Julian - Interview 33

Age at interview: 61

Brief Outline:

Julian has prostate cancer. He is in a Phase 1 trial of a drug (a PARP inhibitor) which may stop cancer cells regrowing in people like him who have the BRCA2 genetic mutation. This mutation increases the risk of prostate and other cancers.

Background:

Julian is a research scientist and author, married, with 3 adult children. Ethnic background/nationality' White English Jewish.

More about me...

Members of Julian’s family carry the BRCA2 genetic mutation, which increases the risk of breast and ovarian cancer in women and prostate cancer in men. The mutation is more common in families of Eastern European Jewish origin. They first discovered this when one of Julian’s sisters had breast cancer and then ovarian cancer. Julian had a genetic test about six years ago which showed he carried the mutation, but at that point he was perfectly well. Then four years ago in 2004 he noticed blood in his urine and a biopsy showed he had prostate cancer. A bone scan showed the cancer had spread to his pelvic bone.

 

Because the cancer had already spread, he was told it was not worth having radical treatments such as surgery or radiotherapy. Instead, he was given a drug which blocks the production of hormones in the prostate which normally help cancer cells to survive. This worked for a while, and then he was given a different drug when the first one stopped working. When the second drug stopped working, Julian discussed further options with his consultant. He had read about a new drug (a PARP inhibitor) which it was hoped would stop cancer cells re-growing in people like him who have the BRCA2 genetic mutation. It turned out there was a Phase 1 trial of this drug at a nearby specialist hospital, to which Julian had been previously referred, and Julian asked to take part.

 

There were some concerns about whether he should take part. A Phase 1 trial is when a treatment is at an experimental stage, and researchers still need to find out what side effects there are, how severe they are, and what dosage is best. All participants take the new drug, unlike a Phase Three trial in which two or more different treatment are being compared and people are allocated randomly to receive one of them. As Julian still feels generally very well, the doctors wanted to be sure he understood the risk of possible unpleasant side effects and longer term damage, and could decide whether it was worth this risk. Julian himself felt that he wanted to take this chance of possible benefit to himself, and as someone who works in a cancer research institute there was also ‘an element of scientific curiosity’. Given the risk to his own daughters if they have inherited the BRCA2 mutation, he also felt taking part in the research might help them directly in future.

 

So far he has been well on the drug, apart from a bit of nausea and stomach discomfort. He has been on the trial for about eighteen months, and it seems to have worked well for him. His level of PSA (prostate-specific antigen, a marker of how the cancer is changing) has gone steadily down and is now stable, and his bone tumours seem to be stable or reducing. He feels very lucky to have had this opportunity, and has been impressed by the quality of care at the specialist hospital. He hopes he will be able to help the research further by taking the drug long enough to see what the longer term risks are, if any.

 

Julian asked to be referred to a specialist hospital to take part in a Phase 1 trial. His...

And at this point another factor entered into the story. I had read, and they had also mentioned to me, that there had been some basic science papers published about a year previously, which showed that there was a potentially a rather good treatment that might be available, an experimental treatment, which would specifically destroy cancer cells that arose in people who are carriers of the BRCA2 mutation or the BRCA1 mutation. So I read the papers and I thought it was very persuasive and likely this might be good for me. And I talked to one of the researchers who was doing the work about what the prospects were, what the worries were about side effects and so on, bad consequences of taking the drug, and was rather reassured. So I was quite keen to get enrolled in the trial, which I knew was now going on. So I had long discussions with the specialists, with the consultants at the hospital that was looking after me. They were a bit uneasy about putting me onto this trial. So this is a phase 1 trial, a trial of a drug which had never been used in people before, certainly not in the long term, never been used for cancer before, and was in principle quite a worrying sort of drug because it interfered with the action of a protein in cells which is very plentiful, and controls all sorts of very fundamental processes to do with DNA repair.

 

So on the one hand the drug was a little bit worrying, as most phase 1 trial drugs are, and on the other hand I was perfectly well, so I’d been diagnosed at an early stage in my disease, the hormone treatment had kept it well under control, I’d never really had any bad symptoms and I felt healthy and well. So in the ordinary course of things, if it were not for the existence of this trial, the recommendation would be that I should just carry on, and then there were palliative things that could be done eventually if the cancer, when the cancer got bad.

