Following the publication of two landmark studies in the United States,1,2 laryngeal preservation with combined chemoradiotherapy has become standard practice as opposed to laryngectomy for patients with locally advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group trial adopted induction chemotherapy followed by radiation as standard of care, which was then primarily replaced by concomitant chemoradiotherapy, based on the results of RTOG 91-11, both utilizing surgery as salvage rather than surgical intervention upfront. Although many patients enjoy functioning voices and relatively normal swallowing, allowing for improvements in quality of life and self-image, late toxicities related to chronic aspiration and radiation-related chondritis remain problematic, leaving us to question who the ideal candidates for organ preservation vs surgical resection really are.
In the ASCO Clinical Practice Guideline Update, published in the Journal of Clinical Oncology by Forastiere et al3 in January 2018 and reviewed in this issue of The ASCO Post, an expert panel reviewed the pivotal phase III trials, meta-analyses, and long-term follow-up reports from January 2005 through May 2017. The authors conclude that laryngeal preservation remains the standard of care for the majority of patients with locally advanced disease. However, an emphasis is now being made for primary surgery for early T1/T2 disease, as well as for those with advanced T3 and T4a tumors. Endoscopic surgery for early-stage disease and laryngectomy for those with bulky, advanced disease improve survival as well as functional outcomes due to the avoidance of radiation at the onset. With a high negative predictive value at 12 weeks,4 positron-emission tomography (PET) imaging as opposed to planned nodal neck dissections will also avoid unnecessary surgery if imaging demonstrates no residual disease and clinical exams are negative, again circumventing the probable chances of long-term neck dysfunction.
Role of Surgery
The ultimate goal of organ preservation is survival, but functional outcomes and quality life are equally important to patients. Although patients with lower volumes of disease and good-functioning vocal cords generally do well with chemotherapy and radiation, 20% to 30% still require salvage surgery, which can be difficult and can lead to less-than-desirable results. This then raises the question of how best to personalize care. Moreover, is there an ideal way to select patients for laryngectomy or chemoradiotherapy? For many years, investigators at the University of Michigan have selected patients for upfront chemoradiotherapy vs surgery based on response to a single cycle of chemotherapy, including those with T4 cancers.
If our focus is only on cure, we may win the battle by improving survival but ultimately lose the war if we are not conscious of the functional and psychosocial needs/desires of our patients.— Francis Paul Worden, MD
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In a recent report,5 168 patients were evaluated using this approach. A total of 66% attained laryngeal preservation and 18% required salvage surgery after chemoradiation, with an excellent overall survival rate of 75%. Although this method seems very appealing and perhaps useful, since it can avoid the complications of late surgery by selecting patients for laryngectomy before radiation exposure, bioselection with chemotherapy has yet to be endorsed outside of a few institutions. In further exploratory work from Michigan, researchers identified several predictive and prognostic biomarkers in pretreatment specimens, but they failed to identify a single molecular biomarker with enough power to predict those who will ultimately fail to respond to chemoradiotherapy after responding to induction chemotherapy or a biomarker that could select patients for surgery upfront.6
Need for Biomarkers
As practicing clinicians, we need to rely on biologic response to disease rather than a mechanistic response to chemotherapy. So, in place of chemotherapy, is there a better way to select patients for treatment? As we move into the era of personalized medicine and next- generation sequencing, evaluation of the tumor microenvironment will become even more important to our patients.
Among tumors in humans, squamous cell carcinomas of the head and neck are quite immunosuppressive. Of the immune-infiltrating tumors, head and neck cancers have the highest regulatory T-cell (Treg)/CD8-positive T-cell infiltration ratio and the highest median Treg infiltration.6 Following salvage laryngectomy, Hoesli et al7 reported improvements in disease-free and disease-specific survival in patients with laryngeal cancer whose CD8-positive tumor-infiltrating lymphocytes are elevated.
The programmed cell death ligand 1 (PD-L1) inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) are now approved for recurrent/metastatic disease.8,9 The combinations of PD-L1 inhibitors with targeted modulators of Treg function, such as cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and indoleamine 2,3-dioxygenase (IDO) inhibitors, may provide even further therapeutic benefit. We eagerly await the results of ongoing combination studies, as well as trials incorporating immune modulators with radiation therapy, all of which may impact the future of laryngeal preservation.
Focus on Quality of Life
Until newer organ-preserving strategies are developed, we must for now rely on our standard treatments with surgery and platinum-based chemotherapy with radiation. Additionally, we must also consider what is most important in selecting patients for surgery, radiation, or chemoradiotherapy, focusing particularly on our efforts to preserve quality of life. Although combined-multimodality treatments have improved survival and increased disease control for locally advanced cancers, they come at a price. Acute and long-term adverse effects greatly impact function and ultimately a patient’s sense of well-being. Our ultimate goal is to cure patients, but alterations in speech, eating, and appearance can lead to social isolation, depression, and suicide. Studies have demonstrated that improvements in quality of life beyond one’s ability to speak are primarily related to betterment of emotional well-being, lack of pain, and fewer depressive symptoms.1,10 Additionally, laryngectomy does not negatively impact long-term quality of life with successful rehabilitation, again suggesting the appropriate incorporation of surgery or endoscopic resection for patients who qualify for these procedures.11,12
With this in mind, the authors of the newly updated guideline should be highly commended for their additional recommendations for comprehensive pretreatment evaluations of voice and swallowing in all patients. If our focus is only on cure, we may win the battle by improving survival but ultimately lose the war if we are not conscious of the functional and psychosocial needs/desires of our patients.
Although comprehensive evaluations of speech and swallowing can guide treatment strategies, it is the expertise of the multidisciplinary care team that ultimately ensures the improvements in quality of life and functional outcomes. Vast heterogeneity exists among T1 and T2 tumors, for example, and the decision to proceed with endoscopic surgery vs radiation therapy can only be made by those with experience. Similarly, patients with advanced disease selected for nonsurgical interventions must be carefully assessed for their ability to maintain cord mobility and function.
Complicating matters further, a large number of patients with laryngeal cancer present with comorbid illness, often as a result of extensive tobacco consumption, limiting their abilities to receive more aggressive care. American national databases show better survival rates in patients with laryngeal cancers who receive their care at high-volume centers,13 and Lassig et al14 have reported a 20% improvement in overall survival in patients treated in an academic setting. Due to the complexity of the multimodality therapies we deliver, all patients should be evaluated initially by a comprehensive multidisciplinary team and ideally receive care from those who are highly trained.
Closing Thoughts
The newly updated guidelines for larynx-preservation strategies are not radically different from those published in 2006. However, they do capitalize on the pertinent role for surgery as well as the need for comprehensive pretreatment evaluations. As we continue to advance the field of laryngeal preservation, we must continue to be mindful of what is vitally important to our patients, particularly quality of life as it relates to functionality and overall well-being. Fundamentally, our patients need a “voice,” both literally and figuratively. ■
Dr. Worden is a medical oncologist in the Department of Internal Medicine, Division of Medical Oncology, University of Michigan, Ann Arbor.
DISCLOSURE: Dr. Worden has received funding for clinical trials from Merck, Bristol-Myers Squibb, and AstraZeneca.
REFERENCES
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