Risk and Clinical Risk Factors Associated With Late Lower Cranial Neuropathy in Long-term Oropharyngeal Squamous Cell Carcinoma Survivors

Abstract

IMPORTANCE Lower cranial neuropathy (LCNP) is a rare, but permanent, late effect of radiotherapy and other cancer therapies. Lower cranial neuropathy is associated with excess cancer-related symptoms and worse swallowing-related quality of life. Few studies have investigated risk and clinical factors associated with late LCNP among patients with long-term survival of oropharyngeal squamous cell carcinoma (OPSCC survivors). OBJECTIVE To estimate the cumulative incidence of and identify clinical factors associated with late LCNP among long-term OPSCC survivors. DESIGN, SETTING, AND PARTICIPANTSThis single-institution cohort study included disease-free adult OPSCC survivors who completed curative treatment from January 1, 2000, to December 31, 2013. Exclusion criteria consisted of baseline LCNP, recurrent head and neck cancer, treatment at other institutions, death, and a second primary, persistent, or recurrent malignant neoplasm of the head and neck less than 3 months after treatment. Median survival of OPSCC among the 2021 eligible patients was 6.8 (range, 0.3-18.4) years. Data were analyzed from October 12, 2019, to November 13, 2020.MAIN OUTCOMES AND MEASURES Late LCNP events were defined by neuropathy of the glossopharyngeal, vagus, and/or hypoglossal cranial nerves at least 3 months after cancer therapy. Cumulative incidence of LCNP was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were fit. RESULTS Among the 2021 OPSCC survivors included in the analysis of this cohort study (1740 [86.1%] male; median age, 56 [range, 28-86] years), 88 (4.4%) were diagnosed with late LCNP, with median time to LCNP of 5.4 (range, 0.3-14.1) years after treatment. Cumulative incidence of LCNP was 0.024 (95% CI, 0.017-0.032) at 5 years, 0.061 (95% CI, 0.048-0.078) at 10 years, and 0.098 (95% CI, 0.075-0.128) at 15 years of follow-up. Multivariable Cox proportional hazards regression identified T4 vs T1 classification (hazard ratio [HR], 3.82; 95% CI, 1.85-7.86) and accelerated vs standard radiotherapy fractionation (HR, 2.15; 95% CI, 1.34-3.45) as independently associated with late LCNP status, after adjustment. Among the subgroup of 1986 patients with nonsurgical treatment, induction chemotherapy regimens including combined docetaxel, cisplatin, and fluorouracil (TPF) (HR, 2.51; 95% CI, 1.35-4.67) and TPF with cetuximab (HR, 5.80; 95% CI,) along with T classification and accelerated radiotherapy fractionation were associated with late LCNP status after adjustment. CONCLUSIONS AND RELEVANCEThis single-institution cohort study found that, although rare in the population overall, cumulative risk of late LCNP progressed to 10% during the survivors' lifetime. As expected, clinical factors associated with LCNP primarily reflected greater tumor burden and treatment intensity. Further efforts are necessary to investigate risk-reduction strategies as well as surveillance and management strategies for this disabling late effect of cancer treatment.

Human organ donor-derived vagus nerve biopsies allow for well-preserved ultrastructure and high-resolution mapping of myelinated and unmyelinated fibers

“…Although an individual malignancy may contribute to a neuropathy, multiple treatment modalities for malignancies may more commonly compromise peripheral nerve health. For instance, radiation therapy applied to the neck and thorax may induce peripheral neuropathy, including mononeuropathy of the vagus nerve 38 – 40 . Drug-induced neurotoxicity, including a painful peripheral neuropathy, is a common adverse effect during the treatment course of many malignancies and may require dose reduction or cessation of chemotherapeutic agents 41 , 42 .…”

Risk factors associated with patient‐reported fatigue among long‐term oropharyngeal carcinoma survivors

“…We acknowledge the relatively small number of patients with late lower cranial neuropathy in our study leading to wide confidence intervals. However, this association was expected as we previously reported an association between late lower cranial neuropathy and worse cancer treatment‐related symptoms, including mean fatigue scores and problems with swallowing, mucus, choking, and voice and speech, in this sample of OPC survivors 13,20,31 . Patients with late lower cranial neuropathy experience substantial swallowing impairment, which over time can contribute to compromised nutritional status characterized by malnutrition, anorexia, anemia, micronutrient insufficiency, cachexia, and other symptoms 13,20 .…”

“…Cigarette smoking status was determined as follows: participants who smoked less than 100 cigarettes in their lifetime were classified as never smokers; those who smoked more than 100 cigarettes but had quit at least 6 months before diagnosis were considered former smokers at the time of diagnosis 29,30 ; and finally, current smokers at the time of diagnosis were further categorized into those who quit subsequently and those who continued to smoke and were smokers at the time of the survey 29,30 . Late lower cranial neuropathy was defined as onset 3 or more months after the end of OPC treatment and included lower cranial neuropathy of cranial nerves IX (glossopharyngeal), X (vagus), and XII (hypoglossal) 31 . Details are provided in previous publications 13,31 .…”

“…Late lower cranial neuropathy was defined as onset 3 or more months after the end of OPC treatment and included lower cranial neuropathy of cranial nerves IX (glossopharyngeal), X (vagus), and XII (hypoglossal) 31 . Details are provided in previous publications 13,31 . Information on patient‐reported thyroid problems was collected from the OPC survivorship survey question: “Since your cancer treatment, has a doctor or other health professional told you that you have: A thyroid problem?” with yes/no/do not know as response options.…”

Supportive Care in Head and Neck Cancers: Multidisciplinary Management

“…9 He noted a recent study out of MD Anderson that looked at the risk of lower cranial neuropathy in almost 2,000 patients with oropharyngeal cancer. 10 "Their numbers at 5 years pretty much agree-at around 2%although this risk increases with even longer follow-up," he added. The study also suggested some other risk factors for late cranial neuropathy, including accelerated radiation and neurotoxic chemotherapy agents.…”