 

But I wanted to have a go [laughs] on the phase 1 trial, and they acknowledged there was a reasonable case, so they discussed with me at great length and discussed with one or two colleagues whether it was appropriate for me to go on to this trial. And eventually it was decided, yes, I would.

Testing treatments that target people with cancer who have the BRCA genetic mutation may be of...

I do have some mild side effects. I get intermittently every day a little bit of nausea and stomach discomfort but it’s not terrible. And most of the other patients also have had only mild side effects. A few people have had more troubling things.

 

In the long term, nobody knows what the effect of the drug might be, so I’m quite interested in staying alive for long enough to see what the long term side effects are. And I’ve got strong reasons to be interested in that question, because I’ve got three daughters and they’re at risk, and so it would be nice to know whether they should consider taking the drug, you know, if something goes wrong, or even taking the drug prophylactically to prevent disease from ever developing. That’s something that would not be contemplated now.

 

Because we don’t have the evidence about long term side effects, and as I say, it’s potentially quite a worrying drug.

 

But it’d be, you know, if I live a good long time then that would be a bit of evidence that maybe it’s a good idea to start the drug treatment very early and maybe even before any disease is apparent.

 

Have they been tested for the mutation?

 

No, they haven’t. They know the situation, but we thought, my wife and I thought that they should be left to make their own decision about whether to get tested.

 

So they’ve not had tests so far.  

Julian joined a Phase 1 prostate cancer trial hoping it would benefit him, but also to help find...

I think it was the idea that I should go for the treatment that was most likely to benefit me, and so the - there was also an element of sort of scientific curiosity. I was quite keen to take part in an experiment, an interesting experiment, and of course pleased if there was benefit to other people. And as time goes by and as I am stable on this drug I’m more and more thinking about that aspect of benefit to other people, in terms of finding out what the long term consequences are of the drug. So if the consultant put it to me that maybe I’d be on the drug so long that all the cancer cells were eliminated and I need no longer continue with the drug, I’d be inclined to say, “Well, I think I should continue, because then we’ll find out when the drug is safe in the long term.”

 

Do you know how long they’re, I mean are they just going to give it to you indefinitely at the moment. Is that the plan?

 

That’s the plan at the moment, yeah.

 

Okay, yep.

 

Yeah.

 

And I think you said the trial is now finished in the sense that they’ve recruited everyone.

 

The phase 1 trial is complete and so they’re not recruiting for the phase one trial any more.

 

But there are phase 2 trials going ahead, that is trials which - so phase - I should explain it - a phase 1 trial aims really just to check toxicity of the drug. How big a dose can you tolerate and are there terrible side effects which would discourage you from using the drug? And then a secondary goal of a phase 1 trial is to begin to see whether the drug is effective. But the primary goal is a more basic thing, just toxicity and dosage adjustment.

 

So that phase 2 trials that are going on now are aimed more at finding out how effective it is in selected smallish groups of patients, and there are several of those trials going on, some in England, some in other countries. More than one drug company is involved, so there are alternative drugs that target this same enzyme. And some of them are restricted to patients with breast cancer, for example, others to patients with ovarian cancer. I am a rarity as a prostate cancer patient with an identified BRCA mutation, and I think at least one of the trials leaves open the possibility of recruiting people like me with BRCA2-dependant prostate cancer.

Julian describes the high quality of care and monitoring in his Phase 1 trial.

But, as I say, I think I’ve just been extremely lucky. And I should also say I’ve been treated extremely well by the hospital that I went to. So when you start the phase one trial you have to go into hospital for a week while they check on how the drug is behaving in your body. And I’ve always found the nurses and all the staff are extremely friendly and remarkably cheerful. That was the impressive thing about this specialist cancer hospital, what a cheerful atmosphere it had, in spite of the fact that people were often very ill there.

 

So I don’t know if I should say a bit more about the details--

 

Yeah, and what it was like.

 

--of the trial and what it was like.

 

Yes.

 

So once the decision was made, then there was an adjustment to be made to my previous hormone targeted drugs, so I stopped one of those. I had to wait a few weeks for that to clear out of the system and then went into the hospital for a week, or maybe it was less than a week, anyway, for a few days, in which time lots of blood samples were taken. I was given the drug. The rate of clearance of the drug from my body was monitored. The response of my cells to the drug was also checked with a clever method that involved plucking hair from your eyebrows and then doing some microscopic staining on it to see what how the cells were behaving and seeing if they were responding to the drug in the way that was anticipated.

