European Journal of Cancer (2014) 50, 963– 971
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Review
Clinical management of epithelial ovarian cancer during pregnancy q Donata Grimm a, Linn Woelber a, Fabian Trillsch a, Gunhild Keller-v.Amsberg b, Sven Mahner a,⇑ a b
Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Department of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Available online 23 January 2014
KEYWORDS Epithelial ovarian cancer Pregnancy Pregnancy preserving surgery Chemotherapy
q
Abstract Epithelial ovarian cancer (EOC) in pregnancy is a rare situation. Due to its low incidence with a consecutive lack of clinical trials many questions regarding indication of different treatment approaches are unanswered. This article discusses the current literature to elaborate recommendations for the management of EOC during pregnancy. A literature search of diagnostic approaches and treatment strategies for EOC complicated by pregnancy was performed. We reviewed the available information with emphasis on surgery as well as chemotherapeutical treatment options. EOC in pregnancy is often diagnosed at early stage and no data support that concurrent pregnancy influences the growth rate or propensity for spread of EOC. Radical cytoreduction of all visible tumour followed by subsequent systemic chemotherapy is the standard treatment of EOC in most non-pregnant women. In pregnant women, however, chemotherapy as well as radical surgery should be avoided in the first trimester because of teratogenesis and high abortion rates. Besides induced abortion followed by classic management of EOC, pregnancy preserving surgery, followed by chemotherapy in the second or third trimester, timely delivery as well as neo-adjuvant chemotherapy with subsequent completing surgery appear to be viable treatment options. Conclusions: Since there is only very limited information regarding the optimal therapeutic approach to EOC during pregnancy, each case needs to be addressed individually. Treatment in specialised centres should be intended especially in this rare and challenging situation. Ó 2014 Elsevier Ltd. All rights reserved.
Research Support: This study was funded by internal departmental sources.
⇑ Corresponding author at: Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf,
Martinistrasse 52, 20246 Hamburg, Germany. Tel.: +49 407410 52510; fax: +49 407410 40070. E-mail address: [email protected] (S. Mahner). 0959-8049/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2013.12.020
964
D. Grimm et al. / European Journal of Cancer 50 (2014) 963–971
1. Introduction Ovarian masses complicate pregnancy with an overall incidence of 2.4–5.7% [1,2]. Some studies even report a higher incidence possibly explained by an increasing use of ultrasound as a routine antenatal evaluation and delay of childbearing to an older age [3–5]. Leiserowitz et al. reported 87 ovarian cancers (OC) diagnosed from 9375 ovarian masses during pregnancy with a resulting malignancy rate of 0.93% [6]. Others report an overall incidence of ovarian malignancies of 1 in 15.000 to 1 in 32.000 pregnancies [6–8]. In a population-based hospital registry study in the U.S. OC was the fifth most common cancer diagnosed during pregnancy, following breast, thyroid and cervical cancer as well as Hodgkin lymphoma [9]. The histological types of OC in pregnant and nonpregnant women are generally similar [10]. Histological differentiation is epithelial in approximately 50%, germ cell and stromal tumours are found in 30% [5,11]. In the remaining 20% rare tumour entities are diagnosed (e.g. sarcomas and metastases of other malignancies, etc.) [12]. However, epithelial ovarian cancer (EOC) is more commonly reported in pregnant patients than germ cell tumours, contrary to what is being observed in non-pregnant patients of the same age group in which the distribution is vice versa. The current review therefore focuses on the treatment of EOC in pregnant women. Management of EOC in pregnant women (diagnostic approach, surgical procedures as well as chemotherapy regimens) differs from that in non-pregnant women and depends upon stage, type, gestational age (GA) and metastatic spread [8,13–16]. This article reviews the current literature to elaborate suggestions for clinical management of EOC diagnosed during pregnancy. 2. Methods We reviewed the available literature on treatment of EOC during pregnancy with emphasis on surgical and chemotherapeutical strategies. A Medline database search was performed using the key words: ‘ovarian tumour’ and ‘pregnancy’. We selected studies reporting on malignant tumours with emphasis on EOC [6–8,17– 19]. With regard to chemotherapeutical agents we systematically searched for drug names (such as ‘cisplatin’, ‘carboplatin’ and ‘paclitaxel’) and ‘pregnancy’. 3. Results 3.1. Diagnostic considerations EOC is diagnosed either during pregnancy, coincidental at time of delivery (e.g. during caesarean section), or in the puerperium. Except in cases of an acute
abdomen by ovarian torsion [20,21], ovarian tumours in pregnant (and non-pregnant) women are usually clinically unapparent and only incidentally found at ultrasound examination or surgery [22,23]. During pregnancy the clinical examination of ovarian masses is exceedingly difficult. Generally, in the first trimester vaginal and in the 2nd and 3rd trimester abdominal ultrasound is performed. Criteria for suspected malignancy are similar to those in non-pregnant women [24]. Adnexal masses that persist until the second trimester, or are larger than 5 cm in diameter, or have solid or mixed solid and cystic ultrasound characteristics are suspicious and should be surgically resected [6,19,25–27]. In most cases vaginal and abdominal ultrasound examination are sufficient to indicate surgery [16,28]. In some cases additional imaging like magnetic resonance imaging (MRI) might be useful e.g. to distinguish between degenerating myoma and ovarian neoplasm [19,29]. CA 125 is often physiologically elevated in pregnancy with wide spontaneous fluctuations, mainly at first trimester and immediately after delivery because of chorionic invasion [30]. In 2nd and 3rd trimester CA 125 levels are low in maternal serum but high in the amniotic fluid [12]. If EOC is proven, CA 125 levels can be best determined postpartum as baseline evaluation.
