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Small Cell Lung Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]Purpose of This PDQ SummaryThis PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of small cell lung cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board. Information about the following is included in this summary:
This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions. Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations. This summary is available in a patient version, written in less technical language, and in Spanish. General Information About Small Cell Lung CancerSome 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 summary on Levels of Evidence for more information.) Related Summaries Other PDQ summaries containing information related to lung cancer include:
Statistics Estimated new cases and deaths from lung cancer (small cell lung cancer and non-small cell lung cancer combined) in the United States in 2009:[1]
Small cell lung cancer (SCLC) accounts for approximately 15% of bronchogenic carcinomas. The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.[2] 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. Compared with other cell types of lung cancer, SCLC is more responsive to chemotherapy and radiation therapy; however, a cure is difficult to achieve because SCLC has a greater tendency to be widely disseminated by the time of diagnosis. It is the cancer most commonly associated with paraneoplastic syndromes, including the syndrome of inappropriate antidiuretic hormone secretion, paraneoplastic cerebellar degeneration, and Lambert-Eaton myasthenic syndrome.[2] Limited-Stage Disease 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), and most 2-year disease-free survivors come from this group. 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.[3,4,5,6] Patients diagnosed with LD who smoke should be encouraged to stop smoking before undergoing combined-modality therapy because continued smoking may compromise cure rates.[7] Improved long-term survival has been shown with combined modality therapy.[6,8][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.[9] Adding TRT increases absolute survival by approximately 5% over chemotherapy alone.[8,10] 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.[4,11,12][Level of evidence: 1iiA] Prophylactic cranial radiation prevents central nervous system (CNS) recurrence and can improve survival in patients who have had a complete response to chemoradiation.[13,14][Level of evidence: 1iiA] Extensive-Stage Disease Patients with tumors that have spread beyond the supraclavicular areas are said to have extensive-stage disease (ED) and have a worse prognosis than patients with LD. Median survival of 6 to 12 months is reported with currently available therapy, but long-term disease-free survival is rare. Prognostic Factors The pretreatment prognostic factors that consistently predict for prolonged survival include good performance status, female gender, and LD.[15,16,17,18,19] Patients with involvement of the CNS or liver at the time of diagnosis have a significantly worse outcome.[15,16,17,18] A number of biochemical factors including serum sodium, alkaline phosphatase, and lactate dehydrogenase have also been found to independently correlate with outcome.[16,20] Regardless of stage, the current prognosis for patients with SCLC is unsatisfactory despite improvements in diagnosis and therapy made during the past 25 years. 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:
Cellular Classification of Small Cell Lung CancerReview of pathologic material by an experienced lung cancer pathologist is important prior to initiating treatment of any patient with small cell lung cancer (SCLC). The current classification of subtypes of SCLC is:[1]
SCLC arising from neuroendocrine cells forms one extreme of the spectrum of neuroendocrine carcinomas of the lung. Neuroendocrine tumors include low-grade typical carcinoid, intermediate-grade atypical carcinoid, and high-grade neuroendocrine tumors including large-cell neuroendocrine carcinoma 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 a proliferation of small cells with the following morphological features: [2]
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 reserved to tumors with pure SCLC histology. SCLC associated with large-cell neuroendocrine carcinoma (LCNEC) is diagnosed as SCLC combined with LCNEC. Although the diagnosis can usually be made based on cell morphology using light microscopy, additional pathological evaluation may be of value if the diagnosis is uncertain. Electron microscopy shows dense-core neurosecretory granules 100 nm in diameter.[3] 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 NSCLC, these findings are rare in patients with SCLC.[4] References:
