Some 15 months ago, we reported the initial, primary results of the TOAD trial, which showed an overall survival benefit for immediate as opposed to delayed initiation of androgen deprivation therapy (ADT) in non-metastatic patients considered to be inappropriate for curative therapy.
At that time, Duchesne and her colleagues stated that, during the first 2 years of the trial, the men treated with immediate ADT exhibited a small but clinically significant deterioration in their quality of life compared to the men managed with delayed ADT. This is hardly a big surprise.
A new paper by Duchesne et al. has now reported more detail about the quality of life of the patients enrolled in the TOAD trial.
According to this new paper:
- At 6 and at 12 months after enrollment and randomization into the trial
- Sexual activity was significantly lower in the immediate therapy group than in the delayed therapy group.
- Patients in the immediate therapy group had significantly more hormone treatment-related symptoms than those in the delayed therapy group (but these differences were below the level of clinical significance).
These two findings are unsurprising since most of the men in the delayed therapy group didn’t start to receive ADT until nearly 2 years after they were enrolled in the trial!
However, the authors also report that
- There were no statistically significant differences between the two groups as regards
- Global health-related quality of life over 2 years from randomization
- Global quality of life, physical functioning, role functioning, or emotional functioning, fatigue, dyspnea, insomnia, or feeling less masculine over the entire 5 years after randomization
- Hot flushes, nipple symptoms, and breast symptoms were clinically significantly higher in the immediate therapy group than in the delayed therapy group over the entire 5 years of follow-up after randomization.
As we were careful to point out in our original report on the TOAD trial, this was a complex if “real word-like” study. And the authors have fully acknowledged the issues involved.
We believe that what the TOAD study has done includes the following:
- It has added to the data set suggesting that early and immediate use of ADT in appropriately selected patients may have a small but significant overall survival benefit compared to delayed ADT.
- It has shown that such a survival benefit only becomes evident after about 5 years on therapy.
- It has suggested that the overall effects of early ADT on the quality of life of appropriately selected patients is probably relatively small as compared to those associated with delayed ADT (but those effects are “real”).
What the TOAD study has not done, however, is equally important:
- It has not shown that there is a major impact on overall or on prostate cancer-specific survival from early as opposed to delayed ADT (e.g., an additional survival of 1 year or more in 50 percent of the patients).
- It has not shown that the early side effects of early ADT are “negligible” for the men who are most affected.
We are therefore left in much the same situation as we have been for most of the past 30 years with regard to timing of initiation of ADT. There are potential risks and there are potential benefits. In the end, only an individual patient is going to be able to make the “best” decision for himself about when he wants to start ADT — after careful consultation with his doctors. And that “best” decision could still prove to be wrong! But …
One could reasonably argue that for those men who still have a high level of sexual function and are in a couple that places a high level of priority on their sex life, delayed ADT may be a better option that immediate ADT if there is no urgent need to initiate ADT. Conversely, for those men who prioritize the extent of their life as compared to the quality of their sex life, immediate initiation of appropriate ADT may be the better option compared to delayed ADT.
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: ADT, androgen, delayed, deprivation, immediate, quality of life, survival, TOAD |
THE "NEW" PROSTATE CANCER INFOLINK 
So what’s the definition of appropriately selected patient who will benefit from early use of ADT? Did the trial specify this class of patient?
Bob
Bob:
(a) Here’s the link to the original trial protocol.
(b) The trial basically included patients who fell into one of two categories, as follows: Group 1: Men with PSA relapse after initial curative therapy (n = 261) who were not good candidates for any other forms of savage therapy and Group 2: Men considered to have non-curable disease at initial diagnosis (n = 32), but excluding any men with evident metastatic disease.
I’ve got to say that I learned a lot from the TOAD RCT. Before TOAD there were a couple of retrospective studies that suggested that there was no risk in delaying salvage ADT in the setting of no detectable metastases, and low and stable PSA. I had assumed that delaying ADT would also delay castration resistance, and ADT-associated deterioration of QOL, so why rush it?
After TOAD, I questioned all of my previous assumptions. The 5-year data is certainly not definitive, but so far, I’ve learned a few things:
• Killing off the hormone-sensitive cells earlier, and reducing their load, seems to trump the effect of selecting for castration-resistant cells.