3.2. Preoperative considerations Surgery in pregnant women is more difficult and carries several risks. Therefore, risks related to pregnancy and risks related to presumed OC must be balanced deliberately. Preoperatively, a multidisciplinary discussion involving experienced gynaecological oncologists, obstetricians, psychologists and anaesthesiologists is highly desirable [19]. Thorough foetal ultrasound before initiation of surgery (or chemotherapy) is advisable for surgical planning as well as for judicial reasons. Further decision making regarding surgery for adnexal masses is depended upon the GA (Fig. 1). Medically induced abortion followed by standard treatment of EOC is a potential option especially in the first trimester. If a pregnancy preserving approach is warranted, surgery and chemotherapy should be avoided during 1st trimester because of higher abortion rates [8,22], most likely due to disruption of the corpus luteum [31]. If the procedure is indispensable progestin support with daily intramuscular injection of 100 mg progesterone or a 100 mg transvaginal suppository every 12 h should be provided postoperatively [32]. The safest period for elective surgical intervention is during the 2nd trimester. Corticosteroids for foetal lung maturation should be applied at least 48 h prior to surgery for GA between 24 and 34 weeks if laparoscopy or laparotomy is indicated semi-electively [33]. Prophylactic perioperative tocolytic therapy is controversial [22]: Visser et al. [34] indicate that at least in the 2nd
D. Grimm et al. / European Journal of Cancer 50 (2014) 963–971
1st trimester
2nd trimester
965
3rd trimester
Consider pregnancy termination followed by standard treatment
Consider treatment delay with close observation
Progesterone suppository (until 16 weeks GA)
If possible, radical pregnancy conserving surgery (laparotomy)
Lung maturation (24-34 weeks GA)
Neoadjuvant CTX
FIGO IA-IIA
Staging with unilateral or bilateral salpingo-ophorectomy, peritoneal washings, omentectomy, multiple peritoneal biopsies, appendectomy, lymphadenectomy
Tocolysis (24-34 weeks GA)
Thromboprophylaxis 1x40mg enoxaparin s.c.
Diagnostic pregnancy conserving surgery (laparoscopy or laparotomy)
Delivery (Preterm induction of labor and vaginal delivery or cesarean section)
FIGO IIB-IV
Radical cytoreduction
Postoperative CTX if indicated
Radical surgery following delivery (laparotomy)
Secondary total abdominal hysterectomy and bilateral salpingo-ophorectomy and completion of surgery if not yet performed
Fig. 1. Suggested Algorithm for perioperative management in (suspected) pregnancy-associated ovarian cancer (CTX, chemotherapy; GA, gestational age).
