Chemotherapy for Breast Cancer During Pregnancy: An 18-Year Experience From Five London Teaching Hospitals
http://www.100md.com
《临床肿瘤学》
the Breast Unit, Royal Marsden Hospital
Royal Free Hospital
Guy's, King’s, and St Thomas' Cancer Centre, London, United Kingdom
ABSTRACT
PURPOSE: The rare association between breast cancer and pregnancy means that few oncologists gain an expertise in this area. In particular, there are few published data concerning the use of chemotherapy for breast cancer during pregnancy. In this retrospective case series, we describe the experiences of five hospitals in London, United Kingdom, and how they manage this condition.
PATIENTS AND METHODS: Retrospective searches were performed at five London hospitals in order to identify women who received chemotherapy for breast cancer while pregnant.
RESULTS: Twenty-eight women were identified who had received chemotherapy for breast cancer during pregnancy. Twenty-four women received adjuvant or neoadjuvant chemotherapy for early breast cancer, and four women received palliative chemotherapy for metastatic disease. A total of 116 cycles of chemotherapy were administered during pregnancy. Sixteen women were treated with anthracycline-based chemotherapy and 12 received cyclophosphamide, methotrexate, and fluorouracil. All but one of the women were treated after the first trimester. One spontaneous abortion occurred in the woman treated during her first trimester
otherwise, there were no serious adverse consequences for the mothers or neonates.
CONCLUSION: These data provide evidence that in terms of peripartum complications and immediate fetal outcome, chemotherapy can be safely administered to women during the second and third trimesters of pregnancy.
INTRODUCTION
It has been estimated from 32 case series over a period of several decades that 0.2% to 3.8% of breast cancers occur during pregnancy.1 This incidence may rise as women delay their pregnancies until later in life, and as the number of premenopausal women with breast cancer grows.2,3 Pregnancy complicates the management of breast cancer because the need for treatment to maximize chances of survival for the mother have to be balanced against the potential risks to the fetus. This is particularly the case when the use of chemotherapy is proposed in a pregnant woman. Adjuvant chemotherapy has a well-established role in improving survival for women with early breast cancer.4 Delays or modification of adjuvant treatment to ensure the birth of a healthy infant could potentially compromise maternal survival. It is therefore important to establish what treatments are safe for both mother and the developing fetus during pregnancy. Owing to the rarity of this association and the infrequent use of chemotherapy in pregnancy, most existing reports are anecdotal. This retrospective series is the largest published thus far and documents data from five hospitals concerning the use of chemotherapy for breast cancer in pregnant women.
PATIENTS AND METHODS
Patients who had undergone treatment with cytotoxic chemotherapy for breast cancer during pregnancy were identified from a search of the prospectively maintained Royal Marsden Hospital (London, United Kingdom) breast unit database. This search covered the period from 1986 to 2003. Additional cases were sought based on physician and nursing recall at the Royal Free, Whittington, Guy's, and King’s College Hospitals (all institutions, London, United Kingdom), covering the period from 1990 to 2003. Among them, these institutions see approximately 1,500 patients with new diagnoses of breast cancer annually. After ethical approval and retrospective patient consent (whenever possible) was acquired, a 36-item questionnaire was completed directly from patients' medical records. Details regarding diagnostic and staging investigations, standard histopathologic parameters, hormone-receptor, and human epidermal growth factor receptor 2 (HER2) status were recorded, if available. Patients were classified as having inflammatory breast cancer on the basis of clinical findings (diffuse erythematous indurated skin) or histologic evidence of the invasion of dermal lymphatics. Information was recorded regarding pre- and postpartum treatments and, in particular, types and doses of chemotherapy and their toxicities. Obstetric information documented included gestational age at diagnosis, complications of pregnancy, labor, and delivery, including fetal complications and congenital abnormalities.
RESULTS
Baseline Characteristics
Sixty-three women who were pregnant at the time of diagnosis or relapse of breast cancer were identified
28 of these women went on to receive chemotherapy while pregnant. Of these 28 women, 24 were diagnosed with stage I-IIIB disease: stage I (two women), stage II (11 women), and stage III (11 women
staging was done using the American Joint Committee on Cancer revised staging system for breast cancer5). An additional four patients were treated for metastatic disease (stage IV). Of the four patients treated for metastatic disease, two had stage IV breast cancer at presentation and two had relapsed while pregnant. The median maternal age at diagnosis was 33 years (range, 28 to 42 years). The median gestational age at diagnosis was 17 weeks (range, 4 to 33 weeks). The median duration of symptoms before histologic confirmation of diagnosis was 9 weeks (range, 2 weeks to 12 months).
