- Email: [email protected]
Chemotherapy for Advanced Stage Non-Small Cell Lung Cancer
Chemotherapy for Advanced Stage Non-Small Cell Lung Cancer Amir T. Fathi, MD, and Julie R. Brahmer, MD, MSc Non-small cell lung cancer (NSCLC) is a common, often fatal malignancy, and is most frequently diagnosed in the advanced stage. Systemic chemotherapy for advanced (Stage IIIB and IV), inoperable NSCLC has evolved over the course of the last few decades. Survival advantage was first noted with platinum chemotherapy, with ultimate development of platinum-containing doublet combinations, which have now become standard of care in the treatment of advanced NSCLC. Over the course of the last few years, multiple nonplatinum combinations have also been demonstrated to be efficacious, and the addition of bevacizumab to existing doublet regimens has improved outcomes in this population of patients. Maintenance regimens for advanced stage NSCLC are currently under extensive investigation. Clinical trials have also recently demonstrated increased efficacy for agents such as docetaxel and pemetrexed in the second line setting for refractory disease. Semin Thorac Cardiovasc Surg 20:210-216 © 2008 Elsevier Inc. All rights reserved. KEYWORDS non-small cell lung cancer, systemic therapy, advanced stage, combination chemotherapy
T
he majority of non-small cell lung cancers are diagnosed at advanced stages, either as inoperable stage III or stage IV malignancies. Stage IV non-small cell lung cancer (NSCLC), the cytotoxic treatments for which this article will attempt to outline and summarize, has a uniformly dismal prognosis and is considered incurable.1 The mainstay of treatment for this group of patients is systemic chemotherapy. Until the 1990s, the role of chemotherapy in advanced stage NSCLC was debatable. Treatments were often quite toxic and initial attempts at using alkylating chemotherapeutic agents actually adversely affected survival in patients.2 Beginning in the 1980s, platinum-based therapies were studied extensively in randomized trials and though response rates were often low, these treatment regimens did seem to improve symptom control and quality of life. Meta-analyses of these trials ultimately displayed a survival advantage in patients though these were often modest, with a median survival of 16 to 26 weeks and 1 year survival rates of about 15% to 25%.2
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. Address reprint requests to Julie R. Brahmer, MD, MSc, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, Room G94, 1650 Orleans Street, Baltimore, MD 21231-1000. E-mail: [email protected]
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1043-0679/08/$-see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semtcvs.2008.09.002
The low response rates achieved with first generation platinum-based regimens prompted a search for newer, more effective agents and combinations in the treatment of advanced stage NSCLC. The chemotherapeutic agents studied during this period were the taxanes, paclitaxel and docetaxel, the antimetabolite, gemcitabine, the topoisomerase I inhibitor, irinotecan, and a vinca alkaloid, vinorelbine. These single agents provided objective rates of 20% or higher in metaanalyses of phase II and III trials.2 Cisplatin or carboplatin in combination with these agents have become the standard of care. No one regimen has been found to be superior. However, the regimens differ in their administration schedules and toxicities.
Chemotherapy for Advanced NSCLC: Combination Regimens The eventual emergence of next generation combination regimens significantly impacted the standard of care for patients with NSCLC. Two randomized trials compared cisplatinbased doublets versus single agent cisplatin therapy. One trial demonstrated a higher response rate with a vinorelbine/ cisplatin combination as opposed to lone cisplatin (26% versus 12%) with a significant median overall survival advantage for the combination (8 months versus 6 months).3 The other trial compared gemcitabine and cisplatin with single agent
Chemotherapy for advanced stage NSCLC cisplatin and demonstrated a significant improvement in response rate with the use of the combination (30.4% versus 11.1%). Overall survival was also significantly improved for patients receiving the combination (9.1 months versus 7.6 months) in this phase III study.4 The above prompted two subsequent trials, one by the Eastern Cooperative Oncology Group (ECOG) and the other by the European Organization for Research and Treatment of Cancer (EORTC). These trials compared the then standard lung cancer combination of cisplatin and etoposide (cisplatin and teniposide in the EORTC trial) with the combination of cisplatin and a novel agent, paclitaxel. The ECOG trial noted superior survival in the paclitaxel based regimens, with a median survival of 9.9 months versus that of 7.6 months in patients who had received cisplatin and etoposide.5 The EORTC trial revealed a superior response rate of 41% versus 28% favoring the paclitaxel containing regimen but there was no difference in median survival between the two groups. This trial also noted that the paclitaxel/cisplatin arm demonstrated better palliation parameters.6 The above findings established cisplatin plus a novel agent as standard of care in patients with advanced stage NSCLC. Other randomized trials comparing novel agent/platinum combinations soon emerged. The Southwest Oncology Group (SWOG) randomized 408 patients with stage IIIB or IV NSCLC to study arms comparing vinorelbine and cisplatin versus paclitaxel and carboplatin. The two regimens were well tolerated and led to similar response rates, median survival times, and 1 year survival rates.7 A much more ambitious trial was conducted by ECOG comparing four doublet regimens, with the cisplatin/paclitaxel arm as the reference treatment arm. The three experimental treatment arms were cisplatin/gemcitabine, cisplatin/docetaxel, and carboplatin/ paclitaxel. Eligible patients were randomized to the four arms. No significant differences were found across these doublets in median survival, overall response rate, or 1 year survival rate. Time until progression of disease was longer in the cisplatin/gemcitabine arm but this was thought to be offset by increased renal toxicity. This finding was also possibly affected by differences in tumor assessment schedules between the arms. Differences in toxicity rates were seen among the groups, noted in comparison to the cisplatin/paclitaxel arm. First, patients in the cisplatin/gemcitabine arm exhibited significantly higher numbers of grade 3 and 4 anemia and thrombocytopenia but fewer numbers of febrile neutropenia. Overall, the carboplatin/paclitaxel arm exhibited a significantly lower total number of grade 3 and 4 toxicities, mainly fewer episodes of high grade nausea/vomiting and febrile neutropenia. All these regimens are now felt to be appropriate potential treatments for patients with advanced stage NSCLC. The fewer episodes of toxicity noted in the carboplatin/paclitaxel arm may suggest this regimen to be more appropriate in low performance status patients. In addition, the presence of a significant renal comorbidity may render cisplatin-based regimens less favorable in some patients.8 Docetaxel has also been studied in combination with platinum agents. The TAX 326 study group conducted a large multi-center phase III study, randomizing 1,218 patients
211 with advanced NSCLC to three arms: docetaxel and cisplatin (DC), docetaxel and carboplatin (DCb), and vinorelbine and cisplatin (VC). The DC arm demonstrated a significantly improved median survival time (11.3 months versus 10.1 months) and response rate (31.6% versus 24.5%) over the VC arm. There was no significant difference in survival or response rate between the DCb and VC arms. One- and 2-year survival rates were 46% versus 41% and 21% versus 14% in the DC and VC arms, respectively. This study managed to demonstrate that a docetaxel/platinum combination is an effective treatment alternative for first-line use in patients with advanced disease.9 A very recent phase III study by Scagliotti and coworkers assessed the combination of pemetrexed with cisplatin in first line therapy of advanced NSCLC. Pemetrexed, an inhibitor of multiple folate dependent enzymes, is already widely used as a second line option in NSCLC. This large study of 1,725 patients demonstrated that the combination of cisplatin and pemetrexed was noninferior to the cisplatin/gemcitabine doublet in the overall population (overall survival 10.3 months versus 10.3 months for the two groups). In addition, the patients in the pemetrexed/cisplatin arm experienced fewer grade 3 and 4 cytopenias and episodes of neutropenic fever. Interestingly, there were some notable differences in outcome in patients with specific histologies. The cisplatin/ pemetrexed combination was found to be superior in patients with adenocarcinoma (overall survival of 12.6 months versus 10.9 months) and large cell carcinoma (overall survival of 10.4 months versus 6.7 months). In contrast, the cisplatin/gemcitabine combination was superior in patients with squamous cell histologies (overall survival of 10.8 months versus 9.4 months). These results appear to indicate that pemetrexed and cisplatin is an effective and tolerable option in advanced NSCLC. It also suggests that certain doublet combinations appear to be more appropriate for specific histologies of NSCLC, and that the histologic type should be considered in the choice of treatment.10
