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Lung Cancer

Sequential, Alternating, and Maintenance/Consolidation Chemotherapy in Advanced Non-Small Cell Lung Cancer: A Review of the Literature

^aMedical Oncology A, Disease Management Team – Lung Cancer, National Institute for Cancer Research, Genoa, Italy; ^bDepartment of Medical Oncology, University Hospital of Udine, Udine, Italy

Key Words. Chemotherapy design strategies • Advanced non-small cell lung cancer • Sequential chemotherapy • Alternating chemotherapy • Maintenance/consolidation chemotherapy

Correspondence: Francesco Grossi, M.D., Medical Oncology A, National Institute for Cancer Research, Largo Rosanna Benzi 10, 16132 Genoa, Italy. Telephone: 39-010-560-0665; Fax: 39-010-560-0850; e-mail: francesco.grossi{at}istge

Received September 5, 2006; accepted for publication January 17, 2007.

	Learning Objectives

Top Learning Objectives Abstract Introduction Methods Sequential Chemotherapy in NSCLC Alternating Chemotherapy in... Consolidation/Maintenance... Conclusions Disclosure of Potential... References

 
After completing this course, the reader will be able to:

1. Describe the new chemotherapy design strategies (i.e., sequential, alternating, and maintenance/consolidation chemotherapy).
   
2. Identify potential advantages and drawbacks of these new strategies in advanced NSCLC.
   
3. Discuss the results of clinical trials testing sequential, alternating, and maintenance/consolidation chemotherapy in advanced NSCLC.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Methods Sequential Chemotherapy in NSCLC Alternating Chemotherapy in... Consolidation/Maintenance... Conclusions Disclosure of Potential... References

 
A platinum-based doublet with a third-generation agent (paclitaxel, vinorelbine, gemcitabine, docetaxel) represents the standard first-line treatment for advanced non-small cell lung cancer patients with good performance status (PS). Traditional chemotherapy provides response rates of 20%–40% and a median survival of 8–10 months. In an attempt to improve its outcome, alternative schedules have been proposed, namely sequential, alternating, and maintenance/consolidation therapy.

Sequential chemotherapy with a platinum-based doublet followed by a single agent is feasible in patients with good PS; preliminary results from randomized phase III trials with combination chemotherapy as a comparator are promising, suggesting similar efficacy and a better toxicity profile for the sequential arm. The use of sequential single agents is an option for elderly and frail patients unsuitable for a platinum-based combination.

Based on trials published so far, it is unlikely that an alternating chemotherapy strategy will be proven superior to standard chemotherapy in patients with good PS. However, sufficient evidence exists that it could be appropriate in the elderly or in unfit individuals

Consolidation/maintenance chemotherapy may provide additional benefit for patients achieving disease control after standard first-line chemotherapy. Better results are seen when maintenance consists of an agent that has proven active in the induction phase. Further evaluation of this strategy, as well as of consolidation/maintenance therapy with targeted agents, is warranted.

In conclusion, these approaches may improve the outcome in selected patients with advanced non-small cell lung cancer, but further results from randomized trials are needed. In the meantime, sequential, alternating, and maintenance/consolidation therapy should still be considered investigational.

Disclosure of potential conflicts of interest is found at the end of this article.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Methods Sequential Chemotherapy in NSCLC Alternating Chemotherapy in... Consolidation/Maintenance... Conclusions Disclosure of Potential... References

 
In the past decades, major improvements have been achieved in the treatment of advanced non-small cell lung cancer (NSCLC), and the role of chemotherapy in this setting has been definitely established. The current standard treatment for patients with good performance status includes first-line treatment with a platinum-based two-drug regimen (doublet) for a maximum of six cycles in the absence of unacceptable toxicity or progressive disease [1]. However, despite the introduction of new, active agents (gemcitabine, taxanes, vinorelbine, irinotecan, pemetrexed), the prognosis of advanced NSCLC patients is still dismal, with first-line chemotherapy response rates usually in the range of 20%–40% and with a median survival time of approximately 8 months [1]. In patients with progressive disease after first-line chemotherapy and good performance status, a second-line treatment with single-agent docetaxel is recommended [1]. A recent phase III trial demonstrated pemetrexed to be as effective as docetaxel in this setting, with a more favorable toxicity profile [2]. However, the response rate to second-line chemotherapy, either docetaxel or pemetrexed, is <10%.

