Gemcitabine and Cisplatin Combination in Early-Stage Non-Small-Cell Lung Cancer

ABSTRACT: A number of randomized clinical trials now support theconclusion that the combined-modality regimen that includes gemcitabine (Gemzar)and cisplatin (Platinol) may improve survival in disseminated non-small-celllung cancer. Cisplatin is considered to be the "backbone" of thiscombination chemotherapy due to its proven activity. The regimen of gemcitabineand cisplatin has been tested and is now considered among the most activecombinations in the treatment of disseminated non-small-cell lung cancer. [ONCOLOGY15(Suppl 6):40-42, 2001]

Introduction

In non-small-cell lung cancer surgical resection is possible in only 20%to 30% of all cases, mainly because of locally advanced disease and highincidence of distant metastases. For early-stage resectable non-small-celllung cancer, 5-year survival is 60% for stage I, 40% for stage II, and 20% forlimited stage IIIA; in case of mediastinoscopy positive N2 disease, 5-yearsurvival drops to 5% to 10%. According to historical series, the 5-year survivalis 0% in unresectable, locally advanced, bulky stage IIIA or IIIB disease.[1,2]The overall 5-year survival across all stages of non-small-cell lung cancerranges between 8% and 12% both in Europe and the United States, mainly becauseof early dissemination of disease, which precludes the possibility of anylocoregional treatment (surgery or radiation therapy). Therefore, it seems quiteclear that the overwhelming majority of non-small-cell lung cancer patientsrequires an effective systemic treatment to improve these dismal survivalfigures.

A meta-analysis, conducted in 1995, of all randomized trialsfocusing on the role of chemotherapy in non-small-cell lung cancer showed asmall but significant survival benefit in favor of cisplatin- (Platinol)-basedsystemic chemotherapy across all stages.[3] The results of this meta-analysishave stimulated the use of chemotherapy in addition to locoregional treatment inthe management of locally advanced non-small-cell lung cancer.

In the past 15 years, preoperative or neoadjuvant chemotherapyhas been widely employed in the treatment of stage IIIA disease in many phase IItrials and in some small phase III randomized studies.

Preoperative phase II chemotherapy studies, as exemplified bythe Memorial Sloan-Kettering and Toronto experiences with the MVP regimen(mitomycin [Mutamycin], vinblastine, cisplatin) have shown improved survivalcompared with historical controls, with median survival of 15.5 to 19 months and5-year survival consistently around 18% vs 9% for historical controls.[4,5]

These favorable results have been validated by three small,randomized trials which seem to indicate that neoadjuvant therapy in stage IIIAimproves survival. Unfortunately, the results cannot be considered conclusivebecause of the premature interruption of these studies on the basis of interimanalysis data and a possible worse selection of patients in the control armwhich consisted of surgery alone. In the Pass et al trial (27 stage IIIA N2patients), both median survival (28.7 months vs 15.5 months) and disease-freesurvival (12.7 months vs 5.8 months) seem to favor the neoadjuvant chemotherapyarm, but statistical significance was not reached.[6]

Two subsequent studies from M. D. Anderson Cancer Center and theSpanish Lung Cancer Group showed a statistically significant improvement insurvival for those patients who received preoperative chemotherapy vs surgeryalone.[7,8] The design of these trials was very similar: induction chemotherapyconsisted of cyclophosphamide (Cytoxan, Neosar), etoposide, and cisplatin in theM. D. Anderson experience, and mitomycin, ifosfamide (Ifex), and cisplatin inthe Spanish study. The survival advantage conferred by induction chemotherapywas maintained after 3 and 5 years of follow-up.

New Agents in Neoadjuvant Chemotherapy

Until the early 1990s, the regimens used in phase II/III studiesas induction chemotherapy always consisted of the double or triple combinationsof cisplatin with old active drugs such as etoposide, mitomycin, vincaalkaloids, and ifosfamide. During the 1990s, a number of new drugs withdifferent mechanisms of action showed important activity as single agents in non-small-celllung cancer: the nucleoside analog gemcitabine; the microtubulin inhibitorspaclitaxel, docetaxel (Taxotere), and vinorelbine (Navelbine); and thetopoisomerase I inhibitors irinotecan (CPT-11, Camptosar) and topotecan(Hycamtin) showed response rates greater than 20%. In patients with metastaticnon-small-cell lung cancer, these new agents in combination with a platinumcompound (either cisplatin or carboplatin [Paraplatin]) have demonstratedsuperior response rates and/or survival compared with cisplatin alone or olderplatinum-based combinations.[9]

In particular, gemcitabine and cisplatin in combination haverevealed a strong synergism in preclinical models.[10] In three different largerandomized trials of advanced non-small-cell lung cancer, this new regimen hasshown a survival advantage vs cisplatin alone [11] and higher response ratesthan etoposide/cisplatin[12] and the mitomycin/ifosfamide/cisplatincombination.[13] On the basis of this activity in advanced disease, this regimenhas been tested in several phase II studies in the more favorable stage III non-small-celllung cancer as induction chemotherapy to surgery or radiotherapy.

In 1996, the EORTC initiated a phase II trial to define thetoxicity and activity of this new regimen as an induction treatment for patientswith stage III N2 non-small-cell lung cancer, within a large ongoingrandomized trial comparing surgery with radiotherapy after neoadjuvantchemotherapy.[14] Forty-seven patients received gemcitabine 1,000 mg/m² on days1 through 8 and 15 and cisplatin 100 mg/m² on day 2, every 4 weeks. Of the 47eligible patients, 33 had objective responses (70.2%, 95% confidence interval[CI] = 55.1%-82.7%) with three complete and 30 partial responses. Resectionswere considered complete in 71% of these patients who underwent thoracotomy.Median survival was 18.9 months, and 1-year survival was 69%. Grade 3/4thrombocytopenia occurred in 60% of patients without any episodes of bleedingand caused withholding of gemcitabine on day 15 in 48% of the courses.

