Chemotherapy as cause of refractory severe headache in a case of small-cell lung cancer

Abstract

Small-cell lung cancer (SCLC) is a very fast growing form of cancer and is characterised by early metastasis. As a result, chemotherapy is the mainstay of treatment. Platinum-containing combination regimens are the current treatment of choice for limited stage-SCLC and extensive stage SCLC. Various adverse effects after cisplatin and etoposide chemotherapy include nausea, nephrotoxicity, cardiotoxicity, hepatotoxicity, neurotoxicity, alopecia, gastrointestinal toxicity and myelosuppression. However, severe headache has not been reported yet. Here, we report one such case of severe refractory headache postcisplatin and etoposide chemotherapy which responded only to change in chemotherapy regime. All pertinent causes of headache were ruled out prior to changing the chemotherapy regimen.

Background

Small-cell lung cancer (SCLC) is an aggressive malignant disease, with the majority of patients presenting with distant metastasis at diagnosis. As SCLC is a chemo sensitive tumour, rapid symptomatic improvement is often seen with chemotherapy. The first-line treatment of extended stage SCLC currently consists of chemotherapy with a platinum derivative and etoposide; a combination that was first reported to be effective in the treatment of SCLC in 1985.¹ Cisplatin treatment has been linked to side effects like nausea, nephrotoxicity, cardiotoxicity, hepatotoxicity and neurotoxicity,² whereas adverse effects of etoposide include alopecia, gastrointestinal toxicity and myelosuppression.³ However, severe headache has not been reported as consequence of either cisplatin or etoposide chemotherapy.

Here, we report case of a 58-year-old man with SCLC without any history of primary headache. This patient had new-onset severe headache after cisplatin and etoposide chemotherapy, which resolved after changing chemotherapy regimen to carboplatin and irinotecan.

Case presentation

A 58-year-old man, with a smoking history of 30 years, presented to pulmonary clinic with right sided chest pain, dry cough, shortness of breath and swelling in neck and anterior chest wall for 1 month. On evaluation, CT scan (CT) of thorax demonstrated enlarged subcarinal and right hilar lymph node (size 5×6 cm). As patient was not fit to undergo bronchoscopy, patient underwent Endoscopic Ultrasound -guided fine needle aspiration cytology (FNAC) from subcarinal lymph node and was diagnosed as small-cell carcinoma on histopathology. He was started on chemotherapy with first-line chemotherapy agent cisplatin and etoposide. USG Doppler neck showed bilateral internal jugular vein thrombosis. Hence, he was put on anticoagulation with low molecular weight heparin.

After 3 days of first cycle of chemotherapy, the patient had severe debilitating headache associated with photophobia, nausea and vomiting. Headache was severe in intensity, holocranial, pressure type, aggravated on talking, coughing and standing and interfered with his daily activity (grade 3 of International Headache Society 4-grade category scale). There was no associated neurological deficit. The headache was not relieved with oral analgesics Non steroidal anti-inflammatory drugs (NSAIDS) and tramadol. MRI of brain with contrast was done which was normal. No intracranial space-occupying lesion (SOL) was found. MR venography (MRV) did not reveal any findings of central venous sinus thrombosis. The patient was started on intravenous morphine for refractory headache. He responded to morphine at 1 mg/hour and morphine was continued for 2 days before he was discharged.

The patient had similar episode of severe headache and vomiting 2 days after second cycle of chemotherapy. This time cerebrospinal fluid (CSF) analysis was done: CSF cytologyand other biochemical parameters were normal. CSF manometry revealed normal CSF pressure. After no relief from oral NSAIDs and intravenous tramadol he was again started on intravenous morphine infusion, but this time he required significantly higher doses (approximate 8–10 mg per hour) for analgesia. After 1 day of morphine infusion, the patient reported relief in headache and intravenous morphine was gradually tapered over 1 day.

During next two cycles of chemotherapy, regimen was changed to carboplatin and irinotecan, in view of severe headache post chemotherapy. No postchemotherapy headache was observed in next four cycles and patient had clinical improvement during his follow-up.

Investigations

CT thorax and abdomen

Multiple enlarged, conglomerated mediastinal lymph nodes in pretracheal, paratracheal, subcarinal and right hilar region of 5×6 cm. Centrilobular emphysema present in both lungs. Soft-tissue density lesion of 0.2×1.3 cm in right adrenal gland.

Endoscopic ultrasound guided FNAC

From subcarinal lymph node: metastatic deposits of small-cell carcinoma.

High-resolution sonography of neck with venous Doppler

Isoechoic lesion in right lobe of thyroid of size 7×4×6 mm, bilateral internal juglar venous thrombosis with extension into brachicephalic veins, bilateral cervical lymphadenopathy of size 13×8 mm at level III right side.

FNAC (thyroid)

Colloid nodule.

MRI of brain

Non-specific white matter changes in bilateral cerebral hemispheres. No intracranial SOL found.

MRI three-dimensional time of flight angiogram

All carotid arteries are normal in course, calibre and branching pattern.

MRV of brain

No obvious filling defect in cerebral venous sinuses.

CSF investigations

CSF glucose: 82.53 mg/dL.

CSF protein: 28.0 mg/dL.

CSF cytology: 0–1 cells/hpf.

No malignant cells seen.

CSF Gram stain and culture sensitivity: no organism isolated.

CSF KOH (Potassium Hydroxide) mount: no fungal element seen.

