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Ann Thorac Surg 2006;82:1802-1807
© 2006 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Prospective Study of Adjuvant Chemotherapy for Pulmonary Large Cell Neuroendocrine Carcinoma

Akira Iyoda, MDa, Kenzo Hiroshima, MDb, Yasumitsu Moriya, MDa, Yuichi Takiguchi, MDc, Yasuo Sekine, MDa, Kiyoshi Shibuya, MDa, Toshihiko Iizasa, MDa, Hideki Kimura, MDd, Yukio Nakatani, MDb, Takehiko Fujisawa, MDa,*

a Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
b Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan
c Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan
d Division of Thoracic Diseases, Chiba Cancer Center, Chiba, Japan

Accepted for publication May 22, 2006.

* Address correspondence to Dr Fujisawa, Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670 Japan. (Email: fujisawat{at}faculty.chiba-u.jp).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) have a very poor prognosis, but the benefit of adjuvant chemotherapy for these patients has not been established. We performed a prospective analysis of adjuvant chemotherapy for patients with completely resected pulmonary LCNECs to assess the effect of adjuvant chemotherapy.

METHODS: The adjuvant mixture consisted of cisplatin and VP-16 and was administered after surgery to 15 patients with LCNECs from 2000 to 2005. We compared patient survival with historical data for LCNEC patients treated without platinum-based adjuvant chemotherapy after surgery.

RESULTS: There were no differences in age, gender, surgical methods, and staging between the adjuvant chemotherapy group and the control group. Median follow-up was 33 months for the adjuvant group and 42 months for the control group. Of the 15 patients in the adjuvant chemotherapy group, 2 patients had disease recurrence and 1 died of interstitial pneumonia. The overall survival rate at 2 and 5 years of patients with adjuvant chemotherapy was 88.9%. The overall survival rate between patients with adjuvant chemotherapy and the historical control group was significantly different.

CONCLUSIONS: Adjuvant chemotherapy consisting of cisplatin and VP-16 after surgery appears promising for the improvement of the prognosis for patients with completely resected LCNECs, and it should be evaluated further in larger multi-institutional trials.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
In the 1970s, pulmonary neuroendocrine tumors were classified into the three histologically defined categories of typical carcinoid, atypical carcinoid, and small cell lung carcinoma (SCLC). Atypical carcinoid tumors have more evident cytologic atypia cellularity and focal necrosis than typical carcinoid tumors; however, they are less clinically aggressive than SCLCs.

More recently, Travis and colleagues [1] recognized a fourth high-grade neuroendocrine tumor of the lung, namely large cell neuroendocrine carcinoma (LCNEC), which has been categorized as lying between atypical carcinoid and SCLC in terms of clinical aggressiveness. In 1999, the World Health Organization classified LCNEC as a variant of large cell carcinoma [2]. LCNEC has neuroendocrine differentiation detected by immunohistochemistry or electron microscopy and neuroendocrine morphologic features.

Studies of patients with pulmonary LCNEC have reported that outcomes are very poor, even for early stage disease [3, 4]. LCNEC tumors have high proliferative activity, and survival rates of patients with LCNEC are similar to those of patients with SCLC [5, 6]. Therefore, although LCNEC is generally classified as a non-SCLC, these findings suggest that LCNEC would be better classified as a high-grade neuroendocrine tumor comparable with SCLC.

The effect of combined modality therapy for patients with LCNEC has not been established. We have suggested previously that patients with pulmonary large cell carcinoma with neuroendocrine features, including patients with LCNEC, should receive adjuvant chemotherapy after surgery. In our retrospective study of patients with large cell carcinoma with neuroendocrine features, we found that patients who received adjuvant chemotherapy had a better prognosis than patients who did not receive adjuvant chemotherapy [7]. In this study, we prospectively analyzed adjuvant chemotherapy after surgery for patients with LCNEC and compared the results of this treatment with results derived from retrospective studies of LCNEC patients at our institution. The main objective of this study was to compare the effect of treatment and no treatment after surgery on overall and disease-free survival of patients with completely resected LCNEC.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
The study was a one-arm, nonrandomized clinical study of primary pulmonary LCNEC patients whose tumors were resected surgically at Chiba University Hospital and Chiba Cancer Center between October 2000 and April 2005. LCNEC has evidence of neuroendocrine differentiation detected by immunohistochemistry or electron microscopy and the following neuroendocrine morphologic features: (1) neuroendocrine morphology such as organoid nesting, palisading, rosettes, and trabeculae; (2) a high mitotic rate of at least 11 per 2 mm2 (10 high-power fields); (3) necrosis (often large zone); (4) cytologic features of a non-small cell carcinoma, including large cell size, low nuclear-to-cytoplasm volume ratio, vesicular or fine chromatin, or frequent nucleoli, or a combination of these.

