Treat immediately or delay treatment? This is the ongoing question about androgen deprivation therapy (ADT) in men with prostate cancer who have relapsed based on rising prostate-specific antigen (PSA) concentrations or men who have been diagnosed with incurable but asymptomatic disease.
Last year, the Timing of Androgen Deprivation (TOAD) trial reported favorable survival for immediate ADT compared with delayed treatment; the results were published in Lancet Oncology, as reported by Medscape Medical News at the time.
Now come the results for health-related quality of life (HRQoL) outcomes over a 5-year time period, published online July 28 in Lancet Oncology.
Overall, there was no “demonstrable effect on overall functioning or health-related quality of life” between the two treatment groups, with one exception.
“Immediate use of androgen-deprivation therapy was associated with early detriments in specific hormone-treatment-related symptoms,” report the researchers, led by Gillian M. Duchesne, MD, from the Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.
In comments to Medscape Medical News, Fred Saad, MD, from the University of Montreal Hospital Center, Quebec, Canada, and author of a related commentary, said, “One expected to see an HRQoL difference between immediate versus delayed ADT users, and one doesn’t.”
Referring back to the previous survival results, he said, “We never expected to see a survival difference at 5 years for treating immediately with ADT. It is the hardest endpoint for a study.”
“And now with the HRQoL data, it obliges us to rethink the paradigm that immediate ADT is more harmful than delayed,” Dr Saad continued.
QoL Results
The TOAD trial was an unblinded, randomized, multicenter, phase 3 trial that enrolled 293 men with PSA-relapsed prostate cancer (261 men) after curative therapy and 32 men with incurable, asymptomatic prostate cancer.
Patients were randomly assigned to immediate (n = 142) or delayed (n = 151) ADT, with a recommended interval of at least 2 years.
As previously reported, the 5-year overall survival favored immediate ADT (91.2% vs 86.4% for delayed ADT; P = .047).
For this latest study, the researchers used a QoL questionnaire (QLQ-C30) to assess global QoL, physical functioning, role functioning, emotional functioning, fatigue, and pain. The analysis also focused on hormone treatment–related symptoms (hot flushes, sore or enlarged nipples or breast, and feeling less masculine), sexual activity and functioning, shortness of breath, and sleep problems.
No significant between-treatment group differences were seen in scores for global quality of life (–1.56), physical functioning (–0.19), role functioning (–0.97), emotional functioning (–1.30), sexual function (–0.34), fatigue (1.78), and pain (1.61).
Steady deteriorations in global QoL, physical functioning, and role functioning of about 10 points over 5 years were noted for both treatment groups.
With respect to ADT-related symptoms, the most significant were hot flushes and sore or enlarged nipples or breasts, with effects significant for immediate vs delayed treatment.
At 6 months, there was a significant difference between the groups in sexual activity: The mean score for sexual activity was 10.40 for the immediate treatment group and 29.20 for the delayed treatment cohort (P < .0001). The difference of 18.80 points exceeded the clinically significant threshold of 10 points, the researchers note.
However, this clinically significant difference did not hold after 2 years.
In addition, scores for hormone treatment–related symptom were significantly higher for the immediate therapy group than for the delayed treatment group (15.97 vs 8.48, respectively) at 6 months and also at 12 months (17.07 vs 9.32). Although this difference was statistically significant, the differences between the two groups at 6 and 12 months fell short of the 10 points noted for clinical significance, the researchers note.
“This detailed quality-of-life analysis provides evidence that expands the understanding of the effects of androgen-deprivation therapy on health-related quality of life in these specific patient cohorts as to the risk-benefit balance of when to intervene,” the TOAD study authors comment.
“The TOAD trialists should be congratulated for taking up the challenge to establish both the efficacy and quality-of-life differences between early and delayed androgen-deprivation therapy,” Dr Saad writes in his commentary.
“It is a difficult study to undertake and many [other] studies were terminated prematurely for lack of enrollment,” he commented in an interview.
We’ve been asking this question for a long time.
“We’ve been asking this question for a long time,” Dr Saad told Medscape Medical News. He explained that ADT is typically reserved for men with metastatic disease and, in the PSA era, it was generally believed that clinicians were overtreating, which affected HRQoL.
“This study answers some of the questions and makes us re-examine the merits for not delaying ADT for appropriate patients,” he said.
