Tolerability and side-effect profile of capecitabine/bevacizumab

The toxicity data were reassuring. The capecitabine toxicities were similar to what was already reported in the literature, and the bevacizumab toxicities were as expected based on the Phase II results. About 20 percent of patients experienced hypertension requiring intervention. Ten to 20 percent of patients experienced proteinuria, although rarely severe, and no Grade IV events were reported.

Grades I and II bleeding were slightly increased, but Grade III bleeding was extremely uncommon and not increased by the addition of the antiangiogenic agent. There was a slight increase in thrombosis, predominantly deep vein thrombosis and line-associated thrombosis, but no increase in serious thrombotic events or pulmonary embolism with the combination.

ECOG-E2100 trial: Phase III trial of paclitaxel with or without bevacizumab in patients with previously untreated metastatic breast cancer

This study takes bevacizumab to the next step. It moves the use of this agent to newly diagnosed, locally recurrent or metastatic patients and combines it with paclitaxel — a combination for which we have a lot of preclinical synergy data.

Bevacizumab is a targeted therapy, yet we currently treat patients based on the history of their disease rather than molecular factors. We need to determine how to select the patients most likely to respond to this type of therapy, but we don’t know which factors are going to be predictive.

This study is prospectively collecting primary tumor tissue, serum and urine samples for investigation of potential surrogates of response to VEGF targeted therapies. We hope VEGF is predictive, but it’s technically difficult to measure and be certain that what you’re measuring reflects the tumor, and not the white blood cells, macrophages and platelets.

Single-agent capecitabine for metastatic breast cancer

When discussing the trial, I told this patient that capecitabine was one of the best therapies for her disease and that if she was randomized to the capecitabine-alone arm, she would receive exactly what I would have given her if the trial was not a possibility or didn’t exist. She was disappointed when she first learned she was not randomized to the investigational arm, but she has a wonderful, supportive spouse who reminded her that they knew when they agreed to enter the trial that this might happen, and she was still receiving the best I had to offer. That quickly turned her around and she was willing to continue with the study.

It would have been reasonable to consider other single agents, such as vinorelbine or gemcitabine, but even off-study I believed that capecitabine was the best choice for her. She did not want to miss teaching days, so oral therapy was a real advantage and she didn’t have alopecia. She tolerated the treatment very well. She had a dose reduction for Grade II hand-foot syndrome after her first cycle of therapy, and she did not require any other dose modifications.

After two cycles of capecitabine, she had a complete response with all visible and palpable evidence of her disease completely gone. Her chest wall discomfort disappeared as well, and she was completely symptom-free. It was an amazing response — minimal toxicity, symptoms gone, she felt well and she was able to continue teaching.

Selecting a taxane schedule for progression following adjuvant taxane therapy

Phase II data in patients with metastatic disease who received an adjuvant taxane show that you can switch to another taxane or use the same taxane on a different schedule and still obtain some additional response. I have certainly done that, but when considering the alternatives, it’s not my first choice. Not because there’s data that says it wouldn’t work — it just doesn’t feel right. It’s an agent the patient already tried, it didn’t produce the desired results and I have a number of other options. Typically, I will discuss it with patients and tell them that at some point we’re likely to come back to the taxanes, but I prefer to try other therapies first.

Discrepancies between the findings of investigators and an independent review facility

The capecitabine with or without bevacizumab trial included a detailed process for reporting findings to an independent review facility. Chest, abdominal and pelvic CTs were taken at every assessment point and sent to the reviewers, regardless of the patient’s status. All sites had the same type of Polaroid cameras to take photos of skin lesions with rulers in the image. And all of the physicians’ clinical notes were sent after they were censored to ensure they did not indicate to which treatment group the patient was assigned.

Still, as we’ve seen in other trials, the independent review facility rated responses eight to ten percent lower than the investigators. Part of that is probably realistic — some of the patients we say are responding probably don’t quite meet the strict criteria set forth by the study — but part of that is the difficulty of assessing a patient whom you cannot examine.

This patient was one for whom there was significant discrepancy between the independent reviewers’ and the investigators’ assessments. When this patient had a complete response following capecitabine, the independent review facility reported her as stable. I would have done the same if I had been part of the independent review facility. While they have my physical exam notes telling them the chest wall is no longer indurated and the nodules are gone, they have no way to independently verify that. They use the clinical data to document progression, but regression on physical exam can’t be verified, so the best they can do is call it stable disease.

In addition, they have to rely on photos that may not document skin changes well, particularly in darker-skinned women. This Hispanic patient had an intense hyperpigmentation following radiation. When her disease progressed, the skin lesions covered the radiation field and extended beyond it. Even though those lesions disappeared following two cycles of capecitabine, the hyperpigmentation from radiation was still visible. So, the independent review facility could only look at those photos and say, “This is not normal,” and label her disease as stable while we reported a complete response.

Treatment of a second primary and progression in advanced breast cancer

This patient had a very interesting course. She continued on capecitabine but came off study for progression, which was actually a second primary breast cancer without recurrence of the previous extensive chest wall disease. We repeated all of her systemic staging, and there was absolutely nothing. She had a modified radical mastectomy and continued the capecitabine.

Four and a half months later; her cancer recurred with bilateral chest wall involvement that was actually worse on the side that was not radiated. Whether it was recurrence of two primary tumors, I don’t know, but it was a curious pattern. She was treated with single-agent vinorelbine and had an excellent response.

Palliation of persistent, localized breast cancer

I’ve had a couple of patients with persistent, localized breast cancer, which can be intensely painful and socially isolating. It’s difficult to put on normal clothes when there’s a weeping, sometimes bleeding, often super-infected wound wrapping around one’s chest. I’ve had several patients who don’t want to be around people because they’re self-conscious about the offensive odor.

Pain control is also very difficult. This patient didn’t like the grogginess she experienced with narcotics, and the drugs we use for neuropathic discomfort didn’t help much. We tried some topical anesthetics, but as the disease became more extensive, there was a problem with systemic absorption, so we’re not able to use those anymore. Women with this type of localized disease tend not to have a lot of visceral disease. It’s certainly not the quality of survival for which we strive.

Quality of life and continued treatment for advanced disease

This is a truly amazing woman and I’m honored to care for her. She knows of my reservations regarding further treatment because we’ve discussed it several times. Yet, when I last saw her two weeks ago, the question utmost in her mind was, “How can you get me back to the classroom, because I need to finish out the year?” All she ever wanted to do was teach. She’s taught me an incredible amount, and she’s still a teacher whether she’s in a classroom or not.

She is a very strong-willed woman who would probably rate her quality of life higher than I would at this point. She typically refuses to take analgesics and I’ve had to adjust how I ask her about pain because she usually says, “It’s okay.” Now I go one step further and ask, “Would other people say the pain medication is working well enough?” And then she’ll admit that maybe it could be better. So, we continue adjusting doses and schedules of her treatments so that she can to be in the classroom as much as possible, because that’s what’s most important to her.

This is a difficult situation. I can certainly come up with agents that she’s not received, but we’re likely to have diminishing returns with increasing toxicity, and I’m concerned that I’ve made her feel worse, not better. I’ve tried very hard to get her to think about not having additional chemotherapy, but she is not quite ready to make that transition. In this situation, I think her opinion still trumps mine.

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