Immunohistochemical staining was done using a polyclonal antichromogranin A antibody (Nichirei Corporation, Tokyo, Japan), a monoclonal anti-synaptophysin antibody (DAKO, Glostrup, Denmark), and an antineural cell adhesion molecule (NCAM) antibody (Zymed Technologies, Invitrogen, South San Francisco, CA). Neuroendocrine differentiation was identified by positive immunohistochemical staining for chromogranin A, synaptophysin, or NCAM.

The Institutional Review Board of Chiba University Hospital approved all protocols and procedures. Study patients (adjuvant chemotherapy group) who had given informed consent were included in the study if they had pathologically documented LCNEC and had undergone a complete surgical resection with dissection of hilar and mediastinal lymph nodes. Other inclusion criteria were an age between 45 and 80 years, the absence of preoperative anticancer treatments, synchronous multiple cancers, and a Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

On laboratory analysis, study patients had to have a leukocyte count of at least 4000/mm3, a platelet count of at least 100,000/mm3, a hemoglobin level of at least 10 g/dL, serum aspartate aminotransferase and alanine aminotransferase levels of no more than twice the upper limit of the normal range, a serum creatinine level of no more than 1.5 times the upper limit of the normal range, and an absence of severe postoperative complications such as pneumonia or empyema.

Patients underwent preoperative computed tomography of the thorax and upper abdomen (or abdominal ultrasound), brain magnetic resonance imaging, and a radionuclide bone scan. Postoperatively, patients underwent a complete medical history and physical examination including pathology TNM staging and documentation of ECOG performance status.

After pathologic diagnosis of their surgical specimens as LCNEC, patients received two courses of adjuvant chemotherapy with cisplatin (CDDP at 80 mg/m2, day 1) and VP-16 (100 mg/m2, days 1 to 3) 1 or 2 months postoperatively. Toxicity caused by chemotherapy was evaluated using National Cancer Institute Common Toxicity Criteria.

The retrospective portion of the study involved a chart review of LCNEC patients whose tumors were resected surgically at Chiba University Hospital between 1987 and September 2000. The patients without platinum-based adjuvant chemotherapy comprised the historical control group (control group). These patients' medical histories also included curative surgery with dissection of hilar and mediastinal lymph nodes and an absence of severe postoperative complications such as pneumonia or empyema. Patients with limited surgery or incomplete resection were not included. Gender, age, surgical procedure, adjuvant chemotherapy, times of recurrence and death, and patient outcome were culled from the medical records.

The Fisher exact test was used to compare binomial proportions. The {chi}2 test was used to assess differences in gender, surgical procedures, and tumor stages between the different treatment groups. The unpaired t test was used to detect significant differences in patient ages. The Mann-Whitney U test was used for analyzing patient tumor size and smoking index. Survival times were calculated from the date of surgery until the time of recurrence (disease-free survival) and the time of death (overall survival), and they were evaluated with the Kaplan-Meier method [8]. The curves obtained were compared with the log-rank test. Statistical significance was set at p < 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
Between October 2000 and April 2005, we treated 22 patients with LCNEC. Of these, 7 patients were excluded from the study because of incomplete resection, renal dysfunction, early recurrence, or no informed consents. In the prospective arm, therefore, 15 men with LCNEC were enrolled in the adjuvant chemotherapy group. These patients received a lobectomy with lymph node dissection followed by adjuvant chemotherapy consisting of CDDP and VP-16. Thirteen of the study subjects completed 2 courses of adjuvant chemotherapy, and 2 subjects had only 1 course. During the course of treatment, 7 patients showed grade 3 blood toxicity, and 3 patients showed grade 4. One patient had grade 3 gastrointestinal toxicity. No patient died of complications related to adjuvant chemotherapy. Examination of patient clinical characteristics revealed no significant differences between the prospective group and the control group, including postoperative complications and performance states (Tables 1, 2, and 3). Go Go