Stage Information for Small Cell Lung CancerStaging procedures for small cell lung cancer (SCLC) are important in distinguishing patients with disease limited to their thorax from those with distant metastases. 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 limited-stage disease (LD). If extensive-stage disease (ED) is confirmed, further evaluation should be individualized according to the signs and symptoms unique to the individual patient. Standard staging procedures include:
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. No universally accepted definition of this term is available, and patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from LD by various groups. 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). 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.[1,2,3] Other Staging and Prognostic Factors The role of positron emission tomography (PET) is still in evolution. SCLC is fluorodeoxyglucose avid at the primary site and at metastatic sites. The largest experience to date evaluated 120 patients with LD SCLC or ED SCLC.[4] Eight percent of patients were upstaged, and 2.3% of patients were downstaged. PET was more sensitive and specific than CT scans for non-brain distant metastases. In a small series of 24 patients with LD by conventional staging, 8.3% of patients were upstaged to ED.[5] 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 staging accuracy is uncertain. 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. Although tumor, node, metastasis (TNM) staging has been applied in small series of patients with SCLC treated either with surgery alone or with combined modality therapy including surgery, a simpler staging system based on the anatomical extent of the disease as proposed originally by the Veterans Administration Lung Study Group (VALG) is commonly used to determine if patients have LD or ED.[5] In the VALG staging system, LD is defined as disease confined to one hemithorax, which can be safely encompassed within a tolerable radiation field. Patients with LD are treated with chemotherapy and thoracic radiation, whereas, for the most part, patients with ED (distant hematogenous metastases) receive only chemotherapy. The International Association for the Study of Lung Cancer (IASLC) revised the VALG classification [5] in accordance with the TNM system.[6] In the IASLC system, the LD definition is consistent with TNM stages I to IIIB, and ED is limited to patients with distant metastases. According to the 1989 IASLC staging system for SCLC, ipsilateral and contralateral supraclavicular nodes and hilar or mediastinal nodes are included in LD. However, in the era of conformal techniques and increasing radiation dose for SCLC, it is likely no longer appropriate to treat all patients with LD in the same way, and radiation fields may be determined using more precise nodal categories. The IASLC conducted an analysis of clinical TNM staging for SCLC using the sixth edition of TNM staging system for lung cancer.[3] Survivals for patients with clinical stages I and II are significantly different from those of stage III with N2 or N3 involvement.[2] 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). The analysis suggests that, in the context of clinical trials in LD, accurate TNM staging may be critical and stratification based on TNM stage may be important.[2] References:
Treatment Option OverviewNote: 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 summary on Levels of Evidence for more information.) Chemotherapy improves the survival of patients with limited-stage (LD) or extensive-stage (ED) small cell lung cancer (SCLC), but it is curative in only a minority of patients.[1,2] Because patients with SCLC tend to develop distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival.[3] With incorporation of current chemotherapy regimens into the treatment program, however, survival is prolonged, with at least a 4- to 5-fold improvement in median survival compared with patients who are given no therapy. The combination of platinum and etoposide is the most widely used standard chemotherapeutic regimen.[4,5,6][Level of evidence: 1iiA] No consistent survival benefit has resulted from increased dose intensity or dose density, altered mode of administration (e.g., alternating or sequential administration) of various chemotherapeutic agents, or maintenance chemotherapy.[7,8,9,10,11][Level of evidence: 1iiA] SCLC is highly radiosensitive and thoracic radiation therapy improves survival of patients with LD and ED tumors.[12,13,14][Level of evidence: 1iiA] Prophylactic cranial radiation prevents central nervous system recurrence and may improve the long-term survival of patients who have responded to chemoradiation therapy [15,16,17][Level of evidence: 1iiA] and offers palliation of symptomatic metastatic disease. About 10% of the total population of 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).[4] The overall survival at 5 years is 5% to 10%.[4,5,6,14] Despite treatment advances, the majority of patients with small cell lung cancer (SCLC) die of their tumor even with the best available therapy. Most of the improvements in the survival of patients with SCLC are attributable to clinical trials that have attempted to improve on the best available and most accepted therapy. Patient entry into such studies is highly desirable. Information about ongoing clinical trials is available from the NCI Web site. References:
Limited-Stage Small Cell Lung CancerNote: 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 summary on Levels of Evidence for more information.) Combined modality treatment with chemotherapy and thoracic radiation therapy (TRT) is the standard treatment for patients with limited-stage disease (LD) small cell lung cancer (SCLC). Mature results of prospective randomized trials suggest that combined modality therapy produces a modest but significant improvement in survival of 5% at 3 years compared with chemotherapy alone.[1,2,3,4][Level of evidence: 1iiA] The combination of platinum and etoposide with TRT is the most widely used treatment regimen. Clinical trials have consistently achieved median survivals of 18 to 24 months and 40% to 50% 2-year survival rates with less than a 3% treatment-related mortality.[3,4,5,6,7][Level of evidence: 1iiA] As noted above, no consistent survival benefit has resulted from increased dose intensity or dose density, administration of additional drugs, altered modes of administration of various chemotherapeutic agents, or maintenance chemotherapy.[8,9,10,11,12,13,14,15][Level of evidence: 1iiA] The optimal duration of chemotherapy for patients with LD SCLC is not clearly defined, but no improvement exists in survival after the duration of drug administration exceeds 3 to 6 months. The preponderance of evidence available from randomized trials indicates that maintenance chemotherapy does not prolong survival for patients with LD SCLC. The optimal dose and timing of TRT remain controversial, and multiple clinical trials and meta-analyses addressing the timing of TRT have been published, with the weight of evidence suggesting a small benefit to early TRT (i.e., TRT administered during the first or second cycle of chemotherapy administration).[3,4,5,6,8,9,10,16,17,18,19][Level of evidence: 1iiA] The amount of time from start to completion of TRT in LD SCLC may also impact on overall survival (OS). In an analysis of four trials, the completion of therapy in less than 30 days was associated with an improved 5-year survival rate (relative risk = 0.62; 95% CI, 0.49–0.80; P = .0003).[19][Level of evidence: 1iiA] Both 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 for 3 weeks compared with once-daily radiation therapy to 45 Gy given for 5 weeks (26% vs. 16% at 5 years, P = .04).[16][Level of evidence: 1iiA] Esophagitis was increased with twice-daily treatment. Twice-daily radiation therapy has not been broadly adopted. Once-daily fractions to higher doses of greater than 60 Gy are feasible and commonly used; their clinical benefits are yet to be defined in phase III trials.[20][Level of evidence: 3iiiA] The current standard treatment of patients with LD SCLC should be a combination containing etoposide and cisplatin with chest radiation. The optimal therapeutic approach in older patients remains unclear. A population analysis showed that increasing age was associated with a decreased performance status and increased comorbidity.[21] Elderly patients were less likely to be treated with combined chemoradiation therapy, more intensive chemotherapy, and prophylactic cranial irradiation (PCI). Elderly patients were also less likely to respond to therapy and had poorer survival outcomes. Whether this was a result of age and its associated comorbidities or suboptimal treatment delivery remains uncertain. No specific phase III trial in elderly patients with LD SCLC has been reported; however, three secondary analyses of cooperative group trials have been published evaluating outcomes in patients 70 years or older.[22,23,24] The survival outcomes for the elderly patients were identical to their younger counterparts in both trials. The elderly patients experienced more toxic effects, particularly hematologic, compared with younger patients. There was a significant increase in treatment-related mortality in the INT-0096 trial comparing etoposide and cisplatin with either once-daily or twice-daily radiation (1% for patients <70 years vs. 10% for patients =70 years; P = .01).