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Original Articles: General Thoracic

Neoadjuvant and Adjuvant Chemotherapy in Resected Pulmonary Large Cell Neuroendocrine Carcinomas: A Single Institution Experience

^a Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
^b Thoracic Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
^c Thoracic Service, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
^d Thoracic Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York

Accepted for publication May 9, 2011.

^_* Address correspondence to Dr Sarkaria, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (Email: sarkarii{at}mskcc.org).

Presented at the Forty-seventh Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31–Feb 2, 2011.

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

 
Background: Pulmonary large cell neuroendocrine carcinomas (LCNEC) are aggressive neoplasms with poor prognosis. The role of neoadjuvant and adjuvant therapies in these tumors remains uncertain.

Methods: We performed a retrospective review of a prospective database. Kaplan-Meier estimates of overall survival (OS) were determined and compared across prognostic factors using log-rank analysis and the Cox proportional hazards model.

Results: One hundred patients with resected LCNEC were identified from 1992 to 2008. Of these, 54% were male and 98% current or former smokers (mean 60.3 pack-years). Twenty-two patients received neoadjuvant platinum chemotherapy with a response rate of 68% (15 of 22). Eighty percent (80 of 100) underwent lobectomy and 11% (11 of 100) pneumonectomy with a 90% (90 of 100) complete resection (R0) rate. Seventy-one percent (71 of 100) were stage I-II, and 20 of 71 received platinum adjuvant chemotherapy. Mean OS was 40 months. Univariate factors associated with decreased OS included male gender (p = 0.007), increasing tumor (T) stage (p = 0.004), and stage III–IV disease (p = 0.04). Stage IB patients fared significantly worse than IA (p = 0.006). Multivariate analyses identified male gender (hazard ratio [HR] 2.3, p = 0.007), comorbid pulmonary disease (HR 2.3, p = 0.012), and pathologic stage (HR = 2.2, p = 0.011) as associated with risk of death. Univariate analysis in stage IB-IIIA completely resected (R0) patients receiving combination platinum-based induction and (or) adjuvant chemotherapy showed a trend toward improved OS (median survival 7.4 vs 2 years, p = 0.052).

Conclusions: The LCNEC has a high response rate to platinum-based neoadjuvant chemotherapy. Resected advanced-stage patients receiving combination neoadjuvant and (or) adjuvant chemotherapy may have a survival advantage. These therapies should be considered in resectable patients with LCNEC.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

 
Large cell neuroendocrine carcinomas (LCNEC) represent an aggressive subset of non-small cell lung cancers within the spectrum of pulmonary neuroendocrine tumors, including typical carcinoids, atypical carcinoids, and small cell lung cancers (SCLC) [1–3]. Histologically, these tumors are characterized by organoid palisading rosettes, high mitotic rates, necrosis, large cell size, low nuclear to cytoplasmic ratios, nucleoli, and immunohistochemical presence of neuroendocrine markers including synaptophysin, chromogranins, or CD56 (neural cell-adhesion molecule) [4]. Clinical outcomes of patients with LCNEC are similar to SCLC, with 5-year survival rates reported from 15% to 57% [5–11].

Although the relative rarity of these tumors makes them difficult to study in large numbers, adjuvant chemotherapy has been shown to have probable benefit in LCNEC [12–16]. The role of neoadjuvant therapy remains unstudied. The purpose of this study was to determine the impact of these therapies in patients undergoing surgical resection for LCNEC. To our knowledge, this is the largest single-institution series reported in LCNEC to date.

