Elsevier

The Lancet Oncology

Volume 18, Issue 9, September 2017, Pages 1192-1201
The Lancet Oncology

Articles
Health-related quality of life for immediate versus delayed androgen-deprivation therapy in patients with asymptomatic, non-curable prostate cancer (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial

https://doi.org/10.1016/S1470-2045(17)30426-6Get rights and content

Summary

Background

Androgen-deprivation therapy in patients with prostate cancer who have relapsed with rising prostate-specific antigen concentration only (PSA-only relapse), or with non-curable but asymptomatic disease at diagnosis, could adversely affect quality of life at a time when the disease itself does not. We aimed to compare the effect of immediate versus delayed androgen-deprivation therapy on health-related quality of life over 5 years in men enrolled in the TOAD (Timing of Androgen Deprivation) trial.

Methods

This randomised, multicentre, open-label, phase 3 trial done in 29 public and private cancer centres across Australia, New Zealand, and Canada compared immediate with delayed androgen-deprivation therapy in men with PSA-only relapse after definitive treatment, or de-novo non-curable disease. Patients were randomly assigned (1:1) with a database-embedded, dynamically balanced algorithm to immediate androgen-deprivation therapy (immediate therapy group) or to delayed androgen-deprivation therapy (delayed therapy group). Any type of androgen-deprivation therapy was permitted, as were intermittent or continuous schedules. The European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaires QLQ-C30 and PR25 were completed before randomisation, every 6 months for 2 years, and annually for a further 3 years. The primary outcome of the trial, reported previously, was overall survival, with global health-related quality of life at 2 years as a secondary endpoint. Here we report prespecified secondary objectives of the quality-of-life endpoint. Analysis was by intention to treat. Statistical significance was set at p=0·0036. The trial was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12606000301561, and ClinicalTrials.gov, number NCT00110162.

Findings

Between Sept 3, 2004, and July 13, 2012, 293 men were recruited and randomly assigned; 151 to the delayed therapy group and 142 to the immediate therapy group. There was no difference between the two groups in global health-related quality of life over 2 years from randomisation. There were no statistically significant differences in global quality of life, physical functioning, role functioning, or emotional functioning, fatigue, dyspnoea, insomnia, or feeling less masculine over the entire 5 years after randomisation. Sexual activity was lower in the immediate therapy group than in the delayed group at 6 and 12 months (at 6 months mean score 29·20 [95% CI 24·59–33·80] in the delayed group vs 10·40 [6·87–13·93] in the immediate group, difference 18·80 [95% CI 13·00–24·59], p<0·0001; at 12 months 28·63 [24·07–33·18] vs 13·76 [9·94–17·59], 14·86 [8·95–20·78], p<0·0001), with the differences exceeding the clinically significant threshold of 10 points until beyond 2 years. The immediate therapy group also had more hormone-treatment-related symptoms at 6 and 12 months (at 6 months mean score 8·48 [95% CI 6·89–10·07] in the delayed group vs 15·97 [13·92–18·02] in the immediate group, difference −7·49 [–10·06 to −4·93], p<0·0001; at 12 months 9·32 [7·59–11·05] vs 17·07 [14·75–19·39], −7·75 [–10·62 to −4·89], p<0·0001), but with differences below the threshold of clinical significance. For the individual symptoms, hot flushes were clinically significantly higher in the immediate group (adjusted proportion 0·31 for delayed therapy vs 0·55 for immediate therapy, adjusted odds ratio 2·87 [1·96–4·21], p<0·0001) over the 5-year period, as were nipple or breast symptoms (0·06 vs 0·14, 2·64 [1·61–4·34], p=0·00013).

Interpretation

Immediate use of androgen-deprivation therapy was associated with early detriments in specific hormone-treatment-related symptoms, but with no other demonstrable effect on overall functioning or health-related quality of life. This evidence can be used to help decision making about treatment initiation for men at this disease stage.

Funding

Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia, Tolmar Australia.

