Rationale for Non-Platinum Chemotherapy in Advanced NSCLC

ABSTRACT: During the past decade, five new cytotoxic drugs have beenintroduced that are active against non-small-cell lung cancer (NSCLC). Theseagents include vinorelbine (Navelbine), paclitaxel (Taxol), docetaxel(Taxotere), gemcitabine (Gemzar), and irinotecan (CPT-11, Camptosar). Usedalone, these drugs display activity comparable to cisplatin. The combination ofcisplatin and one of the newer drugs produces better survival than treatmentwith cisplatin (Platinol) alone. Randomized studies of chemotherapy regimensthat include these newer drugs have demonstrated improved survival, fewer sideeffects, or both, compared with earlier standard combinations such ascisplatin/vindesine or cisplatin/etoposide. Docetaxel and perhaps some of theother newer drugs are of value for patients previously treated withplatinum-containing regimens. Future studies should determine whethercombinations of these newer drugs are superior to cisplatin-containing regimens.Although improved survival is the most important factor in defining the bestregimen in non-small-cell lung cancer, additional considerations includepatient tolerability, costs of administration, and the rationale for and abilityto include noncytotoxic agents (such as inhibitors of signal transductionpathways or angiogenesis) into the therapeutic program. [ONCOLOGY 15(Suppl8):29-34, 2001]

Introduction

The current American Society ofClinical Oncology (ASCO) treatment guideline for selected patients with metastatic non-small-cell lungcancer is up to eight cycles of platinum-based chemotherapy.[1] Thisrecommendation is based on several lines of evidence. Cisplatin (Platinol) isone of the most active drugs in non-small-cell lung cancer (NSCLC), with asingle-agent response rate of approximately 20%. In many different preclinicalmodels, platinum is synergistic with other chemotherapy drugs and withradiation. The superiority of platinum-containing chemotherapy was suggested bya retrospective analysis of the Southwest Oncology Group (SWOG) database, whichshowed that patients who are treated with platinum-containing regimens livedlonger than similar patients treated with non-platinum regimens.[2]

Cisplatin-Based Chemotherapy

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

Most of the clinical trials included in the meta-analysisevaluated regimens in which cisplatin was paired with either etoposide orvindesine. Other regimens popular during that time paired cisplatin withvinblastine, mitomycin (Mutamycin), doxorubicin, cyclophosphamide (Cytoxan,Neosar), or ifosfamide (Ifex). Studies that compared the most active regimenscomposed of these agents reported a median survival of 6 to 9 months.[4-6]Another meta-analysis that included clinical studies published between 1976 and1995 suggested that combination chemotherapy provided no significant survivaladvantage compared with single-agent cisplatin.[7] Because etoposide, doxorubicin, mitomycin, and vinca alkaloids other than vinorelbine (Navelbine) haverelatively modest single- agent activity in NSCLC, it is not surprising thatregimens that combined these drugs with cisplatin were only marginally (if atall) better than cisplatin alone.

Other Regimens

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

Paclitaxel-Based Regimens

As a single agent, paclitaxel produces a response rate ofapproximately 20%. Two recent European studies evaluated the combination ofcisplatin and paclitaxel in patients with advanced non-small-cell lung cancer.In one study, cisplatin/paclitaxel was compared with cisplatin alone,[8] and inthe other study, cisplatin/paclitaxel was compared to the combinationcisplatin/teniposide (Vumon).[9] Although neither study demonstrated adifference in median survival time, both reported improved quality of life amongpatients who received cisplatin and paclitaxel (Table1).

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

The Eastern Cooperative Oncology Group (ECOG) performed arandomized 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-hourinfusion at 135 mg/m² per cycle), and paclitaxel 250 (cisplatin and paclitaxelas a 24-hour infusion at 250 mg/m² per cycle with granulocyte colony-stimulatingfactor [G-CSF (Neupogen)] support). Survival was better in bothpaclitaxel-containing arms than in the control arm, but the difference reachedstandard levels of statistical significance only if results of the twopaclitaxel-containing groups were combined (1-year survival of 39% vs 32%, P =.048). Patient tolerability and preservation of quality of life were fairlycomparable with the different regimens.