Chemotherapy for Advanced NSCLC: Sequential and Maintenance Regimens Sequential therapies involving three agents have been studied in advanced NSCLC populations. One early phase II study evaluated 37 patients with advanced stage III and IV disease who were administered three cycles of carboplatin and gemcitabine, followed by three cycles of paclitaxel. The response rate was 31%, with two reported complete responses. The median survival time was 9.8 months, with a 1 year survival rate of 36%.11 In another phase II study, 40 patients received carboplatin and paclitaxel for two to four cycles, followed by docetaxel for four cycles. Although only a fraction of patients received docetaxel, the response rate was reported as 23.6%, median survival time was 6.7 months, and 1 year survival was 37.5%.12 A German multicenter randomized trial compared docetaxel and gemcitabine chemotherapy for six cycles (DG) with cisplatin and gemcitabine for three cycles followed by
A.T. Fathi and J.R. Brahmer
212 Table 1 Trials of Nonplatinum Doublet Regimens for the Treatment of Advanced NSCLC
Phase 1-year survival Overall response rate Median survival
Gemcitabine and Paclitaxel19
Gemcitabine and Docetaxel21
Irinotecan and Docetaxel22
Irinotecan and Docetaxel23
Gemcitabine and Vinorelbine25
III (509 patients) 41.4% 35.0%
III (317 patients) 38.0% 33.9%
II (39 patients) 42.2% 23.0%
II (108 patients) 40.0% 32.0%
III (503 patients) 31.0% 25.0%
9.8 months
10.0 months
10.8 months
11.5 months
8.0 months
docetaxel for three additional cycles (CG ¡ D). The CG ¡ D arm displayed a nonsignificant increase in the overall response rate versus the DG doublet arm; there were no differences in median survival.13 In recent years, the concept of maintenance therapy has been increasingly investigated in patients with advanced NSCLC. To date, the role for maintenance therapy has not been proven as large randomized trials have yet to demonstrate benefit from ongoing chemotherapy beyond three to six cycles. However, a few agents have yielded promising results as a maintenance option. A meta-analysis pooling data from multiple studies suggested that compared with historical controls, patients who had received maintenance paclitaxel on a weekly schedule had a significantly longer median survival time (75 weeks versus 58 weeks) and that this regimen was well tolerated.14 In another study by Fidias and coworkers, those patients who had responded to a regimen of carboplatin and gemcitabine were randomized to either docetaxel maintenance therapy or to docetaxel therapy only at the time of disease progression. Though only a small number of patients (n ⫽ 109) were assessed, response rates in the maintenance arm were significantly higher (42% versus 6%). Final survival results from this study are still pending.15 A phase III study evaluated gemcitabine as a maintenance agent, in which 352 patients with advanced NSCLC received cisplatin and gemcitabine for four cycles, and those who responded were randomized to maintenance gemcitabine versus BSC. The median time to progression was significantly longer in the maintenance arm (3.5 months versus 2 months) but no significant difference in overall survival was noted.16 The feasibility of this study however has helped prompt a larger clinical trial of maintenance gemcitabine, which is ongoing. Pemetrexed, an agent frequently employed in the second line setting for NSCLC, has also been recently investigated for maintenance therapy given its favorable toxicity profile.14
Nonplatinum-Based Double Agent Combinations in NSCLC Platinum-based combination chemotherapy has become standard treatment for good performance patients with advanced NSCLC. However, given the relatively high toxicity of platinum agents, especially cisplatin, studies have increasingly examined nonplatinum containing doublet regimens (Table 1). A phase II study assessed the activity and toxicity
profile of the gemcitabine and paclitaxel combination in 39 patients. The regimen was noted to be active, with an overall response rate of 38.2% and a reported median survival time of 148 days. Grade 3/4 neutropenia was noted in 43% of patients, however, and four died from treatment related causes. Other early phase studies also looked at this combination and have demonstrated response rates ranging from 24% to 47%, with acceptable toxicity profiles.17-19 Based on the above, the Hellenic Cooperative Oncology Group (HeCOG) enrolled a total of 509 patients in a Phase III study comparing the standard carboplatin and paclitaxel (PC) regimen to the nonplatinum doublet of gemcitabine and paclitaxel (PG). The overall survival time was similar in both groups, 10.4 months for those patients receiving PC and 9.8 months for those receiving PG. The higher observed response rate (35% versus 28%) in the PG group was not statistically significant. Toxicity was reported to be relatively mild and well-tolerated in both groups.19 The similar degree of activity and toxicity of the combined gemcitabine and paclitaxel therapy has prompted further studies of this and other nonplatinum combinations. A multicenter phase II Greek trial assessed the combination of docetaxel and gemcitabine in 51 patients with advanced NSCLC. The overall response rate was 37.5%, with a median survival time of 13 months, and a 1 year survival rate of 50.7%. The toxicity profile was acceptable, with a rather low incidence of hematologic toxicity.20 The same investigators conducted a randomized trial with 317 patients, comparing docetaxel and gemcitabine (DG) with docetaxel and cisplatin (DC). Preliminary results from this study revealed no differences in response rate, overall survival time, or 1 year survival rate. However, hematologic toxicity (grade 3/4 neutropenia) and gastrointestinal toxicities were significantly milder in the DG arm. The authors concluded that cisplatin was no longer a mandatory component of a doublet regimen for the treatment of advanced NSCLC.21 Another combination, docetaxel and irinotecan, was investigated by the Hellenic Oncology Research Group (HORG). This multicenter phase II study noted an overall response rate of 23%, a median survival time of 10.8 months, and a 1 year survival rate of 42.2% in a group of 39 patients with advanced NSCLC. The study also reported grade 4 neutropenia in 10.3% of patients and grade 4 diarrhea in 23.1% of patients.22 A Japanese group, following up on an earlier phase I trial of docetaxel and irinotecan with promising results, conducted a randomized phase II trial, comparing docetaxel and
Chemotherapy for advanced stage NSCLC
213
irinotecan (DI) with docetaxel and cisplatin (DC). There were no significant differences in overall response rate (32% for the DI arm and 37% for DC) or overall survival (46 weeks in the DI arm and 50 weeks in the DC arm). However, 1- and 2 year survival rates were lower in the DI arm (40% and 18%. respectively) versus the DC arm (47% and 25%, respectively) and though the toxicity profiles were different between the two groups, overall toxicity was not reduced in those patients receiving docetaxel and irinotecan, who experienced less grade IV neutropenia but more diarrhea and thrombocytopenia.23 From 1999 to 2001, multiple phase II studies looked at the nonplatinum combination of gemcitabine and vinorelbine (GV) and reported overall response rates that ranged from 26% to 59%, with median survival rates of 8 to 9 months.24 Multiple phase III trials followed. One was performed by an Italian group, which compared GV to the cisplatin/vinorelbine and cisplatin/gemcitabine combinations in patients with advanced NSCLC. This study found response rates and quality of life parameters for GV that were similar to the cisplatin based doublets. No significant differences were noted in overall survival.25 In summary, several nonplatinum-containing doublet regimens appear to have similar efficacy as their platinum-containing counterparts. They appear to be fairly well tolerated and the reported toxicity seems to be acceptable. As a result, they can now serve as alternatives for patients in whom the use of platinum may not be ideal, such as in certain poor performance or elderly populations.
