Integration of Vinorelbine into Chemotherapy Strategies for Non-Small-Cell Lung Cancer

Meta-analyses of randomized clinical studies comparing combination chemotherapy versus "best supportive care" for advanced non-small-cell lung cancer have revealed a small, but statistically significant survival advantage for patients who receive chemotherapy. However, overall increases in lifespan have been short, and the great majority of patients die within 1 year of diagnosis. In the last few years, several new drugs with promising activity have been identified. Of these, vinorelbine has already been shown to increase survival rates in randomized clinical trials. In particular, one such trial showed the combination of vinorelbine and cisplatin to result in statistically superior survival rates, compared with "standard" therapy of cisplatin and vindesine, and with single-agent vinorelbine. A second study comparing vinorelbine to fluorouracil/leucovorin also demonstrated a survival benefit for patients treated with vinorelbine. Therefore, the combination of vinorelbine and cisplatin represents one new option for initial therapy of newly diagnosed stage IV non-small-cell lung cancer.

Introduction

According to current statistics, lung cancer is the third most common cancer in the United States and continues to be the leading cause of cancer death for both males and females [1]. Non-small-cell-lung cancer represents 70% to 80% of newly diagnosed lung cancers. Most patients have an advanced stage of disease at the time of initial diagnosis.

The treatment of patients with advanced non-small-cell lung cancer has proven to be difficult [2-5]. Until recently, the use of chemotherapy was considered to be of doubtful value [5]. However, recent randomized studies demonstrating improved survival in patients with stage III [6-10] and stage IV non-small-cell lung cancer [11-15] as a result of the use of chemotherapy have given rise to renewed optimism. This article will review the recent experience with the
use of chemotherapy in stage IV non-small-cell lung cancer and will describe the results obtained with vinorelbine (Navelbine), a novel vinca alkaloid, in this disease.

Status of Chemotherapy as Palliative Treatment

Most patients with advanced non-small-cell lung cancer present with stage IV disease. An additional 20% to 30% may present with unresectable stage III disease. All patients with stage IV disease and some of those with stage IIIB disease (ie, positive pleural effusion or supraclavicular lymph node involvement) are treated with palliative intent. Whereas the majority of patients will require local palliative measures at some point during the course of their disease, treatment is usually based on the use of systemic chemotherapy. Historically, drugs with modest reproducible single-agent activity in non-small-cell lung cancer have included cisplatin (Platinol), mitomycin (Mutamycin), ifosfamide (Ifex) , etoposide (VePesid), and the vinca alkaloids vinblastine and vindesine (Eldisine; available in Europe) [2,16-19].

Activity of these agents is defined by single-agent response rates of 15% or greater in phase II studies. Almost all responses have been partial only and of short duration, usually lasting 3 to 6 months. Other agents, including doxorubicin and carboplatin (Paraplatin), also have been shown to have activity [20-23], although response rates tend to be less than 15%. Carboplatin has not been compared directly with cisplatin as a single agent in randomized studies of non-small-cell lung cancer, but nevertheless is frequently used in clinical practice in place of cisplatin due to its ease of administration and more acceptable toxicity profile [23].

Combination Chemotherapy

In order to increase the effectiveness of systemic therapy, combinations of single chemotherapy agents have been investigated. During the 1970s, such combinations included the CAMP regimen (cyclophosphamide, Adriamycin, methotrexate, and procarbazine) developed at the University of Chicago. In a single institution trial, this combination had a 26% response rate in 160 patients [24].

Cisplatin-Based Regimens--Subsequent clinical trials focused on cis-platin based combination chemo- therapy [25]. Among the regimens tested were the popular combinations of etoposide and Platinol (EP regimen), cisplatin and vinblastine, and the MVP regimen consisting of mitomycin, vinblastine, and Platinol [21,26-28]. Phase II studies suggested the possibility of higher response rates with these regimens than with "first-generation" regimens, such as CAMP.

There also have been direct comparisons of cisplatin-based chemotherapy with non-cisplatin-based combination regimens. Although some of these studies confirmed increased response rates for the cisplatin-containing regimens, there was no consistent pattern of increased survival. Jett [29] summarized six such trials and found a significant survival benefit for the cisplatin-containing regimen in only two studies [30,31].

