Neoadjuvant immunochemotherapy for pulmonary large-cell neuroendocrine carcinoma: case report

doi:10.21203/rs.3.rs-3331090/v1

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Case Report

Neoadjuvant immunochemotherapy for pulmonary large-cell neuroendocrine carcinoma: case report

https://doi.org/10.21203/rs.3.rs-3331090/v1

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published 14 Apr, 2024

Read the published version in Journal of Cardiothoracic Surgery →

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Background: Pulmonary large-cell neuroendocrine carcinoma (pLCNEC) represents a rare malignancy characterized by its aggressive behavior and a notably high recurrence rate. Remarkably, there is currently no established standard treatment protocol for this condition.

Case Description: In this report, we present an intriguing case of pLCNEC diagnosed at clinical-stage IIB. This case involves a 64-year-old man with a smoking history spanning four decades. In our approach, we initiated a course of neoadjuvant chemotherapy in combination with pembrolizumab, administered for two cycles prior to surgical resection. This innovative treatment strategy resulted in a significant pathological response, culminating in a major pathological remission (MPR). As of the time of composing this report, the patient has been diligently monitored for 33 months post-surgery, exhibiting no indications of recurrence, and has demonstrated exceptional tolerance to the entire treatment regimen.

Conclusions: We have first reported a clinically successful case of neoadjuvant combination chemotherapy with pembrolizumab in the treatment of pLCNEC. This case offers promising clinical insights and suggests that this therapeutic approach could be a viable option for managing pLCNEC.

pLCNEC

Neoadjuvant immunochemotherapy

MPR

case report

Pulmonary large-cell neuroendocrine carcinoma (pLCNEC), classified as a distinct entity within the spectrum of pulmonary neuroendocrine tumors, was originally proposed by Travis et al. in 1991(1). The incidence of pLCNEC accounts for 2.1–3.5% of all lung cancer cases. Currently, a universally accepted standard treatment regimen for pLCNEC is notably absent, with surgery being recommended as the primary approach for patients deemed suitable for resection. Nonetheless, the 5-year survival rate for surgically managed patients ranges only from 13–57% (2). Moreover, the landscape of neoadjuvant therapy for unresectable pLCNEC remains ill-defined, primarily due to the limited availability of data. Nevertheless, it is noteworthy that neoadjuvant chemotherapy has emerged as an effective modality for enhancing the resectability of these tumors. In this report, we share a compelling clinical case of pLCNEC, demonstrating a major pathological remission (MPR) following neoadjuvant combined chemotherapy with pembrolizumab.

A 64-year-old gentleman, who had been a smoker for four decades, was admitted to the hospital in January 2020 after the discovery of pulmonary space-occupying lesions during a routine physical examination he had undergone over the previous three months. An enhanced chest computed tomography (CT) scan revealed a larger mass, measuring up to 36*28mm in its maximum cross-section, along with a small, solitary nodule with a diameter of 9mm in the right lower lobe. Subsequent Positron Emission Tomography (PET)-CT imaging disclosed that the larger mass exhibited malignancy, with a standardized uptake value (SUV) of 20.2, while the smaller nodule was identified as a metastatic lesion with an SUV of 2.3. No enlarged lymph nodes or distant metastases were detected. A CT-guided percutaneous lung biopsy confirmed the diagnosis of poorly differentiated non-small cell carcinoma for the larger mass, while immunohistochemical analysis revealed positivity for CK7 and Ki67, with only partial positivity for chromogranin A. Based on these findings, the patient was diagnosed with LCNEC at clinical stage IIB (cT3N0M0).

For treatment, we initiated neoadjuvant chemotherapy combined with pembrolizumab, administering two cycles at three-week intervals. Following these two cycles of immunochemotherapy, a reevaluation through enhanced chest CT indicated substantial reductions in both lesions, constituting a partial response (PR) according to efficacy assessment criteria. The dynamic radiological changes are visually represented in Figure 1. Subsequently, a right lower lobectomy and systemic lymphadenectomy were successfully performed 23 days after the last therapy.

Postoperative pathology confirmed large-cell neuroendocrine carcinoma, with a major pathological remission (MPR) achieved, characterized by only a small amount of residual carcinoma tissue (<5%) and a tumor bed size of 2.0×1.5 cm, accompanied by fibrous hyperplasia, inflammatory cell infiltration, and histiocytic reaction. Immunohistochemical staining corroborated the biopsy results, and no signs of lymph node metastases were identified. The TNM stage was downgraded to ypT1bN0M0 IA2. The patient was discharged just five days following the surgery without any significant in-hospital complications. The same immunochemotherapy regimen was administered for two additional cycles, and the patient exhibited only mild anorexia throughout the treatment, demonstrating excellent tolerance. To date, the patient has been followed up for 33 months and remains in excellent health, with no evidence of recurrence or metastases.

