Integration of Vinorelbine into Chemotherapy Strategies for Non-Small-Cell Lung Cancer
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.
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 . 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 . 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.
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 .
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 .
Cisplatin-Based Regimens--Subsequent clinical trials focused on cis-platin based combination chemo- therapy . 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  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  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 . 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) . 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 , although this was not consistently supported . Gandara et al  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) . 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.
Pretreatment Patient Characteristics
Stanley et al analyzed the pretreatment patient characteristics of more than 5,000 patients with inoperable non-small-cell lung cancer . 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  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  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  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.
In addition to these clinical pretreatment patient characteristics, molecular parameters have been investigated as prognostic factors. Slebos et al  determined that the presence of a K- ras mutation has adverse prognostic significance; this was subsequently confirmed in other studies . Similarly, Lee et al  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  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.
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 . 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 . Of interest, both improved survival and decreased cost  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 . 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 . 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 . This approach is not yet universally accepted, however .
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.