Chemotherapy in Metastatic Non–Small-Cell Lung Cancer

ABSTRACT: Over the last decade, a group of new agents with differing mechanisms of action have shown great promise in early clinical studies in non–small-cell lung cancer (NSCLC). These include the taxanes docetaxel (Taxotere) and paclitaxel (Taxol); the nucleoside analog gemcitabine (Gemzar); the vinca alkaloid vinorelbine (Navelbine); the topoisomerase-I inhibitor irinotecan (Camptosar, CPT-11); and the bioreductive agent tirapazamine. Cisplatin (Platinol), which has been the “backbone” of combination chemotherapy in patients with NSCLC because of its proven single-agent activity, has been examined in combination with these agents as well as radiation and surgery in numerous trials. This article summarizes trials of these combination therapies in the treatment of NSCLC. [ONCOLOGY 14(Suppl 5):15-27, 2000]

Introduction

Lung cancer is the leading cause of cancer death. Approximately 85% of patients diagnosed with this neoplasm die from their disease. Complete surgical resection and cure can be considered in only 25% of cases.[1] Of the estimated 164,100 people in the United States who will be diagnosed with lung cancer in 2000,[2] 75% will have non–small-cell lung cancer (NSCLC) and the majority will die either of micrometastatic disease from tumors that initially appeared to be surgically resectable or from surgically unresectable locally advanced or metastatic disease.

Despite this grim picture, recent therapeutic advances may justify cautious optimism about future gains in the battle against lung cancer. Over the last decade, a group of new agents with differing mechanisms of action have shown great promise in early clinical studies in NSCLC. These include the taxanes docetaxel (Taxotere) and paclitaxel (Taxol), the nucleoside analog gemcitabine (Gemzar), the vinca alkaloid vinorelbine (Navelbine), the topoisomerase-I inhibitor irinotecan (Camptosar, CPT-11), and the bioreductive agent tirapazamine.

New Chemotherapeutic Agents in Combination Therapy

Having demonstrated activity as single agents, these new agents are now being evaluated in combination, mostly with cisplatin (Platinol, CDDP) (Tables 1, 7). Cisplatin has been the “backbone” of combination chemotherapy in patients with NSCLC because of its proven single-agent activity. In particular, therapy with cisplatin is associated with a relative lack of myelosuppression, a unique cytocidal mechanism of action, and the resultant possibility of synergistic cytotoxicity when combined with other agents. The latter has been confirmed in in vitro studies when cisplatin was used in combination with etoposide (VePesid, VP-16).[3,4]

Paclitaxel and Cisplatin-Based Therapy

In preclinical studies of the combination of cisplatin and paclitaxel, it was found that paclitaxel inhibited the repair of DNA adducts formed by platinum agents.[5] Preclinical studies have proven these agents to be synergistic when used in combination in in vitro models.[6] Phase I and II trials determined that the combination of cisplatin and paclitaxel was feasible. Rowinsky et al showed that paclitaxel at doses ranging from 135 mg/m² to 170 mg/m² administered over 24 hours with cisplatin 75 mg/m² was well tolerated.[7] When paclitaxel was administered following cisplatin, there was an increased incidence of grade 4 neutropenia. However, this same response was not observed when paclitaxel was administered prior to cisplatin and was attributed to a possible decrease in paclitaxel clearance due to the effect of cisplatin on the cytochrome P-450 system.[8] Subsequent trials found that paclitaxel at 200 to 250 mg/m² was tolerated and could be administered to patients with cisplatin when given with G-CSF granulocyte colony-stimulating factor (G-CSF, filgrastim, [Neupogen]) support (Table 2). Phase I and II studies demonstrated that when cisplatin is combined with paclitaxel, response rates of 31% to 47% are achieved.[9-12]

The Eastern Cooperative Oncology Group (ECOG) attempted to corroborate these results in a randomized phase III study of the combination of paclitaxel and cisplatin (Table 2).[13] The ECOG study was also designed to evaluate the dose-intensity for paclitaxel by including two doses of paclitaxel in combination with cisplatin. For the trial, 560 patients were randomized to one of three arms: (1) cisplatin 75 mg/m² plus etoposide 100 mg/m² (PE) administered intravenously on days 1-3 with cycles repeated every 3 weeks; (2) cisplatin 75 mg/m² plus paclitaxel 135 mg/m² administered over 24 hours (PT); or (3) cisplatin 75 mg/m² plus paclitaxel 250 mg/m² given over 24 hours with G-CSF support (PT-G).

