Impact of neurofibromatosis type 1 with plexiform neurofibromas on the health-related quality of life and work productivity of adult patients and caregivers in the UK: a cross-sectional survey.

BACKGROUND: Plexiform neurofibromas (PN) are complex, benign nerve-sheath tumours that occur in 30-50% of patients with neurofibromatosis type 1 (NF1), a rare, genetic disorder. PN are associated with substantial, heterogeneous morbidities that impact health-related quality of life (HRQoL), including affecting motor function and causing pain, though HRQoL and work productivity data are scarce. This UK cross-sectional study explored HRQoL and work productivity in adult patients with NF1 PN and caregivers of paediatric patients. METHODS: Adult patients and caregivers of paediatric patients self-enrolled in an online survey (March-April 2021). Outcomes included EQ-5D-5L, PROMIS® GH and INF1-QOL (adult patients only), and EQ-5D-5L, CarerQol and WPAI (caregivers only). Utilities were estimated from EQ-5D-5L responses using the UK crosswalk value set. Linear regression models explored univariable associations between adult patient characteristics and HRQoL. RESULTS: Mean (± standard deviation) EQ-5D utility in adult patients with NF1 PN was 0.65 (± 0.29; n = 35; age-/sex-matched norm: 0.89 [± 0.04]). Moderate-extreme pain/discomfort and anxiety/depression were reported by 14/35 (40.0%) and 18/35 (51.4%) patients, respectively. Mean PROMIS® GH physical and mental health scores were 43.6 (± 9.19) and 41.7 (± 11.5; n = 35; matched norm: 50.0 [± 10.0]). Mean INF1-QOL score was 11.03 (± 6.02; n = 33). Chronic itching, at least one symptom, at least one comorbidity, PN location at extremities (arms/legs) and pain were associated with worse HRQoL scores. Mean caregiver EQ-5D utility was 0.72 (± 0.24; n = 8; age-/sex-matched norm: 0.88 [± 0.03]). Moderate pain/discomfort and moderate-severe anxiety/depression were reported by 4/8 (50.0%) and 2/8 (25.0%) caregivers, respectively. Mean CarerQol score was 69.3 (± 13.9; n = 8). Mean WPAI regular activity productivity loss was 36.3% (± 31.6%; n = 8). CONCLUSIONS: NF1 PN worsens adult patient and caregiver HRQoL compared to the general population, notably affecting pain and discomfort, anxiety and depression and caregiver productivity.

Patient-centered outcomes in the POLO study of active maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.

BACKGROUND: The phase 3 POLO study demonstrated a significant progression-free survival (PFS) benefit and preserved health-related quality of life (HRQOL) for active maintenance treatment with olaparib vs placebo in patients with metastatic pancreatic cancer and a germline BRCA mutation. Here, we present a post hoc analysis of the patient-centered outcomes: time without significant symptoms of disease progression or toxicity (TWiST) and quality-adjusted TWiST (Q-TWiST). METHODS: Patients were randomized 3:2 to maintenance olaparib (300 mg tablets twice daily) or placebo. Overall survival time was divided into TWiST, toxicity (TOX; time before disease progression with significant symptoms of toxicity), and relapse (REL; time after disease progression until death or censoring). Q-TWiST was the sum of TWiST, TOX, and REL, each weighted by HRQOL utility scores during the relevant health-state period. A base-case and three sensitivity analyses were performed using differing definitions of TOX. RESULTS: In total, 154 patients were randomized (olaparib, n = 92; placebo, n = 62). TWiST was significantly longer for olaparib than placebo in the base-case analysis (14.6 vs 7.1 months; 95% CI, 2.9-12.0; p = .001) and all sensitivity analyses. No statistically significant benefit for Q-TWiST was observed in the base-case analysis (18.4 vs 15.9 months; 95% CI, -1.1 to 6.1; p = .171) or the sensitivity analyses. CONCLUSION: These results support the previous findings that maintenance olaparib significantly improves PFS relative to placebo without compromising HRQOL and demonstrate that the clinically meaningful benefits of olaparib persist even when symptoms of toxicity are considered.

Health-Related Quality of Life of Patients with Metastatic Pancreatic Cancer: A Systematic Literature Review.

