Cancer treatment during pregnancy ‘a constant balancing act’

Cancer during pregnancy traditionally has been a rare phenomenon.

Through the last third of the 20th century, about 1 in 1,000 pregnant women developed a malignancy, according to French researchers.

However, a paper by Lee and colleagues published in BJOG: An International Journal of Obstetrics and Gynaecology revealed a startling trend. Results of the population-based study, designed to assess pregnancy-associated cancers in Australia, suggested incidence increased by nearly 70% between 1994 and 2008.

Some experts suggest an increase in pregnancy-associated cancers is inevitable because a higher percentage of women are waiting until they are older to have children. Yet, Lee and colleagues determined only 14% of cancers diagnosed during the 14-year study period were due to increased maternal age.

More frequent interaction with health services during pregnancy, as well as improved diagnostic techniques, likely increased the rate of detection, Lee and colleagues concluded.

“[Also], although the genetic and environmental origins of pregnancy-associated cancers are likely to pre-date the pregnancy, … the hormones and growth factors necessary for fetal growth may accelerate tumor growth,” the researchers wrote.

The detection of cancer during pregnancy creates formidable challenges.

A clinician’s ultimate responsibility is to the mother, according to Blase N. Polite, MD, MPP, assistant professor of medicine at the University of Chicago and a HemOnc Today Editorial Board member.

“At the same time, you cannot ignore the life of the baby, both on the emotional level as well as from the ethical perspective,” Polite said in an interview. “Sometimes these two things contradict each other. This requires a constant balancing act through the course of treatment.”

HemOnc Today spoke with several physicians about the complexities associated with cancer diagnosis and treatment during pregnancy, as well as the evolution of treatment guidelines for this patient population.

Difficulty of diagnosis

In the Australian study, Lee and colleagues determined the incidence of pregnancy-associated cancers increased from 112.3 per 100,000 maternities in 1994 to 191.5 per 100,000 in 2007 (P<.001). One-third (33.3%) of malignancies diagnosed during the study period were melanomas, and about one-fifth (21%) were breast cancers.

The increased incidence was particularly apparent among women aged 15 to 44 years.

Overall incidence of pregnancy-associated cancer in that cohort was 49% higher than what would have been expected based on rates in the general population. Ratios of observed-to-expected rates in that age group were 2.22 (95% CI, 2.05-2.41) for melanoma, 1.54 (95% CI, 1.35-1.75) for thyroid and other endocrine cancers, 1.36 (95% CI, 1.15-1.59) for lymphohematopoietic cancers, 1.23 (95% CI, 1.11-1.36) for breast cancer and 1.2 (95% CI, 1.03-1.38) for gynecologic cancers.

Maternal age ≥40 years had the highest adjusted odds ratio (HR=4.34; 95% CI, 3.57-5.29), but that only explained 7.3% of cancers diagnosed during the study period, researchers wrote.

The first challenge related to pregnancy-associated cancer is diagnosis, according to Don S. Dizon, MD, director of the Oncology Sexual Health Clinic at Massachusetts General Hospital Cancer Center.

“The female body goes through considerable physical changes during pregnancy,” Dizon told HemOnc Today. “Sometimes it can be difficult to distinguish something that occurs normally during pregnancy from something that is suspicious or abnormal.”

For example, as pregnant women develop milk ducts for breast feeding, breasts often become heavy with extra fluid. They can double in size, making it difficult to detect small lumps, and fears about how imaging scans may affect the baby’s development may limit diagnostic options.

Malignant melanoma is another example. Pregnant women often develop moles, and they can darken during gestation. Mischaracterization can cause diagnostic delay and have potentially deadly consequences.

“Sometimes, a physician cannot conceive the possibility of cancer occurring during pregnancy,” Fedro Alessandro Peccatori, MD, PhD, director of the Fertility and Procreation Unit at the European Institute of Oncology. “There is a real cognitive gap — [a belief that] the good and the evil cannot go together.”

Treatment consistency

Breast cancer is the most common malignancy diagnosed during pregnancy, according to the American Cancer Society.

It traditionally has been detected in about 1 in every 3,000 pregnant women. However, incidence appears to be increasing as more women delay childbearing, according to a literature review by Litton and colleagues.

