After a single dose (120 mg) of degarelix to support my ST-ADT in conjunction with pelvic lymph node IMRT, my Testosterone level is castrate (>20 ng/dl). I added this as estradiol patches were slow to get there (T = 63 after 2 weeks).
And I am feeling surprisingly good as previously reported with no hot flashes, good energy and perhaps only a trace of "brain fog". So I have wondered how long the effects of degarelix will last. Will the single dose be sufficient to give T suppression for 3+ months of ST-ADT, or would I need to repeat it monthly if I was not also on the estradiol patches?
The following article provides a good and full review. The time to maximum effect (Cmax) after an initial dose is just 40 hours! And T drops just as quickly. The terminal half-life is 43 days with a single dose and 28 days on maintenance (80 mg/month). So the duration from a single dose may well be sufficient alone to provide 3 months of ST-ADT before T recovers.
The same article also reviews studies showing the benefits over Lupron in QOL issues including mentation, but not for sleep:
"Health-related quality of life
"At the end of CS21, health-related quality of life (HRQoL) [measured using generic Short Form-12 v2 (SF-12) and cancer-specific European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaires] for patients receiving degarelix 240/80 mg versus leuprolide was largely comparable [Gittelman et al. 2011]. However, mean SF-12 scores for the mental component summary and mental health domain were significantly higher (better) with degarelix than with leuprolide. Conversely, leuprolide had a seemingly more favorable effect on insomnia and bodily pain than degarelix; however, the mean increase in insomnia with degarelix may be explained in part by significantly lower baseline insomnia in this group. In patients with metastatic disease, there were significant improvements at month 12 in global health status for degarelix versus leuprolide, as well as role emotional and appetite loss. However, the clinical significance of these findings remains to be determined."
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I think that when cancerous pelvic lymph nodes are discovered, long term ADT (2-3 years) may be necessary. Also, your pelvic LN dose (60 Gy/30 fx) may be too high - but if you have a lot of visceral fat, it may be OK. Most of the recent studies are finding that the irradiated pelvic LN area is inadequate - I'd be wary of a hemi-pelvic dose area.
The GETUG P07 Phase II trial uses 54 Gy/30 for the pelvic node zones with boost to 66 Gy/30 to the targetable oligometastatic nodes. My "boost" dose IG-IMRT is below that.
And they used a single injection of LHRha to provide estimated 6 mo STADT.
Daniel Spratt did a review that does suggest LTADT for Gleason 7 (which I am) if PSA> 1.5. My PSAs 0.2 to .25 for the past 5 years, but was up to 5.0 prior to starting bicalutamide. So I don't know how to integrate that. And the source of that LTSRT recc. was not clear to me.
If that is the boost dose, it may be too low - but that depends on location.
GETUG P07 was not a randomized trial to find the right duration of adjuvant ADT. We don't have prospective data, but this observational trial indicates that long-term adjuvant ADT is best:
Thanks T_A. I appreciate your highlighting these considerations.
5 fractions to go on my IMRT. They do a cone CT before every treatment to align. And check that I have clearance between the high dose CTV and the small bowel via some help from belly fat. (who knew?) So I'm OK there I believe. But I want to be sure the node targeting "boost" is adequate to ensure full treatment. Since we are not using the extreme hypofractionation typical in SBRT (i.e. 60 Gy in 5 Fx), I am uncertain if 58 or 60 Gy in 30 is equivalent, given the Alpha/Beta ratios for PCa.
I found the analysis from Spratt that GP24 described very interesting in the larger consideration of ADT with RT in trials where OS is not primary endpoint.
I didn't realize from your profile that your RT was almost done, or I wouldn't have commented on the dose. No, 60 Gy/5fx and 60 Gy/30 fx are not biologically equivalent. But 60 Gy would never be given for any purpose in 5 fx. What was the boost dose to the known cancerous nodes?
As I said, Spratt's analysis has nothing to do with your situation (which is N1).
The analysis in the Mulderman et al study is beyond my knowledge re: single vs multiple fxs Bioequivalent dosing (BED). They used 16-24 Gy/ single fx; 30 Gy/3 or 50 Gy/5.
