Advances in the Management of Small-Cell Lung Cancer (SCLC)September 2-6, 2007Seoul, KoreaDavid Spigel, MD, The Sarah Cannon Research Institute, Nashville, TN
Approximately 25,000 patients are diagnosed with small-cell lung cancer (SCLC) in the U.S. each year. Despite high response rates with combination chemotherapy, most will not survive beyond two years. Advances in the treatment of limited-stage SCLC with the use of chemoradiotherapy have been important steps forward. As well, progress in non-small-cell lung cancer (NSCLC) and other solid tumors using modern radiation techniques, new chemotherapies, and novel agents has spurred clinical research in SCLC. Some of this preliminary work was presented recently in Seoul, Korea.
Researchers from China reported the outcomes of 122 patients with limited-stage SCLC treated between 1999 and 2004. The majority of patients were treated initially with surgery. Ninety-two patients received post-operative chemotherapy and 19 received post-operative chemotherapy and radiotherapy. The median survival time for the entire group of patients was 38 months. The one, three, and five year survival rates were 83.6%, 50%, and 38%, respectively. Patients who received post-operative chemotherapy had a median survival of 41 months. These authors concluded that multimodality therapy improved survival of patient with SCLC.
Researchers from Japan presented the results of treating patients with limited-stage SCLC treated with hyper-fractionated radiotherapy with concurrent chemotherapy. There were 46 patients in this study who were treated between 1996 and 2004. Chemotherapy was described as dose-intense and administered every three weeks for four cycles. Later regimens included carboplatin and etoposide. The complete response (CR) rate was 59%. The loco-regional relapse rate was 27% and the distant relapse rate was 67% with 40% occurring in the brain. The median survival time was 23 months and the two, three, and five year survivals were 44%, 32%, and 22%, respectively. More recent chemotherapy showed improved two year survival, but similar three and five year survivals.
Researchers from France reported the outcomes of 38 patients with limited-stage SCLC treated with thoracic 3D conformal radiotherapy and concurrent etoposide and cisplatin. All patients in this study had a good performance status. The median follow-up was 26 months. The median disease-free survival was 10.6 months, the median overall survival was 17.6 months and the five year survival rate was 29%.
Prophylactic Cranial Irradiation in Limited-Stage Disease
Researchers involved in an international multi-center trial reported preliminary data on a randomized trial of two doses of prophylactic cranial irradiation (PCI) in patients with limited-stage SCLC. There is evidence that higher doses of PCI are more effective than lower doses, but might be associated with more toxicity. Almost 700 patients were randomized to 25Gy or 36Gy. The data presented suggested that the higher dose was well tolerated and the researchers indicated that updated efficacy results would be reported in 2008.
Researchers from Turkey evaluated a regimen of carboplatin and etoposide for the treatment of patients with extensive-stage SCLC. They reported outcomes of 56 patients treated with this combination. The median number of cycles administered was 4.6. Dose reductions occurred in only 3% of cycles. The CR rate was 25% and the PR rate was 46%. Median overall survival was 337 days and the one year survival was 45%. The two year survival was 13%. These researchers suggest that these results are comparable to other platinum-based regimens.
Researchers from Germany presented the results of a randomized trial comparing surgery and radiotherapy versus radiotherapy alone in patients with extensive-stage SCLC. This study was closed in 2004 after accrual of 98 patients. Chemotherapy consisted of paclitaxel, etoposide and carboplatin (TEC). The response rate to chemotherapy was 93%, and 69 patients were randomized to receive surgery and radiotherapy or radiotherapy alone. All patients received PCI. Toxicity to surgery and radiotherapy was low and manageable. Median survival and median PFS were 15 months in both arms of the study. These authors concluded that multimodality therapy was feasible and worthy of further investigation.
Researchers from Korea have previously reported that a regimen of fractionated irinotecan plus carboplatin is a well tolerated regimen for patients with previously untreated extensive-stage SCLC. Researchers from Japan have also reported that a regimen of carboplatin and irinotecan supported by filgrastim was effective and well tolerated in elderly patients with SCLC.
Researchers from the University of Alabama reported the results of treating 16 patients with extensive-stage SCLC with irinotecan and oxaliplatin followed by etoposide/carboplatin. All but three patients were untreated at the time of study entry. Response data were presented on nine chemo-naive patients: partial response (PR) in five and stable disease in three. This regimen was described as well tolerated except for thrombocytopenia.
A European randomized trial compared a regimen of irinotecan and carboplatin with the standard etoposide and carboplatin regimen in 210 patients with extensive disease. See the median survival, one year survival and complete responses in Table 1.
Table 1: Etoposide/carboplatin versus irinotecan/carboplatin.
These authors reported similar toxicities and concluded that irinotecan and carboplatin resulted in better survival without compromising quality of life compared to more standard etoposide and carboplatin.
