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CANCER INVESTIGATION Vol. 21, No. 1, pp. 87104, 2003

CLINICAL SCIENCE REVIEW

Taxanes in the Treatment of Advanced (Stage III and IV) Non-small Cell Lung Cancer (NSCLC): Recent Developments
George R. Simon, M.D.,1,* and Paul A. Bunn Jr., M.D.2
1

Thoracic Oncology Program, H. Lee Moftt Cancer Center and Research Institute, Tampa, Florida, USA 2 University of Colorado Health Sciences Center, Denver, Colorado, USA

ABSTRACT
Taxanes, paclitaxel, and docetaxel have become the cornerstone of both rst-line and second-line chemotherapy for advanced non-small cell lung cancer (NSCLC). Recently, several pivotal phase III randomized trials have been published. These studies and phase II trials will be discussed. Additionally, studies utilizing a taxane and radiation therapy for resectable and locally advanced NSCLC will be outlined. The article will end with a discussion on newer strategies being currently explored to improve survival in advanced NSCLC. Key Words: Non-small cell lung cancer; Chemotherapy; Radiaion therapy; Cisplatin; Carboplatin; Paclitaxel; Docetaxel; Gemcitabine; Vinorelbine.

INTRODUCTION Among cancers, lung cancer continues to be the most common cause of death for both men and women. One hundred and fty-six thousand deaths were estimated from lung cancer in the year 2001.[1] Pathologists divide lung cancer into the small cell or non-small [non-small cell lung cancer (NSCLC)] histologies. The NSCLCs that include adenocarcinoma, squamous cell carcinoma, and large cell undifferentiated carcinomas comprise about 80% of all newly diagnosed

cases. After diagnosis is established, lung cancers are staged by radiographic, biopsy, and other techniques according to the WHO TNM staging system. Only 20 25% of cases are stage II or I. Most patients of NSCLC (75 85%) present in advanced stages of the disease at which point the disease is largely incurable with a median survival of 8 10 months with taxane-based therapy. In stage IV disease, combination chemotherapy has important palliative effects and produces measurable responses in approximately 30 40% of patients in phase II trials and 20 30% in co-operative group trials, with

*Corresponding author: George R. Simon, M.D., Thoracic Oncology Program, H. Lee Moftt Cancer Center and Research Institute, 12002 Magnolia Drive, Tampa, FL 33612, USA; Fax: (813) 979-3027. 87 DOI: 10.1081/CNV-120005919 Copyright q 2003 by Marcel Dekker, Inc. 0735-7907 (Print); 1532-4192 (Online) www.dekker.com

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two-thirds of the patients showing symptomatic improvement. Complete responses are rare and eventual progression is inevitable. Hence, there is a huge need for the development of newer agents and innovatively designed clinical trials to test these newer agents. One of the more exciting and newer class of anticancer drugs in the treatment of NSCLC are the taxanes. The rst and the prototypic taxane to emerge was paclitaxel (Taxol, Bristol Myers Squibb Oncology, Princeton, NJ). Paclitaxel was rst extracted from the bark of the pacic yew Taxus brevifolia in 1971. The drug was rst approved by the Food and Drug Administration (FDA) in 1992 for the treatment of refractory ovarian cancer. Subsequently, phase II and more recently phase III trials have been published in lung cancer, breast cancer, head and neck cancer, and bladder cancer. Docetaxel (Taxotere, Aventis, Antony, France) is a semisynthetic taxoid produced from the needles of the European yew Taxus baccata. The taxanes act primarily by stabilizing microtubules against depolymerization. The binding site for paclitaxel and docetaxel is identical and is the Nterminal 31 amino acid residue of the b-tubulin subunit in tubulin polymers.[2] The binding afnity of docetaxel is, however, 1.9-fold higher than paclitaxel. The taxanes induce polymerization of tubulin in the presence or absence of factors that are usually essential for this function, such as guanosine triphosphate (GTP).[2] The assembly of GTP-tubulin induced by docetaxel proceeds with a critical protein concentration that is 2.1-fold lower than that of paclitaxel.[2] Additionally, docetaxel induces Bcl2 phosphorylation at concentrations 100-fold less than those required for paclitaxel. The Bcl2 phosphorylation negatively regulates anti-apoptotic activity of Bcl2. Owing to these critical differences, the two taxanes may not be completely cross-resistant. Primary chemo-resistance to paclitaxel continues to be common in NSCLC. In a pivotal study by Monzo et al.,[3] b-tubulin mutations were shown to predict for paclitaxel resistance. Understanding of these and other resistance mechanisms needs further study. Phase I clinical trials with the taxanes began in 1990, with disease-specic clinical trials beginning in 1995. Both taxanes have shown impressive activity in previously untreated patients with NSCLC. Additionally, docetaxel has shown activity in the second-line treatment of metastatic NSCLC and is currently the only FDA approved drug for this purpose. The foci of this review are recently published phase II and phase III trials. Ongoing trials and future directions will also be discussed.

TAXANES IN THE TREATMENT OF STAGE IV (AND IIIB WITH MALIGNANT PLEURAL EFFUSION) NSCLC Randomized Trials with Paclitaxel Several important randomized studies have been published recently with one of the taxanes as the main component. These studies have been outlined in Table 1. In a landmark trial, where paclitaxel plus best supportive care (BSC) was compared with BSC alone in advanced NSCLC, Ranson et al.[4] reported their mature results. A total of 157 patients with stage IIIB or IV NSCLC who had received no prior chemotherapy were randomly assigned to receive either BSC alone (78 patients) or paclitaxel plus BSC (79 patients). Paclitaxel was administered as a 3 hr intravenous infusion at 200 mg/m2 every three weeks. The BSC included palliative radiotherapy, supportive therapy with corticosteriods, antibiotics, analgesics and blood transfusions, and other symptomatic treatment as and when needed. The primary end point of the study was survival. Time to disease progression, response rate, adverse events, and quality of life (QOL) were secondary end points. Survival was statistically signicantly better in the paclitaxel arm as compared to the BSC arm (median survival 6.8 vs. 4.8 months, P 0:037: The QOL was similar for both treatment arms except for the functional activities core, which favored the paclitaxel arm. Hence, the authors concluded that the addition of paclitaxel to BSC not only prolonged survival, but also improved certain aspects of QOL. On a relative basis, paclitaxel reduced the hazard ratio of death by 32%. This is similar to results in breast cancer and is superior to results achieved in lung cancer with cisplatin-based regimens. Two studies that compared the newer paclitaxelbased regimens to the older cisplatin and epipodophyllotoxin-based regimens are outlined below. Bonomi et al.[5] reported the updated results of an Eastern Cooperative Oncology Group (ECOG) trial (ECOG 5592) conducted in previously untreated stage IIIB/IV NSCLC patients. Paclitaxel was administered as a 24 hr infusion in two different dose levels of 135 and 250 mg/m2 [granulocyte-colony stimulating factor (G-CSF) was administered with the 250 mg/m2 arm]. Etoposide was given at a dose of 100 mg/m2 days 1 3. Each regimen was repeated every 21 days and cisplatin in all arms was given at a dose of 75 mg/m2. The characteristics of 599 patients were well-balanced across the three treatment groups. Superior survival was observed with the two paclitaxel regimens. Median survival was 9.9 vs. 7.6 months with etoposide/cisplatin. One-year survival was

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Taxanes in Treatment of Advanced NSCLC

Table 1. Authors Ranson et al. Bonomi et al.

