Team Tough Titties Knockin Out Cancer's blog: "Lung Cancer, Small Cell Carcinoma"

Small cell carcinomas (SCC) commonly arise in the respiratory tract; however, it is not uncommon for these cells to arise in nonpulmonary sites, as extrapulmonary small cell carcinoma (EPSCC). Small cell carcinoma is a distinct clinical and pathologic entity that arises from cells of the amine precursor uptake and decarboxylation (APUD) system. Extrapulmonary small cell carcinoma is estimated to account for approximately 1000 new cancer cases per year in the United States. This number, however, appears to be an underestimation. Most available literature on this condition exists in the form of case reports and retrospective series. The role of local and systemic therapies for extrapulmonary small cell carcinoma treatment is still not clearly defined. Most reports indicate chemotherapy sensitivity and response rates similar to those seen in small cell lung cancer with similar chemotherapeutic regimens. Surgery appears to play a more important role in the management of extrapulmonary small cell carcinoma compared to the role of surgery for small cell lung cancer. Pathophysiology Histologic criteria for diagnosis of extrapulmonary small cell carcinoma are same as those for pulmonary small cell carcinoma, that is appearance of uniform small cells with sparse cytoplasm, dense nuclei, and inconspicuous nucleoli.1 Since extrapulmonary small cell carcinoma has been reported from multiple sites, it is thought that the cell of origin is identical and derives from those originating in neural crest and then migrating to different epithelial sites within the body. These cells are characterized by presence of intracytoplasmic neurosecretory granules and stain positively with chromogranin. Extrapulmonary small cell carcinoma has been reported to arise in almost all body sites except the central nervous system.2,3 Primary sites may include esophagus, salivary glands, gastrointestinal tract (including small intestine and large intestine), pancreas, larynx, cervix uteri, uterus, urinary bladder, prostate, breast, and lacrimal gland in addition to skin, where it is also referred to as Merkel cell carcinoma.4 Like pulmonary small cell carcinoma (lung cancer), small cell carcinomas arising from extrapulmonary sites may be associated with paraneoplastic syndromes, notably syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and hypercalcemia. However, deletions of chromosome arm 3p and c-myc amplification described in small cell pulmonary carcinoma have not been reported in extrapulmonary sites. Frequency United States Approximately 1000 cases of extrapulmonary small cell carcinoma are reported annually, with an overall incidence of 0.1-0.4% of all cancers. International Global incidence of extrapulmonary small cell carcinoma is unknown. Mortality/Morbidity Because most of the literature is retrospective and in the form of case reports, estimating mortality rates is difficult. In addition, not all reported cases are managed uniformly, thereby making it further difficult to estimate prognosis. Long-term survival is, however, reported, especially in those treated with an aggressive multimodality approach. Extrapulmonary small cell carcinoma may have a similar prognosis to that of small cell lung cancer. Those presenting with disseminated disease have a very poor prognosis and short survival time despite management with chemotherapy, radiation therapy, or both. Long-term survival is reported in those presenting with localized disease. Age No predilection for race or sex is clear in the reported literature. However, most of these malignancies develop after the sixth decade of life. Clinical History Extrapulmonary small cell carcinoma is an aggressive neoplasm that enlarges rapidly and disseminates early in the course of illness. Due to multiplicity of sites where it can arise, there are no symptoms or signs specifically attributable to extrapulmonary small cell carcinoma. Patients may present with constitutional symptoms of fatigue, weakness, fever, weight loss, and night sweats. They may also have symptoms referable to the organ of origin, for instance hematuria in cases of bladder tumor, abdominal pain with or without obstruction with small or large bowel involvement, or hoarseness with laryngeal involvement. Physical Physical findings are again limited by the organ system involved and may include prostatic enlargement, skin nodules in case of Merkel cell carcinoma, or enlargement of regional draining lymph nodes. As with pulmonary small cell carcinoma, paraneoplastic syndromes have been described with extrapulmonary small cell carcinoma. Most common of these are hypercalcemia, syndrome of inappropriate secretion of antidiuretic hormone, and secretion of adrenocorticotropic hormone, and patients may present with symptoms and signs of excess calcium, hyponatremia, or