Can CAM help alleviate musculoskeletal symptoms in breast cancer patients from aromatase inhibitors like letrozole?

Given that my specialty is breast cancer surgery, I know that breast cancer patients tend to be very receptive to “natural” treatments of the sort in “complementary and alternative medicine” (CAM), now more “officially” known as “integrative medicine” or, in the case of oncology, “integrative oncology.” Fortunately, the vast majority of patients generally use these treatments alongside their conventional medical care for breast cancer. Unfortunately, I still see maybe once a year a patient who opted to use, for example, naturopathy or traditional Chinese medicine instead of the conventional multimodality treatment consisting of surgery, radiation, chemotherapy (when indicated), Herceptin (for HER2-positive tumors), and hormonal therapy (for estrogen-responsive tumors). It is thus not surprising that the use of alternative medicine and “complementary medicine” are associated with shorter survival among cancer patients. The main argument for the use of “integrative oncology,” though, is not improved survival but allegedly improved symptom control, particularly symptoms that result from side effects of treatment, particularly side effects of chemotherapy and, in breast cancer, hormonal therapy. But is there good evidence that the various unscientific and unproven treatments “integrated” into integrative oncology do this? A recent study suggest that the answer is no, at least for one specific indication, relieving the symptoms due to blocking estrogen activity using a drug called letrozole. Naturally, I couldn’t resist taking a closer look.

Letrozole (trade name: Femara) belongs to a class of drug known as aromatase inhibitors (AI). As the name implies, drugs such as letrozole—and other commonly used AIs such as anastrozole (Arimidex) or exemestane (Aromasin) inhibit an enzyme called aromatase, thus depleting estrogen levels in the peripheral tissues, which is the source of the low levels of estrogen still present in postmenopausal women. (AIs are not used in premenopausal women because the ovaries produce far more estrogen than the peripheral tissues, and inhibiting aromatase won’t significantly decrease estrogen levels; these women are still treated with Tamoxifen.) AIs are used to treat postmenopausal women with estrogen receptor (ER)-positive breast cancer and have been shown to decrease the risk of tumor recurrence and improve overall survival. Unfortunately (and predictably, given their mechanism of action), AIs have significant side effects, most prominently hot flashes and other vasomotor symptoms of menopause, as well as musculoskeletal and joint pain and an increased risk of osteoporosis. These side effects make compliance problematic (a problem shared with Tamoxifen and any other treatments designed to block estrogen activity).

Given how common breast cancer is and how many women are prescribed AIs or Tamoxifen to decrease the risk of cancer recurrence after surgery or to slow the progression of metastatic disease (over two-thirds of breast cancers are ER-positive), unsurprisingly advocates of “integrative oncology” focus on managing side effects of treatment in breast cancer patients. Acupuncture is a particular favorite intervention said to relieve hot flashes and vasomotor symptoms associated with blocking estrogen action. Many have been the studies of acupuncture used to alleviate hot flashes in breast cancer patients undergoing hormonal therapy that I’ve written about, starting in 2007, and they’ve all been basically negative, although several have been spun as “positive” using the usual techniques. Many of these studies don’t contain proper controls or don’t properly blind participants, or, if they do contain a sham acupuncture group, the authors interpret the usual finding that the sham and “true” acupuncture groups had the same improvement in symptoms not as due to placebo effects (the correct interpretation, namely that there is no difference between “true” and sham/placebo acupuncture) but as evidence that acupuncture works. Same as it ever was.

This brings me to the current study, published online in January and scheduled for the April issue of The Breast. One interesting thing about this particular study is that it was funded by…Novartis Pharma GmbH Germany! Yes, indeed! Evil big pharma partially funded an acupuncture study! (Yes, Novartis manufactures letrozole under the trade name Femara.) If big pharma is so against “CAM,” one wonders why it would fund a study like this, one does. It rather undermines the claim by many CAM advocates that the reason treatments like acupuncture aren’t more widely accepted is because pharma is suppressing them. Of course, Novartis has a financial motive here. Side effects from AIs all too commonly lead postmenopausal women to quit taking the drug before completing their 5-10 year course, and obviously Novartis would very much like women with ER-positive breast cancer to complete their courses of letrozole. The funding source also explains an oddity I wondered about in the study, namely: Why does it study only women taking letrozole, rather the broader and more numerous group of women taking AIs? Basically, these investigators in Germany took advantage of a multicenter phase IV postmarketing study of letrozole called PreFace.

