Table 4

Summary of outcomes from higher quality PRO studies in metastatic/advanced disease

References*DiseaseAge of patients
Patients enrolled (n)†Treatments being comparedPrimary endpointResults of the primary clinical endpoint‡OS differenceMain PRO findings
Price et al 2004
Kabbinavar et al 2005
Kabbinavar et al 2008
ColorectalMean: placebo 70.7, experimental 71.3. Median (range): placebo 73.0 (41–90), experimental 71.3 (35–89)209Bevacizumab plus FU/LV versus placebo plus FU/LVOSMedian OS was 16.6 months for the FU/LV/bevacizumab group and 12.9 months for the FU/LV/placebo group (HR 0.79, p=0.16)No difference between treatment armsTime to deterioration in HRQOL was similar between groups as measured by the CCS and TOI-C scores, but was significantly longer in the experimental arm than in the control arm for the FACT-C total score (FACT-C total, δ≥9; HR 0.69; 95% CI 0.49 to 0.98; p=0.0396)
Aparicio et al 2017
Aparicio et al 2016
Aparicio et al 2013
ColorectalMedian (range): 80 (75-91)282FU versus FU plus irinotecanPFSNo significant difference was observed for the median PFS: FU 5.2 months vs irinotecan 7.3 months, HR=0.84 (0.66–1.07), p=0.15.No difference between treatment armsThe median time before deterioration in QoL (measured with VAS) was 11.9 months (95% CI: 3.6-not reached) in FU vs 17.7 months (95% CI: 10.8 to 22.0) in irinotecan (p=0.46). Baseline QoL evaluations were not associated with toxicity, reductions in dose-intensity, or unexpected hospitalisation in multivariate analyses.
Berry et al 2006
Petrylak et al 2004
ProstateMedian (range): 70 (43-88)770Docetaxel plus estramustine versus mitoxantrone plus prednisoneOSMedian OS was longer in docetaxel plus estramustine than in mitoxantrone plus prednisone (17.5 months vs 15.6 months, p=0.02)Improved in the experimental armThere were no statistically significant differences in pain palliation between the treatment arms. The sensitivity analyses showed a consistent lack of statistically significant global QoL differences for the two arms.
Small et al 2002
Ahles et al 2004
ProstateMedian (range): group A 70 (64-75), group B 71 (63-75), group C 70 (65-75)390Suramin at a low dose
(total, 3.192 g/m2), intermediate dose (total, 5.320 g/m2), or high dose (total, 7.661 g/m2)
Response rateThe objective response rate was 9%, 7%, and 15%, respectively (p=0.10). PSA response rates were 24%, 28%, and 34%, respectively
No difference between treatment armsPatients who received low-dose suramin reported improvement in QOL (FACT-General: p<0.01; FACT-Treatment outcome index: p<0.01) and decreased levels of depression (CES-D: p<0.0006) during treatment compared with patients in the intermediate- and high-dose arms. After treatment, all groups experienced equal decreases in FACT and CES-D scores.
Saad et al 2002
Saad et al 2004
Saad et al 2005
Saad et al 2007
Saad et al 2010
Weinfurt et al 2005
ProstateMean±SD: group A 71.8±7.9, group B 71.2±8.0, group C 72.2±7.9. Median: group A 72, group B 72, group C 73643Zoledronic acid at 4 mg, zoledronic acid at 8 mg or placeboProportion of patients having at least one skeletal-related eventA greater proportion of patients who received placebo had skeletal-related events than those who received zoledronic acid at 4 mg (44.2% vs 33.2%; difference=−11.0%, 95% (CI)=-20.3% to -1.8%; p=0.021) or those who received zoledronic acid at 8/4 mg (38.5%; difference vs placebo=−5.8%, 95% CI=-15.1% to 3.6%; p=0.222).No difference between treatment armsPain scores increased more in patients who received placebo than in patients who received zoledronic acid, but there were no differences in QoL scores among the groups.
Salonen et al 2013
Salonen et al 2012
Salonen et al 2008
ProstateMean: 72. median (range): 72 (46-95)554Intermittent versus continuous androgen-deprivation therapyTime to progressionMedian time from randomisation to progression in the IAD and CAD arms was 34.5 and 30.2 months (not statistically significant)No difference between treatment armsSignificant differences in QoL, favouring IAD emerged in activity limitation, physical capacity, and sexual functioning. IAD showed benefits in the treatment of advanced prostate cancer with respect to QoL (P not reported).
Schroder et al 2004
Schroder et al 2000
Collette et al 2003
ProstateMedian (range): 71 (48.9–85.7)310Flutamide versus cyproterone acetateOSThere was no significant difference between arms with respect to OS (p=0.1252)No difference between treatment armsNo differences between groups in sexual function were found.
Green et al 2002
Green et al 2002
Green et al 2004
