There is good news for the approximately 4,000 women estimated to be diagnosed in the United States with lymphoma during pregnancy: A large study (available online ahead of print in the Journal of Clinical Oncology [doi: 10.1200/JCO.2013.49.8220]) has now documented that standard, non-antimetabolite combination chemotherapy administered past the first trimester leads to few complications.
Lymphoma is the fourth most frequent cancer that occurs during pregnancy, with Hodgkin lymphoma (HL) more common that non-Hodgkin lymphoma (NHL).
“Prior to this paper, most publications regarding the occurrence of lymphoma during pregnancy had consisted mainly of case reports or small cases series,” lead author Andrew M. Evens, DO, MSc, Professor of Medicine and Chief of the Division of Hematology/Oncology at Tufts University School of Medicine, said in an interview.
“This is the largest study to date of pregnancy occurring in lymphoma. It provides detailed information on patients that were diagnosed during pregnancy with HL or NHL, and shows that treatment with standard lymphoma therapies—including rituximab and/or non-metabolite combination chemotherapy—beginning as early as 13 weeks—that is, the start of the second trimester—appears to be safe for the fetus and mother.
“Additionally, outcomes for the mothers appeared to be consistent with usual/expected survival rates for the particular lymphoma subtype that was diagnosed.”
Asked for a comment for this article, Jonathan W. Friedberg, MD, the Samuel Durand Professor of Medicine and Oncology at the University of Rochester, N.Y., said, “This presentation of lymphoma is fortunately an uncommon situation. In the past, therapeutic abortion was considered in certain circumstances. This new data should reassure physicians and patients that treatment during pregnancy is effective, and results in minimal maternal fetal complications.”
The study was a multicenter collaboration that examined a cohort of 90 patients with an established diagnosis of lymphoma during pregnancy—50 with NHL and 40 with HL. About two-thirds of the patients received antenatal therapy, mostly combination chemotherapy.
The researchers examined detailed maternal and fetal characteristics, paying close attention, Evens noted, to therapy received in the antenatal period, preterm and perinatal complications, and potential disease and treatment-related prognostic factors that predicted maternal survival.
The patients' median age was 30, and their median time at diagnosis occurred at 24 weeks gestation. Advanced-stage disease was noted in about half of the NHL patients and one-quarter of the HL patients.
“A likely contributing factor to these low rates of advanced-stage disease was the absence of functional imaging as well as less frequent use of other commonly used staging modalities, such as bone marrow biopsy,” Evens said.
Despite the nonstandard and suboptimal staging performed, the researchers identified a high rate of extranodal involvement in patients with NHL in several atypical sites, such as the vagina and ovary. This may relate to increased blood flow to the reproductive organs during gestation, or possibly be due to expression of gestational hormone receptors, he explained.
Pregnancy was terminated in six patients. Among the other 84, one-third had therapy deferred to postpartum. These patients were diagnosed at a median 30 weeks gestation. In comparison, two-thirds of the patients received antenatal therapy with median lymphoma diagnosis at 21 weeks. Nearly all (89%) of these patients received combination chemotherapy, with the most common regimens being standard for the particular lymphoma subtype, he said.
“The decision to use chemotherapy during gestation is an individualized decision by the patient and the provider. The particular clinical scenario, including the type of lymphoma and the timing in gestation when the diagnosis occurs, will greatly inform this decision. If a patient is diagnosed late in the pregnancy—beyond 33 to 34 weeks—and/or has an indolent lymphoma or HL with very low tumor burden, then treatment may be deferred until post-partum.
“If, however, the patient is diagnosed earlier in the pregnancy, especially if the diagnosis is an aggressive NHL subtype, initiation of standard, systemic, non-anti-metabolite therapy, such as rituximab-CHOP, should not be delayed. In this latter scenario, standard therapy should be given with curative intent.”
The treatment approaches used by the researchers were heterogeneous, “although a consistent finding for all patients was the use of antenatal therapy for patients diagnosed earlier in gestation,” he said.
