Case Study
Pneumonectomy after response to gefitinib treatment for lung adenocarcinoma
Asian Cardiovascular & Thoracic Annals 21(4) 482–484 ß The Author(s) 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492312462834 aan.sagepub.com
Yasunobu Funakoshi, Yukiyasu Takeuchi and Hajime Maeda
Abstract A 69-year-old Japanese woman who had never smoked had lung adenocarcinoma harboring epidermal growth factor receptor mutation. After 8 months of gefitinib treatment, salvage pneumonectomy was performed. Microscopic examination showed that non-responsive adenocarcinoma remained although necrosis was prominent. Postoperatively, the patient developed empyema that was successfully managed. The postoperative empyema after treatment with gefitinib should be noted, as well as the finding that residual viable tumor cells remained even after the dramatic radiographic response.
Keywords Antineoplastic agents, non-small-cell carcinoma, gefitinib, epidermal growth factor receptor, salvage therapy
Introduction Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have proven efficacy in advanced non-small-cell lung cancer (NSCLC).1 Here, we report the case of a Japanese woman who underwent salvage pneumonectomy after 8 months of gefitinib treatment. Nonresponsive areas remained even after a dramatic radiographic response.
Case report A 69-year-old Japanese woman who had never smoked, presented with a suspicious lesion on chest radiography. A chest computed tomography (CT) scan revealed a mass measuring 5 cm in diameter in the left lower lobe (cT2aN0M0, stage IB; Figure 1(a) and (b)). Fluorodeoxyglucose positron-emission tomographyCT demonstrated increased uptake with a maximum standardized uptake value of 11.7. Her serum level of carcinoembryonic antigen was 78.8 gmL 1. Thrombocytopenia was found; the platelet count was 69,000/mm3. Transbronchial biopsy confirmed adenocarcinoma. She had been initially diagnosed as operable, but pneumonectomy was needed because the tumor invaded the pulmonary artery proximal to the
lingula branch and just distal to the second carina. She refused surgery then, and systemic chemotherapy was not recommended because of thrombocytopenia. EGFR-TKI treatment was proposed because an EGFR mutation analysis had revealed an exon 19 deletion. Gefitinib was prescribed at a dose of 250 mgday 1 for first-line therapy. Adverse effects were confined to mild skin toxicity (grade 2). After 8 months of treatment, the patient had a good partial response with a size reduction of 40% on chest CT (Figure 1(c) and (d)), and her serum level of carcinoembryonic antigen decreased to 7.1 ngmL 1. Positron-emission tomography-CT after the treatment showed a striking metabolic response with a reduction of the maximum standardized uptake value to 2.6. We performed salvage pneumonectomy and systemic lymphadenectomy. Complete resection was confirmed (ypT2aN0M0, stage IB). On microscopic examination, necrosis with proliferation Department of General Thoracic Surgery, National Organization Toneyama Hospital, Toyonaka, Osaka, Japan
Hospital
Corresponding author: Yasunobu Funakoshi, MD, PhD, Department of General Thoracic Surgery, National Hospital Organization Toneyama Hospital, 5-5-1 Toneyama, Toyonaka, Osaka, 560-8552, Japan. Email: [email protected]
Downloaded from aan.sagepub.com at UNIV OF GEORGIA LIBRARIES on June 1, 2015
Funakoshi et al.
483
Figure 1. Chest computed tomography showing a 50-mm tumor in the left lower lobe before treatment with gefitinib (a) and (b). The shrunken tumor, with a size reduction of 40% after treatment with gefitinib (c) and (d).
of fibroblasts was prominent (Figure 2(a)). However, nonresponsive papillary adenocarcinoma was found (Figure 2(b)), clearly separated from the necrotic areas. Thrombocytopenia resolved after resection of the tumor. Two months after the operation, the patient developed empyema due to methicillin-sensitive Staphylococcus epidermidis. It was successfully managed by washing and curettage using video-assisted thoracoscopic surgery. At the time of the reoperation, the bronchial stump had recovered satisfactorily. Adjuvant EGFR-TKI was not applied because of empyema. Twenty-six months after the operation, the patient was alive without recurrence.
