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Lung Cancer

Potential Treatment Options After First-Line Chemotherapy for Advanced NSCLC: Maintenance Treatment or Early Second-Line?

^aDivision of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy; ^bDivision of Medical Oncology, Second University of Naples, Naples, Italy

Key Words. Advanced NSCLC • Maintenance chemotherapy • Early second-line treatment • Targeted therapies

Correspondence: Cesare Gridelli, M.D., Division of Medical Oncology, "S.G. Moscati" Hospital, Contrada Amoretta, 83100 Avellino, Italy. Telephone: 39-0825-203574; Fax: 39-0825-203556; e-mail: cgridelli{at}libero.it

Received July 16, 2008; accepted for publication January 7, 2009; first published online in THE ONCOLOGIST Express on February 3, 2009.

Disclosures

Cesare Gridelli: Consultant/advisory role: Eli Lilly, Roche, Merck-Serono, Sanofi-Aventis; Paolo Maione: None; Antonio Rossi: None; Marianna Luciana Ferrara: None; Maria Anna Bareschino: None; Clorinda Schettino: None; Paola Claudia Sacco: None; Fortunato Ciardiello: Consultant/advisory role: Roche, Merck-Serono.

The article discusses erlotinib (Roche), used for maintenance; gefitinib (Astra Zeneca), used for maintenance; and pemetrexed (Eli Lilly), used for maintenance.

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

	ABSTRACT

Top Abstract Introduction Definition of Maintenance... Standard Duration of First-Line... Maintenance Treatment with the... Maintenance Treatment with... Meta-Analysis Conclusions Author Contributions References

 
Although substantial progress has been made in the therapeutic options currently available for patients with advanced non-small cell lung cancer (NSCLC), the overall survival profile remains poor for most patients. One of the strategies currently under investigation with the aim of prolonging survival in NSCLC patients is maintenance treatment with either a chemotherapeutic agent or a molecularly targeted agent after first-line chemotherapy. Moreover, this can consist of drugs included in the induction regimen or other noncrossresistant agents. With the currently available data, maintenance treatment with a different noncrossresistant agent (i.e., an early second-line treatment) is perhaps the most promising strategy. The drug chosen for the early second-line treatment should be a well-tolerated agent, considering that patients have just completed a particularly toxic platinum-based chemotherapy. Extending treatment with targeted agents rather than chemotherapy can provide longer progression-free and overall survival times without increasing toxicity. However, at the moment, only progression-free survival has been shown to be consistently superior with maintenance approaches; the evaluation of survival benefits is warranted before defining this strategy as a possible treatment option. Further studies are warranted to establish the role of maintenance chemotherapy in patients with advanced NSCLC.

	INTRODUCTION

Top Abstract Introduction Definition of Maintenance... Standard Duration of First-Line... Maintenance Treatment with the... Maintenance Treatment with... Meta-Analysis Conclusions Author Contributions References

 
Lung cancer is the most common cancer in the world today, in both incidence (in 2002 there were 1.35 million cases diagnosed, representing 12.4% of all new cancers) and mortality (1.18 million deaths occurred in 2002, or 17.6% of the world's total cancer deaths that year) [1]. It is a highly lethal disease: the 5-year survival rate measured by the Surveillance, Epidemiology, and End Results program in the U.S. is 15% [2], and Europe's average is 10% [3], which is only modestly better than the 8.9% observed in developing countries. Non-small cell lung cancer (NSCLC), consisting of squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma, represents around 80% of all lung cancers. Unfortunately, most patients have advanced, unresectable disease at diagnosis, which has a very poor prognosis. Platinum-based chemotherapy is considered standard of care worldwide for patients with NSCLC. Approximately one third of patients obtain an objective response with first-line chemotherapy, and another 20% achieve temporary disease stabilization. Bevacizumab, an anti–vascular endothelial growth factor (VEGF) monoclonal antibody, was demonstrated to have superior efficacy in combination with platinum-based chemotherapy in two phase III randomized trials, compared with chemotherapy alone in the treatment of nonsquamous advanced NSCLC (longer progression-free survival time and survival time in the first trial and only a longer progression-free survival time in the second trial) [4, 5]. Cetuximab is an anti–epidermal growth factor receptor (EGFR) monoclonal antibody approved for use in colorectal carcinoma and head and neck cancer treatment. Very recently, in a phase III randomized trial, the combination of cisplatin and vinorelbine plus cetuximab was demonstrated to be superior, in terms of overall survival (although not superior in terms of time to progression), to the same chemotherapy alone in the first-line treatment of advanced EGFR-expressing NSCLC [6]. Unfortunately, the vast majority of patients ultimately suffer progression. Thus, although substantial progress has been made in the therapeutic options currently available for patients with advanced NSCLC, the overall survival profile remains poor for most patients. One of the strategies currently under investigation with the aim of prolonging survival in NSCLC patients is maintenance treatment after first-line chemotherapy.

