Ovarian failure in long-term survivors of childhood malignancy

Ovarian failure in long-term survivors of childhood malignancy ROBE~K’I‘ .]A\1

J. S’I‘ILLMAN.

M.D

S. S(:HINFEI,D.

ISAAC

SCHIFF,

KICHARD JOEL

D.

M.D. M.D.

GELBEIR.

GRE:ENBERGER,

MARTIN

LAKSON.

NOKMXN

,JAFFE,

FKEDE:RI(:K

PH.D.

M.D. M.S. M.D.

P. 1.1. M.D.

Hostor1, ,2lus.,ach ri.\vtt.\ The frequency and causes of ovarian failure among 182 long-term survivors of childhood cancer were examined. Twenty-two patients (12%) had ovarian failure. Ovarian failure was found in 17 of 25 patients (88%) who had both ovaries within abdominal radiotherapy fields, in five of 35 patients (14%) whose ovaries were at the edge of the treatment field, and in none of 122 patients with one or both ovaries outside of an abdominal treatment field (p < 10-4). The odds for ovarian failure in patients with both ovaries in the field are 19.7 higher than those for other irradiated patients (95% confidence interval, 5.3 to 72.8). Covariate and multivariate analyses of tumor type, age at diagnosis, duration of follow-up, abdominal tumor surgery, abdominal radiotherapy, number of chemotherapeutic agents administered, and cumulative doses of several drugs revealed that the IoFation of the ovaries relative to radiation treatment fields was the only risk factor for subsequent ovarian failure. (AM. J. OBSTET. GYNECOL. 139:62, 1981.)

RADIOTHEKAPY. chemotherapy, and surgery have contributed to improved prognosis for children with diverse cancers.’ However, these treatments can also af’fect normal tissues and produce acute or latent illjuries.” The late sequelae are now recognized more frequently because of increased numbers of long-term ‘( Effects on the reproductive and stesurvi\-ors.‘. roidogenic potentiai of’ the gonad after cancer therapy

in children have been reported but neither- the incidence nor causes of the impairments have been well defined.‘. 5 rThe present study examines the de\eIopment of ovarian failure during foIlow-up in a c0llor.t of 182 women who are long-term survivor-a ot childhood cancer.

Material and methods Study patients. The tumor registr) of the Sidne!, Farber Cancer Institute irk Boston, Massachusetts, provicied a list of 208 female patients ( I) lvho had a cancer diagnosed at between 0 and 17 years of age, (3 who were alive and at least 14 vears of‘ age at tile conclusion of study, (3) who had survived at least .i vears from time of diagnosis. and (-I) who had not undrl gone bilateral ovariectomy. Demographic and cancer therapy data were ohtainetl on each patient through medical record re\ iews. clinic interviews. and phone and letter contacts. ‘I‘wentl-six patients were eliminated from fbrther analysis brcause of inadequate follow-up information such a\ data 011

62

Ovarian failure after childhood malignancy

current menstrual function. Other than their loss to follow-up. these 26 patients were comparable to the remaining group of 182 study patients (88%‘). The mean age at diagnosis of cancer in the 182 patients was 6.9 years (range 0.1 to 17 years) and the mean number of years of follow-up since diagnosis was 16.4 years (6 to 33 years). Tumor diagnoses were distributed as filllows: Wilms’ tumor (53 patients), lymphoma (4 I), soft-tissue sarcoma (24), neuroblastoma (lY), osteogenic sarcoma (15). leukemia (lo), dysgerminoma (4). renal cell carcinoma (3), thyroid carcinoma (3). ependymoma (2). and one each of six other tumors. Therapies.