Phase III randomized trials with paclitaxel. Pts 79 78 599 RR (%) NR NA 27 32 12 41 28 21 17.3 21.3 15.3 27 27 25 28 26 32 26 17 21.8 37.5 MS (mo) 6.8a 4.8 9.6 10 7.7 9.7 9.9 8.8 7.4 7.8 8.2 7.5 7.5 8.3 9.1 8.9 10.7 8.1 8.6 NA NA %1-Yr NR NR 37 39 32 17 18 36 31 31 35 36 33 33 38 37 44 NR NR NA NA [References] [4] [5]

Agents/schedule 3-hr paclitaxel 200 mg/m2 q 21 d best supportive care Best Supportive Care 24-hr paclitaxel 135 mg/m2, cisplatin 75 mg/m2 d1, q 21 d 24-hr paclitaxel 250 mg/m2, cisplatin 75 mg/m2 d1, q 21 d ( G-CSF) Etoposide l00 mg/m2 d1-3, cisplatin 75 mg/m2 d1, q 21 d 3-hr paclitaxel 175 mg/m2, cisplatin 80 mg/m2 d1 q 21 d Teniposide l00 mg/m2, cisplatin 80 mg/m2 d1 q 21 d Gemcitabine l,000 mg/m2 d 1, 8, 15 cisplatin l00 mg/m2 d1, q 28 d Docetaxel 75 mg/m2 d 1, cisplatin d 1, q 21 d 24-hr paclitaxel 135 mg/m2, cisplatin 75 mg/m2, q 21 d 3-hr paclitaxel 225 mg/m2, carboplatin AUC 6, q 21 d 3-hr paclitaxel 225 mg/m2, carboplatin AUC 6. q 21 d Vinorelbine 25 mg/m2/week, cisplatin l00 mg/m2 q 28 d 3-hr paclitaxel 200 mg/m2, carboplatin AUC 6, q 21 d 3-hr paclitaxel 200 mg/m2, cisplatin 80 mg/m2, q 21 d 3-hr paclitaxel 175/mg/m2, carboplatin AUC 6, q 21 d 3-hr paclitaxel 225/mg/m2, carboplatin AUC 6, q 21 d 3-hr paclitaxel 175 mg/m2, cisplatin 80 mg/m2 d 1, q 21 d Ciplatin l00 mg/m2 d 1 q 21 d 3-hr paclitaxel 200 mg/m2, carboplatin AUC 6, q 21 d 3-hr paclitaxel 200 mg/m2 d 1, gemcitabine l000 mg/m2 d 1 & d 8, q 21

Giaccone et al. Schiller et al.

Kelly et al. Gatzemeier et al. Kosmidis et al. Gatzemeier et al. Kosmidis et al.

152 162 288 293 292 290 184 181 279 284 90 88
b

[6] [7]

[8] [9] [10] [11] [12]

63 64

Pts, patients; RR, response rate; MS, median survival; mo, months; NR, not reported; NA, not applicable/available. a Statistically signicant difference. b Total number of patients enrolled in all three arms.

89

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also superior in the two paclitaxel arms with (38 vs. 32%, P 0:048: There was no difference in survival between the two paclitaxel arms. Since paclitaxel at 135 mg/m2 given as a 24 hr infusion plus cisplatin had the best efcacy with the least toxicity, it was picked to be the reference arm in the ECOG 1594 study detailed below. Giaccone et al.[6] of the European Organization for the Research and Treatment of Cancer (EORTC) reported their phase III randomized study comparing cisplatin plus teniposide (arm A) vs. cisplatin plus paclitaxel (arm B). Three hundred thirty-two patients with advanced NSCLC were randomized to receive cisplatin 80 mg/m2 on day one either in combination with teniposide 100 mg/m2 on days one, three, and ve, or with paclitaxel 175 mg/m2 as a 3 hr infusion on day one. Both regimens were given every three weeks. In arm A, there were one complete response (CR) and 44 partial responses (PR), and in arm B, there were two CRs and 61 PRs. There were no signicant differences in the median and one-year survival. (9.8 vs. 9.7 months and 41 vs. 43%, respectively, in arms A and B). The EORTC also reported the QOL assessment performed by certain centers. Arm B achieved a better score at week six for emotional, cognitive, and social functioning, global health status, fatigue, and appetite loss. Hence, although survival was not improved, arm B offered better palliation than arm A. This study used higher doses of teniposide (100 mg/m2) and there was considerable hematologic toxicity in both arms. Several randomized trials compared various new two-drug combinations. One of the most important of these studies reported is the ECOG 1594 study.[7] Approximately, 290 patients were enrolled in each of the four arms, consisting of 24 hr paclitaxel with cisplatin, 3 hr paclitaxel plus carboplatin, gemcitabine with cisplatin, and docetaxel plus cisplatin. The dose and schedule of administration are outlined in Table 1. There was no statistically signicant difference in response rates, median survival, or one-year survival in any of the arms (see Figs. 1 and 2). Time to treatment progression (TTP) was statistically signicantly better with cisplatin plus gemcitabine arm (4.4 vs. 3.5 months) compared to the reference arm of cisplatin and paclitaxel. The cisplatin gemcitabine arm was the only regimen where the cycles followed the four-weekly schedule in contrast to the other three arms where a three-weekly schedule was followed. Severe toxicity (grade III and grade IV) was lowest in the carboplatin/paclitaxel arm, especially in ECOG performance status of two patients. Another similar study of the Southwest Oncology Group (SWOG)[8] compared carboplatin plus 3 hr paclitaxel to vinorelbine plus cisplatin. Approximately

Figure 1. NSCLC.

ECOG 1594: Overall survival of stage IIIB

180 patients were enrolled in each arm. The response rates and median survival were similar at 27% and eight months, respectively. Hematological toxicity and nausea were higher on the vinorelbine cisplatin arm, whereas, peripheral neuropathy was increased in the paclitaxel carboplatin arm. More patients on the vinorelbine cisplatin arm experienced chemotherapy delays due to toxicity. Therefore, the authors favored paclitaxel carboplatin arm to be the reference arm for future studies owing to convenience and improved tolerability. Compared to cisplatin, carboplatin has a more favorable toxicity prole. Gatzemeier reported the results of a Pan-European study[9] in which patients were randomized to receive either carboplatin at an area under the curve (AUC) of 6 mg/mL min and paclitaxel at 200 mg/m2 over 3 hr or paclitaxel in the same dose with cisplatin at 80 mg/m2. A total of 618 patients were randomized with both regimens given every three weeks.

Figure 2. ECOG 1594: Overall survival of patients with stage IV NSCLC.