In addition, Veronesi et al [32] found a superior survival for the combination of cisplatin and etoposide compared with CAMP, whereas the other studies showed no difference in survival [28,33,34]. For example, the Eastern Cooperative Oncology Group (ECOG) randomized patients to MVP vs therapy with vindesine plus Platinol (VP), etoposide plus Platinol (EP), or CAMP [28]. The MVP regimen produced the highest numerical response rate at 31%. However, there were no statistically significant differences between the four regimens in median survival (4.5 months for MVP, 6.5 months for both VP and EP, and 6.2 months for CAMP). Thus, in this study, the higher response rate with MVP did not translate into superior survival, and the study failed to identify a "standard chemotherapy regimen" for advanced non-small-cell lung cancer.

In another randomized study, the Eastern Cooperative Oncology Group compared MVP to single-agent platinum-based chemotherapy (carboplatin or iproplatin) followed by MVP at the time of first progression and to two other combination chemotherapy regimens (vinblastine plus cisplatin and MVP alternating with CAMP) [22]. In this five-arm study, MVP again resulted in the highest response rate (20%), but with a trend toward shorter survival. Patients treated initially with carboplatin had a statistically significantly longer survival than patients treated with the other four regimens; this was observed despite a low response rate (9%) for carboplatin. The median survival of patients receiving carboplatin followed by MVP was 32 weeks (vs 23 weeks for MVP alone), demonstrating the continued need to identify more active chemotherapy.

Cisplatin Dose Intensification--Another subject of interest has been the potential role of cisplatin dose intensification. An early trial of cisplatin-based chemotherapy suggested a positive dose-response relationship when the cisplatin dose was increased from 60 to 120 mg/m²/wk in combination with vindesine [35], although this was not consistently supported [36]. Gandara et al [37] reported the experience of the Northern California Oncology Group (NCOG) with high-dose cisplatin (100 mg/m² on days 1 and 8 of a 4-week cycle). The overall response rate to single-agent, high-dose cisplatin was 33%, with a median survival time of 8.4 months.

Based on this background, the Southwestern Oncology Group (SWOG) initiated a three-arm randomized study comparing standard-dose cisplatin (50 mg/m² on days 1 and 8 of a 28-day cycle) with high-dose cisplatin (100 mg/m² on days 1 and 8) and with high-dose cisplatin plus mitomycin (8 mg/m² on day 1 of a 4-week cycle) [38]. Overall response rates for the three regimens were 12%, 14%, and 27%, respectively (P < 0.05). Complete responses were noted only in the high- dose cisplatin arms (3% and 4%, respectively). However, there were no statistically significant differences in median survival times, which were 7, 5, and 7 months for the standard-dose, high-dose, and high-dose combination arms, respectively. In addition, high-dose cisplatin therapy was reported to result in increased ototoxicity, emesis, and myelosuppression.

Since greater dose intensity of cis-platin was indeed achieved, with actual cisplatin doses of 41 and 39 mg/m²/wk attained in the high-dose arms vs 23 mg/m²/wk for the standard-dose arm, this study refutes the suggestion that doses of cisplatin exceeding 100 mg/m² per cycle might lead to significantly improved therapeutic outcome in stage IV non-small-cell lung cancer.

Prognostic Factors

Pretreatment Patient Characteristics

Stanley et al analyzed the pretreatment patient characteristics of more than 5,000 patients with inoperable non-small-cell lung cancer [39]. In this classic analysis, initial performance status, extent of disease, and weight loss in the 6 months preceding diagnosis were most predictive of survival. O'Connell et al [40] confirmed the significance of performance status in 387 patients with advanced non-small-cell lung cancer. Good performance status was predictive of response to therapy and prolonged survival duration, whereas the presence of bony metastases, an elevated lactic dehydrogenase (LDH) level, male gender, and the presence of two or more extrathoracic involved sites were associated with a poor prognosis.

Finkelstein et al [41] determined prognostic factors in 893 patients who participated in ECOG studies. Good initial performance status, absence of bony metastases, female gender, and weight loss < 5% of pretreatment body weight were associated with improved survival times. Histologic subtype had no influence on survival.

More recently, Albain et al [42] used Cox modeling and recursive partitioning and amalgamation to determine the prognostic independence and significance of host- or tumor-related characteristics in 2,531 patients with extensive-stage non-small-cell lung cancer treated on SWOG protocols. In this analysis, good performance status, female gender, and age 70 years or older were significant independent predictors of increased survival for the entire study population. In a model of only those patients with good performance status, pretreatment hemoglobin levels exceeding 11 g/dL, normal serum LDH and calcium, and the presence of no more than one metastatic site were significant favorable prognostic factors. Of interest, the use of cisplatin was also an independent predictor of improved survival.