Rtr&tion theru@. Ninety-four of the 182 patients (5274) received fractionated external beam radiotherapy COthe abdomen. Available individual radiotherapy field diagrams were utilized to classify the location of each ovary as within, at the edge of, or outside of the irradiated fields with the aid of standardized agecorrelated body mannequins: more precise data on actual ovarian tissue doses could not be calculated. All patients who had received whole pelvic and whole abdominal field irradiation were said to have both ovaries within the field. For patients treated prior to 1968 with a 200 k\‘(p) orthovoltage unit, an ovary located within 10 cm of the margin of a large (2 10 by 10 cm) treatment field or Iocated within 3 cm of the margin of a smaller (< 10 by IO cm) field was considered to be at the edge of the field. An ovary located beyond these ranges was considered to be outside the field. After 1968, when 3 or 8 meV linear accelerators were used, an ovary within 1 cm of’the field margin was considered at the edge and beyond 1 cm was outside the field. When the relative location of the two ovaries differed, the location which provided minimum exposure was used for analysis of association with ovarian failure. An estimated ovarian tissue dose (OTD) was calculated for each ovary based on 100% of the recorded abdominal midplane dose for ovaries within the field, approximately 10% for ovaries at the edge, and approximately 1% for those outside. Contributions from multiple fields or multiple therapy courses were added. The estimated mean OTDs were approximately 3,200 rads (range 1,200 to 5,000) for the 25 patients with both ovaries inside the field, 290 rads (range 90 to 1,000) for the 35 patients with at least one ovary at the edge of the field. and 54 rads (5 to 150) for the 34 patients with at least one ovary outside the abdominal radiation field. The charts for 59 patients who received radiotherapy to nonabdominal sites were also reviewed. The es-

63

timated OTD from scatter radiation for these patients was minimal (<20 I-ads). These 59 patients plus the 29 who received no radiotherapy were considered IO have recei\recl no abdominal irradiation. Chemothuajy. Twenty-one of the 182 patients (12%‘) received no chemotherapy, and 86 (47%) received one agent. Seventy-five patients received multiple agents, either sequentially or in combination: two agents were given to 42 patients and three or more agents were used in 33 patients. Eighteen different agents were employed, and the cumulative milligram dose of the six drugs utilized most frequently was calculated. For each drug, comparison was made of dose administered to those patients with ovarian failure and those without. Analysis of the effects of’ multiple-drug regimens was primarily based upon the number of agents administered because of a wide diversity of drug combinations, doses, and treatment schedules. Surgery. One hundred six patients underwent abdominal surgery. Nine of these also received abdominal radiotherapy, nine received chemotherapy, and 83 received both forms of therapy. In 17 patients surgery involved the reproductive tract: unilateral ovariectomy (five patients), ovariopexy (nine), and hysterectomy (three). Assessment of ovarian failure. Ovarian failure is defined as amenorrhea accompanied by persistent elevation of both serum gonadotropins: follicle-stimulating hormone (FSH) >40 mIU/ml, luteinizing hor mone (LH) >25 mIU/ml, and FSHiLH ratio>l.’ FSH and LH assays were performed by double-antibody radioimmunoassay on plasma obtained prior to institution of hormonal therapy or at least three weeks after its discontinuation.’ In two clinically hypogonadal amenorrheic patients, diagnosis of ovarian t‘ailure was made through a finding of persistently elevated urinary gonadotropin titers of >200 muui24 hours X 3.’ Primary amenorrhea is defined as the lack of spontaneous onset of menstrual function (1) by 14 years of age in the absence of development of secondary sexual characteristics or (2) by 16 years of age with secondary sexual development.’ Secondary amenorrhea is cessation of spontaneous menstrual function for greater than 6 months.” In all study patients with secondary amenorrhea, the abnormality has lasted more than 5 years and has persisted either until the present or until the initiation of replacement hormonal therapy. Statistical analysis. The data were analyzed to determine the differences between the groups of patients with and without ovarian failure. (X-square analyses were used for categorical data such ;IS radiation exposure and log-rank statistics were used to compare the