Vinorelbine-Based Regimens

Vinorelbine is a vinca alkaloid that produces a response rate of30% in patients with non-small-cell lung cancer. A three-arm European studyreported by Le Chevalier et al compared cisplatin/vinorelbine to vinorelbinealone or to cisplatin/vindesine.[13] A total of 612 patients were evaluated.Survival was better for patients treated with cisplatin/vinorelbine, and wassimilar in the other two treatment arms (Table2). A subsequent subset analysisshowed that the survival benefit was limited to patients with good functionalstatus. Patients with a performance status of 2 had similar survival regardlessof the treatment they received.[14]

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

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

Docetaxel in Non-Small-CellLung Cancer

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

Shepherd et al randomly assigned previously treated patients toreceive docetaxel or best supportive care.[21] The docetaxel dose was initially100 mg/m²; because of excessive toxicity it was decreased to 75 mg/m² afterenrollment of half of the patients. Overall, both survival and quality of lifewere better in patients who received docetaxel treatment.[22] This improvementwas particularly marked for patients receiving the 75 mg/m² dose, in whom 1-yearsurvival was 40% compared with 16% in control patients.

In a study by Fossella et al, previously treated patients wererandomized 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 ofvinorelbine or ifosfamide treatment.[23] About one-third of the 373 enrolledpatients were primarily resistant to initial chemotherapy, and a similarpercentage had received at least two previous chemotherapy regimens. Previoustreatment with paclitaxel was permitted, and 37% of patients had received thisdrug 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 theother two treatment arms (21% and 19% in the docetaxel 100 and control groups,respectively). Progression-free survival and quality of life were improved inboth docetaxel arms.[24] At the time of disease progression, more than one-thirdof the patients received additional chemotherapy.

In an attempt to adjust for the effect this poststudy treatmentmay have had on survival, an analysis was performed in which patients werecensored at the time of administration of poststudy chemotherapy. This analysissuggested a survival advantage for both docetaxel arms. Serious toxicities weremore common in the docetaxel 100 arm, but this difference was not statisticallysignificant.

Gemcitabine-Based Regimens

Gemcitabine is also active in non-small-cell lung cancer, andearly reports suggest that it has activity in previously treated patients. Astudy which included 522 evaluable patients compared the combination ofcisplatin/gemcitabine with cisplatin alone.[25] One-year survival wassubstantially better in patients treated with the combination (39% vs 28%) (Table4). Hematologic toxicity was more pronounced with the combination, butnonhematologic toxicity and quality-of-life assessments were similar in the twotreatment groups. Randomized phase II studies that compared gemcitabine withcisplatin/etoposide, and gemcitabine/docetaxel with cisplatin/docetaxel reportedcomparable response rates.[26-28]

A randomized trial comparing cisplatin/gemcitabine withcisplatin/etoposide demonstrated a superior response rate (41% vs 22%) andprogression-free survival (6.9 months vs 4.3 months), with comparable toxicitiesfor the two treatments.[29] A preliminary report of another study, whichcompared gemcitabine/paclitaxel with carboplatin/paclitaxel, reported a higherresponse rate in the gemcitabine/paclitaxel arm.[30]

Irinotecan in Non-Small-CellLung Cancer

The reported activity of irinotecan in advanced non-small-celllung cancer has ranged from 15% to 32%.[31] Two randomized studies from Japancompared the combination of cisplatin/irinotecan with a standard regimen inpatients with previously untreated non-small-cell lung cancer (Table5). Inthe study by Masuda et al, 378 patients were randomly assigned to receivecisplatin/irinotecan, irinotecan alone, or cisplatin/vindesine.[32] In a secondrandomized study, 203 patients received cisplatin/irinotecan orcisplatin/vindesine.[33] Although no survival differences were detectedindividually in these studies, an analysis that combined the data showed thatpatients treated with cisplatin/irinotecan had significantly better 1-yearsurvival than those receiving the control regimen of cisplatin/vindesine.[34]

Conclusions

The results of these clinical studies support the followingconclusions:

Treatment with cisplatin-based chemotherapy producessurvival superior to that achieved with best supportive care.

Several newer drugs (the US Food and Drug Administration-approvedtaxanes, vinorelbine, gemcitabine, and irinotecan) are better tolerated thancisplatin and have at least comparable single-agent activity.

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

The combination of cisplatin and one of these newer drugsproduces survival superior to cisplatin alone.

The combination of cisplatin and one of these newer drugsproduces superior survival, fewer side effects, or both, compared with earlierstandard 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 andone of the newer agents. Based on the SWOG study, the combination ofcarboplatin/paclitaxel appears to be as active as cisplatin/vinorelbine.[11]Preliminary results of an ECOG study, in which patients were randomly assignedto one of four treatment arms (cisplatin/paclitaxel, cisplatin/gemcitabine,cisplatin/docetaxel, or carboplatin/paclitaxel), were reported last year anddemonstrated similar1-year survival rates (ranging from 31% to 36%).[35] If survival is comparablebetween these regimens, then other factors will help to define the best choicefor patients. Other considerations include patient tolerability, cost, ease ofadministration, and rationale for and ability to include noncytotoxic agents(such as inhibitors of signal transduction pathways or angiogenesis) into thetherapeutic program.

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

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

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