The response rates were 12% for the PE control arm, 26% for the PT arm, and 32% for the PT-G arm (P < .001). Median survivals were 9.56 and 9.99 months for the PT and PT-G arms, respectively. This compared favorably with median survival in the PE control arm, which was 7.69 months (P = .091). There was no significant difference when the low- and higher-dose paclitaxel arms were compared. Moreover, a stronger trend for longer survival (P = .051) was observed when the paclitaxel-treated cohort was compared with patients treated with PE. Treatment-related mortality rates for arms PE, PT, and PT-G were similar: 2%, 4.4%, and 5.3%, respectively. The results of this study culminated in the combination of cisplatin and 24-hour infused paclitaxel 135 mg/m² being designated as the control arm for future ECOG trials in metastatic NSCLC.

Paclitaxel and Carboplatin in Combination

Several investigators have combined paclitaxel with carboplatin (Paraplatin), a congener of cisplatin. These trials were designed to reduce the significant nonhematologic toxicity seen with cisplatin. Carboplatin has minimal renal toxicity, reduced neurologic toxicity, and is less emetogenic. The principle toxicities of carboplatin relate to its effects on bone marrow suppression, particularly neutropenia and thrombocytopenia. The results of studies combining carboplatin with paclitaxel as a 3- or 24-hour infusion are summarized in Table 1. This combination has revealed interesting activity with reported response rates of approximately 30% to 50% in phase I or phase II trials in small numbers of patients (n = 10 to 53).

The primary toxicity was neutropenia of short duration. There were relatively few episodes of neutropenic fever. Patients receiving the shorter infusion of paclitaxel experienced peripheral neuropathy, particularly with repeated cycles of treatment. An interesting observation with this combination is the unexpectedly low incidence of significant thrombocytopenia.[14] Investigators have theorized that this is attributable to the protective effect mediated by paclitaxel against carboplatin-induced thrombocytopenia.[15] These studies have also demonstrated that the dosing of carboplatin with paclitaxel delivered over 24 hours is limited by myelosuppression, whereas neurotoxicity is the dose-limiting effect when the same combination is given over 1 or 3 hours.[16]

In most studies, the regimens were scheduled every 3 weeks, except for a study by Johnson in which a 4-week cycle was evaluated.[17] There appears to be an appreciable difference in response rates between the two schedules: the 4-week schedule had a response rate of 27%, whereas the majority of the studies utilizing the 3-week schedule had response rates of 50% or greater.[15,16,18-20] Until the results of ongoing phase III trials are complete, however, the optimal paclitaxel and platinum regimen cannot be defined. Nonetheless, the conclusions reached from studies completed to date have been interpreted as demonstrating that paclitaxel and the platin compounds are active combinations that are well tolerated and can be administered on an outpatient basis every 3 weeks.

The results of three recent phase III trials of platin compounds and paclitaxel vs cisplatin and etoposide or teniposide (Vumon) have recently been presented.[21-23] Belani et al randomized 179 patients to 75 mg/m² cisplatin on day 1, 100 mg/m² etoposide on days 1 to 3 of a 21-day cycle, and 190 patients to carboplatin with an area-under-curve (AUC) of 6 and 3-hour–infused paclitaxel at 225 mg/m².[21] All patients in this study had a performance status greater than 70% and stage III or IV disease (Table 7). Although there was no difference in the incidence of grade 3 or 4 neutropenia between the treatment arms, the incidence of grade 1 to 3 neuropathy was 4% in the taxane-containing arm and 0.6% in the etoposide arm. The response rate was 14% for the control arm compared to 21.6% for the carboplatin/paclitaxel arm. There was no difference in overall survival.

