Contents
24.1 Background . . . 305
24.2 Docetaxel . . . 305
24.3 Pemetrexed . . . 307
24.4 Other Agents on Trial . . . 307
24.4.1 Vinorelbine . . . 308 24.4.2 Gemcitabine . . . 308 24.4.3 Inhibitors of Topoisomerase I . . . 309 24.4.3.1 Irinotecan . . . 309 24.4.3.2 Topotecan . . . 309 24.4.4 Taxanes . . . 309 24.5 Targeted Therapy . . . 310 24.5.1 EGFR Inhibitors . . . 311 24.5.1.1 Gefitinib . . . 311 24.5.1.2 Erlotinib . . . 311 24.5.1.3 Cetuximab . . . 311 24.5.1.4 Neoangiogenesis Inhibitors ± Bevacizumab . . . 311 24.6 Conclusions . . . 311
24.1 Background
Chemotherapy for non-small-cell lung cancer (NSCLC) patients with stage IIIB or IV has only a palliation role, since their disease is incurable and the 5-year survival is less than 2% [1, 2]. Best supportive care (BSC) offers to this group of patients only 3.6 months (range 2.4± 4.9 months), while platinum-based chemotherapy offers an improvement in the median overall survival time of 6±8 weeks. It has also doubled the 1-year survival rate and demonstrated important gains in secondary end points of clinical trials, such as the time to disease pro-gression and the quality of life [3±5]. Based on the re-sults of several randomized clinical trials and meta-ana-lyses, the American College of Chest Physician Lung Cancer Guidelines Committee approved the administra-tion of chemotherapy to fit patients with advanced-un-resectable or metastatic disease, with grade of recom-mendation A. Currently, the platinum-based regimens
comprise the gold standard as first-line treatment for advanced and metastatic.
Despite the undoubted gains from chemotherapy for stage IIIB or IV NSCLC patients, a proportion of ap-proximately 50% of those who have received first-line platinum-based regimens will relapse during treatment or soon after completing it. These patients might be young, with good performance status, and their disease is expressed with only minor symptoms. In addition, clinical oncologists often come across patients with re-fractory disease who are willing to accept considerable toxicity in order to achieve a small prolongation in sur-vival. Once the disease progresses the median survival time is approximately 3months. It is clear that there is strong motivation for these patients to receive second-line chemotherapy [3, 6±10].
24.2 Docetaxel
Until recently the role of second-line chemotherapy was undefined. Fossella and colleagues tried to review the data surrounding this field of chemotherapy, with dis-appointing results. The majority of studies were small single-institute studies in which drug dosages and schedules were totally different and response rates were not reported. Moreover, no phase III clinical trials had been conducted. However, the agent demonstrating the most consistent responses in the second-line setting was docetaxel, which was evaluated in refractory plati-num-based patients in seven phase-II clinical trials. A total of 312 participants received 100 mg/m2 docetaxel
every 3weeks, resulting in response rates ranging from 14 to 24%, median overall survival time greater than 7 months, and 1-year survival rates ranging from 25 to 44% [11].
Docetaxel is a second-generation taxane that is de-rived from the needles of the European yew tree. It has a large spectrum of antitumor activity that is expressed basically by inhibiting microtubule dynamics. The prin-cipal mechanism of action for both taxanes (docetaxel and paclitaxel) is to promote microtubulin assembly
Second-Line Chemotherapy
for Non-Small-Cell Lung Cancer
Eleni Karapanagiotou and Konstantinos N. Syrigos
and stabilize the polymers against depolymerization. Docetaxel has exhibited documented cytotoxicity in murine tumor models and human tumor xenografts, and this preclinical promise has successfully translated into clinical practice. Several clinical trials have proved the efficacy of docetaxel in NSCLC patients in front-line treatment as combination therapy or monotherapy.
