Introduction

Antonio C. Wolff, MD Sidney Kimmel Comphrensive Cancer Center at Johns Hopkins

April 2011 issue: While breast cancer is relatively uncommon in young adults, women increasingly delay pregnancy and childbirth into their fourth decade of life, and sometimes into their 40s. Consequently, we have seen and expect to continue to see an increase in the frequency of breast cancer diagnosed during pregnancy. Much of the available data on disease management and maternal/child outcomes are retrospective, anecdotal, and/or self-reported to various registries. Still, a consistent pattern has emerged over the years, i.e., a coordinated and experienced multidisciplinary health care team is critical to ensure the most optimal outcome for mother and child.

In this column, Dr. Jennifer Litton and Dr. Michael Perry write brief commentaries identifying some of the challenges imposed by this clinical scenario. Despite the limitations in our knowledge, a consistent pattern emerges: breast cancer outcome appears similar to that observed in nonpregnant patients with breast cancer; pregnancy termination is rarely needed; and most children appear to be doing well long-term, with only a small number born with congenital malformation or requiring special-needs care. While hopeful and optimistic, these data must be viewed with some caution in view of the ascertainment bias inherit to their method of collection.

We now know that optimal evaluation of breast masses and staging are possible with an emphasis on imaging studies that limit or avoid radiation exposure such as ultrasound and magnetic resonance imaging, and that surgical intervention for diagnosis and treatment is safe in most cases despite limited data on the use of sentinel node technique during pregnancy. If appropriate, preoperative or postoperative chemotherapy with agents like cyclophosphamide, doxorubicin, and 5-fluorouracil is feasible during pregnancy, while the use of taxanes, trastuzumab, colony-stimulating factors, and radiation therapy should preferentially be delayed until after delivery. A more challenging clinical scenario is the less-common occurrence of pregnancy in women with metastatic disease; decisions about pregnancy termination are difficult, very personal, and must take into account the mother’s safety.

Obstetricians, primary care, and cancer care providers should expect to meet this clinical scenario with increasing frequency. For the sake of our patients and their families, we must all be prepared to act in a coordinated fashion.

Dr. Wolff is an Associate Professor of Oncology in the Breast Cancer Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. Dr. Wolff is a member of the Journal of Clinical Oncology and ASCO Connection Editorial Boards, Co-Chair of the ASCO-CAP HER-2 and Hormone Receptor Testing in Breast Cancer Panels, past Chair of the ASCO Clinical Practice Guidelines Committee, and an ASCO Statesman Award recipient.

Breast Cancer and Pregnancy

Jennifer K. Litton, MD The University of Texas M. D. Anderson Cancer Center

Treating a pregnant patient with breast cancer is a challenging and emotional situation for both the patient and the health care provider. Health care providers have often felt that in order to treat the mother appropriately, they had to recommended pregnancy termination. However, over the past several years, emerging data from case series and cooperation between cancer treatment centers have demonstrated experience in treating pregnant patients with breast cancer optimally while maintaining a viable pregnancy and delivering a healthy infant.^1-3 This has led to multiple publications and expert opinions regarding the care of these patients.

The data that are available, due to the nature of this situation, can never be level I evidence. We will never randomize patients to becoming pregnant during breast cancer or not. Therefore, sharing experience and outcomes in this clinical situation is paramount. As women increasingly are delaying childbearing, the incidence of breast cancer diagnosed during pregnancy is rising, and oncologists are expected to face this situation with increasing frequency in the future.4 The oncologist must effectively counsel each patient as to her individual risk of recurrence, survival, and toxicity in order to help support her decision regarding her pregnancy.

The patient
Mounting evidence has demonstrated that treating the mother in the second trimester with an anthracycline-based regimen can be both effective and safe.^1,5 Additionally, there is building evidence (with now at least 40 reports in the literature) of taxanes being given safely during pregnancy.⁶ Older methotrexate-containing regimens, such as cyclophosphamide/methotrexate/fluorouracil (CMF), should be avoided, as methotrexate is a known abortifacient. Biologicals, such as trastuzumab, have recently been deemed unsafe during pregnancy by the FDA.

Much of the older data and case series that demonstrated worse outcomes for the pregnant patient with breast cancer did not specify the treatments used or extent of delays of initiation of therapy. More recent case series detailing treatment during pregnancy have shown outcomes similar to nonpregnant patients.^7-9

Assembling a multidisciplinary team that can effectively communicate throughout the treatment is essential to providing optimal care for the patient while monitoring the progress of the fetus. Several publications have outlined treatment plans, which include involving the medical oncologist, surgeon, radiation oncologist, and maternal-fetal specialist.^10-11

At our institution, prior to each dose of chemotherapy administered, an ultrasound to evaluate fetal growth, fluid, and placental integrity is completed. We also use ultrasound to evaluate the tumor response to preoperative chemotherapy regimens. Radiation can be given in a timely fashion after the completion of chemotherapy, surgery, and delivery of the fetus.

The child
The long-term data of the children exposed to chemotherapy in utero are accumulating. Few prospectively collected data regarding the children exist. However, there are now multiple self-reporting registries emerging.^1,12-13 To date, there is growing evidence that when anthracycline chemotherapy is given to patients after the first trimester, there is no increase in birth defects.

At this point, there are no specific recommendations for follow-up health care for these children. These registries and cohorts will need to be continually followed over the next several decades, as the children become adults and have children of their own. The collaboration between institutions to provide this information is ongoing and necessary.

Although there is no—and will never be—level I evidence in this challenging clinical situation, the mounting data reported show efficacy and safety when treating women during pregnancy with chemotherapy and surgery. Not offering treatment during pregnancy has the potential of causing significant harm to the patient, and thus the fetus, as delay of therapy may cause further tumor spread both locally and distally, decreasing the overall chance for cure.