Clinical data regarding pLCNEC is scarce due to its low incidence. The treatment landscape for LCNEC remains a subject of controversy. Notably, Rekhtman et al. proposed a molecular categorization of LCNEC into NSCLC-like LCNEC and SCLC-like LCNEC based on next-generation sequencing (3). In the NSCLC-like LCNEC subgroup, mutations in KRAS, serine/threonine kinase 11 gene (STK11)/kelch-like ECH associated protein 1 gene (KEAP1), and TP53 were prevalent, while the SCLC-like LCNEC subgroup exhibited predominant RB1 and TP53 inactivation (4).

Sun et al. conducted research indicating that the SCLC-regimen displayed superior prognosis and objective response rates in advanced pLCNEC compared to the NSCLC-regimen. This observation aligns with the demonstrated efficacy of platinum compounds and taxanes in advanced disease (5). Although surgery stands as the optimal treatment for early pLCNEC, some patients may derive benefits from neoadjuvant therapy, especially if surgical intervention is not feasible at the time of initial diagnosis. A single-center study reported a high response rate of 68% to platinum-based neoadjuvant therapy in 22 patients (6). Nevertheless, the role of neoadjuvant therapy in LCNEC treatment remains under active investigation.

Recent years have seen a phase II clinical study showing that neoadjuvant nivolumab could induce a major pathological remission (MPR) in 45% of resected tumors in NSCLC (7). Furthermore, immunotherapy, such as atezolizumab, has gained approval for first-line treatment, even in SCLC patients, based on results from the IMpower133 trial (8). Despite the limited data available for pLCNEC, our case provides support for the positive influence of immune-neoadjuvant therapy and underscores the synergistic effect of neoadjuvant immunochemotherapy in pLCNEC. In our case, a clinical-stage IIB pLCNEC achieved a partial response (PR) after two cycles of neoadjuvant immunochemotherapy, and the patient underwent surgery with remarkable tolerance throughout the treatment. Postoperative pathology confirmed an MPR with less than 5% residual carcinoma tissue. The same immunochemotherapy regimen was continued for an additional two cycles after the operation. At the latest follow-up, the patient remained in good health with no signs of tumor recurrence. We hypothesize that chemotherapy-induced tumor cell death and the substantial release of tumor antigens triggered a robust and sustained response to immune checkpoint inhibitors (ICIs) through immune activation.

In conclusion, we present the first reported clinically successful case of neoadjuvant combination chemotherapy with pembrolizumab in pLCNEC. We advocate for clinical trials to validate the clinical significance of neoadjuvant immunochemotherapy in pLCNEC. In summary, neoadjuvant immunochemotherapy may indeed represent a clinically viable option for the treatment of pLCNEC.

IRB: Institutional Review Board

pLCNEC: pulmonary large-cell neuroendocrine carcinoma

MPR: major pathological remission

CT: computed tomography

PET: positron emission tomography

PR: partial response

Ethics approval and consent to participate：The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Consent for publication：The publication of data received ethical approval from the Zhongshan Hospital's ethics committee. The patient provided informed written consent for the publication of their case data.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request

Competing interests: The authors declare no potential conflicts of interest.

Funding: None declared.

Authors’ Contributions:

CX analyzed and interpreted the patient data, and was a major contributor in writing the manuscript; GZ suggested improvements and helped revise the work; HZ contributed to the collection and assembly of data; JG provided study materials and patient data; DG was in charge of project administration. All authors read and approved the final manuscript

Acknowledgements: Not applicable

Travis WD, Linnoila RI, Tsokos MG, 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.
Fournel L, Falcoz PE, Alifano M, et al. Surgical management of pulmonary large cell neuroendocrine carcinomas: a 10-year experience. Eur J Cardiothorac Surg. 2013;43:111–4.
Rekhtman N, Pietanza MC, Hellmann MD, et al. Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like Subsets. Clin Cancer Res. 2016;22:3618–29.
Ferrara MG, Stefani A, Simbolo M, et al. Large Cell Neuro-Endocrine Carcinoma of the Lung: Current Treatment Options and Potential Future Opportunities. Front Oncol. 2021;11:650293.
Sun JM, Ahn MJ, Ahn JS, et al. Chemotherapy for pulmonary large cell neuroendocrine carcinoma: similar to that for small cell lung cancer or non-small cell lung cancer? Lung Cancer. 2012;77:365–70.
Sarkaria IS, Iyoda A, Roh MS, et al. Neoadjuvant and adjuvant chemotherapy in resected pulmonary large cell neuroendocrine carcinomas: a single institution experience. Ann Thorac Surg. 2011;92:1180–6. discussion 6–7.
Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med. 2018;378:1976–86.
Horn L, Mansfield AS, Szczęsna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018;379:2220–9.

No competing interests reported.

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Journal Publication

published 14 Apr, 2024

Read the published version in Journal of Cardiothoracic Surgery →

Editorial decision: Revision requested
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You are reading this latest preprint version

Neoadjuvant immunochemotherapy for pulmonary large-cell neuroendocrine carcinoma: case report

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