Stage Information for SCLC

Stage Information for SCLC

·         Staging Systems

·         Limited-Stage Disease

·         Extensive-Stage Disease

·         IASLC-AJCC TNM Staging System

·         Staging Evaluation

Staging Systems

Several staging systems have been proposed for small cell lung cancer (SCLC). These staging systems include the following:

·         American Joint Committee on Cancer (AJCC) Tumor, Node, and Metastasis (TNM).[1]

·         Veterans Administration Lung Study Group (VALG).[2]

·         International Association for the Study of Lung Cancer (IASLC).[3]

Limited-Stage Disease

No universally accepted definition of this term is available. Limited-stage disease (LD) SCLC is confined to the hemithorax of origin, the mediastinum, or the supraclavicular nodes, which can be encompassed within a tolerable radiation therapy port.

Patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from LD by various groups.

Extensive-Stage Disease

Extensive-stage disease (ED) SCLC has spread beyond the supraclavicular areas and is too widespread to be included within the definition of LD. Patients with distant metastases (M1) are always considered to have ED.[3,4]

IASLC-AJCC TNM Staging System

The AJCC TNM defines LD as any T, except for T3-4, due to multiple lung nodules that do not fit in a tolerable radiation field, any N, and M0.[1] This corresponds to TNM stages I to IIIB. Extensive disease is TNM stage IV with distant metastases (M1) including malignant pleural effusions.[3,4]

The IASLC conducted an analysis of clinical TNM staging for SCLC using the sixth edition of the AJCC TNM staging system for lung cancer. Survivals for patients with clinical stages I and II disease are significantly different from those for patients with stage III disease with N2 or N3 involvement.[3] Patients with pleural effusion have an intermediate prognosis between LD and ED with hematogenous metastases and will be classified as having M1 disease (or ED). Application of the TNM system will not change how patients are managed; however, the analysis suggests that, in the context of clinical trials in LD, accurate TNM staging and stratification may be important.[3]

Staging Evaluation

Staging procedures for SCLC are important to distinguish patients with disease limited to their thorax from those with distant metastases. At the time of initial diagnosis, approximately two-thirds of patients with SCLC have clinical evidence of metastases; most of the remaining patients have clinical evidence of extensive nodal involvement in the hilar, mediastinal, and sometimes supraclavicular regions.

Determining the stage of cancer allows an assessment of prognosis and a determination of treatment, particularly when chest radiation therapy or surgical excision is added to chemotherapy for patients with LD. If ED is confirmed, further evaluation should be individualized according to the signs and symptoms unique to the individual patient. Standard staging procedures include the following:

·         A thorough physical examination.

·         Routine blood counts and serum chemistries.

·         Chest and upper abdominal computed tomography (CT) scanning.

·         A radionuclide bone scan.

·         A brain magnetic resonance imaging scan or CT scan.

·         Bone marrow aspirate or biopsy in selected patients in which treatment would change based on the results.

The role of positron emission tomography (PET) is still under study. SCLC is fluorodeoxyglucose (FDG) avid at the primary site and at metastatic sites. PET may be used in staging patients with SCLC who are potential candidates for the addition of thoracic radiation therapy to chemotherapy, as PET may lead to upstaging or downstaging of patients and to alteration of radiation fields resulting from the identification of additional sites of nodal metastases.

Evidence (FDG-PET):

1.     In a study of 120 patients with LD SCLC or ED SCLC, ten patients were upstaged and three patients were downstaged.[5] PET was more sensitive and specific than CT scans for nonbrain distant metastases.

2.     In a small series of 24 patients with LD by conventional staging, two patients were upstaged to ED.[2] Unsuspected nodal metastases were documented in 25% of patients, which altered the radiation plan in these patients. At this time, sensitivity, specificity, and positive- or negative-predictive value of PET scanning and its enhancement of staging accuracy are uncertain.

References

1.     Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70.

2.     Bradley JD, Dehdashti F, Mintun MA, et al.: Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol 22 (16): 3248-54, 2004. [PUBMED Abstract]

3.     Shepherd FA, Crowley J, Van Houtte P, et al.: The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2 (12): 1067-77, 2007. [PUBMED Abstract]

4.     Ihde D, Souhami B, Comis R, et al.: Small cell lung cancer. Lung Cancer 17 (Suppl 1): S19-21, 1997. [PUBMED Abstract]

5.     Brink I, Schumacher T, Mix M, et al.: Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging 31 (12): 1614-20, 2004. [PUBMED Abstract]

Cellular Classification of SCLC

Cellular Classification of SCLC

·         Pathologic Classification

Before initiating treatment of a patient with small cell lung cancer (SCLC), an experienced lung cancer pathologist should review the pathologic material.

