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First Published Online October 9, 2009
The Oncologist, Vol. 14, No. 10, 986-994, October 2009; doi:10.1634/theoncologist.2009-0026
© 2009 AlphaMed Press

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Lung Cancer

New Advances in the Second-Line Treatment of Small Cell Lung Cancer

Jane L. Hurwitza,b, Francis McCoya, Paula Scullinb, Dean A. Fennella,b

aCentre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland; bNorthern Ireland Cancer Centre, Belfast, Northern Ireland

Key Words. Small cell lung cancer • Relapsed • Chemotherapy • BCL-2 • Apoptosis

Correspondence: Dean A. Fennell, M.D., Ph.D., Thoracic Oncology Research Group, Centre for Cancer Research & Cell Biology, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland. Telephone: 44-28-9097-2762; Fax: 44-28-9097-2755; e-mail: d.fennell{at}qub.ac.uk

Received February 15, 2009; accepted for publication September 6, 2009; first published online in THE ONCOLOGIST Express on October 9, 2009.

Disclosures: Jane L. Hurwitz: None; Francis McCoy: None; Paula Scullin: None; Dean A. Fennell: None.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors or independent peer reviewers.


   ABSTRACT
Top
 Abstract
Introduction
 Relapse After First-Line...
 Novel Agent-Based Clinical...
 Conclusion
 Author Contributions
 References
 
Lung cancer is the leading cause of cancer-related death in the U.K., with small cell histology accounting for 15%–20% of cases. Small cell lung cancer (SCLC) is initially a chemosensitive disease, but relapse is common, and in this group of patients it remains a rapidly lethal disease with a particularly poor prognosis. The choice of second-line chemotherapy for patients with relapsed SCLC has been an area of difficulty for oncologists, and until recently there was no randomized evidence for its use over best supportive care (BSC). Topotecan is currently the only drug licensed in Europe and the U.S. for this indication, having been shown in a phase III trial to lead to longer overall survival and better quality of life than with BSC. In this article, we review the current evidence for the use of second-line cytotoxic therapy and also the emerging role of novel agents and targeted therapies in this setting. In particular, we explore the role of the Bcl-2 protein family, which are key regulators of mitochondrial apoptosis and are implicated in resistance to anticancer therapies. SCLC overexpresses antiapoptotic members of the Bcl-2 family in ~80% of cases. Several Bcl-2 inhibitors, including obatoclax, are currently entering clinical trials in SCLC and are an exciting area of drug development in the relapsed setting.


   INTRODUCTION
Top
 Abstract
 Introduction
Relapse After First-Line...
 Novel Agent-Based Clinical...
 Conclusion
 Author Contributions
 References
 
Lung cancer is the most common cancer in the world. In the U.K., there are around 38,000 new cases annually, and it is the leading cause of cancer-related death. Small cell lung cancer (SCLC), which accounts for 15%–20% of all lung cancer diagnoses, is an extremely aggressive disease with particularly poor survival rates (2–4 months without treatment). As in all cancers, treatment of SCLC depends on the stage of the disease, which is classified into limited stage (LS) and extensive stage (ES). LS disease (30%–40%) refers to disease that is confined to one hemithorax that can be safely encompassed into a radiotherapy field and ES disease (60%–70%) refers to any disease outside this [1]. This staging system was originally proposed by the Veterans Administration Lung Study Group [2] and has now been revised by the International Association of Lung Cancer in accordance with the tumor–node–metastasis classification system [3].

SCLC is generally considered a systemic disease, and therefore, surgery rarely plays a role in its management. It is characterized by initial chemosensitivity, and the treatment of choice in the first-line setting is a platinum-based regimen, most commonly cisplatin and etoposide (EP) [4, 5]. In a phase III study by Sundstrøm et al. [4], EP was shown to be superior to cyclophosphamide, epirubicin, and vincristine (CEV), with significantly higher 2- and 5-year survival rates (14% and 5% in the EP arm versus 6% and 2% in the CEV arm, respectively). Carboplatin is an acceptable alternative to cisplatin, with comparable efficacy and a more favorable toxicity profile [6]. Trials of three- and four-drug regimens, dose-intensifying regimens, the addition of third-generation cytotoxic agents (e.g., gemcitabine, taxanes, topotecan), and high-dose chemotherapy have all failed to improve outcomes [7].