trimester, prophylactic tocolytic therapy during surgical intervention can reduce preterm labour and premature delivery. Preoperative tocolytic prophylaxis (Indocin or Terbutaline) was administered in 28 cases, and no uterine contractions occurred in 24 (86%) [34]. Before induction of anaesthesia, the patient should be placed in left lateral oblique position to prevent inferior vena cava compression and supine hypotension syndrome as well as to improve uterine blood flow [35]. Also, proper precautions against maternal aspiration must be implemented [36]. One of the most serious risks to the foetus during maternal surgery is intrauterine asphyxia and must be avoided by maintaining hemodynamic stability and maternal oxygenation. 3.3. General surgical considerations According to FIGO requirements, proper staging of apparently early EOC (
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Review
Clinical management of epithelial ovarian cancer during pregnancy q Donata Grimm a, Linn Woelber a, Fabian Trillsch a, Gunhild Keller-v.Amsberg b, Sven Mahner a,⇑ a b
Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Department of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Available online 23 January 2014
KEYWORDS Epithelial ovarian cancer Pregnancy Pregnancy preserving surgery Chemotherapy
q
Abstract Epithelial ovarian cancer (EOC) in pregnancy is a rare situation. Due to its low incidence with a consecutive lack of clinical trials many questions regarding indication of different treatment approaches are unanswered. This article discusses the current literature to elaborate recommendations for the management of EOC during pregnancy. A literature search of diagnostic approaches and treatment strategies for EOC complicated by pregnancy was performed. We reviewed the available information with emphasis on surgery as well as chemotherapeutical treatment options. EOC in pregnancy is often diagnosed at early stage and no data support that concurrent pregnancy influences the growth rate or propensity for spread of EOC. Radical cytoreduction of all visible tumour followed by subsequent systemic chemotherapy is the standard treatment of EOC in most non-pregnant women. In pregnant women, however, chemotherapy as well as radical surgery should be avoided in the first trimester because of teratogenesis and high abortion rates. Besides induced abortion followed by classic management of EOC, pregnancy preserving surgery, followed by chemotherapy in the second or third trimester, timely delivery as well as neo-adjuvant chemotherapy with subsequent completing surgery appear to be viable treatment options. Conclusions: Since there is only very limited information regarding the optimal therapeutic approach to EOC during pregnancy, each case needs to be addressed individually. Treatment in specialised centres should be intended especially in this rare and challenging situation. Ó 2014 Elsevier Ltd. All rights reserved.
Research Support: This study was funded by internal departmental sources.
⇑ Corresponding author at: Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf,
Martinistrasse 52, 20246 Hamburg, Germany. Tel.: +49 407410 52510; fax: +49 407410 40070. E-mail address: [email protected] (S. Mahner). 0959-8049/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2013.12.020
964
D. Grimm et al. / European Journal of Cancer 50 (2014) 963–971
1. Introduction Ovarian masses complicate pregnancy with an overall incidence of 2.4–5.7% [1,2]. Some studies even report a higher incidence possibly explained by an increasing use of ultrasound as a routine antenatal evaluation and delay of childbearing to an older age [3–5]. Leiserowitz et al. reported 87 ovarian cancers (OC) diagnosed from 9375 ovarian masses during pregnancy with a resulting malignancy rate of 0.93% [6]. Others report an overall incidence of ovarian malignancies of 1 in 15.000 to 1 in 32.000 pregnancies [6–8]. In a population-based hospital registry study in the U.S. OC was the fifth most common cancer diagnosed during pregnancy, following breast, thyroid and cervical cancer as well as Hodgkin lymphoma [9]. The histological types of OC in pregnant and nonpregnant women are generally similar [10]. Histological differentiation is epithelial in approximately 50%, germ cell and stromal tumours are found in 30% [5,11]. In the remaining 20% rare tumour entities are diagnosed (e.g. sarcomas and metastases of other malignancies, etc.) [12]. However, epithelial ovarian cancer (EOC) is more commonly reported in pregnant patients than germ cell tumours, contrary to what is being observed in non-pregnant patients of the same age group in which the distribution is vice versa. The current review therefore focuses on the treatment of EOC in pregnant women. Management of EOC in pregnant women (diagnostic approach, surgical procedures as well as chemotherapy regimens) differs from that in non-pregnant women and depends upon stage, type, gestational age (GA) and metastatic spread [8,13–16]. This article reviews the current literature to elaborate suggestions for clinical management of EOC diagnosed during pregnancy. 2. Methods We reviewed the available literature on treatment of EOC during pregnancy with emphasis on surgical and chemotherapeutical strategies. A Medline database search was performed using the key words: ‘ovarian tumour’ and ‘pregnancy’. We selected studies reporting on malignant tumours with emphasis on EOC [6–8,17– 19]. With regard to chemotherapeutical agents we systematically searched for drug names (such as ‘cisplatin’, ‘carboplatin’ and ‘paclitaxel’) and ‘pregnancy’. 3. Results 3.1. Diagnostic considerations EOC is diagnosed either during pregnancy, coincidental at time of delivery (e.g. during caesarean section), or in the puerperium. Except in cases of an acute
abdomen by ovarian torsion [20,21], ovarian tumours in pregnant (and non-pregnant) women are usually clinically unapparent and only incidentally found at ultrasound examination or surgery [22,23]. During pregnancy the clinical examination of ovarian masses is exceedingly difficult. Generally, in the first trimester vaginal and in the 2nd and 3rd trimester abdominal ultrasound is performed. Criteria for suspected malignancy are similar to those in non-pregnant women [24]. Adnexal masses that persist until the second trimester, or are larger than 5 cm in diameter, or have solid or mixed solid and cystic ultrasound characteristics are suspicious and should be surgically resected [6,19,25–27]. In most cases vaginal and abdominal ultrasound examination are sufficient to indicate surgery [16,28]. In some cases additional imaging like magnetic resonance imaging (MRI) might be useful e.g. to distinguish between degenerating myoma and ovarian neoplasm [19,29]. CA 125 is often physiologically elevated in pregnancy with wide spontaneous fluctuations, mainly at first trimester and immediately after delivery because of chorionic invasion [30]. In 2nd and 3rd trimester CA 125 levels are low in maternal serum but high in the amniotic fluid [12]. If EOC is proven, CA 125 levels can be best determined postpartum as baseline evaluation.