Addition of Bevacizumab to Standard Doublet Therapy Angiogenesis is an important biological process underlying tumor growth and metastasis and malignant cells require a blood supply for oxygen and other factors needed for growth and spread. Early studies have shown that tumors require angiogenesis and an independent vascular system to grow beyond 2 mm. One of the key mediators of angiogenesis is vascular endothelial growth factor (VEGF), which activates a complex array of cell signals leading to angiogenesis and vasculogenesis. Bevacizumab is a humanized monoclonal antibody against human VEGF, which effectively inhibited tumor growth and metastasis in preclinical studies. It appears to partly exert a direct antiangiogenic
effect by binding to and clearing VEGF from the tumor microenvironment but also seems to exert additional effects on tumor vasculature, interstitial pressure, and blood vessel permeability, leading to improved chemotherapy delivery to the malignant cells.26-28 In NSCLC, an earlier randomized phase II trial compared carboplatin and paclitaxel with or without bevacizumab in 99 patients with advanced malignancy. The addition of bevacizumab led to a higher response rate of 31.5% versus 18.8% and modestly improved overall median survival (17.7 months versus 14.9 months). This study also looked at two different doses of bevacizumab, 7.5 mg/kg and 15 mg/kg, and found a slightly higher response rate in the higher-dose group (31.5%) versus the lower-dose group (28.1%), a longer median time to progression (7.4 months versus 4.3 months), and improved median survival (17.7 months versus 11.6 months). The incidence of bleeding and hemoptysis was increased in the bevacizumab arms, with major hemoptysis largely associated with squamous cell histology, tumor necrosis and cavitation, as well as tumor location close to major vessels.28 A much larger, multicenter, phase III study (ECOG 4599) followed, enrolling 878 patients with advanced or recurrent NSCLC, again comparing carboplatin and paclitaxel with or without bevacizumab at a dose of 15 mg/kg. The results of the earlier phase II study were confirmed, with bevacizumab significantly improving response rates (35% versus 15%) and providing an overall survival advantage (12.3 months versus 10.3 months). Although squamous cell histologies were excluded from this trial, a significant increase in bleeding and pulmonary hemorrhage was again noted in the bevacizumab-containing arm, with five therapy-related deaths due to pulmonary hemorrhage.29 A second phase III study, the Avastin in Lung Cancer (AVAiL) trial, evaluated bevacizumab in combination with cisplatin and gemcitabine. The study excluded squamous cell histologies and tumors abutting major vessels. Again, two different doses of bevacizumab were studied (7.5 mg/kg and 15 mg/ kg) and the addition of either dose significantly improved progression free survival and overall response rate (34.1% and 30.4%, respectively, versus 20.1% in the nonbevacizumab containing arm). This now has raised further questions regarding which dose of bevacizumab is appropriate in combination with doublet therapy. The data regarding overall survival time, a secondary endpoint in this study, are still pending.30
Table 2 Addition of Bevacizumab to Combination Therapy of NSCLC Phase II (Johnson et al, 2004)28 Number Arms Overall response rate Median survival
Phase III (ECOG 4599)
Phase III (AVAiL)
18.8%
99 patients CP Plus B7.5 28.1%
CP Plus B15 31.5%
878 patients CP Plus B15 15.0% 35.0%
1043 patients CG Plus CG Plus B7.5 B15 20.1% 34.1% 30.4%
14.9 months
11.6 months
17.7 months
10.3 months
Pending
CP
CP
12.3 months
CG
Pending
CP, carboplatin and paclitaxel; CG, cisplatin and gemcitabine; B7.5, bevacizumab at 7.5 mg/kg; B15, bevacizumab at 15 mg/kg.
Pending
214 Based on the above phase II and III studies (Table 2), bevacizumab has been approved for use in combination with platinum-based doublet regimens in the treatment of advanced NSCLC. Patients with recent hemoptysis or squamous cell cancers should not be treated with bevacizumab, given the risks and complications detailed above. It is also contraindicated in patients with untreated CNS metastases. Other possible side effects and complications to consider are hypertension (including hypertensive emergencies), proteinuria, poor wound healing, and arterial thromboembolism. Therefore, caution is advised in patients with a history of thrombus, uncontrolled hypertension, and renal insufficiency. In addition, bevacizumab should not be initiated at least until 28 days following a major surgery or until the wound is felt to be completely healed.26
Chemotherapy in the Elderly Systemic chemotherapy in older patients with advanced NSCLC can be challenging, given the toxicity profile of platinum-based combination therapies. In this regard, several trials have looked at the single agent vinorelbine in elderly patient populations (aged 70 and over). A small phase II Italian study suggested that this regimen was well-tolerated and provided a response rate of 23%.31 A large multicenter study followed, conducted by the Elderly Lung Cancer Vinorelbine Italian Study Group (ELVIS), comparing single agent vinorelbine with BSC. This study noted an increase in overall survival (28 weeks versus 21 weeks), and an improvement in the 1 year survival rate (32% versus 14%) with single agent vinorelbine. Those patients on the vinorelbine arm also scored better on quality of life parameters and reported less cancer-related symptoms.32 A randomized phase III trial, conducted by the Southern Italy Cooperative Oncology Group (SICOG), compared the combination of gemcitabine/ vinorelbine with single-agent vinorelbine in a similar elderly population of 120 patients. The combination arm demonstrated a significantly better median survival (7.3 months versus 4.5 months) and overall response rates (22% versus 15%). The quality of life parameters worsened further in the single agent arm versus the combination arm.33 However, results somewhat differed in another, larger trial, the Multicenter Italian Lung Cancer in the Elderly Study (MILES). This study randomized 698 elderly patients to three arms: single agent vinorelbine, single agent gemcitabine, and the combination of vinorelbine and gemcitabine. The combination regimen did not improve survival and did appear to result in a greater incidence of toxicity, such as thrombocytopenia, hepatic toxicity, neutropenia, vomiting, fatigue, cardiac toxicity, and constipation than the single agent arms.34 These results suggest that the single agent vinorelbine is well tolerated and improves survival, compared with BSC, in older patients with advanced NSCLC. However, the SICOG analysis appears to indicate that the combination regimen is also an option, though the possible cost of increased toxicity needs to be considered, especially in the elderly.
