Japanese Journal of Clinical Oncology Advance Access published online on July 24, 2007
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hym053
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© 2007 Foundation for Promotion of Cancer Research
Effect of Platinum Combined with Irinotecan or Paclitaxel against Large Cell Neuroendocrine Carcinoma of the Lung
1 Divisions of Internal Medicine and Thoracic Oncology
2 Clinical Laboratory, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan
For reprints and all correspondence: Ikuo Sekine, Divisions of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. E-mail: isekine{at}ncc.go.jp
Received August 16, 2006; accepted March 3, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: The efficacy of chemotherapy in patients with large cell neuroendocrine carcinoma of the lung (LCNEC) remains unclear.
Methods: Of 42 consecutive patients with LCNEC, 22 with measurable disease receiving chemotherapy were enrolled as the subjects of this study. The clinical characteristics and objective responses to chemotherapy in these patients were analysed retrospectively.
Results: The distribution of the disease stage in the patients consisting of 21 males and one female (median age: 67 years; range: 47–78 years) was as follows: stage IIB (n = 1), stage IIIA (n = 1), stage IIIB (n = 5), stage IV (n = 8), and post-operative recurrence (n = 7). Chemotherapy consisted of cisplatin and irinotecan (n = 9), a platinum agent and paclitaxel (n = 6), paclitaxel alone (n = 1), cisplatin and vinorelbine (n = 1), cisplatin and docetaxel (n = 1), and a platinum and etoposide (n = 4). The objective response rate in the 22 patients was 59.1% (95% CI, 38.1–80.1). An objective response was obtained in five of the nine patients receiving irinotecan and five of the seven patients receiving paclitaxel. The progression-free survival, median overall survival and 1-year survival rates were 4.1 months (95% CI, 3.1–5.1), 10.3 months (95% CI, 5.8–14.8) and 43.0% (95% CI, 20.7–65.3), respectively. The median overall survival of the patients treated with irinotecan or paclitaxel was 10.3 months (95% CI, 0–21.8), and the 1-year survival rate of these patients was 47.6% (95% CI, 20.4–74.8).
Conclusion: Our results suggest that irinotecan and paclitaxel may be active against LCNEC.
Key Words: lung cancer • large cell neuroendocrine carcinoma • chemotherapy • irinotecan • paclitaxel
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Neuroendocrine tumors of the lung can be placed in the biological spectrum ranging from typical to atypical carcinoid, which are tumors of low to intermediate grade malignancy, to large cell neuroendocrine carcinomas (LCNEC) and small-cell lung carcinomas (SCLC), which are high-grade malignant tumors. LCNEC was proposed as a separate category by Travis et al. in 1991, who recognized a type of poorly differentiated high-grade carcinoma exhibiting features of neuroendocrine appearance on light microscopy, immunohistochemistry, and/or electron microscopy (1). Several different terminologies and classifications have been proposed to date, and this class of tumors is likely to become widely recognized and included in the updated histological classification of the World Health Organization (2).
The clinical features of LCNEC have not yet been completely clarified. The prognosis of patients with surgically resected LCNEC is intermediate between that of an atypical carcinoid and SCLC, and is the same as that of resected non-small-cell lung carcinoma (NSCLC), except for stage I LCNEC, which has a poorer prognosis than that of stage I NSCLC (3–6). In a multi-institutional study in Japan, it was found that both LCNEC and SCLC were similarly aggressive and that there was no survival difference between the two types of lung cancer (7). In a small case series of LCNEC, we reviewed the records of patients with surgically resected, and patients treated medically who were autopsied before 1995, and determined that the chemosensitivity of LCNEC to cisplatin-based regimens may be intermediate between that of NSCLC and SCLC (8). Third generation cytotoxic agents developed in the 1990s, such as paclitaxel, docetaxel, gemcitabine, vinorelbine and irinotecan, have been shown to be active agents against advanced lung cancer, and combinations of platinum and one of the third generation cytotoxic agents have been shown to be superior in terms of prolonging the survival to the existing platinum-based combinations in both patients with NSCLC and those with SCLC (9–14). In the present study, we conducted a retrospective review of the records of our patients with LCNEC who had been treated with chemotherapy, and analysed the efficacy of the chemotherapy regimens.
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PATIENTS AND METHODS |
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From April 1999 to January 2006, 42 patients were diagnosed as having LCNEC at our institution. Of these, one patient underwent surgery, four were treated with radiation therapy alone, and three received only supportive care. Of the 34 patients who had received chemotherapy, four who had also received concurrent radiotherapy and two without evaluable lesions were excluded from this study. In addition, six patients who entered a phase II trial of cisplatin and irinotecan combination for LCNEC were also excluded from this study, because their results will be published elsewhere. Thus, 22 patients were finally enrolled as the subjects of this study.