Surgery
Seventeen patients underwent surgery while pregnant
10 of the 17 patients had modified radical mastectomies, and seven patients underwent breast-conserving surgery. Fifteen of the 17 patients underwent axillary surgery. The median gestational age at the time of surgery was 16 weeks (range, 5 to 29 weeks). There were no unexpected surgical or anesthetic complications. Four patients had surgery after delivery, following primary chemotherapy received while pregnant. Seven patients did not have surgery
three of these patients received neoadjuvant chemotherapy alone and four received palliative chemotherapy for metastatic disease. All seven of the patients who underwent breast-conserving surgery and seven of the 10 patients who underwent mastectomy while pregnant received postpartum radiation therapy.
Histopathology
Histopathologic characteristics of the 24 patients who presented with stage I to IIIB breast cancer while pregnant are listed in Table 1. The majority of tumors were invasive ductal carcinomas (in 86% of patients for whom this information was available). There were also high incidences of adverse prognostic features, including high tumor grade (74% of patients), lymphovascular invasion (88% of patients), and estrogen-receptor (ER) –negative tumors (42% of patients). Lymph node status was known for 18 patients, of whom 15 (83%) were node positive. Three of the tumors also exhibited inflammatory features.
Chemotherapy
Neoadjuvant chemotherapy was initiated during pregnancy in seven patients for large operable, locally advanced, or inflammatory breast cancers. Adjuvant chemotherapy was administered to 17 patients, and four patients received palliative chemotherapy for metastatic disease. A total of 116 cycles of chemotherapy were administered during pregnancy in this cohort
the median number of cycles administered prepartum was four (range, one to six). The median total number of cycles of chemotherapy administered during and after pregnancy was six (range, four to eight cycles). Fourteen of the patients received chemotherapy prepartum only, whereas the remaining 14 received chemotherapy both during and after pregnancy. The types and doses of chemotherapy administered are listed in Table 2. These chemotherapy regimes were tolerated at full doses without major complications. Three episodes of febrile neutropenia were recorded, but all patients responded to antibiotics with no additional complications. The only other grade 3 or 4 toxicities recorded were lethargy (two patients) and alopecia. Two of the patients also received granulocyte colony-stimulating factor while pregnant. No patients received endocrine therapy or radiotherapy during pregnancy.
Obstetric Characteristics
Obstetric characteristics related to chemotherapy administration are reported in Table 3. The median gestational age at the commencement of chemotherapy was 20 weeks (range, 15 to 33 weeks). Twenty-two patients started chemotherapy in the second trimester and five during the third trimester. One patient received cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy during the first trimester of her pregnancy. She was not aware that she was pregnant at the time of chemotherapy initiation, but had a positive pregnancy test shortly after the first cycle. Unfortunately, she had a spontaneous abortion before her second cycle of treatment. The median interval between the last cycle of chemotherapy and delivery was 28 days (range, 14 to 70 days). Six patients had cesarean deliveries, and an additional seven patients had their labor induced. The median gestational age at delivery was 37 weeks (range, 30 to 40 weeks). Nine children were born before 37 weeks' gestation
one case was as a result of spontaneous onset of labor. The patient who delivered at 30 weeks had an early elective cesarean delivery owing to impending spinal cord compression.
Fetal Outcome
The median gestational age at delivery was 37 weeks (range, 30 to 40 weeks). One child had a hemangioma on his abdomen, but it was not thought to be causally related to chemotherapy exposure. There were no other recorded fetal abnormalities. Birth weight was available for 17 of the infants
the median birth weight was 3.0 kg (1.4 to 3.5 kg). In the infant born weighing 1.4 kg, placental insufficiency was identified as the cause of intrauterine growth retardation, and an elective cesarean delivery was carried out at 32 weeks. However, none of the infants had a birthweight lower than the 10th percentile for gestational age.6 Two of the newborns experienced respiratory distress, and in total five newborns needed to be transferred to neonatal high dependency units.
Maternal Outcome
As of October 2003, the median follow-up period for the women in this report was 40.5 months (range, 7 to 159 months). Two of the women with stage IV disease died within 3 years of diagnosis, and the other two patients are both alive at 1 year of follow-up. At a median of 40.5 months, the combined survival rate for women with stage I to IIIB breast cancer was 67%, and the disease-free survival rate was 63%.