A.T. Fathi and J.R. Brahmer
Chemotherapy for Progressive or Relapsed Disease Until only recently, no single agent or combination therapies had shown any convincing survival benefit in the second line setting for advanced NSCLC. Most studies, using a variety of chemotherapeutic agents, demonstrated response rates of less than 10% and median survival times of 4 months or less. The lone exception was docetaxel, which in phase II studies resulted in response rates of 15% to 22% and median survival times of 5.8 months to 11 months.35 In a randomized phase III trial, a total of 373 patients were randomized to receive docetaxel 100 mg/m2 (D100), docetaxel 75 mg/m2 (D75) versus a control regimen of vinorelbine or ifosfamide (V/I). The overall response rates were significantly higher in the docetaxel arms (10.8% and 6.7% for the D100 and D75 arms, respectively, versus 0.8% with V/I). Time to progression was also longer in the docetaxel arms of the study. Overall survival was not different between the three groups but the 1 year survival rate was greatest in the D75 arm (32%), which was significantly greater than that noted in the V/I arm (19%). Of note, 77% of patients in the D100 arm experienced grade 4 neutropenia compared with 54% in the D75 arm and 31% in the V/I arm.35 Another phase III trial investigating docetaxel randomized 103 patients to three arms: D100, D75, and best supportive care (BSC); 7.1% of the treated patients had a response to chemotherapy. Time to progression was longer for the docetaxel patients (10.7 weeks versus 6.7 weeks for BSC). Also, overall median survival time was improved in the docetaxel arms (7.0 months versus 4.6 months) and this was even more significant in the D75 arm (7.5 months versus 4.6 months). Grade 4 neutropenia was more pronounced in the D100 arm.36 Based on these important results, it was deemed that docetaxel at a dose of 75 mg/m2 should be used in the second line setting for NSCLC patients with an acceptable functional status who have progressed through first line platinum-based therapies. Another agent recently approved for second line use in NSCLC is pemetrexed. Pemetrexed is an antifolate compound targeting multiple enzymes and pathways in folate metabolism. Its main target is thymidylate synthase, critical for the synthesis of purine nucleotides and thymidine.37 An initial phase II trial of pemetrexed in advanced stage NSCLC accrued 33 patients and reported an overall response rate of 23.3%, with no complete responses. The median survival time of all patients was 9.2 months and the 1-year survival rate was 25.3%.38 Another phase II trial assessed the role of pemetrexed in the second line setting. The response rate for all 79 patients was reported as 8.9%, with a higher response rate (14.1%) in patients not pretreated with platinum agents and a lower one (4.5%) in those previously treated with platinum agents. The median survival time for all patients was 5.7 months. The main toxicities were hematologic, with 35% patients developing grade 3/4 neutropenia.39 A subsequent multinational phase III study comparing pemetrexed and docetaxel in 571 previously treated NSCLC patients demon-
Chemotherapy for advanced stage NSCLC strated statistically similar response rates, progression free survival, median survival, and 1 year survival rates. However, patients receiving docetaxel were more likely to experience grade 3/4 neutropenia and related complications.40 Because of this noninferiority to docetaxel, pemetrexed has also been accepted as a second line option in the treatment of NSCLC. In summary, after many years of disappointing results in the second line setting, multiple agents are now available for NSCLC patients who progress through first line therapy. These include docetaxel and pemetrexed. Erlotinib, a targeted EGFR tyrosine kinase inhibitor, has also been approved in this setting and will be discussed in an accompanying review on targeted therapies.
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Conclusions In conclusion, lung cancer is among the most common and fatal malignancies. Its treatment has evolved greatly over the last three decades. Initial chemotherapeutic approaches to advanced NSCLC yielded disappointing results. However, starting in the 1980s, platinum-based combinations improved response rates and survival. More recently, novel nonplatinum-based combinations and the addition of bevacizumab have added to the armamentarium of therapies. Older patients who may not tolerate standard platinumbased combinations have been shown to benefit from single agent chemotherapy. Finally, options for second line therapy are also expanding, with promising agents in this setting, such as docetaxel and pemetrexed.
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cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small cell lung cancer. J Clin Oncol 26:3543-3551, 2008 Edelman MJ, Gandara DR, Lau DHM, et al: Sequential combination chemotherapy in patients with advanced nonsmall cell lung carcinoma: carboplatin and gemcitabine followed by paclitaxel. Cancer 92:146152, 2001 Chiappori A, Simon G, Williams C, et al: Phase II study of first-line sequential chemotherapy with gemcitabine-carboplatin followed by docetaxel in patients with advanced non-small cell lung cancer. Oncology 68:382-390, 2005 Binder D, Schweisfurth H, Grah, C, et al: Docetaxel/gemcitabine or cisplatin/gemcitabine followed by docetaxel in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC): results of a multicenter randomized phase II trial. Cancer Chemother Pharmacol 60:143-150, 2007 Ramalingam S, Belani C: Systemic chemotherapy for advanced nonsmall cell lung cancer: recent advances and future directions. The Oncologist 13:1-13, 2008 (suppl 1) Fidias P, Dakhil SR, Lyss AP, et al: Updated report of a phase III study of induction therapy with gemcitabine ⫹ carboplatin (GC) followed by either delayed vs. immediate second-line therapy with docetaxel (D) in advanced non-small cell lung cancer. J Clin Oncol 24:7032, 2006 (18 suppl) Brodowicz T, Krzakowski M, Zwitter M, et al: Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer 52:155-163, 2006 Bhatia S, Hanna N, Ansari R, et al: A phase II study of weekly gemcitabine and paclitaxel in patients with previously untreated stage