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Patient-reported Outcome Measures in Metastatic Urinary Cancers
EUF-689; No. of Pages 5 E U RO P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Mini Review
Patient-reported Outcome Measures in Metastatic Urinary Cancers Cristiane Decat Bergerot a, Paulo Gustavo Bergerot a, Errol J. Philip b, Sumanta Kumar Pal a,* a
Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA; b University of California San
Francisco, San Francisco, CA, USA
Article info
Abstract
Article history: Accepted February 25, 2019
Patient-reported outcome measures (PROMs) have widely been used to assess treatment-related symptoms in clinical trials and provide insight into the patients’ perspective during treatment. This mini-review sought to outline the benefits of measuring patient-reported outcomes, describe the most common measures used in recent pivotal studies in metastatic urinary cancers, and summarize the main findings published in the last 2 yr. In general, European Organization for Research and Treatment Cancer QLQC30 and Functional Assessment of Cancer Therapy were the most common PROMs used in these trials. PROMs provided important information concerning patients’ quality of life and symptom burden during treatment, including insight into how these drugs may be tolerated in real-world clinical circumstances; however, many still do not assess patients' social and emotional experiences. Based on this mini-review, the combination of a symptomatic toxicity scale and validated quality of life measure represents a reliable strategy to assess patient perspectives during treatment. Patient summary: In this mini-review on patient-reported outcomes measures (PROMs), we explored data from recent pivotal studies in metastatic urinary cancer. We found that all recent clinical trials in metastatic urinary cancers assessed patientreported outcomes, primarily through the use of quality of life measures. We recommend the use of both a symptomatic toxicity scale and a quality of life scale to evaluate PROMs. © 2019 Published by Elsevier B.V. on behalf of European Association of Urology.
Associate Editor: Malte Rieken Keywords: Patient-reported outcomes Quality of life Renal cell carcinoma Urothelial carcinoma Prostate cancer
* Corresponding author. Department of Medical Oncology & Experimental Therapeutics, 1500 East Duarte Road, Duarte, CA 91010, USA. Tel.: +1 626 256 4673; Fax: +1 626 301 8233. E-mail address: [email protected] (S.K. Pal).
1.
Introduction
Patient-reported outcomes (PROs) have been considered in oncology settings since the 1970s when the European Organization for Research and Treatment Cancer (EORTC) and Cancer and Leukemia Group B (CALGB) advocated their inclusion in clinical trials. Representative scales (eg, EORTC-QLQC30 and Functional Assessment of Cancer
Therapy [FACT]) assess core domains and can also address issues specific to certain tumor sites [1,2]. Evidence suggests that symptom assessment with systematic and validated measures can contribute to the comprehensive assessment of a patient’s experience and promote high-quality care. However, in view of challenges in incorporating such measures as part of standard of care (eg, lack of trained professionals, lack of resources and time), PROs became confined
https://doi.org/10.1016/j.euf.2019.02.020 2405-4569/© 2019 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Bergerot CD, et al. Patient-reported Outcome Measures in Metastatic Urinary Cancers. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.02.020
EUF-689; No. of Pages 5 2
E U RO P E A N U RO L O GY F O C U S X X X ( 2 019 ) X X X– X X X
largely to the research domain and their direct influence on patient care became limited. In 2015, the American Society of Clinical Oncology and the European Society of Medical Oncology advocated for the inclusion of quality of life (QOL) assessment in clinical trials [3,4]. Further, recent clinical trials have demonstrated that assessment of PROs can improve clinical outcomes (better QOL, fewer hospitalizations, and longer survival). This finding has renewed interest in PRO use, and is now being recognized as a meaningful and critical element of person-centered care [5,6]. PROs can enhance the comprehensiveness of symptom reporting, improve symptom management, and promote effective communication between patients and providers. Further, highlighting the importance of PROs’ inclusion in clinical trials is their ability to provide additional insight into the tolerability profile and perceived costs of a specific therapy, often aligning more closely with real-world outcomes and patient experiences. With a new era of treatment modalities (molecularly targeted agents) becoming more widely available, the comprehensive assessment of treatment side effects, toxicities, and patient experience is critical. This mini-review outlines the benefits of using PRO measures (PROMs) in clinical settings and describes PRO findings from several pivotal studies in metastatic urinary cancers, highlighting the data published within the last 2 yr. 2.
