You are here: Home: Meet The Professors Vol. 2 2004: Case 3
- Presented in 1995 with a six-centimeter, node-positive (3/8) breast tumor
- Underwent mastectomy
- Tumor was ER-positive, PR-negative, HER2-negative
- Received tamoxifen but discontinued due to hot flashes
- Lost to medical follow-up
- Developed malignant ascites compatible with breast cancer recurrence
 |
| Key discussion points: |
 |
|
Management of patients resistant to treatment |
|
Use of chemotherapy versus hormonal therapy to control malignant ascites |
|
Role of tumor markers in following patients at high risk after adjuvant therapy |
 |
DR WEISS: My patient presented elsewhere in 1995 with a six-centimeter tumor, with three out of eight nodes positive. The tumor was estrogen receptor-positive, progesterone receptor-negative, HER2-negative. She underwent a mastectomy and received tamoxifen for a few months, but the tamoxifen caused hot flashes and she stopped it and was lost to medical follow-up.
DR LOVE: Do you have any more information about why, with this high-risk disease, she decided to stop tamoxifen?
DR WEISS: It didn't make her feel good. She didn't have any cancer present, and she didn't like to be bothered.
She hadn't seen any doctors during the intervening years, and she didn't like the medical structure in general. She presented in August of 2002, seven years later at the age of 79, with malignant ascites. The ascites was tapped and proved to be an ER-positive, PR-negative adenocarcinoma, considered similar, morphologically, to her original disease. Her staging workup also had a small pleural-based density that might have been present in 1995, but we couldn't be sure. That was the first time I saw her.
I had actually seen her after the paracentesis was done. She was desperate about the shortness of breath and the amount of discomfort, and she wanted to do something to make sure it didn't recur. At that point, while in the hospital, she was receptive to just about anything.
DR LOVE: Do you think she would have accepted chemotherapy?
DR WEISS: Yes.
DR LOVE: Do you think she delayed coming in and was aware she had a problem?
DR WEISS: It was quite clear that she had it because this was not mild ascites. It had been developing for some time.
DR LOVE: Gershon, how would you have thought through the options at that point? She's 79 years old, and it's seven years after her first diagnosis. It sounds like her main problem was ascites.
DR LOCKER: Was the histology lobular or ductal?
DR WEISS: It was lobular.
DR LOCKER: This is a very good story for lobular carcinoma, which can present as an "ovarian cancer wannabe" with ascites. The important thing is she had a long disease-free interval and was initially ER-positive. I'm not sure that chemotherapy would provide a higher likelihood of response than hormonal therapy, and it would certainly not give her as good a quality of life. I would consider her a good candidate for hormonal therapy, and I think this is a situation in which aromatase inhibitors might be ideal.
She didn't like tamoxifen, and although I suspect you could get her to take it again if you said it was the only alternative, we're talking about quality of life and patient preference in metastatic disease. For those reasons, I think she should go on an aromatase inhibitor.
DR LOVE: Steve, what about the issue of her compliance if put on an aromatase inhibitor? Would fulvestrant have been a consideration in terms of being more certain that she was receiving her therapy?
DR WEISS: At that point, her son was more involved, so compliance was less of an issue. Developing her trust and establishing a relationship was more essential at that time.
DR LOVE: Peter, how would you assess this situation in terms of chemotherapy versus hormonal therapy, and what type of each?
DR RAVDIN: I agree with Dr Locker. She had a long disease-free interval and really did not fail hormonal therapy in the past, and she's 79 years old. It's reasonable to start such a patient on hormonal therapy. I'm glad you've mentioned fulvestrant because this patient is of questionable medical compliance and with fulvestrant you can be sure she receives therapy. If she fails, you know it's not because of compliance issues.
DR LOVE: Gershon, what would be your assessment of the relative benefits in terms of antitumor effect in this situation — an aromatase inhibitor versus tamoxifen versus fulvestrant?
DR LOCKER: A lot of data suggest that an aromatase inhibitor is better than tamoxifen for first-line therapy for metastatic disease, depending on how you define benefit — whether it's duration of response, disease-free survival, et cetera. Several studies have evaluated these agents.
Generally fulvestrant and anastrozole are equally effective. However, in the study comparing fulvestrant and anastrozole, fulvestrant seemed to be most beneficial in patients with visceral disease, so I generally prefer fulvestrant in those patients. In patients who don't have visceral disease, either fulvestrant or anastrozole is acceptable.
DR LOVE: Could you elaborate more on those data in terms of response in patients with the visceral versus nonvisceral disease?
DR LOCKER: The overall results, which were published about a year ago, showed no significant difference between anastrozole and fulvestrant, but there were a few differences. Admittedly, these were subset analyses. The duration of response seemed to be longer in patients who responded to fulvestrant, and patients who had visceral disease seemed to respond better than those who did not. I think the takeaway message is they're equally efficacious; however, there may be subsets of patients in whom you might prefer to use fulvestrant, particularly those for whom compliance may be an issue or those with visceral disease.