[23] Because the elderly patients enrolled in these phase III trials may not be representative of LD SCLC patients in the general population, caution must be exercised in extrapolating these results to the general population of elderly patients. Patients presenting with superior vena cava syndrome are treated with combination chemotherapy with (for patients with LD SCLC) or without radiation therapy.[25,26] (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.) A small minority of LD patients with adequate pulmonary function and with tumors 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.[27,28,29,30,31][Level of evidence: 3iiiDii] However, patients who have undergone surgery generally have had very limited disease; no randomized trials have been conducted evaluating the addition of surgery to chemoradiation therapy. The only randomized study evaluating the role of surgery in addition to chemoradiation therapy enrolled 328 patients with LD SCLC and found no OS benefit with the addition of pulmonary resection.[32][Level of evidence: 1iiA] Patients who have achieved a complete remission can be considered for administration of PCI. Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system (CNS) metastases within 2 to 3 years after starting treatment.[31,33,34] The majority of these patients relapse only in their brain, and nearly all of those who relapse in their CNS die of their cranial metastases. The risk of developing CNS metastases can be reduced by more than 50% by the administration of PCI.[33] A meta-analysis of seven randomized trials evaluating the value of PCI in patients in complete remission reported improvement in brain recurrence, disease-free survival, and OS with the addition of PCI. The 3-year OS was improved from 15% to 21% with PCI.[33][Level of evidence: 1iiA] Retrospective studies have shown that long-term survivors of SCLC (>2 years from the start of treatment) have a high incidence of CNS impairment.[31,34,35,36,37] Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated.[37] In addition, the majority of patients with SCLC have neuropsychological abnormalities present before the start of PCI and have no detectable decline in their neurological status for as long as 2 years after the start of their PCI.[37] Patients treated for SCLC continue to have declining neuropsychologic function after 2 years from the start of treatment.[35,36,37] 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. STANDARD TREATMENT OPTIONS:
TREATMENT OPTIONS UNDER CLINICAL EVALUATION: Areas of active clinical evaluation for patients with LD SCLC 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., three-dimensional treatment planning), and timing of thoracic radiation. Current Clinical Trials Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with limited stage small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria. General information about clinical trials is also available from the NCI Web site. References:
Extensive-Stage Small Cell Lung CancerNote: 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 summary on Levels of Evidence for more information.) As in limited-stage (LD) small cell lung cancer (SCLC), chemotherapy should be given as a two-drug combination of platinum and etoposide in doses associated with at least moderate toxic effects to produce the best results in patients with extensive-stage disease (ED). Doses and schedules used in current programs yield overall response rates of 50% to 80% and complete response rates of 0% to 30% in patients with ED.[1,2][Level of evidence: 1iiA] A meta-analysis of 19 trials published between 1981 and 1999 showed a significant survival advantage for patients receiving platinum-based chemotherapy compared with those not receiving a platinum agent.[2][Level of evidence: 1iiA] Cisplatin is associated with significant toxic effects and requires fluid hydration, which can be problematic in patients with cardiovascular disease. Carboplatin is active in SCLC, is dosed according to renal function, and is associated with less nonhematological toxic effects. The Hellenic Oncology Group conducted a phase III trial comparing cisplatin and etoposide with carboplatin plus etoposide.[3] The median survival was 11.8 months in the cisplatin arm and 12.5 months in carboplatin-treated patients.[3][Level of evidence: 1iiA] Although this difference was not statistically significant, the trial was underpowered to prove equivalence of the two treatment regimens in patients with either LD or ED. The combination of cisplatin and etoposide remains the gold standard for treatment, although carboplatin plus etoposide is an acceptable alternative for patients unable to tolerate cisplatin.[4] The substitution of irinotecan for etoposide has yielded conflicting results. A phase III study conducted in Japan compared a standard two-drug regimen of cisplatin and etoposide with a combination of cisplatin and irinotecan.