Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: Approach to Treatment and Future Directions

Written by Dan P. Zandberg, MD

Squamous cell carcinoma is the most common cancer that originates in the head and neck. The most frequent primary sites of origin in the United States are oral cavity, oropharynx, larynx, and hypopharynx. While the majority of patients present at a stage where our therapy is with curative intent, if the tumor recurs or the patient has distant metastases, they face significant challenges and there is a great need for improvement in outcomes. We have, however, made progress in the recurrent/metastatic (R/M) setting and we continue to investigate ways to have better outcomes. In this article I will discuss the general approach and treatment options for recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) and future directions in the field. 

Before this discussion it is worth establishing some definitions and framework for the rest of the article. A patient’s head and neck cancer may recur either locoregional or with distant metastases. Locoregional recurrence means that it has recurred at the primary site (for example in the tongue or voice box) and/or in the neck (for example with a new lymph node). Distant metastases means that the cancer has spread beyond the head and neck region to other organs such as the lung, liver, or bone. A patient may have a locoregional recurrence alone, distant metastatic disease alone, or both. Only about 10% of patients present with distant metastases at initial diagnosis and therefore if a patient develops distant metastases, it typically happens at the time of recurrence. In general, HNSCC has a higher chance of locoregional recurrence compared to distant metastases. This article focuses on the general approach to R/M HNSCC for the most common primary sites detailed above (oral cavity, oropharynx, larynx, hypopharynx), understanding that there are nuances to each individual patient. 

In terms of treatments, we have local treatments such as surgery or radiation that can be used to treat a local area and then systemic treatments such as chemotherapy, targeted therapy, or immunotherapy which can affect cancer of the entire body. Very commonly chemotherapy is given at the same time as radiation i.e. concurrent, which is done because the chemotherapy makes the radiation work better on what it is targeting. The choice of local therapies (surgery or radiation) vs. systemic therapy is based on the location of the cancer, which is determined by radiology imaging. For example, does the patient have locoregional recurrence only or does the patient also have distant metastases. This approach is the same for human papillomavirus positive and negative HNSCC patients. 

For patients with locoregional recurrence only (within the primary site or neck) we try to use local approaches for treatment. The initial evaluation is whether the patient can have surgery because surgery is generally associated with the best outcomes. This determination is based on whether the cancer can be removed and whether the patient is a candidate for an operation. The goal of any cancer surgery, including for recurrent HNSCC, is to completely remove all of the cancer. Achieving this goal when there is a locoregional recurrence can be more challenging than at initial diagnosis. If the cancer involves structures such as the carotid arteries or the tissue around the spinal column, this may prevent the cancer from being able to be removed entirely. If the tumor can be removed a patient must be a candidate for the operation meaning they are strong enough medically to tolerate the surgery. If surgery is not an option we then consider radiation. The majority of patients who have a recurrence have had prior radiation to their head and neck. Doing another radiation treatment is called reirradiation. Reirradiation most often is done with concurrent chemotherapy to make the radiation more effective. To do reirradiation the normal tissue around the cancer has to be able to tolerate the radiation and so generally at least 6 months from prior radiation is needed before reirradiation can even be considered. Reirradiation can also be given after a surgery to try and prevent the cancer from coming back when the removed tumor shows high risk features for recurrence. Reirradiation can be done with a technique called IMRT (Intensity Modulated Radiation Therapy), SBRT (Stereotactic Body Radiation Therapy) or Proton radiotherapy. IMRT or Proton radiotherapy is often given as a longer course of radiation over 4-6 weeks whereas SBRT can be delivered in a shorter course of 2-3 weeks for lesions that are small enough to be amenable to this focused technique.