 

And so the first day or two blood samples were taken at frequent intervals, every few hours, so you’d get woken in the night for blood samples to be taken. And then, again I forget all the ins and outs, but roughly speaking after that was over samples were taken at rarer intervals. Then there’s a period of a few months when I had to go once a week to be checked, and after that I dropped back to once a month. So every month I go. I have some blood samples taken. I have my heart function checked because I have some heart difficulties, unrelated to the trial I should say. And I talk to a doctor, not usually the consultant, but usually one of his registrars or assistants. I guess I’m an easy case, because I don’t really have any great problems. And the next day I get the results of my PSA measurements, and they’re quite good about telling me what the results of the tests have been each time.

 

I should say a bit about side effects. So that’s a big issue if you’re in a phase one trial, especially. So the experience, if you - I’ve seen the summaries, descriptions of how the trial has been going so far. There have been some public talks about it by the people running the trial. And the position is that, very roughly speaking, of the people who you would expect to benefit, that is the people who have mutations in either of these two relevant genes, about half show a good response. Most of the people in the trial have had advanced cancer, so they’ve been recruited to a phase 1 trial because other treatments have failed. And that usually means they’ve had quite severe other treatments and quite advanced disease.

 

So I was peculiar, because my disease had never been very advanced but the two standard treatments had failed in a technical sense, but I hadn’t had anything very severe. I’d just had these hormone suppression therapies.

 

Anyway, so it’s understandable that not everybody benefits, even if you might hope that they would, because they’d been very ill in various ways, and also some of the drug treatments that they’ve previously had are ones which, as we now know, are liable to lead to resistance to treatment with this particular drug.<

Julian opted to get copies of any letters to his GP, and asks for updates on his own test results...

Feedback of results. Did they tell you when you first joined the trial whether or not they were going to share the results of the trial with you?

 

I don’t remember. I mean, I’ve always asked about my results and I’ve asked also about the results of the trial in general. And I can’t remember whether I was told explicitly, given a promise, that I would be told about the results.

 

Yeah. But it’s tended to be you asking questions rather than sort of being given a regular up-date or getting a letter?

 

It’s hard to know. I signed up for an option called patient copies of letters to GPs. Anyway, every month when I go for my talk with the people at the hospital that looks after me, a letter is written by the doctors I’ve seen there. It goes to my GP, and a copy of that letter comes to me, so in that sense I always get an up-date on my own case.

 

I think anyone in a phase one trial should be told what the general results of the trial are. They should be involved. Their interest - and they have an interest, I’m sure, almost always, in how the thing as a whole is going, what contribution they’re making to medical knowledge and the well-being of other patients and they should be told.

 

Do you ever meet any of the other patients involved?

 

Well, in two ways, both a bit limited. So when you’re on the ward when you’re first starting the trial, you obviously chat with the patients in the other beds, but often they’re involved in other trials. But anyway, that’s interesting to talk to them. But then there was one other man with prostate cancer who was also a BRCA mutant who was put in touch with me. I was asked would I be willing to talk to him. I said, “Yes, of course.” So I’ve chatted with him on the phone several times, and I’m interested to know how his case is going and he’s interested in mine. I would actually quite welcome a bit more contact with other patients in the trial. I can see it has a potentially a good side and a bad side. You might want to just forget about all these woes. But I’m certainly interested. So few people, I think he and I are the only people with the relevant mutation and prostate cancer that have been involved in the trial. So we’re unique specimens.

 

And I think the drug has benefited him as well. He had a much more advanced disease than me. 

He has sometimes picked up mistakes in the letters sent to his GP from the trial. This is a good...

