Radiation Oncology/SCLC/Overview

Presentation
About 30% have limited stage disease.

Symptoms

 * Clinical presentation: Cough and dyspnea
 * Paraneoplastic syndromes:
 * Lambert-Eaton: progressive muscular weakness similar to myasthenia gravis, but starting with proximal leg muscles, caused by autoantibody to voltage-gated calcium channels)
 * Paraneoplastic encephalomyelitis: multiple neurologic deficits, caused by anti-Hu antibody that cross-reacts with SCLC antigens and neuronal RNA-binding proteins
 * Cushing's syndrome: central obesity (including moon face and buffalo hump), thin skin, hirsutism, striated skin, caused by inappropriate ACTH release
 * SIADH: hyponatremia and fluid overload, caused by inappropriate ADH release

Workup

 * CBC, LFT’s, LDH, electrolytes, Ca++, BUN/Cr
 * bronchoscopy/biopsy, sputum cytology. Thoracentesis rec'd if effusion present.
 * CT chest/liver/adrenal, CT/MRI brain
 * Bone scan or PET (not currently reimbursed by CMS for SCLC).
 * Mediastinoscopy or surgical LN evaluation if T1-T2 N0.
 * Bone marrow involved in 15-30% of patients, but solitary site in only 2-5% of cases, therefore, biopsy not usually obtained

Pathology

 * Malignant epithelial tumor, small cells, scant cytoplasm, high mitotic count
 * In up to 30% of autopsies, areas of NSCLC differentiation, suggesting pluripotent stem cell origin
 * Immunoreactive for keratin, epithelial membrane antigen, TTF-1 and neuroendocrine markers (chromogranin A, NSE, NCAM, synaptophysin) though these alone not sufficient since they are present in ~10% of NSCLC

Staging

 * There are 3 staging systems that are frequently used:
 * AJCC is the official staging in US, which is the same as for NSCLC, but is not routinely used
 * VA Lung Study Group defined "limited disease" and "extensive disease" in 1957 in its inoperable lung trials. Limited stage patients could be treated in a reasonable RT portal. However, patients with ipsilateral pleural effusion and contralateral SCV nodes were not well defined. Some investigators treated these as limited stage, others as extensive stage, and they were typically not accrued onto limited stage trials
 * International Association of Lung Cancer clarified the VA staging in 1989 to include all non-metastatic patients in the limited stage category

AJCC

 * See: Radiation Oncology/Lung/NSCLC/Staging

VA Lung Study Group

 * 1973 PMID 4580860 -- "Keynote address on biostatistics and data retrieval." (Zelen M, Cancer Chemother Rep 3. 1973 Mar;4(2):31-42.)
 * Limited Disease:
 * a) Disease confined to one hemithorax, although local extensions may be present;
 * b) No extrathoracic metastases except for possible ipsilateral supraclavicular nodes if they can be included in the same portal as the primary tumor;
 * (c) Primary tumor and regional nodes which can be adequately treated and totally encompassed in every portal.
 * Extensive Disease:
 * Inoperable patients who cannot be classified as having limited disease.
 * Controversial (not well defined):
 * Ipsilateral pleural effusion
 * Contralateral supraclavicular nodes

International Association of Lung Cancer

 * IASLC; 2007 PMID 18090577 -- "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." (Shepherd FA, J Thorac Oncol. 2007 Dec;2(12):1067-77.)
 * Retrospective. Survival analysis using IASLC and SEER databases
 * Conclusion: TNM staging is recommended for SCLC


 * IASLC; 1989  -- "Staging and prognostic factors in small cell lung cancer; a consensus report." (Stahel RA, Lung Cancer 1989;5:119-26.)
 * Limited Disease: "The classification of limited disease SCLC should include patients with the disease restricted to one hemithorax with regional lymph node metastases, including hiliar ipsilateral and contralateral mediastinal, and ipsilateral and contralateral mediastinal, and ipsilateral and contralateral supraclavicular nodes and should also include patients with ipsilateral pleural effusion independent whether the cytology is positive or negative."
 * Extensive Disease: "The classification of extensive disease SCLC should comprise all patients with sites of disease beyond the definition of limited disease. Thus extensive disease as proposed here is equivalent to stage IV, whereas limited disease is equivalent to stage I-III of the revised TNM system."

Staging Comparison

 * Mainz; 2002 (Germany) PMID 12234695 -- "Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer--what limits limited disease?" (Micke P, Lung Cancer. 2002 Sep;37(3):271-6.)
 * Retrospective. 109 consecutive SCLC patients classified in the 2 staging systems. 21% controversial
 * Conclusion: IASLC staging criteria higher prognostic impact than VALG

Survival

 * No treatment - Median survival - 2-4 months
 * Limited stage - Median survival - 16-24 months. 5-yr survival - 20%.
 * Extensive stage - Median survival - 6-12 months. Few long term survivors.


 * NCI; 2002 (1972-1992) PMID 12237922 -- "Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America." (Janne PA, Cancer. 2002 Oct 1;95(7):1528-38.)
 * Review of 6564 patients on 30 Phase III trials in North America and SEER database outcomes
 * Outcome: Median OS treated 1972-1981 12 months vs. treated 1982-1992 17 months (SS); however only 5/26 RCT showed a significant improvement in OS. SEER database shows improved 5-year OS 5% to 12% (SS)
 * Conclusion: Significant improvement in OS over time

Extrapulmonary small cell carcinoma (EPSCC)

 * E Galanis et al. Extrapulmonary small cell carcinoma. Cancer. 1997 May 1;79(9):1729-36. ( 9128989)
 * Leora Brazg Ferro et al. Extrapulmonary Small Cell Cancer: A New Insight into a Rare Disease. Oncology. 2021;99(6):373-379. ( 33774637)