Author: Mark L. Fuerst
An oncology grand rounds discussion with Sachin Jhawar, MD.
Head and neck squamous cell carcinoma (HNSCC) represents a heterogeneous set of diseases with different features and treatment recommendations. Physicians face challenges in initial treatment decision-making and response assessments, including the changing role of surgery, the incorporation of human papilloma and Epstein Barr virus status, as well as the potential for treatment de-escalation using patient-related and tumor-related factors.
A recent “Oncology Grand Rounds” article in the Journal of Clinical Oncology provides an overview of treating advanced HNSCC when cisplatin is not an option, including concurrent chemotherapy, cetuximab, targeted therapy, and immunotherapy.
In the following interview, the paper’s lead author, Sachin Jhawar, MD, of Ohio State University Comprehensive Cancer Center in Columbus, reviews the main issues.
What is the focus of the article?
We focused on patients with locally advanced disease who would be receiving definitive non-surgical treatment when possible treatment with concurrent cisplatin, delivered either every 3 weeks or weekly, is always the preferred treatment.
We specifically wanted to delve into the subset of patients who we would not recommend to receive cisplatin because of age or comorbidities. This could be concurrent chemotherapy (carboplatin/paclitaxel), concurrent cetuximab, and altered or standard fractionation radiation schedules without systemic therapy, as well as when to consider immunotherapy and palliative radiation for those with recurrent or metastatic disease.
There is also a great deal of institutional preference involved. At our institution, we prefer concurrent carboplatin/paclitaxel in patients who cannot receive cisplatin. Generally, we reserve definitive radiation alone options for patients who are completely ineligible for any systemic therapy.
If definitive therapy would be considered too difficult, or for those who have metastatic disease, still other palliative regimens are available.
When should clinicians consider nivolumab or pembrolizumab?
At this time, immuno-oncology agents such as nivolumab or pembrolizumab are approved and used regularly only in the recurrent or metastatic setting. Even in the recurrent setting, they are generally considered only if surgery or re-irradiation therapy is not an option.
These novel agents should only be considered earlier in a patient’s treatment course in place of more traditional systemic options via a clinical trial.
What are the potential benefits of the combined use of immunotherapy, chemotherapy, and vaccines?
The potential benefits of combination strategies using checkpoint inhibitors and other immuno-oncology treatments, including vaccines, in combination with more traditional therapies including surgery, radiation, and chemotherapy are still being worked out. It is likely that we will first see applications of these newer therapies in the recurrent and metastatic setting, but they may be incorporated earlier into patient care as more data about safety and efficacy emerges.
We have seen regular use of immuno-oncology treatments in other disease sites, and these therapies are being introduced earlier in the treatment course for patients. I would expect a similar pattern to emerge for HNSCC, although we will need to wait for phase III randomized controlled trial data for these immunotherapies to be ready for prime time.
It should be noted, however, that given the heterogeneity of HNSCC, there are certain scenarios in which we are working towards de-escalation of therapy, and addition of more therapies may not be needed.
In the patients with HPV-positive oropharyngeal squamous cell carcinoma and less than 10 pack-year smoking histories, the cure rates are more than 90% with current standard-of-care treatment. We are now working towards de-escalating therapy. It is not clear what role, if any, immuno-oncology will play in these already favorable situations.
What about the potential synergy of molecular targeted agents with radiation?
There are multiple potential targets that could lead to synergy with radiation. Cetuximab actually acts on one of these targets, the epidermal growth factor receptor. Other potential targets that are being studied for combinations with radiation include cell signaling pathways (mTOR, AKT), cancer metabolism, tumor hypoxia, and DNA repair pathways (PARP, ATR).
There are other studies that have been completed or are ongoing that use agents to improve radioprotection of normal tissues. To date, none of these targeted agents are being regularly used on their own or in combination in the care of patients outside of clinical trials.
What improvements with new targeted therapies and immunotherapies do you foresee?
As our understanding of the molecular mechanisms of carcinogenesis, aberrant cancer signaling pathways, and the tumor microenvironment improves, I expect that the number of targets and, therefore, the number of molecular targeted agents will grow. This will lead to a large increase in the number of clinical trials and expansion of our armamentarium against HNSCC.
Similarly, as our understanding of the interplay between cancer and the immune system and mechanism of immune escape improves, I suspect we will be able to improve response rates from immuno-oncology drugs. Currently, only 10% to 20% of patients respond to immuno-oncology treatments, leaving a great deal of room for improvement.
Taken together, this will allow for more individualized, patient-specific care and afford the ability to test novel combinations to improve cure rates. Simultaneously, this will decrease toxicity by choosing the right treatment for the right patient, rather than having a one-size-fits-all approach to therapy.
What’s the take-home message for practicing oncologists?
There is a great deal of change forthcoming in the treatment of HNSCC, but at this time standard-of-care therapy still consists of some combination of traditional cancer therapies, including radiation, surgery, and chemotherapy.