The Importance of Incorporating Patient-Reported Outcomes in Rare Oncology Clinical Trials.

In rare oncology research, integration of patient-reported outcomes (PROs) represents a critical opportunity to enhance trial relevance, improve patient engagement, and generate evidence that truly matters to patients and caregivers. With increasing recognition that traditional clinical endpoints may not accurately portray a full picture of the benefits, risks, and health economics of an anti-cancer therapy, PROs are garnering greater influence as clinically relevant measures of therapeutic impact.

In this article, we explore the importance of implementing PROs in rare oncology to enhance the relevance of clinical trials, inform the interpretation of study results, and guide future research.

 

The Unique Landscape of Rare Oncology Trials

The distinctive challenges inherent to rare cancer clinical research make PROs particularly valuable:

 

  • Statistical power limitations. With small patient populations, achieving statistical significance with traditional endpoints can be challenging. For example, in trials for angiosarcoma, enrolling even 50 patients represents a substantial portion of the annual incidence. PRO data can provide crucial supporting evidence when conventional efficacy signals may be underpowered. A recent review of drugs approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for oncology indications between 2010 and 2020 found that 46 drugs included PRO data in their labels.[1]

 

  • Heterogeneous disease manifestations. Many rare cancers exhibit significant heterogeneity in presentation, progression, and response to treatment. Epithelioid hemangioendothelioma, for instance, can range from indolent to aggressive forms.[2] This diversity makes standardized clinical endpoints challenging to interpret across a small sample, while PROs can capture meaningful treatment benefits regardless of disease subtype.

 

  • Limited standard of care options. For many rare cancers, established treatment paradigms are extremely limited. When evaluating novel therapies without clear comparators, understanding the patient experience may be useful for contextualizing results. In diseases such as advanced soft-tissue sarcoma, where standard chemotherapy has limited efficacy, PRO improvements may represent the only evidence of clinical benefit.[3]
[1] Cella D, et al. Patient-reported outcomes labeling for oncology drugs: Multidisciplinary perspectives on current status and future directions. Front Pharmacol. 2022;13:1031992.
[2] Sardaro A, et al. Epithelioid hemangioendothelioma: An overview and update on a rare vascular tumor. Oncol Rev. 2014;8(2):259.
[3] Judson I, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15(4):415-423.

Potential Benefits of PRO Implementation

Integration of PROs ensures that patient experiences shape the entire development process.

 

  • Early detection and characterization of exposure-response (ER) relationships in early clinical development. PRO instruments designed to capture symptomatic adverse event data may complement traditional ER analysis. In a retrospective case study, ER analysis using PRO-derived data was sensitive enough to identify a known ER relationship for diarrhea when standard Common Terminology Criteria for Adverse Events (CTCAE) could not.[1]

 

  • More meaningful trial endpoints. With the incorporation of PROs, trial endpoints can better reflect what matters most to patients. In rare cancers, where treatments may focus on reduction of symptom burden rather than cure, quality of life improvements may be just as important to patients as survival gains. A phase 3 study of selinexor in advanced unresectable dedifferentiated liposarcoma measured health-related quality of life (HRQoL) outcomes as a secondary endpoint and found a significant reduction in pain, representing a relevant added value of the drug.[2] Notably, more recent phase 1/3 studies of selinexor in combination with ruxolitinib in myelofibrosis included total symptom score as a co-primary endpoint, emphasizing the importance of developing effective treatments with the patients’ goals for care in mind.[3],[4]

 

  • Enhanced patient recruitment and retention. Rare cancer studies often struggle with recruitment. Studies that prioritize the patient and caregiver voice through robust PRO measurement may be more appealing to potential participants. Various studies have demonstrated that integration of PROs into clinical trials and routine cancer care may not only contribute to improved survival and quality of life, but also extend the cancer treatment tolerability period, detect recurrence earlier, and reduce hospitalizations and emergency visits.[5],[6]

 

  • Regulatory alignment. Regulatory bodies are increasingly recognizing the importance of PROs in evaluating treatment benefit. The FDA’s Project Optimus initiative emphasizes PROs for understanding how different doses affect quality of life, tolerability, and overall experience, allowing for better dose optimization, while the Project FrontRunner initiative recommends the use of PROs in earlier settings. Furthermore, the agency has published guidance to industry on Core Patient Reported Outcomes in Cancer Clinical Trials to maximize the regulatory utility of submitted PRO data.