A large randomized phase-III clinical trial (TAX317) has been conducted to determine whether docetaxel as a single agent is effective in the second-line treatment of NSCLC patients. The primary outcome measure was survival and secondary end points were response rate, time to progression, toxicity, and quality of life. Eligible participants were those who had documented progres-sive disease after receiving a platinum-containing (cis-platin or carbo(cis-platin) regimen, but not a taxane. Forty-nine patients received 100 mg/m2 docetaxel and 55
re-ceived 75 mg/m2 docetaxel once every 21 days, while
the control group of 100 patients received only BSC. The docetaxel dosage changed from 100 mg/m2 to
75 mg/m2during the study due to an unacceptably high
toxic death rate in the experimental arm. The results of this trial were really encouraging. The median overall survival was 7.0 months for the chemotherapy arm and 4.6 months for the BSC arm, while the 1-year survival rates for the chemotherapy and BSC arm were 29 and 19%, respectively, and the overall response rate was 7%. The key point of this clinical trial was the docetaxel dosage. Prolongation of median overall survival was seen with both doses of docetaxel, but the most marked improvement was associated with the lower dose, for which the 1-year survival rate was significantly higher, at 37%. Moreover, the prolongation of patients' life was in line with the improvement of patient quality of life (well-being). The quality-of-life analysis demonstrated less worsening of performance status and less common use of tumor-related medications for docetaxel patients. Only 32% of docetaxel patients versus 49% of the BSC arm required morphine-equivalent medication for the pain, and 39% versus 55% patients, respectively, re-quired nonmorphine analgesics. Palliation radiotherapy was required for fewer docetaxel patients (26%) than BSC patients (37%). The safety profile of docetaxel ad-ministration was satisfactory. Grade 3or 4 neutropenia occurred in 67% of those patients administered 75 mg/ m2docetaxel, and only one patient (1.8%) developed
fe-brile neutropenia. Grade 3or 4 anemia occurred in three (5.5%) patients at the lower dose. Severe throm-bocytopenia was observed in less than 1% of the pa-tients, without any reported bleeding episodes. Non-hematological toxicities were similar, although some-times worse for the BSC patients in terms of more asth-enia and neurotoxicity. This trial concluded that good-performance NSCLC patients who have progressed after receiving a platinum-based regimen should be offered the chance of a second-line docetaxel-based chemother-apy with the aim of prolongation of survival as well as
a significant improvement in disease-related symptoms [11, 12].
In another phase III trial (TAX320) that examined the efficacy of docetaxel as second-line chemotherapy in NSCLC patients, 373 patients who had received 1 or more platinum-based regimens with no exclusion of prior exposure to paclitaxel were randomized to 3arms: the first received 100 mg/m2 docetaxel, the second
75 mg/m2 docetaxel (both arms in a cycle of 21 days),
and the control arm was represented by 123patients who received either vinorelbine (n=89) or ifosfamide (n=34). The 1-year survival rate was significantly great-er in docetaxel-treated patients (32% at 75 mg/m2 and
21% at 100 mg/m2) compared to the
vinorelbine/ifosfa-mide-treated patients (19%). There was only a trend to-ward improved overall survival for the docetaxel group, although 26-week progression-free survival was signifi-cantly favored for the docetaxel-treated patients. Both docetaxel arms presented a slight increased hematologi-cal toxicity, the incidence of febrile neutropenia being 8% for those receiving the lower docetaxel dose, com-pared to 1% for the control arm. The nonhematological side effects were similar across treatment groups [13].
A finding from this trial that was of important clini-cal significance was that prior paclitaxel therapy did not predict the likelihood of a patient's response to doc-etaxel. This was proved by the partial response rates be-tween patients with prior paclitaxel therapy (n=91) and those without paclitaxel exposure (n=157), which were rather equivalent at 10.5% and 8.5%, respectively [13].
