Effect of Chemotherapy in Patients With Resected Small-Cell or Large-Cell Neuroendocrine Carcinoma

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Journal of Thoracic Oncology  •  Volume 7, Number 7, July 2012

ORIGINAL ARTICLE

Introduction: Surgical resection of an undiagnosed lung lesion may lead to unintentional removal of small-cell lung cancer (SCLC). The benefit of perioperative chemotherapy in resected SCLC or large-cell neuroendocrine carcinomas (LCNEC) is not clear.

Methods: This retrospective analysis included limited disease SCLC and LCNEC that had been surgically removed between 1979 and 2007 at a single institution. Perioperative treatments were analyzed, and sur-vival followed up. Log rank tests were used to compare overall sursur-vival. Results: Among 74 patients who had a tumor resection, 45 received chemotherapy, four had preoperative radiotherapy, and 21 had post-operative radiotherapy. Eleven patients were women. The median age was 64 in the surgery group and 58 in the surgery plus chemotherapy group, and four and 11 patients in these groups, respectively, had LCNEC. There were 10 node positive tumors and only two incomplete resections in the surgery group versus 27 node positive tumors and three incomplete resections in the surgery plus chemotherapy group. The median follow-up was shorter in the group with surgery alone: 4.5 years (1.4–7) versus 5.8 years (0.6–19.6). Among the patients with a survival or a follow-up of at least 6 months, the median survival was 2.3 and 6.1 years in the surgery (n = 20) and surgery plus chemother-apy (n = 39) groups, respectively, such that the hazard ratio for death was 0.48 (95% confidence interval, 0.24–0.99, p = 0.04).

Conclusion: These results suggest that perioperative chemotherapy may be beneficial in patients with resected SCLC or LCNEC. Key Words: Perioperative chemotherapy, Small-cell lung cancer, Surgery.

(J of Thorac Oncol. 2012;7: 1179–1183)

S

mall-cell lung cancer (SCLC) represents approximately 15% of new cases of lung cancer diagnosed annually.1 It is

an aggressive form of lung cancer that is associated in the vast

majority, approximately 95%, of cases with cigarette smok-ing.2 The most important prognostic factors are disease stage,

performance status, and extent of weight loss. Elevated lactate dehydrogenase level is also associated with a poorer progno-sis.3,4 At diagnosis, approximately 30% of patients with SCLC

have limited disease (LD-SCLC).5,6 Combined modality

treat-ment involving chemotherapy and concurrent thoracic radio-therapy is the current standard of treatment for LD-SCLC, and is followed by prophylactic cranial irradiation for all patients who achieve complete remission.7–10 The median survival is in

the range 17 to 27 months, and the 5-year survival rate is 12% to 23%.5,8,11

SCLC is classically considered a contraindication for surgery because radiotherapy is at least equivalent in terms of local control, and the rate of resectability in SCLC patients is poor.12 However, some centers continue to support

sur-gery for very LD patients because experience suggests that it is possible to achieve a long-term survival in these selected patients.13,14 In daily practice, a small proportion of patients

carrying resectable lung nodules receive a postoperative diagnosis of LD-SCLC. In screening programs, SCLC is diagnosed in 12.6% to 17.1% of patients undergoing nod-ule resection.15,16 Among 12,620 cases of SCLC entered in

the International Association for the Study of Lung Cancer (IASLC) data set used for the 7th edition of the classification of SCLC, surgically treated SCLC represented only 1.3% of all fully staged resected cases in the database and only 2.8% of all SCLC cases.17 Some authors have reported 5-year

sur-vival rates of 30% to 40% for patients who underwent surgical resection before the histological diagnosis of SCLC and who were also given chemotherapy, chest radiotherapy, or both.18,19

In the International Association for the Study of Lung Cancer (IASLC) data set (n = 339), the observed 5-year survival rate was 40% to 56% for patients with stage IIB disease or less, who were initially treated by surgical resection, and 12 % for stage IIIA.17 The rate of adjuvant treatment in this data set of

patients treated mostly between 1990 and 2000 is unknown. In the National Cancer Institute Surveillance Epidemiology and End Results, 247 patients underwent surgical resection for SCLC between 1988 and 2004.20 Of 205 patients with stage

I SCLC who required only lobectomy, the 5-year survival rate was 50.3%. Surveillance Epidemiology and End Result does not provide chemotherapy details but it is assumed that

Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0707-1179

Effect of Chemotherapy in Patients With Resected 

Small-Cell or Large-Cell Neuroendocrine Carcinoma

Nader Abedallaa, MD,* Lise Tremblay, MD,† Charlotte Baey,* Dominique Fabre, MD,‡

David Planchard, MD, PhD,* Jean Pierre Pignon, MD, PhD,* Joel Guigay, MD,*

Cécile Le Pechoux, MD,* Jean Charles Soria, MD, PhD,*

Vincent Thomas de Montpreville, MD,‡ and Benjamin Besse, MD, PhD,*

*Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France; †IUCPQ 2750 Chemin Sainte-Foy, Québec, Québec, Canada; and ‡Department of Surgery, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.

Disclosure: The authors declare no conflict of interest.

Address for correspondence: Benjamin Besse, MD, PhD, Department of Medicine, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France. E-mail address : besse@igr.fr

Journal of Thoracic Oncology

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most, if not all, of these patients received systemic therapy. Despite these reports, the role of surgery has not been estab-lished and the role of adjuvant treatment in resected patients is unknown.21

Large-cell neuroendocrine carcinoma (LCNEC) is a subgroup of large-cell carcinoma and is a type of lung can-cer showing neuroendocrine characteristics similar to that of SCLC.22 A small number of studies suggest that after

com-plete resection of pulmonary LCNEC, an adjuvant treatment combining etoposide and a platinum compound could be of value, but this needs to be confirmed.23,24

In a retrospective study, we assessed the role of che-motherapy before or after a local treatment that in all cases included surgery, comparing the survival of two groups of patients diagnosed with LD-SCLC or early LCNEC: the first group was treated by surgery and chemotherapy combined, and the second by surgery alone.

MATERIALS AND METHODS

This retrospective study included LD-SCLC (according to the staging system of the Veterans’ Administration Lung Study Group) and early LCNEC surgically removed between 1979 and 2007 at the Surgical Centre Marie Lannelongue. We collected data on the patients’ characteristics (sex, age, and smoking status), the type of neuroendocrine tumor (SCLC or LCNEC), stage (according to the 6th edition of the tumor, node, metastasis (TNM) staging system based on the crite-ria established by the American Joint Committee for Cancer and IASLC), the type of surgery and its extent, the periopera-tive treatment (either systemic treatment or radiotherapy) and the outcome (recurrence, metastatic sites, second tumor, and cause of death).

Tumors were classified according to the World Health Organization classification.25,26 LCNEC fulfilled the

follow-ing criteria: neuroendocrine morphology, mitotic rate greater than 10 per 10 high-power field, necrosis, cytologic features of non–small-cell lung cancer (NSCLC), and positive immu-nohistochemical staining for one or more neuroendocrine markers. The neuroendocrine markers used were CD56, chro-mogranin, and synaptophysin. NSCLCs showing neuroendo-crine differentiation (NSCLC-NE) were not included in our series because the relevance of immunohistochemichal neuro-endocrine differentiation in NSCLC that does not show neu-roendocrine morphology is controversial.27

Statistical Analysis

The χ2 test, Fisher’s exact test, t test, and the Wilcoxon

test were used as appropriate to compare the patients who received or did not receive adjuvant treatment. Overall vival (OS) was calculated as the interval from the date of sur-gery until death from any cause or until the date of the last follow-up. Follow-up was assessed by the reverse Kaplan-Meier method.28 OS curves were estimated by the

Kaplan-Meier method and were compared with the log rank test. All p values were two-sided and p values of less than 0.05 were considered significant. Data were analyzed using SAS statisti-cal software (SAS Institute, Cary, NC).

RESULTS

We identified 75 patients with resected SCLC and LCNEC: 42 patients had no preoperative pathological diagno-sis (Table 1). One patient was excluded because of a definitive