In another study of 332 patients, Giaccone et al on behalf of the European Organization for Research and Treatment of Cancer (EORTC) compared paclitaxel (175 mg/m² infused over 3 hours) and cisplatin (80 mg/m²) administered on day 1 of a 21-day cycle with the same dose of cisplatin plus teniposide (100 mg/m² administered on days 1 to 3) of a 21-day cycle.[22] The teniposide-containing arm had a higher incidence of grade 3/4 neutropenia (83%) and thrombocytopenia (36%) than the taxane arm (55% and 2%, respectively), whereas the taxane arm had more grade 2/3 neurotoxicity (29% vs 7%). Response rates favored the taxane arm significantly (41% vs 28%; P = 0.18), however, this did not translate into a survival advantage as the

1-year overall survival rate was 41% in the teniposide arm and 43% in the taxane-containing arm. Gatzemeier compared high-dose cisplatin (100 mg/m²) administered every 3 weeks with cisplatin (80 mg/m²) plus paclitaxel (175 mg/m²) administered every 3 weeks (Table 7).[23] In this study of 414 patients with NSCLC, 70% had stage IV disease and 30% had stage IIIB. Patients in the single-agent arm received a median of three courses of treatment compared with five courses in the combination arm. The response rate in the cisplatin alone arm was 17% vs 26% in the combination arm (P = .0002) and the time-to-disease progression was 2.7 months vs 4.1 months respectively (P = .028). The median survival in the cisplatin arm was 8.6 months vs 8.1 months in the cisplatin plus paclitaxel arm (P = .826). Peripheral neuropathy, neutropenia, and alopecia were worse in the combination treatment arm, whereas nausea/vomiting and constipation were more problematic in the cisplatin arm.

Docetaxel and Cisplatin

This combination has also been evaluated in patients with advanced or metastatic NSCLC. The response rates (25% to 53%) were similar to those seen when paclitaxel was given in combination with cisplatin, with acceptable toxicity. Docetaxel was administered in doses of 75 mg/m² with 75 to 100 mg/m² cisplatin given on an every-3-week schedule.[24-26] The principle toxicity was grade 4 neutropenia. The incidence of febrile neutropenia was approximately 10% among patients who received this combination. The accumulation of peripheral edema appears to be ameliorated by the use of short courses of dexamethasone administered shortly before, and for a few days after, docetaxel.

Vinorelbine and Platinum-Based Chemotherapy

Phase I/II trials established the activity and acceptable toxicities of this combination (Table 1). Gebbia et al reported the results of a phase I/II study of cisplatin 80 mg/m² on day 1 and vinorelbine 25 to 30 mg/m² on days 1 and 8 of a 3-week cycle.[27] An overall response rate of 46% and a median survival of 34 weeks was observed in 30 patients, all of whom had good performance status and either stage III or IV disease. The toxicities were World Health Organization (WHO) grade 3 leukopenia (33%) and injection vein phlebitis (16%). Similar findings were noted by Berthaud et al when vinorelbine 30 mg/m2 weekly was administered with cisplatin 120 mg/m² every 4 to 6 weeks.[28] The median age of the 32 patients in that study was 55 years. Most had an ambulatory performance status with locally advanced metastatic disease. The response rate was 33% and the median survival was 44 weeks.

Three phase III trials have demonstrated the efficacy of the vinorelbine and cisplatin combination. In a study conducted by LeChevalier et al, 612 patients were prospectively randomized to one of three arms: (1) cisplatin 120 mg/m² on days 1 and 29 and then every 6 weeks plus vinorelbine 30 mg/m² weekly; (2) cisplatin 120 mg/m² alone on days 1 and 29 and every 6 weeks plus vindesine (Eldisine) 3 mg/m² weekly for 6 doses and then every other week vs (3) single-agent vinorelbine 30 mg/m² weekly.[29] Approximately 65% of the patients in this study had a performance status of 0 or 1 and stage IV disease. The median age of patients was 60 years. The authors reported response rates favoring the cisplatin plus vinorelbine arm, 30% vs 19% in the cisplatin plus vindesine arm (P = .02).

A modest survival advantage was also found in favor of the cisplatin/vinorelbine combination, with a median survival of 40 weeks compared with 32 weeks for the cisplatin plus vindesine combination (P = .01). Survival in the single-agent vinorelbine arm was similar to that in the vindesine/cisplatin arm, 31 weeks vs 32 weeks, respectively. There was increased myelosuppression with the cisplatin/vinorelbine combination, but less neurotoxicity than with the vindesine/cisplatin combination.