The addition of thoracic radiotherapy to chemotherapy has improved 3-year survival rates by around 5% and has reduced the risk for intrathoracic recurrence by 25% in LS disease [8, 9]. The use of prophylactic cranial irradiation (PCI) has further improved outcomes. A meta-analysis of trials evaluating PCI in SCLC patients with a complete response to first-line chemotherapy showed a significantly lower rate of brain recurrence (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.38–0.57), longer disease-free survival time (HR, 0.73; 95% CI, 0.65–0.86), and longer overall survival (OS) time (HR, 0.84; 95% CI, 0.73–0.97) [10]. Recent evidence has also shown a benefit of PCI for ES patients who have responded to first-line treatment [11]. Advances in the understanding of the underlying biology of SCLC and the relative success of targeted therapies in non-small cell lung cancer (NSCLC) (e.g., bevacizumab and erlotinib) have prompted the exploration of these agents in SCLC. Antiangiogenic agents, growth factor receptor inhibitors, and apoptosis promoters, for example, have all shown potential in first-line phase II studies, but have yet to influence the standard management of SCLC.


   RELAPSE AFTER FIRST-LINE SYSTEMIC THERAPY
Top
 Abstract
 Introduction
 Relapse After First-Line...
Novel Agent-Based Clinical...
 Conclusion
 Author Contributions
 References
 
Despite recent advances in management strategies for SCLC, improvements in survival have been small, and prognosis remains poor, with 5-year survival rates for LS and ES disease of around 10% and 2%, respectively [12]. This reflects the fact that, although SCLC is initially a chemosensitive disease (with response rates to first-line treatment on the order of 70%–90% in LS disease and 50%–60% in ES disease [13]), development of resistance to treatment is a major problem. The majority of patients relapse (~80% of LS patients and almost all ES patients), most commonly within the first year after initial treatment.

The probability of response to second-line therapy can be predicted according to response to first-line treatment, in that patients with "sensitive" disease, that is, who have relapsed beyond 60 or 90 days of completing first-line treatment, are thought to have the greatest potential for benefit from second-line treatment. The term "refractory" has been used to refer to patients who have progressed within 60 or 90 days, and "resistant" has been used to refer to those who did not respond or relapsed during first-line treatment. Performance status (PS) and weight loss at the time of relapse are also associated with a poorer prognosis. Several groups have divided SCLC into two subtypes, "classic" and "variant," based on the expression of specific neuroendocrine markers. There have been reports that this differentiation may be clinically relevant, with the variant subgroup predicting chemoresistance, early relapse, and poorer outcomes, but this remains controversial [14, 15].

Late Relapse
For patients who relapse ≥6 months after initial treatment, consideration should be given to retreatment with the original regimen [16, 17]. Postmus et al. [16] reported response rates of 62% of patients retreated with cyclophosphamide, doxorubicin, and etoposide, with complete response after initial treatment and longer duration of response being more likely to predict response to retreatment.

Early Relapse
The use of second-line chemotherapy in patients who relapse within 6 months is more controversial, because many patients in this group have a poorer PS, and until recently there was no proven benefit of second-line chemotherapy over best supportive care (BSC). Sundstrøm et al. [18] compared a crossover regimen of EP or CEV with BSC in relapsed SCLC patients. Patients had initially been randomized to EP or CEV and then went on to receive the other regimen at the time of relapse (if second-line treatment was felt appropriate by the treating physician). They did report a survival advantage for those receiving second-line treatment over BSC (median OS time, 5.3 months versus 2.2 months); however, this was not a randomized trial, and the BSC group had a worse PS and shorter time to relapse than the treatment group. They found no difference in survival from either of the regimens, EP or CEV. The only significant prognostic factor in the treatment group was PS at relapse.

