It’s time to count chemotherapy as a risk factor for lymphedema

Chemotherapy is not currently considered to be a risk factor for developing lymphedema. Yet there is a small but growing collection of clinical research that appears to indicate otherwise. Is it time to include chemotherapy as a risk factor for lymphedema? How much additional risk might it impart, and is there anything we can do about it?

Lymph node removal and radiation therapy are typically considered to be the primary risk factors for developing lymphedema. But some patients with significant axillary lymph node dissection never develop lymphedema, while others with much less invasive sentinel lymph node biopsy do. How can this be?

There are multiple risk factors involved in developing lymphedema secondary to cancer

The answer is simply that there are additional risk factors involved. We previously reviewed some excellent research that identified a genetic predisposition to developing lymphedema in some cancer patients who go on to develop it. This same study also confirmed some other known risk factors for lymphedema, including obesity, number of lymph nodes removed, type of surgery and radiotherapy, and others. Included in the list of risk factors was chemotherapy.  Several additional studies have also reported an association between breast cancer related lymphedema and chemotherapy. The evidence is mounting.

New research says the type and timing of chemotherapy alters the risk of developing lymphedema

A new study just released further confirms and dissects the role of chemotherapy in the development of lymphedema (ref1). Using a study population of breast cancer patients all of whom had axillary lymph node dissection, the authors evaluated the incidence of lymphedema in those that were treated with no chemotherapy, to those treated with chemotherapy drugs known as ‘taxanes’ (includes Taxol/paclitaxel and Taxotere/docetaxel, the latter which forms part of the FEC-D chemotherapy regimen often used to treat breast cancer).  The authors found that this class of chemotherapy agents were shown to increase the ‘hazard ratio’ by 3 in the adjuvant setting (ie., when chemotherapy was administered after surgery).  In other words, patients treated with taxanes as an adjuvant were three times more likely to develop lymphedema than those who did not receive chemotherapy.

Furthermore, it appears that treatment with taxanes in the neoadjuvant setting (ie., pre-surgery) also increased the risk of lymphedema, but only half as much as for those treated with it post-surgery (although their study had insufficient data to be statistically significant). Their analysis of the risk imparted by other chemotherapeutic agents was inconclusive due to low sample size.

Is this increased risk of lymphedema in patients treated with taxanes logical? How could taxanes be damaging to the lymphatic system? A few underlying mechanisms have been proposed that could plausibly explain the increased risk of lymphedema for those treated with this class of chemotherapy drug. The authors of the above study point out that in experimental models taxanes have been shown to inhibit neolymphangiogenesis (new lymph vessel growth) which may reduce the body’s ability to recover sufficient lymphatic function following surgery or radiation. Taxanes have also been shown to increase vascular permeability, which may overburden an already compromised lymphatic system. Both of these effects could theoretically tip the balance in favour of chronic lymphatic insufficiency.

Implications

Over recent decades there has been a shift towards more conservative cancer surgery and radiation therapy, and increased use of chemotherapy, hormonal therapy and others approaches (collectively known as ‘systemic therapies’). The class of chemotherapy agents known as taxanes have been shown to be particularly effective in treating multiple types of cancers, and their use has been increasing. However, the latest data suggests that breast cancer patients treated with taxane chemotherapy following their surgery need to be aware that they may have a significantly increased risk of developing lymphedema, and should be monitored accordingly. This data also supports the preferential use of taxanes in the pre-operative setting rather than in the post-operative setting to help reduce the risk of lymphedema, although randomized clinical trials are needed to confirm this hypothesis.

Comments? Questions? Feel free to post them below!

References

1. Cariati M., Bains S.K., et al. Adjuvant taxanes and the development of breast cancer-related arm lymphoedema. Br J Surg. 2015, Jun3 [Epub ahead of print].