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  		Table 1. Patient Characteristics of Adjuvant and Control Groups
 

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  		Table 2. Postoperative Condition of Adjuvant and Control Groups
 

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  		Table 3. Pathologic Staging of Adjuvant and Control Groups
 
In the prospective adjuvant group, 2 patients had disease recurrence with pleural dissemination or brain metastasis, 1 patient died of interstitial pneumonia after additional chemotherapy for recurrent tumors, and 13 patients survived without recurrence, with a median follow-up of 33 months (range, 12 to 66 months). The recurrence rate was significantly lower in the adjuvant chemotherapy group than in the control group (Tables 4 and 5). Go


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  		Table 4. Recurrence Rates of Adjuvant and Control Groups
 

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  		Table 5. Prognosis and 2-Year Survival Rate of Adjuvant and Control Groups
 
The overall survival analysis found that the adjuvant chemotherapy group had a significantly better prognosis than the control group (p = 0.0252; Fig 1, Table 6). The 2-year overall survival was 88.9% in the adjuvant chemotherapy group and 65.2% in the control group. The 5-year overall survival was 88.9% in the adjuvant chemotherapy group and 47.4% in the control group, with a median follow-up 42 months (range, 3 to 125 months).


Figure 1
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  		Fig 1. Overall survival curves for adjuvant chemotherapy and control groups. Patients with adjuvant chemotherapy (top line) have a significantly better prognosis than control patients (bottom line) (p = 0.0252).

 

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  		Table 6. Overall and Disease-Free Survivals for Adjuvant and Control Groups
 
The disease-free survival analysis found that the adjuvant chemotherapy group had a significantly better prognosis than the control group (p = 0.0133; Fig 2, Table 6). The disease-free survival rates at 2 and 5 years were 86.7% in the adjuvant chemotherapy group and 47.8% and 34.8% in the control group.


Figure 2
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  		Fig 2. Disease-free survival curves for adjuvant chemotherapy and control groups. Patients with adjuvant chemotherapy (top line) have a significantly better prognosis than control patients (bottom line) (p = 0.0133).

 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
In general, the curative treatment for patients with non-SCLC is surgical resection. Pelosi and colleagues [9], however, reported that stage 1 adenocarcinomas with neuroendocrine differentiation were clinically aggressive tumors, and Hiroshima and colleagues [10] reported that stage 1 adenocarcinomas with neuroendocrine differentiation had a particularly poor prognosis. Previously, we reported [3] that patients with LCNEC features had a significantly poorer prognosis than patients with classic large cell carcinoma, although most LCNECs have traditionally been classified as non-small cell carcinomas. These reports indicate that non-small cell carcinomas have a range of biologic behavior and that non-SCLC with neuroendocrine differentiation may be associated with especially poor prognosis.

LCNEC was classified by the World Health Organization in 1999 as a variant of large cell carcinomas, which has both neuroendocrine morphology and neuroendocrine differentiation. LCNEC has an aggressive behavior. Patients with LCNEC showed significantly poorer survival after surgical resection than patients with classic large cell carcinoma, even for early stage disease [3, 6]. These studies suggested that patients with LCNEC had a high risk for development of recurrent tumors and that intervention is necessary to improve the prognosis.

The optimal treatment for LCNEC has not been determined. Zacharias and colleagues [11] reported that patients with LCNEC and large cell carcinoma with neuroendocrine morphology, which are aggressive tumors, had a good prognosis if they underwent complete tumor resection with systematic nodal dissection. However, several large studies have shown that LCNEC patients treated with curative resection had a very poor prognosis, even for early stage disease (Table 7) [4, 12–14]. Surgical resection alone, therefore, does not appear to improve the prognosis of patients with LCNEC.


