Monitoring of Neurological Symptoms, Treatment Tolerance, and Quality of Life Using the Resilience PRO Electronic Patient-reported Outcome Application in Patients With IDH-mutated Glioma

IDH-mutant gliomas Isocitrate dehydrogenase-mutant (IDH-mutant) gliomas are diffusely infiltrating primary brain tumors characterized by somatic mutations in the IDH1 or IDH2 genes. The WHO Classification currently recognizes two subtypes of IDH-mutant gliomas: oligodendrogliomas (grade 2 or 3), which are IDH-mutant and 1p/19q codeleted, and astrocytomas (grade 2, 3, or 4), which are IDH-mutant. Both subtypes represent approximately 25% of diffuse gliomas, which are the most common malignant primary brain tumors in adults. These tumors typically present with seizures in patients between the ages of 20 and 40. Brain magnetic resonance imaging (MRI) usually shows a slowly growing, infiltrative tumor on T2/FLAIR sequences. Contrast enhancement is variable and more frequently seen in newly diagnosed high-grade (i.e., grade 3 or 4) tumors or in recurrent high-grade tumors that have progressed from a lower grade (i.e., grade 2) lesion. In gliomas, IDH mutations are associated with improved prognosis and an increased benefit from chemotherapy and radiation therapy compared to tumors with IDH-wild-type status. However, IDH-mutant gliomas cannot be cured by surgery, radiation therapy, or chemotherapy and are associated with significant disease- and treatment-related morbidity, leading to premature death. After an initial period of responsiveness to available therapies, these tumors typically progress to a more refractory state, with increased tumor infiltration in the brain and worsening neurological and general symptoms. IDH mutations are early events in gliomagenesis and remain detectable throughout the disease course, making them compelling molecular targets.

Standard of care approaches Current guidelines recommend that patients with IDH-mutant gliomas undergo maximal safe surgical resection, followed by sequential radiation therapy and chemotherapy, or a watch-and-wait approach based on several "high-risk" factors. These high-risk criteria, derived from retrospective or post-hoc studies, include WHO grade, age, pre- and post-operative tumor volume, tumor growth, and the presence of neurological symptoms. Since none of these criteria are universally accepted to initiate adjuvant treatment, decisions are typically based on a combination of these factors, physician judgment, and patient preferences. For patients with grade 3 or 4 IDH-mutant gliomas, as well as a subset of grade 2 IDH-mutant gliomas (i.e., high-risk patients), radiation therapy with concurrent or adjuvant chemotherapy is recommended. Three widely used protocols include: radiation with concurrent and adjuvant temozolomide (TMZ); radiation with adjuvant TMZ; or polychemotherapy with procarbazine, CCNU, and vincristine (PCV). For patients with grade 2 IDH-mutant gliomas who undergo gross total resection and have favorable prognostic factors, a watch-and-wait approach can be considered. In patients with grade 2 IDH-mutant gliomas with residual or recurrent disease not requiring immediate radiation or chemotherapy, the INDIGO trial demonstrated a progression-free survival (PFS) benefit of the IDH1/2 inhibitor vorasidenib compared to placebo. Based on these results, vorasidenib (Voranigo) has been approved by the FDA for adult and pediatric patients 12 years and older with grade 2 IDH-mutant gliomas following surgery, including those with gross total resection. Vorasidenib has also been approved in additional geographies such as Canada, Australia and and in Europe.

Issues with quality of life and neurocognition Most patients with IDH-mutant gliomas exhibit prolonged survival with good quality of life and preserved daily activities (e.g., family, work) at diagnosis. This has prompted several research groups to consider deferring cytotoxic treatments in selected patients to mitigate the short- and long-term side effects, such as potential neurocognitive decline from radiation therapy and chemotherapy. Although data suggesting neurocognitive deterioration with radiation therapy largely come from older studies that did not use modern techniques, more recent studies suggest limited cognitive impairment after a relatively short follow-up. Both radiation therapy and chemotherapy effectively prolong survival but are associated with risks of acute and late toxicities. For instance, most patients receiving radiotherapy and PCV chemotherapy experience general, gastrointestinal, and hematological side effects, often requiring treatment interruptions, adjustments, or even transfusions. Due to these side effects, most patients receiving these treatments must at least partially interrupt work and normal activities, and are less likely to return to work afterward. For patients managed with a watch-and-wait strategy, there is a need for strategies that prolong PFS and delay further treatments without adversely affecting quality of life. The INDIGO trial was the first to demonstrate the efficacy of IDH inhibitors in gliomas, showing that vorasidenib is well tolerated and prolongs PFS in selected patients with grade 2 IDH-mutant gliomas with recurrent or residual disease after surgery. Based on the INDIGO trial results, vorasidenib is expected to become the standard of care for patients with grade 2 IDH-mutant gliomas post-surgery, allowing selected patients to safely defer radiation therapy and chemotherapy. In appropriately selected patients, it is anticipated that radiation therapy and chemotherapy, along with their potential toxicities, can be postponed. Treatment decisions are expected to be influenced by regulatory labeling, clinical guidelines, local tumor board practices, and patient preferences.

Disease- and Treatment-Related Symptoms Patients with IDH-mutant glioma frequently experience symptoms such as fatigue, seizures, headaches, cognitive impairments (primarily attentional), and mood changes, which can significantly affect their health-related quality of life (HRQoL). Disease progression and treatment-related toxicities are the two primary factors driving the decline in HRQoL in this population. These symptoms can be exacerbated by side effects from available therapeutic options, such as chemotherapy, radiation therapy, or targeted IDH inhibitors. In this context, it is crucial to consider the combined effects of these treatments on patient symptoms and HRQoL. Given that this population is young and otherwise healthy, with long-term survival exceeding 10 years after diagnosis, it is essential to consider not only on longevity but also on overall functioning and HRQoL when making treatment decisions. Assessing quality of life has therefore become a key parameter in phase III clinical trials and observational studies under real-world conditions.

Monitoring Patient-Reported Outcomes (ePROs) with the Resilience PRO Tool The Resilience PRO digital medical device (DMD; CE-marked class IIa) enables remote monitoring of patients treated for cancer who are receiving systemic therapy. Resilience PRO has been positively evaluated by the French National Health Authority (HAS) and included on the LATM list under its brand name. Resilience PRO sends validated weekly questionnaires to patients (NCI PRO-CTCAE ePatient Reported Outcomes [ePROs]), inquiring about treatment- and disease-related symptomatic adverse events. The associated alert algorithm, equivalent to those used in the STAR and PRO-TECT studies, allows for the proactive management of severe or worsening symptoms by the healthcare professional receiving the alert. Additionally, Resilience PRO provides patients with personalized access to a mobile app that offers resources aimed at improving education, self-management, and patient engagement. These innovations lead to clinical benefits (improved quality of life, reduced morbidity, and increased overall survival), as well as organizational benefits (reduced emergency room visits and hospitalizations) and economic advantages.