CHEMOTHERAPY CAN BE USED SAFELY AFTER FIRST TRIMESTER OF PREGNANCY

A cancer diagnosis can be devastating, but is even more traumatic when the patient is pregnant. A new study offers some reassurance to pregnant patients and their physicians.
The results of the small study, presented during a presidential session here at the 2011 European Multidisciplinary Cancer Congress, show that children who were exposed to chemotherapy in utero did not appear to suffer any detrimental effects in terms of general health and neurologic and cardiac functioning.
Treating cancer in pregnant women is complex. One issue, in particular, is the ethics of treating a woman with chemotherapy, "but there are no good data that describe the ethics," said lead author Frederic Amant, MD, PhD, assistant professor, gynecologic oncologist, and head of the scientific section of gynecologic oncology at Katholieke Universiteit in Leuven, Belgium.
In Europe, there are approximately 2500 to 5000 cases of cancer diagnosed during pregnancy every year; however, it remains unclear how systemic chemotherapy affects the development of the fetus, he said.
This is a common situation, and one that many doctors face, said Michael Baumann, MD, PhD, a radiation oncologist from the University of Technology, Dresden, Germany, and president of the European CanCer Organisation. "That is why this study is so important," he said.
There are a lot of data related to radiotherapy and its use in pregnancy, said Dr. Baumann, who moderated a press briefing during which the highlights of this study were presented. " That there are now good data on chemotherapy.... This is a paradigm shift that we see here."
Neuro and Cardiac Function Normal
In their study, Dr. Amant and colleagues looked at the potential negative effects of in utero exposure to chemotherapy. Participants ranged in age from 18 months to 18 years. Of the 140 children currently in the study, complete data are available for 70.
The children were all evaluated at birth and approximately every 2 years after. Their general health was assessed, and they underwent neuropsychologic testing to assess intelligence, verbal and nonverbal memory, attention, working memory, and behavior.
The mean gestational age at cancer diagnosis was 18.1 weeks, and a total of 236 cycles of chemotherapy were given in the cohort.
About half of the women were diagnosed with breast cancer (51%), and 26% were diagnosed with hematologic cancers. Other diagnoses included cervical cancer, ovarian cancer, and malignancies of the brain, skin, and colorectum. Half of the patients (50%) received chemotherapy, and 38% underwent surgery and received chemotherapy. Treatment was given at a median gestational age of 17 weeks (range, 12 to 37 weeks).
The median gestational age of the children at birth was 35.7 weeks, and intrauterine growth retardation was observed in almost 21% of the children.
Cardiac function was evaluated by electrocardiography and echocardiography. It was necessary to assess for possible cardiac problems because the majority of these women were given anthracyclines, explained Dr. Amant. In breast and gynecologic cancers, "anthracyclines are very important. The majority of children — almost 80% — were exposed to anthracyclines, which can pass through the placenta, so it is very important to assess heart function."
The median follow-up was almost 2 years, although some were followed for up to 18 years.
At birth, no congenital heart defects were observed, and cardiac function was normal. Most of the children had adequate neurologic function and normal cardiac function, explained Dr. Amant; rates were similar to those seen in the general population.
High Rate of Premature Birth
Premature birth was very common in this population, with 47 of the 70 children born before 40 weeks of gestation (66%), and 7 born at 26 to 32 weeks.
Although cognitive development was in the normal range for the majority of the cohort, children who fell below the normal parameters tended to be premature. Because developmental delay is common in children who are premature, Dr. Amant explained, they are unable to tell if these issues are related to chemotherapy exposure.
"We can't exclude the effects of chemotherapy in preterm children," he told Medscape Medical News. "They do worse, we know that, but whether it's the prematurity or the chemotherapy — that is an unanswered question."
Because the majority of the children have done well, Dr. Amant surmised that the cognitive issues in those born premature are not related to the chemotherapy.
Normal findings were observed in 64 children (91.4%), which conforms to the general population.
Developmental Issues in Twins
Two serious problems emerged with a set of twins who were born at 32.5 weeks of gestation. The mother had been treated for leukemia. The male twin was autistic and had other serious neurodevelopmental delays and problems; the female twin also had some degree of neurodevelopmental delay.
Although prenatal exposure to chemotherapeutic agents cannot be completely ruled out, Dr. Amant feels that it was probably not the cause of the severe problems observed in the male twin. Geneticists who studied the data tend to think that the child had some sort of syndrome, he pointed out, which was not related to the chemotherapy. "But we can't rule it out right now," he said.
The high rate of prematurity seen in this study was not caused by chemotherapy, but was most likely related to the strategy of delivering the baby as soon as it becomes viable and then beginning chemotherapy, explained Dr. Amant.
Chemotherapy Should Not Be Feared
"Our message is that we prefer to give chemotherapy until the baby is mature; after the baby is delivered, we continue maternal treatment," said Dr. Amant. "The baby loses 2.5 IQ points for each week that he or she is delivered early."
"We think that the baby has less trauma from chemotherapy than from prematurity," he explained. "In our setting, this changes how we treat patients."
This is not a perfect study, Dr. Amant acknowledged; it was both retrospective and prospective, and had a relatively short follow-up.
"But we think that the fear of chemotherapy should no longer be an indication to terminate a pregnancy, and it should no longer be a reason to delay maternal treatment, which can affect maternal prognosis," Dr. Amant explained.
More Data Needed
"We are quite confident that these children will continue to perform normally, but we need more follow-up and more children," he said. "Right now, the group is too small to make a statement on clinical practice change."
George Pentheroudakis, MD, PhD, who acted as discussant for the paper, agrees that a longer follow-up is needed.
Although the study showed that chemotherapy can be administered with reasonable safety after the first trimester of pregnancy, there are still a number of unanswered questions, noted Dr. Pentheroudakis, who is from the University of Ioannina, Greece.
There are a few children in the study with severe neurocognitive deficits, he pointed out, noting that more careful interpretation of the results is needed. In addition, the "course of these deficits over time" need to be determined.
Undetected cardiac toxicity is a potential problem for these children. Although the electrocardiogram and echocardiogram are good tools, they might not be sensitive enough for the early detection of subclinical cardiac damage, he said.
Also, there was a high incidence of prematurity in the cohort. "What are the causes of prematurity," he wondered. "Is it maternal age, the presence of cancer,...or the cancer treatment that was administered?
Much is still unknown about the long-term effects of chemotherapy exposure, said Dr. Pentheroudakis. "We don't know about fertility or germ cell mutagenesis in the children and their future offspring. More data are needed."
For now, on the basis of these data, the fear of chemotherapy is not a reason to delay treatment that can affect maternal prognosis, he said. "It seems that chemotherapy can be administered with reasonable safety after the first trimester, and there is emerging evidence that the mid- and long-term health of these children is normal."