Rationale for Non-Platinum Chemotherapy in Advanced NSCLC

Introduction

The current American Society of Clinical Oncology (ASCO) treatment guideline for selected patients with metastatic non-small-cell lung cancer is up to eight cycles of platinum-based chemotherapy.[1] This recommendation is based on several lines of evidence. Cisplatin(Drug information on cisplatin) (Platinol) is one of the most active drugs in non-small-cell lung cancer (NSCLC), with a single-agent response rate of approximately 20%. In many different preclinical models, platinum is synergistic with other chemotherapy drugs and with radiation. The superiority of platinum-containing chemotherapy was suggested by a retrospective analysis of the Southwest Oncology Group (SWOG) database, which showed that patients who are treated with platinum-containing regimens lived longer than similar patients treated with non-platinum regimens.[2]

Cisplatin-Based Chemotherapy

This impression was confirmed by a 1995 meta-analysis of 52 randomized clinical trials conducted between 1965 and 1991 that included more than 9,000 patients.[3] This meta-analysis demonstrated that compared with best supportive care, cisplatin-based chemotherapy improved median survival by 6 weeks and survival at 1 year from 5% to 15%. Whether this modest increase in survival was offset by the toxicity of chemotherapy was not evaluated in these studies.

Most of the clinical trials included in the meta-analysis evaluated regimens in which cisplatin was paired with either etoposide or vindesine. Other regimens popular during that time paired cisplatin with vinblastine(Drug information on vinblastine), mitomycin(Drug information on mitomycin) (Mutamycin), doxorubicin(Drug information on doxorubicin), cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar), or ifosfamide(Drug information on ifosfamide) (Ifex). Studies that compared the most active regimens composed of these agents reported a median survival of 6 to 9 months.[4-6] Another meta-analysis that included clinical studies published between 1976 and 1995 suggested that combination chemotherapy provided no significant survival advantage compared with single-agent cisplatin.[7] Because etoposide(Drug information on etoposide), doxorubicin, mitomycin, and vinca alkaloids other than vinorelbine (Navelbine) have relatively modest single- agent activity in NSCLC, it is not surprising that regimens that combined these drugs with cisplatin were only marginally (if at all) better than cisplatin alone.

Other Regimens

During the past decade, however, several drugs have been introduced that are at least as active as cisplatin. In addition to vinorelbine, these drugs include paclitaxel(Drug information on paclitaxel) (Taxol), docetaxel (Taxotere), gemcitabine(Drug information on gemcitabine) (Gemzar), and irinotecan(Drug information on irinotecan) (CPT-11, Camptosar).

Paclitaxel-Based Regimens

As a single agent, paclitaxel produces a response rate of approximately 20%. Two recent European studies evaluated the combination of cisplatin and paclitaxel in patients with advanced non-small-cell lung cancer. In one study, cisplatin/paclitaxel was compared with cisplatin alone,[8] and in the other study, cisplatin/paclitaxel was compared to the combination cisplatin/teniposide (Vumon).[9] Although neither study demonstrated a difference in median survival time, both reported improved quality of life among patients who received cisplatin and paclitaxel (Table 1).

Preliminary results of a study comparing the combination of carboplatin(Drug information on carboplatin) (Paraplatin)/paclitaxel to cisplatin/etoposide reported comparable survival with both combinations.[10] Febrile neutropenia occurred less frequently in patients receiving carboplatin and paclitaxel, but myalgias and neuropathy were more common. The SWOG reported preliminary results of a study that compared carboplatin/paclitaxel to cisplatin/vinorelbine.[11] No difference in survival was noted. However, fewer patients dropped out of the carboplatin/paclitaxel arm, suggesting that this regimen is better tolerated.

The Eastern Cooperative Oncology Group (ECOG) performed a randomized study comparing cisplatin/etoposide to cisplatin/paclitaxel.[12] Patients were randomly assigned to one of three treatment arms: control (cisplatin and etoposide), paclitaxel 135 (cisplatin and paclitaxel as a 24-hour infusion at 135 mg/m² per cycle), and paclitaxel 250 (cisplatin and paclitaxel as a 24-hour infusion at 250 mg/m² per cycle with granulocyte colony-stimulating factor [G-CSF (Neupogen)] support). Survival was better in both paclitaxel-containing arms than in the control arm, but the difference reached standard levels of statistical significance only if results of the two paclitaxel-containing groups were combined (1-year survival of 39% vs 32%, P = .048). Patient tolerability and preservation of quality of life were fairly comparable with the different regimens.