I am left puzzled as I don't know how to interpret the "isodose lines" and "BED" for the alpha/beta assumptions. Specifically: Is 58 Gy in 28 Fx enough?
"The variability of the relationship between dose-response and histology, as illustrated by Greco et al (18), underscores the importance of analyzing data in a histology-specific manner when determining the most appropriate prescription dose for a particular type of tumor. To our knowledge, before the present study, no clear dose-response data existed for oligometastatic PCa. Jereczek-Fossa et al (19) recently reported outcomes of a cohort of patients treated for recurrent or metastatic PCa using a range of SBRT doses, with a median dose of 30 Gy in 4.5 fractions. The 30-month progression-free survival rate was 42.6%, and no clear dose-response data emerged. Muacevic et al (20) reported 95.5% 2-year control of osseous PCa metastasis treated with single-fraction SBRT, with doses ranging from 16.5 to 22 Gy. Reports from other groups have indicated 100% MC with schedules of 50 Gy in 10 fractions (21, 22) and 30 Gy in 3 fractions (22, 23)."
"Is 58 Gy in 28 fx enough?" So that was the dose received by half of your pelvic LNs? If so, that was more than enough - in fact, it was very high. What I think may not be enough is the area covered by the radiation, and the duration of ADT.
Muldermans mentions an α/β factor of 1.5 which is usually used for prostate cancer. So your 56 Gy in 28 Fx (2 Gy per fraction) results in a BED of 130. This is sufficient. Piet Ost recommends a BED of more than 100 to control a lesion.
Thank you. Very interesting BED calculator. And my two PSMA positive nodes are getting boost to 61.2 Gy. I'm confident the treatment plan is a good one.
I have become very interested in the science and the empiric practice of clinical bioradiology. I found this series of online lectures and powerpoints that is free on the ASTRO website. It is out of UCLA and is aimed for residents/fellows in radiation oncology.
On the question of whether you can just stay with the initial dose for 3 months before starting the monthly maintenance doses, I'm guessing that the answer is no. I'm not basing that on half-life calculations from the article, but on the dosing instruction in the FDA label which says: "The first maintenance dose should be given 28 days after the starting dose." See: accessdata.fda.gov/drugsatf... page 2.
It is possible that there is no good reason for injecting the second dose in 28 days and it just happens that that was the only approach tested in the clinical trials and therefore the only dose approved by the FDA. However, it seems to me to be dangerous to assume that's true in the absence of any information supporting it. Also, be aware that the half-life calculations aren't like half-lives for most other drugs. They are based on "... a consequence of a very slow release of the drug from the depot that is formed at the injection site." (from the article you cited) and the depot release may have different characteristics from the more usual biochemistry of degradation and/or elimination of drugs in the body. The drug concentration decline may not be equal at all stages of the decline.
You can try calling or emailing Ferring Pharmaceuticals and posing the question to them. See: ferringusa.com/contact/ You may just get an answer like "No, don't do that", but if you're lucky, they might explain why. You might do better to email with a written explanation of why you are asking in the hope that the person who handles the email will pass it on to one of their technical staff. With a phone call you'd just have to hope that the person answering the phone communicates your concern correctly.
I understand that degarelix injections can be painful. Many doctors switch their patients to Lupron or equivalent after the first degarelix dose. I don't know if that works as well or not, though obviously some doctors think it does and Ferring themselves say: "By day 28, both groups (degarelix and leuprolide) achieved equivalent testosterone levels." See: firmagon.com/different-adva... and look at the graphic text under the "Day 1 ... Day 14" chart.
It would be interesting to have data on testosterone levels in a cohort to see how long it actually maintains castrate levels. But I will simply follow my own serial T levels and I can maintain ADT status for as long as I choose with the estradiol patches. Degarelix is a fine alternative as well. But for me Lupron etc are horrible and I will not use LHRh agonists again. They are inferior.
