Chinese-German Journal of Clinical Oncology

December 2007, Vol. 6, No. 6, P601–P602

DOI  10.1007/s10330-007-0135-z

Unusual side effect and dramatic response from gefitinib as first-line use in a male-patient with bronchioloalveolar carcinoma Haizhu Song, Longbang Chen Department of Oncology, Jinling Hospital, Clinical Medicine School of Nanjing University, Nanjing 210002, China Received: 1 August 2007 / Revised: 15 September 2007 / Accepted: 30 September 2007 Abstract  A 45-year-old man with bronchioloalveolar carcinoma was treated with gefitinib. The most severe side effect was hemorrhagic cystitis but he had a dramatic response. Key words  bronchioloalveolar cell carcinoma; gefitinib; hemorrhagic cystitis

A 45-year-old man presented with a one-month history of cough and expectoration. He sought medical attention after the symptoms did not improve with over-thecounter medications and an empiric course of antibiotics. On February 14, 2007, he was examined by computed tomography (CT) scan of the chest demonstrated a 3.0 × 4.0 cm right lower lobe mass with multiple pulmonary nodules in both lungs and mediastinal lymphadenopathy (Fig. 1). Adenocarcinoma cells were detected in sputum smears. Medical history was pertinent for 20 to 40 packyears of smoking in the past 20 years. According to the radiographic and pathological findings, this patient was diagnosed as bronchioloalveolar carcinoma. Initial treatment was with gefitinib (Iressa, AstraZeneca Pharmaceuticals, Wilmington, DE) 250 mg po once daily since February 28, supported by the expanded access program (EAP). The patient had a definite improvement of respiratory symptoms after a week, while rash, acne, dry skin and pruritus appeared, especially in the skin of forehead, cheeks and chest wall. He kept on taking gefitinib and his rash temporarily worsened but then receded spontaneously during the third week. On March 12, 12 days later since the gefitinib administration, chest CT scan showed significant decrease in the sizes of the right lower lobe mass and nodules in both lungs (Fig. 2). After 4 weeks of gefitinib therapy, total gross hematuria was noted, accompanied with irritative voiding symptoms (dysuria, frequency, urgency, and burning). He was deprived of sleep because of hypogastralgia and nocturia. The laboratory tests demonstrated microhematuria (≥ 250 red blood cells/μL and 10 white blood cells/μL). The medistream Correspondence to: Longbang Chen. Email: [email protected]

urine was cultivated for 48 hours and there were no more than 1000 CFU/mL of bacterium. The serum ALT was 183 U/L and the AST was 128 U/L. Considering that hemorrhagic cystitis and abnormal liver function were related to his medications, we ceased his oral gefitinib on April 16. Oral and intra-venous fluid replacement, urine alkalinizing agents, osmotic diuretics, hemostasis agents and sodium 2-mercaptoethane sulfonate (Mesna) were used to treat his hemorrhagic cystitis. Liver function protecting agents including glutathione and bifendate were given at the same time. On April 19, chest CT proved further improvements of both lungs (Fig. 3). After a week the symptoms of hemorrhagic cystitis improved and gross hematuria disappeared. The urine analysis showed 10 red blood cells/μL and no white blood cells. His liver function gradually improved and returned normal soon. On May 4, he began to resume gefitinib therapy. No irritative voiding symptoms occurred any more, and the weekly liver function tests showed that serum ALT and AST levels remained normal. Then the patients had been clinically well without any symptoms except for skin dryness and a slight rash till July 2007. Gefitinib is an oral anticancer agent which inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR), and then blocks the process of cancer progression. It is first granted for use in patients with non-small cell lung cancer (NSCLC) progressing after standard chemotherapy. Gefitinib is generally thought to be safer than other anticancer agents and tolerated better by patients. The common adverse effects of gefitinib reported in the recommended 250 mg daily

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Fig.  1  On February 14, 2007, prior to the treatment, CT scan of the chest demonstrated a 3.0 × 4.0 cm right lower lobe mass with multiple pulmonary nodules in both lungs and mediastinal lymphadenopathy Fig.  2  On March 12, 2007, 12 days later since the gefitinib administration, chest CT scan showed significant decrease in the sizes of the right lower lobe mass and nodules in both lungs Fig.  3  On April 19, 2007, 46 days later since the gefitinib administration, chest CT proved further improvements of both lungs

dosage include diarrhea, rash, acne, dry skin, nausea and vomiting. Interstitial lung disease has been reported with overall incidence of approximately 1%. However, the side effect of hemorrhagic cystitis has rarely been reported [1]. The mechanisms of gefitinib induced hemorrhagic cystitis are still unclear. Presumably it is the effect of gefitinib on the EGFR signaling pathway in bladder epitheliums. Patients on gefitinib or other EGFR tyrosine kinase inhibitors who develop irritative voiding symptoms (dysuria, frequency, urgency, and burning) should be advised to seek medical attention promptly, and therapy should be interrupted. A thorough investigation should be done as soon as possible, with appropriate treatment given immediately upon confirm of hemorrhagic cystitis. The results of randomized double-blind clinical trials showed candidates of gefitinib were seen primarily in certain subsets, including women, never to minimal smokers, those of East Asian descent and adenocarcinomas (ADC) [2] , especially those of ADC with bronchioloalveolar features [3]. Recent trials have reported that patients with certain EGFR tyrosine kinase mutation and increasing of EGFR gene copy number were more sensitive to gefitinib therapy [4, 5]. But few researches have reported whether

the mutation would cause a more severe toxicity. This patient was a middle-aged man with a smoking history, but of East Asian descent and has bronchioloalveolar cell carcinoma. During the 2-month targeted therapy of gefitinib as first-line use, the dramatic effect was observed.

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