Molecular Parameters

In addition to these clinical pretreatment patient characteristics, molecular parameters have been investigated as prognostic factors. Slebos et al [43] determined that the presence of a K- ras mutation has adverse prognostic significance; this was subsequently confirmed in other studies [44]. Similarly, Lee et al [45] demonstrated a correlation between the absence of blood group antigen A and a shorter survival time.

Additional prognostic information utilizing molecular biology is being generated [46] and may aide in the determination of prognostic subgroups and, possibly, a differential choice of therapy for tumors expressing specific biologic markers in the near future.

Chemotherapy vs Best Supportive Care

Given the limited activity observed with first- and second-generation combination chemotherapy regimens, randomized studies comparing the effect of chemotherapy vs best supportive care (ie, no chemotherapy) on survival were initiated. The first of these studies was reported by Cormier et al [47]. In this small study, only 40 patients were randomized to either best supportive care or a non-cisplatin-based chemotherapy regimen. Nevertheless, improved survival was demonstrated for chemotherapy-treated patients.

To date, at least eight such studies have been reported [47-54]. Three of these individually demonstrated a statistically significant benefit for chemotherapy-treated patients [47-49], whereas the other five indicated a trend toward improved survival with chemotherapy that did not achieve statistical significance. Thus, in balance, these studies tend to favor chemotherapy over best supportive care. The largest and best known of these studies compared cisplatin and vindesine vs CAP (cyclophosphamide, Adriamycin, and Platinol) vs best supportive care [48]. Of interest, both improved survival and decreased cost [55] resulting from the use of chemotherapy were demonstrated.

In order to more accurately assess the impact of chemotherapy on survival, four meta-analyses have also been performed, with similar conclusions (Table 1) [12-15]. The most recent of these utilized updated individual patient data [14]. The preliminary report of this analysis also suggested a beneficial effect from the use of chemotherapy for cisplatin-based studies. Rates of 1-year survival were estimated to be 16% vs 26% in favor of patients receiving chemotherapy, with an increase in median survival from 6 to 8 months.

Quality-of-life data have been collected in some trials, but to date, no firm conclusions regarding chemotherapy in non-small-cell lung cancer have been formulated. One might postulate a psychological benefit and increased quality of life afforded by specific anticancer therapy, in addition to the potential benefit of prolonged survival time. In the Canadian randomized study, patients receiving chemotherapy had a lower incidence of disease-related complications [55]. This indirect assessment also suggests a beneficial impact on quality of life by chemotherapy.

In summary, chemotherapy for stage IV non-small-cell lung cancer has been demonstrated to result in a small, but statistically significant, increase in survival time, with objective response rates of approximately 30%. Given this information, it might be suggested that newly diagnosed patients with this disease should be offered chemotherapy, with the goal of prolonging life and decreasing tumor-related symptoms [15]. This approach is not yet universally accepted, however [56].

A "best" standard chemotherapy regimen for non-small-cell lung cancer has not been established. Therefore, the identification of additional single agents and combinations with higher activity and less toxicity is a high priority. Several promising new drugs are currently undergoing testing in non-small-cell lung cancer [57-59]. These include the taxanes (paclitaxel [Taxol], docetaxol [Taxotere]), camptothecan analogs (irinotecan, topotecan, and 9-amino camptothecan), gemcitabine (Gemzar), and vinorelbine.

Vinorelbine

Of these drugs, vinorelbine has so far undergone the most thorough clinical testing in non-small-cell lung cancer. In addition, vinorelbine was recently approved by the FDA for the first-line treatment of ambulatory patients with advanced non-small-cell lung cancer. In the following sections, the clinical data generated to date for this compound will be reviewed.

Pharmacology

Vinorelbine is a semisynthetic vinca alkaloid that differs from earlier vinca alkaloids in that it has a substitution on the catharanthine rather than the vindoline moiety of the molecule (Figure 1) [60,61]. Like the other vinca alkaloids, vinorelbine exerts its cytotoxic effect by binding to tubulin, the basic protein subunit of cellular microtubules, resulting in disruption of the mitotic spindle apparatus during metaphase. Vinorelbine has been demonstrated to have inhibitory effects on the polymerization of mitotic microtubules equal to those of vinblastine or vincristine but to have a lesser effect on axonal microtubules [62]. Since neurotoxicity of vinca alkaloids is postulated to derive from damage to axonal microtubules, a more favorable therapeutic index of vinorelbine has been postulated. Clinical experience to date does suggest a low incidence of clinically significant neurotoxicity with vinorelbine.