Discussion EGFR-TKI has dramatic efficacy in more than 70% of advanced NSCLC with EGFR gene mutations.1 Some patients with inoperable NSCLC demonstrated a downstaging of their cancer to operable status after gefitinib treatment.2,3 Kappers and colleagues4 also reported that the response to treatment with erlotinib can be fast, with a complete pathological response achieved after only 3 weeks of treatment. The response to EGFR-TKI, such as gefitinib and erlotinib, is mostly within 3 to 4 weeks. The most common adverse events are skin rash and diarrhea, which are reversible on discontinuation of treatment.1 Lara-Guerra and colleagues5 reported that preoperative gefitinib treatment in the short term was well tolerated in terms of minimal
toxicity and no additional surgical risk. However, preoperative EGFR-TKI treatment may be associated with impaired wound healing and infection. In this case, it was difficult to extract the drain tube promptly because of postoperative bleeding and then postoperative empyema, perhaps due to antidromic infection from the skin, although skin wound healing was not impaired. The skin rash may be connected to methicillin-sensitive Staphylococcus epidermidis. Thus it is necessary to note that wound infection and postoperative empyema may occur as a result of a skin rash, if surgery is planned after treatment with EGFR-TKI. Takamochi and colleagues3 reported that despite dramatic radiographic downstaging after gefitinib treatment, most patients had further advanced pathologic stages than their preoperative clinical stages. Hishida and colleagues2 also stated that initially expressed systemic disease was essentially unchanged even after a dramatic radiologic response to gefitinib. In this case, nonresponsive papillary adenocarcinoma was clearly separated from the fibrous scar, macroscopically as well as microscopically. It should be noted that residual viable tumor cells remained after the dramatic radiographic response to gefitinib treatment. As well as in the present case, EGFR-TKI treatment could be an option for neoadjuvant therapy in advanced adenocarcinoma. The reoperative EGFRTKI treatment strategy should be reevaluated in the neoadjuvant setting for early disease as well as locally advanced but operable disease.2 Although there is a low
Downloaded from aan.sagepub.com at UNIV OF GEORGIA LIBRARIES on June 1, 2015
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Asian Cardiovascular & Thoracic Annals 21(4)
Figure 2. Histological findings of the resected tumor (hematoxylin eosin stain). (a) Massive necrosis with proliferation of fibroblasts. (b) Non-responsive papillary adenocarcinoma.
rate of adverse events and high compliance, as well as a satisfactory response rate after 28 days of preoperative treatment in patients with early NSCLC, the safety and feasibility of surgery in patients taking EGFR-TKI for a long period have not yet been confirmed.5 The optimal duration of EGFR-TKI treatment, the timing of surgery, and the role of adjuvant EGFR-TKI treatment should be investigated in the future. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflicts of interest statement None declared.
2. Hishida T, Nagai K, Mitsudomi T, Yokoi K, Kondo H, Horinouchi H, et al. Salvage surgery for advanced nonsmall cell lung cancer after response to gefitinib. J Thorac Cardiovasc Surg 2010; 140: e69–e71. 3. Takamochi K, Suzuki K, Sugimura H, Funai K, Mori H, Bashar AH, et al. Surgical resection after gefitinib treatment in patients with lung adenocarcinoma harboring epidermal growth factor receptor gene mutation. Lung Cancer 2007; 58: 149–155. 4. Kappers I, Klomp HM, Burgers JA, Van Zandwijk N, Haas RL and van Pel R. Neoadjuvant (induction) erlotinib response in stage IIIA non-small-cell lung cancer. J Clin Oncol 2008; 26: 4205–4207. 5. Lara-Guerra H, Waddell TK, Salvarrey MA, Joshua AM, Chung CT, Paul N, et al. Phase II study of preoperative gefitinib in clinical stage I non-small-cell lung cancer. J Clin Oncol 2009; 27: 6229–6236.
References 1. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–957.
