Nicholas Pavlidis1 and George Zarkavelis1
(1)
Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece
Nicholas Pavlidis
Email: npavlid@uoi.gr
Keywords
PregnancyLung cancerSystemic treatmentSurvivalPlacenta and fetal invasionThymomas
Lung Cancer
Introduction
The purpose of this chapter is to review the therapeutic management and outcome of thoracic tumors during pregnancy. Solid gestational malignant tumors of the lower respiratory tract are rarely documented. Among the chest malignancies diagnosed during pregnancy, lung cancer is the most common cancer followed by thymomas and very rarely by pleural mesothelioma.
Cancer diagnosed during pregnancy is a rare phenomenon complicating one out of 1000 pregnancies. The most frequent diagnosed cancers are obviously those with a peak incidence during woman’s reproductive years such as breast and cervical cancer, melanoma, and lymphoma. Lung, gastrointestinal, and urological epithelial malignancies are very rarely diagnosed during gestation [1–3].
Lung cancer is one of the most common killers in developed societies with high cancer-related mortality [4]. Although the incidence of lung cancer is still low during pregnancy, it will be probably increased due to both cigarette smoking in young women and to delaying childbearing to later in life [1].
Non-small cell lung cancer (NSCLC) is the most frequent histological type accounting for 80 % of all cases, followed by small cell lung cancer (SCLC) which constitutes the rest 20 % of patients. Usually, both types of lung cancer are diagnosed in advanced stages where treatment is mainly palliative. Overall survival remains poor. It is generally characterized as a clinically aggressive disease with high predilection to involve placenta and/or fetus.
During the last 15 years, 66 cases of lung cancer, mostly NSCLC, have been reported in the literature [5, 7–12].
Reported Cases
We searched the Medline and the International Cancer in Pregnancy registration study (CIP study; www.cancerinpregnancy.org) registered with clinical/trials. Gov, number NCT00330447).
Demographics
Since 1998, 66 pathologically confirmed gestational lung cancer cases have been published. The median patients’ age was 36 years old, ranging from 17 to 45 years, and the median maternal gestational age was 27.3 months [5–12].
Histopathologically, the most common type was NSCLC. Eighty-two percent of patients were diagnosed with NSCLC, while only 18 % with SCLC.
Smoking history was present in 35 % of pregnant mothers and absent in 27 %, and no information was available for the rest of the patients.
Ninety-seven percent of patients were diagnosed in advanced clinical stages (III–IV) indicating that lung cancer during pregnancy doesn’t behave as a slowly growing tumor (Table 16.1) [5, 7–12].
Table 16.1
Demographics of patients with gestational lung cancers: literature review
|
Total number of cases (%) |
|
|
Number of patients (total) |
66 |
|
Median age (years) |
36 (17–45) |
|
Gestational week at diagnosis |
27.3 (8–38) |
|
Histopathology |
|
|
NSCLC |
5.4 (8 %) |
|
SCLC |
12 (18 %) |
|
Smoking history |
|
|
Absent |
18 (27 %) |
|
Present |
23 (35 %) |
|
Unknown |
25 (38 %) |
|
Stage |
|
|
Early (I–II) |
1 (1.5 %) |
|
Advanced (III–IV) |
64 (97 %) |
|
Unknown |
1 (1.5 %) |
Treatment and Outcome
Thirty-four patients (51.5 %) were treated postpartum and 16 (24 %) during gestational period. Platinum-based chemotherapy was administered in 40 patients (60.5 %), whereas five patients (7.5 %) received targeted treatment, four with erlotinib or gefitinib and two with crizotinib. All of these patients were positive for EGFR or EML4-ALK mutations. Only three patients were treated with palliative radiotherapy. No major responses to chemotherapy have been observed, while targeted treatment offered disease stability for several months. Nevertheless, not adequate data are available to support the use of targeted treatment during pregnancy.
Maternal survival was very poor. Twelve percent died within 1 month during postpartum period, and 70 % had an overall survival of a few months. Only 12 patients, mainly those diagnosed with early-stage disease, experienced longer survival.
