小细胞肺癌

DOI: 10.1378/chest.123.1_suppl.259S 2003;123;259-271 Chest George R. Simon and Henry Wagner Small Cell Lung Cancer This information is current as of August 1, 2005 http://www.chestjournal.org/cgi/content/full/123/1_suppl/259S located on the World Wide Web at: The online version of this article, along with updated information and services, is ISSN: 0012-3692. may be reproduced or distributed without the prior written permission of the copyright holder. 3300 Dundee Road, Northbrook IL 60062. All rights reserved. No part of this article or PDF published monthly since 1935. Copyright 2005 by the American College of Chest Physicians, CHEST is the official journal of the American College of Chest Physicians. It has been by on August 1, 2005 www.chestjournal.orgDownloaded from Small Cell Lung Cancer* George R. Simon, MD, FCCP; and Henry Wagner, MD Among patients with lung cancers, the proportion of those with small cell lung cancer (SCLC) has decreased over the last decade. SCLC is staged as limited-stage disease and extensive-stage disease. Standard staging procedures for SCLC include CT scans of the chest and abdomen, bone scan, and CT scan or MRI of the brain. The role for positron emission tomography scanning in the staging of SCLC has yet to be defined. Limited-stage disease is treated with curative intent with chemotherapy and radiation therapy, with approximately 20% of patients achieving a cure. The median survival time for patients with limited-stage disease is approximately 18 months. Extensive-stage disease is treated primarily with chemotherapy, with a high initial response rate of 60 to 70% and a complete response rate of 20 to 30%, but with a median survival time of approximately 9 months. Patients achieving a complete remission should be offered prophylactic cranial irradiation. Currently, there is no role for maintenance treatment or bone marrow transplantation in the treatment of patients with SCLC. Relapsed or refractory SCLC has a uniformly poor prognosis. In this section, evidence-based guidelines for the staging and treatment of SCLC are outlined. (CHEST 2003; 123:259S–271S) Key words: carboplatin; chemotherapy; cisplatin; etoposide; irinotecan; paclitaxel; prophylactic cranial irradiation; radiation therapy; small cell lung cancer Abbreviations: CAV � cyclophosphamide, adriamycin, and vincristine; CODE� cyclophosphamide, vincristine, doxorubicin, and etoposide; CR� complete response; ECOG� Eastern Cooperative Oncology Group; G-CSF� granulocyte colony-stimulating factor; NSCLC � non-small cell lung cancer; PCI � prophylactic cranial irradiation; PET � positron emission tomography; SCLC� small cell lung cancer; TEP� paclitaxel, etoposide, and cisplatin; TRT� thoracic radiotherapy T his document is the result of a comprehensivereview of the existing guidelines, meta-analyses, and relevant randomized clinical trials on the subject of small cell lung cancer (SCLC). Among lung cancers, the proportion of patients with SCLC has decreased from 17.4% in 1986 to 13.8% in 1998.1 Like non-SCLC (NSCLC), it has a strong association with tobacco use, but its clinical characteristics tend to be more aggressive than NSCLC, and median survival time without treat- ment is between 2 and 4 months. Staging of SCLC Patients are staged according to a two-stage sys- tem, which was developed by the Veterans Admin- istration Lung Cancer Study Group, as having limited- stage disease or extensive-stage disease. Patients with limited-stage disease have involvement re- stricted to the ipsilateral hemithorax within a single radiation port. Extensive-stage disease is defined as the presence of obvious metastatic disease. Patients with limited-stage disease with the presence of con- tralateral hilar and/or supraclavicular nodes and/or with malignant pericardial and/or pleural effusions are excluded from clinical trials for limited-stage SCLC. A complete evaluation of a patient newly diag- nosed with SCLC should consist of a medical history and physical examination, a review of the histopa- thology specimens, a CT scan of the chest and upper abdomen to include the whole liver and the adrenal glands, a bone scan, and a CT scan or MRI exami- nation of the brain. Additionally, complete blood counts, measurement of electrolyte, BUN, and cre- atinine levels, liver function tests, and measurement of lactate dehydrogenase levels should be performed in all patients at baseline. The utility of positron emission tomography (PET) scanning in patients with SCLC has been recently reported in two small prospective studies.2,3 In a study reported by Hauber et al,2 PET scans detected all primary lesions, lymph node metastases, and distant metastases that had been detected by other standard staging procedures. In a second study,3 30 patients with SCLC were evaluated with 36 PET scan examinations, and the *From the H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. Correspondence to: George R. Simon, MD, FCCP, 12902 Mag- nolia Dr, Suite 3170, Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612; e-mail: Simongr@moffitt.usf.edu www.chestjournal.org CHEST / 123 / 1 / JANUARY, 2003 SUPPLEMENT 259S by on August 1, 2005 www.chestjournal.orgDownloaded from results were compared with the sum of the other staging procedures. The results of 23 of the 36 PET scan examinations were concordant with those of the other staging procedures. In seven cases, the PET scan examination resulted in upward staging of the patient, and in one instance the PET scan revealed the presence of a viable tumor when conventional staging procedures had revealed no residual disease. PET scan identified all areas of tumor involvement detected by other staging procedures. A third study102 looked at the accuracy of PET scanning in detecting bony metastases in patients with SCLC and NSCLC, comparing the PET scans to bone scans and single-photon emission CT scans. In this study, PET scans were found to be the most accurate whole-body imaging modality for the screening of bone metastases. These studies suggested that PET scanning is likely to be a useful staging tool in patients with SCLC. However, all the above studies were small, and the experience with PET scan as a staging tool remains largely limited. Until larger prospective studies become available, PET scanning cannot be recommended for routine use in the staging and restaging of patients with SCLC. Recommendation 1. In all patients, the routine staging of SCLC should include medical history and physical examination, complete blood counts, compre- hensive chemistry panels, CT scans of the chest and abdomen, a CT scan or MRI of the brain, and a bone scan. Level of evidence, good; benefit, substantial; grade of recommendation, A 2. For the routine staging of patients with SCLC, PET scanning is not recommended outside of a clinical trial. Level of evidence, fair; benefit, none/negative; grade of recommendation, D Treatment of Extensive Stage SCLC First-Line Treatment Platinum-based chemotherapy remains the main- stay of treatment for extensive SCLC. In a meta- analysis4 of randomized trials (19 trials and 4,054 evaluable patients) comparing a cisplatin-based reg- imen with a non-cisplatin-based regimen, patients randomized to a regimen containing cisplatin had a significant increase in the probability of response and survival with no significant increase in toxicity. De- tailed analyses of the roles of etoposide and cisplatin in the treatment of SCLC have been performed by Berghmans et al5 and were reported in abstract form in September 1999. Thirty-six eligible trials that were performed between 1980 and 1998 were clas- sified into the following four groups: (1) cisplatin vs no cisplatin (1 trial); (2) etoposide (without cisplatin) vs no etoposide (17 trials); (3) cisplatin/etoposide vs no cisplatin/etoposide (9 trials); and (4) cisplatin/ etoposide vs etoposide (9 trials). The authors con- cluded that the use of cisplatin and/or etoposide offered a significant survival advantage to patients with SCLC.5 In another meta-analysis, Chute et al6 evaluated all 21 cooperative group trials performed in North America from 1972 to 1993. Patients with extensive- stage SCLC who were treated during a similar time interval and were listed in the Surveillance, Epide- miology, and End Results database also were exam- ined. Trends were tested in the number of trials and the survival of patients over time. In this analysis, a modest 2-month prolongation in median survival was demonstrated in patients with extensive-stage SCLC. This improvement in survival was independently associated with both cisplatin-based therapy and in the improvement of best supportive care. This meta- analysis again establishes that cisplatin-based chemo- therapy should be the cornerstone of first-line che- motherapy for patients with extensive-stage SCLC. The issue of carboplatin vs cisplatin was recently reviewed by Brahmer and Ettinger,7 who concluded that carboplatin plus etoposide is as effective as cisplatin plus etoposide but is less toxic (except for increased myelosuppression). The Hellenic Oncol- ogy Group conducted a phase III trial103 comparing cisplatin and etoposide with carboplatin and etopo- side. In this study, containing patients with both limited-stage and extensive-stage disease, the me- dian survival time was 11.8 months for cisplatin plus etoposide and 12.5 months for carboplatin plus etoposide. The difference was not statistically signif- icant, although the study was not powered to show equivalence.103 A recent Japanese trial8 compared cisplatin and irinotecan with cisplatin and etoposide. Patients randomized to the cisplatin/irinotecan arm did (sta- tistically) significantly better than the group that was randomized to the cisplatin/etoposide arm (median survival time, 420 vs 300 days, respectively). Confir- matory trials are underway in the United States. Several phase II trials with irinotecan, topotecan, and paclitaxel in combination with either cisplatin or etoposide have been reported, and these have been summarized in Table 1. The issue of adding a third drug to cisplatin and etoposide has been investigated. The Hoosier On- cology Group evaluated the addition of ifosfamide to cisplatin and etoposide in a phase III trial of 171 patients with extensive-stage disease. At the expense of increased toxicity, the 2-year survival rate in- creased from 5 to 13% with the addition of ifos- 260S Lung Cancer Guidelines by on August 1, 2005 www.chestjournal.orgDownloaded from famide.9 Mavroudis et al10 compared the use of paclitaxel, etoposide, and platinum (TEP) with the use of etoposide and platinum. The study was ter- minated early, secondary to a higher number of toxic deaths in the TEP arm. Despite a statistically signif- icant improvement in the time to progression for TEP, there was no difference in overall survival. Recently, another phase III intergroup trial (Cancer and Leukemia Group B 9732) was reported11 com- paring cisplatin and etoposide with or without pac- litaxel in patients with extensive-stage SCLC. No significant survival advantage was seen with the addition of paclitaxel to cisplatin and etoposide in this study. On the other hand, there was an increased incidence of deaths from toxicities in the paclitaxel arm. Recommendations 3. Patients with extensive-stage disease should receive platinum-based chemotherapy. Level of evidence, good; benefit, substantial; grade of recommendation, A 4. Patients achieving a complete remission (CR) should be offered prophylactic cranial irradia- tion (PCI). Level of evidence, fair; benefit, small; grade of recommendation, C Maintenance Treatment The topic of maintenance therapy in patients with SCLC was extensively reviewed in the journal Lung Cancer in 1998.12 Several randomized trials have demonstrated that 4 to 6 months of treatment is equal to prolonged treatment when survival is con- sidered as the end point. In the meta-analysis re- ported by Sculier et al,12 13 published randomized trials were included. One showed a statistically sig- nificant difference in survival in favor of mainte- nance therapy, 5 studies showed survival advantage in subgroups of patients, 1 study showed significantly shorter survival times with maintenance therapy, and 6 studies showed no difference. The Eastern Coop- erative Oncology Group (ECOG) conducted a phase III trial in which patients showing a response to therapy or patients whose disease stabilized after receiving four cycles of cisplatin and etoposide were randomized to observation alone or to four cycles of topotecan therapy.13 Despite an improvement in progression-free survival, there was no difference in overall survival between the two groups. Treatments other than chemotherapy for mainte- nance are currently being investigated in ongoing clinical trials. A phase III randomized trial is cur- rently underway testing the efficacy of anti-GD3 immunization as maintenance treatment. Metallo- proteinase inhibitors and inhibitors of angiogenesis also are being investigated in this fashion. Recommendation 5. For patients with extensive-stage or limited- stage SCLC achieving a partial or CR, there is no evidence, outside of a clinical trial, for Table 1—Phase II Trials of SCLC Patients Receiving Combination Chemotherapy vs Untreated Patients* Treatment Patients, No. Responders, No. Response Rate Survival† ReferenceCR PR Total % 95% CL Mo 1-Yr Rate, % CEC 46 10 32 42 91 79–98 18‡ 22 69 TEP 38 6 28 34 90 75–97 12 70 TEP 23 5 14 19 83 61–95 11 46 71 Cisplatin-irinotecan 35 10 20 30 86 70–95 13 21.7 72 Cisplatin-vinblastine-MMC 30 1 21 22 73 66–96 6 73 Cisplatin-etoposide-all-trans-RA 22 1 9 10 45 24–68 11 41 74 Cisplatin-paclitaxel-G-CSF 34 3 20 23 61 53–8 8 75 Topotecan-paclitaxel 28 6 11 17 60 41–79 14 76 Etoposide-irinotecan 50 33 66 51–79 12 77 Paclitaxel-carboplatin 69 5 37 42 61 48–72 12 78 Paclitaxel-irinotecan 11 4 1 5 45 17–77 79 Paclitaxel-doxorubicin 16 1 3 4 25 7–52 80 Cisplatin-docetaxel 20 0 11 11 55 32–77 81 Topotecan-paclitaxel 13 8 69 39–91 14 82 Topotecan-paclitaxel 15 10 5 15 100 78–100 83 CPT 18 3 10 13 72 47–90 84 EPE 12 6 6 12 100 74–100 85 *CEC � cisplatin-etoposide-carboplatin; MMC� mitomycin C; RA� retinoic acid; CL� confidence limits; CPT� cisplatin-paclitaxel-topote- can; EPE� etoposide-paclitaxel-epirubicin; PR� partial response. †Values given as median. ‡Includes 14 patients with stage IIIB and stage IV disease. www.chestjournal.org CHEST / 123 / 1 / JANUARY, 2003 SUPPLEMENT 261S by on August 1, 2005 www.chestjournal.orgDownloaded from maintenance treatment. Level of evidence, good; benefit, none/negative; grade of recom- mendation, D Treatment of Relapsed or Refractory SCLC Despite high initial response rates to chemother- apy (ie, 45 to 75% CRs) reported in patients with limited-stage disease and 20 to 30% CRs in patients with extensive-stage disease, the response duration is usually short with a progression-free survival time of approximately 4 months for patients with extensive- stage disease and 12 months for patients with limited- stage disease. Most patients are destined to relapse, and the prognosis of this group of relapsed patients is poor. Patients who relapse � 3 months after first- line therapy are commonly called refractory, and patients who relapse 3 months after therapy are called sensitive. Patients with late relapses after receiving initial therapy may be retreated with the same induction regimen used initially. Patients whose disease progresses early after induction therapy and who are in satisfactory clinical condition, should be offered a second-line regimen. In a randomized multicenter study, von Pawel et al101 compared cyclophosphamide, adria- mycin, and vincristine (CAV) with topotecan as a single agent in patients who relapsed at least 60 days after the completion of initial therapy. A total of 211 patients were enrolled in the study. The response rate was 24.3% in patients who were treated with topotecan and was 18.3% in patients treated with CAV (p � 0.285). The median times to disease progression were 13.3 weeks for pa- tients in the topotecan arm and 12.3 weeks for patients in the CAV arm. The median survival time was 25 weeks for patients receiving topotecan and 24.7 weeks for those receiving CAV. The propor- tion of patients who experienced symptom im- provement was greater in the topotecan arm than in the CAV group for four of the eight symptoms evaluated. The authors concluded that topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms. However, toxicity rates were high in both arms of the study, and alternative dose schedules of topotecan are currently being evaluated. Several recently re- ported phase II trials in patients with relapsed/ refractory SCLC are summarized in Table 2. Recommendation 6. Patients with SCLC who have relapsed follow- ing an initial response to treatment or who are refractory to the initial treatment should be offered further chemotherapy. The chemother- apy offered will depend on the duration of response after receiving first-line chemother- apy or the lack of response to first-line chemo- therapy (ie, sensitive relapses vs refractory pa- tients). Level of evidence, fair; benefit, small/ weak; grade of recommendation, C Treatment of Elderly Patients With Extensive-Stage SCLC Approximately 25% of patients with SCLC are � 70 years of age (ie, elderly). The performance status and the physiologic status of the patient should guide treatment decisions rather than the patient’s chronologic age. It is clear that patients with good performance status (ECOG level 0 or 1) and normal organ function should be treated with optimal che- motherapy (and with radiotherapy, if indicated) as in their younger counterparts. Similar outcomes of elderly patients with limited-stage SCLC have been shown in the intergroup trial 0096 in which cisplatin, etoposide, and thoracic radiotherapy were adminis- tered once a day or twice daily.14 The National Cancer Institute of Canada performed a retrospec- Table 2—Phase II Trials of SCLC Patients Receiving Combination Chemotherapy: Refractory or Relapsed Patients* Treatment Patients, No. Responders, No. Response Rate, % Survival† ReferenceCR PR Total Mo 1 Yr Rate, % Etoposide-irinotecan 24 3 14 17 71 9 86 Cisplatin-topotecan 28 1 7 8 29 87 Etoposide-hexmethylmelamine 30 1 5 6 22 5 21 88 Irinotecan-paclitaxel 11 1 4 5 45 89 Carboplatin-paclitaxel 18 0 3 3 17 90 *See Table 1 for abbreviations not used in the text. †Values given as median. 262S Lung Cancer Guidelines by on August 1, 2005 www.chestjournal.orgDownloaded from tive review15 of their BR3 and BR6 trials and also concluded that age did not appear to impact the delivery, tolerance, or efficacy of thoracic irradiation in the combined-modality management of patients with limited-stage SCLC. Greater myelosuppression is to be expected since equivalent exposure to a drug will lead to more myelosuppression in the elderly compared to their younger counterparts. This has been shown to be the case at least for etoposide.16 Greater ancillary support will be required in the elderly. However, despite treatment delays elderly patients with good performance status have similar prognoses to those of younger patients. Elderly patients with poor performance status or with compromised organ function may be offered single-agent chemotherapy or polychemotherapy in attenuated doses. However, several randomized studies17,18 have indicated that such “gentler” che- motherapy is inferior to optimal combination chemo- therapy. Options available to these patients include the following: oral etoposide for 14 days combined with carboplatin on day 1 every 28 days19; abbrevi- ated chemothera