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Taxanes in Treatment of Advanced NSCLC

91

Response rates, median survival and 1-year survivals for carboplatin/paclitaxel vs. cisplatin/paclitaxel were 25% vs. 28% (P=0.45), 8.5 months vs. 9.8 months (P=0.019) and 33% vs. 38%, respectively; the 2-year survival rates were 9% and 15%, respectively. Overall quality of life (EORTC Q & Q-C30 and LC-13) were similar in the two arms with more thrombocytopenia and neutropenia in the carboplatin arm and more nausea, vomiting and nephrotoxicity in the cisplatin arm. However, only 76% of the planned carboplatin dose was delivered compared to 98% of the cisplatin dose and this may explain the signicant survival difference favoring the cisplatin arm. The effect of paclitaxel dose intensity was examined, in the carboplatin paclitaxel combination by the Hellenic Co-operative Oncology Group.[10] Chemotherapy naive patients with inoperable NSCLC were randomized to receive either carboplatin at AUC of 6 mg/mL min and paclitaxel at 175 mg/m2 (group A) or the same dose of carboplatin and paclitaxel at 225 mg/m2 (group B). Both drugs in both groups were given on day one every 21 days. In group A, the response rate was 25.6%, whereas, in group B the response rate was 31.8%. The difference was not statistically signicant. The median time to progression favored the high-dose paclitaxel arm with 4.3 vs. 6.4 months P 0:044: The median survival was 9.5 months for group A vs. 11.4 months for group B P 0:16: The one-year survival was 37% for group A and 44% for group B with the Pvalue being 0.35. In this study, the best prognostic factor for one-year survival was the response rate. There were increased neurotoxicity and leucopenia in the high-dose paclitaxel group. However, there were no toxic deaths reported in either arm. The authors concluded that the higher-dose paclitaxel prolongs the median time to progression but at the expense of increased neurotoxicity and leucopenia. In a study from Germany, Gatzemeier et al.[11] compared the cisplatin paclitaxel combination with single agent cisplatin alone. Four hundred fourteen previously untreated patients with advanced NSCLC (stage IIIB/IV) were treated with either single agent cisplatin (100 mg/m2 day one, every 21 days) or cisplatin (80 mg/m2 day one, every 21 days) plus 3 hr paclitaxel (175 mg/m2 day one, every 21 days). There was signicantly higher response rate (26 vs. 17%, P 0:028 and signicantly longer time to progression in the cisplatin/paclitaxel arm but there was no difference in median survival (8.6 months for platinum alone vs. 8.1 months for cisplatin plus paclitaxel). It is likely that therapy at the time of progression in the single agent cisplatin arm accounted for the similar survival despite the superiority in time to progression seen in the

cisplatin/paclitaxel arm. It is also possible that better results would have been achieved with a higher paclitaxel dose of 225 mg/m2. The QOL was similar overall between the two arms. Another Hellenic Oncology Group trial published by Kosmidis et al.[12] compared paclitaxel 200 mg/m2 as a 3 hr infusion and carboplatin AUC of 6 mg/mL min given on day one with paclitaxel in the same dose with gemcitabine 1000 mg/m2 given on days one and eight. Both regimes were repeated every three weeks for a maximum of six cycles in previously untreated patients with advanced NSCLC. Sixty-three patients were randomized to group A (carboplatin/paclitaxel) and 64 to group B (gemcitabine/paclitaxel) with a median follow up of 4.6 months. Preliminary results showed that both combinations were well tolerated when administered in full doses. Grade III IV neutropenia was generally mild but was more prominent in group A. Thrombocytopenia was insignicant in both arms. There was a trend towards higher response rates in favor of group B (37.5 vs. 21.8%), although the time to disease progression did not differ signicantly (7.25 vs. 7.1 months). Mature data are awaited. Summarizing the above data, paclitaxel was found to be better than BSC, not only in improving survival (with a 32% reduction in the hazard ratio of death) but also in improving the QOL. It has become clear that most new two-drug, platinum-containing regimens are essentially identical to each other with respect to efcacy. The paclitaxel carboplatin combination was found to be as effective, less toxic, and best tolerated in several of the studies. The optimal dose of paclitaxel, when used in combination with a platinum compound, in NSCLC is still an issue of debate. However, most investigators would prefer the higher dose of 225 mg/m2, especially in patients with good performance status. In one Phase III randomized trial, cisplatin yielded superior median survival to carboplatin when combined with paclitaxel. Higher percentage of cisplatin dose delivered in the cisplatin arm may have accounted for the difference.[9] Two other randomized trials showed that the cisplatin paclitaxel combination was better than either cisplatin etoposide[5] or cisplatin teniposide.[6] A nonplatinumcontaining doublet (gemcitabine paclitaxel) was found to be similar in survival to a platinum-containing doublet (carboplatin paclitaxel) in a recently reported phase III randomized trial.[12] This trial provided the proof of principle that a nonplatinum-containing doublet and a platinum-containing doublet could be comparable in efcacy and survival in the rst-line treatment of advanced NSCLC.

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Randomized Trials with Docetaxel in Previously Untreated Patients Several phase III studies have been completed using docetaxel in previously untreated patients. These are summarized in Table 2. Roszkowski et al.[13] reported their nal results comparing docetaxel at 100 mg/m2 every three weeks plus BSC compared to BSC alone in patients with advanced NSCLC. Two hundred patients were enrolled, following a 2:1 randomization schema where for every patient enrolled to the BSC alone arm, two patients were enrolled to the docetaxel arm. Median survival was 6.0 months for the docetaxel arm vs. 4.6 months for the BSC arm. One-year survivals were 25 vs. 15% in favor of docetaxel P 0:012: Importantly, QOL was statistically signicantly better in the docetaxel arm with a decrease in the need for palliative radiation, pain medications, and hospitalization. Not surprisingly, the incidence of neutropenia and the need for antibiotics were higher in the docetaxel arm. This study corroborated the result of the paclitaxel vs. BSC study[4] where the use of a taxane statistically signicantly improved survival and QOL as compared to BSC in advanced NSCLC patients. Docetaxel combined with cisplatin, with both drugs given at 75 mg/m2 every three weeks, was shown to be equivalent to three other two-drug combinations in the ECOG 1594 study[7] summarized in Table 1. Two hundred ninety-three patients were enrolled in the docetaxel cisplatin arm with a 17.3% response rate and a median survival of 7.4 months and a 31% one-year survival. Recently, a phase III randomized trial was completed (TAX 326) that enrolled 1220 advanced NSCLC. This three-arm study compared docetaxel (75 mg/m2) plus cisplatin (75 mg/m2) given every three

weeks vs. docetaxel (75 mg/m2) and carboplatin (AUC of 6 mg/mL min) vs. the reference arm of vinorelbine (25 mg/m2) weekly and cisplatin 100 mg/m2 given every four weeks.[14] There were no statistically signicant differences in toxicity in any of the arms. However, a larger percent of the planned chemotherapy was actually delivered (97 vs. 68%) in both the docetaxel arms compared to the vinorelbine arm. Cisplatin/taxctere arm had a statistically signicantly superior overall survival as compared to the cisplatin/vinorelbine arm. Quality of life parameters were also superior for the taxctere arm. To determine whether nonplatinum-containing combinations could replace platinum-containing combinations, Georgoulias et al.[15] conducted a phase II randomized trial in chemotherapy-nave advanced metastatic NSCLC patients comparing docetaxel (100 mg/m2 given on day one) plus cisplatin (80 mg/m2 given on day two) with G-CSF given on days 3 9 (DC arm) with gemcitabine (1100 mg/m2 given on days one and eight) plus docetaxel (100 mg/m2 given on day eight) with recombinant G-CSF given on days 9 15 (DG arm). Cycles in both arms were given every 21 days until progression. A total of 375 patients were enrolled with 180 evaluable patients in the DC arm and 167 evaluable patients in the DG arm. There was no statistically signicant difference in response rates (31% for DC vs. 34% for DG), median survival (12 months for DC vs. 11 months for DG), and one-year survival (46% for DC vs. 41% for DG). The similarity of results indicates that both platinum-containing and nonplatinum-containing combinations are acceptable for therapy for advanced NSCLC patients. Summarizing the randomized studies with the use of docetaxel in previously untreated patients with advanced NSCLC, docetaxel plus BSC provided better palliation and improved survival when compared to BSC alone.[13] In the ECOG 1594 trial, cisplatin plus docetaxel provided

Table 2. Author Roszkowski et al. Schiller et al. Belani et al.