corticosteroid excess depending upon the severity and rate of development of endocrine abnormality. Causes Etiology of extrapulmonary small cell carcinoma is unknown. While some authors have reported an association with tobacco smoking, others have not found a strong causative correlation with tobacco. (Separate summaries on prevention of lung cancer and screening for lung cancer are also available in PDQ.) Without treatment, small cell carcinoma of the lung has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. Compared with other cell types of lung cancer, small cell carcinoma has a greater tendency to be widely disseminated by the time of diagnosis, but is much more responsive to chemotherapy and irradiation. Because of its propensity for distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival.[1] With incorporation of current chemotherapy regimens into the treatment program, however, survival is unequivocally prolonged, with at least a 4- to 5-fold improvement in median survival compared with patients who are given no therapy. Furthermore, about 10% of the total population of patients remain free of disease over two years from the start of therapy, the time period during which most relapses occur. However, even these patients are at risk of dying from lung cancer (both small and non-small cell types).[2] The overall survival at 5 years is 5% to 10%.[2-4] At the time of diagnosis, approximately 40% of patients with small cell carcinoma will have tumor confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited stage disease, and most 2-year disease-free survivors come from this group. In limited stage disease, median survival of 16 to 24 months with current forms of treatment can reasonably be expected.[5-7] A small proportion of patients with limited stage disease may benefit from surgery with or without adjuvant chemotherapy; these patients have an even better prognosis. Patients with tumor that has spread beyond the supraclavicular areas are said to have extensive stage disease and have a worse prognosis than patients with limited stage. Median survival of 6 to 12 months is reported with currently available therapy, but long-term disease-free survival is rare. The pretreatment prognostic factors which consistently predict for prolonged survival include good performance status, female gender, and limited stage disease.[3,8,9] Patients with involvement of the central nervous system or liver at the time of diagnosis have a significantly worse outcome.[3,8-10] In general, patients who are confined to bed tolerate aggressive forms of treatment poorly, have increased morbidity, and rarely attain 2-year disease-free survival. However, patients with poor performance status can often derive significant palliative benefit and prolongation of survival from treatment. Regardless of stage, the current prognosis for patients with small cell lung cancer is unsatisfactory even though considerable improvements in diagnosis and therapy have been made over the past 10 to 15 years. Therefore, all patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis. CELLULAR CLASSIFICATION Review of pathologic material by an experienced lung cancer pathologist is important prior to initiating treatment of any patient with small cell lung cancer. The intermediate subtype of small cell carcinoma and the more readily recognized lymphocyte-like or "oat cell" subtype are equally responsive to treatment. The current classification of subtypes of small cell lung cancer are:[1] small cell carcinoma mixed small cell/large cell carcinoma combined small cell carcinoma (small cell lung cancer combined with neoplastic squamous and/or glandular components) There is increasing evidence that light microscopy has some limitations as a means of classifying bronchogenic carcinomas, particularly small cell carcinomas. Electron microscopy, which can detect neuroendocrine granules, may help to differentiate between small cell and non-small cell cancers.[2] Neuroendocrine carcinomas of the lung represent a spectrum of disease. At one extreme is small cell lung cancer, which has a poor prognosis. At the other extreme are bronchial carcinoids, with an excellent prognosis after surgical excision.[3] Between these extremes is an unusual entity called well-differentiated neuroendocrine carcinoma of the lung.