Submitted May 11, 2007
Accepted September 10, 2007
Treatment-related risk factors for premature menopause following Hodgkin's lymphoma
Marie L. De Bruin, Jeannine Huisbrink, Michael Hauptmann, Marianne A. Kuenen, Gabey M. Ouwens, Mars B. van 't Veer, Berthe M.P. Aleman, and Flora E. van Leeuwen*
Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, Netherlands
Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht, Netherlands
Department of Bioinformatics and Statistics, Netherlands Cancer Institute, Amsterdam, Netherlands
Department of Hematology, Erasmus MC, Daniel den Hoed Cancer Center, Rotterdam, Netherlands
Department of Radiotherapy, Netherlands Cancer Institute, Amsterdam, Netherlands
* Corresponding author; email: f.v.leeuwen{at}nki.nl.
We conducted a cohort-study among 518 female 5-year Hodgkin's lymphoma (HL) survivors, aged 14 to 40 years (median 25 years) at treatment (1965-1995). Multivariable Cox regression was used to quantify treatment effects on risk of premature menopause, defined as cessation of menses before age 40. After a median follow-up of 9.4 years, 97 women had reached menopause before age 40. Chemotherapy was associated with a 12.3-fold increased risk of premature menopause compared to radiotherapy alone. Treatment with MOPP/ABV significantly increased the risk of premature menopause (Hazard ratio [HR] 2.9), although to a lesser extent than MOPP treatment (HR 5.7). Alkylating agents, especially procarbazine (HR 8.1) and cyclophosphamide (HR 3.5) showed the strongest associations. Ten years after treatment, the actuarial risk of premature menopause was 64% after high cumulative doses of procarbazine (>8.4 g/m2), and 15% after low doses (
4.2 g/m2). The cumulative risk of menopause at age 40 did not differ much according to age, but time to premature menopause was much longer in women treated at early ages. As long as alkylating agents will be used for curing HL, premature menopause will remain a frequent adverse treatment effect, with various clinical implications.
