Source: www.medpagetoday.com
Author: Kristin Jenkins, contributing writer, MedPage Today

In patients with head and neck malignancies, studies show that the significant acute and long-term toxicities and poor quality of life (QOL) associated with postoperative radiation therapy (PORT) can be improved by selectively reducing larger radiotherapy volumes. This includes treating just one side of the neck.

In patients with locally advanced head and neck squamous cell carcinoma (HNSCC), however, locoregional failure rates with the omission of PORT to the pathologically uninvolved neck (PN0) have been less clear. As a result, PORT has historically been delivered to the PN0 neck, with several studies showing high rates of regional control ranging from 95% to 100%. Notably, consensus clinical practice guidelines continue to recommend the use of bilateral irradiation of node-negative necks.

However, results from a prospective phase II study in 72 patients with primary HNSCC and high-risk pathology features now suggest that PORT to the PNo neck can be eliminated without sacrificing excellent disease control or QOL. At a median follow-up of 53 months, absolute regional control in the unirradiated neck was 97%, even though 67 patients (93%) had stage III/IV disease and 71% of tumors involved or crossed midline.

No patient received contralateral neck PORT, and 17 patients (24%) were treated for the primary neck tumor only, said Wade Thorstad, MD, of Washington University in St. Louis, and colleagues. The 5-year rates of local control, regional control, progression-free survival, and overall survival (OS) were 84%, 93%, 60%, and 64%, respectively, they reported in their study in the Journal of Clinical Oncology.

The study also showed that QOL measures were not significantly different from baseline at 1 year and 2 years post-completion of PORT (P>0.05).

“Our study demonstrated that this approach is safe and results in excellent control in a high-volume center where physicians are sub-site specialists,” Thorstad told the Reading Room. “All patients had complete preoperative staging and were discussed in a multidisciplinary setting. In this context, we feel this approach is reasonable, although confirmatory studies are needed.”

Has Been Ongoing Challenge
Achieving optimal disease control using the smallest volumes of QOL-destroying radiotherapy remains an ongoing clinical challenge for clinicians managing various subgroups of patients with HNSCC. What’s more, uncertainty about how to find the right balance between survival and QOL may have been seeded almost 50 years ago.

In October 1971, results from a seminal review of metastasis in previously untreated patients with HNSCC were presented at the annual meeting of ASTRO, then called the American Society of Therapeutic Radiologists and now the American Society for Radiation Oncology. In that presentation, Robert Lindberg, MD, of the University of Texas MD Anderson Cancer Center in Houston, included detailed maps of the seven common regions of metastasis seen on admission in 2,044 previously untreated patients.

Meanwhile, evidence for the impact of larger radiotherapy volumes on patients’ QOL has continued to accumulate. In 2009, a review of dysphagia related to treatment for HNSCC confirmed that the severity of radiation-associated effects on the tongue, larynx, and pharyngeal muscles is directly related to dosimetry.

The review authors noted that in addition to dysphagia and aspiration — recognized as potentially devastating complications of irradiation of the head and neck — the acute side effects of radiotherapy in HNSCC include xerostomia, hoarseness, erythema, and desquamation of the skin. Potential late sequelae include osteonecrosis, dental decay, trismus, hypogeusia, subcutaneous fibrosis, thyroid dysfunction, esophageal stenosis, hoarseness, and damage to the middle or inner ear.

Although radiation-induced xerostomia is also the most commonly reported late side effect, swallowing problems and the risk of aspiration remain the dose-limiting toxicity.

In the last 2 decades, advances in treatment technology have made significant strides towards improved survival that does not forfeit QOL. The widespread adoption of three-dimensional intensity-modulated radiation therapy (IMRT) in locally advanced HNSCC has made it possible to selectively restrict treatment volumes, sparing normal tissue.

A 2014 analysis of 50 consecutive survivors of locally advanced HNSCC at the University of California-Davis Comprehensive Cancer Center provided evidence for improved long-term QOL with IMRT. Five years after bilateral neck IMRT, the vast majority of patients reported being satisfied with their QOL. Using the University of Washington Quality of Life (UW-QOL) questionnaire, 41 of 50 patients (82%) rated their overall QOL as “outstanding” or “very good.”

At 5 years, the lowest domain score on the UW-QOL questionnaire was salivary function. Nevertheless, 42 patients (84%) reported saliva “of normal consistency” or “less saliva than normal but enough.” Although eight patients (16%) said they had “too little saliva,” none reported having “no saliva.”

In a 2017 study, Thorstad and colleagues reported that unilateral IMRT delivered oncologic outcomes similar to those of bilateral IMRT in 154 patients with surgically treated squamous cell carcinoma of the palatine tonsil. There were no contralateral neck recurrences in the unilateral IMRT group. In addition, patient self-reports indicated that those treated unilaterally had less acute toxicity, less need for use of gastrostomy tubes, and better QOL than patients treated bilaterally.

“Significant controversy remains regarding the use of unilateral RT in some subgroups of patients with palatine tonsillar cancer, particularly in those with N2b neck disease,” the study authors noted. “[Although] the 2011 American College of Radiology (ACR) appropriateness criteria recommended bilateral RT for this subgroup of patients, some authors challenged this recommendation.”

As far back as 1999 — the year that IMRT was introduced — the Brazilian Head and Neck Cancer Study Group reported that radiotherapy volumes could be safely reduced using unilateral rather than bilateral neck treatment in patients with PN0 necks. The findings showed that the rates of 5-year OS, neck recurrence, and complications were similar in both groups. When PORT was omitted in 83 patients with PN0 necks, there were only three treatment failures.

In Australia, experience at the Peter MacCallum Cancer Center at the University of Melbourne also appears to support the potential use of unilateral radiation therapy for lateralized tonsil primaries, even with advanced ipsilateral nodal disease. Results from a 2013 retrospective review of all 167 tonsillar cancer patients treated with curative intent (1990-2002) showed that the 5-year rates for local, nodal, locoregional, and distant failures were 14%, 4%, 18%, and 8%, respectively. The majority (58%) of patients had stage IV disease, and 86% were current or ex‐smokers. There were no contralateral nodal failures in 58 patients treated unilaterally, even though 33% had N2a, N2b, or N3 nodal disease.

Evidence for improved morbidity with IMRT restricted to the ipsilateral neck is also growing. In 2011, the phase III randomized controlled PARSPORT study demonstrated significant functional and overall QOL benefits in pharyngeal squamous cell carcinoma (T1-4, N0-3, M0) with the use of parotid-sparing IMRT compared with conventional radiotherapy.

In 94 patients treated at six radiotherapy centers in the U.K., significant recovery of saliva secretion was seen at 12 and 24 months with IMRT compared with conventional radiotherapy. Clinically significant improvements in dry mouth-related and global QOL scores were also reported. At 2 years, there were no significant differences in non-xerostomia late toxicities, locoregional control, or OS between the groups.

In 2007, results from a Danish study in patients with cancer of the oropharynx showed that ipsilateral radiotherapy of curative intent did not negatively influence locoregional control or survival compared with bilateral radiotherapy. In fact, the researchers found that the only factors that differed between the two treatment groups were primary tumor extension outside the tonsillar fossa and T stage.

However, the significant difference in adverse effects seen in patients who received ipsilateral treatment were compelling. These patients experienced a 50% reduction in moderate to severe treatment side effects compared with those treated with bilateral radiotherapy. This included all radiotherapy-induced morbidity — xerostomia, dysphagia, hoarseness, atrophy, and edema — with the exception of fibrosis.

Note:
Thorstad reported a financial relationship with Elekta; several co-authors also disclosed financial relationships with industry.