Phase III randomized trials with docetaxel in previously untreated NSCLC patients. Agents/Schedule Pts 200
a

MS 6.0 4.6 NR NR NR 12 11

%1-Yr 25 15 NR NR NR 46 41

[References] [13] [7] [14]

Georgoulis et al.

Docetaxel 100 mg/m q 21 d Best supportive care ECOG-1594 (see Table 1) Docetaxel 75 mg/m2, cisplatin 75 mg/m2 q 21 d Docetaxel 75 mg/m2, carboplatin AUC 6 q 21 d Vinorelbine 25 mg/m2 q 7 d, cisplatin 100 mg/m2 q 21d Docetaxel 100 mg/m2/d, cisplatin 80 mg/m2 d2 Gemcitabine 100 mg/m2 given d2, d8

1220a

375a

[15]

Pts, patients; MS, survival in months; NR, not reported. a Total patients enrolled in all arms.

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Taxanes in Treatment of Advanced NSCLC Table 3. Study/Author Tax 317/Shepherd et al. Tax 320/Fossela et al. Phase III randomized trials with docetaxel in previously treated patients with NSCLC. Agents/Schedule Docetaxel 100/75 mg/m2 q 21 days Best supportive care Docetaxel 100 mg/m2 q 21 days Docetaxel 75 mg/m2 q 21 days Vinorelbine 30 mg/m2/Weekly or ifosfamide 2 gm/m2 3 days q 3 weeks Pts 49/55 100 125 125 123 RR (%) 6 NA 11a 6a 0.8 MS 7.0a 4.6 5.5 5.7 5.6 1-Yr (%) 37a 11 32a 32a 10

93

[References] [16] [17]

Pts, patients, RR, response rate, MS, median survival in months, NA, not applicable. a Statistically signicant difference between docetaxel and comparator arm.

equivalent response rates and survival as compared with carboplatin plus paclitaxel and cisplatin plus gemcitabine.[7] Docetaxel, when paired with a platinum compound gave similar survival rates to docetaxel paired with gemcitabine, again suggesting the equivalence of platinum-containing doublet and a nonplatinum-containing doublet.[15] A large phase III trial comparing cisplatin plus docetaxel, carboplatin plus docetaxel, and cisplatin and vinorelbine has been completed. Cisplatin/taxctere arm had a statistically signicantly superior overall survival as compared to the cisplatin/vinorelbine arm. Taxctere arms demonstrated benet in the quality of life parameters measured.

Randomized Trials with Docetaxel in the Second-Line Setting Two important phase III studies have been reported with docetaxel in the second-line setting and the results are summarized in Table 3. In the rst trial, (TAX 317)[16], docetaxel was compared with BSC. One hundred patients were randomized to the BSC arm. Docetaxel at 100 mg/m2 every three weeks was given to 49 patients. Owing to a 22% incidence of febrile neutropenia, 55 additional patients received docetaxel at a lower dose of 75 mg/m2 every three weeks. The median survival in the combined docetaxel arms was 7.0 months vs. 4.6 months in the BSC arm. This difference was statistically signicant. There was no signicant difference in survival between the two docetaxel groups. Additionally, there was a 37% one-year survival in the docetaxel arm compared to an 11% one-year survival in the BSC arm (see Fig. 3). In addition to a prolongation of survival, there was a signicant improvement in the QOL in the docetaxel arm compared to the BSC arm. The need for palliative radiation therapy, pain medication, and hospitalization was reduced in the docetaxel arm.

However, the need for antibiotics was increased in the docetaxel group. In this pivotal trial, the role for secondline chemotherapy for advanced NSCLC was established. In addition to an improvement in survival, an improvement in QOL was also demonstrated. The docetaxel dose of 75 mg/m2 is preferred to the 100 mg/m2 dose owing to comparable efcacy and reduced toxicity. In a second phase III randomized study (TAX 320), docetaxel at 100 mg/m2 was compared to docetaxel at 75 mg/m2, or to vinorelbine or ifosfamide, at the time of a commonly used second-line chemotherapy for advanced NSCLC.[17] There was no restriction in the number of prior cycles. There was a 11% PR rate for docetaxel at 100 mg/m2, 6% PR for docetaxel given at 75 mg/m2, and 1% PR for vinorelbine or ifosfamide. The median survival in the docetaxel 100 mg/m2 arm was 5.5 months compared to 5.7 months for the docetaxel 75 mg/m2 arm. The median survival in the vinorelbine/ifosfamide arm was 5.6 months. The one-year survival was 32% in the 100 mg/m2 arm, 32% in the 75 mg/m2 arm, and 10% in the vinorelbine/ifosfamide arm. The survival differences

Figure 3. vs. BSC.

TAX 317: Overall survival of taxotere 75 mg/m2

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nonrandomized studies, while not sufcient to establish superiority over older treatments can be compared with historical controls of advanced NSCLC treated with earlier cisplatin-based regimens, which achieved median survivals of around 26 weeks, and one-year survival rates of approximately 25%. These trials are summarized in Tables 4 7.

Phase II Trials with Paclitaxel and a Platinum Compound

Figure 4. Tax 320: Effect of prior paclitaxel on survival.

were statistically signicant. Administration of prior paclitaxel did not affect the probability of response to docetaxel (see Fig. 4). Thirty-one percent of the patients in the docetaxel 100 mg/m2 arm and 42% of patients in the docetaxel 75 mg/m2 received prior paclitaxel. Hence, docetaxel is still a viable second-line option in patients who have failed previous paclitaxel containing regimens. The 75 mg/m2 dose of docetaxel offered better palliation with an improved therapeutic index.

Table 4 summarizes four phase II trials where paclitaxel was combined with a platinum compound. Three studies reported results with a combination of paclitaxel and carboplatin. In one study,[18] paclitaxel was administered over 1 hr, while in two studies,[19,20] 3 hr infusions were used. The response rates in these studies ranged from 29 to 55%. The median survivals ranged from 41 to 55 weeks and the one-year survival rates ranged from 38 to 55%. A single phase II trial studied the combination of paclitaxel (135 mg/m2 over 3 hr) and cisplatin (75 mg/m2).[21] This study reported a response rate of 50%, but no survival data were included.

Phase II Trials with Chemotherapy Doublets Containing a Taxane While several of the phase III trials described above demonstrate improvement in outcome of post1990 drugs over older agents in the treatment of NSCLC, many questions remain as to how to exploit their activity. In many instances, the regimen best suited for treatment has not been clearly identied not just in terms of QOL or cost-effectiveness, but also in terms of dosing and scheduling. To address these issues, phase I and II studies of newer drugs continue to be executed. The majority of these trials combine cisplatin or carboplatin with a taxane. These Phase II Trials with Docetaxel and a Platinum Compound Three recent studies with docetaxel and cisplatin[22,23] or carboplatin[24] have been published and outlined in Table 5. The objective response rates ranged from 33 to 48%. The median survival was reported in only one of these trials (34 weeks), with a one-year survival rate of 35%. There are no obvious efcacy differences between the study results whether the study used docetaxel or paclitaxel or whether the taxane was combined with cisplatin or carboplatin. Not surprisingly,

Table 4. [References] [18] [19] [20] [21] 1-hr 3-hr 1-hr 1-hr paclitaxel paclitaxel paclitaxel paclitaxel

Phase II trials of platinum paclitaxel combination in advanced NSCLC. Agents/Schedule Pts 65 53 47 32 ,IV 29 20 32 8 RR (%) 19 29 18 16 (29%) (55%) (38%) (50%) MS 41 55 51.8 NR 1-Yr (%) 38 55 49 NR

200 mg/m , carboplatin AUC 5, q 21 d 200 mg/m2, carboplatin AUC 6, q 21 d 130 225 mg/m2, carboplatin 230375 mg/m2, q 28 d 135 mg/m2 d1, cisplatin 75 mg/m2 d2, q 21 28 d

Pts, patients; ,IV, number of evaluable patients with nonmetastatic disease; RR, number of evaluable patients with PR or CR; MS, median survival of evaluable patients (weeks); %1-Yr, percentage of evaluable patients alive at 1 year; NR, not reported.

