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━━ Background. Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), is effective against lung cancer positive for echinoderm microtubule-associated protein-like 4 (EML4)-ALK. However, cases with acquired resistance to crizotinib have also been reported. Pemetrexed (PEM), a multitargeted antifolate, has been widely used as not only first-line, but also as second-line and later chemotherapy of adenocarcinoma of the lung. Case. A 39-year-old woman received a diagnosis of adenocarcinoma of the lung with right hilar and mediastinal lymph node swelling, pericardial effusion, and multiple liver and bone metastases. Treatment with erlotinib and carboplatin+paclitaxel+bevacizumab was ineffective for her liver metastases. As the lung cancer was EML4ALK-positive, the patient was treated with crizotinib as part of a clinical study, resulting in a partial response. However, 7 months later, treatment was terminated because the liver metastases had re-enlarged and brain metastases had appeared. Consequently, the patient received combined chemotherapy consisting of PEM and carboplatin as fourth-line treatment; she showed good response, with shrinkage of the liver metastases observed after 2 courses. After 4 courses of combined chemotherapy, treatment with PEM only was continued. Gamma-knife radiosurgery was performed for a single brain metastasis, which had been detected after the eighth course (26th week) of treatment. No re-enlargement of the liver metastases was seen, as confirmed by an abdominal CT scan after the 11th course (35th week); however, treatment was terminated after the 13th course (including 9 courses of PEM only) due to a diagnosis of carcinomatous meningitis during the 43rd week. Conclusion. In the present case, PEM showed long-term efficacy as fourth-line chemotherapy against EML4-ALK-positive adenocarcinoma of the lung after the development of acquired resistance to crizotinib. However, additional cases are needed to confirm the efficacy of PEM in patients with EML4-ALK-positive lung cancer. (JJLC. 2012;52:242-247) KEY WORDS━━ Lung cancer, EML4-ALK, Crizotinib, Pemetrexed Reprints: Masahide Mori, Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, 5-1-1 Toneyama, Toyonaka-city, Osaka 560-8552, Japan (e-mail: mmori@toneyama.go.jp). Received October 19, 2011; accepted February 28, 2012. 要旨━━ 背 景.echinoderm microtubule-associated protein-like 4( EML 4)-anaplastic lymphoma kinase (ALK)肺癌に対し,ALK阻害剤である crizotinib が有用 である.一方,葉酸代謝拮抗剤である pemetrexed(PEM) は,肺腺癌に対し 1次だけでなく 2次以降の治療にも広 く用いられている.症例.39 歳女性,非喫煙者.右肺下 葉原発の肺腺癌で,右肺門・縦隔リンパ節腫大,両側肺 内転移,心嚢液貯留,多発肝・骨転移を認めた.erlotinib, 1国立病院機構刀根山病院呼吸器腫瘍内科. 別刷請求先:森 雅秀,国立病院機構刀根山病院呼吸器腫瘍内 科,〒560-8552 大 阪 府 豊 中 市 刀 根 山 5-1-1 (e-mail: mmori@ toneyama.go.jp). 受付日:2011 年 10 月 19 日,採択日:2012 年 2 月 28 日. (肺癌.2012;52:242-247) 2012 The Japan Lung Cancer Society Lung Cancer with EML4-ALK Successfully Treated with Pemetrexed―Mori et al Japanese Journal of Lung Cancer―Vol 52, No 2, Apr 20, 2012―www.haigan.gr.jp 243 Table 1. Examination on First Admission Hematology Biochemistry Tumor Markers RBC 347×104/mm3 TP 6.1 g/dl CEA 488.0 ng/ml↑ Hb 10.0 g/dl Alb 3.4 g/dl CA19-9 860.0 IU/ml↑ Hct 30.3% T-Bil 0.74 mg/dl CYFRA 7.3 ng/ml↑ WBC 5070/mm3 AST 51 IU/l↑ proGRP 18.9 ng/ml Neut 80.1% ALT 53 IU/l↑ Lymph 10.4% γ-GTP 192 IU/l↑ KL-6 4295.6 IU/l↑ Mo 6.9% LDH 713 IU/l↑ Eosino 2.1% ALP 755 IU/l↑ Baso 0.5% AMY 85 IU/l Plt 31.0×104/mm3 CK 33 IU/l UA 3.3 mg/dl Serology BUN 6.9 mg/dl CRP 1.88 mg/dl↑ Cre 0.65 mg/dl Na 139 mEq/dl K 4.5 mEq/dl Cl 101 mEq/dl Ca 8.4 mg/dl carboplatin(CBDCA)+paclitaxel+bevacizumab の 治 療はともに多発肝転移に対し無効であった.EML4-ALK 陽性で,crizotinib の治験に参加し partial response(PR) となったが,7ヶ月目に多発肝転移の増大および新たに 多発脳転移が確認され投与を終了した.4次治療として CBDCA+PEMの投与を行い,2クール後に肝・脳転移 の縮小を認め,5クール目から PEM単剤による維持療法 へ移行した.8クール後(26 週目)に単発脳転移の再発 を認めガンマナイフ照射を施行した.11 クール後(35 週目)の胸腹部CTでも再増大はなく,PEMの投与は 13 クール(単剤で 9クール)まで行ったが,43 週目に癌性 髄膜症と判明し投与終了した.結論.EML4-ALK肺腺癌 に対し,crizotinib に耐性化した後,4次治療としての PEMが著効し長期間病勢制御が可能であった症例を経 験した.ALK肺癌への PEMの有効性についてはさらに 検討を要する. 索引用語━━肺癌,EML4-ALK,クリゾチニブ,ペメト レキセド

haigan

A Case of Adenocarcinoma of the Lung Successfully Treated with Pemetrexed as Fourth-line Chemotherapy for Multiple Liver Metastases After Acquired Resistance to Crizotinib