	DEFINITION OF MAINTENANCE TREATMENT

Top Abstract Introduction Definition of Maintenance... Standard Duration of First-Line... Maintenance Treatment with the... Maintenance Treatment with... Meta-Analysis Conclusions Author Contributions References

 
Maintenance treatment is the prolongation of the treatment duration with the administration of additional drugs at the end of a defined number of initial chemotherapy cycles, after achieving tumor control in an individual patient [7, 8]. In the absence of significant toxicity, maintenance should be administered until evidence of progressive disease. Alternatively, when therapy is continued for a defined time, the term "consolidation treatment" is more appropriate. Maintenance treatment consists of either a chemotherapeutic agent or a molecularly targeted agent; moreover, it consists of drugs included in the induction regimen or other noncrossresistant agents. If a noncrossresistant agent is used as maintenance treatment after induction chemotherapy, we can define maintenance therapy as an early second-line treatment. In maintenance trials, the population is heterogeneous. In some studies, only patients achieving a complete or partial response are candidates to receive maintenance chemotherapy; in other studies, patients with stable disease at the end of induction chemotherapy are also eligible. Furthermore, the induction phase may be considered as an in vivo drug sensitivity assay to select patients who achieve a complete/partial response or stable disease and who are more likely to benefit from additional maintenance chemotherapy with one of the drugs included in the induction regimen.

	STANDARD DURATION OF FIRST-LINE CHEMOTHERAPY

Top Abstract Introduction Definition of Maintenance... Standard Duration of First-Line... Maintenance Treatment with the... Maintenance Treatment with... Meta-Analysis Conclusions Author Contributions References

