Honoring Patient Preferences in Personalized Medicine
Honoring Patient Preferences in Personalized Medicine
Editor's Note:
An expert panel comprising Drs. George W. Sledge, Fatima Cardoso, Eric P. Winer, and Martine J. Piccart-Gebhart looked at the treatment of breast cancer -- past, present, and future -- as part of an education session at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO®). Dr. Lidia Schapira caught up with Dr. Winer after the session to tease out of him a few more comments on the discussion.
Dr. Schapira: The book that was compiled for this education session starts out with a big pitch for living well and dying well with breast cancer. Could you talk more about what you and the other panelists meant by that comment?
Dr. Winer: George Sledge touched on that today. The treatment of advanced breast cancer is science and art. The science part, of course, is trying to provide the most effective treatment in the context of the patient's disease, and the art is trying to figure out how that matches with a patient's preferences and desires. Beyond that, however, there comes a time in the course of almost everyone's illness when there is a need to back off from some of the more (I'm avoiding the word "aggressive") side-effect-producing therapies, and focus on comfort measures and making sure patients accomplish the goals they set for the end of their lives. In truth, there are people who just don't want to deal with those issues, but there are many who do.
Dr. Schapira: When do you, as a compassionate doctor, start to talk about these issues with patients?
Dr. Winer: I have always found that conversations about end-of-life issues are an extension of the dialogue I have been having with the patient the whole time I have been taking care of her. It's about setting realistic goals, but you also have to maintain some sense of optimism.
Most of us do not spend a great deal of time thinking about the end of our lives. There is a time and a place for these thoughts, and if you shut them out completely, there are unanticipated consequences. For the most part, when you are taking care of people, you give them space to talk about the issues of death and dying and what may happen if treatment isn't working. You also let them know that you are taking care of them so that when they leave the office and the hospital, they can go on with life and worry about their children or their work or their next trip and not focus excessively on their health and prognosis.
Dr. Schapira: Do you talk to patients about survival medians and means?
Dr. Winer: I never give medians and means. I tend to speak in generalities, but I can be more specific. It depends on what the patient wants. The closest I come to medians and means is telling somebody who wants more concrete information that I think that it would be unlikely, but not impossible, if she lived beyond a certain date.
Dr. Schapira: There has been a lot of talk at ASCO® this year and last year about personalized therapy, which involves not only the biology of the tumor and exploitation of the natural biological targets but also the patient's preferences. How does that work in practice? How much time do you spend discussing the patient's preferences and discussing trade-offs when you actually make a recommendation for treatment?
Dr. Winer: I spend a fair amount of time doing that. Particularly when we are talking about a choice of chemotherapy agents, or joining a trial as opposed to receiving a standard treatment -- much of that is about preference. It is relatively rare that there are stark differences between the outcomes achieved with different treatments. So, given the choice between something that is better tolerated and worse tolerated, the choice is usually pretty clear, and it is something we have to talk about.
I also think that if you have been taking care of a patient for a while, you get to know something about her preferences, and you don't necessarily have to discuss options in detail every time. I always find it challenging, as I am sure you do, when I first start taking care of someone who is changing physicians mid-course. She may be coming to see me because she is going on a trial or just interested in making a change. In that setting, I often see a patient much more frequently than I would otherwise, just because I need to get to know her and get a sense of her preferences.
Dr. Schapira: I know you are a committed trialist and that perhaps the answer for many patients would be to encourage them to go on a trial in the setting of metastatic disease. One-on-one with patients, how do you assess their readiness or their interest in participating in a trial?
Dr. Winer: It varies from patient to patient. Working in a place that is known to conduct clinical research, we see patients who are relatively hungry for trial participation, so that I find patients are often anxious to hear about trials.
I often remind patients that the true beneficiaries of clinical trials are not the patients on the trials, but the next generation, and I do that for 2 reasons. First, to the extent that patient is behaving in an altruistic manner, she can feel good about doing something for others. Second, a patient has to understand that the trial is not necessarily the be-all and end-all. The hope with any trial is that it is going to be better for that person than the standard treatment, but if we knew that, it wouldn't be a trial. It would be standard treatment.
There are, of course, situations in which a trial is pretty far along. For example, a drug such as T-DM1, which we heard about today, has been in trials for 5 or 6 years, and I have known for over 4 years that T-DM1 is a remarkable drug. I don't have any trouble recommending that a person participate in a T-DM1 trial, but this is a relatively unusual situation.
Dr. Schapira: There is so much debate about the proper endpoint for trials -- whether progression-free survival (PFS) is a valid endpoint, or whether we should focus on overall survival. Which side do you take in this raging debate?
Dr. Winer: It seems to me that there are only 2 important endpoints for all trials in any setting, whether it's cancer, diabetes, or hypertension. Those 2 endpoints are survival and quality of life. Nothing else really matters. It's all about how long and how well someone lives.