“The greatest risk for breast cancer is age. As women age, the risk for breast cancer will go up regardless of other features,” Erica L. Mayer, MD, MPH, assistant professor of medicine at Harvard Medical School and senior physician in the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, told HemOnc Today. “To date, there have been no other risk factors or other exposures that are thought to be contributing to changes in the incidence of breast cancer during pregnancy.”

Women who become pregnant while young and have many pregnancies may be at lower risk for breast cancer later in life because they are exposed to less estrogen, according to the American Cancer Society. Conversely, women who have no children and those who had their first pregnancy after age 30 demonstrate a slightly higher risk for breast cancer.

“When we treat breast cancer during pregnancy, we actually have two patients,” Mayer said. “The challenge is to balance the risks and benefits in order to maximize the health of the woman, and to minimize any risks or potentially adverse outcomes in the developing infant.”

Despite that delicate balance, pregnancy typically should not prompt clinicians to dramatically alter or scale back their approach to care, Mayer said.

“The treatment for women who are pregnant should — as closely as possible — approximate the treatment we offer nonpregnant patients,” Mayer said.

Of course, there are exceptions.

One setting in which treatment approaches often must be adjusted is when pregnant patients have HER-2–positive disease.

“HER-2–directed therapies are not safe at any time during pregnancy,” Mayer said. “However, sometimes treatments cannot be delayed until a pregnancy is completed. In these situations, we have to carefully balance the risks and benefits, and consider whether we can move forward with a potentially modified treatment plan, or whether it would be preferable for a woman to end her pregnancy and receive standard care.”

Another traditional exception to the uniform treatment approach has been the use of sentinel lymph node biopsy, long avoided in pregnant patients due to concern about its potential for fetal harm. Recent study results, however, suggest that concern may not be warranted.

Mayer and colleagues conducted a retrospective chart review to assess the safety and efficacy of sentinel lymph node biopsy (SNB) in pregnant women with breast cancer.

The study — published in August in Annals of Surgical Oncology — included 47 women who were clinically node-negative and underwent surgery while pregnant. Twenty-five (53.2%) underwent SNB using either 99 m-Technetium (99-Tc) or methylene blue dye.

Mayer and colleagues reported successful mapping in all patients, no complications associated with SNB, and no increased rate of fetal abnormalities.

“In our analysis, SNB in pregnant breast cancer patients appeared to be safe and accurate using either methylene blue or 99-Tc,” Mayer and colleagues concluded. “This is one of the largest reported experiences of SNB during pregnancy; however, numbers remain limited.”

Antenatal therapy for lymphoma

Until recently, literature available to guide clinicians during the treatment of pregnant patients with lymphoma — the fourth most frequent cancer that occurs during pregnancy — was limited to case reports and small case series.

A multicenter retrospective analysis, published last year in Journal of Clinical Oncology, filled that evidence gap.

Andrew M. Evens, DO, MSc, director of Tufts Cancer Center and director of the lymphoma program at Tufts University School of Medicine, and colleagues assessed treatment, complications and outcomes of 90 patients (median age, 30 years; range, 18-44) diagnosed with lymphoma during pregnancy.

Fifty patients had non-Hodgkin’s lymphoma and 40 had Hodgkin’s lymphoma. Median diagnosis occurred at 24 weeks gestation.

Pregnancy was terminated in six patients. Twenty-eight patients deferred therapy to postpartum.

The other 56 (67%) patients underwent antenatal therapy. Most (89%) received combination chemotherapy. In most cases (66%), antenatal therapy was started in the second trimester (median initiation, 25 weeks gestation; range, 13 to 37 weeks).

Researchers reported an 82% overall response rate and a 64% complete response rate among patients who underwent antenatal therapy.

Evens and colleagues reported no differences in median infant birth weight between the antenatal therapy and deferred treatment groups (2,670 g vs. 2,665 g; P=.74), although they observed a trend for infants to be small for gestational age in the antenatal therapy group (41% vs. 9%; P=.09).

The researchers reported no differences in perinatal events or maternal complications between treatment groups.