The Southwest Oncology Group (SWOG) conducted a second randomized trial evaluating vinorelbine in combination with cisplatin.[30] In this study, 432 patients with advanced or metastatic NSCLC and good performance status were randomized to receive either cisplatin 100 mg/m² once every 4 weeks or cisplatin 100 mg/m² once every 4 weeks plus vinorelbine 25 mg/m² weekly. The combination of cisplatin plus vinorelbine elicited a superior response rate compared to single-agent cisplatin, 26% vs 12%, respectively (P = .0002). Overall median survival and 1-year survival favored the combination arm with a median survival of 8 months and 1-year survival of 36% vs 6 months and 20%, respectively (P = .0018), in the single-agent arm. As expected, the combination arm had a much higher incidence of WHO grade 3/4 neutropenia (81%) compared with the single-agent cisplatin arm (5%).

Based on the results of their previous randomized trial, the SWOG conducted a second trial in 408 eligible patients with stage IIIB (12%) and stage IV (88%) NSCLC. Patients were randomized to receive either vinorelbine plus cisplatin (VC) or paclitaxel plus carboplatin (PC).[31] There was no difference in response rate (27% for each arm), median survival (8 months for each arm), or 1-year survival (36% for VC and 33% for PC). Economic and quality-of-life parameters were compared. The preliminary analysis revealed no differences in quality of life, but a significant difference in pharmacoeconomic data favoring the VC arm.

Santammagio et al have combined carboplatin with vinorelbine in a study in 77 patients with NSCLC. The study had standard inclusion criteria. A response rate of 31% and median survival of 9 months were reported.[32] Toxicities included seven cases of grade 3 nausea/vomiting, two cases of grade 3 granulocytopenia, and six cases of grade 3 anemia.

Gemcitabine and Platinum-Based Therapy

In vitro tissue culture studies with this combination have suggested a potential for synergistic interaction; one of the mechanisms of DNA resistance is the excisional repair of cisplatin-induced DNA damage. Gemcitabine can block this action, as it depletes the deoxyribonucleotide and ribonucleotide pools and binds to and alters the DNA, preventing elongation of the DNA strand.[33,34]

Various schedules have been employed to determine the optimal method of administering this combination. Weekly gemcitabine with monthly cisplatin (given on days 1, 2, or 15 of each 28-day cycle) has been evaluated in five studies. One other study used a weekly dosing schedule for both drugs (Table 5).[35-41] Gemcitabine was administered weekly on days 1, 8, and 15 of a 28-day cycle in all studies. Each of these studies included 30 to 60 patients whose median age was approximately 60 years. The majority of patients had an ECOG performance status of 0 or 1 and had stage IIIB or IV NSCLC. Response rates ranged from 30% to 58% and median survivals from 24 to 52 weeks.

Toxicities were reported as acceptable. The only WHO grade 3 nonhematologic toxicity was nausea/vomiting. When cisplatin was administered on day 1 or 2, there was about a 25% incidence of grade 4 thrombocytopenia compared with 7% when cisplatin was administered on day 15. Alternatively, when cisplatin was administered on day 15, there was a greater incidence of neutropenia (about 20%) compared with roughly 10% when it was given on day 1 or 2. When the dose intensity of gemcitabine in these studies was calculated, it was observed that patients who had received cisplatin on day 15 were more likely to receive all three scheduled doses per cycle of gemcitabine compared with those who received cisplatin on days 1 or 2. A comparative phase III trial would be needed to determine if greater exposure to gemcitabine (when cisplatin is given on day 15) translates into a survival advantage.

Several recently completed and ongoing phase III trials, when mature, will help to elucidate the role of cisplatin and gemcitabine in combination in patients with advanced NSCLC. An example of such a study is a recently completed phase III trial in 135 patients that compared etoposide (100 mg/m² on days 1 to 3) plus cisplatin (100 mg/m² on day 1) with gemcitabine (1,000 mg/m² on days 1 and 8) and the same dose of cisplatin.[42] Both regimens were scheduled every 3 weeks. The treatment arms were well matched, with the median ages of the patients being 58 and 59 years, respectively, and ambulatory performance status in both. All patients had either stage IIIB or IV disease.

The results revealed response rates of 40.6% for the gemcitabine/cisplatin combination compared with 22% for the etoposide/cisplatin combination (P = .02). In this small phase III study, no definitive comments can be made regarding survival, but there was an insignificant trend toward an increase in median survival in favor of the gemcitabine/cisplatin arm (8.7 months) vs the control arm (7.2 months) (P = .18). There were fewer side effects with the gemcitabine/cisplatin regimen; for example, the incidence of grade 3/4 neutropenia was 28% in the gemcitabine/cisplatin arm compared with 56% in the etoposide/cisplatin arm (P = .0009). Nausea and vomiting of grade 3/4 severity occurred in about 17% of both arms; grade 4 thrombocytopenia developed in 16% of patients who received gemcitabine/cisplatin vs 5% in the etoposide/cisplatin arm. There were no serious hemorrhagic events in either arm.