Introduction

Despite improvements in the techniques and results of curative therapies for prostate cancer, a certain proportion of men relapse. This relapse is frequently diagnosed when routine follow-up of prostate-specific antigen (PSA) reveals a rising PSA, indicating recurrent disease. With local failure being relatively uncommon, relapse predominantly relates to the progression of metastatic disease which was undetectable at the time of the primary intervention. Generally the man is asymptomatic when the PSA starts to rise, and it may potentially be years before overt metastasis is detected. Pound and colleagues1 reported the natural history of patients with PSA relapse after prostatectomy. In this population, it took a median of 8 years to develop overt metastasis. This finding is similar for patients treated with primary radiotherapy; Zumsteg and colleagues2 reported a median interval from PSA-only relapse to distant metastasis without androgen-deprivation therapy of more than 5 years. A short relapse-free interval or a rapid PSA doubling time after primary therapy predict early detection of overt metastasis.3 For other patients, the commencement of androgen-deprivation therapy has the potential to cause morbidity and loss of quality of life4 in men with no symptoms from their disease. The optimal timing and type of intervention has not been established for these patients. A parallel scenario exists for asymptomatic, newly diagnosed men who are not considered for curative therapy (because of age or comorbidities): should they be exposed to the potential detriment from androgen-deprivation therapy in the absence of disease-related symptoms?5

Hence, it is important to optimise the timing of when to introduce androgen-deprivation therapy for these men, to try to delay the onset of symptoms of metastatic disease such as bone pain, and potentially to prolong life, while minimising the adverse effects of treatment on otherwise asymptomatic men. In the TOAD (Timing of Androgen Deprivation) trial, we demonstrated that for patients in these scenarios, immediate treatment with androgen-deprivation therapy resulted in an improvement in overall survival compared with delayed introduction of androgen-deprivation therapy.6 However, this benefit must be weighed against negative effects on the patient, particularly when the disease itself is asymptomatic and the treatment can last for several years. Health-related quality of life is a multidimensional concept that includes domains related to physical, mental, emotional, and social functioning, and is used to evaluate the effect that health status has on quality of life. The tradeoffs between survival gain and health-related quality of life deficits are crucial for discussions with the patient about the optimal time to start androgen-deprivation therapy. Health-related quality of life was therefore a key secondary endpoint in TOAD.

Health-related quality of life encompasses patients' perceptions of symptoms of disease and treatment, more distal dimensions such as physical, emotional, social, and cognitive functions, and global assessment of quality of life.7 In TOAD, the primary objective for health-related quality of life was change in global quality of life from randomisation to 2 years, and was reported in the main trial publication.6 In summary, we noted no differences in global health-related quality of life between the two treatment groups; it deteriorated slightly and similarly over time in both groups. However, perceptions of global health-related quality of life could obscure specific effects of androgen-deprivation therapy. Key secondary objectives relating to health-related quality of life therefore focused on the aspects most likely to be affected by prostate cancer or androgen-deprivation therapy, both in the short and longer terms. We report here on the effects of immediate versus delayed androgen-deprivation therapy on these key aspects of health-related quality of life over the first 5 years after randomisation.

Section snippets

Study design and participants

In this randomised, multicentre, open-label, phase 3 trial, eligible men had either PSA-only relapse after definitive treatment for adenocarcinoma of the prostate (including those who had failed attempted salvage therapy; group 1), or those who were asymptomatic but not being considered for curative approaches at diagnosis (group 2); both groups were considered non-curable at the time of study design. Patients were enrolled from 29 public and private cancer centres across Australia, New

Results

Between Sept 3, 2004, and July 13, 2012, 293 participants were recruited; 261 were group 1 patients (PSA-only relapse) and 32 were group 2 patients (non-curable). 142 patients were assigned to immediate therapy and 151 were assigned to delayed therapy (figure 1). The close-out date for follow-up was Feb 26, 2014, allowing a minimum follow-up of 18 months. Three men withdrew shortly after randomisation and were not included in subsequent analyses of health-related quality of life. The

Discussion

Findings from the health-related quality-of-life component of this trial showed that, in general, androgen-deprivation therapy did not have a major detriment in this patient cohort when started early as opposed to delayed until disease progression. When patients with malignancy are diagnosed with incurable disease, the aim of palliative treatments is to improve length and quality of life without undue toxicity. When such a patient is asymptomatic, it is particularly important that the

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