“We’re hopeful that our data provides clinicians and patients with information to help guide these critical and personalized decisions involved in lymphoma occurring during pregnancy,” Evens told HemOnc Today. “This includes, when clinically indicated, that standard chemotherapy given during the second and third trimesters appears to be associated with minimal maternal complications or fetal detriment. In addition, there are low-risk clinical scenarios such as low tumor burden or diagnosis late in gestation whereby therapy can be safely deferred to postpartum. In all cases, care should be closely coordinated with high-risk maternal-fetal medicine, and an overarching goal should be to continue the pregnancy to full term.”

Facing an unknown

In some scenarios, clinicians must make treatment decisions without guidance from peer-reviewed literature.

In 2012, Polite assembled a care team comprised of seven specialists to devise a treatment plan for a 30-year-old woman diagnosed with stage III rectal cancer while pregnant with her first child.

Standard treatment for colorectal cancer includes neoadjuvant chemotherapy plus radiation.

“In this case, there simply was no good way to shield the uterus and the baby from radiation, so this would have killed the baby,” Polite said.

At that time, however, off-clinical trial work at Polite’s institution and elsewhere had shown neoadjuvant chemotherapy alone could be a potentially effective approach.

Based on prior studies of children born to women who underwent chemotherapy for breast cancer while pregnant, Polite believed a similar treatment for his patient would be safe for the unborn child. Before proceeding, he conferred with pharmacists specially trained in how the body reacts to oncology drugs. He also sought input from several fellow physicians across the country.

Polite ultimately decided to proceed with chemotherapy administration and concluded that surgery – as well as radiation, if needed – could wait until after the birth.

The team of physicians and surgeons worked closely to plan and implement each step of treatment, as well as the delivery of the baby. This particular case required academic support, obstetricians and others who specialized in high-risk pregnancies, as well as those who understood pharmacology and the potential impact of treatments during the first trimester.

“We were facing a situation in which we were using drugs, such as oxaliplatin, that didn’t have much of a track record in pregnant patients,” Polite said. “We do have a fair amount of breast cancer literature that focuses on women who were pregnant and were able to go through chemotherapy, but the therapies used in those cases were different. So, we were facing somewhat of an unknown.”

Two years after the mother’s diagnosis, she shows no signs of cancer and the baby is healthy, Polite said.

“She was very insistent that she wanted to be able to find a way to both beat her cancer, but preserve this pregnancy,” Polite said. “She and her husband had delayed for some time having a baby and so the two things were equally important in her mind. Her optimism and steadfastness about what she wanted to do really forced me to listen, think and get somewhat creative in terms of what we could do.”

Pharmacokinetic analysis

Researchers recently evaluated the impact of pregnancy-induced physiological changes on the pharmacokinetics of cancer therapies, as the optimal dosage in pregnant women remains unclear.

Frederic Amant, MD, assistant professor, staff gynecologic oncologist and head of the scientific section of gynecologic oncology at Katholieke Universiteit Leuven in Belgium, and colleagues sought to assess changes in pharmacokinetics during pregnancy in 38 patients with cancer. Treatments included doxorubicin (n=16), epirubicin (n=14), docetaxel (n=3) and paclitaxel (n=5).

Outcomes were compared with those observed in 253 nonpregnant patients (doxorubicin, n=59; epirubicin, n=57; docetaxel, n=32; and paclitaxel, n=105).

Results, published in April in Annals of Oncology, showed the effects of pregnancy on volumes of distribution were <1.32-fold for doxorubicin, <2.08-fold for epirubicin, <1.37-fold for docetaxel and <4.21-fold for paclitaxel.

The calculated dose adjustment requirements were 5.5% for doxorubicin, 8% for epirubicin, 16.9% for docetaxel and 37.8% for paclitaxel. Estimated changes in infusion duration were marginal (<4.2%) for all agents except paclitaxel (-21.4%).

“These data show that chemotherapy is diluted during pregnancy, although the level of dilution differs according to the drug,” Amant told HemOnc Today. “As long as we can show that the prognosis is not affected, we will use the same dosages. However, when a choice among drugs has to be made, the drug with least dilution is preferred.”

Dizon cautioned that, although these data are interesting, whether they warrant routine dose adjustments in pregnant women should only be considered a hypothesis.

