Journal of Thoracic Oncology:
State of the Art: Concise Review
Current Status of Second-Line Treatment and Novel Therapies for Small Cell Lung Cancer
Tiseo, Marcello MD; Ardizzoni, Andrea MD
Oncologia Medica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
Disclosure: The authors declare no conflict of interest.
Address for correspondence: Marcello Tiseo, MD, Oncologia Medica, Azienda Ospedaliero-Universitaria, Parma, Via Gramsci 14, 43100 Parma, Italy. E-mail: firstname.lastname@example.org
Despite high response rates to first-line standard treatment, the great majority of patients with small cell lung cancer (SCLC) will relapse and succumb to their disease rather quickly. In the context of salvage therapy, symptom palliation and quality-of-life improvements, besides survival prolongation, are primary treatment endpoints. A variety of single-agent and multi-agent chemotherapy regimens have been tested with limited success in patients with recurrent SCLC. A number of combination regimens have demonstrated high response rates in second-line settings, but these can be considered only for patients with good performance status. Treatment outcome depends on many factors, including type of response to first-line therapy, treatment-free interval, and performance status. Currently, topotecan represents an effective, tolerable therapeutic option and is the only agent approved for this indication. The management of patients with recurrent disease remains an area of active research. This review provides an update of clinical research on second-line chemotherapy of SCLC and of recent results obtained with novel molecular targeted approaches in both first- and second-line therapy.
The incidence of small cell lung cancer (SCLC) is decreasing in the developed countries, now accounting for approximately 12% to 15% of all bronchogenic tumors, most likely because of changes in smoking habits.1
SCLC is an aggressive tumor with a high propensity for developing early regional and distant metastasis. It is regarded as highly sensitive to both chemotherapy and radiation. Nevertheless, the general perception is that only modest improvement in survival has been achieved during the last 20 years, particularly in the area of drug therapy. Worldwide, the currently accepted standard of care for previously untreated metastatic SCLC patients is combination chemotherapy including cisplatin or carboplatin and etoposide.2 These regimens are usually associated with a rapid objective response in 50% to 80% of patients. Nevertheless, complete responses are seen in a minority of patients, duration of response is short, and overall survival is still very dismal because of early occurrence of chemotherapy-resistant disease.3
GENERAL CONSIDERATIONS ABOUT SECOND-LINE TREATMENT OF SCLC
After the completion of first-line therapy, about 80% of limited-disease patients and virtually all patients with extensive-stage disease will develop disease relapse or progression. Prognosis of this clinical condition is extremely poor, and most of these patients have advanced age, various comorbidities, poor performance status, and numerous tumor-associated symptoms, making them unable to tolerate further aggressive chemotherapy.4,5 Furthermore, many first-line regimens are associated with cumulative toxicities, including nephrotoxicity, neuropathy, and bone marrow suppression; this may limit the possibility of delivering full-dose second-line treatment safely.
Until recently, only one study, published in the late 1980s, provided any evidence that second-line treatment might produce a survival benefit.6 In this British study, patients were randomized among four different chemotherapy strategies, including short (four courses) or long (eight courses) first-line chemotherapy, both followed by either no treatment at relapse or by second-line chemotherapy. The results of this pivotal trial suggest that second-line chemotherapy is beneficial in patients treated with short-term first-line therapy; this is what is currently used in standard practice.
Nevertheless, the final confirmation of the real efficacy of chemotherapy in second-line treatment of SCLC has been obtained only recently, with a registration randomized study of topotecan versus best supportive care (BSC).7 This study has clearly shown that single-agent chemotherapy is able to prolong survival and improve symptoms and quality of life, compared with no active chemotherapy treatment, even in patients with worse prognostic features.
Pretreatment variables that are able to predict clinical outcome in recurrent disease are less well defined than those of newly diagnosed patients.8 Retrospective studies have found a significantly higher probability of response for those patients who had treatment-free intervals of more than 2.6 months.9 The importance of the treatment-free interval is further emphasized by studies investigating the value of rechallenge chemotherapy at relapse. Patients with a longer treatment-free interval may still have a high probability of achieving a second response to the same chemotherapy used in first-line chemotherapy.10–13
Without further prospective testing, a distinction has been made, widely accepted within the oncology community, between patients with so-called sensitive disease: those with a response to first-line therapy and a treatment-free interval of 90 days; and those with resistant disease: those with no response to first-line treatment or relapse within 90 days.14 Nevertheless, it has to be stressed that this definition was designed many years ago and was based only on small, retrospective studies. It has not been further assessed in larger patient series, nor has it been validated in prospective studies. Recent studies with either single-agent chemotherapy7 or combination chemotherapy,15 showing no difference in outcome between sensitive and refractory patients, as classically defined, have put the reliability of this prognostic classification under discussion.
Despite more than 70 published studies of second-line therapy in SCLC, no particular treatment strategy has been clearly demonstrated to be superior to another, and to date, only one chemotherapy agent is registered specifically for this indication.
