Oxford Case Histories in Oncology

Case 3.

Small cell lung cancer during pregnancy

Thankamma Ajithkumar

Case history

A 37-year-old woman presented with pneumonia for which she received intravenous antibiotics. Six months later she re-presented with left-sided chest discomfort and increasing breathlessness. She was 21 weeks pregnant. She was afebrile, and her blood tests were unremarkable. She had a chest X-ray (Fig. 3.1).

Fig. 3.1

Questions

1. What does the chest X-ray show and what are the differential diagnoses?

2. How will you investigate further?

Answers

1. What does the chest X-ray show and what are the differential diagnoses?

The chest X-ray shows a haziness of the left lower zone with a possible left hilar shadow and obliteration of the left costophrenic angle. The differential diagnoses include infection, pleural effusion, interstitial lung disease, pulmonary embolism, drug-induced lung abnormalities, and malignancy.

2. How will you investigate further?

Cancer during pregnancy poses a challenging situation in terms of providing optimal care to the woman without harming the foetus. Radiological investigations should be undertaken only if absolutely necessary and foetal exposure to ionizing radiation should be kept to a safe level. Foetal radiation exposure at a dose of 1mGy is considered to be safe, but foetal exposure at doses of >1–2cGy should especially be avoided during the first trimester (organogenesis) and the second trimester (continuing development of brain, teeth, and eyes) (see Table 3.1). Chest X-ray, ultrasound examination, upper gastrointestinal (GI) endoscopy, bronchoscopy, lumbar puncture, and bone marrow examination are safe. MRI is safe and can be useful for ruling out brain and liver metastases, though gadolinium should be avoided during the first trimester. Abdominal–pelvic CT and radio-isotope scans should be avoided. However, CT scans are not absolutely contraindicated in pregnancy. They can be performed if there is a safe distance between the radiation field and the uterus such as to keep foetal radiation exposure to below 1cGy (e.g. head and neck, extremities, and a limited area of chest) (Table 3.2). A bronchoscopic evaluation and ultrasound scan of the abdomen to rule out liver metastasis are safe. If a radiological physicist is available to calculate the foetal radiation dose, the woman can have a limited CT scan of the chest.

Table 3.1 Radiation dose to uterus/foetus during various radiological investigations

Table 3.2 Foetal radiation dose during radical radiotherapy of various tumour sites

She had a limited CT scan of the chest with abdominal shielding (Fig. 3.2).

Fig. 3.2

Question

3. What does the CT scan show?

Answer

3. What does the CT scan show?

The CT scan shows a bulky mediastinal lymphadenopathy, predominantly on the left side (3.2A) associated with a mass in the left lower lobe of the lung surrounding the left main bronchus, causing narrowing of the lumen (3.2B). There is also associated thickening of the horizontal fissure. No pleural effusion or bone disease is evident on the available scans.

The radiological appearances of different subtypes of lung cancer vary. Small cell lung cancer typically presents as large central masses with atelectasis and extensive mediastinal lymphadenopathy. Squamous cell carcinoma presents as a large central tumour with atelectasis and mediastinal lymphadenopathy. Adenocarcinoma presents as small peripheral lesions with a high propensity for nodal and distant spread. Large cell carcinoma presents as large peripheral lesions with a high propensity for regional lymph nodes and distant metastasis.

Bronchoscopic biopsy showed small cell lung cancer, and abdominal ultrasound did not show any liver metastasis.

Questions

4. What are the challenges in the management of this woman?

5. Outline your management.

Answers

4. What are the challenges in the management of this woman?

From the available information, this woman, who is more than 21 weeks’ pregnant, has a limited stage small cell lung cancer. Small cell lung cancer grows rapidly and the median survival is 2–4 months without treatment. The standard management is concurrent chemoradiotherapy followed by prophylactic cranial irradiation (PCI), which results in a median survival of 15–20 months with 20–40% surviving to 2 years. Her pregnancy is well into second trimester, which makes a medical termination risky. Thus, she needs urgent treatment while continuing pregnancy.

Most chemotherapy drugs have a molecular weight of <600kDa, and therefore can cross the placenta. Chemotherapy during the first trimester is associated with a 17–25% risk of malformations or foetal death and hence is best avoided. Chemotherapy may be given relatively safely during the second or third trimester, with a 5–7% incidence of intrauterine growth retardation, a 5% incidence of still birth, a 5% incidence of premature delivery, a 4% incidence of bone narrow suppression, and a 3–5% incidence of foetal death. There are no data on the safety of new targeted agents.

5. Outline your management.

Radiotherapy is contraindicated at this stage. The best option is to treat her with chemotherapy until elective delivery of the foetus. The standard chemotherapy regimen for small cell lung cancer is cisplatin/etoposide. Cisplatin has been used safely during pregnancy to treat non-small cell lung cancer, ovarian cancer, and cervical cancer at a dose similar to the standard dose in a non-pregnant woman. However, there are limited data on the safety of etoposide in pregnancy.

A multidisciplinary approach, including input from gynaecologists and neonatologists, is needed to coordinate care of the woman and her foetus. The patient can be treated with chemotherapy until 3 weeks prior to elective delivery.