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Taxanes in Treatment of Advanced NSCLC Table 5. [References] [22] [23] [24] Phase II trials of platinumdocetaxel combinations in advanced NSCLC. Agents/Schedule Docetaxel 75 mg/m2, cisplatin 75 mg/m2, q 21 d Docetaxel 75 mg/m2, cisplatin 75 mg/m2, q 21 d Docetaxel 75 mg/m2, carboplatin AUC 6, q 21 d Pts 56 42 41 , IV NR 8 12 RR (%) 48 33 37 MS NR 33.6 34 55

95

%1-Yr NR 35 35 55

Pts, number of evaluable patients; ,IV, number of evaluable patients with nonmetastatic disease; RR, number of evaluable patients with Pr or CR; MS, median survival of evaluable patients (weeks); %1-Yr, percentage of evaluable patients alive at 1 year; NR, not reported.

convenience and nonhematological toxicities favored carboplatin over cisplatin.

Phase II Trials of Taxane Gemcitabine Combinations Another combination of two-new drugs is taxane plus gemcitabine. Four phase II trials are summarized in Table 7. One of these studies used paclitaxel and gemcitabine in a four-week schedule,[29] while three studies[30 32] combined docetaxel and gemcitabine in a three-week schedule. The results of these studies were fairly similar, with response rates ranging from 29 to 41% (average 36%). Only one trial[30] reported a median survival of 52 weeks with a one-year survival rate of 51%. These results are very similar to cisplatincontaining trials, which suggests that these regimens could be substituted for regimens containing cisplatin.

Phase II Trials of Docetaxel Plus Vinorelbine There have been many studies that combined two nonplatinum compounds with one another to eliminate the toxicity associated with cisplatin and to determine if there might be superior results compared to the platinum combinations. Four phase II trials combining docetaxel and vinorelbine are summarized in Table 6. The doses and schedules of the drugs varied considerably. One of these trials used a very dose-intensive approach, with vinorelbine (45 mg/m2) and docetaxel (60 mg/m2) being given every two weeks with G-CSF support.[25] This trial reported a response rate of 54% and a one-year survival rate of 86%. These results are clearly superior to the others described above. Given the small sample size and the fact that this was a single-institution study, further studies using this approach will be required before this aggressive approach can be adopted. The other studies using more conventional dose schedules showed response rates of 20 37%, with median survivals of 20 36 weeks and one-year survival rates of 24 35%.[26 28] These results more closely resemble those of other two-drug combinations. When the results of these four trials are combined, the overall response rate was 37% among 138 patients.

Summary of Phase II Trials With such an array of phase II trials containing a taxane, it is often difcult to draw any meaningful conclusions. Table 8 summarizes the results of such trials. Response rates ranged from 36 to 41%. None of these combinations stand out as being markedly superior or inferior, and the 85% condence limits overlap among all these combinations. The median survivals reported in these studies ranged from as low as 20 weeks to as high as 55 weeks and one study reported a one-year survival rate of 86%. There is no scientic way to recommend any

Table 6. [References] [26] [25] [27] [28] Vinorelbine Vinorelbine Vinorelbine Vinorelbine

Phase II trials of docetaxelvinorelbine combinations in advanced NSCLC. Agents/Schedule Pts

2

,IV 11 3 6 4

RR (%) 15 (37%) 19 (54%) 7 (20%) 10 (37%)

MS 20 . 28 NR 36

%1-Yr 24 86 NR 35

25 mg/m d1, docetaxel 100 mg/m d2, q 21 d 45 mg/m2, docetaxel, 60 mg/m2, q 21 d 15 mg/m2 d1, 8, 15, docetaxel, 60 mg/m2 d1, q 21 d 15 45 mg/m2, docetaxel, 50 60 mg/m2, q 14 d

41 35 35 27

Pts, number of evaluable patients; ,IV, number of evaluable patients with nonmetastatic disease; RR, number of evaluable patients with PR or CR; MS, median survival of evaluable patients (weeks); %1-Yr, percentage of evaluable patients alive at 1 year; NR, not reported.

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96 Table 7. Phase II trials of taxanegemcitabine combinations in advanced NSCLC. [References] [29] [30] [31] [32] Agents/Schedule 3-hr paclitaxel 150 mg/m2, gemcitabine 2000 mg/m2, d1, 15 q 28 d Docetaxel 100 mg/m2 d8, gemcitabine 900 mg/m2 dl, 8 q 21 d Docetaxel 75 80 mg/m2 d1, gemcitabine 800900 mg/m2 dl, 8, q 21 d Docetaxel 75 mg/m2 d8, gemcitabine 1000 mg/m2 dl, 8 q 21 d Pts 88 51 22 14 , IV 30 15 NR 0

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RR (%) 31 (35%) 19 (37%) 9 (41%) 4 (29%)

MS NR 52 NR NR

%1-Yr NR 50.7 NR NR

Pts, number of evaluable patients; ,IV, number of evaluable patients with nonmetastatic disease; resp, number of evaluable patients with Pr or CR; MS, median survival of evaluable patients (weeks); %1-Yr, percentage of evaluable patents alive at 1 year; NR, not reported.

one of these combinations over another. Still, some conclusions can be drawn. It is likely that many of these combinations without cisplatin can be substituted for combinations with cisplatin. Carboplatin can be substituted for cisplatin with greater convenience and less toxicity in combination with any of the newer nonplatinum compounds.

TAXANES AND RADIATION IN THE TREATMENT OF UNRESECTABLE STAGE III (WITHOUT MALIGNANT PLEURAL EFFUSION) NSCLC Paclitaxel and docetaxel arrest cells in the G2/M phase of the cell cycle. Cells are most susceptible to radiotherapy in this phase, and therefore, it was only logical to combine a taxane with radiotherapy. Hence, many studies have attempted to combine a taxane with radiation to achieve synergistic effects. Some of these studies are outlined below.

