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Dr. Julie Doughty: Clinical Trial Results of Letrozole vs. Tamoxifin

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Dr. Julie Doughty discuss the Breast International Group’s (BIG-198) Clinical Trial Results of Letrozole (Femara) vs. Tamoxifin.

So i’m very happy to welcome dr. julie dowdy consultant breast and endocrine surgeon at the western infirmary in glasgow scotland here we’re at the 32nd annual san antonio breast cancer symposium and i’d bet you’re tired very tired yes but you’re making time to talk to us about actually a study that was presented here a very important study that was presented a couple

Of days ago from the breast international group the big 198 study and what it reported on was a significant survival benefit for those patients who took from ara also known as letrozole versus tamoxifen after surgery those women were hormone receptor-positive early breast cancer patients and the results were very significant and that’s what we’re going to talk about

Yeah well the big 198 study is a very large study of over 8,000 patients where women were randomly assigned to either letrozole for five years or tamoxifen that’s the main part of the study now that study when it reported early on there was a highly significant benefit in favor of patients who took letrozole in terms of disease-free survival and the data and safety

Monitoring committee felt they had it reached the boundary so the patients in the trial who were on tamoxifen they were informed they were on tamoxifen and given that option to take letrozole now that’s not the first time that that’s happened in a study it’s happened in mi-17 and it’s happened in all the herceptin studies and when patients go into trials you know

It’s a big deal for a patient to accept to go into a trial and if a trial is significant then i think we have a duty to inform patients and give them the choice of taking the better drug now because that’s happened that’s complicated the final results of b or 98 and that’s why this meeting we’ve done this other analysis called that in sense inverse probability of

Sensor wagering analysis which is a complicated thing but i’m happy to explain that to you and let me say it again it’s called inverse probability censoring waiting not waiting w/e i ght ing what is it well that is a test which has been done before in clinical trials and it’s really when you stop a trial and give patients the option to take another drug when you

Analyze that trial so in big won 9-8 the 25% of patients who stop tamoxifen but took letrozole are still included in the tamoxifen arm for analysis so what that means is you haven’t got any more – pure patient populations of five years of tamoxifen of five years letrozole so that analysis is the intention to treat and in any clinical trial the intention to treat

Is the robust scientific way to do an analysis however in this study we know from every other study so if you look at the ies study our new abc sg any study where patients start with tamoxifen and then getting aromatize inhibitor they will do better than five years of tamoxifen so because 25% of women actually got that approach they will do better than if they had

Five years of tamoxifen so the intention-to-treat will underestimate the true benefit of letrozole so the the crossover happens for ethical reasons well it i mean if if you are in if patients are in a trial and the early results shows it’s highly significant you know we have to inform patients of the results and patients and physicians can then discuss with the

Patients whether they want to take the newer drug and this isn’t as i said the first time this has happened you know and all the herself in trials as soon as those first results came out all the patients who got placebo got herceptin so it’s such an important message about the integrity and the importance of clinical trials and so when someone who’s viewing this

May be on the fence do i do a clinical trial you don’t get less than the standard of care but your participation may result in the turning point exactly and if if the result is highly significant early on you know now the monitoring committees will will inform patients of those results and then patients are then given the option to take that newer therapy which i

Personally think is very important it does make trial analysis more difficult and that’s why we’ve had to do this but at the end of the day you know it’s about patients and about what’s right for a patient what’s the best we can give a patient and then just again to clarify for our viewers that letrozole is the generic name and and patients commonly know the drug

Is tomorrow so this has got to be very meaningful to clinicians and now i’m wondering where you see this happening as far as adaptation within in practice well i mean i think just to go back to this analysis what when the big one-oh nate was presented last year we had the intention to treat analysis and we also had a sense that analysis and the sense analysis is

Where you take out the patients who got left resolved so all you’ve got left is the patients who are on tamoxifen but if you had died okay so for the survival of man if an analysis if you died in that tamoxifen group clearly you can’t then get letrozole so the sensored analysis you’ve got more deaths and that will overestimate the benefit of letters also the true