 
The first American Society of Clinical Oncology (ASCO) guidelines, published in 1997 [9], addressed the appropriate duration of therapy in this setting, and cited a single trial that randomly assigned 74 patients to two to three cycles of a nonplatinum-based combination regimen compared with continuous treatment. That trial did not show a significant difference in survival. Based on this trial, ASCO recommended that no more than eight cycles be delivered to patients with stage IIIB/IV NSCLC. However, in most clinical trials evaluating various strategies in this population, the median number of cycles delivered was typically three to four, suggesting that either the disease was refractory to treatment or the patient could not tolerate the toxicities of treatment beyond three to four cycles. Smith et al. [10] were the first to address the question of the duration of therapy in advanced NSCLC by random assignment of 308 patients to three, compared with six, cycles of mitomycin, vinblastine, and cisplatin. They were unable to demonstrate any advantage from six cycles, because the response rates, times to disease progression, and overall survival times were identical in the two arms. However, it should be noted that the majority of patients enrolled in the prolonged arm of that trial did not receive more than three cycles of therapy. A second trial randomly assigned 230 patients with stage IIIB/IV disease to four cycles of carboplatin plus paclitaxel (arm A), compared with the same treatment until progression (arm B) [11]. The primary endpoints were survival and quality of life. The median survival time and 1-year survival rates were 6.6 months and 28% for arm A and 8.5 months and 34% for arm B, respectively (log-rank p =.63). Rates of hematologic and nonhematologic toxicities were similar in the two arms, except for neuropathy (higher in the prolonged arm). There were no differences in quality of life. In conclusion, that study showed no overall benefit in terms of survival, response rate, or quality of life to continuing treatment with carboplatin plus paclitaxel beyond four cycles in advanced NSCLC. The patients enrolled in the prolonged arm had a longer progression-free survival time, albeit with heightened toxicity. A third trial randomly assigned 297 patients with advanced NSCLC to either three or six cycles of carboplatin plus vinorelbine; no response, survival, or quality-of life differences were demonstrated [12]. A consistent theme in all these trials is the increasing risk for cumulative toxicity characteristic of the regimen used when longer durations are delivered. For example, in the trial using carboplatin plus paclitaxel, after four cycles, the rate of grade 2–4 neuropathy was 19.9%; after eight cycles, 43% of patients continuing on treatment had developed grade 2–4 neuropathy. These data led ASCO to change the recommendation regarding the duration of therapy in this setting in 2003 [13]. The new guidelines stated that treatment should be stopped at four cycles for patients not responding to treatment, and no more than six cycles should be administered for any patient. Recently, Park et al. [14], representing the Korean Cancer Study Group, reported on a trial addressing whether four or six total cycles of platinum-based chemotherapy is optimal in those patients who have nonprogressing disease following their initial two cycles of the same chemotherapy. Based on trials from the Southwest Oncology Group, nonprogression at 2 months, also known as the disease control rate, was recently shown to be a powerful predictor of survival with platinum-based chemotherapy [15]. The trial by Park et al. [14] investigated duration of therapy in a patient population whose disease had demonstrated sensitivity to platinum-based chemotherapy before random assignment, arguably representing the patient population with the highest probability of benefiting from an extended duration of therapy. Park and colleagues failed to demonstrate any benefit with regard to response rate or survival using a noninferiority design for six compared with four total cycles, despite demonstrating a significantly longer time to disease progression. Interestingly, patients randomly assigned to four cycles were more likely to receive second-line treatment, had less toxicity, and regained their functional status more rapidly than patients randomly assigned to six cycles.

Thus, these initial findings are consistent with those of previous trials addressing the question of treatment duration, and we concluded that prolonging the duration of first-line chemotherapy beyond four to six cycles is not justified in clinical practice [16].

	MAINTENANCE TREATMENT WITH THE SAME DRUGS USED IN THE INDUCTION REGIMEN

Top Abstract Introduction Definition of Maintenance... Standard Duration of First-Line... Maintenance Treatment with the... Maintenance Treatment with... Meta-Analysis Conclusions Author Contributions References

 
Chemotherapy
At the 2005 ASCO meeting, Belani and colleagues reported an update of a randomized phase II trial exploring the feasibility of maintenance therapy with weekly paclitaxel versus observation, following three cycles of carboplatin plus paclitaxel as initial therapy [17, 18]. Of the 401 patients enrolled, 130 entered the maintenance chemotherapy phase. Patients were at first randomized to one of four different schedules of paclitaxel plus carboplatin. Then, patients who responded at week 16 (n = 130) were randomly assigned to either weekly paclitaxel therapy (70 mg/m², 3 of 4 weeks) or observation. Only patients who achieved at least a partial response were randomized. The median survival times were 76 weeks and 29 weeks for patients receiving maintenance chemotherapy and observation, respectively. The 1- and 2-year survival rates were 69% and 33% versus 25% and 9%, respectively. Improvements in survival were associated with minimal toxicity. Despite a longer time to progression and median survival time in patients randomized to receive maintenance therapy, no conclusions can be drawn because the trial was designed to determine the optimal schedule for the administration of the carboplatin plus paclitaxel combination and not powered to address the role of maintenance therapy with weekly paclitaxel in patients with advanced NSCLC.