If PFS is used, it should be a meaningful surrogate for either survival or quality of life. Sometimes PFS is a meaningful surrogate for survival. If the therapy is not very toxic and, in a symptomatic patient, the symptoms are kept under control, then PFS is probably a reasonable surrogate for quality of life, although that has not always been demonstrated.
Dr. Schapira: For metastatic breast cancer, if we have to give chemotherapy, treatment recommendations generally favor single-agent chemotherapy. Are there times when you would think of combination chemotherapy?
Dr. Winer: There are, but when I think the situation through, I am usually less enthusiastic. Once in a while, I use a combination. The problem is that the times when you want to give combination therapy is when a patient is sicker, but that means she also is at greater risk for toxicity. Combination therapy leads to a higher response rate and a longer time to progression, but no difference in survival.
It's not clear to me that there is benefit in giving someone combination chemotherapy. I have someone at the moment who has never received an anthracycline, and we were going to give her single-agent Adriamycin® (doxorubicin hydrochloride; Pfizer; New York, New York) because Doxil® (doxorubicin hydrochloride liposome injection; Janssen Biotech, Inc; Horsham, Pennsylvania) currently is not available. I decided to give her Adriamycin and cyclophosphamide, and you might legitimately ask why. I reasoned that cyclophosphamide is an active drug that would allow me to give a little less Adriamycin, and I know the combination can be given safely.
Dr. Schapira: I have heard you comment at several meetings in the past couple years that we will be able to select patients who won't need chemotherapy in the era of targeted therapies. Can you give 1 or 2 examples that really excite you and that you think are very promising?
Dr. Winer: T-DM1 is one example. Although technically it is chemotherapy, it is linked to trastuzumab, and a very small dose of the DM1 is delivered selectively to the HER2-positive cancer cell. There is also growing evidence that dual blockage for HER2-positive breast cancer -- whether with lapatinib and trastuzumab or pertuzumab and trastuzumab -- is a particularly effective treatment. I suspect that there are some patients with early-stage disease who could do well with those biologic therapies alone.
Dr. Schapira: What is coming down the pike that excites you?
Dr. Winer: For HER2-positive breast cancer, I think we will see more and more women cured of their early-stage disease. Very few will relapse, and for those who present with more advanced disease, we are going to be able to control the disease for many years -- and for some, perhaps indefinitely.
We have bigger challenges when it comes to triple-negative breast cancer and estrogen-receptor-positive metastatic breast cancer. Patients with advanced estrogen-receptor-positive disease can survive for many years on hormonal therapy, but this is not true for all patients. And those with advanced triple-negative breast cancer tend to do far more poorly than we would like.
Dr. Winer: I do worry in this era of targeted therapy that people will become convinced that we simply need to find a mutation and then pick an appropriately targeted drug. We can't forget that we still need to conduct clinical trials. Not every key that looks like it will fit into a lock will actually turn it, and the same is likely to be the case with new drugs. I also worry that emphasis on targeted therapy has given people license to ignore fundamental statistical principles. We need to distinguish between hypotheses and firm conclusions.
Dr. Schapira: I counted about 8 trials looking at PI3 [phosphoinosotide 3]-kinase inhibitors on the board, 2 more with mTOR [mammalian target of rapamycin], half a dozen with combined treatments, and then some more with other targets. Martine Piccart's slide had 20 such trials. So, what you are saying is that we should be excited about the opportunity and the innovation and to learn valuable lessons, but be careful not to rush to a conclusion.
Dr. Winer: There are several common mutations in breast cancer, but, as Martine Piccart pointed out, the truth is that we don't know that all those mutations are going to turn out to be relevant, and many them are essentially bystanders.
Dr. Schapira: My last question is personal. In the past 6 months to 1 year of practice, what has moved you the most?
Dr. Winer: I take care of a very young woman who has had HER2-positive breast cancer for 5 years. For more than 4 years, she has had brain metastases, with excellent control of her extra-central nervous system disease. Now, unfortunately, she is coming to the end of her life. She is at home, unable to get out of bed, and is being cared for by her 35-year-old husband. Brain metastases represent a huge problem we have to face -- this problem of brain metastases for both HER2-positive and potentially for triple-negative breast cancer.
It has not been easy watching her go through this. Of course, it's very different for me than it is for her family, who are just tortured to see her go through this illness. What is most remarkable is that she has made her peace with breast cancer and her likely fate. She has been able throughout this illness to say that some people are dealt one hand and some another, and you have to cope the best way you can. She is a remarkable person, and someone who I will remember for as long as I am on this earth.
