In issuing final draft guidance on the coverage of treatment with denosumab (Xgeva) for patients with metastases to the bones, the National Institute for Clinical Excellence (NICE) in England again has excluded men with prostate cancer-induced metastases to bone.
The full text of the NICE media release is available on line. NICE (provisionally) recommends use of denosumab for the prevention of skeletal-related events in patients with bone metastases from breast cancer and in patients
with bone metastases from solid tumors (other than breast or prostate) who would otherwise be prescribed bisphosphonates.
According to the “fine print”, during consultation on the very first draft of guidance on the use of denosumab in England, NICE’s Appraisal Committee determined that
… bisphosphonates should not be used as the comparator for denosumab in people with bone metastases from prostate cancer. This is because, according to NICE guidelines [on management of prostate cancer] , bisphosphonates are recommended as a treatment for pain relief (a use which denosumab is not licensed for) and not to prevent skeletal-related events. Therefore, the Appraisal Committee concluded that the main comparator for this group of patients should be best supportive care.
Data submitted to the Appraisal Committee during the second consultation on this draft guidance did in fact suggest that
… bisphosphonates are prescribed for people with bone metastases from prostate cancer but the committee noted a wide variety of reasons for their use. The committee concluded that the data was not robust and there should continue to be regard for the recommendations included in the NICE guideline on prostate cancer.
NICE’s Appraisal Committee then concluded that best supportive care should remain the main comparator to denosumab and not bisphosphonates.
Something about this decision doesn’t seem right to The “New” Prostate Cancer InfoLink.
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: bone, denosumab, metastasis, NICE, Xgeva |
THE "NEW" PROSTATE CANCER INFOLINK 
I agree that something seems to have got lost in translation.
It seems that denosumab demonstrably mitigates bone metastasis. However, although bone metastasis is often painful, denosumab data apparently focused on clinical signs, not on pain. It’s unfortunate that nobody saw fit to gather sufficiently robust data on pain relief at the same time.
It seems that bisphosphonates are “recommended” for people with bone metastases to obtain pain relief. (BTW, I wonder if NICE is conflating “pain relief” with “palliative care”, as is sometimes done in the U.S. — except by insurance companies, which maintain a separate lexicon, classifying Lupron, for example, as a “palliative”!) However, bisphosphonates are merely “prescribed” for other reasons, apparently(?) without there being any “recommendation” regarding their use as mitigators of metastasis.
So: Because the questions asked of denosumab were clinical, not symptomatic, and because the official “recommendation” for bisphosphonates diverges from the way it is actually used, the end result is that the efficacy of denosumab [for anything] is not to be officially compared with the efficacy of bisphosphonates [for anything].
And without being officially able to compare one metastasis-mitigating, pain-relieving agent (denosumab) against another metastasis-mitigating, pain-relieving agent (bisphosphonates), NICE says one must instead compare apples to alligators rather than to quinces.
Although I can imagine data sets that support such a bizarre conclusion, I can’t help suspecting this ruling is not 100% evidence-based …
Paul:
You should be aware that LHRH receptor agonists like Lupron are actually all approved by the US FDA very specifically for “palliative treatment of advanced prostatic cancer” (see the Lupron prescribing information). Thus it is hardly fair to accuse the insurance industry of maintaining and applying a “separate lexicon.” There has never, ever been any substantiated evidence that, when used on their own, such drugs do anything clinically significant (for men with prostate cancer) other than palliate the pain associated with metastatic disease to bone.
Indeed, something seems wrong. Perhaps this text is incomplete and confused, as follows. First, what is a “provisional” recommendation in this case? No answer. Second, In the first paragraph of the media release denosumab in the form of XGEVA is recommended for one use. But at point 12b. denosumab is not recommended for therapy-induced bone loss in non-metastatic prostate cancer (open the link to see that). I am pretty sure, thanks to an earlier discussion here, that 12b. concerns Prolia, not Xgeva. They are chemically identical and differ only in quantity per dose. I was confused earlier: I did not know about the quantitative difference. Perhaps the writers of this NICE text don’t know this either, say, because they never heard of Prolia. I’ll admit that I am so confused that my text might be nonsensical.
PS. The reason given for the non-recommendation in 12b. is that Amgen supplied no evidence about the effects of denosumab (Prolia??) for the use indicated in 12b. That’s strange. Why didn’t Amgen supply that evidence?
Dear George:
I can certainly tell you that: (a) the provisional nature of this recommendation is very clear. It is provisional because it is a final draft recommendation, and NICE’s draft recommendations always have to be followed by a period for public comment.
I can also tell you that: (b) I am quite sure that NICE understands the distinction between Xgeva and Prolia. NICE does what it does for a living, and it works with highly regarded experts to help NICE do it, with full input from the manufacturers, who scrutinize every word of NICE’s utterances like hawks because they significantly affect the manufacturers’ potential revenue (and not just in England; other countries also watch what NICE is saying about specific drugs). Of course this doesn’t mean NICE can’t sometimes make strange decisions (inscrutable to mere amateurs like me). I don’t think this text is either incomplete or confused. I do think it is very difficult to follow and to parse.