In a phase III trial, Brodowicz et al. [19] treated chemotherapy-naïve patients with stage IIIB/IV NSCLC with gemcitabine plus cisplatin. Patients achieving an objective response or disease stabilization following initial gemcitabine plus cisplatin therapy were randomized (in a 2:1 fashion) to receive maintenance gemcitabine (1,250 mg/m² on days 1 and 8 every 21 days) plus best supportive care or best supportive care only. Three hundred fifty-two patients were enrolled. Following initial therapy, 206 patients were randomized and treated with gemcitabine (n = 138) or best supportive care (n = 68). Time to progression favored the gemcitabine arm; it was 6.6 months and 5 months for the gemcitabine and best supportive care arms, respectively, whereas values for the maintenance period were 3.6 months and 2.0 months, respectively (p < .001 for both). The median overall survival time from the time treatment was initiated was 13.0 months for patients in the gemcitabine maintenance arm and 11.0 months for patients in the best supportive care arm (p = .195). The toxicity profile was mild, with neutropenia the most common grade 3 or 4 toxicity. The authors concluded that maintenance therapy with gemcitabine, following initial therapy with gemcitabine plus cisplatin, was feasible and produced a significantly longer time to progression than with best supportive care alone (Table 1).

These two trials represent the first evidence of an improvement in treatment outcomes using chemotherapy with targeted therapies in the first-line treatment of advanced NSCLC, and also represent a successful maintenance treatment strategy. However, it is not possible to determine from these results the extent of benefit from the addition of the new drug (bevacizumab) versus its use as maintenance.

Recently, Patel et al. [20] reported the results of a phase II trial in chemotherapy-naïve, stage IIIB (effusion) or IV nonsquamous NSCLC treated with 500 mg/m² pemetrexed, carboplatin to an area under the concentration–time curve (AUC) of 6, and 15 mg/kg bevacizumab. Treatment was repeated every 21 days for six cycles. For patients with stable disease or a partial response, 500 mg/m² pemetrexed and 15 mg/kg bevacizumab were continued every 21 days until disease progression or toxicity. Fifty-one patients were enrolled: 30 patients (60%) completed six or more cycles of therapy and seven patients (14%) completed 18 cycles of therapy. Treatment was well tolerated, with no grade >3 hemorrhagic events and no grade 3 or 4 hypertension reported. Forty-nine patients were evaluable for response: one complete response and 23 partial responses were observed, for an overall response rate of 49% (95% CI, 35%–61%). The median time to progression was 7.2 months and the median survival time was 14.0 months. The authors concluded that treatment with pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab in patients with advanced nonsquamous NSCLC is feasible with an acceptable toxicity profile. Moreover, the encouraging activity has justified further development of this regimen.

Cetuximab (Erbitux®; ImClone Systems, Inc., New York) is an anti EGFR monoclonal antibody approved for use in colorectal carcinoma and head and neck cancer treatment. Recently, in a phase III randomized trial, the combination of cisplatin and vinorelbine plus cetuximab was demonstrated to be superior, in terms of overall survival, to the same chemotherapy alone in the first-line treatment of advanced EGFR-expressing NSCLC [6]. About 1,100 patients were randomized, and cetuximab was administered in combination with chemotherapy and as maintenance until progressive disease. The median survival duration was 11.3 months for the cetuximab arm, versus 10.1 months for the chemotherapy-alone arm (HR, 0.871; p = .0441). Preliminary results of prespecified subgroup analyses suggest a greater benefit in white patients independent of histology and a generally better prognosis in Asians. As in the bevacizumab trials, it is not possible to extrapolate the extent of benefit from the addition of the new drug (cetuximab) versus the role of maintenance treatment with cetuximab. However, it is of interest that the survival curves start to separate at the end of induction chemotherapy when cetuximab maintenance begins (the curves separate later in the total population and much earlier in the white population). This seems to underline a potential survival effect for maintenance treatment.