DISCUSSION
The purpose of conducting this retrospective review was to provide more information to breast cancer specialists and obstetricians faced with a pregnant patient with breast cancer requiring chemotherapy. We are aware of only two case series of a similar size: a French national survey7 and a series from The University of Texas M.D. Anderson Cancer Center (Houston, TX).8 The French national survey was a retrospective study based on a postal questionnaire sent to clinicians involved in the management of breast cancer diagnosed during pregnancy. Data were acquired on the histologic and clinical characteristics, treatment, obstetric complications, and pregnancy outcome of 20 women treated with chemotherapy for breast cancer while pregnant. The M.D. Anderson Cancer Center series was a prospectively designed study where patients with primary or recurrent breast cancer diagnosed during pregnancy were managed with locoregional therapy and a standard chemotherapy protocol as clinically indicated. The chemotherapy regimen used was doxorubicin 50 mg/m2 continuous infusion over a period of 72 hours, cyclophosphamide 500 mg/m2 on day 1, and bolus fluorouracil 500 mg/m2 on days 1 and 4. In the initial publication, data were presented on 24 women, two of whom had recurrent disease, and one of whom received chemotherapy during her first trimester.8 An update of this series including 39 patients has also been presented in abstract form.9
The pathologic characteristics of the tumors treated were similar to those reported in other series, in that the majority of tumors were high-grade invasive ductal carcinomas.7,10 Twenty-five of 28 patients in this study presented with pathologic lymph node involvement or metastatic disease
similarly Middleton et al10 found that only 2 of 39 patients presenting with breast cancer during pregnancy had stage I disease. Patients with breast cancer who are pregnant at the time of diagnosis have previously been shown to present with more advanced disease than matched nonpregnant patients in some,11,12 but not all,13 case-control studies. Of the 19 women with stage I to IIIB breast cancer for whom ER status was available, eight were estrogen-receptor–negative. ER-negative tumors are known to be more common in younger women,14 but in case control studies, ER-negative tumors have been shown to be more frequent in pregnant patients than in age-matched controls.11,13,15 It has also previously been observed that breast cancer in patients who are pregnant often demonstrate lymphovascular invasion, and are relatively frequently HER2-positive, though whether their frequencies are any different to those in age-matched controls is not known.11,15
The use of cytotoxic drugs during pregnancy is complicated by the potential for teratogenicity as demonstrated in animal studies, together with the risk of other direct toxic effects on the mother and fetus. During the first trimester, the fetus is undergoing organogenesis, and therefore is at its most susceptible. Chemotherapy at this stage may be associated with spontaneous abortions or an increased risk of fetal malformations.16 One of the patients in this series, and two patients in the French national survey were exposed to chemotherapy during the first trimester, and all underwent spontaneous abortions.7 However, the one patient exposed to chemotherapy during the first trimester (11 weeks) in the M.D. Anderson series experienced no apparent adverse effects.8 When live births do occur, historical studies suggest that fetal malformation rates are between 7.5% and 17%.17-20 Because of the high rates of pregnancy loss and fetal malformations, chemotherapy is generally avoided during the first trimester.
Beyond the first trimester, the use of cytotoxic chemotherapy does not appear to increase the risk of malformations. In this series, none of the 27 children exposed to chemotherapy in the second or third trimesters had congenital malformations. Sixteen of these children had been exposed to anthracyline-based chemotherapy. In the M.D. Anderson series, 23 children were exposed to anthracyline-based chemotherapy in the second and third trimesters (doxorubicin, cyclophosphamide, and fluorouracil at the doses previously described) and similarly no malformations were reported.8 Our series also included 12 patients who received CMF chemotherapy. In the first trimester, methotrexate is particularly associated with birth defects, but we can find no evidence of such an effect later in pregnancy. The French national survey identified 18 patients who received a variety of chemotherapy regimes during the second and third trimesters of pregnancy, and no fetal malformations were identified.7 Four of these patients received vinorelbine, which has previously been administered with no fetal complications.21 Case reports also describe the use of docetaxel and paclitaxel in the second and third trimesters respectively, with no adverse effects.22,23 There is no evidence from animal studies that granulocyte colony-stimulating factor is teratogenic, and there are reports of its use during pregnancy (Medical Information Department, personal communication, April 2003).24 Two patients in the current series also received granulocyte colony-stimulating factor with no significant adverse effects.
The toxic effects of cytotoxic agents are not restricted to fears over teratogenicity. Pre-eclampsia, preterm labor, intrauterine death, and low birth weights have all been reported in previous series.7,8,20,25 However, it is not known whether the incidences of these complications are in excess of those in the normal population and what the contribution of chemotherapy is relative to the effects of the underlying disease. Nine of the children were delivered before 37 weeks, and in one case premature delivery occurred as a result of spontaneous onset of preterm labor. In the remainder, early delivery was explained by induced labor or cesarean delivery in order to optimize the timing of delivery relative to chemotherapy, or, in one case, to allow treatment of spinal cord compression. Intrauterine growth retardation is likely to be underestimated in retrospective studies, though one case each was identified in the French national survey and the current study. Of the 17 babies in this series for whom birth weights were available, two had low birth weights (< 2.5 kg). Increased neonatal morbidity and mortality are recognized sequelae of intrauterine growth retardation and low birth weight (< 2.5 kg) in the normal neonatal population.26 However, none of the infants in this series and only one infant in the M.D. Anderson series had a birth weight lower than the 10th percentile for gestational age.8
Maternal and neonatal sepsis and hemorrhage are potential complications of myelosuppression, which can effect both mother and fetus at the time of delivery.7,8,27,28 No such complications were observed in this cohort, though the mean interval between delivery and the last cycle of chemotherapy was 30 days, minimizing the risk of neutropenia at the time of delivery.