Well, perhaps ‘confused’ is not the best word to describe what I am getting at. I’m thinking of point 12.b in the media release. I think that concerns bone-mineral loss induced by androgen deprivation therapy. Prolia, not XGEVA, is often prescribed for that; XGEVA is not. My point is, that the media release seems ambiguous. For it appears to use the same word, “denosumab,” in two ways: in the first paragraph for XGEVA and in 12.b for (I think) Prolia. These are different products (although both are denosumab).
Now, 12b. ends with “(terminated appraisal).” If you click on 12b.’s link you will get a page about denosumab’s use as stated in 12b. There we are told that denosumab is not recommended for “therapy-induced bone loss … because no evidence submission was received from the manufacturer [Amgen] or sponsor of the technology.” That wording seems strange to me. Either my analysis is correct or the text is so hard to parse that I got it wrong.
Quite … Neither you nor I can quite grasp what the evidence is for their conclusions … or how they have used the available evidence to reach those conclusions. However, just because the explanation may be less than transparent does not necessarily make it the wrong decision! It just makes it very difficult to follow the logic (and you are, after all a teacher of logic!).
Of course it doesn’t make it wrong. Here’s an example I often use. It is not very controversial. You and I know *that* 2 + 2 = 4. But I guarantee you that, since nobody knows what numbers are (whatever a particular thinker says), nobody knows what (say) a sum really is. So in general, you can know that a sentence is true without knowing fully what it means.
I think I have the Prolia problem at least partly sorted out. The media release is dated August 17, 2012. I looked again at 12b.’s link and noticed that the negative recommendation by NICE of Prolia for therapy-induced reduction in bone mineral density was made in 2010. Then, using this and another link (that I cannot find now), I saw two reasons for this advice. First, that Amgen had not — by 2010 — provided any or enough evidence, and second, that Prolia had not been in use long enough to be reasonably sure that all long-term side effects were known.
Now, the media release dataed August 17 concerns only Xgeva, hence not Prolia. I erred by not seeing the 2010 date for Prolia. I guess 12b. is included only for reference, not as a statement of present advice about Prolia. The sole remaining question is: What happened between 2010 and August 17, 2012? I am pretty sure that Prolia is used in the UK now, to treat ADT-induced reduction of bone mineral density. I know it was approved by the FDA and its Swedish equivalent in, I think, 2011.
Dear George:
Denosumab in the dosage form known as Prolia was indeed approved by NICE (in 2010) — exclusively for use “as a treatment option for the prevention of osteoporotic fragility fractures in postmenopausal women who are at risk and for whom oral bisphosphonates are unsuitable.” It is not approved for the treatment of reduction of bone mineral denisty in men (with prostate cancer or any other condition).
Dear Sitemaster,
Thanks for the correction about Prolia in the UK. The NICE approval text is interesting. There is some food for thought there.
Dear Sitemaster,
I am beginning to understand why the text linked to above on 18 August does not mention approval of Prolia for therapy-induced reduction of bone mineral density. With my usual chutzpah I called NICE this morning, and got connected with the Inquiries department. I explained the problem and was told that NICE is still investigating Prolia for ADT patients, and will probably publish a report in November 2013. So, if this is correct, it is not the case that Prolia was “not approved” (words of Sitemaster) for the function, but simply that no decision has as yet been reached about it.
George:
I think we are way beyond the hair-splitting phase here. If Prolia “was not given an approval” for any indication related to prostate cancer, then it was (passively) “not approved.” However, more importantly, the dosing form of denosumab called Prolia is not approved in the USA or in Europe for any indication related to prostate cancer (or men). In Europe it is approved specifically for “the treatment of osteoporosis in postmenopausal women at increased risk of fractures.” I think whoever you spoke to at NICE is as confused as we were. Amgen cannot market Prolia in Europe for use in the treatment of men — for any reason.
Dear Sitemaster,
Here is a Dutch news report from 2011. The very beginning says that Prolia is reimbursed (terugbetaald) for the two functions we are interested in.
My apologies. This report is Belgian, and is written in Dutch. That language is one of the two official languages of Belgium, the other being French. To be clear, the report implies that Prolia is covered by some Belgian insurance scheme, for the two functions we are interested in. The report neglects to state that the quantity of denosumab differs in the two applications in which we are interested. Instead, it uses the word “Prolia,” to name the medicine used in both applications. This usage is wrong, but that is beside the point right now. This mistake probably confused some Belgian doctors at least as much as everything about this is confusing us.
Well … All that tells me is that everyone is confused! If you look at the EMEA approval for Prolia, it does indeed state that:
“Prolia is used to treat osteoporosis (a disease that makes bones fragile) in women who have been through the menopause and have an increased risk of fracture (broken bones). Prolia reduces the risk of fractures in the spine and elsewhere in the body, including in the hip.
“Prolia is also used to treat bone loss in men receiving treatment for prostate cancer that increases their risk of fracture. Prolia reduces the risk of fractures in the spine.”
The EMEA approval for Xgeva, by comparison, states:
“Xgeva is used to prevent bone complications in adults with a solid tumour that has spread to the bone. These complications include fractures (breaks in the bone), spinal compression (when the spinal cord is compressed by the bone), or complications requiring radiotherapy (treatment with radiation) or surgery.”
I give up.