In an attempt to minimize docetaxel toxicity, three clinical trials were conducted whereby the standard dose of 75 mg/m2 every 3weeks was compared to one
weekly dose of 33 mg/m2. In a landmark analysis of a
total of 524 patients, no significant differences were found for either response rates or toxicity. The median time to progression and the overall survival were rather similar between arms, while the weekly administration of docetaxel was associated with less hematological tox-icity, the rate of severe neutropenia being particularly lower. In conclusion, weekly docetaxel represents an-other option for patients at risk for severe neutropenia and its consequences [14±16].
Although the recent advances in chemotherapy are welcome, the outcome expectations from chemotherapy administration remain slim. In economical terms, is it cost-effective to administer docetaxel as palliation ther-apy? A retrospective economic evaluation of docetaxel clinical trial (TAX 317) was undertaken using data from the 63patients using the Canadian health-care system in 1999. This analysis concluded that the cost per life-year gained by using docetaxel at the recommended dose of 75 mg/m2was approximately US$20,000, which
is similar to the care expenditures for palliative che-motherapy of other solid tumors [17].
There is an increasing body of evidence suggesting that the administration of second-line treatment in fit
patients who are experiencing progressive disease after receiving platinum-containing regimens is recom-mended. In this context, the USA Food and Drug Ad-ministration (FDA) and the European Agency for the Evaluation of Medical Products approved Docetaxel as standard treatment in the second-line setting.
24.3 Pemetrexed
Patients who are candidates for second-line chemother-apy expect only a modest prolongation of life and a bet-ter quality of life with minimal disease symptoms. They are eager to receive chemotherapy, but at the same time are reluctant to spend a considerable part of their lim-ited life in hospital due to treatment-related complica-tions. Due to its toxicity profile, docetaxel is still greeted with a degree of unease and there have been at-tempts to identify new compounds with the same effi-cacy but reduced toxicity. One such compound, a novel chemotherapeutic agent, is pemetrexed (Alimta). It is the first multitargeted antifolate with minimal pyrimi-dine nucleus differences from the common antifolates. Pemetrexed inhibits more than one enzyme in the cell cycle, including thymidylate synthase, dihydrofolate re-ductase, glycinamide ribonucleotide formyl transferase, aminoimidazole carboxamide ribonucleotide formyl-transferase, and is implicated in the inhibition of pyri-midine and purine synthesis. The fact that a tumor is composed of a heterogeneous group of cells with vary-ing predominant enzymes may provide an explanation regarding the multitargeted cytotoxid mechanisms of action of pemetrexed [18].
Several trials on the efficacy and toxicity of peme-trexed in malignant mesothelioma and NSCLC patients have been conducted; these have found an increase in the response rates of accrued patients, but also in-creased side effects of the treatment. A retrospective analysis of serious adverse events was performed conse-cutively. Plasma levels of homocysteine, which represent a surrogate for folate nutritional status, and plasma lev-els of methylmelonic acid, which is an indicator of B12 vitamin status, were markedly elevated in patients with neutropenia, thrombocytopenia, and nonhematologic toxicities such as infection, mucositis, and diarrhea. There was also an increased death rate related to this new agent. After treatment with pemetrexed, patients were prescribed a daily dose of 350±1,000lg acid folic and 1,000lg vitamin B12, given intramuscularly every 9 weeks, resulting in a considerable improvement in drug toxicity [19±21].
Based on the results of several phase II clinical trials, Hanna and coworkers conducted a large phase III clini-cal trial in an attempt to examine the superiority of pemetrexed compared to docetaxel, the standard sec-ond-line chemotherapy. In the largest phase III clinical
trial of second-line therapy, 571 NSCLC patients were accrued who had documented disease progression after receiving only 1front-line regimen. Of these, 283pa-tients received 500 mg/m2 of pemetrexed once every
21 days with acid folic and vitamin B12 supplementa-tion, and 288 patients received 75 mg/m2 docetaxel in
the same cycle. Both arms received dexamethasone pre-medication. From the randomized patients, 90% had previously been treated with platinum regimens and 28% with taxanes regimens. This study met the primary and secondary endpoints. The overall response rates were 9.1% for the pemetrexed-treated group and 8.8% for docetaxel-treated group; both groups had the same 1-year survival rate. With regard to toxicity, pemetrexed presented a more safety profile with less episodes of hospitalization related to drug administration and fe-brile neutropenia (Table 24.1). The requirements for granulocyte colony-stimulating factor were increased in the docetaxel arm. Notably, due to vitamin B12 and acid folic supplementation, pemetrexed-related myelotoxicity, diarrhea, and mucositis were limited. The prophylactic use of dexamethasone lessened the occurrences and in-tensity of skin rash [22].