The other important point is that other studies argue that you can use one and switch to the other. Third-line aromatase inhibitors are efficacious after fulvestrant and vice versa. These are more like anecdotal studies. In this woman, the reason I would choose the pills is that I think she may be more compliant because it may be less intrusive.
DR LOVE: She doesn't have bone metastases, so she's not coming in for a bisphosphonate infusion every month, which may also be a consideration.
DR LOVE: Dr Cartwright, how would you have thought through this situation?
DR CARTWRIGHT: I would have considered giving her chemotherapy. Hormonal therapy takes six to 12 weeks to see a response with malignant ascites, and your chance of achieving a response is only 20 or 30 percent. You're going to have to be tapping her every week or so. If she were willing to take chemotherapy, I'd probably give her chemotherapy with the idea of switching her to hormonal therapy when the ascitic fluid is under control.
DR LOVE: Finally, we have a bit of controversy. Does anyone else have any thoughts in terms of chemotherapy versus hormonal therapy and type of hormonal therapy? Dr Freedman?
DR FREEDMAN: I would give her hormonal therapy. The things that influence me the most are her age, menopausal status, long disease-free interval, estrogen receptor status, the site of metastases and the fact that perhaps a malignant effusion is more like soft tissue and lymph node. I would use fulvestrant in this situation because I would be concerned about compliance and I wouldn't know if she was ever actually taking the anastrozole or letrozole.
I've also seen lobular carcinoma acting in a more aggressive fashion, and sometimes that influences me to recommend chemotherapy in an adjuvant situation in which maybe I would only give hormonal therapy if it were a ductal carcinoma.
DR LOVE: Peter, this concept of compliance is one about which we haven't really seen a lot of literature. Ann Partridge from Dana Farber published a paper evaluating compliance with adjuvant tamoxifen, and it actually demonstrated significant noncompliance. What do we know from the medical literature about whether or not patients in this situation are reliable in terms of taking their medication?
DR RAVDIN: I can't definitively quote the medical literature, but it's certainly something to think about in patients who might have economic or social difficulties in getting their medicine. Although I've never seen this published, the half-life of tamoxifen is about a half a week to a week. If you miss a couple doses or even a couple days' worth of tamoxifen, it probably wouldn't affect your tamoxifen blood levels significantly. The half-life of aromatase inhibitors, however, is much shorter, so there is a possibility that if you were noncompliant you might lose a lot of the effectiveness of the aromatase inhibitors by taking them intermittently.
DR GRABELSKY: I probably would have chosen fulvestrant also. I'd be concerned about compliance issues, and you're going to be seeing this woman frequently, at least initially. In terms of traveling back and forth to receive the injection, I don't see that being a big hurdle. I know for our patients, the cost of prescription medications plays a role. Fulvestrant is covered by Medicare, whereas anastrozole and letrozole are not covered, and the patient would have to pay for them out of pocket. That is often an issue for my patients.
I've heard commentaries in the past about loading doses of fulvestrant. In this patient, for whom you're looking for a rapid response, is there any data about initially giving a more frequent schedule of fulvestrant to try to get a quicker response?
DR LOVE: Gershon, clinical trials are evaluating this concept of a loading dose of fulvestrant. What are your thoughts on that?
DR LOCKER: The original fulvestrant trial had a 125-milligram randomized arm that was stopped quickly because it was less efficacious, so we already have prospective data suggesting there may be a dose-response phenomenon. Whether it's a dose-response phenomenon or the need to load the tissues up is not clear, but this is under active investigation. This is still a work in progress but for now, 250 milligrams once a month is the standard dose.
DR LOVE: Dr Dresdner?
DR DRESDNER: The question is whether she'll show up for therapy. The injection is, at least, a good reason to bring her back to the office. Obviously, if her son is making decisions, compliance may be less of an issue, but in my own practice, patients sometimes just don't show up.
DR LOVE: Steve, can you give us a follow-up?
DR WEISS: By the time she showed up at my office a week after discharge from the hospital, her ascites was coming back fairly significantly. That pushed me toward using chemotherapy up front, and I started her on single-agent weekly paclitaxel. I gave her a total of 10 weekly doses and she had a rapid response with complete resolution of the ascites. However, her markers never really came down.
At that time she was significantly fatigued, but she was happy that the ascites wasn't coming back. I think that was the positive motivator for her to keep returning. We discussed the various options and I started her on letrozole, which produced a gradual decline in her tumor markers. By June 2003 it bottomed out at 112, then slowly began to climb back up, reaching the 500s by March 2004. She remained clinically asymptomatic with no more ascites.
DR LOVE: Do you think she was taking the pills?
DR WEISS: Yes; her son lived with her at that time, and she came to all her appointments. I have since become her primary care doctor. Surprisingly, she has towed the line pretty well. She makes a lot of comments, but she does what she needs to do.