REINDUCTION THERAPY OR RECHALLENGE
The evidence in favor of the repetition of the same chemotherapy used during induction (reinduction or rechallenge therapy) is based on four old (1983–1988), small (6–37 patients) retrospective series (Table 1).10–13 Response rates, obtained with various regimens in patients with a wide range of treatment-free intervals, varied from 50% to 67%, which is not far from what is achieved in first-line chemotherapy and seems higher than that generally obtained with non-cross-resistant regimens in prospective studies (about 20%).14 Whether this high response rate is attributable simply to patient selection or to a true efficacy of this strategy in sensitive relapse remains uncertain. In fact, in one prospective phase II study of single-agent topotecan in relapsed SCLC, patients with disease-free intervals of more than 6 months obtained a response rate of 57%, similar to that obtained with combination reinduction chemotherapy.16 A final proof of the superiority of one strategy (reinduction) over the other (non-cross-resistant chemotherapy) will require a prospective randomized study, which is currently being planned.
CYCLOPHOSPHAMIDE, DOXORUBICIN, AND VINCRISTINE
Because most patients are induced with platinum-etoposide, a chemotherapy program based on cyclophosphamide, doxorubicin, and vincristine (CAV) to treat recurrent disease seems a logical option. Several nonrandomized studies, including nearly 200 patients overall, have reported objective responses in the order of 8% to 15%.17,18 The only available randomized study compared the CAV regimen with single-agent intravenous topotecan. Main efficacy parameters were similar for the two types of treatment, but topotecan seemed to provide greater symptom improvement than did CAV. Patients receiving topotecan experienced significant improvements in breathing difficulty, anorexia, fatigue, and daily activity, with less neutropenia.19 Nevertheless, symptom improvement was not a primary endpoint of this study, and it was not assessed with a validated instrument. In addition, this trial was not designed to prove noninferiority of one treatment over the other. Therefore, whether CAV and topotecan are truly equally effective remains to be proven definitively.
Most of the knowledge currently available on salvage treatment of SCLC is attributable to the development in this indication of a single drug, topotecan. Topotecan is a water-soluble, semisynthetic derivative of camptothecin that has a noncomplete, overlapping toxicity profile with other agents used in the treatment of SCLC. Topotecan has evidenced significant antitumor activity and symptom palliation in both chemo-sensitive and chemo-resistant SCLC.20
Topotecan is characterized by manageable, noncumulative myelosuppression and a generally favorable nonhematological safety profile. This drug is currently approved for the treatment of patients with SCLC who have failed or relapsed after first-line chemotherapy and who are not candidates for reinduction.
The clinical profile of topotecan has been established in several phase II studies16,21–23 and confirmed in randomized phase III trials (Table 2).7,19,24 In phase II studies, topotecan has demonstrated a response rate ranging from 11% to 31% in chemo-sensitive patients and from 2% to 7% in chemo-refractory ones, with median survival rates of 25 to 36 weeks and 16 to 21 weeks, respectively.16,21–23
The approval of topotecan in the United States and, subsequently, in Europe was based primarily on data from three phase III trials.7,19,24 One trial, as previously reported, compared intravenous topotecan with CAV.19 A second trial comparing oral versus intravenous topotecan found both formulations to be similarly well tolerated and effective in this patient population (median overall survival, 33.0 weeks versus 35.0 weeks).24 The better hematological toxicity profile suggests that oral topotecan may be a preferable therapeutic modality, especially for patients with poor performance status, offering greater ease of use for treating physicians and better convenience to patients.25,26 In the third trial, addition of oral topotecan to BSC was associated with a significant increase in median overall survival compared with BSC alone (25.9 weeks versus 13.9 weeks; p = 0.01).7 In addition, patients on topotecan had slower quality-of-life deterioration and greater symptom control. Interestingly, benefits in survival and quality of life were evident even in the worse patient subgroups, such as those with poor performance status and refractory disease.
Although the recommended starting dose of topotecan is 1.5 mg/m2 on days 1 through 5 of a 21-day cycle, advanced age, extensive pretreatment, prior platinum therapy, prior radiotherapy, and renal impairment are potential risk factors for increased myelosuppression during topotecan therapy.20 Lower-dose topotecan regimens have been evaluated in attempts to minimize hematological toxicity and to maintain the efficacy of topotecan in patients at higher risk. Results from these studies suggest that topotecan at doses of 1.0 to 1.25 mg/m2 on a 5-day schedule, or 1.25 to 1.5 mg/m2 on a 3-day schedule or weekly (4.0 mg/m2/week) schedules may be more appropriate for patients with associated risk factors.20,27
Reversible, nonoverlapping, nonhematological toxicities and in vitro antitumor synergy with platinum agents, taxanes, and topoisomerase II inhibitors may make topotecan an ideal candidate for use in combination with other chemotherapy agents. Topotecan was tested with cisplatin, either in first- or second-line treatment, and with other drugs. All of these combinations are feasible and active.20 Further investigations are needed to demonstrate an improved efficacy of topotecan-based combination regimens compared with single-agent treatment in the second-line setting.