Patient-reported outcome measures
A variety of measures have been developed to assess constructs related to symptom burden, mood, physical function, social support, QOL, and distress, and many are
validated measures to assess PROs in the context of a clinical trial (Table 1). Ideally, PROM should be brief and valid, but also provide insight into the patient experience beyond physical symptomatology. The assessment of QOL has long been the preferred measure to gain a broader understanding of the patient experience, with the EORTC-QLQC30 [1] and FACT [2] representing the most widely used measures in this domain. These scales are simple and brief, and their subscales are sensitive to detect changes over time. These scales have widely been used in the medical field and have been translated into different languages, and many include disease-specific modules to better identify disease and treatment-related symptoms. QOL measures provide insight into patient experience across several domains, can help identify patient concerns, and provide a validated quantitative report that can be tracked longitudinally and compared with existing national and international normative data. In the context of clinical trials, the Food and Drug Administration has established core concepts that a PROM should assess in clinical trials, including adverse events, physical functioning, and disease-related symptoms [7]. Efforts are also underway to define PRO best practices, and increase the relevance and interpretability of PRO data. The Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) represents one example of a PROM that can provide greater detail of the context of clinical trials [8]. This measure can help inform tolerability data, and the determination of dose selection and overall benefit. Further, the existing data on safety and tolerability obtained through PRO-CTCAE can be
Table 1 – PROMs available for use in oncology studies. Survey
Average time
Items
Focus
Assessment time
EORTC-QLQC30 [1]
10–15 min
30 items
7d
FACT-G [2]
10–15 min
27 items
FKSI-19 [12]
10–15 min
EuroQol (EQ-5D-5L) [13,27]
5 min
BPI [20] BFI [14] MDASI [15] PRO-CTCAE [8]
10 min 5 min (short form) 5 min 6 min –
19 items 5 items 5 items 1 visual analogue scale 32 items 9 items (short form) 4 items 13 items 124 items
Functional, physical, emotional, social, and cognitive questions Physical, social/family, emotional, and functional well-being Disease-specific scale Symptoms and concerns related to treatment effectiveness in advanced kidney cancer Mobility, self-care, usual activities, pain/ discomfort, and anxiety/depression Severity and impact of cancer-related pain
NIH PROMIS [28]
5 min
4–8 items per symptom
Distress thermometer [29]
2–3 min
Edmonton Symptom Assessment Scale [30] Memorial System Assessment Scale [31]
7d
7d 7d 24 h 24 h 24 h 7d
5 min
1 item 35 problems 9 items
Severity and impact of cancer-related fatigue Psychological and physical symptoms 78 Symptomatic treatment toxicities Symptoms can be selected to build a studyspecific custom form Global health, distress (depression, anxiety, anger), physical symptoms (fatigue, pain, nausea/vomiting, sleep), cognitive function, and others Distress level Psychosocial and physical needs Psychosocial and physical symptoms
10–15 min
32 items
Psychological and physical symptoms
7d
7d
7d 7d
BFI = Brief Fatigue Inventory; BPI = Brief Pain Inventory; EORTC = European Organization for Research and Treatment Cancer; FACT = Functional Assessment of Cancer Therapy; FKSI–19 = Therapy Kidney Cancer Index; MDASI = M.D. Anderson Symptom Inventory; PRO-CTCAE = Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events; PROM = patient-reported outcome measure.
Please cite this article in press as: Bergerot CD, et al. Patient-reported Outcome Measures in Metastatic Urinary Cancers. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.02.020
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used to guide clinical decision making, and help physicians provide patient-centered care, assisting in the identification of patients who might benefit from different treatment regimens.
similar efficacy (pazopanib vs sunitinib) and evaluated its association with QOL. In this study, a great proportion of patients preferred pazopanib (lower incidence of physical toxicities), reporting a better QOL [16].
3.
PROM in recent pivotal studies in urinary cancers
3.2.
3.1.
Renal cell carcinoma
Trials have also shown promising results for metastatic urothelial carcinoma. Cisplatin-based combination chemotherapy is still the first option to treat this cancer. However, this regimen is associated with a high prevalence of treatment-related side effects, being not an appropriate option for a certain group of patients (eg, frail patients, multiple comorbidities). Immunotherapy has been tested, and preliminary data have supported its use and tolerability, as in the IMvigor211 trial (atezolizumab vs chemotherapy), in which QOL initially deteriorated, but returned to baseline after several cycles and was maintained thereafter [17]. A similar finding was noted in KEYNOTE-052 (pembrolizumab), showing that QOL has been maintained or has even improved [18]. Both studies utilized the EORTC-QLQC30 [1] to assess PROs over time (Table 2).