Background: Metastatic pancreatic cancer (mPaC) has a poor prognosis and available treatments provide only moderate improvements in survival. Preserving or improving health-related quality of life (HRQoL) is therefore an important treatment outcome for patients with mPaC. This systematic review identified HRQoL data in patients with mPaC before and after treatment, compared these with data from the general population, and reported the effects of different mPaC treatments on HRQoL. Methods: Searches were performed in Embase, PubMed, and the Cochrane Library from January 2008 to May 2021, and the articles identified were screened for HRQoL data in patients with mPaC. Abstracts from relevant congresses were also manually searched. Publications included were randomized controlled trials and observational studies written in English that reported HRQoL data for adult patients with non-resectable mPaC who were on or off treatment. Results: Thirty relevant publications were identified and HRQoL scores were collected. Overall, baseline mean scores from the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), 5-dimension EuroQol questionnaire (EQ-5D), and Functional Assessment of Cancer Therapy-General (FACT-G) for newly diagnosed and previously treated patients with mPaC were worse than those of the general population. Baseline scores were generally better for previously treated patients than for newly diagnosed patients, indicating that mPaC treatments preserve or improve HRQoL. Identified publications also reported changes in HRQoL following first- or subsequent-line chemotherapy. When reported, 10 studies found improvements in overall HRQoL compared with baseline scores, four reported no changes in overall HRQoL after treatment, and six found deteriorations in overall HRQoL. Conclusion: Patients with mPaC had worse HRQoL than the general population. Available anti-cancer therapies can improve or preserve HRQoL.

Burden Among Caregivers of Pediatric Patients with Neurofibromatosis Type 1 (NF1) and Plexiform Neurofibroma (PN) in the United States: A Cross-Sectional Study.

INTRODUCTION: Patients with neurofibromatosis type 1 (NF1) may develop plexiform neurofibromas (PNs) that can cause disfigurement, pain, and dysfunction, and may even be life-threatening. Studies have indicated NF1-PN can substantially impact the quality of life (QoL) of pediatric patients. However, research on caregiver burden is scarce. METHODS: Caregivers of pediatric patients ages 2-18 years with NF1-PN in the USA were recruited through the Children's Tumor Foundation to participate in an online cross-sectional survey (December 2020-January 2021). Caregiver burden was measured using the Zarit Burden Interview (ZBI), and productivity loss from patientcare was measured using the Work Productivity and Activity Impairment questionnaire, adapted for caregiving (WPAI:CG). RESULTS: Ninety-five caregivers were recruited with a median age of 44.0 years. Most were female (88.4%), white/Caucasian (85.3%), and did not have NF1 or PN (86.3% and 89.5%, respectively). Commonly reported health conditions among caregivers include anxiety (48.4%) and depression (34.7%). On the ZBI (range 0-88; higher = greater burden), mean (SD) scores were 23.0 (13.8) and 12.7% of caregivers reported moderate-severe (scores 41-60) or severe burden (scores 61-88). Fifty-six caregivers were employed and working in the 7 days prior to completing the WPAI:CG. They reported missing an average of 6.9% of their working hours and an average reduction of 17.3% of on-the-job effectiveness, contributing to 22.3% loss in work productivity. Among all 95 caregivers, an average of 17.2% of regular daily activities were impaired. CONCLUSIONS: The burden among caregivers of pediatric patients with NF1-PN is considerable and underscores an unmet need for better disease management.

Health-related quality of life scores of metastatic pancreatic cancer patients responsive to first line chemotherapy compared to newly derived EORTC QLQ-C30 reference values.

BACKGROUND: Metastatic pancreatic cancer (mPC) and its treatments significantly impact health-related quality of life (HRQoL). POLO, a randomized, double-blind, placebo-controlled phase 3 trial evaluated the efficacy of olaparib as maintenance therapy in germline BRCA mutated mPC patients who had not progressed during ≥16 weeks of first-line platinum-based chemotherapy. HRQoL was assessed using the EORTC QLQ-C30. To enhance score interpretation, we derived reference values for treatment-naïve mPC patients from the literature. METHODS: A targeted literature review identified EORTC QLQ-C30 baseline values in treatment-naïve mPC patients. Reference values were calculated by deriving means from studies meeting inclusion criteria, with scores from 0 to 100 (higher scores indicate better QoL/functioning but worse symptoms). For POLO patients, means were calculated using pooled baseline data across study arms. RESULTS: Four studies met inclusion criteria. Depending on the specific scale, sample sizes ranged from n = 466 to n = 639. Compared to newly derived reference values, POLO patients reported markedly better HRQoL scores at baseline across most scales, with eight scales showing differences of ≥10 points. POLO patients' HRQoL scores were often close to or better than general population norm data. CONCLUSIONS: This is the first study to systematically derive EORTC QLQ-C30 reference values for mPC. POLO patients had better HRQoL scores than those in the literature and similar to general population data. Comparatively high HRQoL of POLO patients are likely due to effects of prior first-line treatment and resolution of chemotherapy-related symptoms, response shift, or a combination. Newly derived reference values can enhance interpretation of mPC patients' HRQoL. TRIAL REGISTRATION: The POLO trial was registered on 9 July 2014 with ClinicalTrials.gov as NCT02184195.