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  		Table 7. Reports on 5-Year Survival Rates of Patients with Large Cell Neuroendocrine Carcinoma
 
No one had demonstrated a significant benefit of adjuvant chemotherapy in the treatment of non-small cell carcinoma before 1995 [15]. Several authors recently presented reports that referred to the effect of adjuvant chemotherapy for non-SCLC [16–18], and adjuvant chemotherapy was strongly recommended for patients with non-SCLC after complete tumor resection. For neuroendocrine tumors, Graziano and colleagues [19] reported that non-SCLC with neuroendocrine differentiation was associated with an increased likelihood of response to chemotherapy. We previously [7] studied adjuvant chemotherapy for large cell carcinomas with neuroendocrine features, including LCNEC, and proposed that adjuvant chemotherapy could prolong the overall survival of stage 1 patients. Rossi and colleagues [13] recently reported that adjuvant chemotherapy based on CDDP plus VP-16 was effective for patients with LCNEC. These studies were retrospective, however.

We prospectively analyzed adjuvant chemotherapy for LCNEC. We found that adjuvant chemotherapy improved the prognosis of patients. Patients with LCNEC are prime candidates to undergo adjuvant chemotherapy because treatment after surgery markedly improves their survival rate, whereas the rate of the effectiveness in a previous study of non-SCLC was about 5% [17]. Most studies addressing the use of adjuvant chemotherapy after complete surgical resection of non-SCLC have administered three to four cycles of chemotherapy, and most patients that received chemotherapy after resection of SCLCs received four to six cycles of adjuvant chemotherapy. These protocols have been used for advanced lung carcinomas, however, and severe complications sometimes occurred [20].

In this study, we used only two cycles for patients with LCNEC because we wanted to avoid severe complications. Our results revealed that our protocol was safe and effective for patients with LCNEC. We may, however, try four cycles or more of adjuvant chemotherapy for advanced LCNEC patients because our treatment was not sufficient to improve the prognosis of such patients with LCNEC. Patients with pathologically advanced stages were included in our study because pulmonary or lymph node metastases were not detected preoperatively and induction chemotherapy had not been given.

The reason why adjuvant chemotherapy may be effective for patients with LCNEC is not known. The clinical features of LCNEC are similar to SCLC [5]. Przygodzki and colleagues [21] and Hiroshima and colleagues [22] showed that LCNEC was more akin genetically to SCLC. A recent study reported that the response rate of LCNEC to cisplatin-based chemotherapy was comparable to that of SCLC, with a response rate of 50% for one complete response case [23]. These data support the hypothesis that adjuvant chemotherapy is effective for patients with LCNEC. In addition, Filosso and colleagues [24] reported preliminary analyses from a small and retrospective study that suggested that adjuvant therapy with octreotide was effective in patients with LCNEC of the lung.

Because LCNEC is a comparatively rare tumor and its population is small, it has been difficult to conduct randomized controlled clinical studies to study the effectiveness of adjuvant chemotherapy. Therefore, accurate diagnosis is important because patients with LCNEC have a very poor prognosis, and more LCNEC patients are needed for clinical investigations of novel therapeutic approaches.