3.2. Preoperative considerations Surgery in pregnant women is more difficult and carries several risks. Therefore, risks related to pregnancy and risks related to presumed OC must be balanced deliberately. Preoperatively, a multidisciplinary discussion involving experienced gynaecological oncologists, obstetricians, psychologists and anaesthesiologists is highly desirable [19]. Thorough foetal ultrasound before initiation of surgery (or chemotherapy) is advisable for surgical planning as well as for judicial reasons. Further decision making regarding surgery for adnexal masses is depended upon the GA (Fig. 1). Medically induced abortion followed by standard treatment of EOC is a potential option especially in the first trimester. If a pregnancy preserving approach is warranted, surgery and chemotherapy should be avoided during 1st trimester because of higher abortion rates [8,22], most likely due to disruption of the corpus luteum [31]. If the procedure is indispensable progestin support with daily intramuscular injection of 100 mg progesterone or a 100 mg transvaginal suppository every 12 h should be provided postoperatively [32]. The safest period for elective surgical intervention is during the 2nd trimester. Corticosteroids for foetal lung maturation should be applied at least 48 h prior to surgery for GA between 24 and 34 weeks if laparoscopy or laparotomy is indicated semi-electively [33]. Prophylactic perioperative tocolytic therapy is controversial [22]: Visser et al. [34] indicate that at least in the 2nd
D. Grimm et al. / European Journal of Cancer 50 (2014) 963–971
1st trimester
2nd trimester
965
3rd trimester
Consider pregnancy termination followed by standard treatment
Consider treatment delay with close observation
Progesterone suppository (until 16 weeks GA)
If possible, radical pregnancy conserving surgery (laparotomy)
Lung maturation (24-34 weeks GA)
Neoadjuvant CTX
FIGO IA-IIA
Staging with unilateral or bilateral salpingo-ophorectomy, peritoneal washings, omentectomy, multiple peritoneal biopsies, appendectomy, lymphadenectomy
Tocolysis (24-34 weeks GA)
Thromboprophylaxis 1x40mg enoxaparin s.c.
Diagnostic pregnancy conserving surgery (laparoscopy or laparotomy)
Delivery (Preterm induction of labor and vaginal delivery or cesarean section)
FIGO IIB-IV
Radical cytoreduction
Postoperative CTX if indicated
Radical surgery following delivery (laparotomy)
Secondary total abdominal hysterectomy and bilateral salpingo-ophorectomy and completion of surgery if not yet performed
Fig. 1. Suggested Algorithm for perioperative management in (suspected) pregnancy-associated ovarian cancer (CTX, chemotherapy; GA, gestational age).
trimester, prophylactic tocolytic therapy during surgical intervention can reduce preterm labour and premature delivery. Preoperative tocolytic prophylaxis (Indocin or Terbutaline) was administered in 28 cases, and no uterine contractions occurred in 24 (86%) [34]. Before induction of anaesthesia, the patient should be placed in left lateral oblique position to prevent inferior vena cava compression and supine hypotension syndrome as well as to improve uterine blood flow [35]. Also, proper precautions against maternal aspiration must be implemented [36]. One of the most serious risks to the foetus during maternal surgery is intrauterine asphyxia and must be avoided by maintaining hemodynamic stability and maternal oxygenation. 3.3. General surgical considerations According to FIGO requirements, proper staging of apparently early EOC (