Preclinical studies with vinorelbine indicated activity against several tumor cell lines representing leukemia, small-cell lung cancer, non-small-cell lung cancer, breast and colon cancer, and melanoma [63]. Similarly, vinorelbine displayed activity against murine tumors and human tumors xenografted into nude mice, including squamous cell carcinoma of the lung [63]. Preclinical studies testing the interaction of vinorelbine with other cytotoxic agents indicated possible synergistic activity of vinorelbine in combination with cisplatin [63] and paclitaxel [64].

In a clinical phase I study conducted by Mathe et al [65], the maximum tolerated dose of vinorelbine was identified as 27.5 to 35 mg/m²/wk, with granulocytopenia being the dose-limiting toxicity. Neurotoxicity was noted to be mild. These findings were confirmed by Favre and Serage [66]. In most subsequent clinical trials, vinorelbine doses of 30 mg/m²/wk have been administered [67].

Pharmacokinetics

The pharmacokinetics of vinorelbine were characterized by Jehl et al [68]. Following intravenous administration of 30 mg/m² of vinorelbine in 20 patients, blood and urine samples were collected for 144 and 48 hours, respectively. Vinorelbine pharmacokinetics were characterized by a three-compartment model with a Cmax of 1,130 ± 139 ng/mL (standard error of the mean). The total body clearance and volume of distribution were 1.26 ± 0.09 L/h/kg [48.6 ±
4.1 L/h/m²] and 75.6 ± 9.2 L/h/kg [2,918.4 ± 307.2 L/m²]. The elimination half-life was calculated at 42 ± 5 hours. The urinary excretion of vinorelbine represented 11% of the administered dose; hepatic clearance was postulated to be the major pathway of vinorelbine elimination.

Marquet et al described the pharmacokinetics of vinorelbine in eight patients [69]. Again, a triexponential plasma concentration vs time curve was reported with a long terminal half-life of 45 hours and a high volume of distribution. Pharmacokinetic parameters were demonstrated to exhibit wide interindividual variations.

Oral Formulation--An oral formulation of vinorelbine has also been developed. Rowinsky et al recently reported on a pharmacokinetic analysis in which patients received either oral or intravenous vinorelbine at doses of 100 mg/m² and 30 mg/m², respectively [70]. Oral vinorelbine was reported to have a triphasic drug disposition with large central and steady-state volumes of distribution (0.66 ± 0.46 L/kg and 20.02 ± 8.55 L/kg, respectively). The terminal half-life was long at 18 hours, and the high clearance rate approached hepatic blood flow. Absorption was rapid with a Tmax of 0.91 ± 0.22 hours. The bioavailability of oral vinorelbine was low at 27% ± 12%. There was moderate intraindividual variability in bioavailability (coefficient of variation, 32%). Grade 3 or 4 neutropenia occurred in 63% of patients. Nausea, vomiting, and diarrhea were also common.

Zhou et al also investigated the pharmacokinetics of oral vinorelbine [71]. In this study, 19 patients were treated with doses ranging from 50 to 200 mg/wk. The absorption of vinorelbine was rapid, with a Tmax of .9 to 1.75 hours, and the Cmax ranged from 71 to 833 ng/mL. The clearance was estimated to be 0.43 to 1.45 L/h/kg, and a large volume of distribution and long terminal half-life were demonstrated.

Lucas et al have reported on the effects of food or divided dosing on the bioavailability and pharmacokinetics of oral vinorelbine [72]. Preliminary pharmacokinetic data suggested that food slightly decreases the bioavailability of vinorelbine and its Cmax values. Divided doses yielded 94% of the total area under the curve observed after a single dose given during a fasting state. Thus, administration of oral vinorelbine with food or in divided doses had little effect on drug absorption.

Phase II Studies

Depierre at al [73] treated 83 patients who had unresectable, measurable or evaluable disease and who had not received prior chemotherapy or radiotherapy with vinorelbine (30 mg/m²/wk). Of 78 eligible patients, the majority had a performance status of 1 or 2 and stage IIIB or IV disease, and 57 patients (74%) had squamous cell histology. The mean weekly vinorelbine dose administered was 29 mg/m².

Among the 78 eligible patients, the objective response rate was 29% (31% for measurable disease vs 27% for evaluable disease). Median response duration was 34 weeks. The median survival time for all 78 patients was 33 weeks, and the 1-year survival rate was approximately 30%. Two toxic deaths were observed related to neutropenic sepsis. Other side effects consisted predominantly of granulocytopenia (21% of cycles). Neurotoxicity consisted mainly of decreased deep tendon
reflexes.

A Japanese phase II study also demonstrated significant activity of vinorelbine in previously untreated patients [74].