The potential long-term effects of exposing the fetus to chemotherapy include gonadal dysfunction, impaired physical and neurologic development, and germ cell mutagenesis resulting in carcinogenesis and teratogenicity in subsequent generations.29 However, follow-up of children is often short and reports concerning long-term development are uncommon. The most comprehensive cohort to date describes 84 children born to mothers who were treated with combination chemotherapy during pregnancy for hematologic malignancies.30 At a median follow-up of 18.7 years, normal physical, neurologic, and psychological development was observed, with no reports of malignancies in the 84 first-generation children or in the 12 second-generation children.
Given that some transplacental transfer of anthracyclines may occur, fetal cardiotoxicity following maternal exposure to anthracyclines is another long-term concern.31,32 No cases of fetal cardiotoxicity were recorded in one large review33-35 of the use of anthracyclines in pregnancy, and no echocardiographic changes were observed when a child was monitored in utero. Unfortunately, this case series and many others on this topic are unable to adequately address such late adverse effects owing to a lack of long-term follow-up and the bias introduced by their retrospective nature. For these reasons, the ongoing analysis of the M.D. Anderson data and new prospective databases such as that initiated by the German Breast Group are of utmost importance.36
The data presented in this series provide evidence that in consideration of peripartum complications and immediate fetal outcome, chemotherapy can be safely administered to women during the second and third trimesters of pregnancy. The literature reviewed also indicates that there are unlikely to be serious adverse long-term effects on the fetus, though large prospective series are needed to confirm this. Nonetheless, on the basis of the current evidence women should not be denied the potential benefits of chemotherapy because they are pregnant at the time of diagnosis of breast cancer.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank Penny Howard, Professor John Yarnold, Geraldine Walsh, and Sarah Pearson for their help in preparing this article.
NOTES
Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Wallack MK, Wolf JA Jr, Bedwinek J, et al: Gestational carcinoma of the female breast. Curr Probl Cancer 7:1-58, 1983
Ventura SJ: First births to older mothers, 1970-1986. Am J Public Health 79:1675-1677, 1989
Ranstam J, Janzon L, Olsson H: Rising incidence of breast cancer among young women in Sweden. Br J Cancer 61:120-122, 1990
Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998
Singletary SE, Allred C, Ashley P, et al: Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 20:3628-3636, 2002
Lubchenco LO, Hansman C, Dressler M, et al: Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation. Pediatrics 32:793-800, 1963
Giacalone PL, Laffargue F, Benos P: Chemotherapy for breast carcinoma during pregnancy: A French national survey. Cancer 86:2266-2272, 1999
Berry DL, Theriault RL, Holmes FA, et al: Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 17:855-861, 1999
Gwyn K, Theriault R, Sahin A, et al: Treatment of breast cancer during pregnancy using a standard protocol: Update of the M.D. Anderson experience. Proc Am Soc Clin Oncol, 20:18b, 2001 (abstr 1821)
Middleton LP, Amin M, Gwyn K, et al: Breast carcinoma in pregnant women: Assessment of clinicopathologic and immunohistochemical features. Cancer 98:1055-1060, 2003
Ishida T, Yokoe T, Kasumi F, et al: Clinicopathologic characteristics and prognosis of breast cancer patients associated with pregnancy and lactation: Analysis of case-control study in Japan. Jpn J Cancer Res 83:1143-1149, 1992
Zemlickis D, Lishner M, Degendorfer P, et al: Maternal and fetal outcome after breast cancer in pregnancy. Am J Obstet Gynecol 166:781-787, 1992
Bonnier P, Romain S, Dilhuydy JM, et al: Influence of pregnancy on the outcome of breast cancer: A case-control study—Societe Francaise de Senologie et de Pathologie Mammaire Study Group. Int J Cancer 72:720-727, 1997
Li CI, Daling JR, Malone KE: Incidence of invasive breast cancer by hormone receptor status from 1992 to 1998. J Clin Oncol 21:28-34, 2003
Aziz S, Pervez S, Khan S, et al: Case control study of novel prognostic markers and disease outcome in pregnancy/lactation-associated breast carcinoma. Pathol Res Pract 199:15-21, 2003
Nicholson HO: Cytotoxic drugs in pregnancy: Review of reported cases. J Obstet Gynaecol Br Commonw 75:307-312, 1968