OTHER CHEMOTHERAPY AGENTS
Several other agents, including paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan have been investigated as second-line treatments of SCLC (Table 2).5,14,28
Paclitaxel has been found to have a response rate of 20% to 29% in patients with refractory SCLC.29,30 It also has been studied within combination regimens (with carboplatin,31,32 doxorubicin,33,34 gemcitabine,35,36 or cisplatin and ifosfamide37) in phase II trials with relatively small numbers of patients with both sensitive and refractory disease. The data from these studies demonstrate that the different tested regimens were active (response rates from 25% to 73.5%) and well tolerated as salvage treatments in SCLC patients. The most impressive result, which would require confirmation in a larger patient population, is probably the 73% response rate achieved with the combination of paclitaxel and carboplatin in refractory SCLC.31
Docetaxel has been evaluated as monochemotherapy in this setting in a phase II trial, showing an activity of 25%.38 In addition, gemcitabine and vinorelbine also have shown single-agent activity in recurrent SCLC patients. Gemcitabine has been shown to have an overall response rate of 12% to 13% as a second-line treatment in two phase II studies,39,40 but a third trial has shown no response in either sensitive or resistant patients.41 The gemcitabine-irinotecan combination has been studied extensively. Five phase II trials have had conflicting results, reporting response rates ranging from 10% to 50% and having different conclusions, especially for refractory patients.42–46 Gemcitabine also has been tested in association with docetaxel47 and vinorelbine,48,49 with disappointing results, particularly in refractory disease. Activity of vinorelbine as a single agent has been reported to be 16% and 12.5% in two studies that had 25 and 24 SCLC relapsed patients, respectively.50,51
Response rates for irinotecan were similar to those of topotecan, both in patients with sensitive disease (30%) and in patients with refractory disease (less than 10%), with a median survival ranging from 5 to 7 months.52 CPT-11 also has demonstrated interesting activity when combined with etoposide, cisplatin, carboplatin, and ifosfamide.52
In summary, it can be concluded that most agents tested in the second-line treatment of SCLC have shown some degree of activity. Nevertheless, the uneven distribution of sensitive versus refractory patients in the various studies, and the lack of comparative trials, prevent any conclusions about the superiority of one agent over the other. More recently, new chemotherapy agents such as amrubicin and pemetrexed have been tested in the second-line treatment of SCLC.
Amrubicin is a completely synthetic 9-aminoanthracycline that functions as a topoisomerase II inhibitor. Two phase II studies with amrubicin in a Japanese population with previously treated SCLC have shown impressive results.53,54 The first study administered amrubicin at doses of 40 mg/m2 per day on days 1 through 3, with cycles repeated every 21 days for a total of four cycles. The primary endpoint was an objective response. To be eligible, patients must have received one or two previous chemotherapeutic regimens, with at least one regimen containing a platinum agent. Sixty patients were enrolled: 44 with chemo-sensitive disease and 16 with refractory disease. Interestingly, the response rate was around 50% in both sensitive and refractory patients. The overall median survival time was 11.2 months, with a 1-year survival rate of 44.1%.53 The second, smaller study by Kato and colleagues enrolled 35 patients who had received one or two previous chemotherapy regimens. These patients were given amrubicin at doses of 45 mg/m2 per day for 3 days. Thirty-four patients were evaluable, 24 of whom had sensitive relapses and 10 of whom had resistant relapses. Response to treatment was again similar in the two prognostic subgroups: 50% and 60% in the sensitive- and refractory-relapse patients, respectively. The overall survival rate was 9.2 months, with a 1-year survival rate of 26.5%.54 Although the efficacy of amrubicin is certainly impressive, particularly in the group of refractory patients, toxicity is also significant. Grade 3/4 neutropenia rate was 83% in the first study (febrile neutropenia occurred in 5%) and 97% in the second (febrile neutropenia occurred in 35%). Amrubicin is currently being developed in both first- and second-line SCLC treatment; in particular, a randomized phase III trial of amrubicin versus topotecan is planned in sensitive and refractory patients.
Pemetrexed, a multitargeted antifolate recently approved for use in mesothelioma and in second-line treatment of non-small cell lung cancer, does not seem to have much activity in SCLC. Data from two phase II studies of 43 patients (20 with chemo-sensitive disease and 23 with chemo-resistant disease) and 34 patients (22 with chemo-sensitive disease and 12 with chemo-resistant disease) who had received prior chemotherapy regimens were presented.55,56 In the first trial, 500 mg/m2 of pemetrexed was administered intravenously every 3 weeks, with vitamin supplementation and dexamethasone prophylaxis. Only two patients achieved partial responses, and two others demonstrated stable disease. The predetermined criteria for increasing the sample size to 96 patients were, therefore, not met.55 In the second trial, with pemetrexed in doses of 900 mg/m2 for a maximum of four courses, the response rate was too low (4.5% and 2.9% in sensitive and refractory patients, respectively) to recommend single-agent pemetrexed for second-line chemotherapy in the treatment of SCLC.56 Pemetrexed is not being developed further for second-line treatment, but a large noninferiority trial has been launched recently for first-line treatment.
Given the limited improvements obtained with last-generation chemotherapy agents in the treatment of SCLC, high priority is currently given to research of novel molecular target agents. Nevertheless, to date, no targeted therapies have been found to alter the clinical history of SCLC.57 In this section, the most promising agents and pivotal trials in the first- and in second-line treatment of SCLC patients are reviewed (Table 3).