The new therapeutic era in metastatic renal cell carcinoma has brought remarkable improvements in overall survival and treatment response rates. New treatment modalities have been approved, and nowadays vascular endothelial growth factor tyrosine kinase inhibitors, mammalian target of rapamycin, and checkpoint inhibitor immunotherapy are the primary and secondary systemic modalities for patients with metastatic disease. Clinical trials have shown that these new drugs have produced less severe toxicity. PROs from the most recently published phase III trial have shown improvement in symptoms and QOL. For example, in the METEOR trial (cabozantinib vs everolimus), patients reported less fear of cancer recurrence [9]. CheckMate214 (nivolumab/ipilimumab vs sunitinib) showed significant improvements in QOL [10]. Finally, although the QOL data have not yet been published, atezolizumab/bevacizumab versus sunitinib (IMmotion151) has shown some promising results, as the drug combination has decreased disease-specific symptoms [11]. These trials assessed PROs with the Functional Assessment of Cancer Therapy Kidney Cancer Index (FKSI-19) [12], FACT-G [2], EuroQol (EQ-5D-5L) [13], Brief Fatigue Inventory (BFI) [14], EORTC-QLQC30 [1], and M.D. Anderson Symptom Inventory [15] (Table 2). Further, there is one innovative study (PISCES) that assessed patient preference for treatments with
3.3.
Urothelial carcinoma
Metastatic prostate cancer
New therapeutics for metastatic prostate cancer have markedly improved overall survival. These patients maintain therapy with androgen deprivation, which can frequently elicit disease-related symptoms (eg, bone pain, fatigue, reduced physical functioning), and also with shortand long-term treatment side effects (eg, fatigue, sexual function, hot flashes, enlargement of nipples and breasts, sleep disturbance). In Table 2, we review PROs associated
Table 2 – Results from recent representative pivotal studies in advanced genitourinary cancers utilizing PROMs. Trial
Cancer type
Protocol no.
Phase
PROM
Outcome
METEOR [9]
Renal cell carcinoma
NCT01865747
III
FKSI-19, EQ-5D-5L
IMmotion151 [11]
Renal cell carcinoma
NCT02420821
III
MDASI, BFI, FKSI-19
CheckMate214 [10]
Renal cell carcinoma
NCT02231749
III
FKSI-19, FACT-G, EQ-5D-3L
IMvigor211 [17]
Urothelial carcinoma
NCT02302807
III
EORTC QLQ-C30
KEYNOTE-052 [18] CHAARTED [25] STAMPEDE [26]
Urothelial carcinoma Prostate cancer Prostate cancer
NCT02335424 NCT00309985 NCT00268476
II III III
TERRAIN [21] LATITUDE [22]
Prostate cancer Prostate cancer
NCT01288911 NCT01715285
II III
EORTC QLQ-C30 FACT-Prostate EORTC-QLQC30 + prostatespecific 25 items FACT-Prostate, EQ-5D, BPI BPI-SF, BFI, FACT-Prostate, EQ5D-5L
Improvement in symptoms, with exception for diarrhea and nausea Maintained QOL Fewer disease-specific symptoms QOL data not shown Fewer symptoms Improvement in QOL QOL initially deteriorated, but returned to baseline after several cycles; maintained QOL thereafter Improvement or stable QOL Not available Not available
SPARTAN [23] PROSPER [24]
Prostate cancer Prostate cancer
NCT01946204 NCT02003924
III III
FACT-Prostate, EQ-5D-3L FACT-Prostate, EQ-5D-5L, BPI
Improvement in QOL Improvement in symptoms (pain, fatigue) and in QOL Longer time to deterioration in functional status (pain, fatigue) Prolonging time to QOL deterioration Maintained QOL Improvement in QOL and pain symptoms
BFI = Brief Fatigue Inventory; BPI = Brief Pain Inventory; EORTC = European Organization for Research and Treatment Cancer; FACT = Functional Assessment of Cancer Therapy; FKSI–19 = Therapy Kidney Cancer Index; MDASI = M.D. Anderson Symptom Inventory; PROM = patient-reported outcome measure; QOL = quality of life.
