.
Metastatic spread
Patients who demonstrate growth of cancer outside of the original head and neck site or lymph nodes of the head and neck have developed distant metastases, and are considered to have incurable disease. As mentioned above, some of these patients have demonstrated complete resolution of their disease with immunotherapy, but that is a minority. In addition, there is a group of patients with limited metastatic spread that have better outcomes, and treatment of their disease will be described below in further detail. Most patients with metastatic spread have tumors that appear most often in the lungs, liver, and bones, but also sometimes occur in the lymph nodes of the chest or abdomen, or even in the skin, amongst other uncommon sites. Patients may have symptoms based on the location of the tumors (bone tumors causing pain, for example), but are often asymptomatic or only demonstrate mild systemic symptoms such as weight loss, fatigue, or loss of appetite.
In terms of treatment, it should be noted that the NCCN guidelines for metastatic disease mentioned give preference to clinical trial enrollment for patients who have developed metastatic spread. Although patients are often, understandably, very worried about receiving experimental therapy because they may miss out on the more effective standard therapy, it should be noted that the standard therapies have been largely ineffective for decades in terms of delivering long term disease control for patients with metastatic spread. Even though there has been demonstrable improvement in outcomes in patients with metastatic disease using immunotherapy, the majority of patients eventually progress and succumb to their disease. Therefore, it is imperative that new agents are developed and that novel combinations of treatments are found which will improve the outcomes of patients with both advanced local/regional recurrences or metastatic spread of disease. This can only happen through the altruism of patient participation in clinical trials.
The first step in treating the patient with metastatic disease is to assess their performance status. Those with significant irreversible health issues or cancer related symptoms may actually fare worse with treatment, and may be best served with palliative care/hospice. Although patients often think of this as “giving up,” it is rather a very appropriate service to address the multitude of physical, psychological and social issues that arise at the end of life. Good clinical trials have actually shown palliative care services EXTEND the lives of patients when they are incorporated early in the care of the patient with incurable cancer.
For those able to receive treatment for metastatic spread, treatment again consists mainly of systemic therapies: cytotoxic chemotherapy, cytotoxic chemotherapy combined with cetuximab, or immunotherapy. For those who have a significant burden of symptoms but are still able to receive systemic therapy, single agent rather than combination therapy is recommended. For those with a minimal burden of symptoms and a good ability to participate in the daily activities of life, multi-agent systemic therapy is the treatment of choice after clinical trial enrollment, and can consist of the agents discussed in the local/regional recurrence setting above. Usually, if the cancer becomes resistant to the current regimen, the patient is switched to new regimens until the patient is unable to tolerate further therapy or the cancer grows beyond the control of any therapy. At that time, palliative care services are essential for symptom control, end of life planning, and psychological counseling.
Oligometastatic disease
Over the past 40 years, it has become more and more apparent that, regardless of cancer, there are patients who develop limited metastatic spread of cancer who may be cured by local therapy to the site of spread. Limited metastatic spread is called “oligometastatic” disease, and classically has been defined as having 1-5 metastases. The curative potential of patients with oligometastatic disease was first shown in patients with colorectal cancer with limited spread to the liver; up to 25% of these patients were cured with resection of the primary tumor and metastases in the liver. This was an important finding, because we now know that the metastatic tumors themselves can spread to other areas, not just the primary tumor. Over the years, reports of patients with other cancers with limited metastatic spread, who do well with local therapy to the site of spread, have emerged, including patients with breast cancer, prostate cancer, sarcoma, and even lung cancer. More recently, studies have shown that patients with limited metastatic head and neck cancers, particularly from the oropharynx, may have prolonged survivals after treatment of their sites of limited metastatic disease.
Treatment for oligometastatic disease can be surgery or radiation, usually SBRT. The latter is used because the sites of spread have usually not been radiated before, and are often in organs which can tolerate a large, destructive dose of radiation to a small part of the organ. These treatments can be delivered in as little as one treatment of radiation, and are associated with control rates of upwards of 90%. In cases where disease responds to systemic therapy and comes back in limited spots (oligorecurrent), or if most of the disease disappears except for a few spots (oligopersistent), SBRT can be used to ablate the recurrent or persistent areas in these patients as well. It has been difficult to accrue patients to clinical trials testing the hypothesis behind this treatment, as more and more clinicians believe it to be unfair to withhold such treatment in these situations.
Conclusions
The treatment of recurrent disease is an extremely difficult and nuanced situation for the head and neck patient. Local/regional recurrence is likely best treated with surgery. The application of repeat courses of chemoradiation afterward have to be considered carefully. Repeat courses of chemoradiation as a definitive treatment can be effective in a minority of patients, but are usually mostly palliative. In the patient not eligible for surgery, clinical trial enrollment is encouraged. Although systemic therapy for local/regional recurrence or distant spread were associated with poor survival for decades, recent improvements including immunotherapy are changing the landscape and allowing for more multimodality management, including the aggressive treatment of oligometastatic, oligorecurrent and oligopersistent disease.
Editor’s Note: Geoffrey Neuner is a radiation oncologist in Baltimore. He completed his residency in 2011 at the University of Maryland Medical Center after graduating from Eastern Virginia Medical School in 2006. He currently is a radiation oncologist with Radiation Oncology Healthcare, PA. Dr. Neuner is the main consulting radiation oncologist for the Milton J. Dance, Jr. Head and Neck Center, a private head and neck cancer treatment and rehabilitation center. He has a diverse private practice, but concentrates on the treatment of patients with head and neck, breast and prostate cancers