Taxanes Given Concurrently with Radiation Therapy Paclitaxel Given Concurrently with Radiation Some of the recently published innovative studies where paclitaxel was combined with radiation are outlined below and in Table 9. The preliminary results

of a phase I trial using such a combination were reported by Rathmann et al.[33] In this trial, 29 patients with inoperable stage II IIIB NSCLC were treated with two neoadjuvant cycles of carboplatin and paclitaxel. This was followed by 68 Gy of radiation given concurrently with daily paclitaxel. Twenty-six patients were evaluable for toxicity, and the dose-limiting toxicity was esophagitis at the 15 mg/m2 dose level. A daily paclitaxel dose of 10 or 6 mg/m2 in combination with radiotherapy was recommended for further study. Oral et al.[34] from Spain enrolled 18 patients to a weekly paclitaxel schedule at a dose of 16 mg/m2 with continuous hyperfractionated accelerated radiotherapy (CHART). They reported 80% response rates to this concurrent chemo/radiotherapy schema. Survival data were not available from this preliminary report. The CHART was given at three daily fractions of 1.5 Gy each, and was given continuously for 12 days to a total dose of 54 Gy. Kirkbride et al.[35] used two-weekly paclitaxel with concurrent radiotherapy in locally advanced stage III NSCLC. In the phase II segment of their trial, 17 patients were enrolled and administered 120 mg/m2 of paclitaxel every two weeks. The overall response rate to this dose of paclitaxel and concurrent radiation was 78%. The median survival for all patients was 16 months and the one-year survival was 64%. The authors concluded that this combination was active with tolerable toxicity. Another variation in the use of paclitaxel was tested by Lau et al.[36] In their phase I/II trial, they used

Table 8. Agents Taxane platinum Taxane vinorelbine Taxane gemcitabine Tot Studies 7 4 4

Phase II trials of taxane combinations in advanced NSCLC. Pts 336 138 175 Resp 138 (41%) 51 (37%) 63 (36%) MS 34 55 20 36 52 MS Studies 4 3 1 %1-Yr 35 55 24 86 51 1-Yr Studies 4 3 1

Tot Studies, number of studies reporting results; Pts, number of evaluable patients; Resp, number of evaluable patients with PR or CR; MS, median survival of evaluable patients (weeks); MS studies, number of studies with median survival data; %1-Yr, percentage of evaluable patients alive at 1 year; 1-Yr Studies, number of studies with 1-year survival rate.

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Table 9. Unresectable stage III NSCLC: phase II and/or nonrandomized trials. Concurrent taxane-radiotherapy for locally advanced NSCLC. [References] [33] [34] [35] [36] [37] [38] Stage II IIIB IIIA, IIIB IIIA, IIIB III IIIA, IIIB IIIA, IIIB Therapy Daily T with RT Weekly T with CHART T with RT Biweekly T RT D RT Weekly D with RT Pts 29 18 17 NR 35 30 RR NR 80 78 80 80 57.7 MS NR NR 16 20 NR 15.9 LTS NR NR 64 (1-yr) 20 (3-yr) 60 (1-yr) 51 (1-yr)

Pts, number of patients; RR, response rate (%); MS, median survival (months); LTS, long-term survival rate (%); MVP, mitomycin C vindesine cisplatin; VP, vindesine cisplatin; alt, alternating; RT, radiotherapy; AHRT, accelerated hyperfractionated RT; PE, cisplatin etoposide; S, surgery; P, cisplatin; C, carboplatin; CCRT, concurrent chemo/radiotherapy; PFE, cisplatin 5-urouracil etoposide; D, docetaxel; T, paclitaxel; CHART, continuous hyperfractionated accelerated RT; CPT-11, irinotecan; NR, not reported; pI/II, phase I/II trial.

bi-weekly paclitaxel with concurrent standard-fractionation radiotherapy given in daily fractions of 1.8 2.0 Gy to a total dose of 61 Gy. After encountering esophagitis and skin desquamation at the 40 mg/m2 dose level, they selected 35 mg/m2 for the phase II component of the trial. They reported an overall response rate of 80% to this combination, with a median survival of 20 months and a three-year survival of 20%. Docetaxel Given Concurrently with Radiation Therapy These phase I/II studies are quite small in size and are outlined in Table 9. Koukourakis et al.[37] from Greece reported the largest trial with docetaxel. Thirty-ve patients with stage IIIA and IIIB NSCLC were treated concurrently with docetaxel and radiotherapy. Docetaxel was given in doses of 30 mg/m2 weekly with standardfractionation radiotherapy. Complete response of chest disease was observed in 12 of the 35 patients, giving a CR rate of 34%. Partial responses were seen in 16 of the 35 patients, giving a PR rate of 46%. The overall response rate was 80%. The overall survival and local progression-free survival rates at one-year were 60 and 48%, respectively. The major toxicity was esophagitis: 17% percent of patients had grade III esophagitis requiring a two-week delay in their treatment. The authors concluded that docetaxel combined with radiotherapy was a promising approach that deserves further testing. Aamdal et al.[38] from France also used weekly docetaxel given concurrently with radiotherapy for stage IIIA and IIIB locally advanced NSCLC patients. In this trial, 42 patients were initially enrolled, of whom 30 were evaluable. An overall response rate of 57.7%, including six CRs was reported. The median survival was 15.9 months, with a 51.2% one-year survival. No major hematological toxicities were observed. Therefore, the

combination of docetaxel and radiotherapy was shown to be safe and effective. Neoadjuvant Chemotherapy Followed by Denitive Local Therapy Recently, four studies were reported where neoadjuvant chemotherapy was given alone for several cycles followed by denitive local therapy in the form of surgery, radiotherapy, or concurrent chemo/radiotherapy. These studies are summarized in Table 10 and detailed below. Mattson et al. conducted a phase III trial where denitive local therapy (arm A) in the form of either surgery or radiotherapy was compared with three cycles of neoadjuvant therapy with docetaxel followed by denitive local therapy i.e., surgery or radiotherapy (arm B). In the neoadjuvant therapy arm docetaxel was administered at 100 mg/m2 every three weeks for three cycles. A total of 274 patients were accrued in both arms. There was a trend towards superior median (15 vs. 13 months) and one-year survival (59 vs. 51%) in arm B. These differences were not statistically signicant. However, this study underscored the feasibility of administering neoadjuvant chemotherapy prior to denitive local therapy. The CALGB[39] conducted a randomized phase II study of two cycles of induction chemotherapy of three different two-drug combinations, followed by two additional cycles of the same drugs given concomitantly with radiotherapy. Cisplatin was administered at 100 mg/m2 on days 1, 22, 43, and 64 in all three arms. In arm 1, gemcitabine was given at 1250 mg/m2 on days 1, 8, 22, and 29, and at 600 mg/m2 on days 43, 50, 64, and 71. In arm 2, paclitaxel was given at 225 mg/m2 over 3 hr on days one and 22, and at 134 mg/m2 on days 43 and 64. In arm 3, vinorelbine was given at 25 mg/m2 on days 1, 8,

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Table 10. Unresectable stage III NSCLC: phase II and/or nonrandomized trials (neoadjuvant chemotherapy followed by concurrent taxaneradiotherapy for locally advanced NSCLC). [References] [39] [40] [41] [43] Stage IIIA, IIIB IIIA (N2), IIIB IIIA, IIIB IIIA, IIIB Therapy CT 2 CT 2 with CCRT PTN 2, CCRT PTN 69.9 Gy (1.2 cGy b.i.d.) DP 2 CCRT (64.6 Gy) l DP 1 TC 2 RT with RSR13 Pts 181 31 20 52 RR 54 87 81 87 MS 18 16
a

LTS 66 (1-yr) 35 (3-yr) NR 68 (1-yr)

NR

Pts, number of patients; RR, response rate (%); MS, median survival (months); LTS, long-term survival rate (%);CT, chemotherapy; CCRT, concurrent chemo/radiotherapy; RT, radiotherapy; C, carboplatin; PTN, cisplatin paclitaxel vinorelbine; AHRT, accelerated hyperfractionated RT; DP, docetaxel cisplatin; NR, not reported. a Median survival not reached after 21 months of follow-up.