Please cite this article in press as: Bergerot CD, et al. Patient-reported Outcome Measures in Metastatic Urinary Cancers. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.02.020
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with studies of novel endocrine therapy. In the scope of this review, we do not include older pivotal trials assessing radionuclide therapy (radium-223) or vaccine therapy (sipuleucel-T), although these studies certainly have relevant QOL considerations. The studies included herein have measured PROs using the FACT-Prostate [19], EQ-5D-5L [13], Brief Pain Inventory [20], BFI, and EORTC-QLQC30 [1] (Table 2). Effects of these drugs on PROs showed improvement in physical symptoms (LATITUDE and PROSPER) and maintenance/improvement in QOL (TERRAIN, LATITUDE, PROSPER, and SPARTAN) [21–24]. Data from CHAARTED [25] and STAMPEDE [26] trials are eagerly awaited.
manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. Patient-reported Outcome Measure in Metastatic Urinary Cancers: C.D. ffBergerot, P.G. Bergerot, E.J. Philip, S.K. Pal
References [1] Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-oflife instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–76.
4.
Conclusions
[2] Cella DF, Tulsky DS, Gray G, et al. The functional assessment of cancer therapy scale: development and validation of the general
The inclusion of PROMs in clinical trials has provided important insight into the benefits and costs of new treatment modalities. The growing recognition of the role of PROMs in clinical trials has been encouraging and will help elucidate fully the benefits of a new era of treatments for patients with metastatic urinary cancers. However, challenges remain in establishing a standardized approach to PROM assessment (eg, which battery of tests to use, which time point to assess patients) that would enable data to be compared across different studies and fully realize the benefits of integration of comprehensive PROMs in clinical trials. The current review established the use of a symptomatic toxicity scale (eg, PRO-CTCAE) in combination with a valid QOL measure (eg, FACT-G) as an effective approach to gaining a comprehensive understanding of patient experience and the tolerability/toxicity profile. This information can provide unique insight into the potential real-world barriers to treatment adherence, and guide the development of clinical guidelines and consensus documents. Perhaps most importantly, integration of PROMs can help facilitate and improve communication between patients and their health care team, and thus promote well-informed decision making, prompt management of symptoms, and greater satisfaction with care.
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Author contributions: Sumanta Kumar Pal had full access to all the data in the study and takes responsibility for the integrity of the data and the
2018;36:757–64. [10] Cella D, Grünwald V, Escudier B, et al. Patient-reported outcomes of
accuracy of the data analysis.
patients with advanced renal cell carcinoma treated with nivolu-
Study concept and design: C.D. Bergerot, P.G. Bergerot, Philip, Pal.
mab plus ipilimumab versus sunitinib (CheckMate 214): a random-
Acquisition of data: C.D. Bergerot, P.G. Bergerot, Philip, Pal. Analysis and interpretation of data: C.D. Bergerot, P.G. Bergerot, Philip, Pal.
ised, phase 3 trial. Lancet Oncol 2019;20:297–310. [11] Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: a randomized
Drafting of the manuscript: C.D. Bergerot, P.G. Bergerot, Philip, Pal.
phase III study of atezolizumab plus bevacizumab vs sunitinib in
Critical revision of the manuscript for important intellectual content: C.D.
untreated metastatic renal cell carcinoma (mRCC). J Clin Oncol
Bergerot, P.G. Bergerot, Philip, Pal. Statistical analysis: None.
2018;36(suppl 6):578. [12] Rothrock NE, Jensen SE, Beaumont JL, et al. Development and initial
Obtaining funding: None.
validation of the NCCN/FACT symptom index for advanced kidney
Administrative, technical, or material support: None.
cancer. Value Health 2013;16:789–96.
Supervision: Pal. Other: None.
[13] Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:1727–36.