Sandler et al reported the results of an international, randomized phase III study of gemcitabine and cisplatin vs cisplatin alone in chemotherapy-naive patients with advanced or metastatic NSCLC.[43] Patients were randomized to receive either cisplatin 100 mg/m² IV on day 1 of a 28-day cycle, or the combination of cisplatin 100 mg/m² IV on day 1 plus gemcitabine 1,000 mg/m² IV on days 1, 8, and 15 of a 28-day cycle. Patient characteristics included Karnofsky performance status of 70 to 100, and stage IIIA to IV disease. Patients with central nervous system metastases were not eligible. Patient characteristics were evenly matched between the two treatment arms.

Nonhematologic toxicity was mild. Hematologic toxicity was more pronounced in the combination arm, with grade 3/4 neutropenia occurring in 21.7%/35.3% of patients compared to 3.3%/1.2% in the cisplatin arm. The incidence of neutropenic fever was less than 5% in either arm. Grade 3/4 thrombocytopenia occurred in 25%/25.4% of patients in the combination arm vs 2.8%/0.8% of patients in the cisplatin arm. There were no serious hemorrhagic events related to thrombocytopenia in either arm. A significant improvement in response rate (30.4% vs 11.1%, P < .0001), median time-to-disease progression (5.6 vs 3.7 months, P = .0013), and overall survival (9.1 vs 7.6 months, P = .004) favored the combination of gemcitabine plus cisplatin.

Gemcitabine/Cisplatin vs Mitomycin/Ifosfamide/Cisplatin

The Italian Lung Cancer project has reported the results of their randomized phase III trial in patients with chemotherapy-naive advanced or metastatic NSCLC (Table 2).[13,20,21,23,29-31,42-44,54] From January 1996 through February 1997, 307 patients were randomized to receive either (1) mitomycin (Mutamycin) 6 mg/m² and ifosfamide (Ifex) 3 mg/m² on day 1 and cisplatin 100 mg/m² on day 2 (MIC), or (2) cisplatin 100 mg/m² on day 2 plus gemcitabine 1,000 mg/m² on days 1, 8, and 15 (GC).[44] Both regimens were repeated every 28 days. Patient characteristics included ECOG performance status 0 to 2, and previously treated brain metastases. Only patients with stage IIIB disease having either supraclavicular lymph nodes or malignant pleural effusions were included. Patient characteristics were similar for both treatment arms.

The response rate in the GC arm was significantly higher than in the minmum inhibitory concentration (MIC) arm, 38% vs 26% (P = .03). There was no difference in median survival, 8.6 months vs 8.8 months, respectively. Toxicity was principally hematologic with grade 3/4 thrombocytopenia and neutropenia occurring in 48% vs 22% and in 28% vs 26% in the GC and MIC arms, respectively. Nonhematologic toxicity was mild and consisted of nausea/vomiting (18% vs 23%) and alopecia (39% vs 12%).

Irinotecan and Platinum-Based Chemotherapy

Phase I/II trials of irinotecan administered in combination with cisplatin in patients with previously untreated advanced NSCLC have been completed (Table 1).[45-47] Phase II doses of irinotecan included 30 to 70 mg/m² without G-CSF [48] and 70 to 90 mg/m² with G-CSF support[47] scheduled for the first 3 weeks of each 4-week cycle. Cisplatin 80 mg/m² was given on day 1 of each cycle. The two studies conducted in Japan reported response rates of approximately 48% to 54%. The incidence of grade 3/4 neutropenia was 46% and that of grade 3/4 diarrhea, 20%.

More recently, DeVore et al dosed irinotecan at 60 mg/m² on days 1, 8, and 15, and cisplatin at 80 mg/m² on day 1 of a 28-day cycle and reported a response rate of 28.9% in 52 patients, with a median survival of 9.9 months.[45] Grade 3/4 toxicities included nausea (33%), diarrhea (17%), and neutropenia (46%).