I restaged her: CAT scan, bone scan and PET scan were negative despite the high tumor marker, and she remained asymptomatic. Two months ago I started her on fulvestrant, and she is still asymptomatic.
DR LOVE: Gershon, would you have switched her therapy based purely on the tumor marker, even though the ascites resolved?
DR LOCKER: I probably wouldn't switch her therapy, but that may be a minority point of view. I generally don't use tumor markers to follow these patients because my view is that we're palliating the patient's symptoms. I'm not sure that early intervention in second- or third-line therapy translates into a survival advantage.
I just follow how the patient is doing. I can understand the argument for following tumor markers because you don't want to wait until her ascites recurs, but there is also the option of treating her the way you did before — with chemotherapy and then hormones. No, I wouldn't have switched her. I would have kept her on the aromatase inhibitor.
DR LOVE: Peter, you participated in another meeting we had in San Antonio about a year ago, and we had a "mini war" about the issue of tumor markers in metastatic disease. In a patient like this, who's clinically stable and in whom ascites has not recurred, do you think tumor markers should be an indication to switch therapy?
DR RAVDIN: I don't think we're absolutely compelled to follow tumor markers, because our major objective is palliation. If the patient doesn't have any symptoms, it's certainly reasonable to just follow her performance status.
I've found tumor markers advantageous when patients develop severe symptoms. If the markers go up, I tell the patient, "We could stay the course here." If the patient says, "I'm feeling great and I want to continue this therapy," I think it's reasonable to continue if you don't have any other evidence of disease progression. I use tumor markers to decide when to get radiology involved. For a patient like this, I probably would have been drawing markers. When you see three or four markers consistently going up, the physician and patient almost always decide to switch. I probably would have switched her, particularly when her tumor markers got so high.
DR LOVE: Dr Weiss, how is she tolerating the fulvestrant?
DR WEISS: She tolerated the fulvestrant without the slightest bit of difficulty. She is a thin woman, so we split the injections.
DR LOVE: You mentioned she had a pleural-based density. Has that changed during this time?
DR WEISS: I didn't see it in the last scans, so I'm assuming it was there and went away. It's below the sensitivity of a PET scan. I couldn't really call this measurable disease. DR LOVE: I'm curious about your experience with a patient who's doing well with metastatic disease but has rising tumor markers. Dr Joshua?
DR JOSHUA: Most of the patients who are postmenopausal and have metastatic disease only in the bones, and the only other things we can follow on a regular basis are the tumor markers. It's very difficult in everyday practice to ignore the markers or tell the patient, "Yes, it has gone up by 100 points, but you're doing well. Let's continue the same treatment."
I have several patients like that, and they don't want to continue the same treatment. Every time I go to a meeting, I hear the experts saying, ignore the markers. When you go to the clinics, it's not easy.
DR LOVE: I love the dichotomy between research leaders and community practices. Dr Shah, what's your experience with this situation?
DR SHAH: If tumor markers go up and the patient is asymptomatic and the scans are stable, we have this discussion repeatedly, and I suggest a scan based on tumor markers. I scan them at that point to make sure there's no obvious disease progression. If there isn't, I don't change treatment.
DR FAVIS: When you originally started this patient on weekly paclitaxel, her ascites regressed but it didn't change the markers. The tumor markers don't seem to coincide with the amount of her disease.
DR LOVE: Is that something you've seen clinically?
DR FAVIS: To be perfectly honest, I almost never get tumor markers. I don't find them to be helpful.
DR WEISS: It's uncommon to see this dichotomy. We all have chronic lymphocytic leukemia patients and we watch their white counts go up, and we tell the patients, "Don't worry about a thing. We'll treat you when the time comes." Sometimes that works, but for other patients the fear of cancer, a painful bone metastases or another event is overwhelming. We have to accommodate those patients.
DR LOVE: We also have the issue of the family and a very involved son. Where do the two of them fit into this in terms of their approach? Are they calm or anxious about the markers?
DR WEISS: The son is a pleasure. He's very calm and willing to wait when we want, but the mother is upset. She's very afraid of the ascites, and it has become a very big issue for her. She does not want to have more problems with ascites for as long as possible.
DR LOVE: Did she ever express a sense of guilt or regret that she hadn't taken the tamoxifen?
DR WEISS: Not to me.
DR LOVE: Dr Grabelsky, is regret about earlier treatment decisions something you see in patients who have a recurrence with metastatic disease?
DR GRABELSKY: I have a personal experience in that regard. My mother had breast cancer and she relapsed nine years later. She received chemotherapy and tamoxifen but discontinued the tamoxifen after a very short period of time. When she relapsed, that was a big regret for her.
DR LOVE: A lot of times I wonder if patients have regret that we don't hear about because we don't ask about it. With your mother, you were very tuned into it. I wonder whether her physician was aware of how she felt.
DR GRABELSKY: I don't think he ever discussed that with her.
Select publications
|