Protein farnesylation is the covalent addition of a farnesyl (15-carbon) group to the cysteine residue located in several G-proteins involved in cell signaling, such as the Ras protein, which is crucial for membrane interaction. R115777 (Zarnestra) is an oral farnesyl transferase inhibitor that has been tested in a multicenter phase II trial in sensitive relapse SCLC patients.58 This agent has shown no significant activity as a single agent in second-line treatment, with remarkable renal toxicity.
c-Kit targeting was believed to be a promising biological therapeutic strategy, given the frequent overexpression (around 70% of cases) of this stem cell factor-binding tyrosine kinase receptor in SCLC. Imatinib mesylate, the prototype of c-Kit tyrosine kinase inhibitors, has been shown to produce in vitro growth inhibition of SCLC cell lines expressing c-Kit.59 In addition, this targeted therapy has been found active in patients with other c-Kit-positive tumors, such as GIST. Contrary to expectations, three phase II trials have not shown any activity of imatinib in SCLC patients.60–62 The most likely explanation for these findings lies in the subsequent observation that SCLC cells do not bear constitutive mutations in the target coding genes, as GIST and CML cells do.63
Unlike non-small cell lung cancer, SCLC tumors and cell lines do not express at all, or express in very small amounts, epidermal growth factor receptor (EGFR); consequently, the use of EGFR inhibitors (gefitinib, erlotinib) in SCLC has not been shown to be worthwhile.64 Nevertheless, gefitinib has been shown to inhibit EGFR signaling in SCLC cell lines that express the receptor even at a low level, suggesting the occasional presence of functional EGFR in SCLC.65 A phase II trial of gefitinib in patients with relapsed neuroendocrine tumors, in which 18 of 19 patients had SCLC, failed to demonstrate any responses.66 Nevertheless, two independent groups have reported two cases of response to gefitinib in never-smoker SCLC patients with EGFR mutation, suggesting that EGFR tyrosine kinase inhibitors may be a treatment option for a small subset of SCLC tumors that express functional EGFR.67,68
The mammalian target of rapamycin is a downstream mediator in the phosphoinositide 3-kinase/AKT signaling pathway, which plays a central role in regulating cellular growth and proliferation. There are several mammalian target of rapamycin inhibitors that have entered clinical trials, including CCI-779 (temsirolimus), which has demonstrated antitumor activity in a number of cancer models. Preliminary results of a randomized phase II trial of temsirolimus after induction chemotherapy for extended SCLC have been reported.69 Eighty-seven patients have been randomized to two dose levels of temsirolimus (25 or 250 mg) weekly until disease progression. The median progression-free survival and the median overall survival for all patients were 2.2 and 7.8 months, respectively, with a slight increase for the higher-dose arm (progression-free survival, 1.8 months versus 2.5 months; overall survival, 6.5 months versus 9 months).
Neoangiogenesis (evaluated through microvessel count) and overexpression of vascular endothelial growth factor are abundant in SCLC and are associated with poor prognosis.70 For this reason, SCLC is believed to be an ideal model for testing antiangiogenic drugs; in fact, most of these are being evaluated in clinical trials.
Thalidomide is known to possess both immunomodulatory and antiangiogenic properties. At a dosage of 100 to 500 mg/day, the main toxicities of thalidomide are fatigue, nausea, and vomiting. In a phase II trial, thalidomide (100 mg per day, for up to 2 years) was administered concomitantly to carboplatin plus etoposide in 25 SCLC patients, with evidence of objective responses in 68% of cases and a median overall survival of 10.2 months.71 As a maintenance treatment, thalidomide was studied in other two studies: one phase II and one phase III, respectively.72,73 In the first study, 30 patients with metastatic SCLC not progressing after first-line chemotherapy received 200 mg of thalidomide per day as maintenance therapy, starting 3 to 6 weeks after completion of chemotherapy.72 Toxicity was minimal; median survival from the time of initiation of induction chemotherapy was 12.8 months, with a median duration on thalidomide of 79 days. In the second study, thalidomide maintenance treatment was evaluated in a phase III trial by the Federation National de Centres de Lutte contra le Cancer Group in France.73 Ninety-two extensive-SCLC patients with performance status up to 2, age <70 years, were randomized to placebo or thalidomide (400 mg per day planned; reduced to 200 mg in half of the patients) starting after two cycles of induction treatment with cisplatin, cyclophosphamide, doxorubicin, and etoposide. Overall survival was 8.7 and 11.7 months for placebo and thalidomide, respectively (p = 0.03). A large, randomized UK trial has been recently closed; this should confirm or deny the role of thalidomide in SCLC.
Other antiangiogenic agents such as ZD6474 (oral inhibitor of tyrosine kinase activity of either EGFR and vascular endothelial growth factor receptor) and bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, are under phase II evaluation in SCLC.57 In particular, bevacizumab was tested as a maintenance therapy after carboplatin-irinotecan and radiotherapy in 57 patients with limited SCLC.74 Safety, response rate (80%), and survival (15 months) of chemoradiotherapy and then bevacizumab compare favorably with standard treatment for limited SCLC. Randomized studies to assess the role of bevacizumab in improving overall survival in SCLC are being planned.
