Limited-Stage Small-Cell Lung Cancer: Therapeutic Options

Almost 40% of patients with newly diagnosed small-cell lung cancer (SCLC) have disease confined to the ipsilateral hemithorax and within a single radiation port, ie, limited-stage disease. The median survival for this group of patients after treatment is approximately 15 months, with one in every four patients surviving 2 years. Current optimal treatment consists of chemotherapy with platinum/etoposide, given concurrently with thoracic radiation. Surgery may represent an option for very early-stage disease, but its added value is uncertain. Prophylactic cranial irradiation (PCI) is used for patients with limited-stage SCLC who have achieved a complete response following initial therapy, as it decreases the risk of brain metastases and provides an overall survival benefit. Newer targeted agents are currently being evaluated in this disease and hold the promise of improving current outcomes seen in patients with early-stage disease.

Small-cell lung cancer (SCLC) makes up almost 15% of all cases of lung cancer[1] and is diagnosed almost exclusively in individuals with a history of smoking.[2] The current World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC) classification includes two subtypes: SCLC (with a pure SCLC histology) and combined SCLC (mixture of SCLC with any non-small-cell type).[3] The tumor has a characteristic histologic appearance with small, round-to-fusiform cells that have scant cytoplasm, fine granular nuclear chromatin, and absent nucleoli. Extensive necrosis is common as is a high mitotic rate, with an average of 80 mitoses per 2 mm² area.[3] Approximately two-thirds of patients with SCLC are diagnosed with advanced disease, which tends to have an aggressive clinical course, often with paraneoplastic syndromes. In this review, we will focus on the therapeutic options currently available for the management of the 30% to 40% of patients who have limited-stage SCLC at diagnosis.

Staging System

Two systems are currently used to stage SCLC-the tumor-node-metastases (TNM) classification[4] and the Veterans Administration Lung Study Group (VALSG) limited disease-extensive disease system. The VALSG system is probably more clinically relevant. Based on this classification, limited-stage disease is confined to the ipsilateral hemithorax and within a single radiation port (TNM stages I through IIIB), whereas extensive-stage disease includes metastatic disease outside the ipsilateral hemithorax. The International Association for the Study of Lung Cancer (IASLC) defines limited stage as absence of distant metastatic disease.[5] Micke et al compared outcomes of patients of 21 patients with limited disease according to the IASLC system but extensive disease by the VALSG criteria, and noted a higher discriminatory power with the IASLC system.[6] Nonetheless, the VALSG system continues to be widely utilized, probably because of its simplicity.[7]

Controversies exist regarding the stage of patients with ipsilateral pleural effusion and supraclavicular and contralateral mediastinal lymph node involvement. Do they have limited or extensive disease? Patients with an isolated pleural effusion make up about 2% to 7% of patients with limited-stage disease.[7,8] Although most trials involving combined-modality therapy for limited disease excluded patients with isolated pleural effusions,[9-11] two studies have found that the survival of patients with isolated pleural effusions was nearly identical to patients with limited-stage SCLC and no effusion.[8,12]

Supraclavicular lymph node involvement is seen in approximately 5% of patients with otherwise limited disease, and may predict for a slightly inferior survival.[13,14] The significance of supraclavicular lymph node involvement may be due to a correlation with the presence of distant metastases.[14] Patients with contralateral hilar or mediastinal lymph node involvement and no evidence of distant metastases, pose a unique challenge to the clinician given the paucity of data available to guide decision-making. Trials exploring aggressive multimodality approaches have tended to exclude patients with contralateral mediastinal or hilar lymph node involvement, possibly to reduce the radiation fields and, thereby, pulmonary toxicity.[15,16]

These issues might assume even greater significance as better treatment options become available for limited-stage disease. In a retrospective analysis, Shepherd et al reviewed records of 264 patients with limited-stage SCLC and found that those with no clinical evidence of mediastinal lymph node involvement had a better median survival compared to patients with mediastinal or supraclavicular node involvement, pleural effusion, or bronchial obstruction.[17]

Prognostic Factors

A majority of patients with SCLC relapse following initial therapy despite initial response to chemotherapy and radiation, and median survival of patients with limited-stage SCLC ranges from 14 to 18 months.[18] Approximately 25% of patients with limited-stage and less than 5% of patients with extensive-stage disease are alive 2 years after the diagnosis.[18]

The most important adverse prognostic factors are poor performance status (higher than Eastern Cooperative Oncology Group [ECOG] level 2).[13,19,20] and extensive-stage disease at presentation.[19] However, the prognostic significance of these variables diminishes with time, probably because few patients survive this disease. Other poor prognostic factors include weight loss,[19] an elevated lactate dehydrogenase level,[20-22] male gender,[13,19,22] an elevated level of alkaline phosphatase,[23] and a low hemoglobin.[24] The impact of these latter variables is limited and only applicable to certain groups of patients in the studies that identified them. Not all of these factors had prognostic importance in all reports, and caution should be exercised when discussing prognosis with individual patients based on these criteria.