Based on data obtained from this clinical trial, in the summer of 2004 the USA FDA approved pemetrexed as a single-agent chemotherapy agent as an alternative to docetaxel in the second-line setting for NSCLC patients.
24.4 Other Agents on Trial
New agents have been tested in several clinical trials in the treatment of NSCLC patients, as monotherapy or in combination regimens. They can be divided into the following classes: mitotic spindle inhibitors (vinorel-bine), antimetabolites (gemcita(vinorel-bine), inhibitors of topo-isomerase I (irinotecan and topotecan), and taxanes (paclitaxel and docetaxel). If we exclude docetaxel and pemetrexed, which have been approved for use by the FDA as second-line chemotherapy agents, the new agents represent some options as salvage therapy in dif-ferent combinations.
Table 24.1. Phase III clinical trial: Pemetrexed vs. Taxotere.
G-CSFGranulocyte colony-stimulating factor
Toxicity Docetaxel Pemetrexed
Grade 3/4 neutropenia 40.2% 5.3% Febrile neutropenia 12.7% 1.9% Infections with grade 3/4
neutropenia 3.3% 0%
Requirements for G-CSFa 19.2% 2.6% Hospitalizations related to drug 13.4% 1.5%
Alopecia 37.7% 6.4%
24.4.1 Vinorelbine
Vinorelbine is a semisynthetic derivative of vinca rosea, the Madagascar periwinkle, which is used as an antimito-tic agent through its property of affecting the dynamics of spindle microtubules. Vinca alkaloids interact with tubu-lin subunits to prevent microtubule assembly, and conse-cutively induce chromosome segregation in dividing cells and cause aneuploidy. Vinorelbine has shown interesting results with respect to response rates, time to progres-sion, and median overall survival when was tested as sin-gle, first-line treatment; its basic treatment-related toxic-ity is neutropenia. It has been involved in few clinical trials as second-line treatment, and with moderate re-sults. There were no responses in two studies of patients who had previously failed to respond to platinum-based regimens, and in a third study a response rate of 20% was reported but with no other information [23±25].
Patient preference and the need for fewer visits in hospital, as well as concerns and difficulties with intra-venous access have driven the development of oral vi-norelbine. Several clinical trials have tried to evaluate the feasibility and safety profile of oral vinorelbine in treatment of recurrent NSCLC patients [26].
The feasibility of vinorelbine as an active agent in the salvage therapy of NSCLC patients has been explored in clinical trials in combination with other active agents such as platinol, carboplatin, docetaxel, and irinotecan. Ongoing studies are evaluating the tolerability and activ-ity of these combinations. Those studies evaluating the efficacy of vinorelbine in combination with either plati-nol or carboplatin are based on small numbers (range 17±44) of pretreated patients and use different regimens and schedules, although encouraging results regarding to objective responses and 1-year survival rate with ac-ceptable toxicity have been presented [27±30].