Matrix metalloproteinases (MMPs) are a family of enzymes responsible for remodeling the extracellular matrix, which is important in tumor invasion, angiogenesis, and metastatic processes. In SCLC, increased expression of MMPs and their tissue inhibitors has been reported and has provided the rationale for clinical trials of synthetic MMP inhibitors.75 Research in this area has been stopped after the results of a phase III randomized trial of marimastat, a synthetic MMP inhibitor, versus placebo after induction chemotherapy for SCLC became available.76 This large trial (532 patients) demonstrated that the treatment with marimastat did not result in an improved survival (median time to progression of 4.3 months versus 4.4 months and median overall survival of 9.3 months versus 9.7 months for marimastat and placebo, respectively) and had a negative impact on quality of life. A similar outcome was obtained with another MMP inhibitor, BAY 12-9566 (tanomastat).57
ANTI-BCL-2 AND APOPTOSIS-INDUCTION THERAPIES
The majority of SCLC cell lines express the antiapoptotic protein bcl-2; this may represent one mechanism by which this tumor rapidly becomes resistant to chemotherapy. Suppression of bcl-2 levels through the use of G3139 (oblimersen), an antisense oligonucleotide complementary to the mRNA encoding bcl-2, might increase the antitumor efficacy of cytotoxic therapy. After being tested in two phase I trials in combination with paclitaxel (second line)77 and with carboplatin and etoposide (first line),78 respectively, oblimersen has been evaluated in a randomized phase II trial combined with carboplatin and etoposide versus chemotherapy alone in the first-line treatment of extensive-stage SCLC. Initial results demonstrate objective responses in 67% in the oblimersen arm, with a trend for a higher incidence of grade 4 toxicity. Final analyses of efficacy and toxicity data are awaited.79
Proteasome inhibitors target the 26S proteasome, a major component of the ubiquitin proteasome pathway responsible for intracellular protein degradation. Cancer overexpression of 26S proteasome results in accelerated degradation of regulatory proteins, leading to uncontrolled cell division. Inhibition of 26S proteasome leads to accumulation of these regulatory proteins, disruption of the cell cycle, and inhibition of cell growth. Among these mechanisms, breakdown inhibition of the inhibitory protein I-κB, which inhibits the nuclear factor-κB pathway,80 seems to be the most crucial one. Under stress conditions, including exposure to chemotherapy or ionizing radiation, I-κB is phosphorylated, prompting ubiquitination and degradation by the proteasome. This allows release of nuclear factor-κB, which activates transcription of a number of genes involved in a variety of cellular functions, such as growth factors, cytokines, antiapoptotic factors, and cell-adhesion molecules. Bortezomib (PS-341) has been the first proteasome inhibitor to be evaluated in clinical trials. In SCLC cell lines, bortezomib has been shown to reduce bcl-2 levels via inhibition of nuclear factor-κB activity, thereby inducing apoptosis.81 Nevertheless, in a phase II trial of single-agent bortezomib in platinum-pretreated extensive-stage SCLC patients, only one partial response was reported out of 57 evaluable patients.82 It has been suggested that a greater effect may be achieved if proteasome inhibition is combined with a proapoptotic trigger such as chemotherapy.
Numerous tumor cell-surface antigens have been identified as potential target for immunotherapy in SCLC. Bec2 (mitumomab) is an anti-idiotypic mouse IgG2b monoclonal antibody that mimics the ganglioside GD3 expressed on the surface of most SCLC tumors, combined with bacillus Calmette-Guérin as an immune adjuvant. The hypothesis is that active immunization could alter the natural history of the disease by eradicating micrometastases, thereby improving survival in patients with SCLC who have completed induction therapy. This approach has shown promising results in a pilot study83 and has been tested subsequently in a phase III European Organization for Research and Treatment of Cancer study (SILVA trial), in which 515 patients with limited SCLC were randomized to receive Bec2 or no treatment as maintenance after standard treatment.84 In this trial, vaccination with Bec2/bacillus Calmette-Guérin demonstrated no an impact on any outcome measure in patients with limited-disease SCLC after standard chemoradiation.
The tumor-suppressor gene p53 plays an essential role as a regulator of cell growth and differentiation, and it is mutated in 90% of SCLCs.85 Preclinical studies have shown that the induction of an anti-p53 cytotoxic T-lymphocyte response selectively kills tumor cells and spares normal cells.86 In a recently reported trial, 29 patients with extensive SCLC who had received induction chemotherapy were treated with a vaccine consisting of dendritic cells transduced with the full-length wild-type p53 gene delivered via an adenoviral vector.87 In this study, p53-specific T-cell responses were observed in 57% of patients. Nevertheless, only one objective clinical response was observed. Of note, the response rate to subsequent chemotherapy was 61.9% (75% of patients who developed a p53-specific response versus only 30% of p53 nonresponders; p = 0.08)—higher than that usually seen in the second-line setting. The precise mechanism behind this apparent effect is unclear and needs further elucidation.
BB-10901 is an immunoconjugate of the cytotoxic maytansinoid drug DM1, with a humanized version of the murine monoclonal antibody N901. It binds with strong affinity to the CD56 antibody, which is expressed in a variety of tumor types, including SCLC. On binding to CD56, the drug is internalized and DM-1 is released, inhibiting tubulin polymerization and, therefore, causing cell death. In preclinical studies, BB-10901 has shown marked efficacy against SCLC xenograft models, and in an ongoing phase II clinical trial it has shown two partial responses and another minor response in 10 patients with relapsed SCLC.88
Relapsed SCLC still represents a challenge, both for treating physicians and for oncology researchers. Although significant improvements in the quantity and quality of survival can be achieved with currently available treatments, the overall results remain largely unsatisfactory, and there is an obvious need for further advances. The interest among clinical oncologists and the pharmaceutical industry in such a tremendous disease seems to have diminished more so than has the number of SCLC cases. Setting up clinical trials assessing novel therapeutic strategies in SCLC is difficult compared with other tumor types, but doing so is absolutely necessary.
Topotecan is an important addition to our armamentarium for the treatment of relapsed SCLC, but it remains the only approved therapy after the failure of first-line chemotherapy. Although topotecan has demonstrated consistent, reproducible antitumor activity, which translates into survival extension and quality-of-life improvement, hematological toxicity and the 5-day intravenous schedule remain as problems. The availability of a topotecan oral formulation will partially overcome these limitations. In addition, the role of topotecan in combination regimens and in comparison with rechallenge therapy or other non-cross-resistant regimens has yet to be clarified. At any rate, the development of more effective, tolerable treatments remains an unmet medical need. Among the new chemotherapy agents under development, amrubicin deserves attention, given the promising activity demonstrated in preliminary studies.
