Optimal Duration of ADT with Definitive RT for Intermediate and High Risk

Optimal Duration of Androgen Deprivation Therapy (ADT) with Definitive Radiotherapy for Prostate Cancer: An Individual Patient Data (IPD) Meta-Analysis from the International MARCAP Consortium (2022)

"Purpose/Objective(s)

For men with intermediate- and high-risk prostate cancer receiving definitive radiotherapy, the ideal duration of ADT to improve overall survival (OS) is unclear. Additionally, actual treatment duration received, given the low and variable patient compliance with long-term ADT, has not been compared with intention-to-treat (ITT) duration. Recent retrospective data suggest that the optimal ADT duration may exert a continuous non-linear benefit (Kishan et al., JAMA Onc 2022), and herein we aim to assess this in the MARCAP consortium of randomized trials.

Materials/Methods
A meta-analytic framework was generated to determine the optimal duration of ADT. An IPD meta-analysis performed by the MARCAP consortium using 13 randomized trials (EORTC 22863 and 22961, GICOR/DART, ICORG 9701, PCS III and IV, TROG 96.01 and RADAR, and NRG/RTOG 8610, 9202, 9408 and 9910). Both ITT and treatment received ADT durations were analyzed. Inverse probability of treatment weighting (IPTW) was performed to assess the effect of ADT duration with adjustments for age, PSA, Gleason score, cT-stage, radiotherapy dose, pelvic nodal radiotherapy use, and mid-trial enrollment year. Multivariable additive Cox models were then used to model the association between the primary endpoint of OS and ADT duration. Secondary endpoints included prostate cancer-specific survival (PCSM) and other-cause mortality (OCM). A pre-specified sensitivity network meta-analysis (NMA) of EORTC 22961 (6 vs 36 months), PCS IV (18 vs 36 months), and TROG RADAR (6 vs 18 months) was also performed.

Results
There were 10,266 patients included with a median follow-up of 11.3 (IQR: 9.5-14.5) years. On ITT meta-analysis, there were significant improvements in OS from extending ADT from 9 to 18 months (HR 0.77, 95%CI 0.68-0.86, p< 0.0001) and from 18 to 28-36 months (HR 0.78, 95%CI 0.68-0.89, p=0.0002). The optimal duration of ADT for OS on ITT analysis was 28 months, which was not impacted by RT dose (p=1.0). ADT duration based on compliance data demonstrated the optimal ADT duration was actually 21 months for OS. These findings were consistent on the sensitivity NMA. Optimal ADT durations based on PCSM was ≥36 months, while 0 months was optimal for OCM with a 0.5% increase in OCM HR per month (HR 1.005 95%CI 1.002 - 1.008), and HR = 1.19 (95% CI 1.06 - 1.33) for 36 vs 0 months.

Conclusion
For men enrolled in the context of randomized trials, after accounting for much of the non-compliance with durations of ADT beyond 18 months, we demonstrate that 21 months is optimal for OS in men with intermediate- and high-risk prostate cancer. While longer durations of ADT provide incremental benefit on PCSM, this must be balanced against potential worsening of OCM, cost, and quality of life."

Djin

Thanks for posting. I have forward the studies to a friend of mine who just started ADT and radiation for his multiple G9 PCa. I'm sure he will discuss with his medical team.

Jim

Warrior 22: better to remove this post. You started a new thread; lets focus on that one.

warrior22 said...

Don't see original though. ( ? )

No, the internet did not eat your post: here it is:
https://www.healingwell.com/community/default.aspx?f=35&m=4306487

Hi Melaine. Yes, the above paper looks at ADT duration with RT as the primary treatment (not surgery followed by SRT).

I'm not well-versed in the question of whether and how long to add ADT to salvage therapy after RP, did I see very much when I searched quickly just now. If this were me, I would want to research these questions and ask my medical team about these issues:

-- The role of ADT is clear in the presence of metastases, but what is the purpose of adding ADT to RT if the recurrence following surgery is thought to be confined to the pelvis? And for these purposes, is there evidence that ADT does this effectively?

--If the presumption is that there are already micrometastases, does the ADT serve to halt their growth/spread? What happens when you stop the ADT?

--I'm assuming that the role of ADT is not to make any local recurrence more vulnerable to the RT in the post-radiation period, but I could be wrong. I would think that with no prostate, the radiation can easily reach the malignant cells.

--The literature seems to be growing with papers on the adverse effects of ADT. So not only is there the question of increased risk for conditions (e.g. cardiac problems), but there is also the question of quality of life (e.g. cognitive impairment/decline), so:

--How much do you risk by postponing any ADT until/unless there is clinical recurrence outside the pelvis (i.e., evidence of mets on scans)?

-- After a (tentative) ADT duration is decided on and begun, is it adjusted shorter or longer by some ongoing or periodic criteria (PSA, imaging. adverse events?) down the road? I

-- Does whether or not you add ADT (or its duration) affect the size of the salvage radiation field (e.g., prostate fossa only vs. whole-pelvis)? If wide or whole-pelvis, how much does that increase the risk of a second primary tumor (e.g., bladder or bowel) in the future?

-- Would it be possible to have the SRT and, assuming a drop in PSA, continue to monitor the PSA and begin ADT only if need be? Did your husband have the Decipher test? If the test came back low risk for mets, it could support keeping the ADT duration shorter or even postponing it. (Keep in mind, of course, that low risk doesn't mean no risk).

Perhaps you could ask the docs for the name of the papers that back up their ADT recommendations. I agree, the trick is known exactly which men in any study showed benefit, and whether your husband falls in that group. Are these men who all went on to have metastatic PCa? Did men who got ADT with their SRT (and before their mets appeared) survive longer than men who started ADT only later, when mets appeared? Or did adding ADT after SRT result in fewer men going on to develop mPCa?

Do your docs have personal and/or institutional outcomes for their own patients regarding ADT addition and duration for men with your husband's profile? This can be a further source of data. It may be anecdotal, but may also be of value.

While it may be difficult, I would look at what literature is available and try to see which cohort your husband most closely matches. In other words, you are not trying to come up with a standard of care regime that is right for all men with local recurrence, but a plan for your husband's specific case, which is why I brought up the Decipher test.

Please take these as "mud against the wall" questions that are the issues that I would want illuminated if this were me facing salvage therapy (which it might be one day!). I'm not trying to advocate for this or that position regarding ADT.

Use the answers/info you get when you ask questions to formulate new, more specific questions. Clearly, you'll reach a point where the current state of medicine won't have the answers you want, but at least you'll come close to obtaining all available info and current thinking about this issue.

If it comes down to crunch time and are given info by the doc(s) you trust and told (or learn by your research) that your husband has to decide between options that have equal chances of success, don't be afraid to ask your doc(s) the question "If this were your brother asking for himself, what would you advise." Some docs may normally be reluctant to offer anything beyond standard of care advice or the results of recent trials, but might give you their opinion if nudged.

Chin up!

Djin