• While the effect on survival was minor in just 5 years, the effect on mortality was significant — cut in half! That tells me that there are at least some men (perhaps those with significant comorbidities?) who may live longer if the systemic intervention is started sooner rather than later. (Incidentally, I now understand the importance of looking at overall survival and not just prostate cancer-specific survival.)
• The vast majority of men in TOAD were started with intermittent hormone therapy, and hormone therapy may have meant anything from a few bicalutamide pills a week to full-on ADT3. But on the average, their quality of life was not diminished by starting earlier. So that means that the symptoms of the disease came to outweigh the symptoms of iADT, or that the symptoms were not burdensome.
• It also means that waiting for metastases to become detectable so that they can be treated with metastasis-directed therapy is probably not a good idea. I’m not sure if metastasis-directed therapy is ever a good idea absent systemic therapy. But that’s another story.
Dear Allen:
Don’t get me wrong. The TOAD study is fascinating … but it does come with problems.
It was much smaller than originally intended. Most (89%) of the enrollees were from a specific category of men who had failed first-line radiation therapy. The numbers of patients who died (from all causes and from prostate cancer) were also small. The time frame over which patients were entered into the trial was something like twice as long as was originally intended. Dr. Duchesne and her colleagues are very conscious of these facts, which is why their conclusions have been cautious.
One of the things that we have learned very clearly from some of the recent, larger trials is that everyone has been underestimating time to median overall survival in patients with non-metastatic (and early metastatic) hormone-sensitive prostate cancer. I am therefore also rather cautious about over-interpretation of data from a trial like this in which just 46/293 patients (15.7%) died during the course of the trial. This, of course, correlates with your comment about “the importance of looking at overall survival and not just prostate cancer-specific survival.”
The sad thing is that the TOAD trial initially had the potential to be definitive! If it had had 500+ patients followed for 7 years it probably would have been.
I would have been eligible for this trial in “Group 2: Men considered to have non-curable disease at initial diagnosis (n = 32), but excluding any men with evident metastatic disease.”
The following two findings reflected my experience during 14 years of IADT3:
“There were no statistically significant differences between the two groups as regards
— Global health-related quality of life over 2 years from randomization
— Global quality of life, physical functioning, role functioning, or emotional functioning, fatigue, dyspnea, insomnia, or feeling less masculine over the entire 5 years after randomization.”
In fact I was surprised at how good my general health was during the first 5 years (31 months on the major drugs during that period) and later. I kept working during the first 4 years, and initially after diagnosis I expected to take a lot of sick leave. It turned out that I needed extremely little sick leave, and my attendance at work was considerably better than most of my work mates. I suspect that a very good diet after diagnosis played a role.
Overall median survival in non-metastatic hormone-sensitive and early metastatic prostate cancer
Hi Sitemaster, I’m replying to your comment of August 11, 2017 at 6:44 am. As always, thank you for your awesome work in keeping us well informed.
Facing my own challenging case from December 1999, I have paid close attention to this matter. It didn’t take long to begin to suspect that many prominent members of the prostate cancer research community were getting this wrong -– in other words, greatly underestimating survival for these patients, as reflected in your comment: “One of the things that we have learned very clearly from some of the recent, larger trials is that everyone has been underestimating time to median overall survival in patients with non-metastatic (and early metastatic) hormone-sensitive prostate cancer.”
It wasn’t actually “everyone”, just the vast majority. For instance, medical oncologist Dr. Mark Scholz had been saying for years that those on ADT fall into two groups before developing castrate resistance, which of course is an earlier event than death: one group that can stay on ADT indefinitely, and the other group with an average success without castrate resistance of about 10 years (with secondary ADT after that). He was saying that in the days before a slew of beneficial drugs for advanced prostate cancer became available in recent years. His statement reflected his own clinical experience but also published research; my recollection is that Memorial Sloan-Kettering Cancer Center (MSKCC) was involved in some of it. He and MSKCC were not the only ones. Also, regarding metastatic disease, as noted in comments on other articles, back in 2004 Drs. Oefelein, Aggarwal and Resnick (from Case Western in Cleveland) reported that their chart review of 254 patients on ADT showed that “Median survival after hormone refractory prostate cancer developed in patients initially staged with and without skeletal metastasis was 40 and 68 months, respectively.”
Particular thanks to you for helping us become aware of these shifts in what had been considered orthodox views.