[4] It has been referred to as malignant carcinoid, metastasizing bronchial adenoma, pleomorphic carcinoid, nonbenign carcinoid tumor, and atypical carcinoid. Like small cell lung cancer, it occurs primarily in cigarette smokers, but it metastasizes less frequently. The 5-year survival rate is greater than 50% in some series, and surgical cure appears possible in most stage I patients. Careful diagnosis is important, however, since the differential pathologic diagnosis from small cell lung cancer may be difficult. Staging procedures are important in distinguishing patients who have disease limited to their thorax from those who have distant metastases. Determining the stage of cancer by nonsurgical means allows a better assessment of prognosis and identifies sites of tumor that can be evaluated for response. Also, the choice of treatment is usually influenced by stage, particularly when chest irradiation or surgical excision is added to chemotherapy for patients with limited stage disease. Staging procedures commonly used to document distant metastases include bone marrow examination, computed tomographic or magnetic resonance imaging scans of the brain, computerized tomographic scans of the chest and the abdomen, and radionuclide bone scans. Because occult or overt metastatic disease is present at diagnosis in most patients, survival is usually not affected by small differences in the amount of locoregional tumor involvement. Therefore, the detailed TNM staging system developed for lung cancer by the American Joint Committee on Cancer (AJCC) is not commonly employed in patients with small cell carcinoma. This international staging system is outlined in detail in the PDQ summary on non- small cell lung cancer. A simple 2-stage system developed by the Veterans Administration Lung Cancer Study Group is more commonly used for staging small cell lung cancer patients.[1] Limited stage Limited stage small cell lung cancer means tumor confined to the hemithorax of origin, the mediastinum, and the supraclavicular nodes, which can be encompassed within a "tolerable" radiation therapy port. There is no universally accepted definition of this term, and patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from limited stage by various groups. Extensive stage Extensive stage small cell lung cancer means tumor that is too widespread to be included within the definition of limited stage disease above. Patients with distant metastases (M1) are always considered to have extensive stage disease.[1,2] TREATMENT OPTION OVERVIEW Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information. In small cell lung cancer, the majority of patients die of their tumor despite state-of-the-art treatment. Most of the improvements in survival in small cell lung cancer are attributable to clinical trials which have attempted to improve on the best available, accepted therapy. Patient entry into such studies is highly desirable. Methods under clinical evaluation in small cell lung cancer include adding chest radiation to chemotherapy regimens, varying drug doses in current regimens, alternating different combinations of chemotherapy, using different schedules of chemotherapeutic agents, and using new drug regimens composed of standard and new agents. Prospective randomized trials have not demonstrated a consistent survival advantage for patients treated with higher doses of chemotherapy.[1,2] One retrospective review of chemotherapy trials did not show consistent evidence for improved response rates or survival with more dose-intense chemotherapy regimens.[3][Level of evidence: 1iiA] Even chemotherapy of the intensity used in autologous bone marrow transplant regimens has not clearly been shown to improve survival in patients with small cell lung cancer.[4] The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations. LIMITED STAGE SMALL CELL LUNG CANCER Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information. In patients with small cell lung cancer, combination chemotherapy produces results that are clearly superior to single-agent treatment, and moderately intensive doses of drugs are superior to doses that produce only minimal or mild hematologic toxic effects. Current programs yield overall objective response rates of 65% to 90% and complete response rates of 45% to 75%. Because of the frequent presence of occult metastatic disease, chemotherapy is the cornerstone of treatment of limited stage small cell lung cancer. Combinations containing two or more drugs are needed for maximal effect. Mature results of prospective randomized trials suggest that combined modality therapy produces a modest but significant improvement in survival compared with chemotherapy alone. Two meta-analyses showed an improvement in 3-year survival rates of about 5% for those receiving chemotherapy and radiation therapy compared to those receiving chemotherapy alone.[1,2] Most of the benefit occurred in patients less than 65 years of age. Combined modality treatment is associated with increased morbidity and, in some trials, increased treatment-related mortality from pulmonary and hematologic toxic effects; proper administration requires close collaboration between medical and radiation oncologists.[3] In general, those studies showing a positive effect for combined modality therapy employed thoracic irradiation early in the course of treatment, concurrently with chemotherapy.