IIIB and IV non-small cell lung cancer. Lung Cancer 38:73-77, 2002 Giaccone G, Smith EF, van Meerbeeck JP, et al: A phase I-II study of gemcitabine and paclitaxel in advanced non-small-cell lung cancer patients. Ann Oncol 11:109-112, 2000 Kosmidis P, Mylonakis N, Nicolaides C, et al: Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non small cell lung cancer: a phase III randomized trial. J Clin Oncol 20:3578-3585, 2002 Georgoulias V, Kouroussis C, Androulakis N, et al: Front-line treatment of advanced non-small cell lung cancer with docetaxel and gemcitabine: a multicenter phase II trial. J Clin Oncol 17:914-920, 1999 Georgoulias V, Samonis G, Papadakis E, et al: Comparison of docetaxel/ cisplatin to docetaxel/gemcitabine as first-line treatment of advanced non-small cell lung cancer: early results of a randomized trial. Lung Cancer 34:S47-S51, 2001 Ziotopoulos P, Androulakis N, Mylonaki E, et al: Front-line treatment of advanced non-small cell lung cancer with irinotecan and docetaxel: a multicenter phase II study. Lung Cancer 50:115-122, 2005 Yamamoto N, Fukuoka M, Negoro SI, et al: Randomized phase II study of docetaxel/cisplatin vs docetaxel/irinotecan in advanced non-small cell lung cancer: a west Japan thoracic oncology group study. Br J Cancer 90:87-92, 2004 Han JY, Lee DH, Song JE, et al: Randomized phase 2 study of irinotecan plus cisplatin versus gemcitabine plus vinorelbine as first-line chemotherapy with second-line crossover in patients with advanced nonsmall cell lung cancer. Cancer 113:388-395, 2008 Gridelli C, Gallo C, Shepherd FA, et al: Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21:3025-3034, 2003 Manegold C: Bevacizumab for the treatment of advanced non-small cell lung cancer. Expert Rev Anticancer Ther 8:689-699, 2008 Jain RK: Normalizing tumor vasculature with anti-agiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987-989, 2001 Johnson DH, Fehrenbacher L, Novotny WF, et al: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22:2184-2191, 2004
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216 29. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. New Engl J Med 355: 2542-2550, 2006 30. Manegold C, Von Pawel J, Zatloukal P, et al: Randomized, doubleblind, multicenter phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): BO17704. J Clin Oncol 25, 2007 (20 suppl) (abstract LBA 7514) 31. Gridelli C, Perrone F, Gallo C, et al: Vinorelbine is well tolerated and active in the treatment of elderly patients with advanced non-small cell lung cancer: a two-stage phase II study. Eur J Cancer 33:392-397, 1997 32. Gridelli C: The ELVIS trial: a phase III study of single-agent vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer. The Oncologist 6:4-7, 2001 (suppl 1) 33. Frasci G, Lorusso V, Panza N, et al: Gemcitabine plus vinorelbine yields better survival outcome than vinorelbine alone in elderly patients with advanced non-small cell lung cancer. A Southern Italy Cooperative Oncology Group (SICOG) phase III trial. Lung Cancer 34:S65-S69, 2001 34. Gridelli C, Perrone F, Gallo C, et al: Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung
35.
36.
37. 38.
39.
40.
Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 95:362-372, 2003 Fossella F, DeVore R, Kerr R, et al: Randomized phase-III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced nonsmall cell lung cancer previously treated with platinum containing chemotherapy regimens. J Clin Oncol 18:2354-2362, 2000 Shephard F, Dancey J, Ramlou R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 8:2095-2103, 2000 Stinchcombe TE, Socinski MA: Considerations for second-line therapy of non-small cell lung cancer. The Oncologist 13:28-36, 2008 (suppl 1) Rusthoven JJ, Eisenhauer E, Butts C, et al: Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced nonsmall cell lung cancer: a phase II study. J Clin Oncol 17:1194-1199, 1999 Smit EF, Mattson K, von Pawel J, et al: ALIMTA (pemetrexed disodium) as second-line treatment of non-small-cell lung cancer: a phase II study. Ann Oncol 14:455-460, 2003 Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589-1597, 2004
T
he majority of non-small cell lung cancers are diagnosed at advanced stages, either as inoperable stage III or stage IV malignancies. Stage IV non-small cell lung cancer (NSCLC), the cytotoxic treatments for which this article will attempt to outline and summarize, has a uniformly dismal prognosis and is considered incurable.1 The mainstay of treatment for this group of patients is systemic chemotherapy. Until the 1990s, the role of chemotherapy in advanced stage NSCLC was debatable. Treatments were often quite toxic and initial attempts at using alkylating chemotherapeutic agents actually adversely affected survival in patients.2 Beginning in the 1980s, platinum-based therapies were studied extensively in randomized trials and though response rates were often low, these treatment regimens did seem to improve symptom control and quality of life. Meta-analyses of these trials ultimately displayed a survival advantage in patients though these were often modest, with a median survival of 16 to 26 weeks and 1 year survival rates of about 15% to 25%.2
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. Address reprint requests to Julie R. Brahmer, MD, MSc, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, Room G94, 1650 Orleans Street, Baltimore, MD 21231-1000. E-mail: [email protected]
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1043-0679/08/$-see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semtcvs.2008.09.002
The low response rates achieved with first generation platinum-based regimens prompted a search for newer, more effective agents and combinations in the treatment of advanced stage NSCLC. The chemotherapeutic agents studied during this period were the taxanes, paclitaxel and docetaxel, the antimetabolite, gemcitabine, the topoisomerase I inhibitor, irinotecan, and a vinca alkaloid, vinorelbine. These single agents provided objective rates of 20% or higher in metaanalyses of phase II and III trials.2 Cisplatin or carboplatin in combination with these agents have become the standard of care. No one regimen has been found to be superior. However, the regimens differ in their administration schedules and toxicities.