Masuda et al presented the results of a phase II study in 69 evaluable patients with stage IIIB/IV disease who were treated with 60 mg/m² of irinotecan on days 1, 8, and 15, and cisplatin at 80 mg/m² on day 1 of a 4-week schedule.[46] A response rate of 52% and median survival of 44 weeks was reported, with grade 3/4 neutropenia occurring in 80% of patients and grade 3/4 diarrhea in 46%.

A phase III trial has been reported from Japan comparing the combination of (1) cisplatin 80 mg/m² on day 1 and irinotecan 60 mg/m² on days 1, 8, and 15; (2) single-agent irinotecan 100 mg/m² on days 1, 8, and 15, and the combination of (3) cisplatin 80 mg/m² on day 1 and vindesine 3 mg/m² on days 1, 8, and 15. Responses were observed in 43%, 21%, and 31% of patients in each treatment arm, with 1-year survival rates of 50.3%, 40.7%, and 37.9%, respectively.[49]

Tirapazamine and Cisplatin

Tirapazamine is the first agent belonging to a novel class of bioreductive cytotoxic drugs that are reduced to toxic free radicals in hypoxic tumor cells, inducing breaks in the tumor’s cellular DNA. Tirapazamine was found to have synergistic cytotoxicity preclinically when combined with platin compounds.[50] Phase I and II studies revealed that this is a clinically feasible and promising combination. In these trials, cisplatin was dosed at 75 mg/m² and tirapazamine at 260 to 390 mg/m² every 3 weeks. Entry criteria included ambulatory performance status, stage III or IV disease, and bidimensional disease. Treatment-related toxicities were reversible and included hearing loss (no grade 4), nausea, and vomiting. Response rates for the combination were 19% to 30% (Tables 1 and 2).[51-53]

These promising phase II data were confirmed by a phase III trial in which cisplatin was given at 75 mg/m² with or without tirapazamine 390 mg/m² every 3 weeks.[54] Toxicities increased slightly in the combination arm, with acute reversible hearing loss and muscle cramping. The response rate was 27.5% in the combination arm (n = 218) compared with 13.7% (P < .0010) in the cisplatin alone arm (n = 219). This translated into an improvement in 1-year overall survival (33% vs 21%, P = .042).

Non–Platinum-Containing Doublet Combinations

Gemcitabine Plus a Taxane

Given the results of the randomized trials that have clearly established gemcitabine as an active agent in NSCLC, the logical next step is to assess the efficacy and safety of gemcitabine in combination with active agents other than cisplatin. Toward this end, several investigators have conducted trials combining gemcitabine with a variety of agents including the taxanes, vinorelbine, irinotecan, and ifosfamide (Tables 3, 4). In two studies, gemcitabine administered on days 1 and 8 has been combined with paclitaxel administered on day 1 of a 21-day cycle.[55,56] Paclitaxel doses ranged from 150 to 200 mg/m² infused over 3 hours with gemcitabine 900 to 1,000 mg/m².

Georgoulias et al treated 50 patients with NSCLC previously exposed to chemotherapy with this combination and noted a response rate of 22% with a median survival of 14 months.[55] Mild hematologic toxicity (grade 3/4 neutropenia 12%, grade 4 thrombocytopenia 2%) was reported, grade 2/3 neurotoxicity occurred in 32% of patients, and grade 2/3 asthenia in 52%. Giaccone treated 22 chemotherapy-naive patients with NSCLC and reported a response rate of 30.4%. Grade 3/4 neutropenia occurred in 55%, and grade 4 thrombocytopenia in 9% of patients.[56]

Four studies have been conducted with the gemcitabine/docetaxel combination, two of which utilized a 4-week cycle with docetaxel given on day 1 or 15 and gemcitabine given on days 1, 8, and 15.[57,58] Recommended phase II doses of docetaxel were 80 to 100 mg/m² with gemcitabine administered at 800 mg/m². Responses in previously treated patients were 25%[57] and 43%.[58] Spiridonidis reported grade 4 neutropenia in 40% of patients with only three episodes of neutropenic fever.[58] Grade 3/4 thrombocytopenia occurred in 23% of patients. Grade 2/3 asthenia and flu-like symptoms were noted in 30% to 50% of patients in this phase I study. Two other studies used a 3-week cycle with docetaxel given on day 8 and gemcitabine on days 1 and 8.[59,60] Docetaxel doses were 75 to 100 mg/m² and gemcitabine doses were 800 to 1,000 mg/m².