Eighty-two percent of the newborns were born healthy. Metastatic disease to the products of conception was detected in 14 cases, 11 on the placenta and three on the fetuses [5, 7–12] (Table 16.2).
Table 16.2
Treatment and outcome of patients with gestational lung cancer: literature review
|
Number of patients |
|
|
Treatment |
|
|
During gestation |
16 (24 %) |
|
Postpartum |
34 (51.5 %) |
|
No treatment |
9 (13.5 %) |
|
Unknown |
7 (11 %) |
|
Chemotherapy |
40 (60.5 %) |
|
Erlotinib/gefitinib |
4 (6 %) |
|
Crizotinib |
2 (3 %) |
|
Radiotherapy |
3 (4.5 %) |
|
Maternal outcome (from diagnosis) |
|
|
Death 1 month postpartum |
8 (12 %) |
|
Alive in 3–5 months |
26 (39.5 %) |
|
Alive in 6–11 months |
20 (30.5 %) |
|
Alive in 12 months or more |
12 (18 %) |
|
Products of conception (outcome) |
|
|
Abortion (induced/spontaneous) |
6/1 |
|
Healthy baby |
54 (82 %) |
|
Fetal metastases |
3 (4.5 %) |
|
Placental metastases |
11 (17 %) |
|
Unknown |
1 |
Thymic Tumors
Thymic tumors are rare neoplasms with a peak incidence from 55 to 65 years accounting for less than 1 % of adult cancers. According to the World Health Organization (WHO), thymic tumors are classified as thymomas (types A, AB, B1, B2, B3) or as thymic carcinomas (type C). Presenting symptoms include local pain, dyspnea, or superior vena cava syndrome and occur more commonly in association with autoimmune or other immunological diseases.
These tumors are rarely diagnosed during pregnancy. In the literature, there are only 13 cases reported, all of which are thymomas of various WHO types (Table 16.3) [13, 14].
Table 16.3
Thymic tumors in pregnancy
|
Total number |
13 |
|
Median age (years) |
25.5 (19–34) |
|
Median size (at diagnosis) |
7.6 cm (4–17.3) |
|
WHO type |
|
|
A |
1/13 |
|
AB |
2/13 |
|
B1 |
1/13 |
|
B2 |
1/13 |
|
B3 |
3/13 |
|
C |
0/13 |
|
Unknown |
5/13 |
|
Stage (Masaoka) |
|
|
Early (I–II) |
2 (15 %) |
|
Advanced (>II–Iva) |
9 (70 %) |
|
Unknown |
2 (15 %) |
|
Treatment |
|
|
Resection |
6/13 (46 %) |
|
Radiation |
6/13 (46 %) |
|
Chemotherapy |
1/13 (8 %) |
|
Pregnancy termination |
2/13 (15 %) |
|
No treatment |
1/13 (8 %) |
|
Survival |
4 months–4 years |
Pleural Mesothelioma
Malignant pleural mesothelioma in pregnancy is an extremely rare neoplasm. There is only one report published in 2000 with a 37-year-old pregnant woman presented at 18 weeks with thoracic and shoulder pain, massive pleural effusion, and a large thoracic mass. Biopsy was compatible with an undifferentiated sarcomatoid pleural mesothelioma [15].
Discussion
Female lung cancer mortality is still rising in Europe, whereas there is evidence that smoking women have a double risk of developing lung cancer compared to male population [16, 17]. However, the analysis of the present data revealed that less than half of pregnant women with lung cancer had a positive smoking history. Therefore, it becomes obvious that cigarette smoking is not the only etiological factor in these young women. In addition, there are scarce available data showing that the EGFR and ALK activation mutations are present in these patients [12].
NSCLC of adenocarcinoma type was the most frequent histology accounting for almost 80 % of the cases. More than 90 % of the reported patients presented with locally or disseminated advanced disease, indicating that lung cancer during pregnancy seems to have an aggressive behavior.