22, and 29, and at 15 mg/m2 on days 43, 50, 64, and 71. After two induction cycles, radiotherapy consisting of 200 Gy fractions/day to a total dose of 60 Gy was given starting with the third cycle. The toxicity was comparable for the three arms, with the major toxicities being thrombocytopenia, granulocytopenia, and esophagitis. The CR plus PR rate was 27% for arm 1, 27% for arm 2, and 45% for arm 3. The median survival for all patients was 18 months and the one-year survival rate was 66%. There was no statistically signicant survival difference between the three arms. The authors concluded that four cycles of gemcitabine, vinorelbine, or paclitaxel could be used in combination with cisplatin and safely administered concurrently with radiotherapy. However, all three arms were comparable in toxicity. This study was not powered to detect differences in response rates and survival. Lopez-Picazo et al.[40] enrolled 31 patients with stage IIIA(N2) and IIIB NSCLC to receive 2 4 cycles of cisplatin, paclitaxel, and vinorelbine (PTN) induction chemotherapy, followed by radiotherapy given concurrently with two cycles of PTN given at the beginning and end of radiation. Eight-seven percent of their patients had either CR or PR. They had a median survival of 16 months and a three-year survival rate of 35%. These excellent results will need conrmation in larger randomized trials as with studies of triplet therapy in stage IV disease; randomized trials will be necessary to determine if the increased toxicity and expense of three drugs is justied by improvement in survival. Nyman[41] from Sweden used docetaxel and cisplatin as induction chemotherapy in 20 patients with stage IIIA and IIIB NSCLC. Concurrent radiotherapy (up to 64.6 Gy) was given with one additional cycle of docetaxel and cisplatin. The response rate after induction chemotherapy was 65%, increasing to 81% after radiation. After 21 months of follow-up, the median survival was not reached. Further follow-up is necessary before long-term survival data can be generated.

These phase II studies using induction chemotherapy followed by concurrent chemo/radiotherapy suggest that this treatment approach is feasible. However, before this treatment approach can become standard, more detailed multicentric randomized trials will need to be done. One such trial has completed accrual and is known as the locally advanced multimodality protocol (LAMP) randomized study, which compares carboplatin plus paclitaxel followed by radiotherapy (arm 1), vs. carboplatin plus paclitaxel followed by radiotherapy given concurrently with carboplatin plus paclitaxel (arm 2), vs. carboplatin plus paclitaxel given concurrently with radiotherapy followed by carboplatin and paclitaxel (arm 3). All arms are to be compared to the sequential chemoradiation regime in RTOG-8808 with a median survival of 13.7 months. Two hundred forty-three patients were randomized to this study. An initial report of 80 patients enrolled in arm 2 was published in abstract form.[42] For the 56 patients in whom survival data are available the median survival is 12.5 months. Accrual to this arm has been terminated since no survival improvement was noted when compared to sequential chemo-radiation historical data (RTOG 8808). The preliminary report of the trial was recently updated. Arm 3 emerged as the superior arm with a 16.1 month median survival compared to an 11-month median survival for arm 2 and a 12.5 month median survival for arm 1. More recently Choy et al.[43] reported phase II results of concurrent use of RSR13 (a synthetic allosteric modier of hemoglobin, which decreases the hemoglobin oxygen binding afnity) and radiation therapy after induction therapy with carboplatin and paclitaxel. Fifty-two patients with unresectable stage IIIA and IIIB NSCLC care enrolled on the study overall response ratio was 87%. Estimated one-year survival was 68%. Median survival has not been reached at the time of this report. Summarizing the results from phase II randomized trials, it appears that the median survival for patients treated with concurrent chemo/radiotherapy appears to

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be around 16 months. However, toxicity is higher in patients who receive concurrent chemo/radiotherapy as compared to when chemotherapy and radiotherapy are administered sequentially. In a recently published phase III randomized trial comparing sequential chemotherapy with concurrent chemotherapy, the concurrent approach yielded superior survival that was statistically signicant. However, this study used nontaxane chemotherapy using mitomycin, vindesine, and cisplatin.[44] These ndings were also corroborated by the recently reported RTOG 9410 trial.[45] The need for surgery for patients who are downstaged after combined-modality treatment is under evaluation. A SWOG trial is currently underway to address this issue. Many of the concurrent trials are done with the newer agents, and the logical reason for doing concurrent trials is to take advantage of the radiation-potentiating effects of chemotherapy. There are multiple studies using paclitaxel, docetaxel, and gemcitabine currently underway. The largest clinical experience has been reported with paclitaxel. In these studies, paclitaxel has been given both weekly and three-weekly schedules. The weekly schedules use short infusions, whereas both long- and shortinfusion schemas were used in the three-weekly programs. These studies underscore the feasibility of using full-dose paclitaxel concurrently with radiotherapy. Excessive toxicity was generally not noted in the weekly regimens where paclitaxel was given either alone or with weekly carboplatin. In regimens given every three weeks, a 3 hr infusion of paclitaxel at a dose of 225 mg/m2 with or without carboplatin appeared to be safe.

two-year survival of 47%. This compared favorably with the SWOG 9019 study where the median survival was 15 months, one-year survival was 58%, and two-year survival 34% (see Table 11). To further improve these results, SWOG is planning a study where patients with unresectable stage III disease will be treated in a fashion similar to the SWOG 9504 trial following, which they will be randomized to observation alone or to maintenance therapy with an oral anti-epidermal growth factor receptor tyrosine kinase inhibitor (SWOG 0023) (Iressa, Astra-Zeneca, London, UK).

TAXANES IN STAGE I IIIA NSCLC Pisters et al.[48] reporting for the bimodality lung oncology team (BLOT) recently published their phase II trial where induction chemotherapy was administered prior to surgery in early-stage NSCLC patients. Chemotherapy consisted of paclitaxel 225 mg/m2 over 3 hr and carboplatin at AUC of 6 mg/mL min every 21 days. In the rst phase of the study, 94 patients were scheduled to receive for two cycles preoperatively and three cycles postoperatively. In the second phase of the study, 40 patients were scheduled to receive three preoperative cycles and two postoperative cycles. In the rst phase there were 56 objective responses. Ninety-four patients were enrolled in the study. Fifty-six major objective responses were seen. Complete resection was accomplished in 82 patients (86%). Two postoperative deaths occurred. Five patients had pathologic CRs. Ninety-six percent of patients received the planned preoperative chemotherapy and 45% received the planned postoperative chemotherapy. Estimated oneyear survival is 85% and four-year survival is 58%. Median survival has not been reached. Results in the second phase were similar with high rates of delivery of all three preoperative cycles and a two-year survival rate

Concurrent Chemo/Radiotherapy Followed by Consolidative Therapy with a Taxane The efcacy of concurrent cisplatin/etoposide (PE) and radiotherapy followed by two cycles of consolidative PE in unresectable stage III NSCLC has been previously reported by Albain et al. for the SWOG (S9019).[46] To further extend this benet, in a follow-up phase II study performed by SWOG (9504),[47] radiation therapy (total dose of 61 Gy in 1.8 2.0 Gy fractions) was given concurrently with cisplatin 50 mg/m2 administered on days 1, 8, 29, and 36 and etoposide infused on days 1 5 and 29 33. Consolidative therapy was then given with docetaxel in three-week cycles. In the rst-cycle, docetaxel was given at 75 mg/m2 and if this was tolerated well then for the second and third cycles docetaxel was given at 100 mg/m2. There were 83 evaluable patients with response rate of 63%, median survival of 20 months and one-year survival of 73% and

Table 11. Phase III randomized study between cisplatin (P) gemcitabine (G) vinorelbine vs. cisplatin gemcitabine vs. cisplatin gemcitabine paclitaxel. Response rates and survival gures.[49] Regimen PGV PG PGT Response Rate (%) 44 28 48 MS 51 38 51 1-Year S (%) 47 39 46 2-Year S (%) 15 9 12

MS, median survival in weeks; S, survival in percentages.