Gililland J, Weinstein L: The effects of cancer chemotherapeutic agents on the developing fetus. Obstet Gynecol Surv 38:6-13, 1983
Doll DC, Ringenberg QS, Yarbro JW: Antineoplastic agents and pregnancy. Semin Oncol 16:337-346, 1989
Schapira DV, Chudley AE: Successful pregnancy following continuous treatment with combination chemotherapy before conception and throughout pregnancy. Cancer 54:800-803, 1984
Zemlickis D, Lishner M, Degendorfer P, et al: Fetal outcome after in utero exposure to cancer chemotherapy. Arch Intern Med 152:573-576, 1992
Cuvier C, Espie M, Extra JM, et al: Vinorelbine in pregnancy. Eur J Cancer 33:168-169, 1997
Sood AK, Shahin MS, Sorosky JI: Paclitaxel and platinum chemotherapy for ovarian carcinoma during pregnancy. Gynecol Oncol 83:599-600, 2001
De Santis M, Lucchese A, De Carolis S, et al: Metastatic breast cancer in pregnancy: First case of chemotherapy with docetaxel. Eur J Cancer Care (Engl) 9:235-237, 2000
Losch A, Lahodny J, Petru E: Possible influence of granulocyte colony-stimulating factor and recombinant human erythropoietin on human chorionic gonadotropin secretion during chemotherapy for choriocarcinoma. Gynecol Oncol 83:165-166, 2001
Muller T, Hofmann J, Steck T: Eclampsia after polychemotherapy for nodal-positive breast cancer during pregnancy. Eur J Obstet Gynecol Reprod Biol 67:197-198, 1996
Stoll BJ, Kliegman RM: The high risk infant, in, Behrman RE, Kliegman RM, Jenson HB (eds): Nelson Textbook of Pediatrics, 16th Edition. Philadelphia, PA, WB Saunders Company, 2000, pp 474-485
Murray NA, Acolet D, Deane M, et al: Fetal marrow suppression after maternal chemotherapy for leukaemia. Arch Dis Child Fetal Neonatal Ed 17:F209-F210, 1994 (suppl)
Reynoso EE, Shepherd FA, Messner HA, et al: Acute leukemia during pregnancy: The Toronto Leukemia Study Group experience with long-term follow-up of children exposed in utero to chemotherapeutic agents. J Clin Oncol 5:1098-1106, 1987
Partridge AH, Garber JE: Long-term outcomes of children exposed to antineoplastic agents in utero. Semin Oncol 27:712-726, 2000
Aviles A, Neri N: Hematological malignancies and pregnancy: A final report of 84 children who received chemotherapy in utero. Clin Lymphoma 2:173-177, 2001
Gaillard B, Leng JJ, Grellet J, et al: Transplacental passage of epirubicin [in French]. J Gynecol Obstet Biol Reprod (Paris) 24:63-68, 1995
Karp GI, von Oeyen P, Valone F, et al: Doxorubicin in pregnancy: Possible transplacental passage. Cancer Treat Rep 67:773-777, 1983
Turchi JJ, Villasis C: Anthracyclines in the treatment of malignancy in pregnancy. Cancer 61:435-440, 1988
Garber JE: Long-term follow-up of children exposed in utero to antineoplastic agents. Semin Oncol 16:437-444, 1989
Meyer-Wittkopf M, Barth H, Emons G, et al: Fetal cardiac effects of doxorubicin therapy for carcinoma of the breast during pregnancy: Case report and review of the literature. Ultrasound Obstet Gynecol 18:62-66, 2001
German Breast Group, GBG-29: Breast cancer in pregnancy: Prospective register study for the diagnosis and treatment of breast cancer in pregnancy.(Alistair E. Ring, Ian E. )
Royal Free Hospital
Guy's, King’s, and St Thomas' Cancer Centre, London, United Kingdom
ABSTRACT
PURPOSE: The rare association between breast cancer and pregnancy means that few oncologists gain an expertise in this area. In particular, there are few published data concerning the use of chemotherapy for breast cancer during pregnancy. In this retrospective case series, we describe the experiences of five hospitals in London, United Kingdom, and how they manage this condition.
PATIENTS AND METHODS: Retrospective searches were performed at five London hospitals in order to identify women who received chemotherapy for breast cancer while pregnant.
RESULTS: Twenty-eight women were identified who had received chemotherapy for breast cancer during pregnancy. Twenty-four women received adjuvant or neoadjuvant chemotherapy for early breast cancer, and four women received palliative chemotherapy for metastatic disease. A total of 116 cycles of chemotherapy were administered during pregnancy. Sixteen women were treated with anthracycline-based chemotherapy and 12 received cyclophosphamide, methotrexate, and fluorouracil. All but one of the women were treated after the first trimester. One spontaneous abortion occurred in the woman treated during her first trimester
otherwise, there were no serious adverse consequences for the mothers or neonates.
CONCLUSION: These data provide evidence that in terms of peripartum complications and immediate fetal outcome, chemotherapy can be safely administered to women during the second and third trimesters of pregnancy.