Editor's Note:
An expert panel comprising Drs. George W. Sledge, Fatima Cardoso, Eric P. Winer, and Martine J. Piccart-Gebhart looked at the treatment of breast cancer -- past, present, and future -- as part of an education session at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO®). Dr. Lidia Schapira caught up with Dr. Winer after the session to tease out of him a few more comments on the discussion.
Living Well, Dying Well
Dr. Schapira: The book that was compiled for this education session starts out with a big pitch for living well and dying well with breast cancer. Could you talk more about what you and the other panelists meant by that comment?
Dr. Winer: George Sledge touched on that today. The treatment of advanced breast cancer is science and art. The science part, of course, is trying to provide the most effective treatment in the context of the patient's disease, and the art is trying to figure out how that matches with a patient's preferences and desires. Beyond that, however, there comes a time in the course of almost everyone's illness when there is a need to back off from some of the more (I'm avoiding the word "aggressive") side-effect-producing therapies, and focus on comfort measures and making sure patients accomplish the goals they set for the end of their lives. In truth, there are people who just don't want to deal with those issues, but there are many who do.
Dr. Schapira: When do you, as a compassionate doctor, start to talk about these issues with patients?
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Eric Winer, MD |
Dr. Winer: I have always found that conversations about end-of-life issues are an extension of the dialogue I have been having with the patient the whole time I have been taking care of her. It's about setting realistic goals, but you also have to maintain some sense of optimism.
Most of us do not spend a great deal of time thinking about the end of our lives. There is a time and a place for these thoughts, and if you shut them out completely, there are unanticipated consequences. For the most part, when you are taking care of people, you give them space to talk about the issues of death and dying and what may happen if treatment isn't working. You also let them know that you are taking care of them so that when they leave the office and the hospital, they can go on with life and worry about their children or their work or their next trip and not focus excessively on their health and prognosis.
Dr. Schapira: Do you talk to patients about survival medians and means?
Dr. Winer: I never give medians and means. I tend to speak in generalities, but I can be more specific. It depends on what the patient wants. The closest I come to medians and means is telling somebody who wants more concrete information that I think that it would be unlikely, but not impossible, if she lived beyond a certain date.
Honoring Preferences in Cancer Treatment
Dr. Schapira: There has been a lot of talk at ASCO® this year and last year about personalized therapy, which involves not only the biology of the tumor and exploitation of the natural biological targets but also the patient's preferences. How does that work in practice? How much time do you spend discussing the patient's preferences and discussing trade-offs when you actually make a recommendation for treatment?
Dr. Winer: I spend a fair amount of time doing that. Particularly when we are talking about a choice of chemotherapy agents, or joining a trial as opposed to receiving a standard treatment -- much of that is about preference. It is relatively rare that there are stark differences between the outcomes achieved with different treatments. So, given the choice between something that is better tolerated and worse tolerated, the choice is usually pretty clear, and it is something we have to talk about.
I also think that if you have been taking care of a patient for a while, you get to know something about her preferences, and you don't necessarily have to discuss options in detail every time. I always find it challenging, as I am sure you do, when I first start taking care of someone who is changing physicians mid-course. She may be coming to see me because she is going on a trial or just interested in making a change. In that setting, I often see a patient much more frequently than I would otherwise, just because I need to get to know her and get a sense of her preferences.
When Is a Trial the Right Choice?
Dr. Schapira: I know you are a committed trialist and that perhaps the answer for many patients would be to encourage them to go on a trial in the setting of metastatic disease. One-on-one with patients, how do you assess their readiness or their interest in participating in a trial?
Dr. Winer: It varies from patient to patient. Working in a place that is known to conduct clinical research, we see patients who are relatively hungry for trial participation, so that I find patients are often anxious to hear about trials.
I often remind patients that the true beneficiaries of clinical trials are not the patients on the trials, but the next generation, and I do that for 2 reasons. First, to the extent that patient is behaving in an altruistic manner, she can feel good about doing something for others. Second, a patient has to understand that the trial is not necessarily the be-all and end-all. The hope with any trial is that it is going to be better for that person than the standard treatment, but if we knew that, it wouldn't be a trial. It would be standard treatment.
There are, of course, situations in which a trial is pretty far along. For example, a drug such as T-DM1, which we heard about today, has been in trials for 5 or 6 years, and I have known for over 4 years that T-DM1 is a remarkable drug. I don't have any trouble recommending that a person participate in a T-DM1 trial, but this is a relatively unusual situation.
Endpoint Wars: Progression-Free vs Overall Survival
Dr. Schapira: There is so much debate about the proper endpoint for trials -- whether progression-free survival (PFS) is a valid endpoint, or whether we should focus on overall survival. Which side do you take in this raging debate?
Dr. Winer: It seems to me that there are only 2 important endpoints for all trials in any setting, whether it's cancer, diabetes, or hypertension. Those 2 endpoints are survival and quality of life. Nothing else really matters. It's all about how long and how well someone lives.
