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Is There Any Impact of New Drugs on the Outcome of Advanced NSCLC? An Overview of the Southern Italy Cooperative Oncology Group Trials

on behalf of the Southern Italy Cooperative Oncology Group (SICOG)

Correspondence: Giovanni Pacilio, M.D., Via Manzoni 61 (villa Caporali), 80123-Naples, Italy. Fax: 39081640631; e-mail: cpacilio{at}tin.it

	Abstract

Top Abstract Introduction Cisplatin-GEM-VNR: Phase I... Cisplatin-GEM-VNR: Phase II... Cisplatin-GEM-Paclitaxel: Phase... Cisplatin-GEM-VNR Versus... Discussion Appendix References

 
Lung cancer represents the major cause of cancer-related death in Europe and North America, accounting for 28% of all cancer deaths. Seventy to 80% of all lung cancers are non-small cell lung cancers (NSCLCs), and approximately 75% of these patients present with locally advanced or disseminated disease.

Even though chemotherapy is now recommended in the majority of cases of unresectable NSCLC, it still fails to substantially modify the fate of these patients. In recent years, several active cytotoxic drugs (paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan) have been developed, showing an overall response rate (ORR) <20% in NSCLC. Phase II/III trials testing these new agents in combination with cisplatin have been carried out in recent years with inconsistent results.

Large randomized trials testing cisplatin-paclitaxel, carboplatin-paclitaxel, and cisplatin-gemcitabine regimens have been reported showing no substantial superiority of these combinations over standard treatments. The ORR remained well below 50%, and the median survival times were quite far from one year. These data could suggest that the addition of a single new agent to a platinum compound could be insufficient to substantially improve the prognosis of advanced NSCLC patients.

In view of these disappointing data, the Southern Italy Cooperative Oncology Group has tried to improve the fate of patients with advanced NSCLC by testing new triplet combinations, which combined cisplatin with two rather than one of the newest chemotherapy agents. To avoid an unacceptable increase in toxicity and/or a marked decrease in dose intensity, the standard schedules of administration of the three agents used in these studies were changed, and the schedule changes were evaluated in phase I trials aimed at determining the maximum tolerated dosages of the drugs. Subsequently, phase II and III trials were conducted.

The present paper summarizes the results of the clinical trials either completed or under way and aims to evaluate whether this stategy will result in a substantial prognostic improvement.

Key Words. NSCLC • Chemotherapy trials • Gemcitabine • Vinorelbine • Cisplatin • Survival

	Introduction

Top Abstract Introduction Cisplatin-GEM-VNR: Phase I... Cisplatin-GEM-VNR: Phase II... Cisplatin-GEM-Paclitaxel: Phase... Cisplatin-GEM-VNR Versus... Discussion Appendix References

 
Until the late 1980s, chemotherapy was considered an optional therapeutic approach for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), since it was unclear whether it translated into a substantial survival gain.

Only a few drugs (cisplatin, vinca alkaloids, mitomycin, ifosphamide, etc.) had demonstrated definite antitumor activity in this disease, with a probability of response when used as single agents which did not exceed 20%. Many chemotherapy combinations had been tried, with overall response rates (ORR) not exceeding 40% in controlled trials and median survivals shorter than one year [1].

After many years of debate about the role of chemotherapy in patients with metastatic NSCLC, a meta-analysis of randomized trials comparing chemotherapy (either cisplatin-based or not) with the best supportive care showed a modest but significant survival benefit in favor of cisplatin-containing combination chemotherapy. The same authors also found that the addition of chemotherapy to surgery or radiotherapy improved the prognosis in patients with less advanced disease [2].

Therefore, the key message was that modern chemotherapy regimens might have a role in treating all stages of NSCLC, but that more effective drugs and combinations would be required to obtain a more substantial impact on prognosis.

Recently, several active cytotoxic agents (paclitaxel, docetaxel, vinorelbine [VNR], gemcitabine [GEM], and irinotecan) have been developed, showing an ORR >20% [3]. Phase II/III trials testing these new drugs in combination with cisplatin have been carried out in the last few years, with inconsistent results [4-15].

The cisplatin-VNR regimen fared better than cisplatin or VNR alone or than the cisplatin-vinblastine combination in two large randomized trials conducted in Europe and North America. However, the median survival times remained far below one year in these trials [4, 5].

The combination of paclitaxel with cisplatin or carboplatin has also been widely tested, with response rates ranging from 30% to 50% [6-10]. In particular, the cisplatin-paclitaxel regimen has shown a significantly higher antitumor activity than either cisplatin-etoposide or cisplatin-teniposide in two large multicenter trials, but the differences observed in median survival were not statistically significant [8, 9].

Numerous clinical trials evaluating the role of GEM in the treatment of NSCLC patients have also been recently conducted. In several phase II trials, the cisplatin-GEM combination produced response rates ranging from 40% to 50% with median survival times even exceeding one year [11-12]. This regimen prolonged the survival of patients more than cisplatin alone but less than standard cisplatin-based regimens [13-15].