Picoplatin is an oral or intravenous drug which was designed to overcome platinum resistance and to be less toxic than cisplatin or carboplatin. In November of 2005, picoplatin was granted orphan drug status for the treatment of SCLC by the US Food and Drug Administration. In the SCLC trial presented at the 2007 meeting of the American Society of Clinical Oncology (ASCO), researchers from the US and Russia reported that picoplatin treatment resulted in disease control in almost half of platinum-resistant SCLC patients. This trial included 84 patients with resistant or refractory SCLC treated with intravenous picoplatin. The overall response rate was 9% with 38% having stable disease. Median progression-free survival was 10 weeks and the median survival was 27 weeks. Toxicities appeared to be moderate. These researchers are currently performing a Phase III trial (S-PEAR) which compares picoplatin to best supportive care in patients with refractory or resistant SCLC.
Researchers affiliated with the Picoplatin SCLC Study Group reported data on 77 patients with refractory or resistant SCLC treated with picoplatin. There were no treatment-related deaths and the median overall survival was 28 weeks and median PFS was nine weeks. The response rate was 3% with 52% having disease stabilization. A current randomized trial will compare picoplatin to best supportive care.
Researchers from France have previously reported that the addition of thalidomide to chemotherapy improves survival in patients with extensive-stage SCLC. In the Presidential Symposium of the 12th World Conference on Lung Cancer, researchers from the UK presented the results of a Phase III randomized trial of etoposide/carboplatin with or without thalidomide. They reported that addition of thalidomide did not improve outcomes. This study included 724 patients with extensive or limited disease who had not been previously treated. Thoracic and cranial radiotherapy was given to patients with limited disease. Almost 75% of patients had extensive disease. The median follow-up was 24 months. The following table summarizes the main findings of this trial.
Table 2: Results of a Phase III randomized trial of etoposide/carboplatin with or without thalidomide.
DVT=deep vein thrombosis, PE = pulmonary emboli
These authors concluded that thalidomide in combination with etoposide and carboplatin did not improve progression-free or overall survival in extensive-stage SCLC. There are now two studies of thalidomide in SCLC, one from France with good results and one from the UK with poor results. The reason for these two different conclusions is not clear.
Bevacizumab is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF). VEGF appears to play an important role in tumor angiogenesis, and blocking this activity has an anti-tumor effect. Clinical trials of bevacizumab in multiple tumor types have been carried out for the past few years without evidence of significant clinical activity as a single agent (except in renal cell cancer). However, more recent studies have suggested that combining bevacizumab with chemotherapy can be effective in patients with advanced NSCLC, breast cancer, and colon cancer. A multicenter randomized trial carried out by ECOG has shown that the addition of bevacizumab to carboplatin and paclitaxel improves survival in patients with newly diagnosed advanced or metastatic NSCLC who have not received prior chemotherapy.
The Sarah Cannon Research Institute determined that bevacizumab could be safely added to carboplatin and irinotecan in patients with extensive-stage SCLC. Fifty-one patients were enrolled in this single cohort Phase II study. The objective response rate was 88% (1 CR and 44 PRs) and 6-month time to progression (primary endpoint) was 66% with 42% alive at one year.
Prophylactic Cranial Irradiation in Extensive-Stage SCLC
Approximately two-thirds of patients with SCLC have extensive-stage disease at the time of diagnosis. A large portion of these patients ultimately develop brain metastasis. PCI could potentially reduce the growth of these metastases. According to results recently presented at the 2007 annual meeting of ASCO, PCI following treatment with chemotherapy doubles survival at one year and reduces the risk of developing brain metastasis among patients with extensive-stage disease. At the 12th World Conference on Lung Cancer these data were further evaluated. This trial had previously shown that PCI reduced the risk of brain metastasis from 40% to 15% and was associated with an increase of one year survival from 13% to 27%. The present study presented Quality of Life data. These authors reported that there were significant early side effects from PCI. However, they suggested that global health was not significantly influenced until far beyond the expected median survival. They recommend that all patients with extensive-stage disease SCLC who responded to chemotherapy should routinely be offered PCI.
SCLC continues to be a challenging disease to treat. Despite high response rates and rapid clinical benefit with initial therapy, progress has been slow with standard treatment approaches. However, few patients will experience prolonged benefit from modern therapies. New strategies in care are needed to combat recurrence, improve radiotherapy delivery, and reduce toxicity, and should be studied in prospective clinical trials. It is encouraging to see many studies in SCLC from across the world presented in Seoul. The recent progress with novel therapies in multiple tumor settings such as NSCLC, kidney, breast, and colon cancers provides hope that similar advances will soon be seen in SCLC.
 Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: Analysis of the surveillance, epidemiologic, and end results database. Journal of Clinical Oncology. 2006; 24:4539-4544.
 Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. New England Journal of Medicine. 1992; 327:1618-1624. [Abstract] Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. Journal of Clinical Oncology. 1992; 10:890-895.
 Shi Y, Wang H, Sun K, et al. Exploration of multidisciplinary therapy including surgery in limited disease (LD) stage small cell lung cancer (SCLC): a clinical report of 122 cases from single institute. Journal of Thoracic Surgery. 2007; 2:S833.