Gefitinib and erlotinib are two orally available EGFR tyrosine kinase inhibitors (TKIs). In the first generation of trials of targeted therapies in NSCLC treatment, these two agents were tested in combination with chemotherapy and as maintenance treatment until disease progression after six cycles of platinum-based chemotherapy, with disappointing results. In two large phase III trials, named Iressa® NSCLC Trial Assessing Combination Therapy (INTACT)-1 and INTACT-2, no survival or progression-free survival difference was reported in favor of the additions of gefitinib to platinum-based polychemotherapy (cisplatin plus gemcitabine or carboplatin plus paclitaxel) versus chemotherapy [21, 22]. Similarly, the combination of erlotinib until disease progression with platinum-based polychemotherapy (cisplatin plus gemcitabine or carboplatin plus paclitaxel) was demonstrated to confer no survival advantage over chemotherapy alone in two large phase III randomized trials, named Tarceva® Lung Cancer Investigation and Tarceva® Responses in Conjunction with Paclitaxel and Carboplatin [23, 24]. It is postulated that the erlotinib- and gefitinib-induced G₁ phase cell-cycle arrest may affect the efficacy of chemotherapy when administered simultaneously with EGFR TKIs. However, the role of erlotinib in combination with chemotherapy and as maintenance treatment was re-evaluated at the last ASCO meeting in 2008, with the presentation of a phase II randomized double-blind trial, named FASTACT (First-line Asian Sequential Tarceva plus Chemotherapy Trial) [25]. That trial tested a new combination strategy of erlotinib plus chemotherapy (erlotinib administered not concurrently with chemotherapy, but on days 15–28 of each chemotherapy cycle), which also represented a maintenance strategy because erlotinib was administered until progression. Patients with chemotherapy-naïve stage IIIB/IV NSCLC and a performance status score of 0 or 1 were randomized to receive either 150 mg erlotinib daily or placebo orally on days 15–28 of 4-weekly chemotherapy cycles. Chemotherapy consisted of 1,250 mg/m² gemcitabine i.v. (days 1 and 8) plus either 75 mg/m² cisplatin or carboplatin to an AUC of 5 (day 1) for a maximum of six cycles. Responding patients continued to receive erlotinib or placebo as maintenance treatment until progression or unacceptable toxicity. The primary endpoint was the nonprogression rate (complete responses, partial responses, and stable disease) at 8 weeks using the Response Evaluation Criteria in Solid Tumors. About 150 patients were enrolled and 94% were Asian. Rash-like events were noted in 66% of patients in the erlotinib arm versus 35% of patients in the placebo arm, and diarrhea was observed in 24% and 18% of patients, respectively. Grade 3–4 hematologic toxicities (erlotinib arm versus placebo arm) included neutropenia (14% versus 10%), anemia (7% versus 6%), and thrombocytopenia (5% versus 5%). Thus, the overall safety profiles were similar in the two arms. A statistically significant longer progression-free survival duration was observed in the erlotinib arm (31.3 weeks and 23.7 weeks in the erlotinib and placebo arms, respectively; p = .0175). The tumor response rate was higher in the erlotinib arm (36.8%, versus 24.4% in the placebo arm; p = .089), but the nonprogression rate at 8 weeks was not significantly different for erlotinib compared with placebo (80.3% versus 76.9% in the erlotinib and placebo arms, respectively; p = .51). That trial confirmed that the first-line sequential administration of erlotinib and chemotherapy achieves promising results, and also that maintenance treatment with erlotinib is a promising strategy, in contrast to the data previously observed for gefitinib and erlotinib when administered concurrently with chemotherapy (Table 2).

	MAINTENANCE TREATMENT WITH DIFFERENT DRUGS FROM THOSE USED IN THE INDUCTION REGIMEN (OR EARLY SECOND-LINE TREATMENT)

Top Abstract Introduction Definition of Maintenance... Standard Duration of First-Line... Maintenance Treatment with the... Maintenance Treatment with... Meta-Analysis Conclusions Author Contributions References