Systemic treatment was provided in almost 50 % of the patients during the postpartum period of gestation. Most patients received combination chemotherapy mainly with platinum-based regimens. Both response rates and survival were poor. Overall survival ranges between 3 and 9 months, whereas 12 % of women died within the first month postpartum. Patients with early-stage disease experienced longer survival of 12 or more months [5, 6].
In general, chemotherapy administration during the first trimester is not recommended due to harmful or lethal effects on the fetus. However, selected chemotherapeutic agents such as carboplatin and paclitaxel can be safely provided during the second and third trimesters [18–20].
Targeting anticancer treatment, especially tyrosine kinase inhibitors (TKIs), is not recommended during pregnancy. Nevertheless, there are already six cases published, two with erlotinib, one with gefitinib, one with erlotinib followed by gefitinib, and two with crizotinib [2, 12]. In half of the cases, small molecules were given during an unrecognized pregnancy and in the rest after delivery. No major responses were seen. In addition, no fetuses’ abnormalities or congenital malformations have been observed. Since adequate data on the use of EGFR–TKIs are not available, these agents should be avoided during pregnancy [21].
Usually, pregnant women with cancer are delivering babies without anomalies, although newborn prematurity including complications such as respiratory distress, seizures, or ventricular hemorrhage has been previously reported [1, 2]. Eighty-two percent of babies born in our cohort were found to be completely healthy infants.
Melanoma, cancer of unknown primary, and breast cancer are well-known tumors being most commonly associated with involvement of the products of conception [22, 23]. During the last 20 years, lung cancer has been recognized as an additional tumor with a high predilection to vertical transmission of cancer cells to both placenta and fetus. Up to now, 11 pregnant mothers with lung cancer were found to have placental metastases (17 %), while three fetuses were born with metastatic sites (4.5 %). Due to the relatively high incidence of placental or fetal involvement in gestational lung cancer, it is recommended that placentas should be submitted for histopathological examination along with umbilical cord cytology and neonates should be clinically examined for palpable skin deposits or organomegaly. A close follow-up of all babies every 6 months for 2 years with physical examination, chest X-ray, and liver function tests including serum lactate dehydrogenase is mandatory [5, 23, 24].
In conclusion, gestational lung cancer is becoming an emerging issue, and therefore, both oncologists and gynecologists should be aware of the following related to lung cancer in pregnant women: (a) lung cancer is diagnosed in advanced stages with an aggressive behavior, (b) systemic treatment offers poor results, (c) overall survival is dismal, and (d) placenta and fetus are often involved by transmitted cancer cells, requiring thorough examination of the products of conception. A retrospective as well as a prospective testing for EGFR- and ALK-activating mutations is desperately needed in order to more effectively treat gestational lung cancer.
Thymic tumors and pleural mesotheliomas are extremely rare tumors during pregnancy, and by all means, they are not becoming an emerging issue in daily oncologic practice [13–15].
References
1.
Pentheroudakis G, Pavlidis N. Cancer and pregnancy: Poena magna, not anymore. Eur J Cancer. 2006;42(2):126–40.CrossRefPubMed
2.
Voulgaris E, Pentheroudakis G, Pavlidis N. Cancer and pregnancy: a comprehensive review. Surg Oncol. 2011;20(4):e175–85.CrossRefPubMed
3.
Pentheroudakis G, Pavlidis N. Gastrointestinal, urologic and lung malignancies during pregnancy. Recent results. Cancer Res. 2008;178:137–64.
4.
Jemal A, Siegel R, Ward E, et al. Cancer statistics 2006. CA Cancer J Clin. 2006;56:106–30.CrossRefPubMed
5.
Boussios S, Han SN, Fuscio R, et al. Lung cancer in pregnancy: report of nine cases from an international collaborative study. Lung Cancer. 2013;82:499–505.CrossRefPubMed
6.
Azim Jr HA, Peccatori FA, Pavlidis N. Lung cancer in the pregnant woman: to treat or not to treat, that is the question. Lung Cancer. 2010;67:251–6.CrossRefPubMed
7.