Several attempts have been made to improve the efficacy of first-line chemotherapy. In trials focusing on the role of cisplatin, none of the non–platinum-containing regimens has been proven to be superior [1]. Other trials have shown no advantage for three-drug (triplet) versus two-drug combinations in terms of survival, with worse toxicities when a triplet is used [3]. Finally, studies investigating the optimal treatment duration have demonstrated that prolonged treatment is not beneficial, suggesting that the maximum benefit of chemotherapy is yielded by the first few cycles [1].

Among new molecular targeted therapies, two orally active inhibitors of the epidermal growth factor receptor tyrosine kinase, namely, gefitinib and erlotinib, have been proven to be active as single agents in second- and third-line treatment [1]. However, no advantage has been observed from adding one of these agents to a platinum-based doublet [4]. The addition of bevacizumab, a monoclonal antibody against vascular endothelial growth factor, to standard first-line chemotherapy has improved survival in patients with advanced nonsquamous NSCLC [5].

Recently, alternative designs of treatment schedules other than combination chemotherapy have been proposed, such as sequential, alternating, maintenance, and consolidation chemotherapy. The feasibility of these approaches in lung cancer patients has been timely demonstrated. This review summarizes the rationale, current data, and perspectives of sequential, alternating, consolidation, and maintenance chemotherapy in patients with advanced NSCLC.

	METHODS

Top Learning Objectives Abstract Introduction Methods Sequential Chemotherapy in NSCLC Alternating Chemotherapy in... Consolidation/Maintenance... Conclusions Disclosure of Potential... References

 
Data for this review were identified by searches in the MEDLINE database using the search terms "non-small-cell lung cancer," "sequential," "alternating" or "alternate," "maintenance," "consolidation," and "chemotherapy." Abstracts from the Proceedings of the American Society of Clinical Oncology (ASCO) meetings in the years 1996–2006, from the World Conference of Lung Cancer (WLCC) in the years 2000–2005, from the European Society of Medical Oncology (ESMO) meetings in the years 1998–2004, and from the European Cancer Conference (ECCO) in the years 1999–2005 were also searched for pertinent studies. Abstracts reporting only preliminary results, or marginally related to the topic of this review, were excluded. Trials evaluating the duration of chemotherapy, comparing different durations of the same chemotherapy (i.e., different numbers of cycles of the same regimen), were not included in the analysis of consolidation/maintenance chemotherapy. Phase I–III studies were reviewed. Only reports in English were included.

	SEQUENTIAL CHEMOTHERAPY IN NSCLC

Top Learning Objectives Abstract Introduction Methods Sequential Chemotherapy in NSCLC Alternating Chemotherapy in... Consolidation/Maintenance... Conclusions Disclosure of Potential... References

 
Sequential chemotherapy is the sequential administration of non–cross-resistant chemotherapy for a defined number of cycles. Chemotherapy may be either mono- or polychemotherapy. In a sequential regimen, the switch from one treatment to another does not require documented progression, in contrast to the switch from first- to second-line treatment. Drugs are given as planned, even in the presence of a partial response with no signs of resistance at the end of the first part of the sequence.

Mathematical models support sequential chemotherapy as being superior to concurrent therapy [6, 7]. Indeed, sequential chemotherapy may allow the delivery of a higher number of drugs, the dose of each drug can be optimized, and toxicity can be limited. In a sequential treatment, the evaluation of the response to each drug/drug combination, in order to identify the most active drug(s) as an in vivo chemosensitivity test, may potentially guide the selection of tailored consolidation/maintenance chemotherapy. In addition, the "worst drug rule" can be applied [6]. According to this rule, in order to kill clones resistant to the most active regimen when two non–cross-resistant regimens are available with different activities, the less active regimen should be administered first. However, the dismal outcome and the rapid deterioration observed for NSCLC patients following first-line chemotherapy do not support the application of the "worst drug rule" in this setting.