Cyclophosphamide, doxorubicin, and vincristine (CAV) has been used as second-line treatment after EP and has shown response rates of 13%–28% [19, 20]. i.v. topotecan was compared with CAV in a phase III trial of patients who had relapsed at least 60 days after first-line treatment [21]. This showed comparable response rates (24.3% versus 18.3%; p = .285) and survival times (median survival time, 25 weeks versus 24.7 weeks); however, only topotecan led to better symptom control, with statistically significant improvements in dyspnea, fatigue, anorexia, and effect on activities of daily living. Hematological toxicity was the most common toxicity in both regimes—grade 4 neutropenia was experienced in significantly more courses in the CAV group, whereas grade 4 thrombocytopenia and grade 3 or 4 anemia was more prevalent in the topotecan group. The durations of hematological toxicity were similar in the two groups (as was the rate of infective sequelae) and did not appear to be cumulative.

Oral has been compared with i.v. topotecan in patients with relapsed SCLC and showed similar efficacy and tolerability [22, 23]. In a phase III trial, the overall response rates were 18.3% versus 21.9% for oral and i.v. treatment, respectively, giving a 3.6% difference (95% CI, 12.6%–5.5%), but the trial was unable to demonstrate noninferiority statistically. The times to progression and median survival times were also comparable (11.9 weeks versus 14.6 weeks and 33 weeks versus 35 weeks, for oral and i.v., respectively) as were toxicity and quality of life (QOL) measurements. Approximately 10% of the study population had relapsed <3 months from first-line treatment, but there was no comparison between sensitive and refractory/resistant patients in the study. Intravenous topotecan in combination with carboplatin for relapsed SCLC was recently evaluated in a phase I study [24] and showed a partial response rate of 17.2% (23.8% in patients who were platinum sensitive).

The only randomized study comparing chemotherapy with BSC in the second-line setting comes from O'Brien et al. [25]. That phase III trial compared oral topotecan with BSC in relapsed SCLC patients who were not eligible for standard second-line i.v. chemotherapy. It showed a significantly longer OS time (HR, 0.64; 95% CI, 0.45–0.9) and superior QOL for the topotecan group. The partial response rate for the topotecan group was 7%, with a further 44% gaining disease stabilization, and the median survival times were 25.9 weeks (95% CI, 18.3–31.6 weeks) versus 13.9 weeks (95% CI, 11.2–18.6 weeks) for topotecan and BSC, respectively. The benefit was seen not only in those patients with sensitive disease but also in those with a shorter treatment-free interval (TFI) and poorer PS. Twenty-nine percent and 31% of patients in the BSC and topotecan arms, respectively, had a TFI ≤60 days, and the median survival duration for these groups were 13.2 weeks (95% CI, 7–21 weeks) versus 23.3 weeks (95% CI, 10.7–39 weeks). Thirty-three percent and 27% of patients in the BSC and topotecan arms, respectively, had a PS score ≥2, and median survival durations for these groups were 7.7 weeks (95% CI, 5.3–13.1 weeks) versus 20.9 weeks (95% CI, 13.4–26.9 weeks). Topotecan is therefore currently the only drug licensed in Europe and the U.S. for the treatment of relapsed SCLC (when retreatment with the first-line agent is not appropriate).

It is generally accepted that, if further treatment is to be offered to patients with refractory or resistant disease, it should be with a noncrossresistant regimen. Various alternative drug combinations have been assessed in phase II trials, and these are summarized in Table 1.


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  		Table 1. Summary of phase II trials of cytotoxic agents for relapsed SCLC

 
Pemetrexed, a novel antifolate chemotherapy that is active in NSCLC and mesothelioma, has been explored in two phase II trials as a single agent in relapsed SCLC patients [37, 38]. Both studies included both patients who were sensitive and those who were resistant to first-line chemotherapy, and the study by Socinski et al. [38] employed two dose levels (500 mg/m2 and 900 mg/m2) of the drug. Unfortunately, these studies showed only minimal activity of pemetrexed in this setting. In keeping with these findings, the randomized phase III trial comparing carboplatin–pemetrexed with carboplatin–etoposide in the first-line setting [39] was closed early because of the inferiority of the pemetrexed combination for in terms of progression-free survival (PFS).

