Small Cell Lung Cancer Treatment: Early Stage

16 SMALL CELL LUNG CANCER TREATMENT: EARLY STAGE

Victor van Berkel, MD, PhD • Neal E. Dunlap, MD • Matthew Fox, MD • Alden Klarer, MD, PhD • Kate Alyse Marino, MD • Phuong T. Ngo, MD • William M. Whited, MD • Mehran Yusuf, MD

SURGERY FOR EARLY STAGE SMALL CELL LUNG CANCER

William M. Whited, MD, Kate Alyse Marino, MD, Matthew Fox, MD, Victor van Berkel, MD, PhD

A 73-year-old gentleman with a past medical history of chronic obstructive pulmonary disease (COPD), hypertension (HTN), and a 50 pack-year cigarette smoking history presents to your office after a screening computed tomographic (CT) scan found a 1-cm mass in the right lung lower lobe. His primary care physician orders a percutaneous biopsy, which returns as small cell lung cancer (SCLC). What further workup does this patient need? Which subgroup of patients would be surgical candidates?

Learning Objectives:

1. Understand the diagnostic workup for patients with SCLC.

2. How is SCLC staged, and what are the recent changes to the staging system?

3. What is the ideal treatment approach to patients with early stage SCLC?

In the United States, there are approximately 234,000 patients diagnosed with lung cancer annually, with only 10%-15% of cases being SCLC.¹ Despite SCLC being less common, it is a particularly deadly and aggressive type of lung cancer, with patients often having metastatic disease at the time of diagnosis.² SCLC has been traditionally staged as extensive stage (ES) or as limited stage (LS) disease; the purpose of this simple dichotomous staging system is to identify patients who may be candidates for local control of disease.³ The cornerstone of treatment for SCLC has been chemotherapy due to the majority of patients having ES disease at the time of diagnosis.⁴ The focus of this chapter is on patients with LS disease and what role surgery plays in the treatment of SCLC.

PRESENTATION

Unfortunately, for patients diagnosed with SCLC over two-thirds will have metastatic disease at the time of diagnosis.⁵ Symptoms of SCLC are typically broken down into either local or distant symptoms. Symptoms of local disease include shortness of breath, cough, hemoptysis, and chest pain. Symptoms of metastatic or advanced disease include weight loss, weakness, lymphadenopathy, and anorexia. In addition to the traditional symptoms mentioned, SCLC can present with a variety of paraneoplastic syndromes.⁶

Over two-thirds of patients with SCLC will have metastatic disease at the time of diagnosis.

• Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): Affects approximately 15% of patients with SCLC. SIADH is characterized by hyponatremia along with high urine osmolality. This is caused by ectopic production of antidiuretic hormone. Symptoms and laboratory values typically improve with treatment of SCLC.⁶^,⁷

• Cushing Syndrome: Present in less than 5% of patients with SCLC, Cushing syndrome is caused by ectopic production of corticotropin.⁶ Symptoms can include obesity, hirsutism, glucose intolerance, and acne.

• Lambert-Eaton Syndrome: Results in proximal muscle weakness and is caused by antibodies that target calcium channels.⁶

Screening CT scans have become increasingly more prevalent after the conclusion of the National Lung Screening Trial demonstrated a reduction of lung cancer mortality with the implementation of screening CT scans in at-risk patients.⁸ Recent reports demonstrated a shift toward earlier detection in SCLC patients undergoing screening CT compared to traditional means of detection, with approximately one-third of patients with SCLC detected on screening CT scan having IA disease.⁹

DIAGNOSTIC WORKUP

The diagnostic workup for patients with suspected SCLC is similar to the workup for other types of lung cancer and will include standard thorough history and physical and laboratory evaluation (complete blood count, complete metabolic panel, and serum lactate dehydrogenase). The majority of patients presenting with SCLC often have advanced stage disease at the time of diagnosis, which makes accurately staging patients critically important. High-quality imaging is required to rule out distant metastatic disease; imaging includes CT scan of chest, CT scan of the abdomen, brain magnetic resonance imaging (MRI)/CT scan, in addition to a positron emission tomographic (PET) scan.

High-quality imagining of the chest, abdomen, and brain is required in the workup of SCLC due to the majority of patients having metastatic disease at the time of diagnosis.

Tissue evaluation confirms the diagnosis, with the classic “small blue cells” on light microscopy. Histologic confirmation is required to rule out other neuroendocrine malignancies, such as carcinoid. In patients with LS disease, there is often mediastinal lymph node involvement at time of diagnosis. Invasive mediastinal sampling of suspicious lymph nodes can be performed with mediastinoscopy or endobronchial ultrasound-guided biopsy. Routine bone marrow biopsy is not recommended without evidence of leukopenia or thrombocytopenia.¹⁰

STAGING

In the past, SCLC has been staged differently from other types of lung cancers, which are staged using the tumor, node, metastasis (TNM) system. Defining characteristics of SCLC are its rapid spread and aggressive nature. This resulted in the Veterans Administration Lung Cancer Study Group (VALSG) to propose a simplified dichotomous staging system that classified disease as either ES or LS.³ Originally, patients with LS disease were those with disease limited to 1 hemithorax and which could be included in a single field of radiation. This included mediastinal and ipsilateral supraclavicular lymph node disease along with locally advanced disease, including laryngeal nerve and superior vena cava involvement. Patients with evidence of metastatic disease, including contralateral hilar or supraclavicular lymph node involvement, along with malignant pleural or pericardial effusion were classified as ES. The International Association for the Study of Lung Cancer (IASLC) subsequently updated the VALSG staging system to define LS as all non-metastatic disease.

