'Unexpected': Age 35 Key to Ovarian Function After Chemo for HL

Fran Lowry

October 04, 2018

Age is an important determinant of ovarian function recovery after chemotherapy for advanced Hodgkin's lymphoma, regardless of which regimen is used, according to new research that surprised investigators.

In a secondary analysis of the Risk Adopted Therapy in Lymphoma (RATHL) trial, recovery of ovarian function was reduced in women older than 35 years even when they were treated with regimens considered to have less gonadotoxicity.

The analysis also showed that the less toxic regimens had very little impact on a woman's ability to conceive, as long as she was younger than 35 years. The study was published in the October issue of The Lancet Oncology.

The current regimen of choice for many patients with Hodgkin's lymphoma is doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). If response to ABVD is inadequate, then treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone (BEACOPP) is warranted.

However, female gonadal toxicity is high with BEACOPP, resulting in amenorrhea in about 95% of women older than 30 years.

"The main finding we had was the impact of age on recovery of ovarian function after what we thought was relatively nonovarian toxic chemotherapy in the women who received ABVD," lead author Richard A. Anderson, MD, MRC Center for Reproductive Health at the University of Edinburgh, Scotland, told Medscape Medical News. "This finding was unexpected."

The analysis also confirmed that BEACOPP was, indeed, more gonadotoxic than ABVD.

"People have known for a while that BEACOPP is more toxic than ABVD on ovarian function. We very much anticipated that, and there will be no surprise to anyone in lymphoma research by this finding. What we may not have anticipated was how fully ovarian function was achieved in younger women treated with less gonadotoxic ABVD," Anderson said.

The secondary analysis included 67 women who had participated in the RATHL trial. They were aged 18 to 45 years with 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 to 3. 

Participants were treated with 2 cycles of ABVD or AVD followed by an interim PET-CT scan. If that scan was negative, patients continued ABVD or AVD for 4 more cycles. Participants with positive PET scans were escalated to treatment with BEACOPP for 4 cycles.

Anderson and his team used antimullerian hormone (AMH) concentrations as a biomarker of ovarian reserve.

Of the 67 women, 57 received ABVD or AVD and 10 women received BEACOPP.

AMH concentrations decreased during both ABVD and BEACOPP treatments.

At 1 year after chemotherapy, AMH concentrations recovered to a median of 10.5 pmol/L (interquartile range [IQR], 4.3-17.3 pmol/L) in the ABVD group.

However, in the BEACOPP group, little recovery was seen, with AMH concentrations showing a median of 0.11 pmol/L (IQR, 0.07-0.20 pmol/L).

As noted above, age affected the extent of ovarian function recovery.

AMH recovery in patients 35 years or older was 37% (range, 27% to 47%) of their concentrations before treatment with ABVD-AVD. In contrast, women younger than 35 years showed a full recovery of their AMH levels (P < .0001).

Follicle-stimulating hormone recovery to < 25 IU/L occurred in 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 < .0001).

"We were a bit surprised that in this circumstance, where we were using relatively less toxic therapy, the older ovary just didn't seem to be able to take that as well as the younger ovary," said Anderson, a reproductive medicine specialist.

Women with Hodgkin's lymphoma should be referred for fertility preservation counselling as soon as they are diagnosed, he said.

"The oncologist or the oncology nurse could raise the subject, or it could be the patient herself. Depending on how the health system works, they would then refer her to the reproductive team. In a more free and easy system as exists in the United States, the patient might directly ring a reproductive specialist. At any rate, the oncologist should at least raise the issue," he said.

The results of this secondary analysis also show the value of AMH as a biomarker of the toxic effects of chemotherapy on the ovaries during and after different chemotherapy regimens for advanced Hodgkin's lymphoma, Anderson added.

More Precise Information

In an accompanying editorial, Matteo Lambertini, MD, Institut Jules Bordet, and Isabelle Demeestere, MD, Université Libre de Bruxelles, Belgium, write that this analysis "provides more precise information than previous reports to counsel women with Hodgkin's lymphoma on gonadal damage induced by ABVD, AVD, or BEACOPP."

In an interview with Medscape Medical News, Lambertini noted that, even though gonadotoxicity with ABVD and AVD therapy is very low, all women should be counseled about the potential risk of ovarian damage and fertility preservation procedures should be discussed with them.

"They may need to receive BEACOPP if they do not respond to ABVD, so even though they may start with the less toxic regimen, they still need to be counseled, ideally at the time of their diagnosis if they are interested in having babies in the future," Lambertini said.

"This study highlights the importance of discussing access to options for fertility preservation in women older than 35 years, irrespective of chemotherapy type, and in women receiving BEACOPP, irrespective of their age," he said.

Anderson reports nonfinancial support from Roche diagnostics and a grant from the Medical Research Foundation. Lambertini reported no relevant financial relationships. The RATHL trial was funded by Cancer Research UK, and the ovarian substudy by the Medical Research Foundation.

Lancet Oncol. 2018;19:P1328-1337, P1264-1266.

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