1 Departments of Hematology and Bone Marrow Transplantation, 2 Oncology, 3 Obstetrics & Gynecology, Rambam Medical Center & Bruce Rapaport Faculty of Medicine, Technion, Haifa, Israel 31096
4 To whom correspondence should be addressed. Email: e_dann{at}rambam.health.gov.il
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Abstract |
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Key words: fertility/GnRH analogue/lymphoma/post-chemotherapy
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Introduction |
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Materials and methods |
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Results |
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With a median follow-up of 70 months (ranging 2399 months), 12 out of 13 patients (92%) experienced recovery of ovarian function. Eight patients conceived spontaneously, five of them following GnRH analogue co-treatment during the chemotherapy course and 12 healthy babies were delivered. Four women delivered singleton neonates each, another three patients had two successful deliveries each and one patient delivered twins (Table I). One patient, aged 40 years, who did not receive GnRH analogue, experienced premature ovarian failure.
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Discussion |
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Chemotherapy protocols including alkylating agents are frequently associated with gonadal toxicity. They may be detrimental even to resting and immature oocytes and possibly damage pre-granulosa cells of primordial follicles (Meirow, 2000). The available data suggest that >90% of females treated with CHOP do preserve ovarian function, possibly due to a relatively low cumulative dose of cyclophosphamide, totalling 4.5 to 6 g/m2.
The POF rate was reported to be as high as 6090% in the application of regimens with higher doses of alkylating agents, used as conditioning for stem cell transplantation (Salooja et al., 2001).
The British Medical Research Council study (MRC AML 10) trial for patients with acute leukaemia revealed that hormonal disorders were more common in autologous or allogeneic bone marrow transplantation, 58 or 78% respectively, compared with 23% in a cohort of patients who had intensive consolidation chemotherapy. The infertility among women post transplantation was 64 versus 12% post intensive consolidation (Watson et al., 1999).
Apparently, POF correlates with age and cumulative dose of the alkylating agent. Time schedule may also play a role. The cumulative cyclophosphamide dose given in the study protocol (812 g/m2) is within the range of doses given during stem cell transplantation. Yet, the time schedule and dose intensity are different and the incidence of POF is considerably lower (8 versus 6090%) in the former protocol. Most patients undergoing high-dose chemotherapy have been exposed to a primary regimen followed by salvage regimen. They acquired cumulative gonadal damage, which makes it hard to compare their results with those of the patients receiving the first line protocol. The use of GnRH analogue in combination with chemotherapy may possibly have a protective effect on oocytes (Blumenfeld et al., 2002). However, this has been demonstrated by a few centres in non-randomized studies (Fox et al., 2001
; Pereyra-Pacheco et al., 2001
; Recchia et al., 2002
). These results await confirmation and mechanisms need to be elucidated. Its impact is likely to be dependent on patients' age, chemotherapeutic agents used, cumulative doses of chemotherapy, and schedule. Although the study protocol causes only a minimal impairment to the reproductive function, seven out of 13 patients were also treated with GnRH analogue. There was no significant difference whether GnRH analogue was given in respect to subsequent cyclic menses or fertility. Obviously, a larger cohort of patients is needed to determine the possible additional beneficial role of GnRH analogue co-treatment in this protocol.
In conclusion, this report suggests that increasing the dose of cyclophosphamide only, administered during a short period of time, may be an alternative option in the treatment of aggressive NHL, resulting in a minimal rate of gonadal toxicity. The preliminary result of 92% of patients retaining cyclic ovarian function with this protocol awaits validation in a larger series.
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Acknowledgements |
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References |
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Submitted on December 16, 2004; resubmitted on March 8, 2005; accepted on March 8, 2005.
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