Endocrine therapy in the adjuvant setting

Adjuvant endocrine therapy in premenopausal women

In premenopausal women, I believe the standard option for adjuvant endocrine therapy, and the only one I would advocate outside of a clinical trial, is tamoxifen. We don’t know whether adding ovarian ablation or suppression to chemotherapy and tamoxifen in premenopausal patients improves efficacy, and we need to consider long-term toxicity issues. I haven’t utilized ovarian suppression with an aromatase inhibitor outside of a clinical trial.

I believe in hormone therapy, and I believe ovarian ablation or suppression adds some benefit; however, I suspect it’s likely to be quite small. One of my goals for therapy in premenopausal women at very high risk with ER-positive tumors is to induce menopause, and if chemotherapy doesn’t accomplish this, I may add ovarian suppression, although I don’t advocate that for the majority of patients. Oncologists are aware that aromatase inhibitors alone are not likely to benefit premenopausal women, but they may be less aware that a good fraction of premenopausal women won’t be completely suppressed with the standard doses of an LHRH agonist. Certainly, when oncology nurses learn that a patient on an aromatase inhibitor is menstruating, they need to alert the physician immediately.

— Kathy D Miller, MD

ATAC trial: Anastrozole versus tamoxifen as adjuvant therapy in postmenopausal patients

The 68-month follow-up data from the ATAC trial show that patients who received anastrozole up front had a significant decrease in the relapse rate and in contralateral breast cancer over and above what we saw with tamoxifen, which is a striking finding (Howell 2005; [1.1]). The incidence of contralateral malignancy was also reduced by an additional 40 or 50 percent with anastrozole, and that has some implications for future prevention trials and prevention strategies. The side effects of tamoxifen and anastrozole are quite different. The most common side effects of anastrozole are the musculoskeletal myalgias and arthralgias, particularly an arthritic-type stiffness seen in the small joints of the fingers and hands. There was also an increase in osteoporosis and fractures with anastrozole. Side effects in the tamoxifen group were vaginal symptoms — increased discharge and bleeding — and an increased risk of endometrial cancer and blood clots.

Typically, breast cancer recurrence rates peak at two years, come down a little and then rise again at five years. I was not surprised that in the ATAC trial anastrozole blunted the peak at two years. With every effective therapy that we have studied — both hormone therapy and chemotherapy — you tend to see the greatest absolute benefit in the first couple of years when the relative risk of recurrence is highest. The differences start looking smaller as the risk of recurrence starts to plateau with longer follow-up.

— Kathy D Miller, MD

Clinical impact of quality-of-life data from the ATAC trial

Tamoxifen has benefited many women, but it has probably reached its “sell-by” date, and I believe soon we’ll see aromatase inhibitors (AIs) become primary adjuvant therapy for breast cancer. I’m very excited by the data from the IES and ATAC trials (Coombes 2004, Howell 2005). The efficacy data is good news, but it’s important for these patients to understand the side-effect profiles because these women generally have a good prognosis and some may not even need adjuvant therapy (1.2).

In the ATAC trial, arthralgias were more common in women receiving anastrozole. The difficulty in assessing these symptoms in all of the adjuvant AI trials that targeted postmenopausal women is that, with age, women are probably experiencing more arthralgias and osteoarthritis anyway. Anastrozole had a slight advantage in terms of vasomotor complaints (Fallowfield 2004a). Patients on tamoxifen experienced more vaginal discharge, to the extent of wearing pads, while patients on anastrozole complained of vaginal dryness, which led to painful intercourse and a loss of interest in sex.

Nurses need to be aware of all the things women experiment with to relieve side effects, such as hot flashes. To date, black cohosh, red clover and other phytoestrogens have not demonstrated a dramatic benefit over placebo in relieving the vasomotor symptoms associated with endocrine therapy. For patients to feel confident in their healthcare provider, they need to feel their provider is aware of all the tips they read about in magazines or see on shows dealing with healthcare.

All women with early breast cancer fear recurrence, so it is important to stress to patients that we know tamoxifen is an effective agent, but anastrozole provides an extra 26 percent benefit to the 50 percent reduction in risk of recurrence that we were already getting with tamoxifen. For the patient, knowing she is doing something to reduce the risk of contralateral breast cancer or recurrence will be very powerful in reducing her anxiety.