Response rates of 37.5% (Georgoulias) and 44% (Schlösser) were reported in these trials. Georgoulias reported grade 3/4 neutropenia in 8% of patients, all incidences of which were complicated with a febrile episode.[60] Grade 4 thrombocytopenia occurred in only 2% of patients. Grade 2/3 neurotoxicity and asthenia occurred in 8% and 20% of patients, respectively.

Gemcitabine plus Vinorelbine

The combination of gemcitabine plus vinorelbine has been evaluated in five phase I or II studies. Three of these incorporated a 3-week cycle with gemcitabine and vinorelbine administered on days 1 and 8.[61-63] Recommended phase II doses for vinorelbine ranged from 25 to 30 mg/m² and for gemcitabine from 1,000 to 1,250 mg/m². Response rates are listed in Table 4. Dose-limiting toxicity was primarily hematologic. In the largest phase II trial involving 52 previously untreated patients, Lorusso et al reported grade 3/4 neutropenia and thrombocytopenia in 31%/6% and 11%/8% of patients, respectively.[63] Herbst et al combined gemcitabine with vinorelbine, and administered each agent on days 1, 8, and 15 of each 28-day cycle.[64] To date, 22 patients have been treated in this ongoing trial, including 19 with previously treated NSCLC. The response rate is not yet available. Isokangas et al combined gemcitabine with vinorelbine on an every-other-week regimen.[65] The authors, Lilenbaum et al, noted responses in three of the first 11 patients treated, for an overall response rate of 27%.

Other Combinations

Gemcitabine has also been combined with the alkylating agent, ifosfamide. Manegold et al reported on a phase II trial of a fixed schedule of weekly gemcitabine 1,000 mg/m² given on days 1, 8, and 15 with ifosfamide.[66] Ifosfamide at a dose of 1500 mg/m² was administered daily × 5 on days 8 through 12. Cycles were repeated every 4 weeks. A total of 56 patients with previously untreated advanced NSCLC were entered of whom 50 were evaluable for response. Responses were seen in 16 of 50 patients for a response rate of 32%.

Rocha Lima et al reported on the ongoing phase I trial of gemcitabine plus irinotecan.[67] The gemcitabine dose was fixed at 1,000 mg/m² with escalating doses of irinotecan starting at 50 mg/m². Each agent was administered on days 1 and 8 of each 21-day cycle. Patients have completed cohort 3 with an irinotecan dose of 100 mg/m². Further irinotecan dose escalation is ongoing. Kourousis et al combined docetaxel (100 mg/m² given on day 2) and vinorelbine (25 mg/m² given on day 1) and cycled the combination every 21 days.[68] Although this active regimen induced 15 responses (32.6%), there was significant toxicity: 15 of these chemotherapy-naive patients had grade 4 neutropenia, and 11 had neutropenic fever. Consequently, this schedule has not been recommended for further use.

Triplet Combinations

The next question to be investigated was whether adding a third drug to a combination regimen would increase activity without excessive toxicity. The following studies addressed this question.

Gemcitabine Plus Paclitaxel Plus Carboplatin or Cisplatin

There have been four studies combining gemcitabine plus paclitaxel plus either carboplatin or cisplatin. Two studies combined gemcitabine with paclitaxel and carboplatin.[69,70] In both studies 1,000 mg/m² of gemcitabine was administered on days 1 and 8 of a 21-day schedule with paclitaxel and carboplatin administered on day 1. Response rates and paclitaxel and carboplatin doses are listed in Table 5.

In the largest phase II trial in 63 patients, Hainsworth et al dosed paclitaxel at 200 mg/m² and carboplatin at an AUC of 5, and reported grade 3/4 leukopenia and thrombocytopenia in 51% and 43% of patients, respectively. The response rate was 48%. Fifteen patients had neutropenic fevers.[69] The incidence of grade 3/4 fatigue and neuropathy was 12% and 7%, respectively. Kelly et al reported on a phase I/II study that established paclitaxel 175 mg/m² administered over 3 hours plus carboplatin at an AUC of 5 as the recommended phase II dose.[70] The dose-limiting toxicity with carboplatin at an AUC of 6 was cumulative thrombocytopenia.

Among the 21 evaluable patients with chemotherapy-naive NSCLC, six patients responded, for a response rate of 29%. Median survival was 10 months. Accrual continues to further define toxicity and activity at the phase II dose.