Management of Limited-Stage Disease

Cytotoxic Chemotherapy

• Active Drugs-Small-cell lung cancer is extremely chemosensitive,[25] and multiple agents have shown activity in this disease, including platinum compounds (cisplatin, carboplatin), camptothecins (topotecan [Hycamtin], irinotecan [Camptosar]), podophyllotoxins (etoposide, teniposide [Vumon]), anthracyclines (doxorubicin, epirubicin [Ellence]), alkylating agents (cyclophosphamide, ifosfamide), taxanes (paclitaxel, docetaxel [Taxotere]), and vincristine.

Trials conducted in the 1970s found that a combination of cyclophosphamide, doxorubicin (Adriamycin)/epirubicin, and vincristine, or CA(E)V, produced high response rates, and a proportion of patients survived for prolonged periods following this therapy.[26-28] As a result, this regimen became the standard of care in the 1980s. When etoposide was introduced and combined with cisplatin (Platinol), initial phase II studies suggested that the response rates with this combination (EP) were superior to those achieved with CAV therapy.[29,30] Randomized trials comparing EP with CA(E)V suggested that EP produced superior response rates and better disease-free and overall survival in patients with limited-stage disease. Although the response rates were also higher in patients with extensive disease, this did not translate into a survival advantage.[31-34]

Because EP seemed to be better tolerated, it evolved to be the current regimen of choice for initial treatment of SCLC. Given the extreme chemosensitivity of SCLC and based on the Goldie-Coldman hypothesis (non-cross-resistant regimens, when delivered in an alternating sequence, can achieve optimal therapeutic benefit), trials using alternating CAV and EP were performed. Although the outcomes with the alternating sequence were slightly better, they did not represent a major improvement.[32-34]

Since cisplatin is associated with multiple potentially severe toxicities, its role has been studied extensively. Benefits of including a platinum compound in the initial management were demonstrated in a meta-analysis that included 19 trials involving more than 4,000 patients.[35] In this analysis, cisplatin-containing regimens resulted in higher response rates and higher probability of survival without an obvious increase in risk of toxic deaths.

• Modifications of the EP Combination-Multiple studies have evaluated alternate agents in an attempt to decrease toxicity. In the first study, carboplatin was used instead of cisplatin in combination with etoposide.[36] This randomized trial compared EP with etoposide/carboplatin, and while no differences in response rates were observed, carboplatin-based therapy was associated with significantly less toxicity. A second study evaluated long-term survival following carboplatin-based chemotherapy with radiotherapy in patients with limited disease.[37] Median survival was 17.4 months, with a 5-year overall survival rate of 20%-findings comparable to those associated with cisplatin-based regimens.

When etoposide was replaced by high-dose epirubicin (100 mg/m²) in a randomized trial, patients randomized to the EP arm showed similar response rates but increased toxicity compared to the cisplatin/epirubicin arm.[38] James et al compared EP with gemcitabine (Gemzar) and carboplatin and found an increased hematologic toxicity but fewer nonhematologic toxicities in the gemcitabine arm.[39]. No survival differences were evident among the two groups. None of these studies have reported quality-of-life data, which would help in treatment selection, and none of these combinations have currently gained favor in the United States.

TABLE 1

Timing of Thoracic Radiation Therapy in Patients With Limited-Stage Small-Cell Lung Cancer

• Multiple-Drug Combinations-The low percentage of patients with limited-stage SCLC who experience long-term survival has led to studies examining the role of multidrug therapy and high-dose therapy with stem cell support in an effort to increase the proportion of long-term survivors. The role of platinum-based triplet therapy has been investigated following the introduction of additional active agents. Phase II studies evaluating the efficacy of adding paclitaxel to a platinum/etoposide combination have demonstrated better 1-year survival (56%-81%) and median survival rates (21-24 months) compared to historical controls.[40-42]

A recent European phase III study compared the combination of carboplatin, etoposide, and paclitaxel with a regimen of carboplatin, etoposide, and vincristine, in both limited- and extensive-disease patients. Patients who received the paclitaxel combination had an improved overall and progression-free survival with fewer hematologic toxicities.[43,44] Also, patients in the paclitaxel arm had better quality of life and physical functioning. However the reference arm used in the study (carboplatin, etoposide, vincristine) is not the standard of care for patients with limited-stage SCLC, and the findings of this trial must be interpreted with that in mind. Hence, the role of paclitaxel in SCLC needs to be validated in randomized phase III trials.