	Patients and Methods

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We performed a retrospective review of a prospectively maintained lung cancer database of all surgically resected pulmonary patients at our institution from 1992 to 2007. All follow-up was current as of December 31, 2008 and included review of medical records, information obtained by contacting outside physicians, and search of the Social Security Death Index (www.ancestry.com) to identify and confirm all death events. Patients were staged according to the 7th edition of the American Joint Commission on Cancer Staging Manual [17]. All resected specimens underwent rigorous central histopathologic review by the study pathologists (G.S., W.D.T.) to confirm the diagnosis of LCNEC, including the presence of the following: (1) neuroendocrine morphology including organoid nesting, palisading, rosettes, and trabeculae; (2) high mitotic rates of greater than 11 per 10 high-power fields; (3) necrosis; (4) cytologic features of non-small cell lung cancers such as large cell size, low nuclear-cytoplasmic ratio, fine chromatin, and (or) frequent nucleoli; and (5) immunohistochemical presence of one or more neuroendocrine markers, specifically synaptophysin, chromogranin, or CD56 [18]. Tumors were categorized as pure LCNEC, or combined LCNEC if mixed with histologic elements of adenocarcinoma, squamous cell carcinoma, or giant cell carcinoma. If LCNEC was combined with SCLC, it was categorized as combined SCLC and removed from the patient cohort.

Basic demographic, clinical, surgical, and pathologic data were collected, as well as data on neoadjuvant and adjuvant therapies. Response to induction chemotherapy was recorded as partial response, stable disease, or progression of disease as per the RECIST (response evaluation criteria in solid tumors) [19]. All available computed tomography scans were reviewed to identify the location of tumors as peripheral or central.

Overall survival (OS) from time of surgery was estimated using the Kaplan-Meier method. Association between OS and clinical characteristics was tested using the log-rank test (for univariate analysis) and the Cox proportional hazards regression stratified by surgery period (before 2001 vs 2001+, separating the cohort of patients into 2 equally sized groups) for multivariate analysis. When studying the effect of induction and (or) neoadjuvant chemotherapy on OS, propensity score analysis was used to minimize the bias related to the nonrandom assignment of treatment. The propensity score (an individual patient's predicted probability of receiving treatment) was calculated using a logistic regression model that included all the covariates likely to impact treatment assignment (age, race, presence of comorbidities, other cancers, T stage, N stage, and forced expiratory volume percent). Then, the effect of chemotherapy on survival was calculated adjusting for propensity score in 2 ways. First, we used a covariate adjusted nonparametric test that adjusted for the propensity score as a continuous covariate. Second, Cox models were estimated within strata defined by propensity score tertiles, and a stratified hazard ratio was estimated for the whole group. The results of the 2 types of adjustment were very similar; therefore, we only report the results based on the adjusted log-rank test. All statistical analyses were performed using R software (http://www.cran.r-project.org). Approval for the study was granted by the Memorial Sloan-Kettering Cancer Center Institutional Review Board.

	Results

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One hundred patients with confirmed LCNEC undergoing resection at our institution during the study period were identified. Patient and tumor demographics are summarized in Table 1. The study population was predominantly non-Hispanic white Caucasian (83%), and 98% were former or current smokers (60.3 mean pack-years). During the last 5 years of the study, the annual incidence of LCNEC at our institution represented 1% to 3% of all lung cancer resections.

Induction Therapy and Response
Twenty-four patients received induction chemotherapy; 22 of these received platinum-based combination therapy (Table 1). Three patients received 4,500 cGy (centiGray) of preoperative mediastinal radiation, and 1 patient received 3,000 cGy of whole brain radiation.

In 2 patients receiving nonplatinum monochemotherapy, 1 had progression of disease and 1 had stable disease as measured by RECIST criteria. In patients receiving platinum-based regimens, 15 of 22 (68.2%) displayed a partial response, with the remaining 7 of 22 (31.8%) having stable disease.

Surgical Data
Surgical resection data are listed in Table 1. Eighty patients underwent lobectomy or bilobectomy, and 11 patients required pneumonectomy. Sixty-three resections were right-sided, and 75 were in the upper lobes. Five resections were performed video-thoracoscopically; 3 of these were lobectomies. Nine patients required intrapericardial resections, 6 patients required chest-wall resection (5 reconstructed), and 3 patients required phrenic nerve resection due to tumor involvement. One patient underwent sleeve resection and 1 patient required major vascular reconstruction. A compete macroscopic and microscopic extent of resection (R0) was achieved in 90 patients.