Survival benefit is somewhere in between the intention-to-treat analysis and the censored and that’s what this ip cw analysis has looked at it’s weighted it’s given a weight to all the patients who said right i’m gonna stop my tamoxifen and take left rizal it’s match those with the other patients and that’s how it’s been analyzed to get a result and the result is as

We thought is in the middle in between the intention-to-treat and the censored and it is significant but we don’t give pvalue for either censored or i pcw analysis that’s the correct thing to do because the groups aren’t perfectly matched because the patients who said right i’m going to change to letrozole weren’t randomly allocated they made that decision themselves

With their physician so you can only give a p-value if there’s absolute no bias between the groups but we know that ipc would be significant if he gave a p-value because the confidence intervals don’t cross one so you know emotionally what was has the energy like for the women psychologically as they were able to make the switch from tamoxifen to letrozole well i

Think if you’ve been in a study if you’ve participated in a study and you get a result and you’re informed of that result and you’re given an option and you know psychologically that’s a big plus thing for a patient isn’t it to think well i’ve taken part in a study that’s actually practice changing and i’m now being given the choice to take that practice change in

Therapy so you know i think women were you know we’re very high you know very happy about it but in there yeah so having seen these results do you feel that there are clinical differences between the available aromatase inhibitors and and that there’s still a role for tamoxifen and the post menopausal hormone responsible well i think i mean tamoxifen is a fantastic

Drug this there’s no doubt about it you know that drug has saved more lives in women with breast cancer than any other therapy we have to date so i think there is still a role for it and groups of patients because you know remember that tamoxifen and the aromatase inhibitors have different side effect profiles and some patients may not be able to tolerate them and

Also for patients with very low risk cancers they may still have enough you know may still have a rule but aromatase inhibitors clearly should be used in people especially who were at high risk of early recurrence and now you know all the differences between the aromatase inhibitors but unfortunately we have no direct head-to-head comparison trial there is going to

Be a trial or the race the trials recruited called face which is a trial where no positive women were randomly allocated to either arimidex or letrozole hopefully that will present 2010 and that will give us the scientifically robust answer to is there a difference between a rumored x and letrozole until that time though you have to make a decision and you know i

Think the big one nine eight results he even though the intention-to-treat which is the robust scientific analysis didn’t show a significant survival benefit it showed a meaningful benefit and a seventy six months there were forty fewer deaths in the women who took letrozole compared to tamoxifen and for me as a clinician you know significant or not that’s a huge

Benefit to patients dr. doughty how long was the study happening before the realization hit that it was time to move women on placebo aren’t you tamoxifen yes yep yes 20 the first analysis was 26 months that was the first planned analysis the primer and pot was disease-free survival and it was highly significant and that’s when that data went to the independent

Safety monitoring committee they looked at the data so it was early on that the trial that that information was was given to patients and because of that 25% if the women taken tamoxifen then opted to take letrozole relatively short period of time well i mean for breast cancer the vast majority oh there is a peak of early recurrence so you know potentially that’s

When you’re gonna see the most benefits in these drugs so and the number of events that was highly significantly different in the two groups so i think it was you know and then that was the plan time for reporting so what are your closing thoughts you’ve been practicing oncology for a bit of time now so as you look at where you were when everything started and

Where we are today your own perspective especially in the era of personalized medicine i think we are moving forward i think we now have in for things that endocrine therapy you know when i started off there was tamoxifen and that was it there was no other drug so now we have you know a much bigger variety of drugs that we can give patients that we can patients who

Were post-menopause in er positive depending on you know if the patient has joint pains if they’ve had dvt zoar if they get men at bad menopausal symptoms you can kinda trying alter the treatment to what their appear suits them i still think however you know herceptin has been an unbelievably fabulous drug for her2 positive breast cancer patients but remember you

Know where i work only eleven percent of breast cancer patients are her2 positive so that’s a small number who can benefit and i think we need to try and get more like you said tailored treatments for patients and we’re moving forward but we’ve still got a long way to go on that well dr. doty thank you for making time and for representing europe at the san antonio

Breast cancer symposium and i hope you get some sleep thank you very much okay thank you

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Dr. Julie Doughty: Clinical Trial Results of Letrozole vs. Tamoxifin By Vital Options International