Downloaded from aan.sagepub.com at UNIV OF GEORGIA LIBRARIES on June 1, 2015
Pneumonectomy after response to gefitinib treatment for lung adenocarcinoma
Asian Cardiovascular & Thoracic Annals 21(4) 482–484 ß The Author(s) 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492312462834 aan.sagepub.com
Yasunobu Funakoshi, Yukiyasu Takeuchi and Hajime Maeda
Abstract A 69-year-old Japanese woman who had never smoked had lung adenocarcinoma harboring epidermal growth factor receptor mutation. After 8 months of gefitinib treatment, salvage pneumonectomy was performed. Microscopic examination showed that non-responsive adenocarcinoma remained although necrosis was prominent. Postoperatively, the patient developed empyema that was successfully managed. The postoperative empyema after treatment with gefitinib should be noted, as well as the finding that residual viable tumor cells remained even after the dramatic radiographic response.
Keywords Antineoplastic agents, non-small-cell carcinoma, gefitinib, epidermal growth factor receptor, salvage therapy
Introduction Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have proven efficacy in advanced non-small-cell lung cancer (NSCLC).1 Here, we report the case of a Japanese woman who underwent salvage pneumonectomy after 8 months of gefitinib treatment. Nonresponsive areas remained even after a dramatic radiographic response.
Case report A 69-year-old Japanese woman who had never smoked, presented with a suspicious lesion on chest radiography. A chest computed tomography (CT) scan revealed a mass measuring 5 cm in diameter in the left lower lobe (cT2aN0M0, stage IB; Figure 1(a) and (b)). Fluorodeoxyglucose positron-emission tomographyCT demonstrated increased uptake with a maximum standardized uptake value of 11.7. Her serum level of carcinoembryonic antigen was 78.8 gmL 1. Thrombocytopenia was found; the platelet count was 69,000/mm3. Transbronchial biopsy confirmed adenocarcinoma. She had been initially diagnosed as operable, but pneumonectomy was needed because the tumor invaded the pulmonary artery proximal to the
lingula branch and just distal to the second carina. She refused surgery then, and systemic chemotherapy was not recommended because of thrombocytopenia. EGFR-TKI treatment was proposed because an EGFR mutation analysis had revealed an exon 19 deletion. Gefitinib was prescribed at a dose of 250 mgday 1 for first-line therapy. Adverse effects were confined to mild skin toxicity (grade 2). After 8 months of treatment, the patient had a good partial response with a size reduction of 40% on chest CT (Figure 1(c) and (d)), and her serum level of carcinoembryonic antigen decreased to 7.1 ngmL 1. Positron-emission tomography-CT after the treatment showed a striking metabolic response with a reduction of the maximum standardized uptake value to 2.6. We performed salvage pneumonectomy and systemic lymphadenectomy. Complete resection was confirmed (ypT2aN0M0, stage IB). On microscopic examination, necrosis with proliferation Department of General Thoracic Surgery, National Organization Toneyama Hospital, Toyonaka, Osaka, Japan
Hospital
Corresponding author: Yasunobu Funakoshi, MD, PhD, Department of General Thoracic Surgery, National Hospital Organization Toneyama Hospital, 5-5-1 Toneyama, Toyonaka, Osaka, 560-8552, Japan. Email: [email protected]
Downloaded from aan.sagepub.com at UNIV OF GEORGIA LIBRARIES on June 1, 2015
Funakoshi et al.
483
Figure 1. Chest computed tomography showing a 50-mm tumor in the left lower lobe before treatment with gefitinib (a) and (b). The shrunken tumor, with a size reduction of 40% after treatment with gefitinib (c) and (d).
of fibroblasts was prominent (Figure 2(a)). However, nonresponsive papillary adenocarcinoma was found (Figure 2(b)), clearly separated from the necrotic areas. Thrombocytopenia resolved after resection of the tumor. Two months after the operation, the patient developed empyema due to methicillin-sensitive Staphylococcus epidermidis. It was successfully managed by washing and curettage using video-assisted thoracoscopic surgery. At the time of the reoperation, the bronchial stump had recovered satisfactorily. Adjuvant EGFR-TKI was not applied because of empyema. Twenty-six months after the operation, the patient was alive without recurrence.