Adjuvant Therapy
Adjuvant therapy is summarized in Table 1. Twenty of 25 (80%) patients receiving adjuvant therapy were given platinum-based regimens. Sixty percent (15 of 25) of these patients received etoposide. Fifteen patients received adjuvant radiation, of which 47% (7 of 15) received between 4,900 and 6,040 cGy. One patient received 1,260 cGy and another 9,500 cGy. Dosage information was not available for the remaining 6 patients.

Recurrence and Survival
Thirty-eight patients recurred. Twenty-three of 38 (60.5%) patients recurred at distant sites, and 9 (26.5%) recurred at local or regional sites. Two patients developed both local-regional and distant recurrence.

Median available follow-up was 2.8 years (interquartile range, 1.9 to 6.5 years), and median OS was 3.4 years (95% confidence interval [CI,] 1.9 to 7.5 years). Factors significantly associated with better OS on a univariate analysis were: early overall stage (OS at 5 years = 58% for stage I/II vs 24% for stage III/IV, p = 0.04, Fig 1 ), less advanced T stage (OS at 5 years = 66% for T1, 44% for T2, 30% for T3/4, p = 0.004; Fig 2 ), N stage (OS at 5 years = 56% for N0/1 vs 24% for N2/3, p = 0.081; Fig 3 ), and female gender (OS at 5 years = 63%, compared with 37% for males, p = 0.007 (Fig 4 ) (Table 2). In a subset analysis of stage I patients, stage IB patients fared significantly worse (OS at 5 years = 26%) than stage IA (OS at 5 years = 72%, p = 0.006; Fig 5 ). In a multivariate analysis, male gender (hazard ratio [HR] = 2.3, 95% CI 1.3 to 4.1), advanced stage at diagnosis (HR = 2.2, 95% CI 1.2 to 4.1), and pulmonary comorbidities (HR = 2.3, 95% CI 1.2 to 4.5) remained significant predictors of worse survival (Table 3). In addition, N stage (adjusted p = 0.046), but not T stage (adjusted p = 0.11) were found to be independently associated with overall survival.

View larger version (32K): [in this window] [in a new window]   Fig 1. Advanced stage III/IV is associated with decreased overall survival in patients with resected large cell neuroendocrine carcinoma. (— = I; ··· = II; ·–· = III/IV.)

View larger version (32K): [in this window] [in a new window]   Fig 2. Tumor T stage is associated with decreased overall survival in patients with resected large cell neuroendocrine carcinoma. (— = T1; ··· = T2; ·–· = T3/T4.)

View larger version (31K): [in this window] [in a new window]   Fig 3. Tumor N stage is associated with decreased overall survival in patients with resected large cell neuroendocrine carcinoma. (— = 0; ··· = 1; ·–· = 2/3.)

View larger version (29K): [in this window] [in a new window]   Fig 4. Male gender is associated with decreased overall survival in patients with resected large cell neuroendocrine carcinoma. (— = female; --- = male.)

View larger version (26K): [in this window] [in a new window]   Fig 5. Stage IB large cell neuroendocrine carcinoma is associated with decreased overall survival compared with stage IA. (— = IA; ··· = IB.)

View larger version (28K): [in this window] [in a new window]   Fig 6. Trend toward improved survival in patients with advanced stage IB–IIIA completely resected (R0) large cell neuroendocrine carcinomas treated with induction and (or) adjuvant platinum-based combination chemotherapy. (— = no; ··· = yes.)

	Comment

Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

Large cell neuroendocrine carcinoma is a rare tumor, and therefore difficult to study. The estimated incidence is 2% to 3% of resected lung cancers, similar to the incidence in this series of 1% to 3% of resected lung cancers per year from the most recent 5 years of the study, 2003 to 2008 [13, 21]. Interestingly, the 80% to 85% male predominance reported by other investigators was not as wide in the current study, with 46% female patients [22]. Only 2 of our patients had never smoked; this fact echoes the 98% to 100% tobacco use rate of LCNEC patients that has been reported in the literature [11].