[5][Level of evidence: 1iiA] The planned enrollment was 230 patients younger than 70 years, however, the trial was stopped early with a total of 154 patients when an interim analysis found a significant difference favoring the irinotecan arm. The median survival in the cisplatin and irinotecan group was 12.8 months (95% confidence interval [CI], 11.7–15.2 months) while it was 9.4 months in the cisplatin and etoposide arm (95% CI, 8.1–10.8 months). The 2-year survival was 19.5% versus 5.2%. Hematologic toxic effects were more severe in the etoposide- and cisplatin-treated patients, while gastrointestinal toxic effects were worse in the irinotecan-treated and cisplatin-treated patients. However, no difference in response rate, median time-to-progression, or overall survival (OS) was reported from a second study that involved 331 patients with ED and compared cisplatin and etoposide with a modified weekly regimen of cisplatin and irinotecan.[6] The modified weekly irinotecan/cisplatin regimen resulted in less myelosuppression but more diarrhea and vomiting.[6][Level of evidence: 1iiA] Another study (SWOG-S0124) compared irinotecan versus etoposide with cisplatin using doses and schedules similar to the original Japanese study. In a randomized trial of 784 patients, the combination of oral topotecan given with cisplatin for 5 days was not found to be superior to etoposide and cisplatin.[7] The 1-year survival rate was 31% (95% CI, 27%–36%) and was deemed to be noninferior as the difference of -0.03 met the predefined criteria of no more than 10% absolute difference in 1-year survival.[7][Level of evidence: 1iiA] No consistent survival benefit has resulted from the addition of a third drug, such as paclitaxel, to etoposide and cisplatin.[8,9] The optimal duration of chemotherapy is not clearly defined, but no obvious improvement in survival occurs when the duration of drug administration exceeds 6 months.[3,10,11] No clear evidence is available from reported data that maintenance chemotherapy will improve survival duration.[12,13,14][Level of evidence: 1iiA] However, a meta-analysis of 14 published randomized trials reported odds ratios for 1- and 2-year OS of 0.67 (95% CI, 0.56–0.79, P < .001 and 0.53–0.86, P < .001, respectively). This corresponded to an increase of 9% in 1-year OS and 4% in 2-year OS.[15][Level of evidence: 1iiA] The role of dose intensification in patients with SCLC remains unclear.[16,17,18,19,20] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[16,17] More recently, a number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[18,19,20,21,22,23,24,25,26] These studies have yielded conflicting results. Four studies have shown that a modest increase in dose intensity (25%–34%) was associated with a significant improvement in survival with no compromise in quality of life (QOL).[18,19,20,21][Level of evidence: 1iiA] Two of three studies that examined combinations of the variables of interval, dose per cycle, and number of cycles (23–25) showed no advantage.[22,23][Level of evidence: 1iiA] The European Organization for Research and Treatment of Cancer reported a randomized comparison (EORTC-08923) of standard dose cyclophosphamide, doxorubicin, and etoposide given every 3 weeks for five cycles versus intensified treatment given at 125% of the dose every 2 weeks for four cycles with granulocyte colony-stimulating factor (GCSF) support.[24] The median dose intensity delivered was 70% higher in the experimental arm; the median cumulative dose was similar in both arms. There was no difference between treatment groups in median or 2-year survival. A randomized phase III trial compared ifosfamide, cisplatin, and etoposide (ICE), which was given every 4 weeks with twice weekly ICE with GCSF and autologous blood support.[25] Despite achieving a relative dose intensity of 1.84 in the dose-accelerated arm, there was no difference in response rate (88% vs. 80%, respectively), median survival (14.4 vs. 13.9 months, respectively), or 2-year survival (19% vs. 22%, respectively) for dose-dense treatment compared with standard treatment.[25][Level of evidence: 1iiA]. Patients who received dose-dense treatment spent less time on treatment and had fewer episodes of infection. A randomized phase II study of identical design reported a significantly better median survival for the dose-dense arm (29.8 vs. 17.4 months, respectively; P = .02) and 2-year survival (62% vs. 36%, respectively; P = .05).[26] However, given the small study size (only 70 patients), these results should be viewed with caution. Patients with ED treated with chemotherapy who have achieved a response can be considered for administration of prophylactic cranial irradiation (PCI). A randomized trial of 286 patients with response following 4 to 6 cycles of chemotherapy compared PCI versus no further therapy with symptomatic brain metastases.[27] The cumulative risk of brain metastases within 1 year was 14.6% in the radiation group (95% CI, 8.3–20.9) and 40.4% in the control group (95% CI, 32.1– 48.6).[27][Level of evidence: 1iiD] Radiation was associated with an increase in median disease-free survival (DFS) from 12.0 weeks to 14.7 weeks and in median OS from 5.4 months to 6.7 months after randomization. The 1-year survival rate was 27.1% (95% CI, 19.4–35.5) in the radiation group and 13.3% (95% CI, 8.1–19.9) in the control group. Radiation had side effects but did not have a clinically significant effect on global health status.[24] Combination chemotherapy plus chest radiation therapy does not appear to improve survival compared with chemotherapy alone in patients with ED SCLC. Radiation therapy, however, plays an important role in palliation of symptoms of the primary tumor and of metastatic disease, particularly brain, epidural, and bone metastases. Chest radiation therapy is sometimes given for superior vena cava syndrome, but chemotherapy alone, with radiation reserved for nonresponding patients, is appropriate initial treatment. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.) Brain metastases are treated with whole-brain radiation therapy. Intracranial metastases from small cell carcinoma, however, may respond to chemotherapy as readily as metastases in other organs.[28,29] More patients with ED SCLC have greatly impaired performance status at the time of diagnosis when compared with patients with LD. 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.[22,30,31,32,33,34,35,36] Prospective randomized studies, however, have shown that patients with a poor prognosis who are treated with conventional regimens live longer than those treated with the single-agent low-dose regimens or abbreviated courses of therapy. A study comparing chemotherapy every 3 weeks with treatment given as required for symptom control showed an improvement in QOL in those patients receiving regular treatment.[33][Level of evidence: 1iiDii] Other studies have tested intensive one-drug or two-drug regimens. A study conducted by the Medical Research Council demonstrated similar efficacy for an etoposide plus vincristine regimen and a four-drug regimen.[34] The latter regimen was associated with a greater risk of toxic effects and early death but was superior with respect to palliation of symptoms and psychological distress.[34][Level of evidence: 1iiC] Studies comparing a convenient oral treatment with single-agent oral etoposide versus combination therapy showed that the overall response rate and OS were significantly worse in the oral etoposide arm.[30,35][Level of evidence: 1iiA][25,26,27] Subgroup analyses of phase II and phase III trials of SCLC patients by age showed that myelosuppression and doxorubicin-induced cardiac toxic effects were more severe in elderly patients than in younger patients and that the incidence of treatment-related death tended to be higher.[36] About 80% of elderly patients, however, received optimal treatment, and their survival was comparable to that of younger patients. The standard chemotherapy regimens for the general population could be applied to elderly patients in good general condition (i.e., performance status of 0–1, normal organ function, and no comorbidity). There is no evidence of a difference in response rate, DFS, or OS in elderly patients compared with younger patients.[28] STANDARD TREATMENT OPTIONS:
TREATMENT OPTIONS UNDER CLINICAL EVALUATION: Areas of active clinical evaluation in ED SCLC include evaluation of new drug regimens, dose intensity, alternative drug schedules, and high-dose chemotherapy. Current Clinical Trials Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with extensive stage small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria. General information about clinical trials is also available from the NCI Web site. References:
Recurrent Small Cell Lung CancerNote: 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 summary on Levels of Evidence for more information.) At the time of recurrence, many small cell lung cancer (SCLC) patients are potential candidates for further therapy. Although second-line chemotherapy has been shown to produce tumor regression, responses are usually short lived; the median survival is rarely more than 12 months and usually less than 6 months after second-line therapy.[1] Response to first-line chemotherapy predicts for subsequent response to second-line therapy. In analogy to other chemosensitive tumors (e.g., Hodgkin lymphoma and ovarian epithelial cancer), two main categories of patients receiving second-line chemotherapy have been described: sensitive and resistant. Sensitive patients have a first-line response that lasted more than 90 days after treatment was completed. These patients have the greatest benefit from second-line chemotherapy. Resistant patients either did not respond to first-line chemotherapy or responded initially but relapsed within 90 days of completion of their primary therapy.[2] Patients with sensitive disease respond to the same initial regimen in approximately 50% of cases; however, cumulative toxic effects may ensue.[3] Results from phase II studies of drugs such as topotecan, irinotecan, and gemcitabine indicate that response rates to agents vary depending on whether patients have sensitive, resistant, or refractory disease.[4,5,6,7,8][Level of evidence: 3iiiDii] A randomized comparison of second-line treatment with either cyclophosphamide, doxorubicin, and vincristine (CAV) or topotecan in patients with sensitive disease reported no significant difference in response rates or survival, but palliation of common lung cancer symptoms was better with topotecan.[7][Level of evidence: 1iiC] A phase III trial comparing chemotherapy with best supportive care (BSC) in relapsed SCLC patients demonstrated that the addition of oral topotecan to BSC significantly increased overall survival and resulted in better symptom control compared with BSC alone.[9] The study enrolled 141 patients with chemosensitive or chemoresistant relapsed SCLC who were unsuitable for further standard intravenous chemotherapy. The median survival times for patients receiving topotecan plus BSC were 25.9 weeks versus 13.9 weeks for BSC alone (P = .01).[10][Level of evidence: 1iiA] A randomized phase III trial (CWRU-SKF-1598) of 304 patients assessed the use of oral topotecan (2.3 mg/m2 /day for 5 days every 21 days) or intravenous topotecan (1.5 mg/m2 /day for 5 days every 21 days). Confirmed response rates were 18.3% and 21.9%, respectively.[11][Level of evidence: 1iiDii] Secondary endpoints of median survival and 1-year survival rates were also similar (33 weeks vs. 35 weeks and 33% vs. 29%, respectively). Patients receiving oral topotecan experienced less grade 4 neutropenia (47% vs. 64.2%) but more diarrhea of all grades (35.9% vs. 19.9%) compared with intravenous topotecan. Quality-of-life (QOL) analysis (using a nonvalidated QOL questionnaire) demonstrated no significant difference between the two arms.[11] Patients with sensitive disease may achieve response to a number of agents including topotecan, irinotecan, taxanes, vinorelbine, paclitaxel, or gemcitabine.[4,5,6,7,8,11,12,13][Level of evidence: 3iiiDii] Response rates to combination agents are generally higher than those reported for single agents;[14,15] however, many studies do not report the patients with sensitive, resistant, or refractory disease. Some patients with intrinsic endobronchial obstructing lesions or extrinsic compression caused by the tumor have achieved successful palliation with endobronchial laser therapy (for endobronchial lesions only) and/or brachytherapy.[16] Expandable metal stents can be safely inserted under local anesthesia via the bronchoscope, which results in improved symptoms and pulmonary function in patients with malignant airways obstruction.[17] 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. Only the rare patient, however, will experience long-term survival following salvage radiation therapy.[18] Patients with central nervous system (CNS) 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.[19] A retrospective review showed that 43% of patients treated with additional chemotherapy at the time of CNS relapse respond to second-line chemotherapy.[20] STANDARD TREATMENT OPTIONS:
Current Clinical Trials Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria. General information about clinical trials is also available from the NCI Web site. References:
Get More Information From NCICALL 1-800-4-CANCER For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. A trained Cancer Information Specialist is available to answer your questions. CHAT ONLINE The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 9:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer. WRITE TO US For more information from the NCI, please write to this address:
SEARCH THE NCI WEB SITE The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered. There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment. FIND PUBLICATIONS The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237). Changes to This Summary (07 / 01 / 2009)The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above. GENERAL INFORMATION ABOUT SMALL CELL LUNG CANCER Updated statistics with estimated new cases and deaths for 2009 (cited American Cancer Society as reference 1). More InformationABOUT PDQ
ADDITIONAL PDQ SUMMARIES
IMPORTANT: This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). Date Last Modified: 2009-07-01
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