Fidias et al. [27], in a phase III randomized trial, assessed the efficacy and safety of docetaxel administered either immediately after gemcitabine and carboplatin induction therapy or upon disease progression, in chemotherapy-naïve patients with advanced NSCLC. That study more appropriately addressed a consolidation rather than a maintenance strategy. After four 21-day cycles, nonprogressors were randomized to either the immediate docetaxel group (75 mg/m² docetaxel administered on day 1 every 21 days, for a maximum of six cycles) or the delayed docetaxel group (patients given best supportive care after randomization and the same docetaxel regimen after first evidence of progressive disease). The overall survival times were not statistically different (p = .0853) in the two docetaxel arms (9.7 months and 12.3 months in the delayed and immediate arms, respectively). A progression-free survival analysis (from randomization to first evidence of progressive disease or death) showed a statistically significant (p < .0001) longer progression-free survival duration in the immediate docetaxel arm (2.7 months and 5.7 months in the delayed and immediate arms, respectively). Moreover, docetaxel given to NSCLC patients immediately after gemcitabine and carboplatin induction did not increase toxicity. In particular, grade 3 or 4 neutropenia occurred in 28.6% and 26.1% of the patients in the delayed and immediate arms, respectively. Quality-of-life results were not statistically different (p = .76) in the docetaxel groups. The authors concluded that the comparison of progression-free survival for the two docetaxel arms suggested a possible clinical benefit for immediate docetaxel therapy. However, although overall survival trended in favor of immediate docetaxel therapy, the overall survival results did not reach statistical significance.

A very relevant phase III, randomized trial was presented by Ciuleanu et al. [28] at the most recent ASCO meeting. In that double-blind phase III trial, the authors compared the efficacy and safety of pemetrexed with those of placebo in patients with stage IIIB/IV NSCLC who had not progressed on four cycles of platinum-based induction chemotherapy (gemcitabine or docetaxel or paclitaxel plus cisplatin or carboplatin). Patients were randomized (in a 2:1 ratio, balanced for stage, ECOG performance status score, sex, response to induction therapy, nonplatinum component of induction therapy, and brain metastases) to either pemetrexed (500 mg/m², day 1) plus best supportive care or i.v. placebo plus best supportive care in 21-day cycles until disease progression. Progression-free survival was chosen as the primary endpoint. The primary analysis of progression-free survival was based on an unadjusted Cox HR (target n = 660, = 0.05, power = 85% to show an HR< 1.00, assuming 462 events and an HR of 0.75). In total, 663 patients were enrolled (pemetrexed, n = 441; placebo, n = 222). Pemetrexed had better efficacy with respect to the progression-free survival time (4.04 months versus 1.97 months in the pemetrexed and placebo arms, respectively; HR, 0.599; 95% CI, 0.49–0.76; p < .00001) and tumor response (disease control rate, 51.7% and 33.3% in the pemetrexed and placebo arms, respectively; p < .001). The preliminary overall survival duration was 13.01 months with pemetrexed and 10.18 months with placebo (HR, 0.798; 95% CI, 0.63–1.01; p = 0.060). Treatment with pemetrexed was globally well tolerated, with no drug-related deaths, and with a 4.3% rate of serious adverse events, versus 0% for placebo, and a 14.3% rate of grade 3 or 4 adverse events, versus 3.6% for placebo (p < .001). In this trial, a prespecified analysis for efficacy by NSCLC histology was performed. In fact, data have recently emerged in the first-line treatment of advanced NSCLC on better outcomes achieved with cisplatin plus pemetrexed than with cisplatin plus gemcitabine in patients with adenocarcinomas and large cell carcinomas; conversely, gemcitabine fared better in patients with squamous histology [29]. These results may be a result of a higher expression level of thymidylate synthase in squamous NSCLC and a lower expression level in adenocarcinomas, leading to less sensitivity to pemetrexed in the squamous histotype and greater sensitivity in adenocarcinoma. A disparity in outcome with pemetrexed in different histotypes of NSCLC (better for patients with adenocarcinoma and large cell carcinoma histologies) was also confirmed in second-line treatment by a retrospective analysis of a docetaxel versus pemetrexed randomized trial [30]. An effect based on histology was also reported in the Ciuleanu et al. [28] trial on maintenance treatment with pemetrexed. In fact, the superior progression-free survival time and disease control rate favoring pemetrexed over placebo vanished for patients with squamous NSCLC (progression-free survival time, 2.43 months versus 2.50 months; p = 0.896; disease control rate, 33.3% versus 34.5%; p = .999 in the pemetrexed and placebo arms, respectively). Conversely, the trend for longer overall survival favoring pemetrexed observed in the analysis of all patients was stronger in patients (n = 482) with nonsquamous NSCLC (including adenocarcinomas, large cell carcinomas, undifferentiated carcinomas, and carcinoma not otherwise specified)—14.4 months versus 9.4 months in the pemetrexed and placebo arms, respectively (p = .005) (Table 3). This is the third randomized phase III trial to show a treatment-by-histology effect for pemetrexed with better efficacy in nonsquamous NSCLC. Thus, the authors concluded that postinduction maintenance therapy with pemetrexed is well tolerated and offers superior progression-free survival to placebo in patients with advanced NSCLC. Moreover, a strong trend favoring pemetrexed over placebo as maintenance treatment in a preliminary overall survival analysis was observed, particularly for patients with nonsquamous NSCLC. The final overall survival results are expected in early 2009.