INTRODUCTION
It has been estimated from 32 case series over a period of several decades that 0.2% to 3.8% of breast cancers occur during pregnancy.1 This incidence may rise as women delay their pregnancies until later in life, and as the number of premenopausal women with breast cancer grows.2,3 Pregnancy complicates the management of breast cancer because the need for treatment to maximize chances of survival for the mother have to be balanced against the potential risks to the fetus. This is particularly the case when the use of chemotherapy is proposed in a pregnant woman. Adjuvant chemotherapy has a well-established role in improving survival for women with early breast cancer.4 Delays or modification of adjuvant treatment to ensure the birth of a healthy infant could potentially compromise maternal survival. It is therefore important to establish what treatments are safe for both mother and the developing fetus during pregnancy. Owing to the rarity of this association and the infrequent use of chemotherapy in pregnancy, most existing reports are anecdotal. This retrospective series is the largest published thus far and documents data from five hospitals concerning the use of chemotherapy for breast cancer in pregnant women.
PATIENTS AND METHODS
Patients who had undergone treatment with cytotoxic chemotherapy for breast cancer during pregnancy were identified from a search of the prospectively maintained Royal Marsden Hospital (London, United Kingdom) breast unit database. This search covered the period from 1986 to 2003. Additional cases were sought based on physician and nursing recall at the Royal Free, Whittington, Guy's, and King’s College Hospitals (all institutions, London, United Kingdom), covering the period from 1990 to 2003. Among them, these institutions see approximately 1,500 patients with new diagnoses of breast cancer annually. After ethical approval and retrospective patient consent (whenever possible) was acquired, a 36-item questionnaire was completed directly from patients' medical records. Details regarding diagnostic and staging investigations, standard histopathologic parameters, hormone-receptor, and human epidermal growth factor receptor 2 (HER2) status were recorded, if available. Patients were classified as having inflammatory breast cancer on the basis of clinical findings (diffuse erythematous indurated skin) or histologic evidence of the invasion of dermal lymphatics. Information was recorded regarding pre- and postpartum treatments and, in particular, types and doses of chemotherapy and their toxicities. Obstetric information documented included gestational age at diagnosis, complications of pregnancy, labor, and delivery, including fetal complications and congenital abnormalities.
RESULTS
Baseline Characteristics
Sixty-three women who were pregnant at the time of diagnosis or relapse of breast cancer were identified
28 of these women went on to receive chemotherapy while pregnant. Of these 28 women, 24 were diagnosed with stage I-IIIB disease: stage I (two women), stage II (11 women), and stage III (11 women
staging was done using the American Joint Committee on Cancer revised staging system for breast cancer5). An additional four patients were treated for metastatic disease (stage IV). Of the four patients treated for metastatic disease, two had stage IV breast cancer at presentation and two had relapsed while pregnant. The median maternal age at diagnosis was 33 years (range, 28 to 42 years). The median gestational age at diagnosis was 17 weeks (range, 4 to 33 weeks). The median duration of symptoms before histologic confirmation of diagnosis was 9 weeks (range, 2 weeks to 12 months).
Surgery
Seventeen patients underwent surgery while pregnant
10 of the 17 patients had modified radical mastectomies, and seven patients underwent breast-conserving surgery. Fifteen of the 17 patients underwent axillary surgery. The median gestational age at the time of surgery was 16 weeks (range, 5 to 29 weeks). There were no unexpected surgical or anesthetic complications. Four patients had surgery after delivery, following primary chemotherapy received while pregnant. Seven patients did not have surgery
three of these patients received neoadjuvant chemotherapy alone and four received palliative chemotherapy for metastatic disease. All seven of the patients who underwent breast-conserving surgery and seven of the 10 patients who underwent mastectomy while pregnant received postpartum radiation therapy.
Histopathology
Histopathologic characteristics of the 24 patients who presented with stage I to IIIB breast cancer while pregnant are listed in Table 1. The majority of tumors were invasive ductal carcinomas (in 86% of patients for whom this information was available). There were also high incidences of adverse prognostic features, including high tumor grade (74% of patients), lymphovascular invasion (88% of patients), and estrogen-receptor (ER) –negative tumors (42% of patients). Lymph node status was known for 18 patients, of whom 15 (83%) were node positive. Three of the tumors also exhibited inflammatory features.
Chemotherapy
Neoadjuvant chemotherapy was initiated during pregnancy in seven patients for large operable, locally advanced, or inflammatory breast cancers. Adjuvant chemotherapy was administered to 17 patients, and four patients received palliative chemotherapy for metastatic disease. A total of 116 cycles of chemotherapy were administered during pregnancy in this cohort
the median number of cycles administered prepartum was four (range, one to six). The median total number of cycles of chemotherapy administered during and after pregnancy was six (range, four to eight cycles). Fourteen of the patients received chemotherapy prepartum only, whereas the remaining 14 received chemotherapy both during and after pregnancy. The types and doses of chemotherapy administered are listed in Table 2. These chemotherapy regimes were tolerated at full doses without major complications. Three episodes of febrile neutropenia were recorded, but all patients responded to antibiotics with no additional complications. The only other grade 3 or 4 toxicities recorded were lethargy (two patients) and alopecia. Two of the patients also received granulocyte colony-stimulating factor while pregnant. No patients received endocrine therapy or radiotherapy during pregnancy.