Chemotherapy for Advanced NSCLC: Combination Regimens The eventual emergence of next generation combination regimens significantly impacted the standard of care for patients with NSCLC. Two randomized trials compared cisplatinbased doublets versus single agent cisplatin therapy. One trial demonstrated a higher response rate with a vinorelbine/ cisplatin combination as opposed to lone cisplatin (26% versus 12%) with a significant median overall survival advantage for the combination (8 months versus 6 months).3 The other trial compared gemcitabine and cisplatin with single agent
Chemotherapy for advanced stage NSCLC cisplatin and demonstrated a significant improvement in response rate with the use of the combination (30.4% versus 11.1%). Overall survival was also significantly improved for patients receiving the combination (9.1 months versus 7.6 months) in this phase III study.4 The above prompted two subsequent trials, one by the Eastern Cooperative Oncology Group (ECOG) and the other by the European Organization for Research and Treatment of Cancer (EORTC). These trials compared the then standard lung cancer combination of cisplatin and etoposide (cisplatin and teniposide in the EORTC trial) with the combination of cisplatin and a novel agent, paclitaxel. The ECOG trial noted superior survival in the paclitaxel based regimens, with a median survival of 9.9 months versus that of 7.6 months in patients who had received cisplatin and etoposide.5 The EORTC trial revealed a superior response rate of 41% versus 28% favoring the paclitaxel containing regimen but there was no difference in median survival between the two groups. This trial also noted that the paclitaxel/cisplatin arm demonstrated better palliation parameters.6 The above findings established cisplatin plus a novel agent as standard of care in patients with advanced stage NSCLC. Other randomized trials comparing novel agent/platinum combinations soon emerged. The Southwest Oncology Group (SWOG) randomized 408 patients with stage IIIB or IV NSCLC to study arms comparing vinorelbine and cisplatin versus paclitaxel and carboplatin. The two regimens were well tolerated and led to similar response rates, median survival times, and 1 year survival rates.7 A much more ambitious trial was conducted by ECOG comparing four doublet regimens, with the cisplatin/paclitaxel arm as the reference treatment arm. The three experimental treatment arms were cisplatin/gemcitabine, cisplatin/docetaxel, and carboplatin/ paclitaxel. Eligible patients were randomized to the four arms. No significant differences were found across these doublets in median survival, overall response rate, or 1 year survival rate. Time until progression of disease was longer in the cisplatin/gemcitabine arm but this was thought to be offset by increased renal toxicity. This finding was also possibly affected by differences in tumor assessment schedules between the arms. Differences in toxicity rates were seen among the groups, noted in comparison to the cisplatin/paclitaxel arm. First, patients in the cisplatin/gemcitabine arm exhibited significantly higher numbers of grade 3 and 4 anemia and thrombocytopenia but fewer numbers of febrile neutropenia. Overall, the carboplatin/paclitaxel arm exhibited a significantly lower total number of grade 3 and 4 toxicities, mainly fewer episodes of high grade nausea/vomiting and febrile neutropenia. All these regimens are now felt to be appropriate potential treatments for patients with advanced stage NSCLC. The fewer episodes of toxicity noted in the carboplatin/paclitaxel arm may suggest this regimen to be more appropriate in low performance status patients. In addition, the presence of a significant renal comorbidity may render cisplatin-based regimens less favorable in some patients.8 Docetaxel has also been studied in combination with platinum agents. The TAX 326 study group conducted a large multi-center phase III study, randomizing 1,218 patients
211 with advanced NSCLC to three arms: docetaxel and cisplatin (DC), docetaxel and carboplatin (DCb), and vinorelbine and cisplatin (VC). The DC arm demonstrated a significantly improved median survival time (11.3 months versus 10.1 months) and response rate (31.6% versus 24.5%) over the VC arm. There was no significant difference in survival or response rate between the DCb and VC arms. One- and 2-year survival rates were 46% versus 41% and 21% versus 14% in the DC and VC arms, respectively. This study managed to demonstrate that a docetaxel/platinum combination is an effective treatment alternative for first-line use in patients with advanced disease.9 A very recent phase III study by Scagliotti and coworkers assessed the combination of pemetrexed with cisplatin in first line therapy of advanced NSCLC. Pemetrexed, an inhibitor of multiple folate dependent enzymes, is already widely used as a second line option in NSCLC. This large study of 1,725 patients demonstrated that the combination of cisplatin and pemetrexed was noninferior to the cisplatin/gemcitabine doublet in the overall population (overall survival 10.3 months versus 10.3 months for the two groups). In addition, the patients in the pemetrexed/cisplatin arm experienced fewer grade 3 and 4 cytopenias and episodes of neutropenic fever. Interestingly, there were some notable differences in outcome in patients with specific histologies. The cisplatin/ pemetrexed combination was found to be superior in patients with adenocarcinoma (overall survival of 12.6 months versus 10.9 months) and large cell carcinoma (overall survival of 10.4 months versus 6.7 months). In contrast, the cisplatin/gemcitabine combination was superior in patients with squamous cell histologies (overall survival of 10.8 months versus 9.4 months). These results appear to indicate that pemetrexed and cisplatin is an effective and tolerable option in advanced NSCLC. It also suggests that certain doublet combinations appear to be more appropriate for specific histologies of NSCLC, and that the histologic type should be considered in the choice of treatment.10
Chemotherapy for Advanced NSCLC: Sequential and Maintenance Regimens Sequential therapies involving three agents have been studied in advanced NSCLC populations. One early phase II study evaluated 37 patients with advanced stage III and IV disease who were administered three cycles of carboplatin and gemcitabine, followed by three cycles of paclitaxel. The response rate was 31%, with two reported complete responses. The median survival time was 9.8 months, with a 1 year survival rate of 36%.11 In another phase II study, 40 patients received carboplatin and paclitaxel for two to four cycles, followed by docetaxel for four cycles. Although only a fraction of patients received docetaxel, the response rate was reported as 23.6%, median survival time was 6.7 months, and 1 year survival was 37.5%.12 A German multicenter randomized trial compared docetaxel and gemcitabine chemotherapy for six cycles (DG) with cisplatin and gemcitabine for three cycles followed by
A.T. Fathi and J.R. Brahmer
212 Table 1 Trials of Nonplatinum Doublet Regimens for the Treatment of Advanced NSCLC
Phase 1-year survival Overall response rate Median survival
Gemcitabine and Paclitaxel19
Gemcitabine and Docetaxel21
Irinotecan and Docetaxel22
Irinotecan and Docetaxel23
Gemcitabine and Vinorelbine25
III (509 patients) 41.4% 35.0%
III (317 patients) 38.0% 33.9%
II (39 patients) 42.2% 23.0%
II (108 patients) 40.0% 32.0%
III (503 patients) 31.0% 25.0%
9.8 months
10.0 months
10.8 months
11.5 months
8.0 months
docetaxel for three additional cycles (CG ¡ D). The CG ¡ D arm displayed a nonsignificant increase in the overall response rate versus the DG doublet arm; there were no differences in median survival.13 In recent years, the concept of maintenance therapy has been increasingly investigated in patients with advanced NSCLC. To date, the role for maintenance therapy has not been proven as large randomized trials have yet to demonstrate benefit from ongoing chemotherapy beyond three to six cycles. However, a few agents have yielded promising results as a maintenance option. A meta-analysis pooling data from multiple studies suggested that compared with historical controls, patients who had received maintenance paclitaxel on a weekly schedule had a significantly longer median survival time (75 weeks versus 58 weeks) and that this regimen was well tolerated.14 In another study by Fidias and coworkers, those patients who had responded to a regimen of carboplatin and gemcitabine were randomized to either docetaxel maintenance therapy or to docetaxel therapy only at the time of disease progression. Though only a small number of patients (n ⫽ 109) were assessed, response rates in the maintenance arm were significantly higher (42% versus 6%). Final survival results from this study are still pending.15 A phase III study evaluated gemcitabine as a maintenance agent, in which 352 patients with advanced NSCLC received cisplatin and gemcitabine for four cycles, and those who responded were randomized to maintenance gemcitabine versus BSC. The median time to progression was significantly longer in the maintenance arm (3.5 months versus 2 months) but no significant difference in overall survival was noted.16 The feasibility of this study however has helped prompt a larger clinical trial of maintenance gemcitabine, which is ongoing. Pemetrexed, an agent frequently employed in the second line setting for NSCLC, has also been recently investigated for maintenance therapy given its favorable toxicity profile.14