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of 75%. A prospective randomized trial comparing three cycles of induction chemotherapy and surgery with surgery alone is currently underway. If the abovementioned phase II results are conrmed, then neoadjuvant chemotherapy followed by surgery could become the standard of care for early-stage NSCLC patients.

TRIPLE DRUG COMBINATIONS CONTAINING A TAXANE Several phase II trials and randomized phase III trials have been published using various drugs in triple drug combinations. One phase III randomized study (containing a taxane) has been completed recently where the combination of cisplatin, gemcitabine, and vinorelbine was compared with cisplatin and gemcitabine, which in turn was compared with cisplatin, gemcitabine, and paclitaxel.[49] The response rates, median survival, one- and two-year survivals are outlined in Table 12, showed a suggestion for benet for the three-drug combination. However, there were study design aws and additional, randomized trials are needed. The SWOG is initiating a randomized trial (SWOG 200X) where the standard arm, paclitaxel at 225 mg/m2, and carboplatin at an AUC of 6 mg/mL min, every three weeks is being compared with the same drugs in the same doses but with tirapazamine added. Until this and other phase III randomized trials are completed a two-drug combination continues to be the standard of care.

TRIALS WITH A TAXANE-CONTAINING DOUBLET IN COMBINATION WITH A BIOLOGICAL AGENT Recently, a phase II randomized trial was reported where an antivascular endothelial growth factor (AntiVEGF) humanized monoclonal antibody (rhumab VEGF, Genentech, South San Francisco, CA), was combined in two different dose levels of 7.5 mg/m2 and 15 mg/m2

every 21 days with paclitaxel and carboplatin or chemotherapy alone followed by the higher dose rhumab VEGF at progression.[50] There was no statistically signicant difference in response rates or survival in any of the three arms although the best results were obtained with the high dose rhumab VEGF arm. Time to treatment progression was improved P 0:02 in the 15 mg/m2 rhumab VEGF arm as compared to carboplatin and paclitaxel arm. Unfortunately, there were six unexpected severe pulmonary hemorrhages in the rhumab VEGF arms of which four were fatal. These occurred in patients with central tumors and/or squamous histology. Therefore, the ECOG has proposed a randomized phase III study in advanced NSCLC patients with a nonsquamous histology comparing carboplatin/paclitaxel alone to carboplatin/paclitaxel plus rhumab VEGF at 15 mg/m2. Nationally, phase III randomized trials are currently underway where carboplatin and paclitaxel is being compared with the same combination in addition to a biological compound. Compounds being studied in this way are Iressa (ZD1839), AG3340, OSI-774, BMS275291, TNP 470, ISIS 3521, and others. Recently, the results of INTACT-I trial were reported which compared carboplatin and paclitaxel plus placebo to carboplatin and paclitaxel plus Iressa. There were no statistically signicant differences in response rates, median survival and 1-year survival. Thus, Iressa failed to add benet to carboplatin and paclitaxel in the rstline treatment of advanced NSCLC. Results of the INTACT-II trial comparing cisplatin and gemcitabine plus placebo to cisplatin and gemcitabine plus Iressa also showed no statistically signicant differences in response rate, median survival and overall survival. Studies similar in design are underway with other targeted agents and the results of these studies are awaited.

NEWER MICROTUBULE STABILIZATION AGENTS The clinical success of paclitaxel and docetaxel stimulated the search for compounds with a similar mode

Table 12. Study SWOG 9504 SWOG 9019 Number of Patients 83 50

Comparison of SWOG 9504 with SWOG 9019.[57] Median Survival (months) 26 15 1-Yr Survival (%) 76 58 2-Yr Survival (%) 53 34 3-Yr Survival (%) 40 18

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of action and has resulted in the identication of these nontaxane chemical classes of natural products: the soil bacteria-derived epothilones A and B (Epo A and Epo B),[51] the marine sponge-derived discodermolide,[52] and the coral-derived Eleutherobins/Sarcodictyins.[53,54] All three classes stabilize microtubules and competitively inhibit the binding of paclitaxel to tubulin polymers, indicating overlap of binding sites.[51] The epothilones, however, display some superior qualities; they are water soluble, can be produced in large quantities through bacterial fermentation, and retain activity against multidrug-resistant cell lines and tumors.[55,56] The epothilones are farthest along in clinical development and are in phase I and II trials in various disease sites.

CONCLUSIONS AND FUTURE DIRECTIONS Taxane therapy has improved the outlook for patients with NSCLC; both paclitaxel and docetaxel reduce the hazard rate of death by 32% compared with BSC. This reduction is greater than that achieved with cisplatin or older cisplatin combinations. Combinations of paclitaxel with cisplatin or carboplatin have been shown to improve survival compared to etoposide and cisplatin. Combinations of paclitaxel or docetaxel plus cisplatin or carboplatin yielded survival results that were equivalent to the very best two-drug combinations. In large, multicenter phase III trials, the two-drug taxane/platinum combinations consistently gave median survival times of eight-months, one-year survival rates of 35 38% and two-year survival rates of 15%. These results compare to median survival of four months, oneyear rates of 10 15% and two-year rates , 5% for BSC and median survival of 6 months, one-year rates of 25% and two-year rates of 5 10% for older cisplatin combinations. While the absolute increase (median 4 8 months) is relatively modest, this represents a 50% reduction in the hazard rate of death. If these results can be reproduced in earlier stages, there will be a marked improvement in the cure rate in NSCLC. Carboplatin is more convenient, better tolerated, and less toxic than cisplatin. When combined with paclitaxel, carboplatin/paclitaxel combination provides efcacy results as good as those achieved with any combination and with superior convenience, tolerability, and toxicity. Both docetaxel and paclitaxel can be combined safely with other new agents including vinorelbine and gemcitabine. These two-drug combinations have similar activity to taxane/platinum combinations and similar toxicity proles to taxane/carboplatin.

Triplet therapy with paclitaxel, gemcitabine, and carboplatin or cisplatin can be delivered safely. Small underpowered studies show higher response rates, and longer survival and increased toxicity rates. Because of the increased cost and toxicity, triplet therapy will remain experimental unless large randomized trials show a survival advantage. Taxane/platinum combinations can be combined readily with newly targeted therapies using full doses of all agents. In many instances, phase II studies have yielded provocative results. Several randomized trials that are in progress hold the promise to provide another small increment in prolongation of survival. Data in earlier stages of NSCLC suggest that taxanes may provide an equivalent reduction in hazard ratio of death that will markedly improve survival. For example, the SWOG found that the addition of docetaxel to their standard chemo-radiation therapy for stage III B patients increases three-year survival from 18 to 40%. In stage IB IIIA disease the BLOT study reported that preoperative paclitaxe/carboplatin was well-tolerated and did not increase operative mortality. The three- and four-year survival rates were much higher than reported in any historical series. Thus, taxanes have a major role in the therapy of NSCLC patients of all stages and histologies. They are likely to be a major part of lung cancer therapy for many years to come.

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