— Lesley Fallowfield, PhD

Side effects with aromatase inhibitors versus tamoxifen

Many patients comment that their hands are stiff on aromatase inhibitors, but we hear less about hot flashes. There are more complaints with tamoxifen — particularly hot flashes and vaginal dryness. We use a lot of venlafaxine and some paroxetine, sertraline and occasionally gabapentin for the vasomotor symptoms.

Very few patients — perhaps less than five percent — actually have to stop treatment because of arthralgias with aromatase inhibitors. Most patients seem to do better after they’ve been on treatment for six to eight weeks. At that point, they’ll often say, “It feels more like I’ve gotten a little older” — the kind of aches and pains that go along with aging. Sometimes some acetaminophen helps that achiness, but patients rarely need anything stronger.

— Anita Rush-Taylor, RN, CCRC

Adjuvant endocrine therapy in postmenopausal women

Discussions with patients regarding adjuvant hormonal therapy now take longer than talking to them about chemotherapy. I believe postmenopausal women need to hear that they have two good options — tamoxifen and aromatase inhibitors. At this point, none of the adjuvant trials with aromatase inhibitors have found an overall survival benefit.

Approximately 80 percent of my postmenopausal patients now receive an aromatase inhibitor initially for adjuvant therapy. With very few exceptions, I use anastrozole because, until recently, it was the only one for which we had up-front data (Howell 2005). We now have up-front data with letrozole (Thurlimann 2005), and while I suspect that major biochemical differences exist between the three aromatase inhibitors, I’m not at all convinced that those translate into clinical differences. However, we don’t have direct comparison data yet, so I tend to stick fairly close to data that are most similar to my patient’s situation.

Tamoxifen is still a very reasonable option for women with low-risk breast cancer who already have significant osteoporosis or significant risk factors for osteoporosis. Approximately 20 percent of my postmenopausal patients still receive tamoxifen.

— Kathy D Miller, MD

Switching endocrine therapy in the adjuvant setting

When we see patients who have been on adjuvant tamoxifen for two or three years, we discuss the switching data with them (Coombes 2004, Jakesz 2004). I was surprised to find that patients do not have a uniformly positive reaction toward switching endocrine therapy. Some patients feel comfortable on tamoxifen and prefer not to switch. They’re happy with the devil they know, rather than trying the unknown, which might be worse.

For patients who have already completed five years of tamoxifen, I discuss continuing therapy with an aromatase inhibitor (Goss 2003). Some women are looking forward to completing their hormone therapy, and they find the idea of extending it even another day very distasteful. Other women prefer to continue some form of treatment because they are uncomfortable with the idea of stopping therapy and think it’s great that there’s something they can do to further reduce their risk of recurrence and new breast cancer.

In the middle, a group of patients exists who struggles with that decision. These women frequently take a month or two off after completing the tamoxifen and then start the aromatase inhibitor. When they see me again in six months, they’ll have been on the aromatase inhibitor for a couple of months and can clearly separate what symptoms are from tamoxifen versus the aromatase inhibitor versus no therapy.

Their own personal experience with side effects can help them decide whether the risk-benefit ratio is favorable for them.

— Kathy D Miller, MD

Most postmenopausal patients completing five years of tamoxifen are interested in switching to an aromatase inhibitor — they want to do something proactive to prevent recurrence. In the study evaluating this strategy, many of the patients who were initially randomly assigned to placebo chose to take letrozole when the trial was unblinded.

— Barbara Thompson, RN

Osteonecrosis secondary to bisphosphonate therapy

We use a good deal of zoledronic acid — we probably have 75 women on it now — and so far we’ve had four patients develop osteonecrosis of the jaw. All of them had been on zoledronic acid for at least a year and a half. Two of the patients recently had dental work, while the other two had not.

The patients generally complain of pain and discomfort toward the back of the jaw. They think they have a toothache, but dental x-rays reveal erosion of the jaw. This condition doesn’t usually require pain medication, although we did have one patient who required minor oral surgery and short-term pain medication.

Once the osteonecrosis is diagnosed, we stop the zoledronic acid and the jaw heals. The pain usually subsides within six to eight weeks. In one patient, we restarted the zoledronic acid four or five months later, but after a couple of doses, the osteonecrosis recurred, so we haven’t tried that again. We are watching these women closely to monitor any progression of bone metastases because that’s an important issue also.

— Barbara Thompson, RN