 

  • More holistic understanding of treatment effects. Early PRO planning allows researchers to capture the full spectrum of treatment impacts. PRO instruments can reveal discrepancies between what the patient experiences and what clinical assessments suggest. They can also be used to measure treatment burden, which is important in rare cancer studies that may require frequent hospital visits, complex administration schedules, or lifestyle modifications. Notably, in a recent study in RET-mutated medullary thyroid cancer, weekly Systemic‑Therapy‑Induced Diarrhea Assessment Tool (mSTIDAT) diaries showed a reduction in diarrhea within the first four weeks, while the median time to first RECIST response was 1.9 months, demonstrating that a disease-specific PRO instrument might reveal therapeutic benefit prior to radiographic response.[7]
[1] Xia H, et al. Use of patient-reported outcomes (PRO) data to complement exposure–response analysis in early clinical cancer drug development
[2] Gounder M, et al. Health-related quality of life and pain with selinexor in patients with advanced dedifferentiated liposarcoma. Future Oncol. 2021;17(22);2923-2939.
[3] Mascarenhas J, et al. Selinexor plus ruxolitinib in JAK inhibitor treatment-naïve myelofibrosis: SENTRY Phase 3 study design. Future Oncol. 2025;21(7):807-813.
[4] Karyopharm. Karyopharm Announces Favorable Change in Co-Primary Endpoint for Pivotal Phase 3 SENTRY Trial in Myelofibrosis. October 31, 2024. Available at https://investors.karyopharm.com/2024-10-31-Karyopharm-Announces-Favorable-Change-in-Co-Primary-Endpoint-for-Pivotal-Phase-3-SENTRY-Trial-in-Myelofibrosis.
[5] Yang LY, et al. Patient-reported outcome use in oncology: A systematic review of the impact on patient-clinician communication. Supportive Care in Cancer. 2017;26(1):41-60.
[6] DiMaio M, et al. The role of patient-reported outcome measures in the continuum of cancer clinical care: ESMO Clinical Practice Guideline. Ann Oncol. 2022;33(9):878-892.
[7] Raez LE, et al. Patient-reported outcomes with selpercatinib treatment in patients with RET‑driven cancers in the phase I/II LIBRETTO‑001 trial. ESMO Open. 2024;9(5):103444.

Practical Considerations for Incorporating PROs

Early integration of patient preference studies or collaboration with patient advocacy groups can provide insight into which outcomes matter most to specific rare cancer populations, guiding both PRO selection and interpretation of benefit-risk profiles. PRO strategy development should begin concurrently with endpoint selection. This parallel approach ensures PROs are not compromised by protocol constraints. Where possible, consider incorporating PROs as co-primary or key secondary endpoints to measure disease-specific symptoms that reflect treatment benefit in ways that traditional endpoints might miss.

The EORTC Core Quality of Life Questionnaire (QLQ-C30) and other general cancer PROs provide valuable comparative data, and the National Cancer Institute (NCI) developed a PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to capture symptomatic adverse events self-reported by patients in cancer clinical trials. In addition to these, rare cancers may need supplemental disease-specific modules. When these do not exist, early development should include adaptation of existing tools with input from patient advocacy organizations. For example, the QLQ-GINET21 Quality of Life Questionnaire was validated as a tool for assessing quality of life in gastrointestinal neuroendocrine tumors.[1]

Electronic PRO collection significantly reduces missing data, a critical concern in small sample trials where each patient’s data carries substantial weight. Systems with automated reminders and real-time compliance monitoring have higher completion rates versus paper-based collection. For geographically dispersed rare cancer populations, coupling PROs with telehealth visits or home-based assessments can reduce participation barriers.

[1] Yadegarfar G, et al. Validation of the EORTC QLQ-GINET21 questionnaire for assessing quality of life of patients with gastrointestinal neuroendocrine tumours. Br J Cancer. 2013;108(2):301-310.

 

Conclusion

The unique challenges of rare oncology trials—small patient populations, limited treatment options, and often aggressive disease progression—make the patient voice particularly valuable. PROs offer a complementary perspective and may even provide clinically meaningful evidence of treatment benefit. By treating PRO data as essential rather than supplementary, researchers can design trials that not only advance scientific understanding but also directly address the needs and priorities of people living with rare cancers.

To learn more about incorporating PROs into rare oncology trials, contact us.