In 2009, the IASLC published a report in which 349 patients with SCLC were analyzed based on the current TNM staging system and found differences in survival based on the TNM groupings, which resulted in the recommendation for the seventh edition of the American Joint Committee on Cancer (AJCC) TNM staging to include SCLC.¹¹ The IASLC again recommended the continued use of the TNM staging system when the 8th edition was released and is what is currently used to stage SCLC.¹²

RESECTION OF EARLY STAGE

Small cell lung cancer is an aggressive type of lung cancer, often with metastatic disease at the time of presentation. Patients with metastatic disease are often treated with 4-6 cycles of cisplatin or carboplatin and etoposide, in addition to thoracic radiation and cranial radiation in select groups of patients.⁴ The focus of this section is to highlight the treatment of patients with non-metastatic disease and the role of surgery in these patients.

The advanced nature of SCLC undoubtedly limits the use of surgical therapies in newly diagnosed patients. However, even in patients with earlier stage disease, the mainstay of treatment is chemotherapy (cisplatin and etoposide) in addition to thoracic radiation. The role of surgery in patients with LS disease after undergoing induction chemotherapy has been studied previously in a randomized prospective trial, which demonstrated no survival benefit to patients undergoing resection compared to chemotherapy followed by thoracic radiation.¹³ One of the biggest flaws of this study is only 19% of enrolled patients had stage I disease, a group that would arguably benefit most from surgery. Despite this limitation, many cite this paper to advocate for the non-surgical treatment of SCLC.

A recent analysis by Wakeman et al. using the National Cancer Database (NCDB) demonstrated a significant improvement in survival in patients with early stage SCLC undergoing surgical resection.¹⁴ Patients with stage I disease undergoing resection had an overall survival of 38.6 months compared to 22.9 months in the non-surgical group (Figure 16-1). An additional subgroup analysis found that patients with stage I and II disease who underwent adjuvant chemotherapy with or without radiation with lobectomy had a median overall survival of 48 months compared to a matched group receiving chemotherapy and thoracic radiation alone. Two recent publications by Yang et al. evaluated the role of surgery followed by adjuvant chemotherapy compared to concurrent chemoradiation using NCDB data.¹⁵^,¹⁶ The authors found improved overall 5-year survival in the patients with N0 disease undergoing surgery followed by adjuvant chemotherapy compared to concurrent chemoradiation (49.2% vs. 32.5%, p < .03).¹⁵ Patients with N1 SCLC undergoing surgery followed by adjuvant therapy had less of a survival advantage compared with those undergoing concurrent chemoradiation.¹⁶ This trial, in addition to other retrospective studies,¹⁷^–¹⁹ would support the role of surgery in selected patients with SCLC, particularly with early stage N0 disease. Despite increasing evidence in support of surgery, only one-third of patients potentially eligible for surgery undergo resection.²⁰

Figure 16-1. Overall survival in the surgical treatment group versus non-surgical treatment group in patients with stage I SCLC. (Data from Wakeam E, Acuna SA, Leighl NB, et al. Surgery versus chemotherapy and radiotherapy for early and locally advanced small cell lung cancer: a propensity-matched analysis of survival. Lung Cancer. 2017;109:78-88.)

There continues to be growing evidence for the role of surgical resection in patients with SCLC. As with other surgical procedures, patient selection is important. When considering surgical resection, accurately staging the disease is critically important. In otherwise appropriate patients with small (T1-2) tumors without any evidence of nodal involvement, surgical resection is appropriate treatment.²¹ Lobectomy with mediastinal lymph node dissection, in an otherwise appropriate patient, should be consider based on recent National Comprehensive Cancer Network (NCCN) guidelines.²² There have been additional reports of when resection would be appropriate in patients with SCLC.¹⁰^,¹¹ These include tumors with a component of NSCLC and stage III disease with mediastinal lymph node involvement if the patient has regression of mediastinal disease after chemotherapy and radiation.

INCREASING ROLE OF SURGERY IN SMALL CELL LUNG CANCER

Small cell lung cancer is an aggressive neuroendocrine tumor of the lung, often with advanced-stage disease at the time of diagnosis. Chemotherapy and radiation have been the mainstay of treatment for the past several decades; however, there is a role for surgical resection in the appropriately selected and accurately staged patient. With the increasing use of screening CT scans and the detection of earlier stage disease, surgery is likely to be an expanding component in the treatment of SCLC.

CHEMOTHERAPY FOR EARLY STAGE SMALL CELL LUNG CANCER

Phuong Ngo, MD

A 64-year-old Caucasian male with a 40 pack-year smoking history was referred by his primary care physician for routine low-dose chest CT given his tobacco use. Imaging showed a 0.9-cm right lower lobe lesion with enlarged left hilar lymphadenopathy. Biopsy of the hilar lymph node returned with evidence of SCLC. PET/CT showed hypermetabolic activity in these lesions without any other disease in the abdomen or pelvis. Brain MRI was negative for metastatic disease. What treatment options are available for this patient?

Learning Objectives:

1. How common is LS SCLC?

2. To what treatment modality is SCLC most sensitive?

3. What are common adjuvant regimens for early stage SCLC?

Only about one-third of SCLC patients present with disease confined to the chest, and only about 5% of patients present with stage I-IIA (T1-2,N0M0). Those with very early disease benefit from surgical resection followed by adjuvant systemic chemotherapy.

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