Financial disclosures: Sumanta Kumar Pal certifies that all conflicts of
[14] Mendoza TR, Wang XS, Cleeland CS, et al. The rapid assessment of
interest, including specific financial interests and relationships and
fatigue severity in cancer patients: use of the Brief Fatigue Inven-
affiliations relevant to the subject matter or materials discussed in the
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Please cite this article in press as: Bergerot CD, et al. Patient-reported Outcome Measures in Metastatic Urinary Cancers. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.02.020
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[15] Cleeland CS, Mendoza TR, Wang XS, et al. Assessing symptom
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resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2018;19:1404–16. [24] Saad F, Penson D, Attard G, et al. MP 52-19 impact of enzalutamide
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[26] James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate
able or metastatic urothelial cancer (KEYNOTE-052): a multicentre,
cancer not previously treated with hormone therapy. N Engl J Med
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2017;377:338–51. [27] EuroQol Group. EuroQol—a new facility for the measurement of
quality of life in men with prostate cancer using the functional
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assessment of cancer therapy-prostate instrument. Urology
[28] Cella D, Riley W, Stone A, et al. The Patient-Reported Outcomes
1997;50:920–8. [20] Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994;23:129–38. [21] Heidenreich A, Chowdhury S, Klotz L, et al. Impact of enzalutamide compared with bicalutamide on quality of life in men with metastatic castration-resistant prostate cancer: additional analyses from the TERRAIN randomised clinical trial. Eur Urol 2017;71:534–42. [22] Chi KN, Protheroe A, Rodriguez-Antolin A, et al. Patient-reported outcomes following abiraterone acetate plus prednisone added to
Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005–2008. J Clin Epidemiol 2010;63:1179–94. [29] Holland JC, Andersen B, Breitbart WS, et al. Distress management. J Natl Compr Canc Network 2013;11:190–209. [30] Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care 1991;7:6–9. [31] Portenoy RK, Thaler HT, Kornblith AB, et al. The Memorial Symptom
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Eur
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Cancer
Please cite this article in press as: Bergerot CD, et al. Patient-reported Outcome Measures in Metastatic Urinary Cancers. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.02.020
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Mini Review
Patient-reported Outcome Measures in Metastatic Urinary Cancers Cristiane Decat Bergerot a, Paulo Gustavo Bergerot a, Errol J. Philip b, Sumanta Kumar Pal a,* a
Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA; b University of California San
Francisco, San Francisco, CA, USA
Article info
Abstract
Article history: Accepted February 25, 2019
Patient-reported outcome measures (PROMs) have widely been used to assess treatment-related symptoms in clinical trials and provide insight into the patients’ perspective during treatment. This mini-review sought to outline the benefits of measuring patient-reported outcomes, describe the most common measures used in recent pivotal studies in metastatic urinary cancers, and summarize the main findings published in the last 2 yr. In general, European Organization for Research and Treatment Cancer QLQC30 and Functional Assessment of Cancer Therapy were the most common PROMs used in these trials. PROMs provided important information concerning patients’ quality of life and symptom burden during treatment, including insight into how these drugs may be tolerated in real-world clinical circumstances; however, many still do not assess patients' social and emotional experiences. Based on this mini-review, the combination of a symptomatic toxicity scale and validated quality of life measure represents a reliable strategy to assess patient perspectives during treatment. Patient summary: In this mini-review on patient-reported outcomes measures (PROMs), we explored data from recent pivotal studies in metastatic urinary cancer. We found that all recent clinical trials in metastatic urinary cancers assessed patientreported outcomes, primarily through the use of quality of life measures. We recommend the use of both a symptomatic toxicity scale and a quality of life scale to evaluate PROMs. © 2019 Published by Elsevier B.V. on behalf of European Association of Urology.
Associate Editor: Malte Rieken Keywords: Patient-reported outcomes Quality of life Renal cell carcinoma Urothelial carcinoma Prostate cancer
* Corresponding author. Department of Medical Oncology & Experimental Therapeutics, 1500 East Duarte Road, Duarte, CA 91010, USA. Tel.: +1 626 256 4673; Fax: +1 626 301 8233. E-mail address: [email protected] (S.K. Pal).
1.
Introduction
Patient-reported outcomes (PROs) have been considered in oncology settings since the 1970s when the European Organization for Research and Treatment Cancer (EORTC) and Cancer and Leukemia Group B (CALGB) advocated their inclusion in clinical trials. Representative scales (eg, EORTC-QLQC30 and Functional Assessment of Cancer
Therapy [FACT]) assess core domains and can also address issues specific to certain tumor sites [1,2]. Evidence suggests that symptom assessment with systematic and validated measures can contribute to the comprehensive assessment of a patient’s experience and promote high-quality care. However, in view of challenges in incorporating such measures as part of standard of care (eg, lack of trained professionals, lack of resources and time), PROs became confined
https://doi.org/10.1016/j.euf.2019.02.020 2405-4569/© 2019 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Bergerot CD, et al. Patient-reported Outcome Measures in Metastatic Urinary Cancers. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.02.020
EUF-689; No. of Pages 5 2
E U RO P E A N U RO L O GY F O C U S X X X ( 2 019 ) X X X– X X X
largely to the research domain and their direct influence on patient care became limited. In 2015, the American Society of Clinical Oncology and the European Society of Medical Oncology advocated for the inclusion of quality of life (QOL) assessment in clinical trials [3,4]. Further, recent clinical trials have demonstrated that assessment of PROs can improve clinical outcomes (better QOL, fewer hospitalizations, and longer survival). This finding has renewed interest in PRO use, and is now being recognized as a meaningful and critical element of person-centered care [5,6]. PROs can enhance the comprehensiveness of symptom reporting, improve symptom management, and promote effective communication between patients and providers. Further, highlighting the importance of PROs’ inclusion in clinical trials is their ability to provide additional insight into the tolerability profile and perceived costs of a specific therapy, often aligning more closely with real-world outcomes and patient experiences. With a new era of treatment modalities (molecularly targeted agents) becoming more widely available, the comprehensive assessment of treatment side effects, toxicities, and patient experience is critical. This mini-review outlines the benefits of using PRO measures (PROMs) in clinical settings and describes PRO findings from several pivotal studies in metastatic urinary cancers, highlighting the data published within the last 2 yr. 2.
