Kathy Miller, MD
Assistant Professor of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine Member, Eastern Cooperative Oncology Group

Edited comments by Dr Miller

Treatment alternatives after progression on adjuvant tamoxifen

If I were to treat this woman today, I would probably start with hormone therapy, even with visceral disease. She’s asymptomatic, has a tumor that is strongly ER-positive and her disease is easy to follow with a simple chest x-ray. It would be reasonable to give this woman additional hormonal therapy with an aromatase inhibitor and repeat her chest x-ray in two or three months to evaluate response. At this stage, hormonal therapy would be more beneficial than chemotherapy in terms of quality of life, and I don’t think it would alter her survival.

I’ve used fairly equal amounts of anastrozole and letrozole in cases like this. I don’t know of any data directly comparing them in practice, and their side effects are similar. We have first-line trials with both agents comparing them to tamoxifen that show — depending on the endpoint — that they are equivalent or superior. As for the adjuvant setting, we don’t yet have any data on letrozole.

Breast reconstruction in patients with metastatic disease

This was the first time I sent a patient with metastatic disease for reconstruction. The plastic surgeon called and asked, “What are you doing here? She has metastatic disease, so what’s the difference?” And I responded, “She has been asking me for this for quite a while now, and she’s still in complete clinical remission. I don’t know how long this is going to last, but it seems like it’s going to be a while. And when it stops working, we’re going to switch to another hormone.” Reconstruction — even with metastatic disease — seemed reasonable, because I hoped she still had several years ahead of her. She fully recovered from the reconstructive surgery and was absolutely delighted to be rid of her prosthesis. She was a large-breasted woman and the inequity in size and stress on her neck and back was difficult for her, so she also had contralateral breast reduction.

Quality of life: Chemotherapy versus hormonal therapy

Quality of life is significantly better for patients on hormonal therapy than on chemotherapy. While this patient tolerated chemotherapy quite well, she still felt pretty weak for several days after each treatment. She experienced some fatigue and nausea, but she was able to maintain her weight. She developed significant neuropathy with the paclitaxel, which was beginning to interfere with her activities at about the time her disease was progressing. She was having difficulty manipulating buttons and holding a pen — certainly not things that we would consider life-threatening toxicities, but certainly lifealtering. She had been active with her church and volunteer activities prior to treatment. Although she remained functional on chemotherapy, it was to a lesser degree. She had to discontinue all of her volunteer activities and didn’t do much other than attend church. After she switched to hormonal therapy, she was able to return to all of her previous activities.

Hormonal therapy after progression on anastrozole

If fulvestrant had been available, I certainly would have considered it. I am not aware of much data evaluating the response to fulvestrant after aromatase inhibitors, but knowing the data after tamoxifen, I expect there are patients who will respond. While the actual response rates for patients progressing on tamoxifen were similar, fulvestrant improved the duration of response by a couple of months compared to anastrozole. That can be very important to a patient.

In the absence of data as to which treatment is going to give the best or longest-lasting response, issues like convenience and compliance become even more important and need to be discussed with the patient. This patient was already being seen every four weeks for her bisphosphonate infusion, so treatment with fulvestrant would not have required extra trips to the clinic.

Some patients prefer receiving one injection a month, versus having to remember to take a pill every day. I recently saw one patient who admitted that she probably took only 10 percent of her adjuvant tamoxifen because she just doesn’t like taking pills and she forgets. When she was suspected of having metastatic disease, she claims she “got religion” about her tamoxifen, but still only managed to take it about 75 percent of the time.

Chemotherapy after progression in the asymptomatic patient

After progressing on hormones for adjuvant therapy and metastatic disease, single-agent capecitabine, paclitaxel or vinorelbine are all reasonable choices for chemotherapy in this patient. The single-agent response rates are similar, but they have different toxicities and different modes of administration. Docetaxel and anthracyclines are very active single agents, but overall their toxicities are more difficult.

Capecitabine is a perfectly valid first-line option for an asymptomatic patient who’s been on hormonal therapy for two or three years, is used to taking pills and is not concerned about hair loss. It eases patients from hormonal therapy into chemotherapy psychologically and in terms of side effects.