The median gestational age at diagnosis of lymphoma for patients who received antenatal therapy was 22 weeks.
A concern regarding use of antenatal chemotherapy is the risk of perinatal complications for the fetus and the mother. The most common preterm complication was induction of labor in one-third of patients.
“Interestingly, there were no differences in maternal complications, perinatal events, or median infant birth weight based on deferred versus antenatal therapy,” Evens said. “This is consistent with recent data in pregnant patients with breast cancer.”
The miscarriage rate identified was about one percent, which is consistent with other cancer-related pregnancy data, he noted.
Timing of Delivery
A critical aspect in the management of cancer during pregnancy is timing of delivery, Evens said. Gestation went to full term in more than half of the patients, with delivery occurring at a median of 37 weeks. “The general goal in all cancer-associated gestations should be to continue the pregnancy to full term. This is critical for appropriate fetal development.”
The data also support prior findings that antenatal chemotherapy with standard regimens (non-antimetabolite) during the second or third trimester does not appear to increase morbidity or mortality for the fetus. This includes in utero anthracyline exposure, which has been shown to not adversely affect maternal or fetal cardiac function, he said.
There were no increased rates of congenital malformations, which is also consistent with prior data. Evens pointed out that none of the patients received antenatal therapy during the first trimester.
At 41 months, three-year progression-free survival (PFS) and overall survival (OS) for the women with NHL were 53 and 82 percent, respectively, and 85 and 97 percent, respectively, for those with HL.
There were eight deaths related to NHL, including five patients with diffuse large B-cell lymphoma, one with peripheral T-cell lymphoma not otherwise specified, one with Burkitt's lymphoma, and one with “double-hit” NHL. Three of these eight patients had received antenatal chemotherapy, and the other four had therapy deferred to postpartum.
There is a paucity of available data assessing potential prognostic factors for survival of patients diagnosed with lymphoma during pregnancy, Evens said. On univariate analysis for NHL, radiotherapy was found to predict inferior PFS, and increased lactate dehydrogenase and poor Eastern Cooperative Oncology Group performance status (ECOG PS) portended worse OS.
“This may in part reflect prompt diagnosis and initiation of therapy, if indicated,” Evens said. For HL patients, nulliparous status and “B” symptoms predicted inferior PFS—an “interesting finding,” he said, that may be related to hormonal alterations. There were no factors in Hodgkin lymphoma that predicted OS.
In NHL, receiving radiotherapy had an adverse impact on progression-free survival, which is likely a reflection of the systemic nature of most aggressive NHL subtypes that were included in this series, Evens said.
“Although the adverse impact of radiotherapy on PFS did not translate to an OS disadvantage, if treatment is considered in NHL, chemotherapy should likely be the first choice,” he said. “In contrast, for HL, there are data showing that in select patients—for example, those with supradiaphragmatic disease—radiotherapy may be successfully used during pregnancy with careful shielding of the fetus.”
Evens noted that patients with low-risk clinical scenarios—i.e., indolent NHL, low tumor burden, and/or late gestational diagnosis—had therapy safely deferred to postpartum. He underscored that there should be close collaboration with the “high-risk” maternal-fetal medicine department throughout the pregnancy—“This is regarding use of all therapy, including supportive care medications, and for appropriate timing of delivery, especially if the patient is undergoing chemotherapy.”
Friedberg, who is also Director of the James P. Wilmot Cancer Center, noted that the study “represents one of the largest multicenter experiences of outcomes for pregnant patients treated for lymphoma in the modern era. There are obviously no randomized trials in this area, and much of the literature is anecdotal. This study has the advantage of multicenter experience, with a relatively large number of patients.”
He said that in his interpretation of the study, “standard prognostic factors for the appropriate disease should definitely be considered.
“Patients should receive treatment based upon the disease characteristics, and time to term. In all cases, consultation with a maternal fetal medicine specialist should be included in the decision-making process. The important message from this data is that patients can be safely treated before giving birth, without obvious adverse outcomes to either mother or fetus.”