Pathologic Classification

The current classification of subtypes of SCLC includes the following:[1]

·         Small cell carcinoma.

·         Combined small cell carcinoma (i.e., SCLC combined with neoplastic squamous and/or glandular components).

SCLC arising from neuroendocrine cells forms one extreme of the spectrum of neuroendocrine carcinomas of the lung.

Neuroendocrine tumors include the following:

·         Low-grade typical carcinoid.

·         Intermediate-grade atypical carcinoid.

·         High-grade neuroendocrine tumors including large-cell neuroendocrine carcinoma (LCNEC) and SCLC.

Because of differences in clinical behavior, therapy, and epidemiology, these tumors are classified separately in the World Health Organization (WHO) revised classification. The variant form of SCLC called mixed small cell/large cell carcinoma was not retained in the revised WHO classification. Instead, SCLC is now described with only one variant, SCLC combined, when at least 10% of the tumor bulk is made of an associated non-small cell component.

SCLC presents as a proliferation of small cells with the following morphological features:[2]

·         Scant cytoplasm.

·         Ill-defined borders.

·         Finely granular "salt and pepper" chromatin.

·         Absent or inconspicuous nucleoli.

·         Frequent nuclear molding.

·         A high mitotic count.

Combined small cell carcinoma includes a mixture of small cell and large cell or any other non-small cell component. Any cases showing at least 10% of SCLC are diagnosed as combined SCLC, and SCLC is limited to tumors with pure SCLC histology. SCLC associated with LCNEC is diagnosed as SCLC combined with LCNEC.

Nearly all SCLC are immunoreactive for keratin, thyroid transcription factor 1, and epithelial membrane antigen. Neuroendocrine and neural differentiation result in the expression of dopa decarboxylase, calcitonin, neuron-specific enolase, chromogranin A, CD56 (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and insulin-like growth factor 1. One or more markers of neuroendocrine differentiation can be found in approximately 75% of SCLC.[3]

Although preinvasive and in situ malignant changes are frequently found in patients with non-small cell lung cancer, these findings are rare in patients with SCLC.[4]

References

1.     Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999.

2.     Brambilla E, Travis WD, Colby TV, et al.: The new World Health Organization classification of lung tumours. Eur Respir J 18 (6): 1059-68, 2001. [PUBMED Abstract]

3.     Guinee DG Jr, Fishback NF, Koss MN, et al.: The spectrum of immunohistochemical staining of small-cell lung carcinoma in specimens from transbronchial and open-lung biopsies. Am J Clin Pathol 102 (4): 406-14, 1994. [PUBMED Abstract]

4.     Kumar V, Abbas A, Fausto N, eds.: Robins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia, Pa: Elsevier Inc, 2005.

General Information About Small Cell Lung Cancer (SCLC)

General Information About Small Cell Lung Cancer (SCLC)

·         Incidence and Mortality

·         Clinical Features

·         Diagnosis

·         Prognosis and Survival

SCLC accounts for approximately 15% of bronchogenic carcinomas.

At the time of diagnosis, approximately 30% of patients with SCLC will have tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited-stage disease (LD).[1] Patients with tumors that have spread beyond the supraclavicular areas are said to have extensive-stage disease (ED).

SCLC is more responsive to chemotherapy and radiation therapy than other cell types of lung cancer; however, a cure is difficult to achieve because SCLC has a greater tendency to be widely disseminated by the time of diagnosis.

Incidence and Mortality

The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.[2]

Estimated new cases and deaths from lung cancer (SCLC and non-small cell lung cancer [NSCLC] combined) in the United States in 2015:[3]

·         New cases: 221,200.

·         Deaths: 158,040.

Clinical Features

Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough, shortness of breath, and dyspnea. Other presenting symptoms include the following:

·         Chest pain.

·         Hoarseness.

·         Malaise.

·         Anorexia.

·         Weight loss.

·         Hemoptysis.

Symptoms may result from local invasion or compression of adjacent thoracic structures, such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases.