Hence, based on the number of drugs delivered in each block of the sequence, we have classified sequential chemotherapy trials into four groups: (a) a doublet followed by a doublet or a triplet, (b) a doublet or a triplet followed by a single agent, (c) a single agent followed by a doublet or a triplet, and (d) a single agent followed by a single agent (Table 1).

Still, randomized phase III trials comparing a doublet followed by a doublet or a triplet with a standard two-drug platinum-based combination failed to demonstrate an advantage for the experimental sequential arm. However, these trials address different questions. In the Alberola et al. trial [11], a non–cisplatin-based sequential treatment was compared with a standard cisplatin-based doublet and a cisplatin-based triplet. The sequential non–platinum-based arm reported a significantly lower response rate than with a platinum-based doublet or triplet, although no significant difference was observed in terms of time to progression and overall survival. The trial by Colucci et al. [8] compared two sequential treatments; the aim of that study was to evaluate the validity of Day's rule [6], it was not designed to test sequential chemotherapy as compared with standard chemotherapy. The trial reported by Gebbia et al. [10] was the only one to compare a cisplatin-based standard doublet—cisplatin plus vinorelbine (CV) or gemcitabine (CG)—with two possible cisplatin-based sequential treatments—gemcitabine plus ifosfamide (GI) followed by CV or the opposite sequence. Although accrual to both experimental arms was stopped early for ethical reasons, once an interim analysis showed that GI was a poorly active regimen, it is noteworthy that the sequence CV GI proved to be equivalent to standard arms in terms of time to progression.

In both the Gebbia et al. [10] and Colucci et al. [8] studies, the "worst drug rule" was not proven: the sequential arm with the less active nonplatinum combination followed by the more active platinum-based doublet was inferior to the opposite sequence in terms of response rate and time to progression.

A Doublet or a Triplet Followed by a Single Agent
Several phase II trials have evaluated the activity and toxicity of a sequence of a combination regimen followed by a single agent [15–22]. Most of these treatments consisted of a platinum-based doublet followed by a taxane, either paclitaxel or docetaxel. Overall, the activity of these regimens is encouraging, in the range of 21%–55%, with mild toxicities.

Based on a phase II trial of gemcitabine plus vinorelbine followed by docetaxel in chemotherapy-naive NSCLC patients [17], Kawahara et al. [23] conducted a randomized phase III trial, comparing the sequential nonplatinum regimen with a standard platinum-based doublet (carboplatin plus paclitaxel). Although preliminary results do not show any benefit in the sequential arm in terms of progression-free survival and overall survival, the toxicity profile favors the experimental treatment, with significantly less myelosuppression, neuropathy, pain, and myalgia [23]. In another randomized phase III trial, Sculier et al. [24] evaluated three cycles of cisplatin plus ifosfamide and gemcitabine followed, in nonprogressing patients, by three more cycles of the same regimen or three cycles of single-agent paclitaxel. No difference in median survival was observed, with a better toxicity profile in the sequential arm [24]. A randomized phase III trial by Fidias et al. [25] of induction therapy with gemcitabine plus carboplatin followed by delayed or immediate therapy with docetaxel was performed in 526 patients with advanced NSCLC. In a preliminary analysis, patients in the immediate docetaxel arm obtained a significantly higher clinical benefit rate than those in the delayed arm (88% versus 63.9%, respectively) [25]. Differences in the design of these randomized trials should be pointed out. In the trial by Kawahara et al. [23], a platinum-based doublet was compared with a sequential non–platinum-based regimen, while in the Fidias et al. [25] and Sculier et al. [24] trials both the experimental and standard arms contained a platinum-based regimen. Furthermore, in the Kawahara et al. [23] trial, patients were randomized from the beginning of therapy, whereas only patients with nonprogressive disease after three or four cycles of chemotherapy were randomized to receive additional cycles of the same chemotherapy or the single-agent chemotherapy in the Fidias et al. [25] and the Sculier et al. [24] trials.

