Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial

Richard A Anderson, Rachel Remedios, Amy A Kirkwood, Pip Patrick, Linsey Stevens, Laura Clifton-Hadley, Tom Roberts, Chris Hatton, Nagesh Kalakonda, Don W Milligan, Pam McKay, Clare Rowntree, Fiona M Scott, Peter W M Johnson, Richard A Anderson, Rachel Remedios, Amy A Kirkwood, Pip Patrick, Linsey Stevens, Laura Clifton-Hadley, Tom Roberts, Chris Hatton, Nagesh Kalakonda, Don W Milligan, Pam McKay, Clare Rowntree, Fiona M Scott, Peter W M Johnson

Abstract

Background: Adverse effects on reproductive function are a key concern in young women treated with chemotherapy for advanced Hodgkin's lymphoma. We aimed to identify risk factors for the extent of ovarian damage in women with Hodgkin's lymphoma treated with different chemotherapy regimens to inform accurate advice on options for fertility preservation.

Methods: We recruited female participants from the randomised phase 3 RATHL trial, aged 18-45 years, based on availability of participants at recruiting sites in the UK. The RATHL trial key inclusion criteria were histologically confirmed classic Hodgkin's lymphoma, stage IIB-IV or IIA with adverse features (bulky disease or more than two sites of involvement), no previous treatments, and a performance status of 0-3. As part of RATHL, participants were treated with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or AVD followed by an interim PET-CT scan. Participants who had negative interim scans (PET score of 1 to 3 according to the Lugano classification) were randomly assigned (1:1) by use of minimisation, stratified by interim PET score and study centre, to continue ABVD or AVD for four more cycles. Participants with positive scans (PET score of 4 or 5) were escalated to treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP-14 or escalated BEACOPP) for four cycles. For the protocol-driven prospective cohort substudy, ovarian function was assessed before treatment, during chemotherapy, and then annually for 3 years by use of serum antimüllerian hormone and follicle-stimulating hormone measurements. The RATHL study is registered with ClinicalTrials.gov, number NCT00678327.

Findings: Between Dec 13, 2010, and Dec 19, 2012, 67 eligible participants were recruited for this prospective cohort study; 57 had received ABVD or AVD (ABVD-AVD group) and ten BEACOPP-14 or escalated BEACOPP (BEACOPP group). Follow-up was fixed at 3 years. Antimüllerian hormone concentrations decreased during both chemotherapy regimens. At 1 year after chemotherapy, antimüllerian hormone concentrations recovered to a median of 10·5 pmol/L (IQR 4·3-17·3) in the ABVD-AVD group, but little recovery was seen after BEACOPP (median 0·11 pmol/L [0·07-0·20]). Age also affected the extent of ovarian function recovery, with antimüllerian hormone recovery in participants aged 35 years or older in the ABVD-AVD group to 37% (SD 10) of their before treatment concentrations, compared with full recovery to 127% (SD 12) in those younger than 35 years (p<0·0001). Follicle-stimulating hormone recovery to less than 25 IU/L occurred for 95% of women younger than 35 years in the ABVD-AVD group by 2 years and was also dependent on age (hazard ratio 0·49, 95% CI 0·37-0·65; p<0·0001).

Interpretation: Reduced recovery of ovarian function observed in women older than 35 years treated with ABVD or AVD compared with younger women indicates that treatment could reduce their reproductive lifespan and supports discussion of fertility preservation before treatment. Women treated with BEACOPP should be informed of its potential high gonadotoxicity. These findings warrant further investigation in large, prospective studies with fertility and reproductive lifespan as outcomes.

Funding: Medical Research Foundation and Cancer Research UK.

Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC-BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Study profile RATHL trial and ovarian function substudy participants who contributed to analysis. ABVD=doxorubicin, bleomycin, vinblastine, and dacarbazine. AVD=doxorubicin, vinblastine, and dacarbazine. BEACOPP=bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone. FSH=follicile-stimulating hormone.
Figure 2
Figure 2
Ovarian function biomarkers at prespecified timepoints per treatment group (A) Concentrations of antimüllerian hormone and (B) follicle-stimulating hormone. All participants included in the substudy were analysed (ABVD-AVD group, n=57; BEACOPP group, n=10). Boxes are median and IQR, bars are ranges. Panel A is plotted on a log10 scale to clearly show the low concentrations seen in the BEACOPP group. ABVD=doxorubicin, bleomycin, vinblastine, and dacarbazine. AVD=doxorubicin, vinblastine, and dacarbazine. BEACOPP=bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone.
Figure 3
Figure 3
Correlations of antimüllerian hormone recovery and before treatment hormone concentrations or age for the ABVD-AVD group Panels show scatter plots of baseline hormone concentration versus concentration at 2 years (A) and versus percentage hormone recovery (B), and age versus hormone concentration at 2 years (C) and percentage hormone recovery (D). All patients in the ABVD-AVD group of the substudy included. Each dot shows antimüllerian hormone concentration or recovery; recovery was calculated for each participant as the concentration at 2 years after treatment as a proportion of the concentration before treatment. In the case of missing data, recovery could not be calculated. Dotted ine shows linear regression. ABVD=doxorubicin, bleomycin, vinblastine, and dacarbazine. AVD=doxorubicin, vinblastine, and dacarbazine.
Figure 4
Figure 4
Recovery of follicle-stimulating hormone concentrations after the end of treatment in evaluable patients from the RATHL trial Kaplan-Meier curves shows recovery of follicle-stimulating hormone concentrations per treatment group (A) and by age group (B). Evaluable female participants (n=391) were divided by chemotherapy regimen received: ABVD or ABVD followed by AVD (ABVD-AVD group), and ABVD followed by BEACOPP-14 or escalated BEACOPP (BEACOPP group). ABVD=doxorubicin, bleomycin, vinblastine, and dacarbazine. AVD=doxorubicin, vinblastine, and dacarbazine. BEACOPP=bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. HR=hazard ratio.

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