24.4.2 Gemcitabine
Gemcitabine is a novel deoxycytidine analogue that has been implicated in the inhibition of DNA and cellular apoptosis. It is a prodrug that, once transported into the cell, is phosphorylated by deoxycytidine kinase into an active form. This active form can be incorporated into the terminal part of elongating DNA strands, inhib-iting the activity of DNA polymerases. Gemcitabine is indicated in combination with cisplatin in the front-line treatment of inoperable NSCLC patients. Response rates of 20% have been demonstrated in several phase II trials, and so gemcitabine has been evaluated in pre-viously treated NSCLC patients at a dosage of 1,000 mg every 3±4 weeks. The published response rates range from 0 to 21% and the median overall survival was be-tween 5.5 and 9 months. The 1-year survival was scarcely reported. In conclusion, these results are not encouraging for the use of gemcitabine as monotherapy in salvage therapy [31±35].
However, better responses were obtained when gem-citabine and vinorelbine were combined in several phase II clinical trials. The number of patients enrolled in these was small and larger studies should therefore be performed. Excluding the Camps study, which en-rolled 16 patients and presented disappointing results with only 1 complete responder, no partial responders, and a median survival of 25 weeks [36], the following studies present a hint of success, which translates into a median survival ranging from 6.5 to 8.5 months and a 1-year survival rate reaching 35%. Further evaluation of this combination is needed and may represent another option for relapsing patients after receiving a platinum± taxane combination in the front-line setting (Table 24.2) [37±42].
Table 24.2. Clinical trials phase II of combination gemcitabine plus navelbine in second-line setting
Hainsworth [37] Kosmas [38] Pectasides [39] Herbst [40] Chen [41] Park [42]
Dose and schedule V 20 mg/m2 G 1,000 mg/m2 days 1, 8, 15, q28d V 25 mg/m2 G 1,000 mg/m2 days 1, 8, q21d V 25 mg/m2 G 800 mg/m2 days 1, 8, q21d V 25 mg/m2 G 900 mg/m2 days 1, 8, 15, q21d V 20mg/m2 G 800 mg/m2 days 1, 8, 15, q28d V 30 mg/m2 G 1,000 mg/m2 days 1, 8, q21d Pts (n) 55 40 39 78 (36) 17 38 Prior CHT (%) 85 100 100 46 100 100 PR (%) 18 22.5 2.6 17 31.3 21 SD (%) 48 32.5 35.9 50 N/R 55 TTP (months) 5 4.5 4.7 N/R 4.6 3.9 Median survival (months) 6.5 7 7.38.5 8.3 8.1 One-year survival (%) 20 17 35 30 34 N/R Grade 3±4 neutropenia (%) 36 33 5.2 67 52.9 28 Grade 3±4 thrombocy-topenia (%) 22 0 0 13.9 17.64 N/R
VVinolrebine,Ggemcitabine,Ptspatients,CHTchemotherapy,PRpartial response,SDstable disease,TTPtime to progression,
24.4.3 Inhibitors of Topoisomerase I
The topoisomerases (I and II) are nuclear enzymes that play a role in DNA synthesis and transcription. The role of both enzymes in the cell cycle is to relieve DNA tor-sional strain by forming a reversible complex with it and by introducing transient enzyme-bridged strand breaks. When the transcription is finished, the enzymes reseal the break and dissociate from the DNA. Topoiso-merase inhibitors play a role in the stabilization of to-poisomerase in a complex with DNA, resulting in dou-ble- stranded DNA break and subsequent programmed cell death. Examples of topoisomerase I inhibitors are irinotecan and topotecan, and these represent an inter-esting class of agents for the treatment of NSCLC.
24.4.3.1 Irinotecan
Preclinical studies suggest that irinotecan has a sub-stantial activity either alone or in combination with other agents in palliation therapy of NSCLC. There are several small studies exploring the efficacy of irinotecan in the second-line setting, reporting response rates be-tween 0 and 29% [43±45]. Unfortunately, when this nov-el agent was added to docetaxnov-el in a combination regi-men and compared to standard second-line chemother-apy docetaxel at 75 mg/m2 in a 3-weekly schedule in
two large phase II clinical studies, not only was there no improvement in response rates and 1-year survival rates, there was also increased gastrointestinal toxicity [46, 47]. Moreover, irinotecan has been studied in phase II clinical trials as a second-line treatment, in more than one combination with docetaxel, vinorelbine, cis-platin, capecitabine, or gemcitabine. The reported re-sults showed response rates ranging between 29 and 48% and median survival ranging between 25 and 32 weeks, while the reported hematologic and nonhem-atologic toxicities were acceptable (Table 24.3) [48±52]. In a phase II study, Georgoulias and coworkers com-pared the combination of irinotecan and gemcitabine
versus irinotecan in docetaxel- and cisplatin-pretreated patients (n=147). The response rates were 18.4% and 4.2%, respectively in the two arms. The combined schedule resulted in a higher response rate but without any improvement in the overall survival [53].