 Shibata T, Koike R, Nakamatsu K, et al. A long-term result by hyperfractionated radiotherapy with concurrent chemotherapy for limited-stage small cell lung cancer (LD-SCLC): a retrospective analysis in a single institution. Journal of Thoracic Surgery. 2007; 2:S832.
 Couraud S, Direito A, Martel L, et al. Once a day (QD) thoracic 3D conformal radiotherapy (XRT) for patients with limited stage small-cell lung cancer (SCLC) treated concurrently with etoposide and cisplatin (EP):Results of a single institution retrospective experience. Journal of Thoracic Surgery. 2007; 2:S831.
 Le Pechoux C, Senan S, Quoix E et al. Initial results from an intergroup Phase III trial evaluating two different doses of prophylactic cranial irradiation (PCI) in patients with limited small cell lung cancer (SCLC) in complete remission (PC199-01, IFCT 99-01, EORTC 2203-08004, RTOG 0212). Journal of Thoracic Surgery. 2007; 2:S389.
 Yilmaz U, Halicolar H, Yapicioglu S, et al. Efficacy of carboplatin (C) and etoposide (E) for extensive stage small cell lung cancer (ED-SCLC). Journal of ThoracicSurgery. 2007; 2:S831.
 Reck M, Baumann M, Gatzemeier U, et al. Surgery and radiotherapy versus radiotherapy in patients with small-cell lung cancer (SCLC) responding to chemotherapy with paclitaxel, etoposide phosphate, and carboplatin (TEC) – analysis of a randomized Phase – II trial. Journal of Thoracic Surgery. 2007; 2:S821.
 Sohn JH, Cho HJ, Chang J, et al. A Phase II trial of fractionated irinotecan plus carboplatin for previously untreated extensive-disease small cell lung cancer. Lung Cancer. 2006; 54:365-370.
 Okamoto H, Naoki K, Narita Y, et al. A combination chemotherapy of carboplatin and irinotecan with granulocyte colony-stimulating factor (G-CSF) support in elderly patients with small cell lung cancer. Lung Cancer. 2006; 53:197-203.
 Francisco R, Harper K, Wang D. Phase II study of sequential targeting regimens with irinotecan/oxaliplatin followed by etoposide/carboplatin in patients with extensive small cell lung cancer (SCLC). Journal of Thoracic Surgery. 2007; 2:S828.
 Hermes A, Bergman B, Bremmes R, et al. Treatment with irinotecan plus carboplatin prolonges survival without compromising quality of life in patients with small cell lung cancer, extensive disease (SCLC-ED). Results of a randomized Phase III trial. Journal of Thoracic Surgery. 2007; 2:S390.
 Bentsion D, Lipatov O, Poliakov I, et al. A Phase II study of picoplatin as second-line therapy for patients with small cell lung cancer (SCLC) who have resistant or refractory disease or have relapsed within 180 days of completing first-line, platinum-containing chemotherapy. Journal of Clinical Oncology. 2007; 25.
 Karlin DA, Breitz H, Baker G, et al. A phse II study of picoplatin monotherapy for patients with small cell lung cancer (SCLC) who have resistant or refractory disease or have relapsed within 180 days of completing first-line, platinum-containing chemotherapy. Journal of Thoracic Surgery. 2007; 2:S424.
 Pujol J, Breton J, Gervais R, et al. A Prospective Randomized Phase III, Double-Blind, Placebo-Controlled Study of Thalidomide in Extended-Disease (ED) SCLC Patients After Response to Chemotherapy (CT): An Intergroup Study FNCLCC Cleo04-IFCT 00-01. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology Conference. Atlanta, GA. 2006. Abstract # 7057.
 Lee S-M, Woll PJ, James LE, et al. A phase III randomized, double blind, placebo controlled trial of etoposide/carboplatin with or without thalidomide in advanced small cell lung cancer (SCLC). Journal of Thoracic Surgery 2007;2:S391, abstract PRS-04.
 Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel with Carboplatin and Placlitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small Cell Lung Cancer. Journal of Clinical Oncology. 2004; 22:2184-2191.
 Spigel DR, Hainsworth JD, Burris HA, et al. Irinotecan, carboplatin, and bevacizumab in untreated extensive stage small-cell lung cancer. Journal of Thoracic Surgery 2007; 2:S391. .
 Slotman B, Faivre-Finn C, Kramer G, et al. A Randomized Trial of Prophylactic Cranial Irradiation (PCI) Versus no PCI in Extensive Disease Small Cell Lung Cancer After a Response to Chemotherapy (EORTC 08993-22993). Proceedings from the American Society of Clinical Oncology Conference. Chicago,IL. 2007. Abstract # 4.
 Slotman BJ, Faivre-Finn C, Kramer GW, et al. Prophylactic cranial irradiation (PCI) in extensive disease small cell lung cancr (ED-SCLC) after response to chemotherapy (EORTC 08993-22993): quality of life (QoL) results. Journal of Thoracic Surgery 2007; 2:S389.