For a patient with locoregional recurrence the decision to recommend surgery and/or reirradiation is complex. Even if a patient’s tumor can be surgically removed and/or be treated with reirradiation, the tumor characteristics including how quickly it has recurred, its location, what the effect would be on a patient’s function and quality of life, and expected cancer outcomes must be balanced together, along with the patient’s goals. Put another way, even though surgery or radiation may be feasible it may not be the best option for particular cases. That is why it is critically important for a patient to have a head and neck surgeon and radiation oncologist that have significant experience with treating these patients. A thorough discussion between physician and patient is always important in cancer care, and especially so with treatment of locoregional recurrence of HNSCC.

If surgery and reirradiation are not options or the patient has distant metastases, then systemic therapy is the primary treatment. Radiation can still be used in a short course for pain relief (palliative radiation) or sometimes as part of the treatment if a patient only has a few distant metastatic areas of cancer. Systemic therapy includes traditional chemotherapy, targeted therapy (drugs that target molecular pathways within the cancer), and immunotherapy. Immunotherapy is a class of medication that works by using the immune system to attack cancer. This can come in the form of vaccines, T cell therapy, and drugs that effect co-signaling molecules. The latter type of immunotherapy takes advantage of the brakes and gas pedals that the immune system already has with drugs that either take the foot off the brake or step on the gas pedal to try to get the immune system to attack the cancer. Specifically, anti-PD-1 monoclonal antibodies (mAb), that take the foot off a brake called Programmed Death One (PD-1), have revolutionized the field including in HNSCC with FDA approvals of nivolumab (OPDIVO) and pembrolizumab (Keytruda) in 2016 for patients that have progressed on platinum chemotherapy already and more recently with pembrolizumab in 2019 as the first line systemic treatment therapy option. Pembrolizumab can be given by itself or with chemotherapy as first line therapy. We check a protein called Program Death Ligand 1 (PD-L1) in a tumor sample and if it is present, pembrolizumab by itself or with chemotherapy can be used, and if it is not there then only chemotherapy plus pembrolizumab is an option. PD-L1 is present in about 85% of patients. For a patient with PD-L1 present, the decision to use pembrolizumab plus chemotherapy vs. pembrolizumab alone is a balance between goals, disease characteristics and potential tolerance. For example, using chemotherapy plus pembrolizumab may lead to a higher likelihood of having the tumor shrink, but also has more side effects compared to pembrolizumab by itself. This decision is also shaped by the disease characteristic, where if a patient has a tumor that is causing significant pain and/or a higher amount of cancer chemotherapy plus pembrolizumab is often considered rather than pembrolizumab by itself, if a patient can tolerate the addition of the chemotherapy. This decision and discussion is always tailored to each patient’s needs.

Clinical trials are critically important in R/M HNSCC in order to continue to improve outcomes. Clinical trials led to the approvals of pembrolizumab and nivolumab in R/M HNSCC and now as a field we look to build upon this success. Trials can be phase I (evaluates the toxicity of a new drug or combination), phase II (evaluates how well it works in a small group of patients), or phase III (a larger randomized confirmatory trial establishing whether it is better than our other current standard of care therapy). In phase III trials the primary goal is to see if a new drug or combination improves how long a patient lives compared to standard of care treatment and if it does that can lead to its approval by the FDA for general usage. At present there are many phase I and phase II trials and even some phase III trials that are ongoing for R/M HNSCC. 

While anti-PD-1 mAb immunotherapy (pembrolizumab, nivolumab) represents a great leap for the field the promise with this therapy is that for those patients that do respond there is a chance of prolonged control. The challenge, however, is that still only a minority of patients receive this benefit, and this has driven the field to investigate through clinical trials how we can get more patients to benefit from immunotherapy. 

