Joint symptoms and other adverse effects of AIs (and a comparison)from SABCS

[Lani]

oint Symptoms and Other Adverse Effects of Aromatase Inhibitors


Zosia Chustecka

December 22, 2006 (San Antonio) — New details about adverse effects associated with aromatase inhibitors (AIs) were reported in several poster presentations during the San Antonio Breast Cancer (SABC) Symposium and were poured over by clinicians eager to learn more about these relatively new products. Three of these drugs have been launched in recent years — anastrozole (Arimidex, AstraZeneca), exemestane (Aromasin, Pfizer) and letrozole (Femara, Novartis) — for use as adjuvant therapy in postmenopausal women with hormone-receptor–positive breast cancer. With their action of blocking estrogen synthesis, they offer an alternative to what has been the standard therapy, the selective estrogen-receptor modifier (SERM) tamoxifen.

One of the presentations concluded that joint symptoms with AIs are more prevalent and more severe than what has previously been described in clinical trials. Katherine Drew, MD, and colleagues from the Herbert Irving Comprehensive Cancer Center at Columbia University, in New York, noted that large adjuvant trials reported in 2002–2004 found the incidence of musculoskeletal disorders was 20% to 30% and that nearly 5% of patients discontinued therapy because of toxic effects.

However, in a cross-sectional study of 200 patients attending the academic practice at Columbia University, they found that 47% reported AI-related joint pain and 44% reported AI-related joint stiffness.

About two thirds of the patients who reported joint symptoms said the symptoms were moderate to severe, with the most common sites affected being knees and hands. Just over half of these women (52%) took oral medications for symptom relief, including nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (paracetamol), while 46% used nonpharmacological interventions (mainly exercise).

Within this sample, the risk of joint symptoms was independent of age and which AI was used or for how long, the researchers commented. It was, however, inversely associated with being overweight and prior tamoxifen therapy, and previous exposure to taxanes was the strongest predictor of AI-related joint symptoms. Patients who had received taxanes were 4 times more likely than others to develop joint pain and stiffness while taking AIs.

"Because the success of AI therapy depends on patients' ability to adhere to treatment recommendations, further studies of interventions that may alleviate these symptoms and improve quality of life are needed," Dr. Crew and colleagues concluded. In a neighboring poster, the same team reported some success with acupuncture for these joint symptoms. A single-group pilot study in 21 women showed improvements in pain and stiffness and a decrease in analgesic use.

[Lani]

Another poster presented findings from an online patient survey carried out by the US advocacy group Breast Cancer Action (BCA). The survey, launched in August 2005, listed 38 adverse events associated with aromatase inhibitors (compiled from FDA-approved product labeling) and also asked whether respondents experienced any other unlisted adverse effects.

Of 612 women who responded, nearly all (96%) reported 1 or more adverse effects. About 30% of women reported discontinuing therapy, most of them (87%) because of intolerable adverse events and 47% because of joint-related problems. More than half of the respondents reported stroke, cough, swelling of arms and legs, flulike symptoms, and anxiety. Other effects included vaginal atrophy and dryness, a rise in cholesterol levels, and general pain. The full report and comments from respondents are available online.

"It's very apparent that some women who responded to the survey are really suffering," commented lead author Marilyn Zivian, PhD, in a statement. "Patients know about side effects before their doctors do — they experience them first-hand," added Barbara Brenner, executive director of BCA. Both women are breast cancer survivors.

Direct Comparison of 3 Products

A direct comparison of the 3 AIs in a phase 1 study in healthy postmenopausal women revealed differences between the drugs, particularly in the effects of these agents on lipid profiles. The Letrozole, Exemestane, and Anastrozole Pharmacodynamics (LEAP) study was reported by a team from the University of Sheffield, in the United Kingdom, in collaboration with researchers from AstraZeneca.

All 3 AIs were associated with modest increases in serum markers of bone turnover and with modest decreases in bone-mineral density (BMD) after 24 weeks of treatment, with no significant differences between agents. The researchers note that long-term administration of AIs has already been associated with a decrease in BMD and an increase in fracture risk and osteoporosis in postmenopausal breast cancer patients.

As exemestane is steroidal in nature (whereas the other 2 products are nonsteroidal), it has previously been suggested that this drug may protect against bone loss. "No evidence of such an effect was detected in this study," the researchers commented. One difference did emerge, however — only exemestane was associated with a decrease in parathyroid hormone (PTH) levels, which may indicate increased bone resorption, they suggested.

The 3 drugs showed differential effects on lipid profiles. Compared with anastrozole, treatment with letrozole and exemestane produced potentially unfavorable changes in lipid profiles of these healthy volunteers, the researchers commented. Treatment with letrozole resulted in a significant increase in triglycerides at 12 weeks, although levels were highly variable during the 36-week course of this study,...

[Lani]

and so this observed increase may have been due to clinical fluctuations and not related to the treatment, they said. Exemestane was associated with an increase in high-density lipoprotein cholesterol and also increases in the ratio of low- to high-density lipoprotein cholesterol and the ratio of apolipoprotein apoB to apoA-1, all of which suggest a possible atherogenic effect, the group commented.


SABC Symposium: Abstracts 2092, 3131, 5068, and 507. Presented December 15 and 16, 2006.

[panicked911]

Lani:
THANK YOU !!! I am not sure clinically what the abstratc true meanig is but it reaffirms exactlu what i have been experiencing - I keep complaiig and the oncs yes me to death - Although it has gotten better w/out herceptain and on glucosimine -
Now if only they can find a 'cure" for the pain and stiffness. This goes beyond a quality of life issue for some of us ...

Susanne