I must say on the matter of letters to GPs what I notice is that even though I’m going to, I think, what I think is one of the best places and the doctors I see I’m sure are excellent, there are almost always minor or very often minor errors in these letters that go to the GP. They’re usually completely trivial errors which really don’t matter, but little factual things that are wrong. Occasionally, they’re more serious, like a case where I had talked about - there’s a drug I take to deal with this side effect that I get of gut discomfort, and I was going to drop the dose from 30 milligrams a day to 15 milligrams a day. But the doctor I spoke to, or the secretary who transcribed his report, misheard, and so on the letter that went to my GP it said I was going to change the dose to 50 milligrams per day [laughs]. It didn’t matter because I was paying attention, and anyway the prescription was something I’d sorted out with my GP, but you could imagine that in other circumstances it cause could cause a problem. But the striking thing was that, with the best will in the world and best staff and very good staff, there were very frequently these little errors.

 

So I thought there’s a lesson in that, and I feel that the lesson is that patients should be involved and should see these messages that go to and fro, see their own progress charts, their drug charts and so on, because they’re the people with the most intense interest in what’s going on, and often they’re the best, most detailed knowledge of the facts.

 

And most likely to pick up the mistakes.

 

Yeah, yeah.

The costs of developing new drugs are high, so Julian thinks investment from drug companies is...

Some people worry about trials being funded by drug companies. Is that an issue for you or does it not worry you at all?

 

No, I don’t think there’s any way of avoiding that. I mean, the sums involved in developing a new drug are enormous, so the estimate is for every drug that succeeds - I mean you must know this better than I do - every drug that succeeds and makes it to market, the cost is something like half a billion pounds, depending a little bit.

 

So that’s an enormous cost which is paid by the drug company that develops the drug. And I suppose you could have government financing that, but as things are, without enormous restructuring of the way that medical services and medical research are funded, it’s unavoidable that drug companies must foot the bill.

 

I suppose the thing that I do worry about, that again is being tackled now in various ways, is the unfairness of allocation of resources. So there are drugs which are desperately needed to treat infectious disease in the third world, for instance, which could benefit enormous numbers of people, which, until recently, have not been developed because the rewards from developing drugs for poor people in poor countries are rather small, even though the benefit of the drug may be huge. But I think foundations like the Gates Foundation are beginning to remedy that problem by providing incentives for drug companies to develop those drugs. 

Julian argues that basic biology research is essential, and may come up with more targeted ways...

It’s the case that most cancers involve some sort of disturbance of DNA repair mechanisms. That’s what makes the cancer cells dangerous, because it makes them very mutable. And so cancer researchers are aware of that and there’s a lot of effort devoted to basic research on how DNA repair mechanisms work, and a lot of awareness that that would be a possible bit of cell function to target with drugs. And it may be that a bigger proportion of cancer research should be devoted to that area, but I don’t really know what the sort of quantitative balance is of research is at moment.

 

One thing I do think is very clear from my story, or from the story of this drug, is that basic biology research is absolutely essential. If you try to work on only those things which have direct and clear application to cancer, you won’t achieve your goals. You need to understand all these things about the basic molecular biology of cells and, you know, my story I think is remarkable because it shows so very clearly how doing that basic research can lead to treatments that really work.

 

And these are quite, I think, rather revolutionary times in cancer research, because our understanding of cells and of cancer pathology has advanced to the point where we can really devise more and more of these rational treatments that tackle the cancer in a quite specific way, and are a huge improvement, potentially, on the sort of blunderbuss chemotherapy methods that have been used mainly up to now.

 

So I’d put in a plea for basic cancer research.

 

Are you worried that basic or kind of blue skies type research is under threat?

 

No, I think it’s, in this country - well, no, I think it’s quite - there’s always a risk. Always there’s a possibility with a new sort of group of politicians or senior bosses of the MRC [Medical Research Council] or whoever it may be, that there’ll be pressure to do less basic research and switch more to translational or clinical research. But at the moment I think the balance is acceptable in this country, and the people who are in responsible positions, like the head of the MRC and so on, have a very healthy view of that necessity for basic research.

 

I mean, you want to supplement the basic research with translational research that puts things into practice, but not to sacrifice the basic research. 

It's very hard for doctors to judge the right level of information to give each person, and for...

It’s very difficult, obviously, for the doctor or whoever it may be that’s talking to you to gauge what level of understanding you already have, so they don’t want to talk baby talk to you, but equally they don’t want to talk above your head. I don’t mind particularly if people talk baby talk to me because I can indicate that I want to know a bit more in detail. I do get irritated with people who talk baby talk and seem unable to go beyond that. So then I take a very dim view. I think, “This guy or this woman doesn’t really understand what they’re doing. They’re just like the repair man that comes to tighten up the screws on the fridge without really understanding what’s going on inside.” And so I feel dissatisfied if the doctor I talk to doesn’t understand, or doesn’t show that they understand what’s going on.