A Single Agent Followed by a Doublet or Triplet
Two phase II trials have been reported so far, with a taxane administered first followed by a platinum-based doublet or triplet [26, 27]. Support for such a sequence is provided by the "worst drug rule." Inconsistent results were reported, with interesting results worthy of further evaluation for the Feliu et al. [26] regimen and disappointing results in terms of response rate and progression-free survival for the Rixe et al. [27] study. It is noteworthy that, in the latter study, cisplatin plus vindesine cannot be considered an optimal doublet as it has been demonstrated to be inferior to other cisplatin and third-generation doublets [28]. In addition, patients achieving a partial or complete response after cisplatin plus vindesine were offered the option to receive three additional cycles of docetaxel, as consolidation. Because of the low response rate, only five patients received consolidation therapy and no conclusions can be drawn.

A Single Agent Followed by a Single Agent
The sequential administration of non–cross-resistant single agents may theoretically reduce toxicity while potentially killing tumor cell subsets with different sensitivity to chemotherapeutic agents.

This approach is particularly appealing in selected patients, such as elderly, impaired performance status, or pretreated patients. Few phase II trials have been reported so far, mainly as preliminary results at meetings. Both platinum-containing and non–platinum-containing regimens have been evaluated. Toxicity is mild and the response rate is promising [29–34].

Sequential Chemotherapy: Conclusions
Sequential chemotherapy is an appealing approach to increase the number of non–cross-resistant agents delivered upfront. A regimen of a platinum-based doublet followed by a single agent, including third-generation agents, is feasible in patients with a good performance status, and has yielded promising results with acceptable toxicity: preliminary results from randomized phase III trials with combination chemotherapy as a comparator suggest similar efficacy, with a better toxicity profile for the experimental arm. So far, a single agent followed by a doublet failed to demonstrate a benefit over classic combination chemotherapy. However, combination chemotherapy might not be the best comparator, because single-agent chemotherapy can be considered as standard for some of these patients.

The use of sequential single agents should only be considered in selected patients, that is, elderly and frail patients who are not candidates for a platinum-based combination.

Further studies should focus on identifying the optimal sequence of drugs/regimens to be used and to define the role of sequential strategy versus classic combination chemotherapy.

	ALTERNATING CHEMOTHERAPY IN ADVANCED NSCLC

Top Learning Objectives Abstract Introduction Methods Sequential Chemotherapy in NSCLC Alternating Chemotherapy in... Consolidation/Maintenance... Conclusions Disclosure of Potential... References

 
Alternating chemotherapy is the alternating administration of non–cross-resistant drugs or drug combinations either for a defined number of cycles or until disease progression. The rationale for alternating chemotherapy is provided by the Goldie and Coldman hypothesis predicting that maximum tumor killing can be achieved when alternating non–cross-resistant agents are used as early as possible and at their optimal doses [35, 36]. In addition, the alternating administration of different drugs may avoid or limit the cumulative toxicity observed with the concomitant administration of the same drug/drug combination. Because of the alternating schedule, the evaluation of the response to each drug/drug combination in order to identify the most active drug(s) is difficult and a tailored maintenance/consolidation treatment with the most active drug/regimen is generally not feasible.

Moving from encouraging experiences with alternating non–cross-resistant chemotherapy in small-cell lung cancer [37], the first trials evaluating this approach in advanced NSCLC date back to the 1980s and early 1990s. At that time, there was growing evidence for the effectiveness of platinum-based combination chemotherapy in this setting, compared with best supportive care (BSC). Etoposide, vindesine, cyclophosphamide, doxorubicin, methotrexate, mitomycin C, and lomustine were the agents most frequently used in combination with cisplatin. In an attempt to improve clinical outcome, three- and four-drug platinum-based combinations were evaluated and were also included in alternating chemotherapy trials (Table 2).

