Summary of outcomes from higher quality PRO studies in metastatic/advanced disease
References* | Disease | Age of patients (years) | Patients enrolled (n)† | Treatments being compared | Primary endpoint | Results of the primary clinical endpoint‡ | OS difference | Main PRO findings |
Price et al 2004 Kabbinavar et al 2005 Kabbinavar et al 2008 | Colorectal | Mean: placebo 70.7, experimental 71.3. Median (range): placebo 73.0 (41–90), experimental 71.3 (35–89) | 209 | Bevacizumab plus FU/LV versus placebo plus FU/LV | OS | Median 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 arms | Time 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 | Colorectal | Median (range): 80 (75-91) | 282 | FU versus FU plus irinotecan | PFS | No 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 arms | The 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 | Prostate | Median (range): 70 (43-88) | 770 | Docetaxel plus estramustine versus mitoxantrone plus prednisone | OS | Median 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 arm | There 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 | Prostate | Median (range): group A 70 (64-75), group B 71 (63-75), group C 70 (65-75) | 390 | Suramin 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 rate | The objective response rate was 9%, 7%, and 15%, respectively (p=0.10). PSA response rates were 24%, 28%, and 34%, respectively (p=0.082). | No difference between treatment arms | Patients 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 | Prostate | Mean±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 73 | 643 | Zoledronic acid at 4 mg, zoledronic acid at 8 mg or placebo | Proportion of patients having at least one skeletal-related event | A 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 arms | Pain 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 | Prostate | Mean: 72. median (range): 72 (46-95) | 554 | Intermittent versus continuous androgen-deprivation therapy | Time to progression | Median 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 arms | Significant 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 | Prostate | Median (range): 71 (48.9–85.7) | 310 | Flutamide versus cyproterone acetate | OS | There was no significant difference between arms with respect to OS (p=0.1252) | No difference between treatment arms | No differences between groups in sexual function were found. |
Green et al 2002 Green et al 2002 Green et al 2004 | Prostate | Mean, SD (range): 73.3, 6.4 (56–86) | 82 | Leuprorelin, goserelin, cyproterone acetate or close clinical monitoring | PRO | Compared 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 applicable | Sexual 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 | Prostate | Median (range): group A 72 (43–93), group B 71 (42–93) | 1717 | Enzalutamide versus placebo | OS, PFS | Treatment 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 arm | Median 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 2013 | Prostate | Median (range): 70 (39-97) | 3040 | Intermittent versus continuous androgen-deprivation therapy | OS, PRO | Median 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 demonstrated | Intermittent 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 | Prostate | Median (range, IQR): group A 75 (56–92, 69–80), group B 73 (49–90, 69–78) | 875 | tE2 or LHRHa | OS, PFS | Data on disease progression and survival are not yet available. | Not applicable | At 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 | Prostate | Median (range): 71 (48–96) | 559 | Enzalutamide versus bicalutamide | PFS | Patients 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 applicable | Risk 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 | Prostate | Median (IQR): arm A 72.9 (67.4–79.05); arm B 77.6 (69.1–83.4) | 202 | Abitarone plus prednisone versus enzalutamide | PSA response rate | Enzalutamide 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 applicable | FACT-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.