TABLE 1.  Baseline Characteristics of the Patients Characteristic Surgery Alone (n = 29) Surgery Plus Perioperative Chemotherapy (n = 45) p Value Age at diagnosis

median (range, year) 64 (49–78) 58 (33–78) 0.12

Male n (%) 25 (86) 38 (84) 0.87 Smoking status: n (%) 0.08 Never 3 (10) 0 (0) Current 16 (55) 32 (71) Former 10 (35) 13 (29) Number of packets median (range) 40 (6–100) 40 (10–80) 0.71 Preoperative diagnosis n (%) 0.002c Unknown 22 (76) 20 (45) SCLC 4 (14) 14 (31) LCNEC 2 (7) 6 (13) Other 1 (3)a 5 (11)b Clinical stage n (%) 0.36d Stage I 15 (52) 19 (42) Stage II 6 (21) 13 (29) Stage III+IV 3 (10) 10 (22) Unknown 5 (17) 3 (7) pTumor category n (%) 0.63e T1 5 (17) 9 (20) T2 15 (52) 20 (44) T3 2 (6) 11 (24) T4 3 (10) 1 (2) Unknown 4 (15) 4 (10) pNodal status n (%) 0.05f N- 15 (52) 15 (33) N+ 10 (34) 27 (60) Unknown 4 (14) 3 (7) Type of surgery n (%) 1.00g Lobectomy 19 (66) 26 (58) Pneumonectomy 8 (28) 13 (29) Bi-lobectomy 1 (3) 5 (11) Segmentectomy 1 (3) 1 (2) Type of resection n (%) 0.01 Complete resection 27 (93) 42 (93) Incomplete resection 2 (7) 3 (7) Postoperative diagnosis n (%) 0.38 SCLC 25 (86) 34 (76) LCNEC 4 (14) 11 (24)

SCLC, small-cell lung cancer; LCNEC, large-cell neuroendocrine carcinomas.

aAtypical carcinoid.

bNon–small-cell lung cancer n = 2, undifferentiated carcinoma n = 3. cUnknown vs. SCLC + LCNEC vs. other.

dStage I vs. stage II vs. stage III+IV. eT1 vs. T2 vs. T3-4.

fN– vs. N+.

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diagnosis of atypical carcinoid so that the analysis included the 74 remaining patients. Forty-five patients underwent surgery combined with perioperative chemotherapy, and 29 underwent surgery alone. Patients’ baseline characteristics are shown in Table 1. Among the 45 patients in the surgery-plus-perioperative chemotherapy group, 10 received a preopera-tive treatment with chemotherapy alone (n = 6), concurrent chemoradiotherapy (n = 3), or radiotherapy alone (n = 1). In the same group, 37 patients received postoperative treatment with chemotherapy alone (n = 16), concurrent chemoradio-therapy (n = 19), or radiochemoradio-therapy alone (n = 2). Three patients received both pre- and postoperative treatment: two had preop-erative chemotherapy with either postoppreop-erative radiotherapy or concurrent chemoradiotherapy, and one had preoperative radiotherapy and postoperative chemotherapy. Most of the systemic therapies involved platinum-based drugs combined with either etoposide (62%) or another agent (13%; cyclo-phosphamide, doxorubicin, metotrexate, or ifosfamide). The remaining 25% patients received a platinum-free regimen. Seven patients received prophylactic cranial irradiation, all of them in the surgery-plus-perioperative chemotherapy group.

The patients in the surgery-alone group were resected earlier during the study (median year of surgery 1998, range, 1979–2007) compared with the chemotherapy group (median year of surgery 2001, range, 1980–2007). Stage was unknown in eight cases (10.8%); 51% cases (n = 34) were at stage I, 29% at (n = 19) stage II, and 20% at (n = 13) stage III–IV (Table 1). Clinical TNM (cTNM), in patients who did not receive preop-erative chemotherapy, was compared with pathological TNM (pTNM). Seven values were missing, and 59 cases were assess-able. In 30 patients (51%), there was no TNM change. The T-factor differed in 12 cases (20%) with underestimation of the cT versus pT in nine cases. The N-factor differed in 21 cases (36%) with underestimation of the cN versus pN in 17 cases.

Only patients whose follow-up was 6 months or more (n = 59) were included in the survival analysis, such that patients who experienced postoperative death or rapidly growing metastatic disease refractory to chemotherapy were excluded. Thus, 15 patients (nine in the group without chemo-therapy) were excluded from the survival analysis: (1) three patients were alive at the time of the last follow-up visit but the follow-up was shorter than 6 months (one in the group with-out chemotherapy and two in the group with chemotherapy), (2) four patients died within 1 month of surgery (considered to be postoperative death), including one patient who died from cancer (all in the group without chemotherapy), and (3) eight patients died between 1 and 6 months after surgery (four in the group without chemotherapy, including one death from can-cer, two deaths from other causes, and one death of unknown cause; and four in the group with chemotherapy, including three deaths from cancer and one death of unknown cause).