Clinical and humanistic burden among pediatric patients with neurofibromatosis type 1 and plexiform neurofibroma in the USA.

PURPOSE: To assess clinical and humanistic burden among pediatric patients with neurofibromatosis type 1 (NF1) and plexiform neurofibroma (PN) in the USA. METHODS: NF1-PN patients aged 8-18 years (treatment-naïve or ≤ 1 month of selumetinib treatment) and their caregivers and caregivers of similar patients aged 2-7 years were recruited through the Children's Tumor Foundation to participate in an online cross-sectional survey (December 2020-January 2021). Caregivers provided data on patients' demographic and clinical characteristics and burden of debulking surgeries. Patients and caregivers provided self-reported or proxy responses to health-related quality of life (HRQoL) questions using validated instruments. RESULTS: Sixty-one patients and 82 caregivers responded to the survey. Median (range) age of patients was 11.5 (3-18) years, and 53.7% were female. Most were treatment-naïve (97.6%), with NF1-PN diagnosis for > 5 years (68.3%). Most patients (59.8%) had > 1 PN and 11.0% reporting > 5 PNs. Common NF1-PN symptoms included pain (64.6%), disfigurement (32.9%), and motor dysfunction (28.0%). Patients and caregiver proxies reported low overall HRQoL and reduced physical, emotional, social, and school functioning. Patients also reported considerable pain severity, interference, daily activity impairments, and movement difficulty. Few patients had received complete resections of their tumors (12.2%). 39.0% reported ≥ 1 debulking surgery, among whom, 15.6% had complications, and debulking surgery-related hospitalizations were common (53.1%). CONCLUSIONS: The clinical and humanistic burden among pediatric NF1-PN patients is substantial. While debulking surgeries are used for symptom management, they are associated with considerable clinical sequelae. Results highlight a need for improved disease management strategies.

Epidemiological and clinical burden associated with plexiform neurofibromas in pediatric neurofibromatosis type-1 (NF-1): a systematic literature review.

PURPOSE: Patients with neurofibromatosis type-1 (NF-1) and associated plexiform neurofibromas (PNs) often have a high burden of illness owing to debilitating symptoms of these tumors and limited management options. To investigate this complex disease, a systematic literature review (SLR) was conducted on the epidemiology of pediatric NF-1 and associated PNs, the burden of illness, and outcomes of surgical resection of these tumors. METHODS: Searches of MEDLINE and Embase (from database inception to October 2019) and conference proceedings (2017-2019) were performed to identify relevant studies. The review methodology was informed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Twenty studies were identified. Evidence confirmed NF-1 is rare but that occurrence may differ geographically. Only limited data on the birth incidence of NF-1 were identified. Prevalence estimates for pediatric NF-1 varied from one per 960 individuals (aged 17 years) to one per 5681 children (aged < 16 years) across five large registry/surveillance studies (each involving > 19,000 individuals). The prevalence of associated PNs was 0-29.6%. PNs carried increased mortality risk in pediatric NF-1 in both studies that explored this potential association. Patients with PNs reported high use of analgesics. The complication rate post-surgery for PNs was around 17-19%. The recurrence rate (18-68%) was dependent on the extent of excision achieved during surgery. CONCLUSIONS: Data suggest NF-1 is a rare disease with increased morbidity and mortality in children with associated PNs. Surgical outcomes for PNs are often poor. These findings suggest significant unmet needs in patients with NF-1-associated PNs.

Natural History and Disease Burden of Neurofibromatosis Type 1 with Plexiform Neurofibromas: A Systematic Literature Review.

Neurofibromatosis type 1 (NF1) is an incurable genetic condition that frequently includes the development of plexiform neurofibromas (PNs) in patients. A systematic literature review was conducted to identify data on the natural history, disease burden, and treatment patterns among patients diagnosed with NF1 and PN, as well as to identify evidence gaps in these areas. MEDLINE and MEDLINE In-Process, Embase, and Cochrane Library Searches were searched using predefined terms. Potential references underwent two phases of screening by two independent researchers. A total of 39 references focusing on populations of patients with both NF1 and PN were included in this review. The wide range of PN-related complications creates a substantial quality-of-life (QOL) burden for patients, including pain, social functioning, physical function impact, stigma, and emotional distress. The severe burden of NF1 with PN on the QOL of patients demonstrates the high unmet need for an effective treatment option that can reduce tumor burden and improve QOL. The heterogeneity of measurement tools used to evaluate QOL and the gap in data evaluating the health economic burden of PN should be the focus of future research.