“Although we want to ensure we are providing optimal therapy to pregnant patients, which includes the most appropriate dosing strategy, we must be cautious, especially since — as the authors point out — there is no data demonstrating that their findings had an impact on prognosis,” Dizon said. “Adjusting doses of chemotherapy may result in an increase in treatment-related toxicities — specifically hematologic toxicities — for both the pregnant patient and her baby. Unfortunately, it remains unlikely that we will see a future trial evaluating this concept — standard vs. pregnancy-adjusted dosing of chemotherapy — prospectively. I think most oncologists feel the same way I do in that it would be a difficult trial to run.”

ESMO guidelines

In 2013, ESMO updated its clinical practice guidelines for the diagnosis, treatment and follow-up of cancer during pregnancy.

The ESMO Guidelines Working Group made several recommendations:

The guidelines also include updated recommendations about systemic treatments and fertility preservation methods in patients with cancer.

“We have learned that chemotherapy can be safely administered after the first trimester in most instances, that radiation therapy and monoclonal antibodies might be postponed after delivery and that pregnancy should be possibly brought to term, thus allowing the best maternal and fetal outcome,” said Peccatori, a member of the guidelines working group. “The real challenge comes from the number of new treatments available, including small molecules, new monoclonal antibodies and the anti-angiogenic drugs. We simply do not have information of their fetal effect, and more research is needed.”

Education and teamwork

The ESMO guidelines also recommend the care of a pregnant women with cancer be managed by a fetal/maternal specialist in addition to an oncologist.

That is wise advice, Dizon said.

“Cancer during pregnancy is an incredibly complex circumstance and oncologists should not be handling these patients on their own,” Dizon said. “The psychosocial impact of being diagnosed with cancer during pregnancy is huge. We need to recognize this and call on other specialists to support the patient and her partner psychosocially.”

Dana-Farber Cancer Institute employs a program that ensures patients diagnosed with breast cancer during pregnancy meet a multidisciplinary team that encompasses medical oncology, surgical oncology, radiation oncology and maternal/fetal medicine, as well as genetics and social work.

“This strategy not only provides the best care for the patient but also very quickly helps answer some of the questions and concerns that may come up at the time of the initial presentation so that we can move forward with the best treatment plan,” Mayer said.

An increased emphasis — both in clinical trials and real-world settings — on the relationship between cancer, its treatments and pregnancy also will pay dividends.

“The statement ‘When you hear hoofbeats, think of horses, not zebras’ holds true for most clinical situations, but not for cancer occurring during pregnancy,” Peccatori said. “A better understanding of the biology of gestational tumors and a higher awareness of their occurrence may favor earlier diagnosis and a more effective treatment. This is why education is so important.” – by Jennifer Southall

References:

American Cancer Society. Pregnancy and breast cancer. Available at: www.cancer.org/cancer/breastcancer/moreinformation/pregnancy-and-breast-cancer. Accessed on Aug. 8, 2014.

Aviles A. Int J Cancer. 2012;131:2678-2683.

Brady MS. J Clin Aesthet Dermatol. 2010;3:22-28.

Evens AM. J Clin Oncol. 2013;31:4132-4139.

Gropper AB. Ann Surg Oncol. 2014;21:2506-2511. Han SN. Ther Adv Med Oncol. 2013;211-219. 

Lee YY. BJOG. 2012;119:1572-1582.

Litton JK. Gestational breast cancer: Epidemiology and diagnosis. Available at: www.uptodate.com/contents/gestational-breast-cancer-epidemiology-and-diagnosis. Accessed on Aug. 8, 2014.

Morice P. Lancet. 2012;379:558-569. 

Nikolin BL. Arch Oncol. 2005;13:31-34.

van Hasselt JG. Ann Oncol. 2014; Published online ahead of print April 8.

For more information:

Frederic Amant, MD, can be reached at Katholieke Universiteit Leuven, Oude Markt 13, 3000 Leuven, Belgium; email: frederic.amant@uzleuven.be.

Don S. Dizon, MD, can be reached at Oncology Sexual Health Clinic, Massachusetts General Hospital Cancer Center, 55 Fruit St., Boston, MA 02114.

Andrew M. Evens, DO, MSc, can be reached at Tufts Medical Center, 800 Washington St., Boston MA 02111.

Erica L. Mayer, MD, MPH, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email: erica_mayer@dfci.harvard.edu.