Patient-reported outcome measures
A variety of measures have been developed to assess constructs related to symptom burden, mood, physical function, social support, QOL, and distress, and many are
validated measures to assess PROs in the context of a clinical trial (Table 1). Ideally, PROM should be brief and valid, but also provide insight into the patient experience beyond physical symptomatology. The assessment of QOL has long been the preferred measure to gain a broader understanding of the patient experience, with the EORTC-QLQC30 [1] and FACT [2] representing the most widely used measures in this domain. These scales are simple and brief, and their subscales are sensitive to detect changes over time. These scales have widely been used in the medical field and have been translated into different languages, and many include disease-specific modules to better identify disease and treatment-related symptoms. QOL measures provide insight into patient experience across several domains, can help identify patient concerns, and provide a validated quantitative report that can be tracked longitudinally and compared with existing national and international normative data. In the context of clinical trials, the Food and Drug Administration has established core concepts that a PROM should assess in clinical trials, including adverse events, physical functioning, and disease-related symptoms [7]. Efforts are also underway to define PRO best practices, and increase the relevance and interpretability of PRO data. The Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) represents one example of a PROM that can provide greater detail of the context of clinical trials [8]. This measure can help inform tolerability data, and the determination of dose selection and overall benefit. Further, the existing data on safety and tolerability obtained through PRO-CTCAE can be
Table 1 – PROMs available for use in oncology studies. Survey
Average time
Items
Focus
Assessment time
EORTC-QLQC30 [1]
10–15 min
30 items
7d
FACT-G [2]
10–15 min
27 items
FKSI-19 [12]
10–15 min
EuroQol (EQ-5D-5L) [13,27]
5 min
BPI [20] BFI [14] MDASI [15] PRO-CTCAE [8]
10 min 5 min (short form) 5 min 6 min –
19 items 5 items 5 items 1 visual analogue scale 32 items 9 items (short form) 4 items 13 items 124 items
Functional, physical, emotional, social, and cognitive questions Physical, social/family, emotional, and functional well-being Disease-specific scale Symptoms and concerns related to treatment effectiveness in advanced kidney cancer Mobility, self-care, usual activities, pain/ discomfort, and anxiety/depression Severity and impact of cancer-related pain
NIH PROMIS [28]
5 min
4–8 items per symptom
Distress thermometer [29]
2–3 min
Edmonton Symptom Assessment Scale [30] Memorial System Assessment Scale [31]
7d
7d 7d 24 h 24 h 24 h 7d
5 min
1 item 35 problems 9 items
Severity and impact of cancer-related fatigue Psychological and physical symptoms 78 Symptomatic treatment toxicities Symptoms can be selected to build a studyspecific custom form Global health, distress (depression, anxiety, anger), physical symptoms (fatigue, pain, nausea/vomiting, sleep), cognitive function, and others Distress level Psychosocial and physical needs Psychosocial and physical symptoms
10–15 min
32 items
Psychological and physical symptoms
7d
7d
7d 7d
BFI = Brief Fatigue Inventory; BPI = Brief Pain Inventory; EORTC = European Organization for Research and Treatment Cancer; FACT = Functional Assessment of Cancer Therapy; FKSI–19 = Therapy Kidney Cancer Index; MDASI = M.D. Anderson Symptom Inventory; PRO-CTCAE = Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events; PROM = patient-reported outcome measure.
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used to guide clinical decision making, and help physicians provide patient-centered care, assisting in the identification of patients who might benefit from different treatment regimens.
similar efficacy (pazopanib vs sunitinib) and evaluated its association with QOL. In this study, a great proportion of patients preferred pazopanib (lower incidence of physical toxicities), reporting a better QOL [16].