[3-6] Studies strongly suggest that minimal tumor doses in the range of 4,000 to 4,500 cGy or more (standard fractionation) are necessary to effectively control tumors in the thorax. The combination of etoposide and cisplatin chemotherapy with concurrent chest radiation therapy has now been used in multiple single institutional studies and in cooperative group studies. These studies have consistently achieved median survivals of 18 to 24 months and 40% to 50% 2-year survival with less than 3% treatment-related mortality.[3-7] Once-daily and twice-daily chest radiation schedules have been used in regimens with etoposide and cisplatin. One randomized study showed a modest survival advantage in favor of twice-daily radiation therapy given over 3 weeks, compared to once-daily radiation therapy given over 5 weeks (26% versus 16% at 5 years, p=0.04). However, esopohagitis was increased with twice-daily treatment.[8][Level of evidence: 1iiA] The current standard treatment of patients with limited stage small cell lung cancer should be a combination containing etoposide and cisplatin plus chest radiation therapy administered during the first or second cycle of chemotherapy administration. The relative effectiveness of 2- to 5-drug regimens and different schedules of chest radiation therapy appear to be similar. A representative selection of regimens incorporating chemotherapy plus chest radiation therapy are listed below. The use of alternating chemotherapy regimens has not proven more effective than the consistent administration of a single regimen.[3,6,7,9-11] The optimal duration of chemotherapy for patients with limited stage small cell lung cancer is not clearly defined but there is no improvement in survival after the duration of drug administration exceeds 3 to 6 months.[3,7,12] There is no evidence from randomized trials that maintenance chemotherapy prolongs survival for patients with limited stage small cell lung cancer.[9,13] Patients presenting with superior vena cava syndrome are treated with combination chemotherapy with or without radiation therapy.[14,15] A small minority of limited stage patients with adequate pulmonary function and with tumor pathologically confined to the lung of origin, or the lung and ipsilateral hilar lymph nodes, may possibly benefit from surgical resection with or without adjuvant chemotherapy.[16-19] Patients with small cell lung cancer treated with chemotherapy with or without chest irradiation who have achieved a complete remission can be considered for administration of prophylactic cranial irradiation (PCI). Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system metastases within 2 to 3 years after starting treatment.[20,21] The majority of these patients relapse only in their brain and nearly all of those who relapse in their central nervous system die of their cranial metastases.[3,7,21] The risk of developing central nervous system metastases can be reduced by more than 50% by the administration of PCI in doses of 2400 cGy.[21] A meta-analysis of 7 randomized trials evaluating the value of PCI in patients in complete remission reported improvement in brain recurrence, disease-free survival, and overall survival with the addition of PCI. The 3-year overall survival was improved from 15% to 21% with PCI.[22][Level of evidence: 1iiA] Retrospective studies have shown that long-term survivors of small cell lung cancer (>2 years from the start of treatment) have a high incidence of central nervous system impairment.[23-25] However, prospective studies have shown that patients treated with PCI do not have detectably different neuropsychological function than patients not treated.[21] In addition, the majority of patients with small cell lung cancer have neuropsychological abnormalities present before the start of cranial irradiation and have no detectable decline in their neurological status up to 2 years after the start of their cranial irradiation.[26] Patients treated for small cell lung cancer continue to have declining neuropsychologic function after 2 years from the start of treatment.[23-25] Therefore, additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before concluding that PCI does not contribute to the decline in intellectual function. Treatment options: Standard: 1. Combination chemotherapy with one of the following regimens and chest irradiation (with or without PCI given to patients with complete responses): The following regimens produce similar survival outcomes: EC: etoposide + cisplatin + 4000-4500 cGy chest radiation therapy [3,7] ECV: etoposide + cisplatin + vincristine + 4500 cGy chest radiation therapy[5] 2. Combination chemotherapy (with or without PCI in patients with complete responses), especially in patients with impaired pulmonary function or poor performance status. 3. Surgical resection followed by chemotherapy or chemotherapy plus chest radiation therapy (with or without PCI in patients with complete responses) for patients in highly selected cases.