• Dose-Dense and High-Dose Therapy With Stem Cell Support-Autologous hematopoietic stem cell transplantation permits the administration of high doses of chemotherapy with a goal of achieving a higher tumor cell kill than possible with standard-dose chemotherapy as well as improved survival.[45] Multiple small phase II trials have been conducted in the United States and Europe, involving patients with both limited and extensive disease, with response rates of 80% to 100% and 2-year survival rates of 0% to 70%.[46]

In the only randomized trial of high-dose chemotherapy and hematopoietic stem cell transplantation, Humblet et al found that although the response rates and relapse-free survival were improved by the high-dose therapy, there was no effect on overall survival due to increased toxicity, including those patients with limited disease.[47] One of the reasons for the lack of improved efficacy with this approach may be the extent of contamination of the leukapheresis product by tumor cells. Perey et al evaluated the bone marrow and leukapheresis samples from patients with SCLC, some of whom had participated in a European Group for Blood and Marrow Transplantation (EBMT) trial of high-dose chemotherapy with stem cell support for SCLC[48] and found that contaminating tumor cells were detected in 34% of leukaphereses (27% for patients with limited disease, 43% for those with extensive disease); the proportion increased to 78% using reverse transcriptase-polymerase chain reaction (RT-PCR) techniques (89% in limited disease and 67% in extensive disease).

Based on these findings, the ongoing EBMT randomized high-dose chemotherapy trial includes two cycles of standard therapy before high-dose therapy to produce in vivo purging of circulating tumor cells before stem cell collection.[46] Given the lack of randomized trial data supporting high-dose chemotherapy with stem cell support, this strategy is not yet confirmed. 

• Dose-No prospective studies evaluating the dose or fraction size for PCI are available. Studies have used doses ranging from 24 to 30 Gy in 8 to 10 fractions, and the current recommendations are for doses between 25 and 36 Gy, given in one of the following schedules: 30 Gy in 15 fractions, 36 Gy in 18 fractions, or 25 Gy in 10 fractions.[53] Recently, a small trial demonstrated the feasibility of twice-daily fractions of 1.5 Gy to a total dose of 30 to 36 Gy.[85] The 15 patients who participated in this protocol were compared to 12 patients who declined participation. At a median follow-up of 20 months, the authors found a 2-year disease-free survival of 54% with twice-daily PCI vs 0% with no PCI (P = .013). In addition, a survival advantage was seen at 2 years for twice-daily PCI (62% vs 23%; P = .032). Neurologic deterioration was similar in the two groups.

• Toxicity-The major factor limiting the widespread use of PCI has been the concern regarding long-term neurotoxicity. However, there are no reliable data to estimate the frequency and severity of the long-term toxicities associated with PCI. Given the survival advantage of PCI, patients who receive PCI tend to live longer and therefore are at greater risk of developing chronic neurotoxicity. In an attempt to investigate the therapeutic usefulness and cost-effectiveness of PCI in patients with limited-stage SCLC in complete remission, Tai et al conducted a retrospective chart review of 98 patients.[86] Using the Q-TWiST method (quality time without symptoms and toxicity) to estimate quality-of-life-adjusted survival, they found that patients who received PCI had a significant improvement in mean Q-TWiST survival.

In another analysis, Lee and associates developed a decision-analytic model to compare quality-adjusted life expectancy (QALE) in a cohort of SCLC patients with or without PCI, by varying survival rates and the frequency and severity of PCI-related neurotoxicity.[87] They found that at current survival rates, PCI offered a benefit over no PCI (QALE = 4.31 and 3.70 for mild toxicity, and 4.09 and 3.70 for substantial toxicity, respectively). The results of these analyses would suggest a benefit to utilization of PCI without undue toxicity. However, they do not substitute for good clinical trials designed with this specific objective in mind.