A recommendation to start a combination of cisplatin/etoposide at the non-pregnant standard dose for four courses followed by elective delivery of the foetus was made.

A chest X-ray after four courses of chemotherapy showed complete resolution of the previously noted left lung shadow. Subsequently she had an elective caesarean section and a healthy baby girl was delivered.

Questions

6. What are the important aspects of delivery and post-partum management?

7. What would be your further management of small cell lung cancer?

Answers

6. What are the important aspects of delivery and post-partum management?

Elective delivery is generally planned after 32–35 weeks’ gestation (earlier in modern neonatal units which have a better outcome for babies) and 3 weeks after the last chemotherapy to allow for full bone marrow recovery of the woman and foetus and for placental drug excretion from the foetus. Since there is a risk of placental metastasis, the placenta should be sent for histopathological examination. The baby needs a full clinical examination for any obvious metastasis. Breast feeding is not recommended during and up to 2–4 weeks after completion of systemic cancer treatment. With platinum-based chemotherapy during pregnancy, there is a concern that any non-renally excreted drug will be retained within the tissue which may affect later development of the child (e.g. neural), although there is little evidence of this. The optimal follow-up of a healthy baby is not known.

7. What would be your further management of small cell lung cancer?

Following delivery, this woman needs re-staging, including a CT scan of the brain, chest, abdomen, and pelvis followed by further treatment. Patients with limited stage small cell lung cancer are treated with chemotherapy along with concurrent radiotherapy, which improves 3-year survival by 5.4%. Patients generally receive four to six courses of platinum-based chemotherapy. Meta-analyses show that early radiotherapy improves long-term survival, and a short time between the first day of chemotherapy and the last day of thoracic radiotherapy is also associated with improved survival. However, there is no evidence to recommend concurrent chemoradiotherapy at this stage, though it is an option. In the absence of progressive disease after initial treatment, PCI is also recommended. This improves 3-year survival by 6% and results in a better disease-free survival and lower cumulative incidence of subsequent brain metastases.

Restaging did not show any evidence of residual disease. She subsequently received radiotherapy to the chest concurrent with the fifth course of chemotherapy, and after six courses of chemotherapy she underwent PCI.

Five months after the completion of PCI, she presented with persistent vomiting for 2 weeks. She denied any headache, convulsions, or chest symptoms. Her ECOG performance status was 0. Clinical examination and CT staging (including of the brain) was normal. She underwent a gadolinium-enhanced MRI scan (Fig. 3.3).

Fig. 3.3

Questions

8. What does the MRI show?

9. How will you manage her?

Answers

8. What does the MRI show?

MRI shows irregular leptomeningeal enhancement. There is also an irregular contrast-enhancing intramedullary lesion in the cervical spinal cord. This appearance is suggestive of leptomeningeal carcinomatosis.

9. How will you manage her?

She needs restaging with CT scan of the chest and abdomen and examination of the cerebrospinal fluid (CSF). CSF examination will show increased opening pressure, increased leukocytes, elevated protein, and decreased glucose. Malignant cells may be seen in >80% of cases. If malignant cells are seen in the CSF, repeat CSF examination will be useful to assess response to and to guide intrathecal treatment.

Since she has radiological evidence of leptomeningeal disease with a threatening lesion in the cervical cord and is of ECOG performance status 0, she would benefit from urgent radiotherapy to the spinal cord, to prevent any potential neurological morbidity (20–30Gy in five to ten fractions), and from intrathecal chemotherapy.

The median survival of untreated patients with leptomeningeal disease is 4–6 weeks. Radiotherapy is useful for relieving symptoms caused by tumour bulk or for ventricular outflow obstruction. Intrathecal chemotherapy increases the median survival to 4–6 months in candidates who are a ‘good risk’ (see Fig. 3.4), with a 1-year survival of 15%. Intrathecal drug administration using an intraventricular reservoir system (Ommaya reservoir) results in a uniform distribution and consistent levels of drug in the CSF space. It is more tolerable for patients and safer than repeated lumbar punctures. The benefit of systemic chemotherapy in the absence of systemic disease is not known.

Progress and follow-up of this case

This patient received intrathecal methotrexate (Fig. 3.4) along with six courses of oral topotecan (second-line chemotherapy for small cell lung cancer). While on maintenance intrathecal methotrexate, she developed pneumonia and died 28 months after her initial diagnosis.

Fig. 3.4

Further reading

Azim Jr AA, Peccatorib FA, Pavlidis N. Lung cancer in the pregnant woman: to treat or not to treat, that is the question. Lung Cancer 2010; 67: 251–256.

Chamberlain MC. Leptomeningeal metastasis. Current Opinion in Oncology 2010; 22: 627–635.

Garridoa M, Claverob J, Huetec A, et al. Prolonged survival of a woman with lung cancer diagnosed and treated with chemotherapy during pregnancy. Review of cases reported. Lung Cancer 2008; 60: 285–290.

van Meerbeeck JP, Fennell DA, De Ruysscher DKM. Small-cell lung cancer. The Lancet 2011; 378: 1741–1755.

Rossi A, Martelli O, Di Maio M. Treatment of patients with small-cell lung cancer: from metaanalyses to clinical practice. Cancer Treatment Reviews 2012; 39: 498–506.