Vinorelbine-Based Regimens

Vinorelbine is a vinca alkaloid that produces a response rate of 30% in patients with non-small-cell lung cancer. A three-arm European study reported by Le Chevalier et al compared cisplatin/vinorelbine to vinorelbine alone or to cisplatin/vindesine.[13] A total of 612 patients were evaluated. Survival was better for patients treated with cisplatin/vinorelbine, and was similar in the other two treatment arms (Table 2). A subsequent subset analysis showed that the survival benefit was limited to patients with good functional status. Patients with a performance status of 2 had similar survival regardless of the treatment they received.[14]

A SWOG study compared cisplatin/vinorelbine to cisplatin alone.[15] Survival at 1 year was significantly better with the combination (36% vs 20%). Although neither of these studies attempted to evaluate quality of life, vinorelbine was well tolerated at active doses. A Japanese study compared the combination regimen MVP (mitomycin/vindesine/cisplatin [Platinol]) to MNP (mitomycin/vinorelbine[Navelbine]/cisplatin [Platinol]).[16] Median survival was significantly better in the group treated with MNP. An Italian trial comparing cisplatin/vinorelbine to MVP reported a similar time to survival and disease progression, but less toxicity, in the group treated with cisplatin and vinorelbine.[17] These studies indicate that treatment with the combination of vinorelbine/cisplatin produces a clinically meaningful benefit for patients with advanced non-small-cell lung cancer compared to cisplatin alone or combinations that include cisplatin and vindesine(Drug information on vindesine).

Two Italian studies have demonstrated that vinorelbine can be safely given to elderly patients, alone or in combination, and significantly improves survival.[18,19] In the first of these studies, vinorelbine, compared with best supportive care, improved survival at 1 year from 14% to 32% and provided a better quality of life.[18] The second study compared the vinorelbine/gemcitabine combination with vinorelbine alone and showed that the combination improved survival at 1 year from 13% to 30%.[19] Palliation of symptoms and quality of life were improved in patients who received the combination. The difference between these two studies in the survival of patients treated with single-agent vinorelbine was presumed to be related to patient selection and underscores the necessity of randomized comparisons of different treatment regimens.

Docetaxel in Non-Small-Cell Lung Cancer

As a single agent, docetaxel(Drug information on docetaxel) appears to be as active as paclitaxel. In a European study, previously untreated non-small-cell lung cancer patients were randomly assigned to receive docetaxel at 100 mg/m² every 3 weeks or best supportive care. Survival and quality of life were improved in the chemotherapy arm (Table 3).[20] Docetaxel is also one of the few drugs that has confirmed activity in patients who have previously received platinum-containing chemotherapy.

Shepherd et al randomly assigned previously treated patients to receive docetaxel or best supportive care.[21] The docetaxel dose was initially 100 mg/m²; because of excessive toxicity it was decreased to 75 mg/m² after enrollment of half of the patients. Overall, both survival and quality of life were better in patients who received docetaxel treatment.[22] This improvement was particularly marked for patients receiving the 75 mg/m² dose, in whom 1-year survival was 40% compared with 16% in control patients.

In a study by Fossella et al, previously treated patients were randomized to receive docetaxel 100 (docetaxel at 100 mg/m² per cycle), docetaxel 75 (docetaxel at 75 mg/m² per cycle), or to a control arm of vinorelbine or ifosfamide treatment.[23] About one-third of the 373 enrolled patients were primarily resistant to initial chemotherapy, and a similar percentage had received at least two previous chemotherapy regimens. Previous treatment with paclitaxel was permitted, and 37% of patients had received this drug as part of their previous therapy. Based on an intent-to-treat analysis, survival at 1 year was superior in the docetaxel 75 group (32%) than in the other two treatment arms (21% and 19% in the docetaxel 100 and control groups, respectively). Progression-free survival and quality of life were improved in both docetaxel arms.[24] At the time of disease progression, more than one-third of the patients received additional chemotherapy.