24.4.3.2 Topotecan
Topotecan is a semisynthetic derivative of camptothecin, which has been approved for the second-line treatment of small-cell lung cancer and ovarian cancer. In several phase II clinical trials in previously untreated patients with advanced NSCLC, the intravenous administration of topotecan at a dose of 1.5±2 mg/m2/day for 5
conse-cutively days resulted in moderate response rates of 15± 16%, and another study reported stable disease in half of the enrolled patients [54±56].
In the second-line setting, topotecan was evaluated in combination with gemcitabine in a small trial. Thirty-five previously treated patients received 0.75 mg/ m2topotecan and gemcitabine 400 mg/m2for 5 days in
a 3-week cycle. A partial response was experienced by 11% of the participants, and another 23% experienced stable disease. The median survival time was 7 months and the 1-year survival rate was 20%. Modest hemato-logic toxicity was observed [57].
An oral formulation of topotecan has been tested in a large, 800-patient study as second-line treatment in NSCLC patients. Topotecan at a dose of 2.3mg/m2
(giv-en orally) for 5 consecutive days in a 21-day cycle has been compared to standard-therapy docetaxel 75 mg/ m2; the trial results are pending.
24.4.4 Taxanes
Paclitaxel, like docetaxel, is a microtubule stabilizer that results in cell cycle arrest and impairment of mitotic progression. Paclitaxel has been investigated extensively in several solid tumors including NSCLC. It has gained a position in the front-line treatment of NSCLC patients Table 24.3. Irinotecan in several combinations as second-line treatment
Font [48] Gonzalez [49] Kakolyris [50] Nakanishi [51] Han [52]
Schedule I 70 mg/m2, D 25 mg/m2days 1, 8, 15, q28 d I 300 mg/m2day 1 V 30 mg/m2days 1, 14, q28d I 100 mg/m2days 1, 8 P 80 mg/m2day 8, q21d I 60 mg/m2 P 30 mg/m2days 1, 8, 15, q28d I 90±100 mg/m2 days 1, 8 C 2,000 mg/m2days 1±14 q21d Pts (n) 51 33 44 21 37 RR% 4348 42 29 45.7
Median survival 8 months 25 weeks 8 months 32 weeks 7.4 months (6-month follow up) One-year survival
(%) 30 N/A N/A 43 N/A
Toxicity Mild Mild Increased Increased Acceptable
in combination with other active agents. Paclitaxel has also been investigated as a single agent in the second-line setting of this target group. The results from sev-eral clinical trials using paclitaxel at very different doses and schedules show a clinical benefit rate ranging from 0 to 42% and median overall survival ranging from 16 to 52 weeks with acceptable toxicities. In summary, pac-litaxel represents a favorable chemotherapeutic approach in this setting (Table 24.4) [58±70].
In an effort to maximize the efficacy of paclitaxel, it was combined with other active agents such as gemcita-bine, cisplatin, and irinotecan in small phase II studies. These combinations resulted in active schemes with ac-ceptable levels of toxicity, but future trials will clarify the role of paclitaxel-based combinations in the salvage therapy of NSCLC patients. In a randomized study in-cluding 71 patients, weekly administration of docetaxel at a dose of 36 mg/m2was compared to weekly
admin-istration of paclitaxel at a dose of 80 mg/m2for 6 weeks
followed by a 2-week rest. Partial response was experi-enced by one and five patients, median time to progres-sion was 74 and 68 days, and the median overall surviv-al was 184 and 105 days with docetaxel and paclitaxel, respectively. Both taxanes showed a discrete efficacy in this population [71].