Switching patients from pills to intravenous therapy can trigger thoughts that they must be really sick and nearing the end. On the other hand, some patients think pills are less effective, which is not true, but we have to work with our patients’ perceptions.

Comorbidities are also a factor in selecting an agent. A diabetic patient with peripheral neuropathy should avoid taxanes or vinorelbine because of potential neuropathic toxicities. Paclitaxel and docetaxel can be problematic for diabetics because of the need for premedication with steroids. Vinorelbine may not be a good choice for women with long histories of constipation.

Switching to a therapy that requires a vascular access device, like a Hickman, is a much bigger step for the patient than for the oncologist. Many patients see it as an end-stage measure, although after they have it in, they are generally delighted with it. But it’s a big step that many patients are not emotionally ready to take, and you won’t be able to administer vinorelbine for more than a few weeks without an access device.

Chemotherapy after progression in the symptomatic patient

In the symptomatic patient with rapidly progressing metastatic disease, treatment is aimed at getting the disease under control in order to improve and prolong the patient’s quality of life. In this situation, we need to shrink the cancer as quickly as possible, with the hopes of then switching to either a less toxic chemotherapy agent or dosing schedule, or to a hormonal therapy.

We have typically used a combination of an anthracycline and a taxane, but the docetaxel/capecitabine combination is equally reasonable. It’s difficult to compare the two combinations. We know there’s a survival advantage with the docetaxel/capecitabine combination, and there’s no survival advantage with an anthracycline/taxane combination.

But that’s a bit of comparing apples and oranges because many of the anthracycline/taxane combinations — including the largest ECOG-1193 trial — included a crossover, and the docetaxel/capecitabine trial didn’t. Had they done the study using the ECOG-1193 model — combination versus each single agent by itself with a crossover in the two single-agent groups — I think they would have seen the same results as ECOG-1193: slightly higher response rates with the combination, a minimal increase in time to progression and no difference in overall survival or quality of life.

The future of targeted therapies

We are moving towards more targeted treatments, but I’m a little less optimistic about how quickly we will get there than I was a few years ago. We hope one day to simply obtain a small sample of the patient’s tumor, grind it up and put it on a microarray, that will spit out 10,000 genes and tell us, “This patient has breast cancer Type 15, which you treat with therapy X, which has a 98 percent survival rate.” In order to reach that point, we need a large volume of a wide variety of tumors from patients who were treated in standard fashions, and then we need to know what happened to them. Then we can start to identify patterns of exquisite sensitivity or incredible resistance to a particular agent. However, our ability to collect tumor samples is a problem because so many of the patients are not at university centers, where research on genomics and proteomics is being conducted.

Looking back at this case, we could not have predicted in advance that this patient would have minimal response to doxorubicin and paclitaxel and an excellent response to both anastrozole and capecitabine. It would have been helpful to have known this information at the onset.

If I had put her on anastrozole initially and switched her to capecitabine when she progressed, she would have died of her stroke without ever having had alopecia, nausea, myelosuppression or any other associated toxicities.

Phase III trial of capecitabine with or without bevacizumab in patients with previously treated metastatic breast cancer

This trial looked at a very refractory group of patients, all of whom had received an anthracycline and a taxane. This patient was in the subset of women who had received these drugs as adjuvant therapy and had not received any therapy for metastatic disease.

We considered designing the trial with a crossover to the bevacizumab arm but didn’t for pragmatic reasons. The trial was designed with progressionfree survival as its primary endpoint, but overall survival was a secondary endpoint.

Efficacy of capecitabine with and without bevacizumab

The efficacy data confirmed the activity of bevacizumab reported in the Phase II trial with a similar patient population. There was a near doubling of response rates in patients receiving the combination of bevacizumab and capecitabine versus capecitabine alone.

The trial enrolled 462 patients and responses were assessed by an independent review facility, as well as by investigators. There is generally a discrepancy between these two groups. Some describe the independent review facility as more objective, while others say it is more cynical.

In this study, the independent review facility reported a lower response rate than the treating physicians. Although the combination therapy increased the response rate, most of the additional responses were short-lived. Therefore, the proportion of long-term responders and the progression-free survival was the same in both groups.

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