Obstetric Characteristics
Obstetric characteristics related to chemotherapy administration are reported in Table 3. The median gestational age at the commencement of chemotherapy was 20 weeks (range, 15 to 33 weeks). Twenty-two patients started chemotherapy in the second trimester and five during the third trimester. One patient received cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy during the first trimester of her pregnancy. She was not aware that she was pregnant at the time of chemotherapy initiation, but had a positive pregnancy test shortly after the first cycle. Unfortunately, she had a spontaneous abortion before her second cycle of treatment. The median interval between the last cycle of chemotherapy and delivery was 28 days (range, 14 to 70 days). Six patients had cesarean deliveries, and an additional seven patients had their labor induced. The median gestational age at delivery was 37 weeks (range, 30 to 40 weeks). Nine children were born before 37 weeks' gestation
one case was as a result of spontaneous onset of labor. The patient who delivered at 30 weeks had an early elective cesarean delivery owing to impending spinal cord compression.
Fetal Outcome
The median gestational age at delivery was 37 weeks (range, 30 to 40 weeks). One child had a hemangioma on his abdomen, but it was not thought to be causally related to chemotherapy exposure. There were no other recorded fetal abnormalities. Birth weight was available for 17 of the infants
the median birth weight was 3.0 kg (1.4 to 3.5 kg). In the infant born weighing 1.4 kg, placental insufficiency was identified as the cause of intrauterine growth retardation, and an elective cesarean delivery was carried out at 32 weeks. However, none of the infants had a birthweight lower than the 10th percentile for gestational age.6 Two of the newborns experienced respiratory distress, and in total five newborns needed to be transferred to neonatal high dependency units.
Maternal Outcome
As of October 2003, the median follow-up period for the women in this report was 40.5 months (range, 7 to 159 months). Two of the women with stage IV disease died within 3 years of diagnosis, and the other two patients are both alive at 1 year of follow-up. At a median of 40.5 months, the combined survival rate for women with stage I to IIIB breast cancer was 67%, and the disease-free survival rate was 63%.
DISCUSSION
The purpose of conducting this retrospective review was to provide more information to breast cancer specialists and obstetricians faced with a pregnant patient with breast cancer requiring chemotherapy. We are aware of only two case series of a similar size: a French national survey7 and a series from The University of Texas M.D. Anderson Cancer Center (Houston, TX).8 The French national survey was a retrospective study based on a postal questionnaire sent to clinicians involved in the management of breast cancer diagnosed during pregnancy. Data were acquired on the histologic and clinical characteristics, treatment, obstetric complications, and pregnancy outcome of 20 women treated with chemotherapy for breast cancer while pregnant. The M.D. Anderson Cancer Center series was a prospectively designed study where patients with primary or recurrent breast cancer diagnosed during pregnancy were managed with locoregional therapy and a standard chemotherapy protocol as clinically indicated. The chemotherapy regimen used was doxorubicin 50 mg/m2 continuous infusion over a period of 72 hours, cyclophosphamide 500 mg/m2 on day 1, and bolus fluorouracil 500 mg/m2 on days 1 and 4. In the initial publication, data were presented on 24 women, two of whom had recurrent disease, and one of whom received chemotherapy during her first trimester.8 An update of this series including 39 patients has also been presented in abstract form.9
The pathologic characteristics of the tumors treated were similar to those reported in other series, in that the majority of tumors were high-grade invasive ductal carcinomas.7,10 Twenty-five of 28 patients in this study presented with pathologic lymph node involvement or metastatic disease
similarly Middleton et al10 found that only 2 of 39 patients presenting with breast cancer during pregnancy had stage I disease. Patients with breast cancer who are pregnant at the time of diagnosis have previously been shown to present with more advanced disease than matched nonpregnant patients in some,11,12 but not all,13 case-control studies. Of the 19 women with stage I to IIIB breast cancer for whom ER status was available, eight were estrogen-receptor–negative. ER-negative tumors are known to be more common in younger women,14 but in case control studies, ER-negative tumors have been shown to be more frequent in pregnant patients than in age-matched controls.11,13,15 It has also previously been observed that breast cancer in patients who are pregnant often demonstrate lymphovascular invasion, and are relatively frequently HER2-positive, though whether their frequencies are any different to those in age-matched controls is not known.11,15
The use of cytotoxic drugs during pregnancy is complicated by the potential for teratogenicity as demonstrated in animal studies, together with the risk of other direct toxic effects on the mother and fetus. During the first trimester, the fetus is undergoing organogenesis, and therefore is at its most susceptible. Chemotherapy at this stage may be associated with spontaneous abortions or an increased risk of fetal malformations.16 One of the patients in this series, and two patients in the French national survey were exposed to chemotherapy during the first trimester, and all underwent spontaneous abortions.7 However, the one patient exposed to chemotherapy during the first trimester (11 weeks) in the M.D. Anderson series experienced no apparent adverse effects.8 When live births do occur, historical studies suggest that fetal malformation rates are between 7.5% and 17%.17-20 Because of the high rates of pregnancy loss and fetal malformations, chemotherapy is generally avoided during the first trimester.