In view of these disappointing data, the Southern Italy Cooperative Oncology Group has tried to improve the fate of patients with advanced NSCLC by testing new triplet combinations, which combined cisplatin with two rather than one of the newest chemotherapy agents.

	Cisplatin-GEM-VNR: Phase I Evaluation

Top Abstract Introduction Cisplatin-GEM-VNR: Phase I... Cisplatin-GEM-VNR: Phase II... Cisplatin-GEM-Paclitaxel: Phase... Cisplatin-GEM-VNR Versus... Discussion Appendix References

 
Since both cisplatin + GEM and cisplatin + VNR were recognized among the most active regimens in NSCLC patients, we conducted a phase I study which aimed at determining the maximum tolerated dosages (MTDs) of GEM and VNR when administered with cisplatin. We decided to adopt a days 1 and 8 every 3-week schedule for all the drugs, since in the previous experiences with the cisplatin-GEM regimen, the administration of GEM on day 15 had often been omitted due to hematologic toxicity [11].

Overall, 31 patients entered the study through five different dose levels. The occurrence of a dose-limiting toxicity (DLT) at first cycle in 33% or more patients of a given cohort was required to halt dose escalation. Two different dose levels, GEM 1,200 mg/m² + VNR 20 mg/m² and GEM 1,000 mg/m² + VNR 25 mg/m², were fairly well tolerated (in both cohorts, DLT occurred in one of the first six patients) (Table 1). The doses of cisplatin, GEM, and VNR on days 1 and 8 recommended for phase II were 50 mg/m², 1,000 mg/m², and 25 mg/m², since in our opinion they provided a better balance of GEM and VNR for dose intensity. Indeed, while a substantial improvement of GEM antitumor activity has not been demonstrated for doses exceeding 1,000 mg/m²/week, there is general agreement that the optimal VNR dose should not be lower than 25 mg/m²/week.

	Cisplatin-GEM-VNR: Phase II Evaluation

Top Abstract Introduction Cisplatin-GEM-VNR: Phase I... Cisplatin-GEM-VNR: Phase II... Cisplatin-GEM-Paclitaxel: Phase... Cisplatin-GEM-VNR Versus... Discussion Appendix References

 
This multicenter phase II randomized trial was aimed at evaluating the therapeutic activity of the cisplatin-GEM-VNR regimen at the MTDs selected in the phase I study.

We chose to randomize patients in order to avoid an overestimation of the activity of the experimental regimen. The previously tested cisplatin-epirubicin-vindesine + lonidamine regimen was used as the standard treatment [17].

The target ORR was set at 45%, with a 30% response rate set as the lowest of interest. According to the Simon two-stage design [18], the planned final sample size was 81 patients for each arm, and at least 31 major responses were required in the experimental arm to consider the new combination worthy of further phase III evaluation.

From October 1995, 111 patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were randomized (57 in the experimental and 54 in the control arm). In December 1996, the randomization was stopped before the planned sample size was reached, since the target number of responses had already been achieved in the experimental arm (32/57 responders). However, 30 additional patients were treated with this regimen in order to obtain a more accurate estimation of its activity.

Four complete responses (CRs) and 46 partial responses (PRs) were recorded among the 87 patients receiving the cisplatin-GEM-VNR combination, for a 57% (95% CI = 46-68) ORR. Two CRs and 18 PRs were observed in the control arm, yielding a 37% (95% CI = 24-51) ORR. Performance status improved in 55% and 37% of patients in the two arms, respectively. The rates of symptom relief in the two arms were 60% and 38%, respectively (Table 2).

View larger version (12K): [in this window] [in a new window]   Figure 1. Cisplatin-GEM-VNR: overall survival.

	Cisplatin-GEM-Paclitaxel: Phase I/II Evaluation

Top Abstract Introduction Cisplatin-GEM-VNR: Phase I... Cisplatin-GEM-VNR: Phase II... Cisplatin-GEM-Paclitaxel: Phase... Cisplatin-GEM-VNR Versus... Discussion Appendix References

 
Since both cisplatin-paclitaxel and cisplatin-GEM combinations were generally considered among the most active regimens in NSCLC patients, we conducted this study to determine the MTD of paclitaxel when combined with fixed doses of cisplatin and GEM in advanced NSCLC patients, and to define the therapeutic activity of this new regimen.

From October 1996 to September 1998, 75 patients with stage IIIB-IV NSCLC, either chemo-naive or pretreated, received fixed doses of cisplatin (50 mg/m²), GEM (1,000 mg/m²), and escalating doses of paclitaxel in a 1-h infusion, all on days 1 and 8, every three weeks.