Results of this prospective study of patients with LCNEC treated with surgery indicate that the addition of postoperative adjuvant chemotherapy consisting of cisplatin and VP-16 is a promising approach for improvement of the prognosis in patients with completely resected LCNEC. The efficacy of this therapy should be evaluated further in larger multiinstitutional trials.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported in part by a Grant-in-Aid for Scientific Research (C)(2) 17591458 from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Travis W, Rush W, Flieder DB, 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;22:934-944.[Medline]
  2. World Health Organization Histological typing of lung and pleural tumours. 3rd ed. Berlin, Heildelberg, Germany: Springer-Verlag; 1999.
  3. Iyoda A, Hiroshima K, Toyozaki T, Haga Y, Fujisawa T, Ohwada H. Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology Cancer 2001;91:1992-2000.[Medline]
  4. Takei H, Asamura H, Maeshima A, et al. Large cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighty–seven cases J Thorac Cardiovasc Surg 2002;124:285-292.[Abstract/Free Full Text]
  5. Iyoda A, Hiroshima K, Baba M, Saitoh Y, Ohwada H, Fujisawa T. Pulmonary large cell carcinomas with neuroendocrine features are high grade neuroendocrine tumors Ann Thorac Surg 2002;73:1049-1054.[Abstract/Free Full Text]
  6. Iyoda A, Hiroshima K, Moriya Y, et al. Pulmonary large cell neuroendocrine carcinoma demonstrates high proliferative activity Ann Thorac Surg 2004;77:1891-1895.[Abstract/Free Full Text]
  7. Iyoda A, Hiroshima K, Toyozaki T, et al. Adjuvant chemotherapy for large cell carcinoma with neuroendocrine features Cancer 2001;92:1108-1112.[Medline]
  8. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations J Am Stat Assoc 1958;53:457-481.
  9. Pelosi G, Pasini F, Sonzogni A, et al. Prognostic implications of neuroendocrine differentiation and hormone production in patients with stage I non-small cell lung carcinoma Cancer 2003;97:2487-2497.[Medline]
  10. Hiroshima K, Iyoda A, Shibuya K, et al. Prognostic significance of neuroendocrine differentiation in adenocarcinoma of the lung Ann Thorac Surg 2002;73:1732-1735.[Abstract/Free Full Text]
  11. Zacharias J, Nicholson AG, Ladas GP, Goldstraw P. Large cell neuroendocrine carcinoma and large cell carcinomas with neuroendocrine morphology of the lung: prognosis after complete resection and systematic nodal dissection Ann Thorac Surg 2003;75:348-352.[Abstract/Free Full Text]
  12. Battafarano RJ, Fernandez FG, Ritter J, et al. Large cell neuroendocrine carcinoma: an aggressive form of non-small cell lung cancer J Thorac Cardiovasc Surg 2005;130:166-172.[Abstract/Free Full Text]
  13. Rossi G, Cavazza A, Marchioni A, et al. Role of chemotherapy and the receptor tyrosine kinases KIT, PDGFRalpha, PDGFRbeta, and Met in large-cell neuroendocrine carcinoma of the lung J Clin Oncol 2005;23:8774-8785.[Abstract/Free Full Text]
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  15. Non-small Cell Lung Cancer Collaborative Group Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials Brit Med J 1995;311:899-909.[Abstract/Free Full Text]
  16. Kato H, Ichinose Y, Ohta M, et al.; Japan Lung Cancer Research Group on Postsurgical Adjuvant ChemotherapyA randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 2004;350:1713-1721.[Abstract/Free Full Text]
  17. The International Adjuvant Lung Cancer Trial Collaborative Group Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell-lung cancer N Engl J Med 2004;350:351-360.[Abstract/Free Full Text]
  18. Winton T, Livingston R, Johnson D, et al. National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer N Engl J Med 2005;352:2589-2597.[Abstract/Free Full Text]
  19. Graziano SL, Mazid R, Newman N, et al. The use of neuroendocrine immunoperoxidase markers to predict chemotherapy response in patients with non-small cell lung cancer J Clin Oncol 1989;7:1398-1406.[Abstract]
  20. Rea F, Callegaro D, Favaretto A, et al. Long term results of surgery and chemotherapy in small cell lung cancer Eur J Cardiothorac Surg 1998;14:398-402.
  21. Przygodzki RM, Finkelstein SD, Langer JC, et al. Analysis of p53, K-ras-2, and C-raf-1 in pulmonary neuroendocrine tumorsCorrelation with histological subtype and clinical outcome. Am J Pathol 1996;148:1531-1541.[Abstract]
  22. Hiroshima K, Iyoda A, Shibuya K, et al. Genetic alterations in early-stage pulmonary large cell neuroendocrine carcinoma Cancer 2004;100:1190-1198.[Medline]
  23. Yamazaki S, Sekine I, Matsuno Y, et al. Clinical responses of large cell neuroendocrine carcinoma of the lung to cisplatin-based chemotherapy Lung Cancer 2005;49:217-223.[Medline]
  24. Filosso PL, Ruffini E, Oliaro A, et al. Large-cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighteen cases and the efficacy of adjuvant treatment with octreotide J Thorac Cardiovasc Surg 2005;129:819-824.[Abstract/Free Full Text]

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