Beyond the first trimester, the use of cytotoxic chemotherapy does not appear to increase the risk of malformations. In this series, none of the 27 children exposed to chemotherapy in the second or third trimesters had congenital malformations. Sixteen of these children had been exposed to anthracyline-based chemotherapy. In the M.D. Anderson series, 23 children were exposed to anthracyline-based chemotherapy in the second and third trimesters (doxorubicin, cyclophosphamide, and fluorouracil at the doses previously described) and similarly no malformations were reported.8 Our series also included 12 patients who received CMF chemotherapy. In the first trimester, methotrexate is particularly associated with birth defects, but we can find no evidence of such an effect later in pregnancy. The French national survey identified 18 patients who received a variety of chemotherapy regimes during the second and third trimesters of pregnancy, and no fetal malformations were identified.7 Four of these patients received vinorelbine, which has previously been administered with no fetal complications.21 Case reports also describe the use of docetaxel and paclitaxel in the second and third trimesters respectively, with no adverse effects.22,23 There is no evidence from animal studies that granulocyte colony-stimulating factor is teratogenic, and there are reports of its use during pregnancy (Medical Information Department, personal communication, April 2003).24 Two patients in the current series also received granulocyte colony-stimulating factor with no significant adverse effects.
The toxic effects of cytotoxic agents are not restricted to fears over teratogenicity. Pre-eclampsia, preterm labor, intrauterine death, and low birth weights have all been reported in previous series.7,8,20,25 However, it is not known whether the incidences of these complications are in excess of those in the normal population and what the contribution of chemotherapy is relative to the effects of the underlying disease. Nine of the children were delivered before 37 weeks, and in one case premature delivery occurred as a result of spontaneous onset of preterm labor. In the remainder, early delivery was explained by induced labor or cesarean delivery in order to optimize the timing of delivery relative to chemotherapy, or, in one case, to allow treatment of spinal cord compression. Intrauterine growth retardation is likely to be underestimated in retrospective studies, though one case each was identified in the French national survey and the current study. Of the 17 babies in this series for whom birth weights were available, two had low birth weights (< 2.5 kg). Increased neonatal morbidity and mortality are recognized sequelae of intrauterine growth retardation and low birth weight (< 2.5 kg) in the normal neonatal population.26 However, none of the infants in this series and only one infant in the M.D. Anderson series had a birth weight lower than the 10th percentile for gestational age.8
Maternal and neonatal sepsis and hemorrhage are potential complications of myelosuppression, which can effect both mother and fetus at the time of delivery.7,8,27,28 No such complications were observed in this cohort, though the mean interval between delivery and the last cycle of chemotherapy was 30 days, minimizing the risk of neutropenia at the time of delivery.
The potential long-term effects of exposing the fetus to chemotherapy include gonadal dysfunction, impaired physical and neurologic development, and germ cell mutagenesis resulting in carcinogenesis and teratogenicity in subsequent generations.29 However, follow-up of children is often short and reports concerning long-term development are uncommon. The most comprehensive cohort to date describes 84 children born to mothers who were treated with combination chemotherapy during pregnancy for hematologic malignancies.30 At a median follow-up of 18.7 years, normal physical, neurologic, and psychological development was observed, with no reports of malignancies in the 84 first-generation children or in the 12 second-generation children.
Given that some transplacental transfer of anthracyclines may occur, fetal cardiotoxicity following maternal exposure to anthracyclines is another long-term concern.31,32 No cases of fetal cardiotoxicity were recorded in one large review33-35 of the use of anthracyclines in pregnancy, and no echocardiographic changes were observed when a child was monitored in utero. Unfortunately, this case series and many others on this topic are unable to adequately address such late adverse effects owing to a lack of long-term follow-up and the bias introduced by their retrospective nature. For these reasons, the ongoing analysis of the M.D. Anderson data and new prospective databases such as that initiated by the German Breast Group are of utmost importance.36
The data presented in this series provide evidence that in consideration of peripartum complications and immediate fetal outcome, chemotherapy can be safely administered to women during the second and third trimesters of pregnancy. The literature reviewed also indicates that there are unlikely to be serious adverse long-term effects on the fetus, though large prospective series are needed to confirm this. Nonetheless, on the basis of the current evidence women should not be denied the potential benefits of chemotherapy because they are pregnant at the time of diagnosis of breast cancer.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank Penny Howard, Professor John Yarnold, Geraldine Walsh, and Sarah Pearson for their help in preparing this article.
NOTES
Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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