In the introduction, the authors write:

According to current guidelines, postmenopausal women with hormone receptor–positive early breast cancer (BC) should receive adjuvant endocrine treatment — i.e., tamoxifen or an aromatase inhibitor (AI) — in order to reduce the risk of recurrence [1,2]. Since AI therapy is more effective in these patients [3, 4, 5, 6], it is a standard treatment in the adjuvant setting [7,8]. However, AIs are known to induce musculoskeletal pain as one of the main side effects [9, 10, 11, 12, 13], so that patients often become noncompliant [11] and discontinue treatment [9,12, 13, 14, 15]. Noncompliance and early cessation of treatment in turn lead to a poorer prognosis [12,16] — emphasizing the importance of maintaining patients’ compliance and persistence. Several pharmacological and nonpharmacological methods aimed at improving therapy adherence with AIs have been analyzed [13,17, 18, 19, 20]. Analgesics or a switch to another antihormone therapy, for instance, significantly reduced pain [19,21,22]. Providing patients with additional information material does not appear to affect compliance and persistence with anastrozole [23]. Although yoga has been reported to significantly improve musculoskeletal symptoms in various trials [17,19,24,25], there are contradictory results in relation to physical activity [18,19,26,27]; and the same applies to acupuncture [19,20,28,29] and other complementary and alternative medicines (CAM) [19,30,31].

No, the data with respect to acupuncture is not “conflicting.” It is negative. (Heck, this study cited was stone cold negative, although the authors tried to spin acupuncture as still potentially effective by handwaving about how “hsame acupuncture “may not be equivalent to placebo,” and this “positive study” cited was only single blind.)

So what did the investigators do for this study? Basically, they took advantage of the design of this study, which, in addition to asking subjects about symptoms due to letrozole use, also asked them about their use of CAM. Patients were divided into those who had been using CAM before starting AI treatment and those who had not:

Letrozole and CAM: Study design

The following data were examined:

Patient information included common epidemiological characteristics, comorbidities, and concomitant medication. There were four prespecified study visits after 6, 12, 24, and 60 months from the time of inclusion in the trial. At the follow-up visits, the patients’ disease status was assessed and they were asked about compliance and adverse events. In addition, to assess musculoskeletal side effects during the first year of the treatment, a pain diary including pain maps and numeric rating scales from 0 (no pain) to 10 (very strong pain) was issued to each patient at the time of inclusion. Patients were asked to document any symptoms at monthly intervals. For months 0, 6, and 12 the diary also included questions regarding the use of CAM. The patients were asked each time whether they were currently using or had in the past used vitamins, high-dose vitamin C, food supplements, mistletoe, enzymes, acupuncture, homeopathy, Chinese herbs/tea, mushrooms, meditation, prayer, relaxation techniques, yoga, t’ai chi, qigong, or bioresonance. Only the data at month 0 — i.e. before the start of endocrine treatment — were evaluated for the present analysis.

The patients in the two groups were pretty well-matched in terms of age, BMI, tumor characteristics. These two graphs tell the tale. The first looked at reported limb pain:

Letrozole and muscle pain

The second looked at reported joint pain (the other major form of pain associated with AIs):

Letrozole and joint pain

Basically, at best there is no difference in pain between the groups, and at worse there is higher pain in the CAM users taking letrozole:

This study shows that patients who were CAM users before AI treatment had generally higher pain values — for myalgia/limb pain as well as for arthralgia — than non-users throughout the observation period. An increase in pain levels of myalgia/limb pain and arthralgia was registered in both patient groups over time, particularly in the first 6 months. Afterwards, pain increase was weaker, but still significant in both groups, except for the non-CAM users regarding myalgia/limb pain. CAM use did not appear to be associated with different changes in pain increase over time. However, a large proportion of the patients, at 64.5%, reported ongoing CAM at the time of diagnosis of breast cancer and before the start of AI treatment.

The authors also did an exploratory analysis of the effect of starting CAM treatments during the first six months of letrozole therapy:

In an exploratory analysis, the pain levels over time were plotted relative to CAM status before AI treatment and after 6 months (Suppl. Fig. 1a and 1b). In general, patients who did not use CAM before and in the first 6 months of AI treatment showed constantly the lowest levels of pain compared to those who used CAM at some point of time. Patients who did not use CAM before AI treatment, but used it later on, did not experience a serious reduction in myalgia/limb pain or arthralgia. Conversely, patients who first used CAM and later stopped it due to reduced symptoms showed a renewed increase in pain, both in myalgia/limb pain and arthralgia.

So starting CAM during the early part of letrozole therapy didn’t make a detectable difference in the pain reported.

Leading to the conclusion:

In conclusion, this study demonstrated that the intensity of pain was generally greater in the CAM group than in the non-CAM group. However, changes in pain increase appeared to be similar in the two patient groups within the first 12 months. Thus, CAM use does not prevent or improve the development of AIMSS. But a large proportion of postmenopausal breast cancer patients (64%) make use of ongoing CAM after a diagnosis of breast cancer. Therefore, because of the risk of non-compliance and treatment discontinuation due to the development of higher pain levels, special attention must be paid to patient education and aftercare in these patients.

Obviously, this study is a retrospective observational study, and there could be biases and confounders not accounted for. One shortcoming is that analgesic drugs weren’t included in the analysis. One might imagine that women who are into CAM might also not have used as many analgesics or other drugs designed to alleviate their letrozole-induced pain. At the very least, this study shows no signal suggesting that “integrative oncology” methods might be effective in alleviating letrozole-induced musculoskeletal symptoms.