Jennifer K. Litton, MD, is an Assistant Professor in the Department of Breast Medical Oncology at The University of Texas M. D. Anderson Cancer Center. Her research interests include pregnancy and breast cancer, genetic testing, the treatment of young patients with breast cancer, and oncofertility.

References

1. Hahn KM, Johnson PH, Gordon N, et al. Cancer. 2006;107:1219-26.
2. Loibl S, von Minckwitz G, Gwyn K, et al. Cancer. 2006;106:237-46.
3. Van Calsteren K, Heyns L, De Smet F, et al. J Clin Oncol. 2010;28:683-9.
4. Andersson TM, Johansson AL, Hsieh CC, et al. Obstet Gynecol. 2009;114:568-72.
5. Mir O, Berveiller P, Rouzier R, et al. Ann Oncol. 2008;19:1814-5.
6. Mir O, Berveiller P, Goffinet F, et al. Ann Oncol. 2010;21:425-6.
7. Beadle BM, Woodward WA, Middleton LP, et al. Cancer. 2009;115:1174-84.
8. Murphy C, Mallam D, Stein S, et al. J Clin Oncol. 2010;28:15s (suppl; abstr 1589).
9. Litton JK, Warneke CL, Hahn K, et al. Proc Breast Cancer Symp. 2010; abstr 105.
10. Amant F, Deckers S, Van Calsteren K, et al. Eur J Cancer. 2010;46:3158-68.
11. Litton JK, Theriault RL. Oncologist. 2010;15:1238-47.
12. Cardonick E, Dougherty R, Grana G, et al. Cancer J. 2010;16:76-82.
13. Avilés A, Neri N. Clin Lymphoma. 2001;2:173-7.

Chemotherapy in Pregnancy

Michael C. Perry, MD, MACP Ellis Fischel Cancer Center, University of Missouri School of Medicine

The frequency of cancer in women of childbearing age is fortunately uncommon; nevertheless, the simultaneous occurrence is an extraordinarily difficult situation for the patient, her family, and the physician, requiring enough face-to-face discussion to ensure that everyone understands all the issues and is as comfortable with the options as possible. Cancer is the leading cause of death in childbearing women, with the most common malignancies being breast, cervix, ovary, leukemia, lymphoma, melanoma, and thyroid.

After a histologic diagnosis has been confirmed, a modified staging approach is used, avoiding ionizing radiation in favor of ultrasound. This may, of necessity, result in understaging. An accurate estimation of the due date is critical as some malignancies can be reasonably predicted to pursue a slower course, with therapy delayed until after birth.

Pharmacokinetic factors
If therapy is considered to be necessary, then pregnancy-associated physiologic changes may change drug pharmacokinetics and require alternate dosing and schedules. The expected increase in cardiac output and plasma volume increases plasma flow and glomerular filtration rate. This, in turn, results in a lowering of the serum creatinine, and pregnancy may amplify the renal excretion of chemotherapeutic agents. The expected increase in total body water and plasma volume can increase the distribution volume for water-soluble drugs, decreasing peak drug concentrations and prolonging half lives. Amniotic fluid also serves as a pharmacologic third space for drugs such as methotrexate, delaying elimination and increasing toxicity.

Pregnancy may also be associated with increased serum levels of certain proteins that may affect plasma concentration and distribution of drugs with low lipid solubility and increased affinity for plasma proteins. An enhancement in hepatic blood flow and hepatic oxidation may occur, which, along with the increased renal excretion, may result in increased drug clearance from the body. A decrease in gastrointestinal motility can affect oral drug distribution, especially late in pregnancy. Other changes include placental transfer, changes in fetal pharmacokinetics, and placental excretion.

Risk factors
Chemotherapy drugs administered in the first week after conception probably produce an “all or nothing” effect—a spontaneous abortion or a normal fetus. In the second and third trimesters, drugs may impair fetal growth and development. Neuronal growth in the brain continues during this period with possible microcephaly, mental retardation, and impaired learning.

Risk factors have been assigned to all drugs based upon the level of risk a drug poses to the fetus during pregnancy. These categories are A, B, C, D, and X. Multiple factors influence the probability of teratogenesis: timing of exposure, dose, frequency of administration, and duration of exposure, as well as individual and genetic susceptibility.

This brief review does not permit a separate listing of each drug, but the antimetabolites are particularly devastating when given in the first trimester, with less deleterious effects from alkylating agents.

To summarize: in the setting of a malignancy in a pregnant woman, a firm diagnosis is required, with a reasonable attempt at staging without ionizing radiation, then a long, thoughtful discussion with the patient about her wishes and possibilities. Knowledge of the physiological changes that accompany pregnancy is critical and the choice of drugs essential.

Michael C. Perry, MD, MACP, is Deputy Director of the Ellis Fischel Cancer Center, where he is Chair of the Scientific Peer Review Committee, as well as the Nellie B. Smith Chair of Oncology. He is also Director of the Division of Hematology and Medical Oncology at the University of Missouri. A past member of ASCO’s Board of Directors, Dr. Perry currently serves on the FDA Oncology Drug Advisory Committee.

Reference

1. Hartley MS, and Doll DC. “Chemotherapy in Pregnancy.” The Chemotherapy Sourcebook 5th edition. Michael C. Perry, ed. Philadelphia: Lippincott Williams & Wilkins, 2011.

Current Controversies in Oncology is a forum for the exchange of views on topical issues in the field of oncology. The views and opinions expressed therein are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology.