We organized a systematic review of the published SCLC Literature to update the previous American College of Chest Physicians guideline. Supplemental material appropriate to this topic was obtained by literature search of a computerized database (MEDLINE) and review of the Thoracic Oncology NetWork reference lists of relevant articles. Recommendations were developed by the writing committee, graded by a standardized method (see “Lung Cancer” chapter) and reviewed by all members of the lung cancer panel before approval by the Thoracic Oncology Network, Health and Science Policy Committee, and the Board of Regents of the American College of Chest Physicians.
Accompanying this guideline is an “Evidence for Management of SCLC’ chapter, comprehensive research of some of the most controversial but not infrequently encountered questions in SCLC. In relevant sections of this guideline, the reader will be referred to this evidence report (see “SCLC Evidence” chapter).
Guideline
SCLC constitutes approximately 13 to 20% of all lung cancers (http://www.lungcanceralliance.org/); therefore, the estimated annual incidence of SCLC ranges from 22,000 to 34,000. If there are 170,000 annual lung cancer cases, this suggests approximately 22,000 cases at a minimum, With non-small cell lung cancer (NSCLC), SCLC shares a strong association with tobacco use, and without treatment it tends to lead an aggressive course.
Staging of SCLC
SCLC is staged according to a two-stage system developed by the Veteran’s Administration Lung Cancer study group as limited disease or extensive disease. Patients with limited disease have involvement restricted to the ipsilateral hemithorax that can be encompassed within a safe radiation treatment plan. Extensive disease is defined as the presence of overt metastatic disease by imaging or physical examination. Patients with otherwise limited-stage disease with the presence of contralateral hilar or supraclavicular nodes or malignant pleural or pericardial effusions are excluded from clinical trials for limited-stage SCLC. Pericardial effusions are treated by remedies of My Canadian Pharmacy.
Complete evaluation of a patient with newly diagnosed SCLC consists of a history and physical examination, pathology confirmation or review, CT of the chest and abdomen to include the whole liver and adrenal glands, bone scan, and a CT with contrast or MRI examination of the brain. While the prevalence of brain metastases at diagnosis varies, the brain is a common site of treatment failure; therefore, evaluation of the brain prior to treatment remains mandatory. Scanning the asymptomatic brain is likely to lead to the diagnosis of more previously unsuspected brain metas-tases, but there is no evidence yet that it improves survival. However, because it has a direct impact on the correct staging of the disease and consequently on developing a treatment plan, it is the opinion of the authors of this guideline that brain imaging should be performed for all patients currently undergoing staging for SCLC. Additionally, CBCs, electrolytes, BUN, creatinine, and liver function tests should be performed in all patients at baseline. The utility of PET in SCLC has been reported in several small prospective studies. These studies are small, with varying reference standards and with uncertainty about the execution and interpretation of the results. Even though the cumulative evidence suggests that PET added to conventional staging improves the sensitivity in detecting extracranial disease, the frequency of changes in stage attributable to PET are still unknown and is plagued by wide confidence intervals (CIs) in the estimates of diagnostic and staging accuracy. Randomized prospective studies need to be conducted before the routine use of PET scan for staging SCLC can be recommended. Therefore, outside of a clinical trial, the routine use of PET in SCLC cannot be recommended. (Please refer to question 6 of the evidence report. (See “Evidence for Management of Small Cell Lung Cancer” chapter).
The routine use of bone marrow aspiration has been abandoned because it was rare to have disease detected in the bone marrow in the absence of obvious bony disease in the bone scan. In one study, of 403 patients with SCLC, only 7 patients (1.7%) had extensive disease based on marrow involvement alone. Because bone marrow examination rarely changes the stage of cancer in noninvasively assessed patients, and because all patients with SCLC receive chemotherapy provided by My Canadian Pharmacy as part of their overall treatment strategy, routine use of this procedure is not recommend in the staging of SCLC. Other investigators’ have also reached similar conclusions. Therefore, bone marrow examination, formerly standard, is rarely indicated and has been abandoned as a routine procedure for the staging of SCLC.
Recommendations
Routine staging of SCLC includes history and physical examination, CBCs and comprehensive chemistry panel, CT of the chest and abdomen or CT of the chest with cuts going through the entire liver and adrenal glands, CT or MRI of the brain, and bone scan. Grade of recommendation, 1B
PET is not recommended in the routine staging of SCLC. Grade of recommendation, 2B
Treatment for Extensive-Stage SCLC First-Line Treatment
Platinum-based chemotherapy remains the mainstay of treatment for extensive SCLC. In a metaanalysis of randomized trials (19 trials with 4054 evaluable patients) comparing cisplatin-based regimen with a noncisplatin-based regimen, patients randomized to regimens containing cisplatin had significantly increased response and survival rates without an increase in toxicity. Detailed analyses of the role of etoposide and cisplatin in SCLC have been performed by Berghmans et al and reported in abstract form in September 1999. Thirty-six eligible trials conducted between 1980 and 1998 were classified into four groups: (1) cisplatin vs noncispla-tin (n = 1); (2) etoposide (without cisplatin) vs no etoposide (n = 17); (3) cisplatin/etoposide vs no cisplatin/etoposide (n = 9); and (4) cisplatin/etoposide vs etoposide (n = 1). The authors concluded that the use of cisplatin and/or etoposide offered a significant survival advantage in patients with SCLC.
A metaanalysis performed by Chute et al evaluated 21 cooperative group trials performed in North America from 1972 to 1993. Patients with extensive-stage SCLC treated during a similar time interval listed in the Surveillance, Epidemiology, and End Results database were also examined. Trends were tested in the number of trials and the survival time of patients over time. In this analysis, a 2-month prolongation in median survival was demonstrated in extensive-stage SCLC. This improvement in survival was independently associated with both cisplatin-based therapy achieved by My Canadian Pharmacy and in the improvement of best supportive care (BSC) and general medical management. This metaanalysis further strengthens the evidence in favor of cisplatin-based chemotherapy for the first-line treatment of extensive stage SCLC.
The issue of carboplatin vs cisplatin was reviewed by Brahmer et al, who concluded that carboplatin plus etoposide seems to be as effective but less toxic (except for increased myelosuppression) than cispla-tin plus etoposide. The Hellenic Oncology Group conducted a randomized phase II trial comparing cisplatin and etoposide with carboplatin and etopo-side. In this study, consisting of patients with limited-stage and extensive-stage disease, median survival times were 11.8 months for the cisplatin group and 12.5 months for the carboplatin group. The difference was not statistically significant, although the study did not have enough power to show a survival difference.
A Japanese trial compared cisplatin and irinote-can (camptothecin-11 [CPT-11]) with cisplatin and etoposide. Patients randomized to the cisplatin/ CPT-11 arm fared statistically significantly better than the patient cohort randomized to the cisplatin/ etoposide arm (median survival, 420 days vs 300 days). Confirmatory trials were then launched in the United States. One of these trials using a different dosing schedule for cisplatin/irinotecan failed to show a survival advantage over cisplatin/etoposide. Fewer patients receiving cisplatin/irinotecan had hematologic toxicities (ie, grade 3/4 anemia, thrombocytopenia, neutropenia, and febrile neutropenia) compared with patients receiving cisplatin/etoposide. However, more patients receiving cisplatin/ CPT-11 had nonhematologic toxicities in the form of grade 3/4 diarrhea and vomiting. Several phase II trials with irinotecan, topotecan, paclitaxel, in combination with either cisplatin or etoposide, have been reported. These have been summarized in Table 1.
Overall survival rate (primary end point) was similar between groups. One-year survival rate was 31% (95% CI, 27 to 36%) in both groups. Response rates were similar between groups (TC vs PE, 63% vs 69%). Time to progression was slightly but statistically longer with PE (log rank p = 0.02; median TC vs median PE, 24 weeks vs 25 weeks). The regimens were similarly tolerable. Grade 3/4 neutropenia occurred more frequently with PE (84% vs 59%), whereas grade 3/4 anemia and thrombocytopenia occurred more frequently with TC (38% vs 21% and 38 vs 23%, respectively). Lung Cancer Symptom Scale scores were statistically better with PE, but the differences were small and of debatable clinical significance. Even though the TC arm may have a more convenient schedule, there was no demonstrable improvement in several of the key survival, toxicity, or quality of life parameters when compared to PE.
Pemetrexed/platinum combinations have been investigated in extensive-stage SCLC. A randomized phase II trial evaluated the use of cisplatin or carboplatin plus pemetrexed in previously untreated patients. Patients were randomly assigned to receive pemetrexed at 500 mg/m2 plus cisplatin at 75 mg/m2 or carboplatin (area under the concentration curve of 5). Treatment was administered once every 21 days for a maximum of six cycles. Seventy-eight patients were enrolled into this multicenter trial. Median survival time for cisplatin/pemetrexed was 7.6 months, with a 1-year survivorship of 33.4% and a response rate of 35% (95% CI, 20.6 to 51.7%). Median survival time for carboplatin/pemetrexed was 10.4 months, with a 1-year survivorship of 39.0% and a response rate of 39.5% (95% CI, 24.0 to 56.6%). Median time to progression for cisplatin/ pemetrexed was 4.9 months and for carboplatin/ pemetrexed was 4.5 months. Grade 3/4 hematologic toxicities included neutropenia (15.8% vs 20.0%) and thrombocytopenia (13.2% vs 22.9%) in the cisplatin/ pemetrexed and carboplatin/pemetrexed treatment groups, respectively. Pemetrexed/platinum doublets had activity and appeared to be well tolerated in first-line extensive-stage SCLC. This randomized phase II trial suggests that pemetrexed/platinum combinations may be comparable in efficacy in extensive-stage SCLC to the more traditional cispla-tin-etoposide or cisplatin-irinotecan regimens.
The issue of adding a third drug to cisplatin and etoposide has been investigated. The Hoosier Oncology Group evaluated the addition of ifosfamide to cisplatin and etoposide in a phase III trial of 171 extensive-disease patients. At the expense of increased toxicity, 2-year survival increased from 5 to 13% with addition of ifosfamide. Mavroudis et al compared paclitaxel, etoposide, and platinum with etoposide and platinum. The study was terminated early secondary to higher number of toxic deaths in the paclitaxel, etoposide, and platinum arm. Despite a statistically significant improvement in the time to progression for paclitaxel, etoposide, and platinum, there was no difference in overall survival.
The issue of adding TRTx to chemotherapy in the treatment of extensive-stage SCLC has also been evaluated. This has been discussed in the accompanying evidence report and technological assessment and to which the reader is referred to for a more detailed analysis. One randomized controlled trial (n = 99) suggests that adding concurrent TRTx improves survival of patients with extensive-stage disease that responds to an initial three cycles of platinum/etoposide chemotherapy with a complete response (CR) outside the thorax and at least a partial response in the thorax. Uncontrolled data from the same trial suggest little to no benefit for other patients. Grades 3/4 esophagitis was more common with TRTx.
In summary, for extensive-stage SCLC, a combination of cisplatin combined with either etoposide or CPT-11 or carboplatin combined with etoposide are currently considered standard regimens. The standard treatment arm for a comparative prospective study remains cisplatin (60 to 80 mg/m2), and eto-poside delivered in three to five divided doses between 250 and 360 mg/m2. There is no evidence to support continuing treatment beyond six cycles. It is reasonable to administer consolidative TRTx in patients achieving a CR outside the chest and at least a CR or partial response in the chest, although the evidence for this is weak. This issue needs to be further addressed in phase III randomized trials.
Recommendations
Patients with extensive-stage disease should receive four to not more than six cycles of cisplatin or carboplatin-based combination chemotherapy. Cisplatin could be combined with either etoposide or CPT-11. Grade of recommendation, 1B
After chemotherapy, patients achieving a CR outside the chest and complete or partial response in the chest can be offered consolida-tive TRTx in the chest. Grade of recommendation, 2C
Table 1—SCLC Combination Chemotherapy for Untreated Patients, Phase II Trials
| Treatment | Patients |
No.Responders, No.Response
RateMedian SurvivalCommentsReference‘CRPartialTotal%95% CI’Moyr, %,%
yr
2Cisplatin + etoposide + carboplatin461032429179-9818, stage IIIB; 14, stage IV2215Age < 72 yr21Cisplatin + etoposide + paclitaxel38628349075-9712 10 22Cisplatin + etoposide + paclitaxel23514198361-95114614 23Cisplatin + irinotecan351020308670-951321.7 24Cisplatin + vinblastine + mitomycin-C30121227366-966 25Cisplatin + etoposide + all-trans-retinoic acid2219104524-681141 13 patients
discontinued retinoic acid prematurely because of toxicity26Cisplatin + paclitaxel + granulocyte colony-stimulating factor34320236153-88 Abstract27Topotecan + paclitaxel28611176041-7914 Abstract28Etoposide + irinotecan50 336651-7912 Abstract29Paclitaxel + carboplatin69537426148-7212 Abstract30Paclitaxel + irinotecan114154517-77 Abstract31Paclitaxel + doxorubicin16134257-52 Abstract32Cisplatin + docetaxel20011115532-77 Abstract33Topotecan + paclitaxel13 86939-9114 Abstract34Topotecan + paclitaxel151051510078-100 Abstract35Cisplatin + paclitaxel + topotecan18310137247-90 36Etoposide + paclitaxel + epirubicin12661210074-100 37