Gemcitabine, paclitaxel, andcisplatin have been combined in two studies.[71,72] Frasci et al reported on their phase I study of escalating doses of paclitaxel starting at 50 mg/m² to 150+ mg/m² on day 1 plus cisplatin 50 mg/m² and gemcitabine 1,000 mg/m² on days 1 and 8 with cycles repeated every 3 weeks.[71] They reported responses in three of 10 previously treated patients and nine of 16 untreated patients. Grade 3/4 neutropenia and thrombocytopenia occurred in 27% and 14% of patients, respectively. Sorensen et al combined paclitaxel 110 mg/m², cisplatin 60 mg/m², plus gemcitabine 800 mg/m², with each drug administered every other week.[72] Responses were seen in 52% of patients. The incidence of grade 3/4 neutropenia was high, 80%, with 86% of patients requiring at least a 1 week delay in treatment. The authors concluded that dose modifications would be required before further study could be undertaken.

Gemcitabine Plus Vinorelbine Plus Cisplatin, Ifosfamide, or Mitomycin

Gemcitabine plus vinorelbine has proven to be a viable combination with manageable toxicity. Investigators have explored the concept of adding a third drug to this combination (Table 6). González Barón et al combined cisplatin on day 1 with gemcitabine on days 1 and 15 plus vinorelbine on days 1 and 8.[73] Cycles were repeated every 4 weeks. Responses were seen in 46% of patients. Grade 3/4 neutropenia occurred in 35% of patients. Other hematologic toxicities were rare.

Dorta et al administered gemcitabine, vinorelbine, and cisplatin on days 1, 8, and 15 with cycles repeated every 28 days. Responses were noted in 33% of patients.[74] Grade 3/4 neutropenia occurred in 50% of patients. Other toxicities were infrequent. Castellano et al administered the combination of gemcitabine and vinorelbine on days 1 and 8 with ifosfamide given on day 1.[75] In this small study (n = 21), responses were reported in 11 patients, for an overall response rate of 52%. Grade 3/4 neutropenia occurred in 49% of patients and grade 2/3 thrombocytopenia in 5%. Nonhematologic toxicity was mild, with grade 2 asthenia and constipation occurring in 28% and 23% of patients, respectively. Gemcitabine has also been combined with cisplatin plus ifosfamide and with vinorelbine plus mitomycin.[76,77]

A multi-institutional phase I/II trial combining irinotecan with carboplatin and paclitaxel has been completed; 73 patients with stage IIIB/IV NSCLC were enrolled.[78] Thirty-three patients participated in the phase I portion of this study. The following dose and schedule for phase II was determined in phase I: paclitaxel 175 mg/m² by 3-hour infusion on day 1, carboplatin AUC 5 infused over 0.5 hours on day 1, and irinotecan 100 mg/m² infused over 1.5 hours on day 1 every 21 days.

Responses were seen in 63% of the 33 patients treated in the phase I trial, (39% with confirmatory x-ray). Due to the phase I nature of the study, not all patients received a confirmatory chest x-ray or CT scan. Median survival was 11.3 months and the 1-year survival rate was 46.9%. The phase II portion of the trial entered 40 patients and responses were seen in 50%. Median survival was 8.8 months. The rate of fever/neutropenia was 30%, which was felt to be unacceptable.

An additional 30 patients are being entered on a modified dosing schedule with the dose of carboplatin lowered to an AUC of 4. The initial experience (8 patients) has suggested a lower rate of fever/neutropenia, but further information is necessary before any conclusions about the tolerability of the revised regimen can be reached.

Conclusions

It is clear that cisplatin-based chemotherapy is superior in terms of survival when compared to supportive care alone. Recently, several new agents have revealed activity both as single agents and in combination with cisplatin or carboplatin. These platin-based combinations have been shown in phase III trials to be superior to either single agent cisplatin (gemcitabine, vinorelbine) or traditional cisplatin-based doublets (paclitaxel, irinotecan). Additional studies are being and/or have been conducted that compare these newer combinations amongst themselves (SWOG 9509 and ECOG 1594). These trials have not revealed significant differences in terms of survival. Further studies are attempting to 1) develop novel doublets that do not include cisplatin in order to reduce toxicity and 2) add a third agent to the previously identified active doublets in hopes of increasing activity without excessive toxicity.

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