Five-year survival has been reported from 15% to 57% for all stages, and 27% to 67% for stage I patients [6, 9–12, 21–25]. Iyoda and colleagues [26] reported a 54.5% 5-year survival rate in stage IA patients with LCNEC compared with 89.3% in those patients with adenocarcinomas or squamous cell cancers. Additionally, LCNEC histology was found to be an independent predictor of poor outcomes. These poor survival rates have led many authors to investigate the role of adjuvant therapies in improving outcomes in these patients.

Rossi and colleagues, in a retrospective analysis of 83 patients with LCNEC [12], found significantly improved outcomes in those receiving adjuvant SCLC-based therapy (cisplatin/etoposide) versus those receiving platinum regimens in combination with other agents. This finding, significant on both univariate and multivariate analyses, led the authors to advocate the use of combination SCLC adjuvant therapy with cisplatin and etoposide in all patients with LCNEC. Iyoda and colleagues, in a small prospective, nonrandomized, single-arm trial [15], reported 5-year survival rates of 88.9% in patients receiving adjuvant cisplatin-etoposide versus 47.4% in a cohort of historical controls not receiving any chemotherapy. Disease-free survival and recurrence rates were also significantly better in patients receiving chemotherapy in this trial. Although biased by size and a predominance of stage I patients in the chemotherapy arm versus stage II and III in the historical control, this study represents the only prospective trial of adjuvant therapy in these patients and suggests some survival benefit with adjuvant platinum-based therapy.

In a small series of patients with LCNEC, Mazières and colleagues [16] reported recurrence in 13 of 18 patients, 10 of whom recurred within 6 months. However, they did report decreased rates of distant recurrence in patients receiving adjuvant chemotherapy. In a larger series of 72 patients, Iyoda and colleagues [14] reported a 50% recurrence rate. Five-year survival in patients with recurrent disease was 12.5% versus 88.7% in those without, with significantly lower recurrence rates found in those patients receiving platinum-based adjuvant therapy. Additionally, disease-free survival was significantly improved in these patients, leading the authors to advocate the uniform use of adjuvant therapy for LCNEC.

When analyzing the patient cohort as a whole, our current study was unable to identify a significant impact on OS, disease-free survival, or recurrence rates in patients receiving platinum-based combination adjuvant therapy alone. This was also true of similar neoadjuvant regimens, despite an encouraging 68% observed response rate to platinum-based preoperative therapy in these patients. Part of the reason for this disparity may be the relatively large number of stage IA patients in our cohort, a subset that did not reach median survival in contrast to previous reports showing poor survival relative to other non-small cell lung cancers (Fig 5) [26]. Most of these patients did not receive neoadjuvant or adjuvant therapies. We therefore selected a cohort of stage IB-IIIA patients who would normally be considered for neoadjuvant therapy and subsequent surgical resection at our institution. In this cohort, patients receiving neoadjuvant and (or) adjuvant platinum-based therapy and complete (R0) surgical resection demonstrated a trend toward improved OS (Fig 6). In the multivariate analysis, male sex, comorbid pulmonary disease, and advanced tumor stage were associated with worse survival.

This study suffers from the inherent treatment selection bias associated with any retrospective analysis comparing treated versus untreated patients. Those patients who received chemotherapy may have been selected among those with better functional status; thus, the effect attributed to treatment could, in reality, be due to patients' more favorable status. To minimize this problem we used propensity score analysis, an established modality, to make inferences in the presence of selection bias. However, we acknowledge that no firm conclusion regarding treatment effect can be drawn from nonrandomized data. Despite being, to our knowledge, the largest study conducted in this population of patients, the relatively small numbers of people receiving adjuvant and neoadjuvant therapies may have left this study underpowered to detect significant differences in survival. Both of these limitations point to the need for larger, randomized, multiinstitutional studies to definitively assess the true impact of these regimens in surgically resectable LCNEC.

Despite these study biases, the current study represents the largest single-institution experience with LCNEC, as well as the only reported study that investigates the use of neoadjuvant therapy in these patients. Our results highlight the following points: (1) LCNEC is a rare entity, and therefore difficult to study; (2) prior primary non-lung cancers are common in patients with LCNEC; (3) LCNEC is a disease of heavy smokers; (4) resected stage IA patients appear to do very well without additional therapy; (5) combined modality therapy potentially improves survival in stage IB-IIIA disease, although preferential roles of induction versus adjuvant approaches remain unanswered; (6) female sex is a strong positive prognostic factor.