Our progressive understanding of most crucial molecular events associated with SCLC progression increases the potential for the development of novel, more effective targeted agents. Maximizing the potential of these drugs and defining their role alongside traditional chemotherapy agents represents a current research priority. Nevertheless,, none of the biological agents tested have met the expectations so far. Recently, there has been some glimmer of hope that the antiangiogenic approach, which has allowed a significant step forward in other malignancies, might lead to improved outcomes in lung cancer patients with small cell histology. Recent data from newer agents belonging to this class allow some cautious optimism for future advances in the treatment of this complex and challenging disease.
1. 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. J Clin Oncol
2. Felip E, Stahel RA, Pavlidis N. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of small-cell lung cancer (SCLC). Ann Oncol
3. Thatcher N, Faivre-Finn C, Lorigan P. Management of small-cell lung cancer. Ann Oncol
4. Postmus PE, Smit EF. Treatment of relapsed small cell lung cancer. Semin Oncol
5. Glisson BS. Recurrent small cell lung cancer: update. Semin Oncol
6. Spiro SG, Souhami RL, Geddes DM, et al. Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign Trial. Br J Cancer
7. O'Brien MER, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol
8. Postmus PE. Second-line for small cell lung cancer: how-to-do-it? Lung Cancer
9. Giaccone G, Donadio M, Bonardi G, et al. Teniposide in the treatment of small cell lung cancer: the influence of prior chemotherapy. J Clin Oncol
10. Batist G, Ihde DC, Zabell A, et al. Small cell carcinoma of the lung: reinduction chemotherapy after late relapse. Ann Intern Med
11. Postmus PE, Berendsen HH, van Zandwijk N, et al. Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur J Cancer Clin Oncol
12. Giaccone G, Ferrati P, Donadio M, et al. Reinduction chemotherapy in small cell lung cancer. Eur J Cancer Clin Oncol
13. Vincent M, Evans B, Smith I. First-line chemotherapy rechallange after relapse in small cell lung cancer. Cancer Chemother Pharmacol
14. Huisman C, Postmus PE, Giaccone G, et al. Second-line chemotherapy and its evaluation in small cell lung cancer. Cancer Treat Rev
15. Ardizzoni A, Manegold C, Debruyne C, et al. European Organization for Research and Treatment of Cancer (EORTC) 08957 phase II study of topotecan in combination with cisplatin as second-line treatment of refractory and sensitive small cell lung cancer. Clin Cancer Res
16. Ardizzoni A, Hansen H, Dombernowsky P, et al. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol
17. Sculier JP, Klastersky J, Libert P, et al. Cyclophosphamide, doxorubicin and vincristine with amphotericin B in sonicated liposomes as salvage therapy for small cell lung cancer. Eur J Cancer
18. Shepherd FA, Evans WK, MacCormick R, et al. Cyclophosphamide, doxorubicin and vincristine in etoposide and cisplatin-resistant small-cell lung cancer. Cancer Treat Rep
19. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol
20. Ardizzoni A. Topotecan in the treatment of recurrent small cell lung cancer: an update. Oncologist
21. Eckardt JR, Gralla R, Palmer MC, et al. Topotecan (T) as second-line therapy in patients (Pts) with small cell lung cancer (SCLC): a phase II study [abstract]. Ann Oncol
22. Depierre A, von Pawel J, Hans K, et al. Evaluation of topotecan (Hycamtin™) in relapsed small cell lung cancer (SCLC). A multicentre phase II study [abstract]. Lung Cancer
23. von Pawel J, Gatzemeier U, Pujol J-L, et al. Phase II comparator study of oral versus intravenous topotecan in patients with chemosensitive small-cell lung cancer. J Clin Oncol
24. Eckardt JR, von Pawel J, Pujol J-L, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol
25. von Pawel J. The role of topotecan in treating small cell lung cancer: second-line treatment. Lung Cancer
26. Treat J, Huang CH, Lane SR, Levin J. Topotecan in the treatment of relapsed small cell lung cancer patients with poor performance status. Oncologist
27. Eckardt JR. Emerging role of weekly topotecan in recurrent small cell lung cancer. Oncologist
28. Chua YJ, Steer C, Yip D. Recent advances in management of small cell lung cancer. Cancer Treat Rev
29. Smit EF, Fokkema E, Biesma B, et al. A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer
30. Joos G, Schallier D, Pinson P, et al. Paclitaxel (PTX) as second line treatment in patients (pts) with small cell lung cancer (SCLC) refractory to carboplatin-etoposide: a multicenter phase II study [abstract]. Proc Am Soc Clin Oncol 2004;22:7211.
31. Groen HJM, Fokkema E, Biesma B, et al. Paclitaxel and carboplatin in the treatment of small-cell lung cancer patients resistant to cyclophosphamide, doxorubicin, and etoposide: a non-cross-resistant schedule. J Clin Oncol
32. Kakolyris S, Mavroudis D, Tsavaris N, et al. Paclitaxel in combination with carboplatin as salvage treatment in refractory small-cell lung cancer (SCLC): a multicenter phase II study. Ann Oncol
33. Sonpavde G, Ansari R, Walker P, et al. Phase II study of doxorubicin and paclitaxel as second-line chemotherapy of small-cell lung cancer (SCLC): a Hoosier Oncology Group Trial. Am J Clin Oncol
34. Garcia-Garcia Y, Montesinos J, Dalmau E, et al. Doxorubicin (D) and paclitaxel (P) as second-line chemotherapy (Ch) of small cell lung cancer (SCLC) [abstract]. Proc Am Soc Clin Oncol 2003;22:1263.