A Japanese trial compared a doublet with a triplet and with an alternating treatment: vindesine and cisplatin (VP) versus mitomycin, vindesine, and cisplatin (MVP) versus etoposide and cisplatin alternating with vindesine and mitomycin (EP/VM) [39]. The response rate observed with the alternating treatment was significantly lower than that obtained with MVP (19% versus 43%; p < .01). However, no differences were reported in terms of median survival (VP, 50 weeks; MVP, 42 weeks; EP/VM, 40 weeks) and toxicity, except grade 3–4 thrombocytopenia, which was higher in the MVP than in the VP arm (22% versus 5%; p < .01) [39].

In a phase III trial, Eagan and coworkers compared the alternating administration of two triplets, namely, cyclophosphamide, doxorubicin, and cisplatin (CAP) and mitomycin, lomustine, and methotrexate (MCM), continued up to progression, with CAP followed by MCM on progression (second-line MCM) [40]. No statistically significant differences were found in terms of response rate (39% in both arms), time to progression (2.1 versus 4.4 months), or overall survival (5.5 versus 6.9 months) between the two treatments [40].

Several phase II trials assessed the activity and toxicity of other alternating regimens containing platinum and second-generation agents [41, 42]. Overall, these trials demonstrated an acceptable toxicity profile but efficacy was disappointing, suggesting no improvement in comparison with other nonalternating classic combinations.

In the past decade, alternating chemotherapy trials including third-generation agents have been conducted. To date, only phase II trials testing either alternating doublets with or without platinum [43–47] or alternating single agents [48–50] have been reported.

In a randomized phase II trial, Pérol et al. [44] evaluated a treatment alternating docetaxel with cisplatin plus vinorelbine. The control arm of this noncomparative trial was cisplatin plus vinorelbine. In the alternating chemotherapy arm, the response rate was low (10.8%, compared with 25% in the control arm). The time to treatment failure, median survival time, and 1-year survival rate were 10.2 weeks, 29.1 weeks, and 39% in the alternating arm compared with 17.3 weeks, 39 weeks, and 42% in the control arm. Although toxicities were similar, early treatment discontinuation as a result of toxic events was more frequent in the alternating arm (23.7% versus 9.7%). These results were disappointing, discouraging further evaluation of this regimen in a phase III trial.

Three phase II trials have evaluated the alternating administration of single-agent chemotherapy. Mattson and coworkers reported an alternating regimen of docetaxel and cisplatin at full doses [48]. A platinum-free regimen of alternating weekly administration of paclitaxel and gemcitabine was reported by Aguiar and coworkers [49]. In a randomized study, Gridelli et al. [50] have compared an alternating regimen of pemetrexed and gemcitabine with single-agent pemetrexed in elderly or poor performance status patients. These treatments were feasible and response, toxicity, and survival data compared favorably with those of platinum-based combination chemotherapy. Comparative trials to confirm these findings are warranted [50].

Dose-dense alternating chemotherapy in advanced NSCLC has also been evaluated. In a phase I study, Vokes and colleagues investigated the feasibility of the rapidly alternating administration of cisplatin plus vinorelbine and docetaxel plus gemcitabine with the prophylactic use of G-CSF [45]. Despite the use of G-CSF, the initial dose intensity could not be maintained because of cumulative myelosuppression; dose reductions and an extension of cycle duration were required [45]. In an attempt to maximize the dose intensity of the agents, multifractionated dosing chemotherapy with alternating doublets or triplets was investigated by Lokich and Colleagues [51]. The rationale for a multifractionated dosing schedule is provided by the possibility that the weekly or biweekly administration of chemotherapy may increase tumor killing by increasing the frequency of tumor cell exposure to antineoplastic drugs and may reduce severe acute toxicity by real-time monitoring and withholding dose fractions with lower grade toxicity. In these dose-finding studies, efficacy results are encouraging; hematologic toxicity is usually dose-limiting and requires the use of G-CSF. No comparative trials have been reported to determine whether multifractionated dosing chemotherapy can improve the activity and toxicity profiles over those of combination chemotherapy. However, the evaluation of dose-dense chemotherapy in a palliative setting aimed at prolonging survival and improving quality of life can be criticized; it should be limited to the neoadjuvant and adjuvant setting.

