Critical appraisal:Chow EJ, Stratton KL, Leisenring WM, Oeffinger KC, Sklar CA, Donaldson SS, et al 2016

Critical Appraisal

Article being appraised

Chow EJ, Stratton KL, Leisenring WM, Oeffinger KC, Sklar CA, Donaldson SS, et al. Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 2016 May;17(5):567-76 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27020005.

Applicable clinical question

Are cancer survivors who received cancer treatment less likely than the general population to conceive or give birth after treatment?

Key Facts

Study Design

cohort study

Study aims:

To establish the effects of contemporary chemotherapeutic drugs on pregnancy in male and female survivors of childhood cancer not exposed to pelvic or cranial radiotherapy.

Number of Patients:

10,938

Included individuals in the Childhood Cancer Survivorship Study who were diagnosed before age 21 years with the most common types of childhood cancer (all leukaemia types, CNS tumour, lymphoma, kidney tumour, neuroblastoma, soft-tissue sarcoma, and bone tumour) and treated at 27 institutions in the USA and Canada between 1970 and 1999, and who survived at least 5 years after diagnosis. To be consistent with national birth data and previous CCSS reports, authors restricted the present analysis to pregnancies and livebirths occurring between ages 15 years and 44 years in individuals who had not received radiotherapy to the pelvis or the brain. Authors also excluded individuals exposed to high-dose scatter radiation to the pelvis and brain. Authors included a random sample of siblings of survivors treated from 1970 to 1986 as a comparison group (in which a randomly selected subset of survivors were asked to identify all their living siblings, from which the sibling closest in age to the survivor was selected and asked to participate); reproductive outcomes for siblings of survivors treated from 1987 to 1999 were not available.

Reported outcome(s):

Proportion of livebirth at 8 and 10 years follow up
Hazard ratio comparision between survivors and siblings for males and females
Harard ratio for particular chemotherapeutic agents.

Results of outcome(s):

After a median follow-up of 8 years (IQR 4–12) from cohort entry or at age 15 years, whichever was later, 4149 (38%) survivors reported having or siring a pregnancy, of whom 3453 (83%) individuals reported at least one livebirth. After a median follow-up of 10 years (IQR 6–15), 2445 (62%) siblings reported having or siring a pregnancy, of whom 2201 (90%) individuals reported at least one livebirth. In multivariable analysis, survivors had a decreased likelihood of siring or having a pregnancy versus siblings (male survivors: hazard ratio [HR] 0·63, 95% CI 0·58–0·68; p<0·0001; female survivors: 0·87, 0·81–0·94; p<0·0001) or of having a livebirth (male survivors: 0·63, 0·58–0·69; p<0·0001; female survivors: 0·82, 0·76–0·89; p<0·0001). In male survivors, reduced likelihood of pregnancy was associated with upper tertile doses of cyclophosphamide (HR 0·60, 95% CI 0·51–0·71; p<0·0001), ifosfamide (0·42, 0·23–0·79; p=0·0069), procarbazine (0·30, 0·20–0·46; p<0·0001) and cisplatin (0·56, 0·39–0·82; p=0·0023). Cyclophosphamide equivalent dose in male survivors was significantly associated with a decreased likelihood of siring a pregnancy (per 5000 mg/m2 increments: HR 0·82, 95% CI 0·79–0·86; p<0·0001). However, in female survivors, only busulfan (<450 mg/m2 HR 0·22, 95% CI 0·06–0·79; p=0·020; ≥450 mg/m2 0·14, 0·03–0·55; p=0·0051) and doses of lomustine equal to or greater than 411 mg/m2 (0·41, 0·17–0·98; p=0·046) were significantly associated with reduced pregnancy; cyclophosphamide equivalent dose was associated with risk only at the highest doses in analyses categorised by quartile (upper quartile vs no exposure: HR 0·85, 95% CI 0·74–0·98; p=0·023). Results for livebirth were similar to those for pregnancy.

Comments on results:

Alkalating drugs and cisplatin were associated with decreased likelihood of male survivors siring pregnancy. Female survivors treated with chemotherapy without radiotherapy to pelvis or brain had few effects on pregnancy. Authors still caution fertility preservation before cancer treatment is important to maximize reproductive potential.

Includes an economic evaluation

no