The HRQoL results are particularly important in light of the greater than 90% adherence with completing HRQoL questionnaires during the 5-year study interval, Dr Saad pointed out. “That is an excellent compliance rate,” he said.
Clinical Implications
While highlighting the finding of no overall difference in QoL between the two treatment groups, Dr Said noted that in this study the difference in QoL detriments needed to be classified as clinically significant (>10 points), which seems to raise the bar high. He suggested that this could lead to the underestimation of the impact of ADT.
The TOAD trialists acknowledge that QoL detriments of less than the generally accepted 10 points are perhaps troublesome for some men.
In particular, they note that the ADT effects on sexual functioning can be “devastating.” “[But] in this pretreated group sexual activity was already low at trial entry (partly related to a previous therapy), and the effect of a further insult in the form of androgen-deprivation therapy might be lessened,” they write.
“I am reassured that on average little difference in HRQoL is seen between immediate and late users of ADT,” Dr Saad told Medscape Medical News.
Nonetheless, he is aware that clinicians regularly see patients whose QoL is severely affected — an effect that can be missed when patients are lumped with those who have less profound symptoms. “As clinicians, we are still obliged to be attentive to those who are severely affected by ADT,” he commented.
He also noted that PSA factors into the psychology of patients. “When a patient sees his PSA go down, he is less likely to be bothered with side effects of therapy, especially when it leads to a longer survival,” Dr Saad told Medscape Medical News. Patients may minimize side effects of treatment when they believe it is helping them live longer, thus leading to an under-reporting of symptoms, he noted in his commentary.
“The results of the study make us rethink about our conservative approach to ADT,” he said. Dr Saad explained that treating early vs treating late is a complicated area and that treating physicians like an easy formula. “Unfortunately, this study tells us that the answers are not as simple,” he said.
But he also hopes that this study does not take physicians to the other extreme in providing early treatment for all patients. “That will be a wrong way to interpret the positive results of this study,” he said.
Dr Saad indicated that in the current climate of thinking of patients’ QoL and the detriments of ADT, he has taken a more conservative approach in treating patients. “This study forces us to look at the individual patient, and now I will work very hard on personalizing treatment,” he said. For Dr Saad, that means factors such as PSA doubling time and Gleason grade will inform his clinical management.
For PSA doubling of more than a year, patient factors will play a role in determining how long to wait before treating with ADT. “Patient factors such as age, life expectancy, other comorbidities, and anxiety levels also need to be part of the equation,” he writes in his commentary.
The study did not address other effects that need to be considered in clinical practice, Dr Saad told Medscape Medical News. These include bone loss, unresolved cardiovascular risk, increased risk for diabetes, and possible cognitive effects, which also must be weighed against the risk for cancer progression.
Dr Saad indicated that some important analyses will emerge from the TOAD trial in the near future. Most important among them will be identifying factors in the immediate ADT users that correlate with survival benefits. “Knowing these factors will help generate an algorithm or a nomogram that will provide the guidance physicians are looking for,” he told Medscape Medical News. “Phenotyping or better describing the patient who will benefit from early ADT will help clinical management,” he said.
However, Dr Saad writes in his editorial, “individual patients need to be counselled on the undeniable fact that some will experience more profound detriments in quality of life than others.”
“Ultimately, knowing who truly requires early therapy and who can safely delay or avoid it should be our goal to minimise the physical and quality-of-life effects of androgen-deprivation therapy,” he concludes.
The TOAD trialists agree. “When such a patient [with incurable disease] is asymptomatic, it is particularly important that the risk-benefit ratio of any treatment offered is taken into account when deciding when and how to treat,” they write.
They note that the information on HRQoL over 5 years provides evidence that physicians need to use in discussing management options in this setting.
The TOAD trialists reason that immediate ADT should be emphasized for men with poor prognostic characteristics (eg, PSA doubling time of less than 10 months) while patients with better prognostic features might wish to delay treatment.
Several study authors report getting fees, support, and grants from industry sponsors, as detailed in the paper. Dr Saad reported receiving grants, personal fees, and nonfinancial support from Sanofi, AbbVie, Takeda, Astellas, Janssen, and Bayer.
Lancet Oncol. Published July 28, 2017. Abstract, Commentary
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