Alternating Chemotherapy: Conclusions
The alternating administration of non–cross-resistant drugs or drug combinations has gained increasing attention in recent years. Based on trials published so far, it is unlikely that an alternating chemotherapy strategy will prove to be superior to combination chemotherapy in advanced NSCLC patients with a good performance status, in terms of activity, survival, and tolerability. Hence, no further evaluation of alternating chemotherapy with currently available cytotoxic drugs is recommended for these patients. However, alternating single-agent chemotherapy may be appropriate in the elderly or in patients with impaired performance status. Several phase II trials have demonstrated that alternating single-agent chemotherapy including third-generation drugs is active and feasible in this setting: further evaluation in randomized phase III trials is required, and besides survival and time to progression, quality of life is a mandatory endpoint in these trials.

	CONSOLIDATION/MAINTENANCE CHEMOTHERAPY

Top Learning Objectives Abstract Introduction Methods Sequential Chemotherapy in NSCLC Alternating Chemotherapy in... Consolidation/Maintenance... Conclusions Disclosure of Potential... References

 
The definition of consolidation versus maintenance is unclear in the literature and these terms are often used with the same meaning. Thus, we considered consolidation and maintenance trials together. Maintenance/consolidation chemotherapy is the prolongation of chemotherapy duration with the administration of additional drugs at the end of a defined number of initial chemotherapy cycles, after achieving a maximum tumor response in an individual patient. In the absence of significant toxicity, maintenance chemotherapy is continued either for a defined time or until evidence of progressive disease. Maintenance/consolidation chemotherapy consists of either a drug included in the induction regimen or another non–cross-resistant agent, used at a relatively low dose. In consolidation/maintenance trials, the population is heterogeneous. In some studies, only patients achieving a complete or partial response are candidates to receive maintenance/consolidation chemotherapy; in other studies, patients with stable disease at the end of induction chemotherapy are also eligible. The rationale for maintenance/consolidation chemotherapy is provided both by the Goldie and Coldman hypothesis [35], stating that the early use of non–cross-resistant agents might increase the probability of killing more cancer cells before resistance arises, and by the Day model [6], indicating that the most active drug/regimens should be used as a consolidation treatment to optimize results. 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/consolidation chemotherapy with one of the drugs included in the induction regimen.

To date, few clinical trials have assessed maintenance/consolidation chemotherapy in advanced NSCLC. Three randomized trials have been published evaluating a third-generation agent (i.e., paclitaxel, gemcitabine, vinorelbine) as maintenance therapy after a platinum-based induction chemotherapy in advanced NSCLC (Table 3). Unfortunately, these trials entered only a small number of patients into the maintenance phase of the study, limiting the statistical significance of the results. In a randomized phase II trial, Belani and coworkers explored the feasibility of maintenance therapy with weekly paclitaxel versus observation, following three regimens of carboplatin plus paclitaxel as initial therapy [52]. Only patients who achieved at least a partial response were randomized. 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. Westeel and colleagues compared maintenance therapy using vinorelbine with observation, after response to induction treatment with two cycles of mitomycin, ifosfamide, and cisplatin (MIC), followed by radiotherapy or four cycles of MIC in stage IIIB or wet IIIB/IV NSCLC, respectively [53]. Despite an improvement in response in 14% of the patients during the maintenance therapy with vinorelbine, no difference was observed in terms of time to progression or survival compared with the observation arm. This disappointing result is consistent with the poor activity reported for vinorelbine in second-line NSCLC following platinum-based chemotherapy [54]. Moreover, the toxicity of maintenance vinorelbine seemed higher than that of vinorelbine given to chemotherapy-naive patients in phase III trials comparing vinorelbine with vinorelbine plus cisplatin [28, 55]. It can be argued whether or not the cumulative toxicity of maintenance vinorelbine can be decreased with a different choice of induction chemotherapy regimen (i.e., a platinum-based third-generation doublet instead of MIC).

Based on the efficacy of pemetrexed in second-line NSCLC, a randomized phase III, double-blind study of maintenance pemetrexed plus BSC versus placebo plus BSC is currently ongoing (the NCT 00102804 trial).