Discussion EGFR-TKI has dramatic efficacy in more than 70% of advanced NSCLC with EGFR gene mutations.1 Some patients with inoperable NSCLC demonstrated a downstaging of their cancer to operable status after gefitinib treatment.2,3 Kappers and colleagues4 also reported that the response to treatment with erlotinib can be fast, with a complete pathological response achieved after only 3 weeks of treatment. The response to EGFR-TKI, such as gefitinib and erlotinib, is mostly within 3 to 4 weeks. The most common adverse events are skin rash and diarrhea, which are reversible on discontinuation of treatment.1 Lara-Guerra and colleagues5 reported that preoperative gefitinib treatment in the short term was well tolerated in terms of minimal
toxicity and no additional surgical risk. However, preoperative EGFR-TKI treatment may be associated with impaired wound healing and infection. In this case, it was difficult to extract the drain tube promptly because of postoperative bleeding and then postoperative empyema, perhaps due to antidromic infection from the skin, although skin wound healing was not impaired. The skin rash may be connected to methicillin-sensitive Staphylococcus epidermidis. Thus it is necessary to note that wound infection and postoperative empyema may occur as a result of a skin rash, if surgery is planned after treatment with EGFR-TKI. Takamochi and colleagues3 reported that despite dramatic radiographic downstaging after gefitinib treatment, most patients had further advanced pathologic stages than their preoperative clinical stages. Hishida and colleagues2 also stated that initially expressed systemic disease was essentially unchanged even after a dramatic radiologic response to gefitinib. In this case, nonresponsive papillary adenocarcinoma was clearly separated from the fibrous scar, macroscopically as well as microscopically. It should be noted that residual viable tumor cells remained after the dramatic radiographic response to gefitinib treatment. As well as in the present case, EGFR-TKI treatment could be an option for neoadjuvant therapy in advanced adenocarcinoma. The reoperative EGFRTKI treatment strategy should be reevaluated in the neoadjuvant setting for early disease as well as locally advanced but operable disease.2 Although there is a low
Downloaded from aan.sagepub.com at UNIV OF GEORGIA LIBRARIES on June 1, 2015
484
Asian Cardiovascular & Thoracic Annals 21(4)
Figure 2. Histological findings of the resected tumor (hematoxylin eosin stain). (a) Massive necrosis with proliferation of fibroblasts. (b) Non-responsive papillary adenocarcinoma.
rate of adverse events and high compliance, as well as a satisfactory response rate after 28 days of preoperative treatment in patients with early NSCLC, the safety and feasibility of surgery in patients taking EGFR-TKI for a long period have not yet been confirmed.5 The optimal duration of EGFR-TKI treatment, the timing of surgery, and the role of adjuvant EGFR-TKI treatment should be investigated in the future. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflicts of interest statement None declared.
2. Hishida T, Nagai K, Mitsudomi T, Yokoi K, Kondo H, Horinouchi H, et al. Salvage surgery for advanced nonsmall cell lung cancer after response to gefitinib. J Thorac Cardiovasc Surg 2010; 140: e69–e71. 3. Takamochi K, Suzuki K, Sugimura H, Funai K, Mori H, Bashar AH, et al. Surgical resection after gefitinib treatment in patients with lung adenocarcinoma harboring epidermal growth factor receptor gene mutation. Lung Cancer 2007; 58: 149–155. 4. Kappers I, Klomp HM, Burgers JA, Van Zandwijk N, Haas RL and van Pel R. Neoadjuvant (induction) erlotinib response in stage IIIA non-small-cell lung cancer. J Clin Oncol 2008; 26: 4205–4207. 5. Lara-Guerra H, Waddell TK, Salvarrey MA, Joshua AM, Chung CT, Paul N, et al. Phase II study of preoperative gefitinib in clinical stage I non-small-cell lung cancer. J Clin Oncol 2009; 27: 6229–6236.
References 1. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–957.
Downloaded from aan.sagepub.com at UNIV OF GEORGIA LIBRARIES on June 1, 2015