 

Have there been some instances where you’ve felt they didn’t really understand the trial or the, the mechanisms involved?

 

Yes, not I should say at the research-oriented hospital that I’ve been to, though even there, there were one or two cases where people I thought seemed a bit dim [laughs]. But anyway, that’s inevitable and one shouldn’t complain too much. People talking above your head I don’t mind, because I’ve got in the habit when I don’t understand something of saying that I don’t understand. It’s quite a difficult habit to cultivate, especially if you’re supposed to understand and know about things. But I would urge patients always to stop and say, “Stop”, and, “Explain that to me. I don’t know what this is or that is.”

 

So where have you been more conscious of this people not really understanding? Is that at the GP’s surgery or?

 

My GP has been fine. He doesn’t lay claim to knowing all the ins and outs of the molecular biology. He says that’s not his concern. He refers me for that, but he’s very good on all the things that he undertakes to do. The specialist hospital has been fine, by and large. But the intermediate place where I was first diagnosed was more uneven, so there are some very good people and some not so good.

The tablets Julian takes are very large and patients find them hard to take, but this is...

I take four tablets in the morning, four in the evening. They’re rather big tablets and rather irritating, annoying to swallow. They sometimes get stuck in your throat and you have to take a big swig of water or eat a bit of bread or something to make them go down.

 

But they’re not, it’s not like having to have an injection every day.

 

No. Presumably they could deal with that just by halving the size and taking more of them, couldn’t they?

 

Well, they could, and I asked, like many of the other patients, I said, “Why do we have to take these great big horrible horse tablets when it’s obvious when you look at the tablet that the thing is only half, the capsule is only half-full.” And they said, “Well, yeah, we understand the annoyance.” But to change the formulation, even in that trivial way to make the tablets half size, would cost them a year in terms of getting all the approvals and checking the pharmaco-dynamics and so on. And the economics of drug trials, as well as the urgency, mean that that’s not really worth it. 

He can see that often a placebo might be safer than the trial drug. But in his case, he feels the...

It’s hypothetical and it’s probably difficult to, to answer, but if you were further down the line--

 

Uh-huh.

 

--and this was a phase three trial--

 

Uh-huh

 

How would you have felt about randomisation and the possibility of being allocated to a group that might not be getting this particular drug?

 

Well, knowing what I know now [laughs], I would be very uneasy about being randomised to the placebo treatment, because I think there’s strong evidence the drug brings a benefit which you couldn’t achieve any other way.

 

But, so if I were to be in a… my sister always made the point that for most trials the ideal thing was to be in the placebo branch of a randomised trial, because then you got very close monitoring from good medical staff and you were likely to do well because of that. And most drugs, trial drugs, didn’t do you all that much good and might hurt you, so [laughs]. However, in this case it’s not like that, I think.

 

*FOOTNOTE' This raises difficult questions about the level of evidence needed before a drug can be said to work. Julian’s personal experience had convinced him the drug was effective in his case. However, although his clinical team felt the drug was promising they also felt there was not yet enough evidence, so they needed to test the drug further in a Phase 2 trial. Sometimes, even when Phase 1 and 2 trials suggest a new drug is promising, when it is compared in Phase 3 trials with the standard treatment in a much wider group of people the results do not show it makes a significant difference. (See ‘Non-randomised trial designs and other research’ and ‘What are clinical trials and why do we need them?’). 

 

It's difficult to advise others, but Julian recommends taking part in a trial, both because it...

For patients who are thinking of enrolling in trials, I’d - I don’t know, it’s so difficult to give advice to other people. I think it’s a good thing to do. I’d encourage it, and there are several reasons. So there’s an altruistic reason - by enrolling in the trial you may help other people, so that’s a very important thing. And there’s a selfish reason as well, and that is if you enrol in a trial you’ll get much closer attention from medical staff than you would otherwise get. And they’ll probably be rather good medical staff as well because they’re active in research and intelligent people who really care about what’s going on with their particular batch of patients. So for both those reasons I’d say, “Yeah, enrol in a trial if you’ve got a chance.”