Hayama M, Chida M, Tamura M, et al. Unexpected rapid growth of estrogen receptor positive lung cancer during pregnancy. Ann Thorac Cardiovasc Surg. 2014;20:325–8.CrossRefPubMed
8.
Sariman N, Levent E, Yener NA, et al. Lung cancer and pregnancy. Lung Cancer. 2013;79:321–3.CrossRefPubMed
9.
Cearisk M, Hostikc S, Sajin M, et al. Gestational lung adenocarcinoma: case report. Int J Surg Pathol. 2014;22(7):663–6.CrossRef
10.
Kim JW, Kim JS, Cho JY, Lee DH. Successful video-assisted thorocoscopic lobectomy in a pregnant woman with lung cancer. Lung Cancer. 2014;85:331–4.CrossRefPubMed
11.
Neves I, Mota PC, Hespanhol VP. Lung cancer during pregnancy: an unusual case. Rev Port Pneumol. 2014;20(1):46–9.CrossRefPubMed
12.
Gil S, Goetgheluck J, Paci A, et al. Efficacy and safety of Gefitinib during pregnancy: case report and literature review. Lung Cancer. 2014;85:481–4.CrossRefPubMed
13.
Hechtman JF, Chepovetisky JA, Strauchen JA, et al. Thymomas diagnosed during pregnancies: two cases in young women without paraneoplastic or autoimmune disease. Ann Diagn Pathol. 2012;16(5):392–6.CrossRefPubMed
14.
McLaughlin SS, Peckham SJ, Enis JA, et al. Young woman with thymoma metastatic to the brain controlled with gross total resection and stereotactic radiosurgery, with a subsequent uncomplicated pregnancy. J Clin Oncol. 2011;29(2):e30–3.CrossRefPubMed
15.
Ramsey PS, Danilenko-Dixon DR, Ramin KD, Ogbwrn Jr PL. Malignant pleural mesothelioma in pregnancy. J Matern Fetal Med. 2000;9(6):373–5.CrossRefPubMed
16.
Wang A, Kubo J, Luo J, et al. Active and passive smoking in relation to lung cancer incidence in the Women’s Health Initiative Observational Study prospective cohort. Ann Oncol. 2015;26(1):221–30.CrossRefPubMedPubMedCentral
17.
Lortet-Tieulent J, Soerjomataram I, Ferlay J, et al. International trends in lung cancer by histological type: adenocarcinoma stabilizing in men but still increasing in women. Lung Cancer. 2014;84(1):13–22.CrossRefPubMed
18.
Azim Jr HA, Peccatori FA, Pavlidis N. Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part I: solid tumors. Cancer Treat Rev. 2010;36(2):101–9.CrossRefPubMed
19.
Azim Jr HA, Pavlidis N, PeccatorI FA. Treatment of the pregnant mother with cancer: a systematic review of the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part II: hematologic tumors. Cancer Treat Rev. 2010;36(2):110–21.CrossRefPubMed
20.
Amant F, Han SN, Gziri MM, et al. Chemotherapy during pregnancy. Curr Opin Oncol. 2012;24:580–6.CrossRefPubMed
21.
Lambertini M, Peccatori FA, Azim Jr HA. Targeted agents for cancer treatment during pregnancy. Cancer Treat Rev. 2015;41(4):301–9.CrossRefPubMed
22.
Pavlidis N, Petheroudakis G. Metastatic involvement of placenta and foetus in pregnant women with cancer. Recent Results Cancer Res. 2008;178:183–94.CrossRefPubMed
23.
Pavlidis N, Peccatori FA, Lofts F, Greco AF. Cancer of unknown primary during pregnancy: an exceptionally rare coexistence. Anticancer Res. 2011;35(1):575–9.
24.
Jackisch C, Louwen F, Schwenkhagen A, et al. Lung cancer during pregnancy involving the products of conception and a review of the literature. Arch Gynecol Obstet. 2003;268:69–77.PubMed