BY EZRA COHEN, MD, FRCPC
Associate Professor, Department of Medicine
Co-Director, Head and Neck Cancer Program
Program Director, Hematology/Oncology Fellowship Program
Associate Director for Education
University of Chicago Comprehensive Cancer Center
In many ways larynx cancer and its treatment epitomizes many of the nuances and considerations involved in treating patients with locally advanced squamous cell carcinoma of the head and neck. Larynx cancer is a disease that presents predominantly with local or locoregional involvement as opposed to manifesting with distant metastasis. Therefore, the great majority of patients will be treated with curative intent; however, the disease and its treatment can have profound effects on function and quality of life. Each patient is then approached with the goal of optimizing survival and minimizing long-term toxicity.
Larynx cancer is a tobacco-associated disease and, as such, the incidence in the United States and most developed countries is declining due to lower smoking rates. Nonetheless, it remains an important entity, where treatment decisions can make an extreme difference in outcome.
The majority of patients that I manage as a medical oncologist have locoregionally advanced disease -- stage III, IVa, or IVb -- where a multidisciplinary approach will be considered, usually consisting of some form of chemoradiotherapy.
Complete staging consists of nasopharygolaryngoscopy to delineate the extent of the primary tumor. At many centers, including our own, a bronchoscopy and esophagoscopy are performed at the same time to exclude the possibility of metachronous primary tumors of the aerodigestive tract. In very advanced cases, consideration is given to tracheostomy, with the realization that the start of radiotherapy can be associated with an increase in edema that can compromise the airway. Correspondingly, if nutrition has been moderately compromised by tumor-related dysphagia, a gastrostomy tube can be placed to restore intake.
Initial imaging usually consists of computed tomography scanning of the neck and chest -- the former with thin cuts through the larynx and the latter to further exclude a second primary tumor or metastatic disease. Rarely, an MRI will be used to help define tumor stage.
Baseline swallowing function is assessed to establish a baseline and guide long-term therapy for speech and swallowing. If an organ preservation approach is considered, the patient will undergo radiation oncology planning.
Upon completion of initial staging and stabilization, we engage patients in a discussion of organ preservation versus primary laryngectomy. The evidence to support a non-surgical primary approach originated with the VA Laryngeal Cancer Study (NEJM 1991;324:1685-1690), which randomized subjects to surgery or sequential chemotherapy and radiotherapy. The non-surgical arm consisted of two cycles of cisplatin/5-fluoropyrimidine (5-FU) followed by a third cycle in responding subjects and radiotherapy. Equivalent survival was reported between the two arms, with approximately two-thirds of subjects in the experimental arm avoiding a laryngectomy. A similar study conducted in Europe in subjects with hypopharyngeal cancer supported these results, and sequential chemoradiotherapy became an accepted standard of care.
Following these results, RTOG 91-11 adopted sequential chemoradiotherapy as the control arm in a Phase III randomized trial in patients with larynx cancer and compared this against concurrent chemoradiotherapy (cisplatin 100 mg/m2 every three weeks with single-daily fractionated radiotherapy) or radiotherapy alone. The five-year results of this study support the benefit of concurrent chemoradiotherapy with respect to larynx preservation, locoregional control, and disease-free survival. Notably, there was no difference in overall survival between the three arms as most recurrences could be salvaged with surgery. Moreover, concurrent chemoradiotherapy was associated with the greatest acute toxicity underscoring the importance of choosing patients appropriately for this approach.
More recently, the optimal neoadjuvant chemotherapy regimen was explored in patients who were candidates for laryngectomy, comparing cisplatin/5-FU with or without docetaxel (TPF). In this study, TPF improved larynx preservation, progression-free survival, and organ function. Therefore, TPF neoadjuvant chemotherapy was administered in a follow-up study that administered three cycles followed by randomization in responding subjects with use of cisplatin-radiotherapy or cetuximab-radiotherapy.
Although both arms appeared equivalent with respect to larynx preservation and survival, a greater percentage of subjects randomized to cisplatin-radiotherapy did not receive the intended therapy while one-fifth continued to report long-term renal toxicity, which strongly suggests that administration of three cycles of cisplatin-containing neoadjuvant chemotherapy followed by three cycles of cisplatin concurrently with radiotherapy is challenging.
At the University of Chicago, we have adopted a non-cisplatin containing concurrent chemoradiotherapy regimen consisting of 5-FU, hydroxyurea, and radiotherapy administered in a split-course, week-on/week-off basis. In patients with stage IV disease, paclitaxel is added to the regimen and radiotherapy is administered in an hyperfractionated manner (150 cGY per fraction) twice daily (TFHX). In fact, this regimen has proven effective with high rates of functional organ preservation. In a retrospective review of patients enrolled in clinical trials employing TFHX, 89 and 90 percent of patients had normal or near normal speech and swallowing function, respectively (Arch Otolaryngol Head Neck Surg 2010;136:1226-1234).
One area in this disease where clinicians remain unreasonably dogmatic is in patients with large-volume T4 tumors. These cancers can extend through cartilage and invade secondary structures. As such, a widely held belief is that function cannot be preserved and that radiotherapy is less effective when cartilage destruction is present. However, one must realize that the appropriate surgery in these patients, laryngectomy, would be offered to a patient with residual disease or non-functioning larynx. Therefore, it is reasonable to attempt chemoradiotherapy in many of these patients.
Our group examined patients treated on clinical trials administering TFHX with large volume larynx cancer (Head Neck 2012;34:1162-1167). Fifty-five patients were identified with five-year overall, disease-specific, and progression-free survivals of 49, 74, and 48 percent, respectively. Moreover, two-thirds of patients had Swallowing Performance Status Scale (SPSS) scores of ≤5, indicating that a gastrostomy tube was not required to maintain nutrition.
There are multiple considerations, therefore, when treating a patient with larynx cancer. Initial steps include staging and ascertaining whether a curative, organ-preservation approach is appropriate. For many patients this will consist of concurrent chemoradiotherapy of cisplatin (100 mg/m2) and single-daily fractionated radiotherapy. For almost two decades we have used an FHX-based regimen in these patients with appreciable success including those with large volume disease.
Current efforts are focused on further stratifying patients based on molecular characteristics of the tumor that will allow greater patient selection for chemoradiotherapy and even guide which agents are likely to be most effective.