Combination Studies With Cisplatin

Berthaud et al conducted a phase I study of vinorelbine plus cisplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer [75]. The goal of the study was to administer both agents at their recommended phase II doses (ie, 120 mg/m² of cisplatin administered every 4 to 6 weeks and 30 mg/m²/wk of vinorelbine). In 32 patients with advanced disease, vinorelbine dose levels were escalated from 20 mg/m²/wk to 25 mg/m²/wk to 30 mg/m²/wk. In that patient cohort, the actual weekly doses of vinorelbine and cisplatin received were 68% and 72%, respectively, of the intended doses.

No responses were observed in 9 patients treated at the 20-mg/m² vinorelbine dose level. Among 21 evaluable patients treated with 25 or 30 mg/m², 7 partial responses (33%, 95% confidence interval, 13% to 53%) were observed. Grade 3 or 4 neutropenia was reported in 67% of patients. No thrombocytopenia was observed. No nonhematologic toxicities exceeding grade 2 were seen (excluding alopecia); grade 1 or 2 paresthesias occurred in 22% of patients, and grade 1 constipation in 3% of patients.

Randomized Studies

Three large randomized studies of vinorelbine in patients with non-small-cell lung cancer have been conducted, two in Europe and one in the United States.

European Studies--Le Chevalier et al conducted a prospective, randomized study comparing single-agent vinorelbine (30 mg/m²/wk) to the combination of vinorelbine (at the same dosage) plus cisplatin (120 mg/m² on days 1 and 29 and then every 6 weeks) and to a "standard-therapy" combination of vindesine (3 mg/m²/wk for 6 weeks and then every 2 weeks) plus cisplatin (120 mg/m² on days 1 and 29 and then every 6 weeks) [76]. Eligible patients in this study had stage III or IV unresectable non-small-cell lung cancer and had received no prior chemotherapy. The primary end point was survival, with secondary end points of response and toxicity. Response was evaluated by means of standard criteria at 10 and 18 weeks of therapy.

The 45 European centers involved in this study treated 612 patients. The characteristics of these patients are summarized in Table 2. The mean duration of treatment was 15 weeks in the two vinorelbine arms and 14 weeks in the cisplatin/vindesine arm. The median number of drug administrations and dose intensity are outlined in Table 3.

Objective responses were observed in 14%, 19%, and 30% of patients treated with vinorelbine, vindesine plus cisplatin, and vinorelbine plus cisplatin, respectively. The response rate to vinorelbine/cisplatin was statistically higher than that seen on the other two study arms. Mean response duration was 7.8 months for vinorelbine, 9.9 months for vindesine/cisplatin, and 9.2 months for vinorelbine/cisplatin. A logistic regression analysis found only treatment regimen and performance status (2 vs 0 to1) to be statistically significant predictors of response.

At a median follow-up time of 26 months, the median survival time was highest for the vinorelbine/cisplatin arm at 40 weeks, compared with 32 weeks for vindesine/cisplatin, and 31 weeks for vinorelbine alone (Figure 2). The difference between vinorelbine/cisplatin and the other two arms was statistically significant, whereas there was no difference between vinorelbine alone and the vindesin/cisplatin combination.

Vinorelbine/cisplatin had a significantly higher rate of neutropenia than the other two regimens. Thrombocytopenia, however, was rarely observed. Grade 3 to 4 neurotoxicity occurred more frequently in the vindesine/cis-platin arm than the two vinorelbine-containing regimens (7% vs 17%).

This study, therefore, demonstrated that the combination of cisplatin and vinorelbine results in a statistically higher response rate and median survival time than the combination of vindesine and cisplatin or vinorelbine alone. Interestingly, there was no statistically significant difference in response rate or survival time between vinorelbine alone and vindesine in combination with cisplatin.

In another European randomized study reported by Depierre et al [77], 231 eligible patients were stratified by participating institution and randomized to receive either vinorelbine alone (30 mg/m²/wk) or the combination of vinorelbine (at the same dosage) plus cisplatin (80 mg/m² every 3 weeks). All patients had stage III or stage IV non-small-cell lung cancer and had received no prior chemotherapy or radiotherapy. Patients with stage III disease were "unacceptable" for surgery or radio-therapy. Patients with brain metastases were excluded. All patients had measurable disease. The majority of patients on both treatment arms had stage IV disease and a performance status of 1.