The histological confirmation of the diagnosis of LCNEC in the medically treated patients was based on examination of biopsy and/or cytology specimens. The histological or cytological diagnosis was reviewed by one of the authors (K.T.). We classified LCNEC according to the histopathological criteria proposed in the WHO classification. Immunohistochemical analysis was performed to confirm the neuroendocrine differentiation of the tumor cells (2).
Clinical information about the cases was obtained from medical records. All patients underwent a chest and abdominal computed tomography, a head computed tomography or magnetic resonance imaging and a bone scintigraphy in clinical disease staging before chemotherapy. The clinical disease staging was reassessed according to the latest International Union Against Cancer (UICC) staging criteria (15). The response to chemotherapy and the survival were assessed retrospectively. The objective tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumor guidelines (16). The survival distributions for overall survival (OS) and progression-free survival (PFS) were estimated according to the Kaplan–Meier method (17). The OS was measured from the date of start of chemotherapy to the date of death or the last follow-up. For PFS, documented disease recurrence was scored as an event. All analyses were performed using the SPSS statistical software (SPSS version 11.0 for Windows; SPSS Inc, Chicago, IL).
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RESULTS |
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The clinical characteristics of the 22 patients are summarized in Table 1. Surgical resected primary tumor, incisional biopsy of metastatic lesion, exploratatory thoracotomy, transbronchial or percutaneous biopsy and cytological examination were positive in seven, five, two, six and two patients, respectively. Thus, the histological diagnosis was made based on examination of a large tumor sample in 14 (63.6%) of the 22 patients. The marked predominance of men and smokers in this study was consistent with the demographic features of our previous LCNEC studies (6–8). One patient with stage IIB received chemotherapy and was enrolled to this study, because surgical resection and definitive radiotherapy were not indicated in this patient because of his poor pulmonary function. Abnormally high serum levels of CEA, NSE and proGRP at the start of chemotherapy were found in 52.4% (11/21), 72.7% (16/22) and 52.4% (11/21) of the patients, respectively.
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The chemotherapy regimens used were as follows: cisplatin (80 mg/m2, day 1) and irinotecan (60 mg/m2, days 1 and 8) (n = 6); cisplatin (60 mg/m2, day 1) and irinotecan (60 mg/m2, days 1, 8 and 15) (n = 3); carboplatin (AUC = 6, day 1) and paclitaxel (200 mg/m2, day 1) (n = 5); cisplatin (80 mg/m2, day 1) and paclitaxel (175 mg/m2, day 1) (n = 1); paclitaxel alone (80 mg/m2, weekly) (n = 1); cisplatin (80 mg/m2, day 1) and vinorelbine (20 mg/m2, days 1, 8 and 15) (n = 1); cisplatin (25 mg/m2, days 1, 8 and 15) and docetaxel (20 mg/m2, days 1, 8 and 15) (n = 1); carboplatin (AUC = 5, day 1) and etoposide (100 mg/m2, days 1–3) (n = 3); cisplatin (80 mg/m2, day 1) and etoposide (100 mg/m2, days 1–3) (n = 1). The median number of chemotherapy cycles was three (range, 1–5). One complete response and 12 partial responses were noted in the 22 patients, yielding an overall response rate of 59.1% (95% CI, 38.1–80.1) (Table 2). An objective response was obtained in five of the nine patients (55.6%) receiving irinotecan and five of the seven patients (71.4%) receiving paclitaxel. The toxicities related to these treatments were, in general, acceptable. Two patients received gefitinib after failure of the first-line chemotherapy, but none of them achieved an objective response. The overall PFS, median OS and 1-year survival rate of all the patients were 4.1 months (95% CI, 3.1–5.1), 10.3 months (95% CI, 5.8–14.8) and 43.3% (95% CI, 21.0–65.6), respectively (Fig. 1). The median OS of the patients treated with irinotecan or paclitaxel was 10.3 months (95% CI, 0–21.8), and the 1-year survival rate of these patients was 47.6% (95% CI, 20.4–74.8).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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In this study, the histological diagnosis of LCNEC was based on examination of a large tumor sample in 14 (63.6%) of the 22 patients, based on biopsies or cytological specimens in the remaining patients (36.4%). Numerous studies have demonstrated that the diagnosis of LCNEC is possible from biopsies or cytological specimens if a sufficient number of tumor cells can be obtained (8,18–21). To establish the pathological diagnosis of LCNEC in this series, we performed a pathological review of the biopsy and cytology specimens, because it was difficult to obtain large specimens of the tumor in these patients with advanced cancer treated medically.