Degarelix injections can be painful if they are not properly administered. Of course they are not painless but the discomfort level is not such that it precludes normal activity. I have continued walking (briskly for 4-5 km) on day 2 of the injection. I have also played 18 holes of golf after 36 hours. On the other hand when I took the first maintenance dose it was quite painful for almost 3 days. I then studied comments in another site which proved quite useful. The injection is subcutaneous so care has to be taken not to give it in muscle. I have a lost of muscle in the abdomen from exercise so I asked the Dr to give it a little on the side where you can use the forefinger and thumb to pick up enough flesh. This is located 2 in below the ribs. Mind you I am 5ft 7 in so has to be adjusted for height. The location ensures that it is above the trouser belt line and will not get pressured under the belt or trouser waist. Once the skin is picked up from the spot the needle is inserted at 45 degrees. The Firmagon should be injected over 30 secs. Then, the needle should be left in for about 30 secs so that no drops trail out from the needle into the skin and flesh. This prevents a painful reaction. Using this method I have in 5 months reached a stage where I am not scared of my Firmagon injection. However, it is important to note that each of us will have different reactions. All the right approach will ensure is that your reaction to the injection is optimally minimized. Of course it might still be most uncomfortable for you in which case you could look at Lupron.
If the pelvic lymph node IMRT takes care of the mets, what is the purpose of the Lu177 treatment eight weeks later?
Lu177 treatment will just treat what can be seen on a PSMA PET/CT. If this does not show any mets, as should be the case at some time after the IMRT radiation, it is futile.
Yes you have identified a key question. If the IMRT will have treated the only lesions identified on the PSMA PET scan. So would 177Lu do anything beneficial? My Theranostics Australia consultant says there is no data to prefer sequencing 177Lu before vs after IMRT for nodal Mets.
However it is reasonable to expect that micro sites of PCa also exist that do not have the cellular mass to be seen on the scans even if they are expressing PSMA. So that would be the reason for doing a 177 Lu PSMA treatment sooner rather than waiting for progression that becomes scan positive. Early seems to be better than later in general with 177 Lu. Given the low toxicity I’m not inclined to wait for clinical trials to answer the question. I appreciate your input.
I am not aware of any doctor in the world who will treat you with Lu177 if no mets can be detected on a PSMA PET/CT. Dr. Hofman in Australia will even request a FDG PET/CT and if that shows mets which are not displayed on a PSMA PET/CT he will not treat with Lu177. Lu177 means "you treat what you see". If you do not see anything on the PSMA PET/CT there is nothing to treat. The side effects of a Lu177 treatment increase with low tumor volume because the ligands attach to healthy cells because there are no PSMA expressing tumor cells they can attach to.
I recommend the following sequence: do the IMRT radiation and wait until new mets become visible, maybe in about a year, if you do no ADT. Then treat these new mets with CyberKnife radiation. Wait for the next recurrence and radiate again with Cyberknife. If there are too many mets for a CyberKnife radiation, or they are located where they cannot be radiated, get a Lu177 treatment. You can extend the time between recurrences using intermittent ADT. In all this should result in a longer time to castration resistance than just starting with ADT now.
Thanks Tango. Yes the SPPORT trial was very valuable in verifying the benefits of STADT with RT. Unfortunately they did not have a PLNRT arm without STADT.
My remaining question concerns the duration of the treatment as they just defaulted to a single injection of a LHRh agonist and did not compare with even shorter regimens. Perhaps 3 months
In this text Dr. Spratt does not refer to the SPPORT trial but questions adjuvant ADT in the GETUG-16 (Carrie) and RTOG 9601 (Shipley) trials for salvage radiation.
"The improvement in MFS [metastases free survival] was not even really a “benefit”. Why?
6months ADT gives ~12months Testosterone suppression and side effects. Delay in MFS at median followup was exactly 12months! Given developing M1 diagnose is common trigger for ADT, you simply delayed mets by duration of Testosterone suppression you induced upfront."
In the following study by Schick the patients with ADT delayed the recurrence for about the length of time they did ADT in addition to the one year I mentioned without ADT:
The median biochemical recurrence free period was about 31 months, ADT was given for 12 months, add six months for testosterone recovery plus one year which you could expect without ADT, adds up to 30 months. So this is about the same result you would get if you would start with ADT one year after radiation.
On the other hand a long delay between radiation treatments may be worth the ADT side effects. I took Bicalutamide to avoid most of these side effects.
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