In an attempt to adjust for the effect this poststudy treatment may have had on survival, an analysis was performed in which patients were censored at the time of administration of poststudy chemotherapy. This analysis suggested a survival advantage for both docetaxel arms. Serious toxicities were more common in the docetaxel 100 arm, but this difference was not statistically significant.

Gemcitabine-Based Regimens

Gemcitabine is also active in non-small-cell lung cancer, and early reports suggest that it has activity in previously treated patients. A study which included 522 evaluable patients compared the combination of cisplatin/gemcitabine with cisplatin alone.[25] One-year survival was substantially better in patients treated with the combination (39% vs 28%) (Table 4). Hematologic toxicity was more pronounced with the combination, but nonhematologic toxicity and quality-of-life assessments were similar in the two treatment groups. Randomized phase II studies that compared gemcitabine with cisplatin/etoposide, and gemcitabine/docetaxel with cisplatin/docetaxel reported comparable response rates.[26-28]

A randomized trial comparing cisplatin/gemcitabine with cisplatin/etoposide demonstrated a superior response rate (41% vs 22%) and progression-free survival (6.9 months vs 4.3 months), with comparable toxicities for the two treatments.[29] A preliminary report of another study, which compared gemcitabine/paclitaxel with carboplatin/paclitaxel, reported a higher response rate in the gemcitabine/paclitaxel arm.[30]

Irinotecan in Non-Small-Cell Lung Cancer

The reported activity of irinotecan in advanced non-small-cell lung cancer has ranged from 15% to 32%.[31] Two randomized studies from Japan compared the combination of cisplatin/irinotecan with a standard regimen in patients with previously untreated non-small-cell lung cancer (Table 5). In the study by Masuda et al, 378 patients were randomly assigned to receive cisplatin/irinotecan, irinotecan alone, or cisplatin/vindesine.[32] In a second randomized study, 203 patients received cisplatin/irinotecan or cisplatin/vindesine.[33] Although no survival differences were detected individually in these studies, an analysis that combined the data showed that patients treated with cisplatin/irinotecan had significantly better 1-year survival than those receiving the control regimen of cisplatin/vindesine.[34]

Conclusions

The results of these clinical studies support the following conclusions:

• Treatment with cisplatin-based chemotherapy produces survival superior to that achieved with best supportive care.

• Several newer drugs (the US Food and Drug Administration-approved taxanes, vinorelbine, gemcitabine, and irinotecan) are better tolerated than cisplatin and have at least comparable single-agent activity.

• Docetaxel and perhaps some of the other newer drugs improve survival in patients previously treated with a platinum-containing regimen.

• The combination of cisplatin and one of these newer drugs produces survival superior to cisplatin alone.

• The combination of cisplatin and one of these newer drugs produces superior survival, fewer side effects, or both, compared with earlier standard combinations such as cisplatin/vindesine or cisplatin/etoposide.

A question that remains unanswered is whether there is a "best choice" among the possible combinations of a platinum drug and one of the newer agents. Based on the SWOG study, the combination of carboplatin/paclitaxel appears to be as active as cisplatin/vinorelbine.[11] Preliminary results of an ECOG study, in which patients were randomly assigned to one of four treatment arms (cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel, or carboplatin/paclitaxel), were reported last year and demonstrated similar 1-year survival rates (ranging from 31% to 36%).[35] If survival is comparable between these regimens, then other factors will help to define the best choice for patients. Other considerations include patient tolerability, cost, ease of administration, and rationale for and ability to include noncytotoxic agents (such as inhibitors of signal transduction pathways or angiogenesis) into the therapeutic program.

Another unanswered question is whether a nonplatinum regimen will prove superior to the best combinations of a platinum agent and one of the newer drugs. Virtually every two-drug combination of the newer agents has been developed, most of which are being tested or will be tested in patients with non-small-cell lung cancer (Table 6). During the next few years, clinical researchers face the challenge to determine efficiently the answers to these questions.

This work was supported in part by grants from the Public Health Service, National Cancer Institute (CA 16359 and CA 75588).