64 Stillman et al.

distrihtttions f’or continuous variates such as age and dt-fig doses.!’ A logistic. regression model was used to sitrtuIt;tneousl~ evaluate aekwal factors which could aftect the incidence of’ o\-arian tailure among itxtcliated patients.” Factors which were considered tar this analyis were owrian radiation exposure (categorized as in, at tlte edge of’. or outside of the field). t~umber of c.hemc)tjil.t-ilI~etiti( agzttts ;idministered, age at diag-ttosis. iltltl ve;tt-s of follo\v-up since diagnosis. Results I‘wenty-two of 18% patients ( 12%) had ovariatt t;iilure. J‘he nwatt LH level was 73..5 k 15 (SEM) tnIU/tnl while the l;SH level \\‘a\ l0Y.X ‘- 8.7 (SEM) mlU/ntl. Eighteen h~cl primary antenorrhea and f’ot~r had seton&t v ;~n~cnorrhca that developed during cancel. rherapy. All 22 patients with ovarian f~iilitre were antong the 0-l patients who had received abdominal radiot herap! (‘I‘able I). Ovarian failure did not develop itt 54 ;tlxton~itlal irradiation paGerits who hxf at least one oval-v oittsidc of the treatment field but did ocxxtt in five of 33 patients ( I-I’jT) with an ovary at the edge of the treatnienf Geld and in Ii of’ 2.5 patients (68%) with bottt ovat-ies lvithin the treatment field (p < 1W’). This tt-end ~iis itltlepentlent of’ chemotherapy. No 0vari;itt failure \~a$ ttoted atrtottg 88 patients ~.ho had ttot ivwived aMotrtinal irradiation. Patienrs with ovarian f’ailure did not dift‘er f‘ront the retnaincter of the patients with regard to mean age at di;tgttosis (7.0 _t I .O yea13 [SEMI versus 6.9 * O.-l) ant1 \e;irs of follo~v-up since diagnosis ( 13.9 ‘- 1.3 yeat-s [SEM] versus Ifi.8 t 0.5). Analysis of‘ the ;iverage C-IItnulatiw nrilligrant dosc~ of’ the six most f‘recfuentl\ crnplo~ed cheiiiotherapetltic agents revealed no consistent or signilicant tlit’fcrences hetweet the groups (‘I’alde II).

In addition, neither tumor type nor aurger\ bvithitt the ~ihtlonien was intlepentletttl~ associatetl \vith devvlc)pmrttt of‘ o\ariatI failiirc. .\Iultib2itiate analysis with the itse of logistic I-egt ~‘4. siott tiiodels was perfi~rnictl to assess the ittflttence of various factors on the o(utt~rence of ourian tailure. ‘l‘hc only significant association wax with ;rlxlontitt;tl t-adiotheraI~y. Among the itxidiated ptknts. thosr wlto had o\aries within tltv field 01 t-xiiatioti Itad ;t significant odds ratio of ovat-ian failut-c of 19.7 (!IXi; coitfidenw ittter\~al .i.!! to i2.X). Comment ‘l‘he incidence of’o\;it-ian failure M’;~s 1‘“/; ;tntcxig 182 long-term sur\:ivor~ of’ chilcihcd tttafigttancirs. :I strong association w15 tot~nd between 0v;iriatt tailurv attcl intensity of’ prior cnxrian t.adiatiott. \vitli S3!? ot. patients deniottstt-atittg ovarian tailure if tltw Iiatl ixceivrtl art\ abdotninal txdiotherap~ and (is!: cll)vriettc ittg ovarian failut-r if I hc c)urics wcrt‘ tktrt-rttinetl to be withitt the radiation field. .l’his associ,itiotl remained after covariate and ntultivariale. atialwes of several potentially confounding factors, including ;igc at diagnosis. years since diagnosis. abdoniin;tl skit-gci3, ciimdative drug dose, antI tttimber of c hentottt~r;ipetrtic agrtlts. .Aldotminal irradiation has been associated xvitlt O\;II ian l’~iilure.” Indeed, iotii/.inq t-adiation h:is bectt iitilized as ;I therapentic means of‘ terminating ovat-iatt fttrtc?iott.” \:er), few data. however, at’e ;~\zilahlc art ovarian fitnction after irradiation in children.” I II the present stud\. the ovat-ies wet-e categorizccf its king x\,ithitt the field 01’ t-adiorherapy, at the etlge of the Iield, or outside treatment fields. T‘ltc threr classe\ indic-ate ovarian irradiation generallv in doses of thousantls, hundreds. and tens of’ rads. respxti\ ?I\, A hi,yh