Nonplatinum-Based Double Agent Combinations in NSCLC Platinum-based combination chemotherapy has become standard treatment for good performance patients with advanced NSCLC. However, given the relatively high toxicity of platinum agents, especially cisplatin, studies have increasingly examined nonplatinum containing doublet regimens (Table 1). A phase II study assessed the activity and toxicity
profile of the gemcitabine and paclitaxel combination in 39 patients. The regimen was noted to be active, with an overall response rate of 38.2% and a reported median survival time of 148 days. Grade 3/4 neutropenia was noted in 43% of patients, however, and four died from treatment related causes. Other early phase studies also looked at this combination and have demonstrated response rates ranging from 24% to 47%, with acceptable toxicity profiles.17-19 Based on the above, the Hellenic Cooperative Oncology Group (HeCOG) enrolled a total of 509 patients in a Phase III study comparing the standard carboplatin and paclitaxel (PC) regimen to the nonplatinum doublet of gemcitabine and paclitaxel (PG). The overall survival time was similar in both groups, 10.4 months for those patients receiving PC and 9.8 months for those receiving PG. The higher observed response rate (35% versus 28%) in the PG group was not statistically significant. Toxicity was reported to be relatively mild and well-tolerated in both groups.19 The similar degree of activity and toxicity of the combined gemcitabine and paclitaxel therapy has prompted further studies of this and other nonplatinum combinations. A multicenter phase II Greek trial assessed the combination of docetaxel and gemcitabine in 51 patients with advanced NSCLC. The overall response rate was 37.5%, with a median survival time of 13 months, and a 1 year survival rate of 50.7%. The toxicity profile was acceptable, with a rather low incidence of hematologic toxicity.20 The same investigators conducted a randomized trial with 317 patients, comparing docetaxel and gemcitabine (DG) with docetaxel and cisplatin (DC). Preliminary results from this study revealed no differences in response rate, overall survival time, or 1 year survival rate. However, hematologic toxicity (grade 3/4 neutropenia) and gastrointestinal toxicities were significantly milder in the DG arm. The authors concluded that cisplatin was no longer a mandatory component of a doublet regimen for the treatment of advanced NSCLC.21 Another combination, docetaxel and irinotecan, was investigated by the Hellenic Oncology Research Group (HORG). This multicenter phase II study noted an overall response rate of 23%, a median survival time of 10.8 months, and a 1 year survival rate of 42.2% in a group of 39 patients with advanced NSCLC. The study also reported grade 4 neutropenia in 10.3% of patients and grade 4 diarrhea in 23.1% of patients.22 A Japanese group, following up on an earlier phase I trial of docetaxel and irinotecan with promising results, conducted a randomized phase II trial, comparing docetaxel and
Chemotherapy for advanced stage NSCLC
213
irinotecan (DI) with docetaxel and cisplatin (DC). There were no significant differences in overall response rate (32% for the DI arm and 37% for DC) or overall survival (46 weeks in the DI arm and 50 weeks in the DC arm). However, 1- and 2 year survival rates were lower in the DI arm (40% and 18%. respectively) versus the DC arm (47% and 25%, respectively) and though the toxicity profiles were different between the two groups, overall toxicity was not reduced in those patients receiving docetaxel and irinotecan, who experienced less grade IV neutropenia but more diarrhea and thrombocytopenia.23 From 1999 to 2001, multiple phase II studies looked at the nonplatinum combination of gemcitabine and vinorelbine (GV) and reported overall response rates that ranged from 26% to 59%, with median survival rates of 8 to 9 months.24 Multiple phase III trials followed. One was performed by an Italian group, which compared GV to the cisplatin/vinorelbine and cisplatin/gemcitabine combinations in patients with advanced NSCLC. This study found response rates and quality of life parameters for GV that were similar to the cisplatin based doublets. No significant differences were noted in overall survival.25 In summary, several nonplatinum-containing doublet regimens appear to have similar efficacy as their platinum-containing counterparts. They appear to be fairly well tolerated and the reported toxicity seems to be acceptable. As a result, they can now serve as alternatives for patients in whom the use of platinum may not be ideal, such as in certain poor performance or elderly populations.
Addition of Bevacizumab to Standard Doublet Therapy Angiogenesis is an important biological process underlying tumor growth and metastasis and malignant cells require a blood supply for oxygen and other factors needed for growth and spread. Early studies have shown that tumors require angiogenesis and an independent vascular system to grow beyond 2 mm. One of the key mediators of angiogenesis is vascular endothelial growth factor (VEGF), which activates a complex array of cell signals leading to angiogenesis and vasculogenesis. Bevacizumab is a humanized monoclonal antibody against human VEGF, which effectively inhibited tumor growth and metastasis in preclinical studies. It appears to partly exert a direct antiangiogenic
effect by binding to and clearing VEGF from the tumor microenvironment but also seems to exert additional effects on tumor vasculature, interstitial pressure, and blood vessel permeability, leading to improved chemotherapy delivery to the malignant cells.26-28 In NSCLC, an earlier randomized phase II trial compared carboplatin and paclitaxel with or without bevacizumab in 99 patients with advanced malignancy. The addition of bevacizumab led to a higher response rate of 31.5% versus 18.8% and modestly improved overall median survival (17.7 months versus 14.9 months). This study also looked at two different doses of bevacizumab, 7.5 mg/kg and 15 mg/kg, and found a slightly higher response rate in the higher-dose group (31.5%) versus the lower-dose group (28.1%), a longer median time to progression (7.4 months versus 4.3 months), and improved median survival (17.7 months versus 11.6 months). The incidence of bleeding and hemoptysis was increased in the bevacizumab arms, with major hemoptysis largely associated with squamous cell histology, tumor necrosis and cavitation, as well as tumor location close to major vessels.28 A much larger, multicenter, phase III study (ECOG 4599) followed, enrolling 878 patients with advanced or recurrent NSCLC, again comparing carboplatin and paclitaxel with or without bevacizumab at a dose of 15 mg/kg. The results of the earlier phase II study were confirmed, with bevacizumab significantly improving response rates (35% versus 15%) and providing an overall survival advantage (12.3 months versus 10.3 months). Although squamous cell histologies were excluded from this trial, a significant increase in bleeding and pulmonary hemorrhage was again noted in the bevacizumab-containing arm, with five therapy-related deaths due to pulmonary hemorrhage.29 A second phase III study, the Avastin in Lung Cancer (AVAiL) trial, evaluated bevacizumab in combination with cisplatin and gemcitabine. The study excluded squamous cell histologies and tumors abutting major vessels. Again, two different doses of bevacizumab were studied (7.5 mg/kg and 15 mg/ kg) and the addition of either dose significantly improved progression free survival and overall response rate (34.1% and 30.4%, respectively, versus 20.1% in the nonbevacizumab containing arm). This now has raised further questions regarding which dose of bevacizumab is appropriate in combination with doublet therapy. The data regarding overall survival time, a secondary endpoint in this study, are still pending.30
Table 2 Addition of Bevacizumab to Combination Therapy of NSCLC Phase II (Johnson et al, 2004)28 Number Arms Overall response rate Median survival
Phase III (ECOG 4599)
Phase III (AVAiL)
18.8%
99 patients CP Plus B7.5 28.1%
CP Plus B15 31.5%
878 patients CP Plus B15 15.0% 35.0%
1043 patients CG Plus CG Plus B7.5 B15 20.1% 34.1% 30.4%
14.9 months
11.6 months
17.7 months
10.3 months
Pending
CP
CP
12.3 months
CG
Pending
CP, carboplatin and paclitaxel; CG, cisplatin and gemcitabine; B7.5, bevacizumab at 7.5 mg/kg; B15, bevacizumab at 15 mg/kg.