In addition, amrubicin (a third-generation anthracycline) has also been investigated as a single agent in the phase II setting, with more promising results. A study by Seto et al. [40] of SCLC patients who had relapsed after one or two prior chemotherapy regimes (one of which had to be platinum based) showed response rates, PFS times, and OS times of 50% and 52%, 2.6 months and 4.2 months, and 10.3 months and 11.6 months, for refractory and sensitive patients, respectively. In the phase I setting, amrubicin has been combined with paclitaxel [41] and irinotecan [42] and appears to be well tolerated. A randomized phase II study of amrubicin versus topotecan in relapsed or refractory SCLC was reported recently [35] and suggests that amrubicin is superior. The overall response rates (primary endpoint) were 38% and 13% (p = .039) and the disease control rates were 79% and 47% (p = .015) for amrubicin and topotecan, respectively. The study also suggested significantly longer OS for patients treated with amrubicin, and a phase III trial to confirm these findings is now recruiting.


   NOVEL AGENT–BASED CLINICAL TRIALS OF SECOND-LINE THERAPY FOR SCLC
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 Abstract
 Introduction
 Relapse After First-Line...
 Novel Agent-Based Clinical...
Conclusion
 Author Contributions
 References
 
The prognosis remains poor for SCLC patients, and we believe that a therapeutic plateau has been reached in terms of cytotoxic-based second-line treatments. Figure 1 shows that, even with increasing response rates, survival times have not been greatly impacted, suggesting an underlying cell population that is resistant to conventional chemotherapy. For this reason, there has thus been a move over recent years to investigate the role of novel agents and targeted therapies in this group of patients [43]. Most of the phase II studies to date have been in the first-line setting; however, some of these agents have been evaluated in patients with relapsed disease.


Figure 1
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  		Figure 1. Summary of data from literature review of phase II and III trials of cytotoxic agents in relapsed small cell lung cancer.

 
Antiangiogenic Agents
Antiangiogenic agents, including bevacizumab, the monoclonal antibody against vascular endothelial growth factor (VEGF) that has been shown to be active in NSCLC, may have a role to play. In the first-line setting, two phase II studies of bevacizumab in combination with chemotherapy in ES SCLC [44, 45] patients have shown promising results, with overall response rates of 69% and 62%. In a phase II trial of bevacizumab and paclitaxel in relapsed SCLC, a disease control rate of 66% (partial response rate of 11.1% and stable disease rate of 55.5%), median PFS time of 13 weeks, and median OS time of 21 weeks were reported [46]. A phase II trial of oral topotecan and bevacizumab in relapsed SCLC is due to open in the near future.

Sorafenib, which targets Raf kinase, VEGF receptor (VEGFR)-2, VEGFR-3, and platelet-derived growth factor receptor β, is currently being evaluated in a phase II clinical trial as a single agent, and in a phase I trial in combination with oral topotecan. AZD2171 is also a multiple kinase inhibitor that is in a phase II trial as a single agent.

Growth Factor Receptor Inhibitors
Growth factor receptor inhibitors have shown disappointing results in this group of patients. Imatinib (a c-Kit tyrosine kinase inhibitor) was evaluated in two phase II studies [47, 48] in relapsed SCLC patients positive for c-Kit, but no objective response or sustained disease stabilization was observed in those studies. Gefitinib, the epidermal growth factor receptor tyrosine kinase inhibitor that has also been shown to be active in NSCLC, unfortunately did not demonstrate activity in patients with SCLC [49].

Inhibition of Downstream Signaling Pathways
The phosphatidylinositol 3' kinase/Akt signaling pathway may be important in the proliferation of SCLC cells [50], and mammalian target of rapamycin (mTOR) plays a central role in this pathway. RAD001 (everolimus) is a novel oral mTOR inhibitor that is currently being evaluated in a phase II study in patients with relapsed SCLC [51]. Preliminary results from that trial show no objective responses, but three patients (19%) achieved stable disease (duration of stable disease, 69–117+ days), and an acceptable toxicity profile was seen.