We previously reported a response rate of 64% in 14 chemo-naïve patients with LCNEC who received cisplatin plus mitomycin, vindesine, or etoposide (8). In that study, however, patients with a diagnosis of poorly differentiated adenocarcinoma, poorly differentiated squamous cell carcinoma, large cell carcinoma and small cell carcinoma were selected, and then a diagnosis of LCNEC was made retrospectively by reviewing autopsy or surgically resected specimens. Thus, they were not consecutive, but highly selected patients. This explains, at least partly, the high response rate in the previous study. On the other hand, in the current study we analysed consecutive patients with a diagnosis of LCNEC that is established before treatment.
Rossi et al. showed that objective responses were observed in six (50%) of 12 patients with metastatic LCNEC who received a platinum and etoposide regimen, while no response was obtained in 15 patients receiving regimens for NSCLC treatment (cisplatin and gemcitabine in 10 patients, gemcitabine alone in two patients, and carboplatin and paclitaxel in three patients) (22). In addition, the patients receiving the platinum and etoposide regimen had a significantly better survival than the patients who received the other regimens (median survival time, 51 months versus 21 months). These survival data, however, sound too good for lung cancer patients with a metastatic disease. Neither patient characteristics nor explanation for such a long survival was presented in this report (22). Another case series of LCNEC showed that three patients with a stage IV disease received platinum-based chemotherapy (cisplatin and etoposide, carboplatin and gemcitabine, and cisplatin, docetaxel and gemcitabine) but none of them achieved an objective response. Of five patients who received gefitinib as salvage therapy, one achieved a partial response (23).
In this study, the clinical response rates of LCNEC to chemotherapy regimens containing irinotecan or paclitaxel were as high as 70%. The published response rates of NSCLC and SCLC to these regimens are 30–33% and 68–84%, respectively (10–14). The PFS of 4.1 months and median OS of 10.3 months were comparable to the results of previous randomized phase III trials that have reported PFS values of 4.1–6.9 months and median OS values of 9.3–12.8 months in extensive-stage disease SCLC (14). Thus, the response rate and survival of LCNEC were comparable with those of SCLC. Although our retrospective review of clinical data revealed heterogeneous approaches in treatment regimens, our results suggested that irinotecan and paclitaxel may be active agents against LCNEC. LCNEC exhibit both features of NSCLC and SCLC in terms of the morphology and immnohistochemistry, and these anti-cancer agents are effective against both of these types of lung cancer. Considered together, the combinations of cisplatin and irinotecan, and carboplatin and paclitaxel may be promising regimens for LCNEC.
To evaluate the efficacy of irinotecan- or paclitaxel-based combined chemotherapy for LCNEC, it is necessary to perform prospective phase II trials. However, such trials for LCNEC may be difficult to perform for the following reasons. First, patient accrual is problematic because LCNEC is a relatively rare tumor and accounts for only about 3% of lung cancer patients treated by surgical resection (6). It took us 7 years to accumulate 22 patients with LCNEC treated with chemotherapy. Besides, some studies have revealed the efficacy of adjuvant chemotherapy for both SCLC and NSCLC (24–26). Thus, when patients treated with platinum-based adjuvant chemotherapy regimens are excluded, few subjects with LCNEC with the diagnosis confirmed based on examination of large tumor specimens may remain. Therefore, these trials may only be possible as multi-institutional studies. Second, because it can sometimes be difficult to define the histology of LCNEC without examination of specimens large enough to appreciate the histological architecture and obtain reproducibility, pathological review by experts panel would be needed in these trials.
In conclusion, our results showed that irinotecan- or paclitaxel-based regimens may be as active against LCNEC as that against SCLC. A phase II multi-institutional trial is under way in Japan to elucidate the efficacy of cisplatin- and irinotecan-based therapy regimens against LCNEC.
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Acknowledgment |
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We would like to thank Mika Nagai for her assistance with the preparation of the manuscript.
Conflict of interest statement None declared.
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References |
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1 Travis WD, Linnoila RI, Tsokos MG, Hitchcock CL, Cutler GB Jr, Nieman L, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol (1991) 15:529–53.[Web of Science][Medline]
2 Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E. World Health Organization International Histological Classification of Tumors. Histological typing of lung and pleural tumors. (1999) 3rd edn. Berlin: Springer-Verlag.
3 Rusch VW, Klimstra DS, Venkatraman ES. Molecular markers help characterize neuroendocrine lung tumors. Ann Thorac Surg (1996) 62:798–809.