Among the 59 patients with a survival and a follow-up of at least 6 months, the median duration of follow-up was 5.8 years (range, 0.6–19.6 years) and 33 died during fol-low-up. Follow-up was shorter for the surgery-alone group (4.5 years; range, 1.4–7.0 years) than for the surgery-plus-perioperative chemotherapy group (5.8 years; range, 0.6–19.6 years). The median survival was 2.3 years (1.4–7.0) for the surgery-alone group and 6.1 years (0.6–19.6) for the group

with perioperative chemotherapy (Fig. 1). The hazard ratio (HR) for death was 0.48 (95% confidence interval [CI], 0.24– 0.99; p = 0.04) for the perioperative chemotherapy group compared with the surgery-alone group. The OS rates at 1, 2, and 3 years were 92%, 79%, and 59%, respectively in the perioperative chemotherapy group, and 85%, 54%, and 48% in the surgery-alone group, respectively.

A sensitivity analysis was performed by censoring follow-up at 3 years (Fig. 2). Thus, a patient who died 3.5 years after surgery was considered to be alive in this analysis. Similarly, a patient still alive after 5 years of follow-up was considered to be living with only 3 years of follow-up. The objective of this analysis was to mitigate the imbalance in the duration of follow-up between the two treatment groups: cen-soring follow-up at 3 years contributes to standardizing the up between the two treatment groups (median follow-up was 3 years for each grofollow-up). The median survival was not reached by 3 years in the group with chemotherapy, because less than 50% of the patients died. For the group without che-motherapy, the median survival was 2.3 years. The HR for

FIGURE 2. Overall survival and sensitivity analysis—censor-ing the follow-up after 3 years.

FIGURE 1. Overall survival according to treatment group: surgery (S) and surgery plus chemotherapy (S + C). 1 2 6 7 9 17 20 3 4 5 5 10 14 18 20 30 35 39 0% 20% 40% 60% 80% 100% 0 1 2 3 4 5 6 7 8 9 10 Years S S+C At risk

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death was 0.58 (95% CI, 0.26–1.31; p = 0.18) for the group that received chemotherapy compared with the group with surgery alone. The OS rates at 1, 2, and 3 years were 85%, 54%, and 48% in the surgery-alone group and 92%, 79%, and 59% in the surgery-plus-perioperative chemotherapy group. We evaluated the impact of prophylactic cranial irradiation (PCI) on survival result. The sensitivity analysis for OS was performed for the population without the seven patients who received PCI (n = 52). The HR for death was 0.60 (95% CI, 0.26–1.39; p = 0.22) for the group that received chemotherapy compared with the group with surgery alone.

We used univariate analysis to study the prognostic value of three factors: the type of surgery (complete versus incomplete), the node status of the patient (pN- versus pN+), and type of cancer (SCLC versus LCNEC). As for the survival analysis, we restricted this analysis to the 59 patients whose follow-up was 6 months or longer. None of these three vari-ables were significantly related to OS.

DISCUSSION

We report the first retrospective study to compare the benefit of the use of perioperative chemotherapy for survival in patients with resected SCLC and LCNEC. Our findings suggest that treatment involving surgery plus perioperative chemotherapy was associated with a significantly longer OS than surgery alone (6.1 years and 2.3 years, respectively) and the HR for death was 0.48 (95% CI, 0.24–0.99; p = 0.04). However, follow-up was shorter for patients in the group without chemotherapy (4.5 versus 5.8), and this may intro-duce a bias in the analysis. We therefore conducted a sensitiv-ity analysis by censoring the follow-up of patients at 3 years. This analysis in a limited population showed a nonsignificant improvement of OS, but the tendency for a benefit was still observed (HR: 0.58 (95% CI 0.26; 1.31, p = 0.18).

The evidence for the benefits of surgery in LD-SCLC is poor. Three studies suggest that surgical resection plus chemotherapy in LD-SCLC is of more benefit than nonsurgical management.13,29,30 A Japanese retrospective

study investigated 91 patients who had undergone pulmonary resection for SCLC.30 The subgroup of 40 patients with

p-stage IA–IIB, who received perioperative chemotherapy was compared with nine patients treated by surgery alone. The 5-year probability of survival for patients with perioperative chemotherapy was 54.9% as compared with 22.2% for patients without chemotherapy (p = 0.015). The poor survival rate of the surgery-alone group may have been because of an excess of comorbidities: when the authors censored patients whose cause of death was other than SCLC, the difference in the 5-year probability of survival did not persist. Lucchi et al. reported the OS of 127 patients who underwent radical resection of SCLC.30 The 20 patients who were treated with