Fedro Alessandro Peccatori, MD, PhD, can be reached at Istituto Europeo di Oncologia, Via Giuseppe Ripamonti, 435, 20141 Milano, Italy; email: fedro.peccatori@ieo.it.

Blase Polite, MD, MPP, can be reached at University of Chicago Medicine, 5841 S Maryland Ave, Chicago, IL 60637; email: bpolite@medicine.bsd.uchicago.edu.

Disclosure: Amant, Dizon, Evens, Mayer, Peccatori and Polite report no relevant financial disclosures.

 

Should pregnancy termination continue to be an option for women with cancer?

Termination needs to be an option.

A 2012 study documented the rising incidence of pregnancy-associated cancers (Lee YY. BJOG. 2012;119:1572-1582).

Approximately 2,000 cancers were diagnosed among 1.3 million pregnancies or during the 12 months after delivery between 1994 and 2008. In addition, the incidence rate for pregnancy-associated cancer increased from 112.3 per 100,000 pregnancies to 191.5 per 100,000 pregnancies.

Chemotherapy, radiation and surgical interventions are tools available to the oncologist to confront these malignancies, and each carries unique risks to both mother and the developing fetus. In addition, the pregnancy itself poses additional risks to — and distinct challenges for — the patient.

First, the diagnosis of cancer in pregnancy often is delayed due to physiologic engorgement that makes examination and tumor detection more difficult. This problem will increase, because breast cancer is the most common cancer diagnosis made during pregnancy and incidence is expected to increase as more women are delaying pregnancy.

Next, the increased vascularity of pregnancy increases the potential for surgical morbidity from greater blood loss. The pregnancy also complicates how to employ chemotherapy and radiation therapy. These are potentially life-saving therapies for the mother, but they may carry risks of devastating teratogenic complications for the fetus.

All alternatives to treat cancer should be available to the patient and, unfortunately, pregnancy termination may need to be considered in order to optimize treatment.

Cancer therapy must remain between the patient, her medical team and her family. Politics should not be allowed to play a role.

 

David P. Cohen, MD, is professor of obstetrics/gynecology and chief of reproductive endocrinology and infertility at University of Chicago Medicine. He can be reached at University of Chicago Medicine, 5841 S. Maryland Ave., Chicago, IL 60611; email: dcohen@babies.bsd.uchicago.edu. Disclosure: Cohen reports no relevant financial disclosures.

Abortion is not a preferred and beneficial option for every patient.

Cases in which a pregnant patient is diagnosed with cancer often are associated with maternal-fetal conflict emphasizing the dilemma of choice having to be made over the maternal or fetal life. However, such a view cannot always be justified because continuing with pregnancy does not by default compromise treatment outcomes or survival rates.

Moreover, motherhood is known to have a positive effect on patients’ overall well-being because it gives motivation to stay well and encourages more optimistic attitudes toward the future.

Current research shows that surgery and some chemotherapy protocols can be applied safely to treat the mother without exposing the fetus to a significant risk, acknowledging that long-term effects of chemotherapy are still unknown — especially concerning future cardiac, cognitive and fertility impairment.

Cancer treatment compatibility with pregnancy also will depend on the type of cancer, how advanced it is and the stage of pregnancy, but proceeding with abortion without sufficient justification that it is performed to preserve the mother’s life could have a negative effect on the patient’s future life, resulting in regret and remorse.

We should not be inclined to associate every cancer-in-pregnancy case with maternal–fetal conflict because it is misleading and does not correspond to current medical knowledge.

Considering the above arguments, abortion is not necessarily a preferred and beneficial option for every patient. A patient’s choice to continue with pregnancy after cancer diagnosis could be a feasible option and should be supported by multidisciplinary team of health care experts who are attentive to each individual patient’s values, understanding of diagnosis and acceptable levels of unknown risks.

Alma Linkeviciute, MSc, is a PhD candidate at the European Institute of Oncology (IEO) and University of Milan, as well as a fellow at Fondazione Umberto Veronesi in Milan, Italy. Her research interests include medical ethics and oncofertility. She can be reached at IFOM-IEO Campus Via Adamello 16, 20139, Milano, Italy; email: alma.linkeviciute@ieo.eu. Disclosure: Linkeviciute reports no relevant financial disclosures.