	META-ANALYSIS

Top Abstract Introduction Definition of Maintenance... Standard Duration of First-Line... Maintenance Treatment with the... Maintenance Treatment with... Meta-Analysis Conclusions Author Contributions References

	CONCLUSIONS

Top Abstract Introduction Definition of Maintenance... Standard Duration of First-Line... Maintenance Treatment with the... Maintenance Treatment with... Meta-Analysis Conclusions Author Contributions References

 
Based on the currently available data, no more than four to six cycles of chemotherapy should be administered as first-line treatment. However, maintenance treatment with a different noncrossresistant agent (i.e., an early second-line treatment) is a promising strategy. The drug chosen for the early second-line treatment should be a well-tolerated agent because patients have just completed a potentially toxic platinum-based chemotherapy. Because of its favorable toxicity profile, pemetrexed is also a promising candidate as maintenance treatment after cisplatin plus pemetrexed induction chemotherapy in nonsquamous tumors. Extending treatment with targeted agents rather than chemotherapy is also an interesting approach. However, at the moment, only progression-free survival advantages have been reported in favor of maintenance approaches, and evidence of survival benefits is warranted before defining this strategy as a possible treatment option. Further studies are warranted to establish the role of maintenance treatment in patients with advanced NSCLC, keeping in mind that quality of life is a priority endpoint.

	AUTHOR CONTRIBUTIONS

Top Abstract Introduction Definition of Maintenance... Standard Duration of First-Line... Maintenance Treatment with the... Maintenance Treatment with... Meta-Analysis Conclusions Author Contributions References

 
Conception/design: Cesare Gridelli, Paolo Maione, Antonio Rossi, Fortunato Ciardiello

Provision of study materials: Cesare Gridelli, Paolo Maione, Antonio Rossi, Marianna Luciana Ferrara, Maria Anna Bareschino, Clorinda Schettino, Paola Claudia Sacco, Fortunato Ciardiello

Collection/assembly of data: Cesare Gridelli, Paolo Maione, Antonio Rossi, Marianna Luciana Ferrara, Maria Anna Bareschino, Clorinda Schettino, Paola Claudia Sacco, Fortunato Ciardiello

Data analysis: Cesare Gridelli, Paolo Maione, Antonio Rossi, Fortunato Ciardiello

Manuscript writing: Cesare Gridelli, Paolo Maione, Antonio Rossi, Marianna Luciana Ferrara, Maria Anna Bareschino, Clorinda Schettino, Paola Claudia Sacco, Fortunato Ciardiello

Final approval of manuscript: Cesare Gridelli, Paolo Maione, Antonio Rossi, Marianna Luciana Ferrara, Maria Anna Bareschino, Clorinda Schettino, Paola Claudia Sacco, Fortunato Ciardiello

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Top Abstract Introduction Definition of Maintenance... Standard Duration of First-Line... Maintenance Treatment with the... Maintenance Treatment with... Meta-Analysis Conclusions Author Contributions References

 

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