Pending
214 Based on the above phase II and III studies (Table 2), bevacizumab has been approved for use in combination with platinum-based doublet regimens in the treatment of advanced NSCLC. Patients with recent hemoptysis or squamous cell cancers should not be treated with bevacizumab, given the risks and complications detailed above. It is also contraindicated in patients with untreated CNS metastases. Other possible side effects and complications to consider are hypertension (including hypertensive emergencies), proteinuria, poor wound healing, and arterial thromboembolism. Therefore, caution is advised in patients with a history of thrombus, uncontrolled hypertension, and renal insufficiency. In addition, bevacizumab should not be initiated at least until 28 days following a major surgery or until the wound is felt to be completely healed.26
Chemotherapy in the Elderly Systemic chemotherapy in older patients with advanced NSCLC can be challenging, given the toxicity profile of platinum-based combination therapies. In this regard, several trials have looked at the single agent vinorelbine in elderly patient populations (aged 70 and over). A small phase II Italian study suggested that this regimen was well-tolerated and provided a response rate of 23%.31 A large multicenter study followed, conducted by the Elderly Lung Cancer Vinorelbine Italian Study Group (ELVIS), comparing single agent vinorelbine with BSC. This study noted an increase in overall survival (28 weeks versus 21 weeks), and an improvement in the 1 year survival rate (32% versus 14%) with single agent vinorelbine. Those patients on the vinorelbine arm also scored better on quality of life parameters and reported less cancer-related symptoms.32 A randomized phase III trial, conducted by the Southern Italy Cooperative Oncology Group (SICOG), compared the combination of gemcitabine/ vinorelbine with single-agent vinorelbine in a similar elderly population of 120 patients. The combination arm demonstrated a significantly better median survival (7.3 months versus 4.5 months) and overall response rates (22% versus 15%). The quality of life parameters worsened further in the single agent arm versus the combination arm.33 However, results somewhat differed in another, larger trial, the Multicenter Italian Lung Cancer in the Elderly Study (MILES). This study randomized 698 elderly patients to three arms: single agent vinorelbine, single agent gemcitabine, and the combination of vinorelbine and gemcitabine. The combination regimen did not improve survival and did appear to result in a greater incidence of toxicity, such as thrombocytopenia, hepatic toxicity, neutropenia, vomiting, fatigue, cardiac toxicity, and constipation than the single agent arms.34 These results suggest that the single agent vinorelbine is well tolerated and improves survival, compared with BSC, in older patients with advanced NSCLC. However, the SICOG analysis appears to indicate that the combination regimen is also an option, though the possible cost of increased toxicity needs to be considered, especially in the elderly.
A.T. Fathi and J.R. Brahmer
Chemotherapy for Progressive or Relapsed Disease Until only recently, no single agent or combination therapies had shown any convincing survival benefit in the second line setting for advanced NSCLC. Most studies, using a variety of chemotherapeutic agents, demonstrated response rates of less than 10% and median survival times of 4 months or less. The lone exception was docetaxel, which in phase II studies resulted in response rates of 15% to 22% and median survival times of 5.8 months to 11 months.35 In a randomized phase III trial, a total of 373 patients were randomized to receive docetaxel 100 mg/m2 (D100), docetaxel 75 mg/m2 (D75) versus a control regimen of vinorelbine or ifosfamide (V/I). The overall response rates were significantly higher in the docetaxel arms (10.8% and 6.7% for the D100 and D75 arms, respectively, versus 0.8% with V/I). Time to progression was also longer in the docetaxel arms of the study. Overall survival was not different between the three groups but the 1 year survival rate was greatest in the D75 arm (32%), which was significantly greater than that noted in the V/I arm (19%). Of note, 77% of patients in the D100 arm experienced grade 4 neutropenia compared with 54% in the D75 arm and 31% in the V/I arm.35 Another phase III trial investigating docetaxel randomized 103 patients to three arms: D100, D75, and best supportive care (BSC); 7.1% of the treated patients had a response to chemotherapy. Time to progression was longer for the docetaxel patients (10.7 weeks versus 6.7 weeks for BSC). Also, overall median survival time was improved in the docetaxel arms (7.0 months versus 4.6 months) and this was even more significant in the D75 arm (7.5 months versus 4.6 months). Grade 4 neutropenia was more pronounced in the D100 arm.36 Based on these important results, it was deemed that docetaxel at a dose of 75 mg/m2 should be used in the second line setting for NSCLC patients with an acceptable functional status who have progressed through first line platinum-based therapies. Another agent recently approved for second line use in NSCLC is pemetrexed. Pemetrexed is an antifolate compound targeting multiple enzymes and pathways in folate metabolism. Its main target is thymidylate synthase, critical for the synthesis of purine nucleotides and thymidine.37 An initial phase II trial of pemetrexed in advanced stage NSCLC accrued 33 patients and reported an overall response rate of 23.3%, with no complete responses. The median survival time of all patients was 9.2 months and the 1-year survival rate was 25.3%.38 Another phase II trial assessed the role of pemetrexed in the second line setting. The response rate for all 79 patients was reported as 8.9%, with a higher response rate (14.1%) in patients not pretreated with platinum agents and a lower one (4.5%) in those previously treated with platinum agents. The median survival time for all patients was 5.7 months. The main toxicities were hematologic, with 35% patients developing grade 3/4 neutropenia.39 A subsequent multinational phase III study comparing pemetrexed and docetaxel in 571 previously treated NSCLC patients demon-
Chemotherapy for advanced stage NSCLC strated statistically similar response rates, progression free survival, median survival, and 1 year survival rates. However, patients receiving docetaxel were more likely to experience grade 3/4 neutropenia and related complications.40 Because of this noninferiority to docetaxel, pemetrexed has also been accepted as a second line option in the treatment of NSCLC. In summary, after many years of disappointing results in the second line setting, multiple agents are now available for NSCLC patients who progress through first line therapy. These include docetaxel and pemetrexed. Erlotinib, a targeted EGFR tyrosine kinase inhibitor, has also been approved in this setting and will be discussed in an accompanying review on targeted therapies.
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11.
12.
13.
14.
Conclusions In conclusion, lung cancer is among the most common and fatal malignancies. Its treatment has evolved greatly over the last three decades. Initial chemotherapeutic approaches to advanced NSCLC yielded disappointing results. However, starting in the 1980s, platinum-based combinations improved response rates and survival. More recently, novel nonplatinum-based combinations and the addition of bevacizumab have added to the armamentarium of therapies. Older patients who may not tolerate standard platinumbased combinations have been shown to benefit from single agent chemotherapy. Finally, options for second line therapy are also expanding, with promising agents in this setting, such as docetaxel and pemetrexed.
15.
16.
17.
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