Clinical trials are ongoing evaluating new combinations of immunotherapies or targeted therapy plus immunotherapy. In the first line setting trials are trying to build on the success of pembrolizumab by combining this drug with new immunotherapies. Newer immunotherapies are mostly administered intravenously, but also includes drugs injected directly into tumors or vaccines delivered into the muscle or skin. The fact that now all R/M HNSCC patients receive pembrolizumab in the frontline setting has also led to a need to improve treatment options after the cancer progresses on this type of immunotherapy and numerous trials are ongoing looking at new combinations. One trial looking at the combination of a targeted therapy called cetuximab and an immunotherapy called monalizumab for this indication is already in a phase III trial (NCT04590963). Additionally, we are trying to find better markers in the blood or tumor that can help us determine who is most likely to benefit from immunotherapy. This is even more important as we continue to have trials with more combination therapies in an effort to someday be able to select the right combination for each patient based on what markers are present on an individual’s tumor. We are taking the first step towards this goal at the UPMC Hillman Cancer Center with a personalized immunotherapy trial for those patients that have progressed on anti-PD-1 mAb immunotherapy (NCT04326257).

Success with immunotherapy in the systemic therapy only setting has led to trials exploring it earlier on after a surgery for locoregional recurrence or in combination with reirradiation in order to improve outcomes. For example, there is a trial open throughout the United States evaluating pembrolizumab alone or with reirradiation compared to reirradiation with chemotherapy after a surgery for locoregional recurrence (NCT04671667). 

Some targeted therapies without immunotherapy are also making headway. The targeted therapy Buparlisib is currently being evaluated in a phase III trial in combination with a chemotherapy paclitaxel compared to paclitaxel alone for patients who have already received anti-PD-1 mAb immunotherapy (NCT04338399). The drug Tipifarnib which targets HRAS mutations in HNSCC has shown promise and is currently being evaluated in a larger trial with the goal of gaining FDA approval (NCT03719690). Doing genotyping on a patient’s tumor to see what mutations are present can be important to selecting a trial that focuses on a particular mutation in a molecular pathway. 

In summary, the general approach to recurrent and/or metastatic HNSCC starts with a determination as to whether a patient has locoregional recurrence only, distant metastases only, or both. For those patients with locoregional recurrence only we evaluate for whether surgery is an option and if not whether radiation would be an option. If neither of these options are possible for locoregional recurrence or the patient has distant metastases, then systemic therapy is the treatment option. Systemic therapy spans traditional chemotherapy, immunotherapy, and targeted therapy. While outcomes need to be improved for all R/M HNSCC patients, we have made significant progress over the past 5 years and with this progress come new questions, treatments, and clinical trials to continue to move the needle, improve survival, and provide hope for these patients. 

As health care providers we recognize the fear and adversity that comes with having recurrent and/or metastatic HNSCC and in an effort to improve care for these patients at our center we developed the UPMC Hillman Cancer Center Recurrent/Metastatic Head and Neck Cancer Specialty Care Clinic (RMCC). This clinic offers streamlined, personalized care for patients with recurrent and/or metastatic head and neck cancers. Located at UPMC Hillman Cancer Center in Pittsburgh, the clinic offers an expedited evaluation by a multidisciplinary team of experts including head and neck surgery, radiation oncology, and medical oncology to establish a diagnosis and/or develop a treatment plan. Through this clinic, patients have access to world class care and novel treatments, including minimally invasive surgeries, immunotherapy, stereotactic radiosurgery, and the latest clinical trials. 

Editor’s Note: Dan P. Zandberg, MD, is an associate professor of medicine and a medical oncologist/hematologist, specializing in the treatment of head and neck and thyroid cancers. He is the Director of the Head and Neck and Thyroid Cancer disease sections for the division of Hematology/Oncology and the Medical Oncology Co-Leader of the UPMC Hillman Head and Neck Cancer Program. He is also the physician lead for the second floor Hillman Cancer Center clinic. His main research focus is in the development of clinical trials with immunotherapy to improve patient outcomes. Recent awards include the 2019 National Cancer Institute (NCI) Cancer Clinical Investigator Team Leadership Award, 2020 Leo Criep, M.D. Excellence in Patient Care Award, and 2020/2021 Castle Connolly Regional Top Doctor. 

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