[16-19] Under clinical evaluation: Areas of active clinical evaluation in limited stage small cell lung cancer include new drug regimens, variation of drug doses in current regimens, surgical resection of the primary tumor, new radiation therapy schedules and techniques (e.g., 3-dimensional treatment planning), and timing of thoracic radiation.[27-29] EXTENSIVE STAGE SMALL CELL LUNG CANCER Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information. As in limited stage small cell carcinoma, chemotherapy should be given as multiple agents in doses associated with at least moderate toxic effects in order to produce the best results in extensive stage disease. Doses and schedules used in current programs yield overall response rates of 70% to 85% and complete response rates of 20% to 30% in extensive stage disease. Since overt disseminated disease is present, combination chemotherapy is the cornerstone of treatment of this stage of small cell lung cancer. Combinations containing two or more drugs are needed for maximal benefit. The relative effectiveness of many 2- to 4-drug combination programs appears similar, and there are a large number of potential combinations. Therefore, a representative selection of regimens that have been found to be effective by at least two independent groups has been provided. Some physicians have administered two of these or other regimens in alternating sequences, but there is no proof that this strategy yields substantial survival improvement.[1-3] Optimal duration of chemotherapy is not clearly defined, but there is no obvious improvement in survival when the duration of drug administration exceeds 6 months.[4,5] There is no clear evidence from reported data that maintenance chemotherapy will improve survival duration.[6-9] Combination chemotherapy plus chest irradiation does not appear to improve survival compared with chemotherapy alone in extensive stage small cell lung cancer. However, radiation therapy plays an extremely important role in palliation of symptoms of the primary tumor and of metastatic disease, particularly brain, epidural, and bone metastases. Chest irradiation is sometimes given for superior vena cava syndrome, but chemotherapy alone (with irradiation reserved for nonresponding patients) is appropriate initial treatment. Brain metastases are appropriately treated with whole-brain radiation therapy. However, intracranial metastases from small cell carcinoma may respond to chemotherapy as readily as metastases in other organs.[9,10] Patients with small cell lung cancer treated with chemotherapy with or without chest irradiation who have achieved a complete remission can be considered for administration of prophylactic cranial irradiation (PCI). Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system metastases within 2 to 3 years after starting treatment.[11,12] The majority of these patients relapse only in their brain and nearly all of those who relapse in their central nervous system die of their cranial metastases.[12-14] The risk of developing central nervous system metastases can be reduced by more than 50% by the administration of PCI in doses of 2400 cGy.[12] Retrospective studies have shown that long-term survivors of small cell lung cancer (>2 years from the start of treatment) have a high incidence of central nervous system impairment.[15-17] However, prospective studies have shown that patients treated with PCI do not have detectably different neuropsychological function than patients not treated.[12] In addition, the majority of patients with small cell lung cancer have neuropsychological abnormalities present before the start of cranial irradiation and have no detectable decline in their neurological status up to 2 years after the start of their cranial irradiation.[18] Patients treated for small cell lung cancer continue to have declining neuropsychologic function after 2 years from the start of treatment.[15-17] Therefore, additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before concluding that PCI does not contribute to the decline in intellectual function. Many more patients with extensive stage small cell carcinoma have greatly impaired performance status at the time of diagnosis when compared to patients with limited stage disease. Such patients have a poor prognosis and tolerate aggressive chemotherapy or combined modality therapy poorly. Single-agent intravenous, oral, and low-dose biweekly regimens have been developed for these patients,[19-22] However, prospective randomized studies have shown that patients with a poor prognosis who are treated with conventional regimens live longer than those treated with the single-agent or low-dose regimens.