35. Domine M, Gonzales J, Larriba S, et al. Gemcitabine and paclitaxel as second line treatment in small-cell lung cancer (SCLC). A multicentric phase II study [abstract]. Proc Am Soc Clin Oncol 2001;20:1263.
36. Dongiovanni V, Buffoni L, Berruti A, et al. Second-line chemotherapy with weekly paclitaxel and gemcitabine in patients with small-cell lung cancer pretreated with platinum and etoposide: a single institution phase II trial. Cancer Chemother Pharmacol
37. Kosmas C, Tsavaris NB, Malamos NA, et al. Phase II study of paclitaxel, ifosfamide, and cisplatin as second-line treatment in relapsed small-cell lung cancer (SCLC). J Clin Oncol
38. Smith JF, Smith IE, Sessa C, et al. Activity of docetaxel (taxotere) in small cell lung cancer. Eur J Cancer
39. Van der Lee I, Smit EF, van Putten JW, et al. Single-agent gemcitabine in patients with resistant small-cell lung cancer. Ann Oncol
40. Masters GA, Declerck L, Blanke C, et al. Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol
41. Hoang T, Kim K, Jaslowski A, et al. Phase II study of second-line gemcitabine in sensitive or refractory small cell lung cancer. Lung Cancer
42. Castellano DE, Ciruelos E, Garcia-Ciron C, et al. Phase II trial of biweekly irinotecan plus gemcitabine combination in refractory or relapsed small-cell lung cancer (SCLC) [abstract]. Proc Am Soc Clin Oncol 2003;21:2710.
43. Domine M, Gonzalez Larriba JL, Garcia Gomez R, et al. CPT-11—gemcitabine for refractory or relapsed small cell lung cancer (SCLC). A Spanish multicentric phase II study [abstract]. Proc Am Soc Clin Oncol 2003;22: 2819.
44. Agelaki S, Syrigos K, Christophylakis C, et al. A multicenter phase II study of the combination of irinotecan and gemcitabine in previously treated patients with small-cell lung cancer. Oncology
45. Schuette W, Nagel S, Juergens S, et al. Phase II trial of gemcitabine/irinotecan in refractory or relapsed small-cell lung cancer. Clin Lung Cancer
46. Rocha-Lima CM, Herndon JE II, Lee ME, et al. Phase II trial of irinotecan/gemcitabine as second-line therapy for relapsed and refractory small-cell lung cancer: Cancer and Leukemia Group B Study 39902. Ann Oncol
47. Agelaki S, Veslemes M, Syrigos K, et al. A multicenter phase II study of the combination of gemcitabine and docetaxel in previously treated patients with small cell lung cancer. Lung Cancer
48. Hainsworth JD, Burris HA 3rd, Erland JB, et al. Combination chemotherapy with gemcitabine and vinorelbine in the treatment of patients with relapsed or refractory small cell lung cancer: a phase II trial of the Minnie Pearl Cancer Research Network. Cancer Invest
49. Rapti A, Agelidou A, Stergiou I, et al. Combination of vinorelbine plus gemcitabine in previously treated patients with small cell lung cancer: a multicentre phase II study. Lung Cancer
50. Fusure K, Kubota K, Kawahara M, et al. Phase II study of vinorelbine in heavily previously treated small cell lung cancer. Oncology
51. Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, et al. Phase II study of vinorelbine (navelbine) in previously treated small cell lung cancer patients. Eur J Cancer
52. Sandler A. Irinotecan therapy for small-cell lung cancer. Oncology (Williston Park)
53. Onada S, Masuda N, Seto T, et al. Phase II trial of amrubicin for treatment of refractory or relapsed small-cell lung cancer: Thoracic Oncology Research Group Study 0301. J Clin Oncol
54. Kato T, Nokihara H, Ohe N, et al. Phase II trial of amrubicin in patients with previously treated small cell lung cancer (SCLC) [abstract]. Proc Am Soc Clin Oncol 2006;24:7061.
