Cancer Treatment Should Not Be Delayed During Pregnancy

Roxanne Nelson

September 28, 2015

VIENNA ― Children with prenatal exposure to cancer and the associated imaging and therapies appear to have normal development at 18 months and 36 months, according to new data presented here at European Cancer Congress (ECC) 2015.

Specifically, chemotherapy did not have any clear adverse effects on growth in the postnatal period or on cognitive or cardiac function.

A total of 129 children from Belgium, the Netherlands, Italy, and the Czech Republic were included in the study and were matched with a control group that was unaffected by maternal cancer during the prenatal period.

There were no significant differences in the mental and physical development of the treatment group and the control group. The number of chemotherapy cycles during pregnancy, which ranged from one to 10, appeared to be unrelated to outcomes.

"Our results show that fear of cancer treatment is no reason to terminate a pregnancy, that maternal treatment should not be delayed, and that chemotherapy can be given," said lead author Frederic Amant, MD, gynecologic oncologist at the University Hospitals Leuven, Belgium, and the Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

Dr Frederic Amant

"The study also shows that children suffer more from prematurity than from chemotherapy, so avoiding prematurity is more important than avoiding chemotherapy," Dr Amant added.

The findings were published simultaneously in the New England Journal of Medicine to coincide with the meeting.

In Belgium, where this study has been running for the past 10 years, there has been a paradigm shift, Dr Amant noted. "Oncologists are now treating cancer in pregnant women ― we hope that this solid research now in the NEJM will influence oncologists around the world and reassure them that it is safe to treat cancer in pregnancy."

He believes that at present there is still concern about this and that pregnancies are being terminated or treatment is being delayed because of these concerns. "We hope that this paper will help to bring about a practice change," he said.

Premature birth was more common among cancer patients, whether or not they had been treated for their cancer, as compared with the general population in the countries participating in the study.

Preterm delivery, defined as delivery before 37 weeks' gestation, was usually the result of a medical decision to induce labor so that cancer treatment could be continued, Dr Amant explained.

"In some cases, preterm delivery was spontaneous, and it is possible that cancer treatment plays a role in this," he said.

Confirms Previous Data

As previously reported by Medscape Medical News, Dr Amant and his group have been studying the effects of prenatal exposure to chemotherapy for several years. Data presented in 2011 suggested that fetal exposure to cancer treatment was not associated with cognitive or cardiac abnormalities.

Last year, at the European Society for Medical Oncology Congress 2014, Dr Amant presented results of a case-control study on the developmental outcome of children exposed to chemotherapy in utero. Again, that study showed that chemotherapy does not adversely affect mental development or cardiac functioning.

However, in discussing the article, Hatem A. Azim, Jr, MD, from the Jules Bordet Institute in Brussels, Belgium, cautioned against the use of chemotherapy during the first trimester. "We can usually wait until the second trimester," he said at the meeting.

Dr Azim noted that "abortion should not be considered except in cases of aggressive disease diagnosed very early in the pregnancy," and that "premature delivery should be avoided unless complications require early induction of labor."

Control Group Added

The current study differs from previous research. Dr Amant pointed out that the combined retrospective and prospective designs from earlier studies limited the interpretation of the results, because the findings reflected results from different tests that were conducted at different ages (16.8 months to 17.6 years of age) and were then pooled together.

"In the previous study, we didn't have a control group, and we included children aged 18 months to 18 years," he said.

In the current study, they enlarged the prospective cohort so that it included only children aged 12 to 42 months. They then evaluated general health status, growth, cognitive development, and cardiac structure and function. These findings were then compared with those for children in a matched control group.

A total of 129 children (median age, 22 months; range, 12 - 42 months) were included in the group whose mothers had cancer (prenatal-exposure group) with a matching number in the control group. The children with prenatal exposure included four pairs of twins. The patients were from Belgium, the Netherlands, Italy, and the Czech Republic.

Children in the prenatal-exposure group were born at a median gestational age of 36 weeks (range, 27 - 41 weeks). A total of 79 children (61.2%) were born preterm, which is a higher than the 6.8% to 8.0% seen in the general population in the participating countries.

During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment at all.

To evaluate outcomes, the children underwent clinical examinations, and a health questionnaire was given to parents. The children were prospectively assessed with a neurologic examination and the Bayley Scales of Infant Development at 18 months, 36 months, or both. A cardiac assessment was performed at 36 months.

Children who were small for their gestational age were more frequently born to mothers with cancer during pregnancy, as compared with the control children. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P = .16).

The investigators also found that there were no significant differences between the two groups in cognitive development, determined on the basis of the Bayley score (P = .08) or on subgroup analyses. In both groups, the median average score was 101 (range, 56-145) in the children exposed to cancer treatment and 50-145 in the unexposed children.

For those exposed to chemotherapy, the median average score was 100, as compared with 99.5 for the control patients. Children exposed to radiotherapy scored an average of 102 vs 105; to surgery alone, 111 vs 102; and to no treatment, 105 vs 97.5.

The gestational age at birth was correlated with the cognitive outcome in both groups of children. There were no differences with regard to the type of chemotherapy administered (anthracyclines, taxanes, and platinum derivatives).

Cognitive outcomes on the Bayley II scale were not related to the number of chemotherapy cycles (r = 0.126; P = .24) or to the estimated fetal dose of radiation (r = 0.110; P = .75).

However, of note, the authors observed that scores tended to increase by an average of 2.2 points for every week in gestational age after controlling for confounders such as age, sex, country, ethnicity, and parental education level. Thus, delays in cognitive development appeared to be related to premature birth, Dr Amant noted.

Cardiac function was assessed in 50 of 54 children in the prenatal-exposure group at age 36 months with the use of electrocardiography and echocardiography; 47 children were included in the analysis. As compared with the control children, there were no significant between-group differences in age, body-surface area, heart rate, or blood pressure.

Results of the echocardiographic examination showed no structural abnormalities in any of the children.

Encouraging News

In an accompanying editorial, Michael F. Greene, MD, from Massachusetts General Hospital, in Boston, and Dan L. Longo, MD, from the Dana Farber Cancer Institute, also in Boston, state that these data should be reassuring to women who are facing a new diagnosis of cancer while they are pregnant.

"Most important, although these women are more likely to deliver prematurely than are women without cancer, the cognitive development of their offspring will be similar to that of children of the same gestational age who were not exposed to maternal cancer and chemotherapy," they comment.

The editorialists caution that prudence suggests avoiding cancer treatment during the first trimester, but treatment during the second and third trimesters is likely to be best for both mothers and their offspring.

Dr Amant agrees that some caution is warranted. The study has limitations, including limitations with regard to the guarantee that all types of chemotherapy are safe. He noted that they also need to look at larger numbers of children as well as greater numbers of children exposed to each individual drug to better document the potential effects of each agent.

In addition, the data cannot be extrapolated to newer drugs, including targeted therapies, and longer follow-up is needed to assess whether there are any long-term toxic effects in cases in which cisplatin was administered before birth.

The study was supported by Research Foundation–Flanders (a clinical investigator grant to Dr Amant and fellowships to two colleagues), Stichting tegen Kanker, Belgian Cancer Plan (Ministry of Health), and KU Leuven; and by a clinical research grant from the University Hospitals Leuven (to Dr Van Calsteren). Dr Amant has disclosed no significant financial relationships. Dr Greene is an associate editor at the New England Journal of Medicine. Dr Longo is employed by the New England Journal of Medicine as deputy editor.

N Engl J Med. Published online September 28, 2015. Full text, Editorial

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