An oral formulation of taxane under the code name BMS-275183has been approved for participation in combination with pemetrexed in a clinical phase I±II study in patients with recurrent pretreated NSCLC [72].
24.5 Targeted Therapy
Even with the introduction of new antineoplastic agents and more effective chemotherapeutic combinations, the prognosis for refractory NSCLC patients receiving sec-ond-line chemotherapy remains dismal. Recently, our knowledge of molecular oncology has significantly in-creased, endorsing recognition of the main signaling pathways that promotes malignant cell transformation. This in turn has raised hopes for the development of a novel therapeutic strategy that would target neoplastic cells, whilst minimizing both damage to noncancerous cells and any side effect resulting from the given thera-py.
Two main representatives of targeted therapy have been explored in this subpopulation of patients, the epi-dermal growth factor receptor (EGFR) pathway inhibi-tors and the neoangiogenesis inhibiinhibi-tors.
24.5.1 EGFR Inhibitors
The EGFR family autocrine pathway plays a critical role in the malignant and metastatic development potential of NSCLC. Ligands binding to their extracellular do-main initiate a molecular cascade that promotes cellular proliferation and differentiation. EGFR targeting can be achieved through two principal mechanisms: (1) through monoclonal antibodies that prevent ligand binding, or (2) by means of small-molecule tyrosine-kinase inhibitors (TKIs) that inhibit the adenosine tri-phosphate binding site of the growth factor receptor. Table 24.4. Paclitaxel as a single agent in phase II clinical trials in the second-line setting
Tan
[58] Murphy[59] Ruch-deschel [60] Hains-worth [61] Nau-man [62]
Socins-ki [63] Chang[64] Juan[65] Socins-ki [66] Sculier[67] Buc-cheri [68] Ceresoli [69] Yasuda[70] Sched-ule 135±400mg/m2, 24-h 175 mg/ m2, 3 -h 175±200 mg/m2, 24-h 250 mg/m2, 24-h 200 mg/m2 135 mg/ m2, 1-h 130±175 mg/m2, 1-h 140 mg/m2, 96-h 50±100 mg/m2, weekly 80 mg/m2, weekly 80 mg/m2, weekly 225 mg/m2, 1-h 100 mg/m2, weekly 80 mg/m2, weekly 80 mg/m2, weekly Pts (n) 11 40 14 16 10 16 131340 62 67 38 55 39 Clinical benefit (%) 9 22.5 28.5 38/0 N/R 31 N/R 37.5 8 27 42 36 31 Median
survival N/R N/R months4 N/R 10months N/R N/R 9.7months 5.2months 4.5months 58weeks N/R 43weeks
One-year survival (%)
N/R N/R N/R N/R 45 N/R N/R N/R 20 19 N/R N/R N/R
Toxicity N/R Mild Mild N/R N/R Mild N/R Mild Mild
Accept-able Mild Mild Accept-able
Gefitinib and erlotinib act as TKIs, while cetuximab is a monoclonal antibody that targets the extracellular do-main of the human EGFR.
24.5.1.1 Gefitinib
Gefitinib has been approved for NSCLC patients as third-line treatment after receiving platinum- and doce-taxel-based regimens. Its approval by the FDA was based on the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL 2) study, which showed a response rate of 10.6% and a symptom improvement rate of 40% without the existence of any randomized trial demon-strating superior survival rates for patients treating with this drug [73]. The data obtained in two clinical studies suggesting the administration of gefitinib as monotherapy and not in combination with chemother-apy is of great clinical importance [74]. Gefitinib treat-ment appears to be more efficacious in nonsmoking women with bronchoalveolar carcinoma. Preliminary results of the SWONG 0126 trial showed a response rate of 12% in previously treated patients [75]. Gefitinib tox-icity is limited to diarrhea and skin rash and is gener-ally well-tolerated.