Future Directions

FIGURE 1

Treatment of Limited-Stage Small-Cell Lung Cancer

Despite various strategies, the overall survival in patients with SCLC has not improved significantly beyond those seen with EP. An increasing fund of knowledge regarding the molecular biology and immunology of SCLC is leading to studies of more targeted agents. Targets that are being investigated currently are discussed below.

c-kit

Nearly one-third of patients with extensive SCLC have c-kit overexpression as demonstrated by immunohistochemistry (IHC).[88,89] The Cancer And Leukemia Group B conducted a trial[90] using imatinib mesylate (Gleevec) at a dose of 400 mg twice daily in patients with c-kit overexpression. The results, however, were disappointing, with no responses and only one patient achieving stable disease. A major reason for the failure of imatinib in this disease could be that the putative cells of origin of SCLC are not completely dependent on the c-kit pathway for development and survival,[91] in contradistinction to hematopoietic stem cells.

bcl-2

The oncogene bcl-2 has a major role in suppressing apoptosis,[92] such that suppression of bcl-2 may increase therapeutic efficacy.[93] Bcl-2 is expressed in 83% to 90% of SCLC[94] and thus represents a potential therapeutic target. In a small trial, the combination of oblimersen (Genasense, an 18-base antisense phosphorothioate oligonucleotide complementary to the bcl-2 mRNA) and paclitaxel was studied in patients with chemorefractory SCLC.[95] No objective responses were observed, but four patients experienced stable disease. An explanation for the failure of the combination to demonstrate any response may have been the low doses of the agents studied. A trial using EP with or without oblimersen is currently underway.

Matrix Metalloproteinase Inhibitors

Matrix metalloproteinases (MMP) are involved in extracellular membrane degradation,[96] a key process enabling the cancer cell to metastasize. The use of protease inhibitors to limit extracellular matrix proteolysis by malignant cells could interfere with tumor cell invasion. A randomized placebo-controlled trial of marimastat, a synthetic oral MMP inhibitor, following chemotherapy for patients with sensitive disease did not show a benefit and instead showed a worsening quality of life.[97] One of the reasons for these disappointing results may be selection of patients for the trial, since MMP expression in the tumor was not studied. Another possibility is the broad-spectrum activity of marimastat; a more targeted MMP inhibitor may provide better results.

Vaccines

Studies on SCLC cell lines suggest that they may express significant levels of GD3, a cell-surface glycosphingolipid antigen.[98] The European Organisation for Research and Treatment of Cancer (EORTC) conducted a randomized phase III study in 515 patients with limited-stage SCLC, comparing vaccination with BEC-2 (an anti-idiotypic antibody that mimics the structure of the GD3 ganglioside) vs follow-up as maintenance measures following standard induction chemotherapy.[99] Although the investigators found no improvement in survival, progression-free survival, or quality of life in the vaccination arm, a trend toward prolonged survival was revealed in patients who developed a humoral response.

Mutations of p53 are the most common genetic abnormalities seen in patients with SCLC.[100,101] The differential expression of mutant p53 between normal and tumor cells could provide a basis for vaccine therapy. Investigators vaccinated patients with extensive-stage SCLC using wild-type p53 gene–transduced dendritic cells via an adenoviral vector.[102] Although only one patient showed a response to the vaccination alone, the researchers found a high rate of response to chemotherapy (61.9%) that immediately followed vaccination. Thus, vaccine therapy might be a useful adjunct to chemotherapy, rather than a primary modality.

Vascular Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) stimulates endothelial cell division and increases vascular permeability, and thus is a key factor in angiogenesis.[103] VEGF–tyrosine kinase inhibitors (TKI) inhibit downstream signaling pathways that are activated following stimulation of the VEGF receptor. Multiple agents with VEGF-TK inhibitory activity are being studied in various malignancies including SCLC. A number of VEGF-TKIs are in development, including ZD6474, PTK787/ZKI222584 (vatalanib), AZD2171, BAY 43-9006 (sorafenib [Nexavar]), SU11248 (sunitinib [Sutent]) and AMG706.[104] Although none of these agents have yet demonstrated a survival benefit in patients with SCLC, it is hoped that-either alone or in combination with conventional cytotoxic agents-they will lead to future breakthroughs and, eventually, improved outcomes in this population.

Conclusions

Current treatment of limited-stage SCLC involves combined-modality treatment with chemotherapy and concurrent thoracic radiation (Figure 1). The most common chemotherapy regimen includes four cycles of etoposide and platinum, preferably cisplatin, in patients with a good performance status. Addition of a third agent, or intensifying therapy further, has not demonstrated a major advantage over standard treatment. With current therapy, patients with limited-stage SCLC have a median survival of 17 months and a 5-year overall survival rate of 12%. Newer targeted agents, particularly those affecting angiogenesis, are currently in clinical trials and promise to have a favorable impact on outcomes in SCLC.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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