PROs Capture What Survival Data Miss in Neuroendocrine Neoplasms

Patient-reported outcomes (PROs) and quality of life (QOL) assessments can distinguish between treatments when standard end points cannot, reveal symptoms that clinicians tend to underestimate, and may even predict survival, making them an essential part of research and care for patients with neuroendocrine neoplasms (NENs), according to Claire K. Mulvey, MD, assistant professor at the University of California San Francisco, who spoke at the 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium.¹

"[NENs] are often a chronic illness, and so how patients live matters as much as how long," Mulvey said.

The clearest NEN-specific example of PROs informing treatment choice comes from the phase 3 NETTER-1 trial (NCT01578239), which compared lutetium Lu 177 dotatate (Lutathera) with high-dose octreotide in patients with progressive, somatostatin receptor-positive midgut neuroendocrine tumors (NETs).² Patients in both arms completed the EORTC QLQ-C30 and QLQ-GINET21 questionnaires every 12 weeks. Patients treated with lutetium Lu 177 dotatate had a significantly longer time to deterioration in global health status, physical functioning, role functioning, and fatigue than those who received high-dose octreotide.

Mulvey also presented evidence that QOL carries prognostic weight. In a study of patients with grade 1 or 2 small intestinal NETs, those with lower QOL summary scores had worse overall survival (OS) than those with higher scores, and large meta-analyses across many cancer types have similarly found that QOL measures are associated with survival.

Routine symptom monitoring with PROs has also improved outcomes in other cancers. In the cluster-randomized PRO-TECT trial (NCT03249090), 52 community oncology practices were randomly assigned to an electronic PRO intervention, in which patients completed weekly symptom surveys online or by telephone, or to usual care.³ Among 1,191 patients with metastatic cancer receiving outpatient systemic therapy, time to deterioration in physical function, symptom control, and health-related QOL was significantly longer in the PRO group, and time to the first emergency department visit was significantly prolonged.

More recently, the SYMPRO-Lung trial (Netherlands Trial Register NL7897), a multicenter, cluster-randomized controlled trial conducted across 14 medical centers in the Netherlands, evaluated weekly symptom reporting for 1 year in adults with stage I to IV lung cancer starting new treatment.⁴ In a post hoc analysis, OS favored the PRO intervention over standard care (HR, 0.80; 95% CI, 0.63-1.00; P = .049), with a similar trend in early- and advanced-stage disease.

Limitations and Evidence Gaps

The evidence for symptom monitoring is not uniform. In PRO-TECT, the primary end point was not met, as there was no difference in OS between study groups at 2 years. Mulvey noted that the trial had issues with balance between randomized centers and the types of patients treated, and that much of it was conducted during the COVID-19 pandemic. The survival finding in SYMPRO-Lung came from a post hoc analysis.

Neither trial enrolled patients with NENs specifically, and Mulvey emphasized that the benefit of routine symptom monitoring has not yet been proven in this population.

"There's less data specifically for neuroendocrine tumors," Mulvey said. "There is data for other cancer types."

The broader NEN QOL literature has its own limitations. There is no consensus on the optimal PRO instrument for trials or clinical practice. A review of QOL studies in patients with NETs found that 27 different survey instruments had been used, with the EORTC QLQ-C30 used far more often than any other, and not every instrument has been validated. Certain groups are also underrepresented in the available data, including patients with lung or gastric primary tumors, high-grade disease, or resected disease, as well as long-term survivors.

A Persistent Symptom Burden

The rationale for measuring PROs in NENs starts with the chronic nature of these diseases. Patients often live with symptoms related to tumor bulk and metastases, hormone overproduction, and the cumulative adverse effects of prolonged treatment. Yet most clinical trials and retrospective studies focus on survival and toxicity rather than on the effect of treatment on QOL.

Several large studies have documented that burden. In the INCA global survey, 1928 participants with NETs from more than 12 countries reported that their disease had moderately or substantially affected many areas of their lives, most often their energy levels and emotional health. A retrospective cohort study of 2721 patients with NETs in Ontario, Canada, found that moderate to severe fatigue, impaired well-being, and anxiety were common and persisted for years after diagnosis.

The prospective NET-PRO study (NCT05064150) enrolled adults with newly diagnosed gastroenteropancreatic or lung NETs at 14 US institutions and included 2537 participants in its baseline analysis.⁵ Fatigue, insomnia, and diarrhea were the most bothersome symptoms overall, and symptoms differed by primary site. Patients with lung NETs reported less diarrhea but more dyspnea, which persisted over time, whereas patients with small bowel NETs reported more diarrhea. Patients with NETs also had worse baseline global health status than the general US population. A smaller Danish study of 231 patients with grade 1 to 3 NENs found that patients who had been cured reported better overall health than those with remaining disease.

Clinicians May Miss What Patients Feel

PROs also matter because patients report symptoms that clinicians may miss. A multicenter European study of 1,933 patient-health care provider pairs from 17 centers in 11 countries, conducted in patients with a range of cancer diagnoses, compared patient and provider ratings of symptoms using the EORTC QLQ-C30.⁶ Providers underestimated symptoms in approximately 1 in 10 patients and overestimated them in only 1%. The highest rates of underestimation were for anorexia and fatigue, which Mulvey described as among the more subjective symptoms assessed.

"Providers were tending to underestimate symptoms more often than to overestimate," Mulvey said.

In her concluding remarks, Mulvey said PROs and QOL assessments can inform future patients about how they may feel and function on different treatments, give clinicians evidence to support changes to practice and shared decision-making, and improve patient outcomes and potentially survival.

"Patients care about this, as do regulators now, so it's important," Mulvey said.

References

1. Mulvey CK. Presented at: 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium; November 5-7, 2026; Las Vegas, NV.

2. Strosberg J, Wolin E, Chasen B, et al. Health-related quality of life in patients with progressive midgut neuroendocrine tumors treated with ¹⁷⁷Lu-Dotatate in the phase III NETTER-1 trial. J Clin Oncol. 2018;36(25):2578-2584. doi:10.1200/JCO.2018.78.5865

3. Basch E, Schrag D, Jansen J, et al. Symptom monitoring with electronic patient-reported outcomes during cancer treatment: final results of the PRO-TECT cluster-randomized trial. Nat Med. 2025;31(4):1225-1232. doi:10.1038/s41591-025-03507-y

4. Hassing MJ, Billingy NE, van den Hurk CJG, et al. Patient-reported symptom monitoring in patients with lung cancer (SYMPRO-Lung trial): long-term, post-hoc survival results of a multicentre, stepped-wedged, cluster-randomised clinical trial. Lancet Oncol. 2026;27(10):1304-1313.

5. O'Rorke MA, et al. Quality of life and care experiences in a US multi-institutional neuroendocrine tumor cohort. J Natl Cancer Inst. Published online March 10, 2026. doi:10.1093/jnci/djag069

6. Laugsand EA, Sprangers MAG, Bjordal K, Skorpen F, Kaasa S, Klepstad P. Health care providers underestimate symptom intensities of cancer patients: a multicenter European study. Health Qual Life Outcomes. 2010;8:104. doi:10.1186/1477-7525-8-104