A large phase III clinical trial involving gefitinib is ongoing, with the purpose of comparing a dose of 250 mg/day (taken orally) to the standard second-line chemotherapy of docetaxel at 75 mg/m2every 3weeks.
The results are pending [76]. 24.5.1.2 Erlotinib
Erlotinib, the other orally available EGFR TKI that dem-onstrated a response rate of 26% in a trial involving pa-tients with bronchoalveolar carcinoma, was evaluated in a large phase III clinical trial compared to placebo. All 731 of the participants, had received 1 or 2 chemothera-peutic regimens and they were randomized in two arms. The results were encouraging. The median sur-vival was 6.7 and 4.7 months, the 1-year sursur-vival rate was 31% and 22%, and the time to progression was 2.23and 1.84 months for the erlotinib- and placebo-treated arms, respectively. Moreover, disease-related symptoms were better controlled in the erlotinib-treated group. Toxicity was limited to rash and diarrhea [77]. 24.5.1.3 Cetuximab
Cetuximab is a recombinant human/mouse chimeric IgG1 monoclonal antibody that targets the extracellular domain of the human EGFR. Its efficacy has been dem-onstrated in solid tumors. A multicenter, open-label, randomized, phase III clinical trial is currently open to recruitment for patients with relapsed NSCLC after fail-ure of initial platinum-based chemotherapy. Four ex-perimental arms are presented: cetuximab plus
docetax-el, cetuximab plus pemetrexed, docetaxel alone, or pem-etrexed alone [78].
24.5.1.4 Neoangiogenesis Inhibitors ± Bevacizumab Bevacizumab is a humanized anti-vascular endothelial growth factor antibody that is currently under investi-gation in a variety of solid tumors. Several ongoing studies are under way in NSCLC in front-line treatment as well as in salvage therapy. Phase II studies explore the efficacy of bevacizumab combinations with erlotinib and/or cetuximab in previously treated NSCLC patients.
24.6 Conclusions
The role of second-line chemotherapy is the subject of a longstanding debate. In 1997, the American Society of Clinical Oncology (ASCO) guidelines stated that it could be neither confirmed nor refuted that second-line che-motherapy improves survival in patients with advanced NSCLC [79]. One year later, the ASCO guidelines stated that second-line treatment may be appropriate for good-performance-status patients for whom an investi-gational protocol is not available or desired, or for pa-tients who respond to initial chemotherapy and then experienced a long progression-free interval off treat-ment [80]. Some years later, two large randomized phase III clinical trials with realistic and appropriate objectives were conducted. These trials showed a super-iority for docetaxel regarding survival prolongation and quality of life when it was compared either to BSC or chemotherapy. In addition, these studies presented an acceptable toxicity profile. As a result, some questions have been answered. Chemotherapy in the second-line setting is of value in fit patients, offering a survival and clinical benefit. The American College of Chest Physi-cians Lung Cancer Guidelines Committee approved the administration of second-line chemotherapy in plati-num-refractory NSCLC patients with grade of recom-mendation B [3]. An alternative to docetaxel che-motherapy is presented by pemetrexed, which achieves the same goals in treatment targets with minor toxici-ties. Moreover, several drug combinations are under in-vestigation in an attempt to be determine the best regi-men with the least toxic profile.
Although current data offer a hint of victory in this war, the research efforts have been driven to molecular oncology. Targeted therapies gain new ground in the second- line treatment of NSCLC patients. New anti-EGFR and antiangiogenesis agents are being widely in-vestigated in phase II and III clinical trials in combina-tion with chemotherapeutic agents or alone. Research advances are orientated toward the adoption of drugs tailored to the tumor's molecular profile, with the aim of greater efficacy and less toxicity.
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