Adaptive RT Fails to Relieve Dry Mouth in Head and Neck Cancer

Use of weekly adaptive radiotherapy (RT) failed to decrease xerostomia (dry mouth) in oropharyngeal cancer patients when compared with standard intensity-modulated RT (IMRT), the phase III ARTIX trial found.

Of the 131 patients included in the French study, mean salivary flow when stimulated with paraffin was no different between the adaptive RT and IMRT arms at 12 months (630 vs 584 mg/min, P=0.64), reported researchers led by Joël Castelli, MD, PhD, of the Centre Eugène Marquis in Rennes, France.

By that point, an identical proportion of patients in each arm (48%) experienced xerostomia, defined as a salivary flow of under 500 mg/min, the group detailed in JAMA Oncology.

"Adaptive radiotherapy appeared to be technically feasible and safe and did not decrease local disease control and survival," Castelli and colleagues wrote. "However, this expensive and intensive process did not translate into a clinical benefit."

Xerostomia in patients with head and neck cancer is mainly caused by damage to the parotid gland from RT, Castelli and colleagues explained. In discussing the rationale behind the study, they noted that the standard therapy of chemoradiation with IMRT has been shown to reduce the dose to the parotid gland and decrease xerostomia.

However, while IMRT is based on a single initial planning CT scan, but "large anatomical variations can be observed during the treatment course. These variations may result in parotid gland overdose and, therefore, an increased risk of xerostomia."

The hope in this trial was that adaptive RT, with its ability to adjust a radiotherapy plan during the treatment course to account for changes in tumor and normal tissue volumes and positions, might be able to reduce the incidence of xerostomia.

Improvement in excretory function of the parotid gland, as assessed by salivary scintigraphy, did favor the adaptive RT arm at 12 months (48% vs 41% with IMRT, P=0.02), but no significant differences in other secondary endpoints were observed, including toxic effects and patient-reported outcomes.

In a commentary accompanying the study, Beth Beadle, MD, PhD, of Stanford University School of Medicine in California, and Annie Chan, MD, of Harvard Medical School in Boston, suggested that there could be several explanations for the failure of adaptive RT to show a benefit in this trial.

For example, they pointed out that the RT doses received by the submandibular gland and oral cavity were higher than expected, while the dose received by the parotid salivary gland was within the normal range.

"It is not surprising that the authors found an increase in parotid outflow (by scintigraphy) and not overall saliva production," wrote Beadle and Chan. "This study underscores the importance of sparing other salivary glands, in addition to the parotid glands, to minimize xerostomia."

The study was conducted at 11 French centers. Adults ages 18 to 75 years with stage III-IVB squamous cell oropharyngeal cancer receiving treatment with chemoradiotherapy were enrolled from July 2013 to October 2018 and randomized to either adaptive RT (n=66) or standard IMRT (n=65). All patients received a total dose of 70 Gy in 35 fractions and concomitant chemotherapy, with cisplatin most common. The median follow-up was 26.4 months.

Participants had a mean age of 60 years, and more than 85% were men. Patients in the adaptive RT arm underwent far more CT scans, with 94% having six or seven scans. In the standard arm, patients had no more than two CT scans.

Mean salivary flow at 12 months was the primary endpoint. At baseline, mean salivary flow following paraffin stimulation was 1,231 mg/min in the adaptive RT group and 1,028 mg/min in the standard arm (P=0.16).

Secondary endpoints included overall survival (OS), progression-free survival (PFS), disease control, and acute and late toxic effects.

OS rates at 12 months were 81.5% in the adaptive RT arm and 86.2% in the standard arm, and no significant differences were seen at 2 years between the two groups, respectively, for any of the following:

• Locoregional recurrence rate: 23.7% vs 22.5%
• Distant metastasis rate: 13.9% vs 18.4%
• OS: 76.9% in each arm
• PFS: 61.5% in each arm

No differences were seen for acute toxic effects either, with the rate of acute xerostomia of grade ≥2 seen in 28.8% of patients in the adaptive RT arm and 23.1% of those in the standard arm. Regarding late toxic effects, the rate of xerostomia of grade ≥2 at 12 months was 51.8% versus 53.5%.

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