surgery alone died within 2 years whereas the 5-year survival rates were 32% for the 92 patients treated with surgery and adjuvant chemotherapy, and 13% for the 15 patients treated with preoperative chemotherapy alone or in combination with adjuvant chemotherapy. Unfortunately, no formal comparison was reported of the survival in the arms with surgery alone and surgery plus perioperative chemotherapy. Moreover, the poor survival of the surgery arm can be explained by the higher

rate of node-positive patients: 75% versus 48% in the surgery and adjuvant chemotherapy arm, respectively. In our study, the benefit of adjuvant chemotherapy was evidenced despite a higher rate of node-positive patients in the chemotherapy arm.

In most published studies, the survival benefit associated with surgery is limited to stage I and II disease.18,19,31,32,17,20,30

This is concordant with our observations. In our series, 80% of patients in the group surgery plus perioperative treatment (chemotherapy, radiotherapy, or both) were stage I or II. In various series of LD-SCLC managed by surgery plus peri-operative chemotherapy, the 5-year OS ranged from 32% to 60%.13,29,30,32,33 It may be difficult to compare these series

because the rate of N2 disease or complete resection may dif-fer among them. Timelines may also be of importance; in our cohort study, 82.5% of patients were operated between 1990 and 2007 with more than half after 2000. In recent years, the rate of lobectomy has increased, the use of platinum-based adjuvant chemotherapy has become more systematic, and workup is more extensive. These various factors may together explain the favorable median survival in our patients (6.1 years, Fig. 1). The use of adjuvant mediastinal radiotherapy may improve OS, as is the case for patients treated with com-bined chemoradiotherapy.7,10,34 The use of PCI did not affect

the results of our sensitivity analysis because results were similar if patients who received PCI were excluded from the analysis.

We are aware that our study has limitations that make it difficult to interpret the results. We have no data on per-formance status (a major prognostic factor) or lactate dehy-drogenase. The TNM-staging system according to the criteria established by the American Joint Committee for Cancer and IASLC is more accurate for classifying SCLC.17,35 It has been

recommended since 2002 but we began our retrospective study in 1979. We therefore had to use the staging system for SCLC introduced by the Veterans’ Administration Lung Study Group as an inclusion criterion to be consistent for all our patients. Preoperative workup was probably suboptimal, given the long inclusion period. This may explain the underes-timation of the cTNM relative to the pTNM, as also observed by Inoue et al.30 Improved imaging (including computed

tomography scanning) and metabolic assessment (positron emission tomography scanning) may allow better selection of patients eligible for surgery. We do not have sufficient data concerning the surgery group to analyze and explain the decision for not using perioperative treatment. Of note, more patients had a node involvement in the chemotherapy group, indicating that physicians may have offered chemotherapy to patients with more advanced disease. No definitive conclu-sion can be made concerning this issue because of the small population examined in this study, its retrospective nature, the difference in follow-up between the two groups, and the heterogeneity of the combined treatments. Nevertheless, this study raises a very important question regarding the ben-efit of perioperative treatment for patients with surgically resected LD-SCLC.

Histology (SCLC versus LCNEC) was not a prognostic factor in our study. Only 15 patients with LCNEC were included in the cohort, of which 11 received adjuvant chemotherapy. In a retrospective cohort of 83 patients with resected LCNEC,

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Rossi et al.24 reported a better survival for the 38 patients who

received adjuvant chemotherapy. Interestingly, the multivariate analyses showed a better outcome for patients receiving a SCLC-targeting regimen (platinum-etoposide) than a NSCLC-targeting regimen (response rate = 15.5 [5.0–47.8], p = 0.0001). A Japanese study reported a 2-year survival of 88% (68–109) for 15 consecutive patients treated by complete resection followed by platinum-etoposide chemotherapy but only 65% (45–84) in a historical cohort of 23 patients treated by surgery alone.36 These results are consistent with the

benefit reported in our study.

Our results suggest that surgical resection combined with adjuvant or neoadjuvant chemotherapy may be an appro-priate option for patients with early disease SCLC or LCNEC. A prospective trial to address this issue would be useful, but may be difficult to run in this setting.

ACKNOWLEDGMENTS

We thank Benjamin Lacas for his help with statistical analysis.

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