3.
PROM in recent pivotal studies in urinary cancers
3.2.
3.1.
Renal cell carcinoma
Trials have also shown promising results for metastatic urothelial carcinoma. Cisplatin-based combination chemotherapy is still the first option to treat this cancer. However, this regimen is associated with a high prevalence of treatment-related side effects, being not an appropriate option for a certain group of patients (eg, frail patients, multiple comorbidities). Immunotherapy has been tested, and preliminary data have supported its use and tolerability, as in the IMvigor211 trial (atezolizumab vs chemotherapy), in which QOL initially deteriorated, but returned to baseline after several cycles and was maintained thereafter [17]. A similar finding was noted in KEYNOTE-052 (pembrolizumab), showing that QOL has been maintained or has even improved [18]. Both studies utilized the EORTC-QLQC30 [1] to assess PROs over time (Table 2).
The new therapeutic era in metastatic renal cell carcinoma has brought remarkable improvements in overall survival and treatment response rates. New treatment modalities have been approved, and nowadays vascular endothelial growth factor tyrosine kinase inhibitors, mammalian target of rapamycin, and checkpoint inhibitor immunotherapy are the primary and secondary systemic modalities for patients with metastatic disease. Clinical trials have shown that these new drugs have produced less severe toxicity. PROs from the most recently published phase III trial have shown improvement in symptoms and QOL. For example, in the METEOR trial (cabozantinib vs everolimus), patients reported less fear of cancer recurrence [9]. CheckMate214 (nivolumab/ipilimumab vs sunitinib) showed significant improvements in QOL [10]. Finally, although the QOL data have not yet been published, atezolizumab/bevacizumab versus sunitinib (IMmotion151) has shown some promising results, as the drug combination has decreased disease-specific symptoms [11]. These trials assessed PROs with the Functional Assessment of Cancer Therapy Kidney Cancer Index (FKSI-19) [12], FACT-G [2], EuroQol (EQ-5D-5L) [13], Brief Fatigue Inventory (BFI) [14], EORTC-QLQC30 [1], and M.D. Anderson Symptom Inventory [15] (Table 2). Further, there is one innovative study (PISCES) that assessed patient preference for treatments with
3.3.
Urothelial carcinoma
Metastatic prostate cancer
New therapeutics for metastatic prostate cancer have markedly improved overall survival. These patients maintain therapy with androgen deprivation, which can frequently elicit disease-related symptoms (eg, bone pain, fatigue, reduced physical functioning), and also with shortand long-term treatment side effects (eg, fatigue, sexual function, hot flashes, enlargement of nipples and breasts, sleep disturbance). In Table 2, we review PROs associated
Table 2 – Results from recent representative pivotal studies in advanced genitourinary cancers utilizing PROMs. Trial
Cancer type
Protocol no.
Phase
PROM
Outcome
METEOR [9]
Renal cell carcinoma
NCT01865747
III
FKSI-19, EQ-5D-5L
IMmotion151 [11]
Renal cell carcinoma
NCT02420821
III
MDASI, BFI, FKSI-19
CheckMate214 [10]
Renal cell carcinoma
NCT02231749
III
FKSI-19, FACT-G, EQ-5D-3L
IMvigor211 [17]
Urothelial carcinoma
NCT02302807
III
EORTC QLQ-C30
KEYNOTE-052 [18] CHAARTED [25] STAMPEDE [26]
Urothelial carcinoma Prostate cancer Prostate cancer
NCT02335424 NCT00309985 NCT00268476
II III III
TERRAIN [21] LATITUDE [22]
Prostate cancer Prostate cancer
NCT01288911 NCT01715285
II III
EORTC QLQ-C30 FACT-Prostate EORTC-QLQC30 + prostatespecific 25 items FACT-Prostate, EQ-5D, BPI BPI-SF, BFI, FACT-Prostate, EQ5D-5L
Improvement in symptoms, with exception for diarrhea and nausea Maintained QOL Fewer disease-specific symptoms QOL data not shown Fewer symptoms Improvement in QOL QOL initially deteriorated, but returned to baseline after several cycles; maintained QOL thereafter Improvement or stable QOL Not available Not available
SPARTAN [23] PROSPER [24]
Prostate cancer Prostate cancer
NCT01946204 NCT02003924
III III
FACT-Prostate, EQ-5D-3L FACT-Prostate, EQ-5D-5L, BPI
Improvement in QOL Improvement in symptoms (pain, fatigue) and in QOL Longer time to deterioration in functional status (pain, fatigue) Prolonging time to QOL deterioration Maintained QOL Improvement in QOL and pain symptoms
BFI = Brief Fatigue Inventory; BPI = Brief Pain Inventory; EORTC = European Organization for Research and Treatment Cancer; FACT = Functional Assessment of Cancer Therapy; FKSI–19 = Therapy Kidney Cancer Index; MDASI = M.D. Anderson Symptom Inventory; PROM = patient-reported outcome measure; QOL = quality of life.