Several phase II trials have evaluated other agents as maintenance therapy in advanced NSCLC following platinum-based induction therapy. Maintenance with interferon-2a [58], interferon- [59], bexarotene [60], uracil-tegafur [8], or BLP25 liposome vaccine [61] seems feasible, but it is unclear whether these agents are really effective.

New molecular targeted agents (i.e., inhibitors of the epidermal growth factor receptor tyrosine kinase) are worth evaluation as maintenance treatment. Recent trials of combination chemotherapy with targeted agents include a maintenance phase with the same agent in monotherapy until disease progression [62–65]. Despite the fact that these studies were not specifically designed to establish the role of consolidation with new drugs in the treatment of advanced NSCLC, unplanned subanalyses for patients treated with maintenance therapy provided interesting results. In particular, in the Iressa® NSCLC Trial Assessing Combination Therapy (INTACT)-2 trial of carboplatin plus gemcitabine with or without gefitinib, in which no survival benefit was reported in the experimental arm, there was a trend toward longer survival in the subgroup of patients with adenocarcinoma who had received chemotherapy for 90 days in the gefitinib 250 mg daily arm, suggesting a possible effect of single-agent gefitinib as maintenance therapy [62]. Indeed, biological agents, with their cytostatic effect, could work best in the presence of minimal disease, maintaining tumor regression after response to chemotherapy. Supported by these preliminary observations, well-conducted randomized studies are needed to further investigate these agents as maintenance treatment.

Consolidation/Maintenance Chemotherapy: Conclusions
Consolidation/maintenance chemotherapy is feasible and may provide additional benefit after standard first-line chemotherapy given for up to six cycles, also referred to as induction chemotherapy. A benefit is likely to be observed when consolidation/maintenance chemotherapy consists of an agent that has been proven to be active in the induction phase. In fact, induction chemotherapy can be considered as an in vivo assay to test the chemosensitivity of each individual patient to the drugs used in the induction phase. Further evaluation of consolidation/maintenance chemotherapy in responding patients, using one of the drugs administered in the induction phase, as well as consolidation/maintenance therapy with targeted agents, is warranted in randomized trials.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Methods Sequential Chemotherapy in NSCLC Alternating Chemotherapy in... Consolidation/Maintenance... Conclusions Disclosure of Potential... References

 
Classic chemotherapy with existing drugs in advanced NSCLC has reached a plateau. In an attempt to improve survival, quality of life, and tolerability, other chemotherapy approaches (i.e., sequential chemotherapy, alternating chemotherapy, and consolidation/maintenance chemotherapy) have been explored. Sequential chemotherapy with a platinum-based doublet followed by a single agent seems to have similar efficacy and a better toxicity profile, compared with a standard platinum-based regimen in patients with a good performance status. For elderly and frail patients who are not candidates for a platinum-based combination, sequential single agents may be considered.

Alternating chemotherapy does not seem to be superior to combination chemotherapy in advanced NSCLC patients with a good performance status, in terms of activity, survival, and tolerability. However, alternating single-agent chemotherapy may be appropriate in the elderly or in patients with impaired performance status.

Consolidation/maintenance chemotherapy with an agent that has been proven to be active in the induction phase may provide additional benefit after standard first-line chemotherapy.

Because of the heterogeneity and the limited number of comparative trials reported so far, the interpretation of results is not univocal and final results of large randomized trials comparing these strategies with standard combination chemotherapy are awaited with interest. In the meantime, sequential, alternating, and consolidation/maintenance chemotherapy should still be considered investigational.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning Objectives Abstract Introduction Methods Sequential Chemotherapy in NSCLC Alternating Chemotherapy in... Consolidation/Maintenance... Conclusions Disclosure of Potential... References

 
F.G. receives support from Sanofi-Aventis.

	REFERENCES

Top Learning Objectives Abstract Introduction Methods Sequential Chemotherapy in NSCLC Alternating Chemotherapy in... Consolidation/Maintenance... Conclusions Disclosure of Potential... References

 

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