55. Hanna N, Ansari R, Bhatia S, et al. Pemetrexed in patients with relapsed small cell lung cancer: a phase II study from the Hoosier Oncology Group [abstract]. Proc Am Soc Clin Oncol
56. Gronberg BH, Sundstrom S, Bremnes R, et al. A phase II study by the Norwegian Lung Cancer Group: pemetrexed as second-line chemotherapy in recurrent small-cell lung cancer [abstract]. Ann Oncol
57. Rossi A, Maione P, Colantuoni G, et al. The role of new targeted therapies in small-cell lung cancer. Crit Rev Oncol Hematol
58. Heymach JV, Johnson DH, Khuri FR, et al. Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer (SCLC). Ann Oncol
59. Krystal GW, Honsawek S, Litz J, et al. The selective tyrosine kinase inhibitor STI571 inhibits small cell lung cancer growth. Clin Cancer Res
60. Johnson BE, Fischer T, Fischer B, et al. Phase II study of imatinib in patients with small-cell lung cancer. Clin Cancer Res
61. Dy GK, Miller AA, Mandrekar SJ, et al. A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study. Ann Oncol
62. Krug LM, Crapanzano JP, Azzoli CG, et al. Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein. Cancer
63. Burger H, den Bakker MA, Stoter G, et al. Lack of c-kit exon 11 activating mutations in c-KIT/CD117-positive SCLC tumor specimens. Eur J Cancer
64. Haeder M, Rotsch M, Bepler G, et al. Epidermal growth factor receptor expression in human lung cancer cell lines. Cancer Res
65. Tanno S, Ohsaki Y, Nakanishi K, et al. Small cell lung cancer cells express EGFR and tyrosine phosphorylation of EGFR is inhibited by gefitinib. Oncol Rep
66. Moore AM, Einhorn LH, Estesb D, et al. Gefitinib in patients with chemo-sensitive and chemo-refractory relapsed small cell cancers: a Hoosier Oncology Group phase II trial. Lung Cancer
67. Okamoto I, Araki J, Suto R, et al. EGFR mutation in gefitinib-responsive small-cell lung cancer. Ann Oncol
68. Zakowski MF, Ladanyi M, Kris MG. EGFR mutations in small-cell lung cancers in patients who have never smoked. N Engl J Med
69. Pandya KJ, Levy DE, Hidalgo M, et al. A randomized, phase II ECOG trial of two dose levels of temsirolimus (CCI-779) in patients with extensive stage small cell lung cancer in remission after induction chemotherapy. A preliminary report [abstract]. Proc Am Soc Clin Oncol 2005;23:7005.
70. Stefanou D, Batistatou A, Arkoumani E, et al. Expression of vascular endothelial growth factor (VEGF) and association with microvessel density in small cell and non-small-cell lung carcinoma. Histol Histopathol
71. James LE, Lee AM. A phase II study of carboplatin/etoposide with thalidomide in small cell lung cancer (SCLC) [abstract]. Lung Cancer
72. Dowlati A, Subbiah S, Cooney M, et al. Phase II trial of thalidomide as maintenance therapy for extensive stage small cell lung cancer after response to chemotherapy. Lung Cancer
73. Pujol JL, Breton J, Gervais M, et al. A prospective randomized phase III, double-blind, placebo-controlled study of thalidomide in extended-disease SCLC patients after response to chemotherapy: an Intergroup Study FNCLCC Cleo04–IFCT 00-01 [abstract]. Proc Am Soc Clin Oncol 2006;24:7057.
74. Patton F, Spigel DR, Greco FA, et al. Irinotecan (I), carboplatin (C), and radiotherapy (RT) followed by maintenance bevacizumab (B) in the treatment (tx) of limited-stage small cell lung cancer (LS-SCLC): update of a phase II trial of the Minnie Pearl Cancer Research Network [abstract]. Proc Am Soc Clin Oncol
75. Michael M, Babic B, Khokha R, et al. Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer. J Clin Oncol
76. Shepherd FA, Giaccone G, Seymour L, et al. Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer. J Clin Oncol
77. Rudin CM, Otterson GA, Mauer AM, et al. A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemo-refractory small-cell lung cancer. Ann Oncol
78. Rudin CM, Kozloff M, Hoffman PC, et al. Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. J Clin Oncol
79. Rudin CM, Salgia R, Wang XF, et al. A randomized phase II study of carboplatin and etoposide (CE) with or without G3139 in patients with extensive stage small cell lung cancer (ES-SCLC) [abstract]. Proc Am Soc Clin Oncol 2005;23:7168.
80. Lara PN, Davies AM, Mack PC, et al. Proteasome inhibition with PS-431 (Bortezomib) in lung cancer therapy. Semin Oncol
81. Mortenson MM, Schlieman MG, Virudachalam S, et al. Reduction in BCL-2 levels by 26S proteasome inhibition with bortezomib is associated with induction of apoptosis in small cell lung cancer. Lung Cancer
82. Johl J, Chansky C, Lara PN Jr, et al. The proteasome inhibitor PS-341 (bortezomib) in platinum-treated extensive-stage small cell lung cancer (E-SCLC): a SWOG (0327) phase II trial [abstract]. Proc Am Soc Clin Oncol 2005;23:7047.
83. Grant SC, Kris MG, Houghton AN, Chapman PB. Long survival of patients with small cell lung cancer after adjuvant treatment with the anti-idiotypic antibody BEC2 plus Bacillus Calmette-Guerin. Clin Cancer Res
84. Giaccone G, Debruyne C, Felip E, et al. Phase III study of adjuvant vaccination with Bec2/Bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organization for Research and Treatment of Cancer 08971-08971B; Silva Study). J Clin Oncol
85. D'Amico D, Carbone D, Mitsudomi T, et al. High frequency of somatically acquired p53 mutations in small cell lung cancer cell lines and tumors. Oncogene
86. Ishida T, Chada S, Stipanov M, et al. Dendritic cells transduced with wild type p53 gene elicit potent antitumor immune responses. Clin Exp Immunol
87. Antonia SJ, Mirza N, Fricke I, et al. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin Cancer Res
88. Fossella F, McCann J, Tolcher A, et al. Phase II trial of BB-10901 (huN901-DM1) given weekly for four consecutive weeks every 6 weeks in patients with relapsed SCLC and CD56-positive small cell carcinoma [abstract]. Proc Am Soc Clin Oncol
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SCLC; Second-line; Target therapy
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