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with studies of novel endocrine therapy. In the scope of this review, we do not include older pivotal trials assessing radionuclide therapy (radium-223) or vaccine therapy (sipuleucel-T), although these studies certainly have relevant QOL considerations. The studies included herein have measured PROs using the FACT-Prostate [19], EQ-5D-5L [13], Brief Pain Inventory [20], BFI, and EORTC-QLQC30 [1] (Table 2). Effects of these drugs on PROs showed improvement in physical symptoms (LATITUDE and PROSPER) and maintenance/improvement in QOL (TERRAIN, LATITUDE, PROSPER, and SPARTAN) [21–24]. Data from CHAARTED [25] and STAMPEDE [26] trials are eagerly awaited.
manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. Patient-reported Outcome Measure in Metastatic Urinary Cancers: C.D. ffBergerot, P.G. Bergerot, E.J. Philip, S.K. Pal
References [1] Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-oflife instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–76.
4.
Conclusions
[2] Cella DF, Tulsky DS, Gray G, et al. The functional assessment of cancer therapy scale: development and validation of the general
The inclusion of PROMs in clinical trials has provided important insight into the benefits and costs of new treatment modalities. The growing recognition of the role of PROMs in clinical trials has been encouraging and will help elucidate fully the benefits of a new era of treatments for patients with metastatic urinary cancers. However, challenges remain in establishing a standardized approach to PROM assessment (eg, which battery of tests to use, which time point to assess patients) that would enable data to be compared across different studies and fully realize the benefits of integration of comprehensive PROMs in clinical trials. The current review established the use of a symptomatic toxicity scale (eg, PRO-CTCAE) in combination with a valid QOL measure (eg, FACT-G) as an effective approach to gaining a comprehensive understanding of patient experience and the tolerability/toxicity profile. This information can provide unique insight into the potential real-world barriers to treatment adherence, and guide the development of clinical guidelines and consensus documents. Perhaps most importantly, integration of PROMs can help facilitate and improve communication between patients and their health care team, and thus promote well-informed decision making, prompt management of symptoms, and greater satisfaction with care.
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Author contributions: Sumanta Kumar Pal had full access to all the data in the study and takes responsibility for the integrity of the data and the
2018;36:757–64. [10] Cella D, Grünwald V, Escudier B, et al. Patient-reported outcomes of
accuracy of the data analysis.
patients with advanced renal cell carcinoma treated with nivolu-
Study concept and design: C.D. Bergerot, P.G. Bergerot, Philip, Pal.
mab plus ipilimumab versus sunitinib (CheckMate 214): a random-
Acquisition of data: C.D. Bergerot, P.G. Bergerot, Philip, Pal. Analysis and interpretation of data: C.D. Bergerot, P.G. Bergerot, Philip, Pal.
ised, phase 3 trial. Lancet Oncol 2019;20:297–310. [11] Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: a randomized
Drafting of the manuscript: C.D. Bergerot, P.G. Bergerot, Philip, Pal.
phase III study of atezolizumab plus bevacizumab vs sunitinib in
Critical revision of the manuscript for important intellectual content: C.D.
untreated metastatic renal cell carcinoma (mRCC). J Clin Oncol
Bergerot, P.G. Bergerot, Philip, Pal. Statistical analysis: None.
2018;36(suppl 6):578. [12] Rothrock NE, Jensen SE, Beaumont JL, et al. Development and initial
Obtaining funding: None.
validation of the NCCN/FACT symptom index for advanced kidney
Administrative, technical, or material support: None.
cancer. Value Health 2013;16:789–96.
Supervision: Pal. Other: None.
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Financial disclosures: Sumanta Kumar Pal certifies that all conflicts of
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Please cite this article in press as: Bergerot CD, et al. Patient-reported Outcome Measures in Metastatic Urinary Cancers. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.02.020