Among the 115 eligible patients receiving vinorelbine alone, 18 objective responses (16%; 95% confidence interval, 9% to 22%) were observed, as compared with 50 responses (43%; 95% confidence interval, 34% to 52%) among the 116 eligible patients in the combination arm. The difference in response rates was statistically significant (P = 0.0001). The median survival time in the vinorelbine alone arm was 32 weeks, as compared with 33 weeks in the vinorelbine/cisplatin arm (a nonsignificant difference). However, the median time to progression was statistically different in the two groups (10 weeks for vinorelbine alone vs 20 weeks for the combination; P = 0.0001).

The major toxicity of both regimens was neutropenia and granulocytopenia. Higher rates of nausea and vomiting and neurologic, renal, and hematologic toxicities were observed on the combination arm. This was reflected in a higher rate of early treatment cessation due to toxicity or patient refusal (3% vs 13%).

The authors concluded that the vinorelbine/cisplatin combination increases objective response rates and time to progression but does not prolong the survival duration of patients compared to vinorelbine alone. Given the single-agent response rate of 16% and median survival time of 32 weeks, the activity of vinorelbine as a single agent in non-small-cell lung cancer was confirmed.

US Study--O'Rourke et al [78], reported on a randomized US study com-paring single-agent vinorelbine (30
mg/m²/wk) with fluorouracil (425 mg/m²/d for 5 days) plus leucovorin (20 mg/m²/d for 5 days), both repeated every 28 days. All patients were chemotherapy-naive and had stage IV disease without brain metastases. The 216 patients enrolled in this study were randomized in a 2:1 ratio to vinorelbine or fluorouracil/leucovorin.

The objective response rate was 12% for vinorelbine, compared with 6% for fluorouracil/leucovorin (a nonsignificant difference). Vinorelbine resulted in a median survival time of 29 weeks, with 25% of patients alive at 1 year, which was superior to the median survival time achieved with fluorouracil/leucovorin (21 weeks, with 15% of patients alive at 1 year; P = 0.02).

Both treatment regimens were well tolerated. The toxicity of vinorelbine consisted primarily of granulocytopenia (grade 3 or 4 in 54% of patients), injection site reactions, constipation, and mild neurotoxicity. On the fluorouracil/leucovorin arm, 24% of patients had grade 3 or 4 granulocytopenia.

This study provides further evidence of the single-agent activity of vinorelbine and its superior activity when compared with another chemotherapy agent. A possible criticism of the trial was the lack of a cisplatin-based control arm. Although fluorouracil/leucovorin is rarely used as "standard therapy," the median survival achieved with fluorouracil in this study (22 weeks) appears to be equal or superior to that reported for best supportive care in randomized studies utilizing best supportive care as a standard. This suggests at least the lack of a negative effect of fluorouracil/leucovorin on survival; median survival rates for best supportive care have ranged from 8 to 16 weeks.

Three-Drugs Regimens--Preliminary data of a randomized study comparing a three-drug regimen of cisplatin, mitomycin, and vindesine vs cisplatin, mitomycin, and vinorelbine in 227 patients with stage IIIB or IV non-small-cell lung cancer have been presented [79]. The two treatment arms utilized the same dosages of cisplatin (120 mg/m² on days 1, 29, and 71) and mitomycin (8 mg/m² on days 1, 9, and 71). Vindesine was given at a dosage of 3 mg/m² weekly for 5 weeks and then every 2 weeks, and vinorelbine was administered at 25 mg/m²/wk for 16 weeks. Response rates were 17% and 25% in the vindesine and vinorelbine arms, respectively (P = 0.16), and overall median survival times were 33 weeks in both arms. For stage IIIB patients, median survival rates were 33 vs 46 weeks favoring the vinorelbine arm, and 1-year survival rates were 23% vs 40% (P < 0.04). For patients with stage IV disease, median survival durations in the two groups were 33 and 27 weeks, respectively.

The authors concluded that substitution of vindesine with vinorelbine does not improve response rates but does result in increased survival rates for patients with stage III disease [79]. A cost comparison of these two drug regimens also favored the vinorelbine-containing regimen [80].

Unresolved Issues--Until recently, FDA-approved drugs for the treatment of non-small-cell lung cancer included methotrexate, doxorubicin, and mechlorethamine. There was uncertainty about what constituted standard therapy for stage IV non-small-cell lung cancer and which regimen should be used preferentially. Recently, vinorelbine was also approved for first-line therapy in patients with advanced non-small-cell lung cancer as either a single agent or in combination with cisplatin. In view of the significant single-agent activity of vinorelbine and the superior activity of the combination of cisplatin and vinorelbine, it may also be suggested that future randomized studies consider the use of vinorelbine (with or without cisplatin) as a control arm.