ProstateMean, SD (range): 73.3, 6.4 (56–86)82Leuprorelin, goserelin, cyproterone acetate or close clinical monitoringPROCompared with baseline, men receiving androgen suppression monotherapy performed worse in two of 12 tests of attention (decreased performance at T2 for men assigned to goserelin, p=0.029) and memory (leuprorelin significantly slower at T2 than at baseline, p=0.012)Not applicableSexual dysfunction increased for patients assigned to goserelin (p<0.001), leuprorelin (p=0.033) and cyproterone acetate (p=0.067), and emotional distress increased in those assigned to cyproterone acetate (p=0.041) or close clinical monitoring (p=0.002).
Beer et al 2014
Loriot et al 2015
Devlin et al 2017
ProstateMedian (range): group A 72 (43–93), group B 71 (42–93)1717Enzalutamide versus placeboOS, PFSTreatment with enzalutamide, as compared with placebo, resulted in an 81% reduction in the risk of radiographical progression or death (p<0.001) and in a 29% decrease in the risk of death (p<0.001)Improved in the experimental armMedian time to deterioration in FACT-P total score was 11.3 months (95% CI 11.1–13.9) in the enzalutamide group and 5.6 months (5.5–5.6) in the placebo groups (p<0·0001). A significantly greater proportion of patients in the enzalutamide group than in the placebo group reported clinically meaningful improvements in FACT-P total score, in EQ-5D utility index and in the VAS scale.
Hussain et al 2013ProstateMedian (range): 70 (39-97)3040Intermittent versus continuous androgen-deprivation therapyOS, PROMedian survival was 5.8 years in the continuous therapy group and 5.1 in the intermittent therapy group (HR for death with intermittent therapy, 1.10; 90% CI, 0.99 to 1.23).Non-inferiority of experimental arm not demonstratedIntermittent therapy was associated with better erectile function and mental health (p<0.001 and p=0.003, respectively) at month three but not thereafter.
Langley et al 2013
Langley et al 2016
Gilbert et al 2017
ProstateMedian (range, IQR): group A 75 (56–92, 69–80), group B 73 (49–90, 69–78)875 tE2 or LHRHaOS, PFSData on disease progression and survival are not yet available.Not applicableAt 6 months, patients on tE2 reported higher global QOL than those on LHRHa (mean difference +4.2, 95% CI 1.2 to 7.1; p=0.006), less fatigue (mean difference −4.3, 95% CI −8.1 to −0.6; p=0.02) and improved physical function (mean difference +5.8, 95% CI 2.8 to 8.8; p<0.001).
Shore et al 2016
Heidenreich et al 2017
ProstateMedian (range): 71 (48–96)559Enzalutamide versus bicalutamidePFSPatients in the enzalutamide group had significantly improved median PFS (15.7 months, 95% CI 11.5 to 19.4) compared with patients in the bicalutamide group (5.8 months, 95% CI 4.8 to 8.1; HR 0.44, 95% CI 0.34 to 0.57; p<0·0001).Not applicableRisk of first deterioration was lower with enzalutamide for FACT-P total (HR 0.64, 95% CI 0.46 to 0.89; p=0.007), FACT-G total (HR 0.70, 95% CI 0.50 to 0.98; p=0.04), Prostate cancer subscale pain (HR 0.74, 95% CI 0.54 to 1.00; p=0.048) and EQ-5D index (HR 0.66, 95% CI 0.47 to 0.93; p=0.02) scores versus bicalutamide.
Annala et al 2018
Khalaf et al 2018
ProstateMedian (IQR): arm A 72.9 (67.4–79.05); arm B 77.6 (69.1–83.4)202Abitarone plus prednisone versus enzalutamidePSA response rateEnzalutamide achieved greater PSA responses than abiraterone, including a higher proportion of patients with PSA decline ≥50% from baseline within 12 weeks (75% vs 54%, p=0.004, Fisher exact test), and a lower proportion of patients with rising PSA as best response within the first 12 weeks of therapy (9% vs 20%, p=0.046, Fisher exact test.Not applicableFACT-P change from baseline over time was better for abiraterone than for enzalutamide in the 75-year model (p=0.003), with no difference in the <75-year model (p>0.9). A higher proportion of patients experienced clinically meaningful worsening with enzalutamide for the physical and functional well-being domains (37% vs 21%, p=0.013; 39% vs 23%, p=0.015).
  • *The full list of references are reported in the online supplementary appendix C.

  • †Overall number of patients recruited in the study regardless of those with a baseline PRO assessment.

  • ‡When an RCT had no primary clinical endpoint, we reported the results of the main secondary clinical endpoint.

  • CCS, Colorectal Cancer Subscale; EQ-5D, EuroQoL-5D; FACT, Functional Assessment of Cancer Therapy; FU/LV, fluorouracil and leucovorin; HRQOL, health-related quality of life; LHRHa, luteinising hormone-releasing hormone agonists; OS, overall survival;PFS, progression-free survival; PRO, patient-reported outcome; PSA, prostate-specific antigen; QOL, quality of life; TOI-C, Trial Outcome Index.