Similar results have been reported in a series of small phase IIstudies of gemcitabine and cisplatin as induction chemotherapy in stage III non-small-celllung cancer. In 1996, we started an Italian prospective phase II trial toevaluate the safety and activity profile of a new, 3-week schedule ofgemcitabine and cisplatin as induction chemotherapy to surgery or radiotherapyin stage IIIA/IIIB non-small-cell lung cancer. A total of 110 patients weretreated with gemcitabine 1,250 mg/m² on days 1-8 and cisplatin 80mg/m² on day2. Ninety males and 20 females were enrolled. The median age was 61 years(range: 39-79) and all patients had 0 or 1 ECOG performance status (49 and 61,respectively). Fifty-five patients had squamous carcinoma, 37 adenocarcinoma, 6large cell carcinoma; and 12 unknown non-small-cell lung cancer. A mediannumber of four courses (range: 2-8) was given. Response assessment showed 69partial responses (62%) and 3 pathologically confirmed complete responses (3%);34 patients (31%) remained with stable disease and only 4 experiencedprogression; 31 patients (28%) underwent thoracotomy and were completelyresected.

Treatment was well tolerated. Twenty-two patients experiencedWorld Health Organization (WHO) grade III neutropenia and 3 developed grade IVneutropenia. WHO grade III and IV thrombocytopenia was recorded in 22 and 12patients, respectively. No toxic deaths were observed.[15]

Neoadjuvant Chemotherapyin Early Stages ofNon-Small-Cell Lung Cancer

In these studies, the activity of the gemcitabine/cisplatincombination in stage III non-small-cell lung cancer is among the highest andcompares very favorably with the results of published phase II and III studies.

Response rates were in the range of 60% to 70%. Surgicalresection and pathologic downstaging of mediastinal lymph nodes occurred in morethan 50% of patients, despite significant initial tumor burden (most patientshad bulky N2 unresectable disease at the start of treatment).

These considerations indicated that the gemcitabine/cisplatincombination is a very active induction chemotherapy and prompted Italianinvestigators to evaluate its role in a more favorable setting, namely stageI/II and selected IIIA resectable cases. Recently, in the United States andEurope, neoadjuvant chemotherapy has been evaluated in early-stage non-small-celllung cancer, both in phase II and III studies. In a multicenter US phase IItrial of 94 patients with T2 N0, T1/2N1; and T3 N0/1 disease, investigatorsdelivered two cycles of carboplatin/paclitaxel followed by surgery and by threeadditional cycles of chemotherapy.[16] Major responses occurred in 56% of cases;4% of patients were completely resected.

In a randomized phase III study of 373 patients, Depierre et alassessed the impact of neoadjuvant chemotherapy (two cycles of MIC regimen)followed by surgery vs surgery alone, on survival in stage I/II and IIIA non-small-celllung cancer.[17] In a Cox regression model adjusted for stage, the effect ofpreoperative chemotherapy was significantly favorable with a relative risk of.77 (P = .05). Disease-free survival was significantly longer (P = .02) and therisk of distant recurrence was significantly lower (P = .01) in the preoperativechemotherapy arm.

After these trials, we designed a randomized study comparingsurgery vs induction chemotherapy with gemcitabine/cisplatin followed by surgeryin early-stage patients. Overall survival will be the main end point of thistrial, which is currently ongoing in Italy.

New Drugs in Combined-Modality Treatment

The 1995 meta-analysis showed that chemotherapy improvessurvival when added to radiotherapy for patients with unresectable stage III non-small-celllung cancer.[3] These data have been recently confirmed by two consecutiveprospective trials from the Cancer and Leukemia Group B (CALGB) and RadiationTherapy Oncology Group (RTOG), both reporting a survival advantage in favor ofsequential chemoradiotherapy vs radiotherapy alone.[18,19] Concurrentcisplatin-based chemoradiotherapy vs sequential radiotherapy alone has also been evaluated in phase IIItrials with promising results: Furuse et al showed that median and long-termsurvival were clearly superior in the concurrent arm of split-course thoracicradiotherapy and MVP chemotherapy vs the sequential arm of MVP before thoracicradiotherapy.[20]

Recently, new drugs have been evaluated by the CALGB in arandomized phase III study exploring sequential and concurrent chemoradiotherapyin unresectable stage III non-small-cell lung cancer. This study was designedto investigate three new combinations plus cisplatin/radiotherapy combinations:cisplatin/gemcitabine, cisplatin/paclitaxel, and cisplatin/vinorelbine. Eachcombination was given initially as induction chemotherapy for two cycles andthen concurrently with radiotherapy. The results of this study are verypromising, with a median survival of 18 months, 1-year survival of 66%, and anacceptable toxicity profile.[21]

Conclusions

The new gemcitabine/cisplatin regimen has been extensivelyevaluated in advanced non-small-cell lung cancer in phase II and phase IIIrandomized trials with a response rate ranging between 21% and 40% and a mediansurvival of approximately 9 months. These data place this combination among themost active regimens in non-small-cell lung cancer and suggest the importanceof a thorough evaluation in more favorable disease stages. The ongoing trials inthe neoadjuvant setting and in the sequential or concurrent approach withradiotherapy in early non-small-cell lung cancer will contribute to define therole of this regimen in the combined treatment of non-small-cell lung cancer.

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