4 Dresler CM, Ritter JH, Patterson GA, Ross E, Bailey MS, Wick MR. Clinical-pathologic analysis of 40 patients with large cell neuroendocrine carcinoma of the lung. Ann Thorac Surg (1997) 63:180–5.
5 Travis WD, Rush W, Flieder DB, Falk R, Fleming MV, Gal AA, et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol (1998) 22:934–44.[CrossRef][Web of Science][Medline]
6 Takei H, Asamura H, Maeshima A, Suzuki K, Kondo H, Niki T, et al. Large cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighty-seven cases. J Thorac Cardiovasc Surg (2002) 124:285–92.
7 Asamura H, Kameya T, Matsuno Y, Noguchi M, Tada H, Ishikawa Y, et al. Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol (2006) 24:70–6.
8 Yamazaki S, Sekine I, Matsuno Y, Takei H, Yamamoto N, Kunitoh H, et al. Clinical responses of large cell neuroendocrine carcinoma of the lung to cisplatin-based chemotherapy. Lung Cancer (2005) 49:217–23.[CrossRef][Web of Science][Medline]
9 Le Chevalier T, Brisgand D, Douillard JY, Pujol JL, Alberola V, Monnier A, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol (1994) 12:360–7.[Abstract]
10 Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol (2000) 18:623–31.
11 Negoro S, Masuda N, Takada Y, Sugiura T, Kudoh S, Katakami N, et al. Randomised phase III trial of irinotecan combined with cisplatin for advanced non-small-cell lung cancer. Br J Cancer (2003) 88:335–41.[CrossRef][Web of Science][Medline]
12 Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med (2002) 346:85–91.
13 Kubota K, Watanabe K, Kunitoh H, Noda K, Ichinose Y, Katakami N, et al. Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol (2004) 22:254–61.
14 Rudd RM, Gower NH, Spiro SG, Eisen TG, Harper PG, Littler JA, et al. Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group. J Clin Oncol (2005) 23:142–53.
15 Sobin LH, Fleming ID. TNM Classification of Malignant Tumors, 5th edn. Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer (1997) 80:1803–4.[CrossRef][Web of Science][Medline]
16 Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst (2000) 92:205–16.
17 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc (1958) 53:457–481.[CrossRef][Web of Science]
18 Marchevsky AM, Gal AA, Shah S, Koss MN. Morphometry confirms the presence of considerable nuclear size overlap between ‘small cells’ and ‘large cells’ in high-grade pulmonary neuroendocrine neoplasms. Am J Clin Pathol (2001) 116:466–72.
19 Kakinuma H, Mikami T, Iwabuchi K, Yokoyama M, Hattori M, Ohno E, et al. Diagnostic findings of bronchial brush cytology for pulmonary large cell neuroendocrine carcinomas: comparison with poorly differentiated adenocarcinomas, squamous cell carcinomas, and small cell carcinomas. Cancer (2003) 99:247–54.[CrossRef][Web of Science][Medline]
20 Hiroshima K, Abe S, Ebihara Y, Ogura S, Kikui M, Kodama T, et al. Cytological characteristics of pulmonary large cell neuroendocrine carcinoma. Lung Cancer (2005) 48:331–7.[CrossRef][Web of Science][Medline]
21 Marmor S, Koren R, Halpern M, Herbert M, Rath-Wolfson L. Transthoracic needle biopsy in the diagnosis of large-cell neuroendocrine carcinoma of the lung. Diagn Cytopathol (2005) 33:238–43.[CrossRef][Web of Science][Medline]
22 Rossi G, Cavazza A, Marchioni A, Longo L, Migaldi M, Sartori G, et al. Role of chemotherapy and the receptor tyrosine kinases KIT, PDGFR alpha, PDGFR beta, and Met in large-cell neuroendocrine carcinoma of the lung. J Clin Oncol (2005) 23:8774–85.
23 Kozuki T, Fujimoto N, Ueoka H, Kiura K, Fujiwara K, Shiomi K, et al. Complexity in the treatment of pulmonarylarge cell neuroendocrine carcinoma. J Cancer Res Clin Oncol (2005) 131:147–51.[CrossRef][Web of Science][Medline]
24 Tsuchiya R, Suzuki K, Ichinose Y, Watanabe Y, Yasumitsu T, Ishizuka N, et al. Phase II trial of postoperative adjuvant cisplatin and etoposide in patients with completely resected stage I–IIIa small cell lung cancer: the Japan Clinical Oncology Lung Cancer Study Group Trial (JCOG9101). J Thorac Cardiovasc Surg (2005) 129:977–83.
25 Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J, et al. Cisplatin-based aduvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med (2004) 350:351–60.
26 Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med (2005) 352:2589–97.
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