CSF Indian ink: negative.

CSF manometry: CSF pressure—14 mm Hg.

Differential diagnosis

The main differential diagnosis in our case was intracranial metastasis, central venous and arterial thrombosis secondary to cisplatin and meningitis. Since the patient is an elderly male without any previous history of headache, all primary causes of headache are ruled out.

We performed MRI brain with contrast to see for any SOL in brain due to small-cell lung carcinoma metastasis. It was not suggestive of any SOL, thus ruling out intracranial metastasis. MRI three-dimensional (3D) time of flight (TOF) was insignificant for arterial thrombosis. MRV showed normal opacification pattern of all dural sinuses thus ruling out central venous thrombosis.

The patients on chemotherapy are prone to central nervous system infections due to immunosuppression. Hence, meningitis needs to be ruled out for postchemotherapy severe headache. In our patient, CSF cytology and culture studies were normal, thus ruling out meningitis.

Idiopathic intracranial hypertension (pseudotumour cerebri) was ruled out by CSF manometry which shows normal CSF pressure of 14 mm Hg.

Treatment

After ruling out all primary and secondary causes of headache in adults, chemotherapy regimen was changed to carboplatin and irinotecan and the patient did not report any headache in next three cycles.

Outcome and follow-up

The change in chemotherapy regimen from cisplatin and etoposide to carboplatin and irinotecan led to significant relief in headache. Over the next three cycles with carboplatin and irinotecan, the patient did not report any headache after chemotherapy. He is symptomatically improved on follow-up at 4 months.

Discussion

Secondary headache in a patient with active malignancy can have many reasons. It can occur due to direct or metastatic infiltration of the brain parenchyma by tumour tissue or due to complications of the treatment of the malignancy. The chemotherapy associated headache is usually due to infection or due to direct effects of chemotherapeutic agents. The patients on chemotherapy are prone to central nervous system infections due to immunosuppression and iatrogenic contamination of CSF at the time of intrathecal chemotherapy. Mild headache has been reported with various chemotherapeutic agents, but severe headache responding only to high doses of morphine has not been reported in English literature.⁴

Vascular (arterial or venous sinus) thrombosis due to chemotherapy is reported with many drugs. Arterial thrombosis has been especially reported with cisplatin which can cause direct vascular toxicity as demonstrated previously in various case series. The reason for this vascular thrombosis is presumed to be arterial spasm secondary to heightened vascular tone and magnesium deficiency (often seen concomitantly with cisplatin therapy) as magnesium plays an important role in maintaining vascular smooth muscle tone.⁵ In our case, MRI 3D TOF angiogram of brain was normal ruling out any intracranial thrombosis. Clarke et al have described central venous sinus thrombosis as a cause of headache after chemotherapy with bleomycin etoposide and cisplatin in a case of testicular carcinoma.⁶ In our patient, MRV revealed normal opacification pattern of all the major dural sinuses ruling out cerebral venous sinus thrombosis

Our patient had no history of primary headache. He described his headache as acute onset with severity score of 9/10, dull pressure like affecting the entire head and associated with photophobia and postural changes with headache worse on standing and straining activities. Headache occurred after 3–4 days of chemotherapy. Orthostatic hypotension was not seen. Comprehensive neurological examination was normal.

Laboratory investigations including complete haemogram, electrolytes, renal and liver function parameters were within normal range. MRI brain with contrast did not reveal any SOL. CSF workup was negative for meningitis and malignant cells. CSF pressure was normal ruling out intracranial hypertension.

Initially, we managed the patient with NSAIDS and oral opioids. However, after no pain relief patient was given intravenous opioids. After ruling out all primary and secondary causes of headache in adults, chemotherapy regimen was changed to carboplatin and irinotecan and the patient did not report any headache in next three cycles. We concluded that either cisplatin or etoposide was the causative agent of severe headache in this patient. The response to change in chemotherapy regimen supports our assumption.

Patient’s perspective.

My father is a patient of small cell carcinoma of lung. He was diagnosed with Small cell carcinoma 5 months back. Before chemotherapy he was having severe chest pain, cough and difficulty in breathing. When the doctor told about his diagnosis of carcinoma we were shocked. We were told of poor prognosis of the disease and possible chemotherapy complications like alopecia, nausea, vomiting and diarrhoea. On the day he was given chemotherapy no complications occurred. We were happy that he did not have any complication. But after 3 days of the first and second cycle he had severe headache along with nausea which was not relieved by any medicine. All investigations to find cause of headache were coming normal. We were feeling helpless seeing him in such agony. He had to be started on morphine infusion after all painkillers didn’t work. After two cycles of chemotherapy, he refused for third cycle due to severe agonising headache which occurred after chemotherapy. However, the doctor assured us to give different chemotherapy regime which can possibly not cause headache. To our relief, no headache occurred after chemotherapy regime was changed. He has recently completed fifth cycle of chemotherapy and remains headache free. After 5 months of first chemotherapy cycle, he is better, with no chest pain, cough and only slight difficulty in breathing on exertion.

Learning points.

• New-onset headache in an elderly patient needs thorough evaluation.

• Refractory headache, not responding to NSAIDs, can be managed by titrating morphine dose to optimal pain relief.

• After ruling out all primary and secondary causes of headache, if severe headache persists after chemotherapy, changing chemotherapy regimen is a valid option to improve patient’s quality of life post chemotherapy.