In conclusion, although no significant improvement in OS was identified, the relatively high response rates to platinum-based neoadjuvant therapy in this population are encouraging. Additionally, our data suggest possible improvement in survival with neoadjuvant and (or) adjuvant platinum-based combination therapy in a select group of stage IB-IIIA patients with completely resected disease. Based on these data, we believe these therapies should be given strong consideration in this patient population. Although the current study does not support the use of these therapies in stage IA patients, others have shown worse outcomes in this patient subset. Until more definitive prospective data are available to corroborate our findings, these therapies may also be considered in early-stage IA LCNEC given the aggressive nature of this disease. Although no advantage to etoposide combination therapy was found in this study, other studies have described preferential success with SCLC-based regimens. Etoposide should be considered as the second agent in platinum-based regimens for these patients.

	Discussion

Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

 
DR THOMAS A. D'AMICO (Durham, NC): That was a great presentation, Dr Sarkaria.

I have a couple of questions. In your summary, the conclusions are the same for neuroendocrine tumors as they are for all lung cancers. We give chemotherapy for large stage IB tumors, for stage II and IIIA, and we use cisplatinum with a vinca alkaloid. Your study shed much light on this poor prognostic tumor, but the conclusions themselves are not really any different than all lung cancers. So we have to get beyond this status to improve our results.

You obviously gave either induction therapy or adjuvant therapy to node-negative patients either preop or postop. How did you decide which patients other than large T size?

DR SARKARIA: For the most part, it was based on preoperative stage, and by and large T stage in node negative patients. Also, if there was suspicion preoperatively of a diagnosis of large cell neuroendocrine carcinoma, there is a bias towards given neoadjuvant therapy. However, that is the rare case, as the diagnosis of large-cell neuroendocrine was almost never made on preoperative biopsies.

DR D'AMICO: And do you know what percentage of the distant metastases were brain first, and do you consider giving prophylactic cranial irradiation for patients with large tumors or other bad prognostic factors after complete resection?

DR SARKARIA: I believe 2 of the stage IV tumors that were treated were actually isolated brain metastases that were first resected, treated with radiation, as well as going on to neoadjuvant therapy and then pulmonary resection.

DR D'AMICO: How about prophylactic cranial irradiation, did you use it?

DR SARKARIA: Although I do not know the exact number off-hand, there was a very small handful of patients that received prophylactic brain irradiation, and certainly no discernible uniform trends in treatment practice or pattern over this retrospective series. It's an excellent question that we will need to look at further, given this tumors similar risk profile to SCLC [small cell lung cancers].

DR JOHN MITCHELL (Aurora, CO): Given the differing results between the literature and perhaps what you folks have seen, how does your institution now deal with completely resected IA patients that turn out to be large-cell neuroendocrine? Do you give adjuvant chemotherapy?

DR SARKARIA: In speaking to our oncologists, there is no clear consensus, and this data here certainly does not support the use of adjuvant therapy, at least in T1A, stage IA. Nevertheless, there is a still a bias by some of our oncologists to give adjuvant therapy with platinum and etoposide even to these stage IA patients given the poor survival profiles seen in other studies. It's important to remember that this is a retrospective analysis of an ultimately small cohort and that better assessment of this would have to be corroborated in randomized, prospective, probably multiinstitutional trials. I think there is no clear consensus, and it may be reasonable to consider adjuvant therapy even in these early stage patients.

	Acknowledgments

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The authors would like to acknowledge Mrs Erlin Daly and Mrs Jennifer Grady for their excellent editorial support.

	References

Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Bernard J. Park Valerie W. Rusch Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sarkaria, I. S. Articles by Rusch, V. W. Search for Related Content PubMed PubMed Citation Articles by Sarkaria, I. S. Articles by Rusch, V. W. Related Collections Lung - cancer