Prosurvival Bcl-2 Family Inhibitors
More promising, perhaps, is the emerging role of apoptosis promoters. Chemotherapeutic agents, including platinum, have been shown to exert their cytotoxic effects by inducing apoptosis via the mitochondrial (or intrinsic) pathway [52]. Apoptosis resistance is therefore not only a hallmark of cancer in general [53] but is also a key mechanism in the failure of chemotherapy [54, 55]. The mitochondrial apoptotic pathway is regulated by the Bcl-2 family of proteins via their interaction with each other. This group of proteins share one or more of the Bcl-2 homology (BH) domains and can be divided into three groups based on their structural and functional characteristics. Bax and Bak are proapoptotic members that contain BH domains 1–3 and are required for chemotherapy-related cell death. Other proapoptotic members have only the BH domain 3 and are therefore termed BH3-only proteins (e.g., Bid, Bim, Bad, Noxa, Puma), and the antiapoptotic members have all four BH domains (e.g., Bcl-2, Bcl-xL, Bcl-w, Mcl-1, A1).

The way in which these proteins interact and cause apoptosis remains controversial, but it is known that, upon activation, Bax and Bak undergo a conformational change, deep insertion into the outer mitochondrial membrane (OMM), and oligomerization [56]. These events ultimately induce mitochondrial outer membrane permeabilization, possibly by the formation of pores or channels in the OMM, which in turn causes release of proapoptotic proteins (e.g., cytochrome-c and Smac) that activate downstream caspases, leading to cell death [57].

The BH3 domain is an amphiphatic {alpha}-helix that binds into a hydrophobic pocket formed by BH domains 1–3 of the multidomain members, and it is through these binding interactions (and the formation of homo- and heterodimers) that the Bcl-2 family members regulate their activity [58]. In this way, Bax, Bak, and BH3-only proteins can be bound to, and inhibited by, the multidomain antiapoptotic members of the family [59, 60]. The way in which the BH3-only proteins interact with other Bcl-2 family members is still unclear, but two theories have emerged over recent years. The "direct activation" model suggested by Letai et al. [61] divides BH3-only proteins into "activators" (Bid, Bim, and possibly Puma), which bind to and activate Bax and Bak, and "dissociators" (Bad, Bik, Noxa), which act by disrupting the constitutive inhibitory binding between antiapoptotic Bcl-2s and Bax, Bak, and BH3-only proteins [62]. An alternative "indirect" model suggests that BH3-only proteins are not required at all for Bax/Bak activation, but only that the inhibitory binding with antiapoptotic Bcl-2s is removed [63]. Figure 2 summarizes the mitochondrial apoptotic pathway.


Figure 2
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  		Figure 2. Summary of the mitochondrial (intrinsic) apoptotic pathway.

Abbreviations: APAF-1, apoptotic peptidase activating factor; IAP, inhibitor of apoptosis proteins.

 
Constitutively high levels of antiapoptotic Bcl-2 proteins have been associated with a more aggressive malignant phenotype [64] and resistance to various chemotherapeutic agents in a wide range of cancers [65, 66]. In SCLC, in particular, Bcl-2 has been reported to be overexpressed in approximately 80% of cases [67]. The importance of Bcl-2 in chemoresistance in SCLC was highlighted by Sartorius et al. [68], who showed that chemoresistant cell lines generated in vitro showed upregulation of Bcl-2. Bcl-2 overexpressing cell lines showed a marked reduction in chemosensitivity, and inhibition of Bcl-2 in resistant cells (by an antisense oligodeoxynucleotide) resulted in chemosensitization.