Ovarian failure affer childhood malignancy

Table II. Median cumulative chemotherapy doses administered malignancy, by radiation exposure and ovarian failure

I

Ouunun

mposure

to 182 female survivors to abdominal

65

of childhood

radiotherapy In or nt edge of field

Nom*

or out offield

(no ovanan

No. oj patuwt.,

~\‘a ovarian

failure)

DI-ug dosage Iq9

No. of patienls

failure

Ovarian

Dr-zig do.tagr f mg)

failurr

No. of putmr.t

Drug

docq-r

(WJ

.-lrtinomyc1nD: l‘otai

+

Single agent

47 29

4.1 4.3

22 15

3.6 4.4

9 7

7.2 6.8

26 12

1,665 ?,810

4 0

1.600

4 0

996 -

13 3

20,175 29.025

3 2

3,683 10,324

7 0

8,560 -

23 6

3.705 4.717

2 1

2,108 20

6 0

2,194

45

9 0

18

10 0

28

20

8 1

31 4

5 1

30 ,1

Chlornnbucil:

‘Ioral Single agent (,~vclopho.~phamlde.

‘Total Single agent Mrthotrrmtr:

Total Single agent I’tnrrittinr: Total Single agent ,Vi~rogm mustard: ‘I’otal Single agent

16 0

-

7 0

-

*No abdominal radiotherapy. tTotal number of patients receiving the drug as either a single agent or in combination

range of radiation exposure dose was found to be strongly correlated with ovarian failure. The finding suggests that less radiation exposure to the gonads would decrease the incidence of subsequent ovarian failure.‘” This can often be accomplished successfully by ovariopesy and lead shielding of the ovaries. *L I3 The techniques of ovarian displacement and shielding, while having no effect themselves on ovarian function,‘” can decrease gonadal irradiation by 80% to 90YC in individuals not undergoing whole pelvic or whole abdominal irradiation.i2 Frequent preservation of ovarian function and fertility have been described after ovariopexy when compared to patients undergoing similar cancer therapy without this ovarian reposition.i2 Gonadal dysfunction has been documented in adult women4 and in male subjects of all ages” after treatment with some chemotherapeutic agents, particularly alkylating agents. This study and other reportsi5. ifi indicate that chemotherapy in female children up to 17 years of age is not a major cause of ovarian failure. During the prepubertal period, the relative quiescence of ovarian stromal cells and oocytes may provide some protection against cytotoxic drugs with cell-cycle specitic activity. In addition, the larger number of oocvtes in children may permit survival of sufficient oocytes to preserve adequate ovarian function during

with other drugs.

early adulthood. Further study is needed to ascertain the frequency and risk factors for premature menopause, oligomenorrhea, nonlethal genetic damage to oocytes, and infertility associated with cancer treatment in childhood. Several factors in the development of ovarian failure could not be examined in the analysis. These include fractionation of radiation doses, time between multiple radiotherapy courses, and additive or synergistic effects of specific drugs. Although our results indicate no influence of chemotherapy, more intensive treatment regimens in current use may have greater effects on fertility and ovarian function. In conclusion, further improvements in treating female children with cancer must be found so that the reproductive and steroidogenic capacity of the ovaries is preserved while the malignancy is cured. According to findings presented in this study, special attention must be given to means of modifving gonadal radiation exposure. The need for this special attention grows as an increasing number of children who survive for a long term will present with late sequelae. such as ovarian failure. We wish to acknowledge William Fine.

the excellent

assistance of

66

Stillman

et al

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