It is currently unknown whether cisplatin in combination with vinorelbine is superior to single-agent cisplatin. This question is currently being addressed in a randomized phase III study conducted by the SWOG. In this ongoing trial, patients with stage IV disease are being randomized to either single-agent cis-platin or the combination of cisplatin and vinorelbine. The data from this study should further elucidate the exact contribution of vinorelbine to the therapy of advanced non-small-cell lung cancer.

Oral Vinorelbine

Oral vinorelbine has also been investigated as a single agent in non-small-cell lung cancer. Vokes et al [81] have presented data on a multi-institutional phase II study in patients with stage IV disease. Eligible patients had measurable disease and no prior chemotherapy. Vinorelbine doses were l00 mg/m²/wk (80 mg/m²/wk for patients with prior radiation therapy). Because of an initial high incidence of grade 4 neutropenia, the dose for all patients was reduced by one capsule (40 mg).

Of 138 patients with measurable disease, 15% achieved a partial response, with an estimated median survival time of 29 weeks. The 1-year survival rate was 22%. The predominant toxicity was granulocytopenia, which was dose-dependent; overall, 48% of patients had grade 3 or 4 granulocytopenia. Other toxicities included nausea (73%), vomiting (61%), diarrhea (56%) and stomatitis (18%).

Thus, response and survival data were similar to those achieved with most other active single agents in non-small-cell lung cancer. Furthermore, the response and survival data with oral vinorelbine were strikingly similar to those achieved with intravenous administration of the drug. However, gastro-intestinal toxicity appeared to be more frequent with the oral formulation.

Other Schedules and Combinations Containing Vinorelbine

Given the activity of vinorelbine as a single agent, both in its intravenous and oral formulations, as well as its superior activity in combination with cisplatin, other schedules and combinations have been investigated. Phase I and II data on several such combination have been published, frequently in preliminary form (Table 4).

Other Cisplatin-Based Regimens--Several investigators have studied additional cisplatin-based combinations [82-85]. Brooks et al [82] have attempted to reduce leukopenia and increase the dose intensity of the cisplatin/vinorelbine combination. They have presented preliminary data on 36 patients with advanced non-small-cell lung cancer treated with cisplatin (100 mg/m² on days 1 and 29 and repeated every 6 weeks) plus vinorelbine given weekly for 5 consecutive doses and then every 2 weeks at 35 mg/m², except on days 8 and 28, when 17.5 mg/m² was given).

A major response rate of 39% was reported. The median white blood cell count nadir was 2,800/mm³, and only 16% of patients were noted to have grade 3 or 4 leukopenia. Febrile neutropenia was observed in three patients. The authors concluded that this schedule allowed for an increased dose intensity of vinorelbine with less leukopenia and response rates seemingly as good those reported with other schedules utilizing this combination.

Drinkard et al [83] have presented an interim analysis of a combination utilizing cisplatin (100 mg/m² intravenously on day 1), continuous-infusion fluorouracil (800 mg/m²/d for 4 days), oral leucovorin (100 mg orally every 4 hours on days 1 through 5), and vinorelbine (20 mg/m²/d on days 1 and 5). Planned escalation of vinorelbine dosage of 25 mg/m² could not be achieved, due to dose-limiting myelosuppression and stomatitis. In a preliminary response analysis, 4 of 16 patients were noted to have a response. A total of 40 patients have been enrolled in this study, and final response and survival analyses are currently in preparation.

A similar regimen was studied by de Cremoux et al [84]. They treated 60 patients with fluorouracil (600 mg/m²/d for 4 days), leucovorin (600 mg/m² over 20 minutes every 6 hours on days 1 through 4), vinorelbine (20 mg/m² on days 1 and 8), and cisplatin (100 mg/m² on day 1). Following a high initial incidence of toxicity, the fluorouracil dose was reduced by 20% and the vinorelbine dose by 10%. Overall, 28 patients (47%) responded (1 complete response). Toxicities consisted of mucositis and neutropenia.

Bensmiene et al [85] have reported on the results of a phase I-II study in which 76 previously untreated patients with non-small-cell lung cancer were treated with a continuous infusion of fluorouracil (650 mg/m²/d for 96 hours), cisplatin (100 mg/m² intravenously on day 1) and escalating doses of vinorelbine (beginning at 18 mg/m² on days 1 and 8). No leucovorin was given. The authors identified 20 mg/m² as a recommended phase II dose of vinorelbine. Partial responses were noted in 24 patients (32%).