The antiapoptotic Bcl-2 proteins, by way of their inhibition of apoptosis, therefore provide potential targets for anticancer therapies. The Bcl-2 prosurvival signaling pathway can be antagonized by bortezomib, which inhibits the 20s proteosome. It was recently evaluated in a phase II trial of relapsed SCLC patients, but showed limited single-agent activity [69]. Another therapeutic approach to modulating Bcl-2 family–mediated apoptosis is using antisense drugs. Oblimersen, an antisense oligonucleotide agent that is complementary to the first six codons of Bcl-2 mRNA, was the first to be evaluated in SCLC in the clinic. That phase II study, in combination with carboplatin and etoposide for chemotherapy-naive patients, failed to show a greater objective response rate or longer survival, however [70, 71]. Possible explanations for the failure of the antisense agent oblimersen are that it may not sufficiently suppress intratumor levels of its target, Bcl-2, and also the fact that functional redundancy exists between Bcl-2 and Bcl-xL. This problem is unlikely to be associated with small-molecule BH3 mimetics.

Small-molecule BH3 mimetics are a class of drug that has emerged over recent years and show great potential in this disease setting. These agents are low molecular compounds that function by binding in the hydrophobic groove of antiapoptotic Bcl-2 family members, thus disrupting their inhibitory interaction with proapoptotic members (Fig. 3). ABT-263 is an orally bioavailable BH3 mimetic, and one of the few agents shown to act as a "pure" BH3 mimetic, that is, is ineffective in the absence of Bax and Bak [72]. It has high binding affinity for Bcl-2, Bcl-xL and Bcl-w, but not Mcl-1 or A1. Resistance to ABT-263 is therefore conferred by high basal expression of Mcl-1. It has shown activity in vitro and in vivo as a single agent and in combination with cytotoxic chemotherapy [73–75]. ABT-263 is being investigated in a phase I/II study in relapsed SCLC. AT-101 (gossypol) is another oral Bcl-2 family inhibitor that is currently being investigated in the phase II setting as a single agent and also in combination with topotecan in patients with relapsed SCLC.


Figure 3
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  		Figure 3. Diagram summarizing the Bcl-2 family of proteins and their interaction with each other. BH3 mimetics act like "dissociator" BH3-only proteins and disrupt the inhibitory binding between pro- and antiapoptotic proteins.

 
Obatoclax mesylate (GX15–070) was identified by chemical library screening and binds all six antiapoptotic proteins [76], including Mcl-1 [77]. It has in vitro activity in a range of tumor types, including SCLC, as a single agent and in combination [78–80]. It has shown in vivo activity in hematological malignancies and is currently under evaluation in a phase I/II trial in combination with carboplatin and etoposide in the first-line treatment of patients with ES SCLC. In the second-line setting, a phase I/II trial in combination with topotecan is currently recruiting.


   CONCLUSION
Top
 Abstract
 Introduction
 Relapse After First-Line...
 Novel Agent-Based Clinical...
 Conclusion
Author Contributions
 References
 
SCLC is one of the leading causes of cancer-related death worldwide and is characterized by initial chemosensitivity followed almost inevitably by relapse. Response to second-line chemotherapy is likely to be higher in those with a good PS and longer time to relapse, and retreatment with the first-line regimen should be considered for those who relapse >6 months after the end of treatment. Various chemotherapy regimens have been evaluated in the phase II setting but none has emerged as significantly more effective than the others. Topotecan has recently been shown to be superior to BSC and is currently the only drug licensed in the second-line setting. Novel therapies are emerging and there is hope that these will improve prognosis for this unfortunate group of patients. In particular, inhibitors of prosurvival Bcl-2 proteins are currently entering the clinical arena and are an exciting prospect aimed at combating drug resistance in first- and second-line treatment for SCLC.


   AUTHOR CONTRIBUTIONS
Top
 Abstract
 Introduction
 Relapse After First-Line...
 Novel Agent-Based Clinical...
 Conclusion
 Author Contributions
References
 
Conception/Design: Dean A. Fennell

Manuscript writing: Jane L. Hurwitz; Paula Scullin, Francis McCoy


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 Abstract
 Introduction
 Relapse After First-Line...
 Novel Agent-Based Clinical...
 Conclusion
 Author Contributions
 References
 

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