ArticlesHealth-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
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
References (24)
- et al.
The natural history and predictors of outcome following biochemical relapse in the dose escalation era for prostate cancer patients undergoing definitive external beam radiotherapy
Eur Urol
(2015) - et al.
Quality of life in men with locally advanced prostate cancer treated with leuprorelin and radiotherapy with or without zoledronic acid (TROG 03.04 RADAR): secondary endpoints from a randomised phase 3 factorial trial
Lancet Oncol
(2012) - et al.
Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial
Lancet Oncol
(2016) - et al.
Adverse effects to quality of life arising from treatment can recover with intermittent androgen suppression in men with prostate cancer
Eur J Cancer
(2006) - et al.
CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment
Semin Radiat Oncol
(2003) - et al.
An international field study of the EORTC QLQ-PR25: a questionnaire for assessing the health-related quality of life of patients with prostate cancer
Eur J Cancer
(2008) - et al.
Analysis and interpretation of health-related quality-of-life data from clinical trials: basic approach of The National Cancer Institute of Canada Clinical Trials Group
Eur J Cancer
(2005) - et al.
Higher sexual interest with androgen receptor inhibitor monotherapy than with castration plus an androgen receptor inhibitor in prostate cancer patients treated with curative radiotherapy, but otherwise small health-related quality of life differences: a randomised prospective 18-month follow-up study
Eur J Cancer
(2016) - et al.
Predictors of time to metastasis in castration-resistant prostate cancer
Urology
(2016) - et al.
Natural history of progression after PSA elevation following radical prostatectomy
JAMA
(1999)