If PFS is used, it should be a meaningful surrogate for either survival or quality of life. Sometimes PFS is a meaningful surrogate for survival. If the therapy is not very toxic and, in a symptomatic patient, the symptoms are kept under control, then PFS is probably a reasonable surrogate for quality of life, although that has not always been demonstrated.
Is Combination Chemotherapy Ever the Right Option?
Dr. Schapira: For metastatic breast cancer, if we have to give chemotherapy, treatment recommendations generally favor single-agent chemotherapy. Are there times when you would think of combination chemotherapy?
Dr. Winer: There are, but when I think the situation through, I am usually less enthusiastic. Once in a while, I use a combination. The problem is that the times when you want to give combination therapy is when a patient is sicker, but that means she also is at greater risk for toxicity. Combination therapy leads to a higher response rate and a longer time to progression, but no difference in survival.
It's not clear to me that there is benefit in giving someone combination chemotherapy. I have someone at the moment who has never received an anthracycline, and we were going to give her single-agent Adriamycin® (doxorubicin hydrochloride; Pfizer; New York, New York) because Doxil® (doxorubicin hydrochloride liposome injection; Janssen Biotech, Inc; Horsham, Pennsylvania) currently is not available. I decided to give her Adriamycin and cyclophosphamide, and you might legitimately ask why. I reasoned that cyclophosphamide is an active drug that would allow me to give a little less Adriamycin, and I know the combination can be given safely.
Has Chemotherapy Had Its Day?
Dr. Schapira: I have heard you comment at several meetings in the past couple years that we will be able to select patients who won't need chemotherapy in the era of targeted therapies. Can you give 1 or 2 examples that really excite you and that you think are very promising?
Dr. Winer: T-DM1 is one example. Although technically it is chemotherapy, it is linked to trastuzumab, and a very small dose of the DM1 is delivered selectively to the HER2-positive cancer cell. There is also growing evidence that dual blockage for HER2-positive breast cancer -- whether with lapatinib and trastuzumab or pertuzumab and trastuzumab -- is a particularly effective treatment. I suspect that there are some patients with early-stage disease who could do well with those biologic therapies alone.
Dr. Schapira: What is coming down the pike that excites you?
Dr. Winer: For HER2-positive breast cancer, I think we will see more and more women cured of their early-stage disease. Very few will relapse, and for those who present with more advanced disease, we are going to be able to control the disease for many years -- and for some, perhaps indefinitely.
We have bigger challenges when it comes to triple-negative breast cancer and estrogen-receptor-positive metastatic breast cancer. Patients with advanced estrogen-receptor-positive disease can survive for many years on hormonal therapy, but this is not true for all patients. And those with advanced triple-negative breast cancer tend to do far more poorly than we would like.
Molecular Mutations and Cautionary Concern
Dr. Winer: I do worry in this era of targeted therapy that people will become convinced that we simply need to find a mutation and then pick an appropriately targeted drug. We can't forget that we still need to conduct clinical trials. Not every key that looks like it will fit into a lock will actually turn it, and the same is likely to be the case with new drugs. I also worry that emphasis on targeted therapy has given people license to ignore fundamental statistical principles. We need to distinguish between hypotheses and firm conclusions.
Dr. Schapira: I counted about 8 trials looking at PI3 [phosphoinosotide 3]-kinase inhibitors on the board, 2 more with mTOR [mammalian target of rapamycin], half a dozen with combined treatments, and then some more with other targets. Martine Piccart's slide had 20 such trials. So, what you are saying is that we should be excited about the opportunity and the innovation and to learn valuable lessons, but be careful not to rush to a conclusion.
Dr. Winer: There are several common mutations in breast cancer, but, as Martine Piccart pointed out, the truth is that we don't know that all those mutations are going to turn out to be relevant, and many them are essentially bystanders.
A Patient's Gift to Her Physician
Dr. Schapira: My last question is personal. In the past 6 months to 1 year of practice, what has moved you the most?
Dr. Winer: I take care of a very young woman who has had HER2-positive breast cancer for 5 years. For more than 4 years, she has had brain metastases, with excellent control of her extra-central nervous system disease. Now, unfortunately, she is coming to the end of her life. She is at home, unable to get out of bed, and is being cared for by her 35-year-old husband. Brain metastases represent a huge problem we have to face -- this problem of brain metastases for both HER2-positive and potentially for triple-negative breast cancer.
It has not been easy watching her go through this. Of course, it's very different for me than it is for her family, who are just tortured to see her go through this illness. What is most remarkable is that she has made her peace with breast cancer and her likely fate. She has been able throughout this illness to say that some people are dealt one hand and some another, and you have to cope the best way you can. She is a remarkable person, and someone who I will remember for as long as I am on this earth.