Vinorelbine/Epidoxorubicin--Gridelli et al [86] studied the combination of epidoxorubicin (Epirubicin) plus vinorelbine in non-small-cell lung cancer with or without granulocyte colony-stimulating factor (G-CSF). In their study of 18 patients, the maximum tolerated dose of epidoxorubicin was 60 mg/m² in combination with vinorelbine at a dosage of 20 mg/m² intravenously on days 1 and 8. In patients treated with G-CSF, the maximum tolerated dose of epidoxorubicin was 90 mg/m². Dose-limiting toxicity was leukopenia (without G-CSF) and thrombocytopenia/anemia (with G-CSF). Three partial responses were observed.

Bakker et al [87] also reported on this combination. In this study, neutropenia was dose-limiting, and a 120-mg/m² dose of epidoxorubicin with vinorelbine (25 mg/m² on days 1 and 8 of a 3-week cycle) was recommended.

Vinorelbine/Ifosfamide--The combination of vinorelbine and ifosfamide has been investigated by three groups. Marantz et al [88] published preliminary data on 18 patients treated with vinorelbine (20 mg/m²/wk) and ifosfamide (2 g/m² with mesna [Mesnex] uroprotection on days 1 and 3), with both drugs repeated every 28 days. Of 18 evaluable patients, 6 (33.3%) had a complete remission and 4 (22%) had a partial response.

Morere at al [89] reported on 20 patients treated with ifosfamide (2 g/m²/d for 3 days with mesna uroprotection) and vinorelbine (25 mg/m2/d on days 1 and 8 of every 3 weeks). Eight (40%) of 20 patients were noted to have a partial response.

Finally, our group at the University of Chicago has described preliminary data on a dose escalation study of this combination [90]. Patients received ifosfamide (1.6 g/m²) on days 1 through 3 with vinorelbine also administered intravenously on days 1 through 3 of a 3-week schedule. Vinorelbine doses were escalated from 15 mg/m2/d to a maximum administered dose of 35 mg/m²/d. Granulocyte colony-stimulating factor was administered at 5 mcg/kg/d starting on day 5 and continuing until neutrophil recovery. We identified 30 mg/m²/d as a recommended phase II dose of vinorelbine. In a preliminary analysis, 8 of 16 patients responded to this combination.

The combination of vinorelbine and ifosfamide appears to have a favorable therapeutic index and is currently planned for formal phase II testing in patients with stage IV non-small-cell lung cancer by the Cancer and Leukemia Group B (CALGB).

Vinorelbine/Carboplatin--Crawford et al [91] have reported on the combination of carboplatin with vinorelbine. In this phase I study, cohorts of patients were treated with carboplatin every 4 weeks utilizing the Calvert formula to achieve an area under the curve of 7, and escalating doses of intravenous vinorelbine (from 15 to 30 mg/m²/d) were administered weekly. Granulocyte colony-stimulating factor was added for dose-limiting neutropenia. At the time of analysis, the maximum tolerated dose had not been reached. Overall, 6 of 22 evaluated patients had a response.

A phase II study of this combination is planned. In addition, a phase I study combining carboplatin with the daily x 3 schedule of vinorelbine [91] has been initiated by this group.

Investigations in Stage III Non-Small-Cell Lung Cancer

In view of the single-agent activity of vinorelbine and its impact on survival rates in stage IV disease, further investigation of this agent as part of a multimodality treatment strategy with curative intent in patients with stage III disease is indicated. The National Cancer Institute of Canada is currently investigating the use of cisplatin and vinorelbine versus observation in patients with completely resected stage III non-small-cell lung cancer. In the United States, the CALGB will initiate a randomized phase II study in patients with stage IIIB non-small-cell lung cancer testing three cisplatin-based combinations given for two cycles as induction chemotherapy followed by an additional two cycles with concomitant radiotherapy. The treatment arms of this feasibility study will include cisplatin/vinorelbine, cisplatin/paclitaxel, and cisplatin/gemcitabine. These and other studies will help define the contribution of vinorelbine to the overall therapy for these stage III patients.

Summary

An increasing role of chemotherapy in the management of patients with non-small-cell lung cancer has been established. Among several new drugs with activity, vinorelbine is the first that has been demonstrated to increase survival in controlled randomized clinical trials. Therefore, it should be considered as a first-line therapy option for patients with newly diagnosed stage IV non-small-cell lung cancer. Further investigation of this drug in novel combinations or schedules is promising and necessary since the identification of regimens with increased activity remains a high priority.

Investigations utilizing vinorelbine as a component of multimodality therapy for patients with earlier-stage disease have been initiated. It is hoped that higher activity will be seen in patients with earlier-stage disease and that cure rates in this setting can be increased further with the integration of vinorelbine into the overall treatment strategy.

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