Infrequently, patients with SCLC may present with symptoms and signs of one of the following paraneoplastic syndromes:

·         Inappropriate antidiuretic hormone secretion.

·         Cushing syndrome from secretion of adrenocorticotropic hormone.

·         Paraneoplastic cerebellar degeneration.

·         Lambert-Eaton myasthenic syndrome.[2]

Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease.

Diagnosis

Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient. Investigations of patients with suspected SCLC focus on confirming the diagnosis and determining the extent of the disease.

The procedures used to determine the presence of cancer include the following:

·         History.

·         Physical examination.

·         Routine laboratory evaluations.

·         Chest x-ray.

·         Chest computed tomography scan with infusion of contrast material.

·         Biopsy.

Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC.[4] Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

(Refer to the Staging Evaluation section in the Stage Information for SCLC section of this summary for more information about tests and procedures used for staging.)

Prognosis and Survival

Regardless of stage, the current prognosis for patients with SCLC is unsatisfactory despite improvements in diagnosis and therapy made during the past 25 years. Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. About 10% of the total population of SCLC patients remains free of disease during the 2 years from the start of therapy, which is the time period during which most relapses occur. Even these patients, however, are at risk of dying from lung cancer (both small and non-small cell types).[5] The overall survival at 5 years is 5% to 10%.[1,5-7]

An important prognostic factor for SCLC is the extent of disease. Patients with LD have a better prognosis than patients with ED. For patients with LD, median survival of 16 to 24 months and 5-year survivals of 14% with current forms of treatment have been reported.[1,6,8,9] Patients diagnosed with LD who smoke should be encouraged to stop smoking before undergoing combined-modality therapy because continued smoking may compromise survival.[10]

Improved long-term survival in patients with LD has been shown with combined-modality therapy.[9,11][Level of evidence: 1iiA] Although long-term survivors have been reported among patients who received either surgery or chemotherapy alone, chemotherapy combined with thoracic radiation therapy (TRT) is considered the standard of care.[12] Adding TRT increases absolute survival by approximately 5% over chemotherapy alone.[11,13] The optimal timing of TRT relative to chemotherapy has been evaluated in multiple trials and meta-analyses with the weight of evidence suggesting a small benefit to early TRT.[1,14,15][Level of evidence: 1iiA]

In patients with ED, median survival of 6 to 12 months is reported with currently available therapy, but long-term disease-free survival is rare.

Prophylactic cranial radiation prevents central nervous system recurrence and can improve survival in patients who have had a complete response to chemoradiation.[16,17][Level of evidence: 1iiA]

Thoracic radiation may also improve long-term outcomes for these patients.[18]

All patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis. Information about ongoing clinical trials is available from the NCI Web site.

References

1.     Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993. [PUBMED Abstract]

2.     Govindan R, Page N, Morgensztern D, et al.: Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 24 (28): 4539-44, 2006. [PUBMED Abstract]

3.     American Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015. Available online . Last accessed January 7, 2015.

4.     Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999.

5.     Johnson BE, Grayson J, Makuch RW, et al.: Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 8 (3): 396-401, 1990. [PUBMED Abstract]

6.     Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996. [PUBMED Abstract]

7.     Lassen U, Osterlind K, Hansen M, et al.: Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years--an analysis of 1,714 consecutive patients. J Clin Oncol 13 (5): 1215-20, 1995. [PUBMED Abstract]

8.     Turrisi AT 3rd, Kim K, Blum R, et al.: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340 (4): 265-71, 1999. [PUBMED Abstract]

9.     Jänne PA, Freidlin B, Saxman S, et al.: Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer 95 (7): 1528-38, 2002. [PUBMED Abstract]

10.                       Videtic GM, Stitt LW, Dar AR, et al.: Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival. J Clin Oncol 21 (8): 1544-9, 2003. [PUBMED Abstract]

11.                       Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992. [PUBMED Abstract]

12.                       Chandra V, Allen MS, Nichols FC 3rd, et al.: The role of pulmonary resection in small cell lung cancer. Mayo Clin Proc 81 (5): 619-24, 2006. [PUBMED Abstract]

13.                       Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992. [PUBMED Abstract]

14.                       Perry MC, Eaton WL, Propert KJ, et al.: Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 316 (15): 912-8, 1987. [PUBMED Abstract]

15.                       Takada M, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20 (14): 3054-60, 2002. [PUBMED Abstract]

16.                       Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract]

17.                       Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract]

18.                       Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract]