Date of Award

Spring 12-2019

Degree Name

Doctor of Philosophy (Medical Science)

Advisor(s)

Dr. Xianglin L. Du, MB MS PhD

Second Advisor

Dr. Katherine A Hutcheson, PhD

Third Advisor

Dr. Linda B. Piller, MD MPH

Abstract

Background: Lower cranial neuropathy (LCNP) is a rare but potentially disabling late effect of radiotherapy (RT) and other head and neck cancer therapies. Survivors who develop late LCNP may experience profound functional impairment with deficits in swallowing, speech, and voice. The aims of this research were: 1) to quantify the cumulative incidence of late LCNP and identify clinical predictors of late LCNP; 2) to investigate the impact of late LCNP on severity of cancer treatment-related symptoms, general functional impairment (GFI), and single item scores of the most severe symptoms; and 3) to quantify the association of late LCNP with swallowing-related quality of life (QoL) and functional status among long-term oropharyngeal cancer (OPC) survivors. Methods: For the first aim of this dissertation the study population included 2,021 OPC survivors (median survival: 6.8 years) who received primary treatment at MD Anderson Cancer Center from 2000 to 2013. A retrospective cohort study was conducted and late LCNP events for all three studies were defined by neuropathy of the glossopharyngeal (IX), vagus (X), and/or hypoglossal (XII) nerves ≥3-months after cancer therapy and abstracted from medical records along with other study variables. For the second and third study, a cross-sectional survey analysis among 889 OPC survivors nested within a retrospective cohort of OPC survivors treated during January 2000 -December 2013 at MD Anderson Cancer Center was conducted (56% response rate). The survey included MD Anderson Symptom Inventory Head and Neck Cancer Module (MDASI-HN) and MD Anderson Dysphagia Inventory (MDADI) among other items. For the first study, cumulative incidence of LCNP was estimated using the Kaplan Meir method with adjustment for competing risks using time to event as the underlying metric. Log-rank test was used to assess differences between groups by LCNP status, and multivariable Cox proportional hazard models were fit. For the second study, the primary outcome variable was the mean of the top 5 most severely scored symptoms from MD Anderson Symptom Inventory Head and Neck Cancer Module (MDASI-HN) out of all 22 core and HNC-specific symptoms. Secondary outcomes included mean MDASI-HN interference scores and single item scores of the most severe symptoms. Multivariate models regressed MDASI-HN scores on late LCNP status adjusting for clinical covariates. Finally, for the third study, multivariate models regressed MDADI scores on late LCNP status adjusting for clinical covariates. Results: For the first study; 4.4% (n=88) OPC survivors were diagnosed with late LCNP with median time to LCNP onset after treatment of 5.4 (range, 0.3-14.1; IQR: 1.6-8.5) years post-treatment. Cumulative incidence of LCNP among all OPC survivors was 0.02 (95% CI: 0.02-0.03), 0.06 (95% CI: 0.05-0.08), and 0.10 (95% CI: 0.08-0.13) at 5 years, 10 years, and 18 years of follow-up, respectively. Multivariable Cox regression identified T4 stage vs T1 stage (HR: 3.82; 95%CI: 1.85-7.86, p=0.000) and accelerated RT fractionation vs standard RT fractionation (HR 2.15, 95%CI 1.34-3.45, p=0.002) independently associated with late LCNP status, adjusting for age, subsite, T-stage, smoking and therapeutic modality. In the second and third, cross-sectional survey analysis study overall, 4% (n=36) of 889 OPC survivors (median survival time: 7 years) developed late LCNP with median time to onset of 5.25 years post-treatment. Late LCNP was significantly associated with worse mean top 5 MDASI-HN symptom scores (coefficient, 1.54; 95%CI, 0.8, 2.2) adjusting for age, survival time, sex, therapeutic modality, T-stage, subsite, type of radiotherapy, smoking, and normal diet prior to treatment. Late LCNP was also associated with single item scores for difficulty swallowing/chewing (coefficient, 2.25; 95%CI, 1.3, 3.1), mucus (coefficient, 1.97; 95%CI, 1.0, 2.9), fatigue (coefficient, 1.35; 95%CI, 0.4, 2.2), choking (coefficient, 1.53; 95%CI, 0.6, 2.4), and voice/ speech symptoms (coefficient, 2.3; 95%CI, 1.6, 3.0) in multivariable models. However late LCNP was not significantly associated with mean interference scores after correction for multiple comparisons. LCNP cases reported significantly worse mean composite MDADI (LCNP: 68.0 vs. no LCNP: 80.2, p<0.001). Late LCNP independently associated with worse mean composite MDADI (β= -6.7, p=0.015, 95%CI: -12.0, -1.3) as well as all MDADI domains after multivariate adjustment. Finally, LCNP cases were more likely to have a feeding tube at time of survey (OR= 20.5; 95%CI, 8.6 to 48.9), history of aspiration pneumonia (OR= 23.5; 95%CI, 9.6 to 57.6), and tracheostomy (OR= 26.9; 95%CI, 6.0 to 121.7).

Conclusion: Risk of late LCNP progressed over time to exceed 10% cumulative risk over survivors’ lifetime even though it is considered a rare late effect. Our prediction model enabled identification of OPC survivors who had T4 tumors and those who received accelerated fractionation RT treatment as having higher risk of late LCNP. In the large survey study, OPC survivors with late LCNP reported significantly worse cancer treatment related symptoms, significantly poorer swallowing-related QOL and had significantly higher likelihood of poor functional status demonstrating the impact of late LCNP on both symptom severity and functional burden. Further, efforts are necessary to investigate the risk and predictors for this disabling late effect of cancer treatment, address severity of treatment related symptoms and optimize swallowing outcomes to improve QoL among growing numbers of relatively younger OPC survivors, who are expected to survive decades after treatment.

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