[21-23] Treatment options: Standard: 1. Combination chemotherapy with one of the following regimens with or without PCI given to patients with complete responses: The following regimens produce similar survival outcomes: CAV: cyclophosphamide + doxorubicin + vincristine [24,25] CAE: cyclophosphamide + doxorubicin + etoposide [26] EP or EC: etoposide + cisplatin or carboplatin [27,28] ICE: ifosfamide + carboplatin + etoposide [29] Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use, including: cyclophosphamide + methotrexate + lomustine [30] cyclophosphamide + methotrexate + lomustine + vincristine [31] cyclophosphamide + doxorubicin + etoposide + vincristine [32] CEV: cyclophosphamide + etoposide + vincristine [33] single-agent etoposide [19] 2. Radiation therapy to sites of metastatic disease unlikely to be immediately palliated by chemotherapy, especially brain, epidural, and bone metastases. 3. Identification of effective new agents is difficult in patients who have previously been treated with standard chemotherapy because response rates to agents, even of known efficacy, are known to be lower than in previously untreated patients. This situation led to the suggestion that patients with extensive disease who are medically stable be treated with new agents under evaluation, with provisions for early change to standard combination therapy if there is no response.[34] Such a strategy has been shown to be feasible, with survival comparable to survival with initial standard therapy, as long as the patients with extensive disease are carefully chosen.[35-37] A variety of other strategies have been proposed, depending on the activity of the new agent in other tumors, in preclinical small cell lung cancer models, or the activity of drug analogs.[38] Active single agents undergoing further evaluation include paclitaxel and topotecan.[39,40] Under clinical evaluation: Areas of active clinical evaluation in extensive stage small cell lung cancer include evaluation of new drug regimens, dose intensity, alternative drug schedules, and high-dose chemotherapy. A meta-analysis of long-term outcomes in extensive stage disease did not show consistent evidence for improved response rates or survival for more intense chemotherapy regimens.[41][Level of evidence: 1iiA] RECURRENT SMALL CELL LUNG CANCER Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information. The prognosis for small cell lung carcinoma that has progressed despite chemotherapy is exceedingly poor regardless of stage. Expected median survival is 2 to 3 months. These patients should be considered for palliative therapy or clinical trials. Patients who are primarily resistant to chemotherapy and those who have received multiple chemotherapy regimens rarely respond to additional treatment. However, patients who have initially responded and relapsed more than 6 months following initial treatment are more likely to respond to additional chemotherapy. While no single chemotherapy regimen should be considered standard, those that have shown activity as second line treatment include oral etoposide, etoposide/cisplatin, cyclophosphamide/doxorubicin/vincristine (CAV), lomustine/methotrexate, and topotecan.[1-8] A randomized comparison of second line treatment with either CAV or topotecan reported no significant difference in response rates or survival, but palliation of symptoms was better with topotecan.[8][Level of evidence: 1iiC] Some patients with intrinsic endobronchial obstructing lesions or extrinsic compression due to tumor have achieved successful palliation with endobronchial laser therapy (for endobronchial lesions only) and/or brachytherapy.[9] Expandable metal stents can be safely inserted under local anesthesia via the bronchoscope, resulting in improved symptoms and pulmonary function in patients with malignant airways obstruction.[10] Patients with progressive intrathoracic tumor after failing initial chemotherapy can achieve significant tumor responses, palliation of symptoms, and short-term local control with external-beam radiation therapy. However, only the rare patient will experience long-term survival following "salvage" radiation therapy.[11] Patients with central nervous system recurrences can often obtain palliation of symptoms with radiation therapy and/or additional chemotherapy. The majority of patients treated with radiation therapy obtain objective responses and improvement following radiation therapy.[12] A retrospective review showed that 43% of patients treated with additional chemotherapy at the time of CNS relapse respond to second-line chemotherapy.[13] Treatment options: 1. Palliative radiation therapy.[11] 2. Salvage chemotherapy can provide some palliative benefit for patients previously sensitive to standard chemotherapy.[2,4-8] 3. Local palliation with endobronchial laser therapy, endobronchial stents, and/or brachytherapy.[9,10] 4. Clinical trials of phase I or phase II drugs. Refer to PDQ or to CancerNet (http://cancernet.nci.nih.gov) for information on clinical trials for patients with recurrent small cell lung cancer.