Five different paclitaxel doses were tested, for an overall 275 delivered cycles. Only pretreated patients (10) were included in the first two levels. Accrual of pretreated patients was stopped at the paclitaxel dose of 75 mg/m², because of the occurrence of dose-limiting thrombocytopenia in three of six patients; dose escalation in chemo-naive patients continued until 150 mg/m². Table 3 outlines the results of the phase I study, including a total of 42 patients (32 chemo-naive). A paclitaxel dose of 125 mg/m² was recommended for phase II, and a total of 39 patients were treated at this level, for an overall 158 delivered cycles. The treatment was generally well tolerated, except by patients enrolled at the last dose level (paclitaxel 150 mg/m²). No treatment-related deaths occurred. Five patients were hospitalized due to sepsis, and packed red blood cell transfusion was required in 13 patients. Grade 4 neutropenia and thrombocytopenia occurred in 23 (31%) and 8 (11%) patients, but this occurred in only nine (23%) and three (8%) of the 39 patients treated at the paclitaxel dose of 125 mg/m². Overall 74/75 patients included in the phase I/II study were evaluable for response. Four CRs and 38 PRs were recorded, for a 57% ORR. Three of the 10 pretreated patients achieved a PR, as compared with four CRs and 35 PRs in the 64 chemo-naive patients (ORR = 61%). Thirty-eight of 39 patients included in phase II were evaluable for response (one patient without measurable disease). Two CRs and 24 PRs were recorded in this group yielding an ORR of 68% (95% CI = 51-82). The quality of life (QOL) score improved in 27/39 (70%) patients after three chemotherapy cycles (Table 4). After a 13-month median follow-up (range: 1-23), the median survival time was 15 months in the 65 chemo-naive patients. The median survival time was not yet reached in the 39 patients included in phase II, where the one-year projected survival was 70% (Fig. 2).

View larger version (10K): [in this window] [in a new window]   Figure 2. Cisplatin-GEM-paclitaxel: overall survival. ____ whole population; – – – cohort of patients treated at the dose of 125 mg/m2 of paclitaxel.

	Cisplatin-GEM-VNR Versus Cisplatin-VNR Versus Cisplatin-GEM

Top Abstract Introduction Cisplatin-GEM-VNR: Phase I... Cisplatin-GEM-VNR: Phase II... Cisplatin-GEM-Paclitaxel: Phase... Cisplatin-GEM-VNR Versus... Discussion Appendix References

 
Interim Analysis of a Phase III Trial
In view of the very promising ORR and median survival time obtained in the previous phase II trial with the cisplatin-GEM-VNR (PGV) combination, we decided to initiate a three-arm phase III study aimed at comparing the impact on survival and QOL of this regimen with that of the cisplatin-GEM (PG) and cisplatin-VNR (PV) regimens. NSCLC patients with locally advanced or metastatic disease aged <70 years and with an ECOG performance status <1 were randomized to receive PGV, PG, or PV. The doses and schedules of the three regimens are detailed in Figure 3.

View larger version (25K): [in this window] [in a new window]   Figure 3. Cisplatin/GEM/VNR versus cisplatin/VNR versus cisplatin/GEM: phase III study design. GEM = GCTB; Cisplatin = CDDP; VNR = VNR.

The survival data of 199 NSCLC cases (PGV = 69, PG = 63, PV = 67) randomized from March 1997 and February 1999 were analyzed by an independent monitoring board. Stage was IIIB or IV in 70 and 129 patients, respectively. At a 15-month (range: 1-23) median potential follow-up, median survival time was 50, 47, and 34 weeks for the PGV, PG, and PV arms, respectively, with a six-month survival probability of 80%, 77%, and 58%, respectively. The difference between the survival curves of the PGV and PV arms was highly significant (p < 0.01) and met the chosen early stopping criteria. Therefore, the accrual of patients was stopped in the PV arm but continued in the PGV and PG arms until the planned final sample size of 120 patients per arm was achieved.

	Discussion

Top Abstract Introduction Cisplatin-GEM-VNR: Phase I... Cisplatin-GEM-VNR: Phase II... Cisplatin-GEM-Paclitaxel: Phase... Cisplatin-GEM-VNR Versus... Discussion Appendix References

 
In spite of the enthusiasm raised by the introduction into clinical practice of several new agents active against NSCLC, in the recent large randomized trials, the combination of platin compounds with these molecules (cisplatin-paclitaxel, carboplatin-paclitaxel, and cisplatin/GEM) has not produced a clear survival gain when compared with standard treatments [8-9, 14-15, 21]. The ORR remained clearly below 50%, and the median survival times far short of one year. These data could suggest that the addition of a single new agent to a platinum compound could be insufficient to substantially improve the prognosis of advanced NSCLC patients. Further efforts, mainly consisting of the development of more aggressive combinations including new truly non-cross-resistant agents, are required.

The main purpose of our above summarized trials was to develop aggressive three-drug regimens combining cisplatin with one or more of the newest agents.

The publication of several pilot trials showing promising response rate and overall survival with cisplatin-GEM regimens moved us to evaluate the possibility of putting GEM, VNR, and cisplatin all together. In order to avoid an unacceptable increase in toxicity and/or a marked decrease in dose intensity, we modified the standard schedule of administration of GEM and cisplatin. All three drugs were given on days 1 and 8 every three weeks. This change allowed us to obtain this goal. In fact, this new regimen proved in the phase I study to be feasible and well tolerated, and all three drugs could be given at a dose intensity similar to that used in the common two-drug regimens.

There are several interesting considerations that can be made on the results of the subsequent phase II randomized trial. First of all, the use of randomization, at least in the first 111 enrolled patients, makes any conclusion regarding the therapeutic efficacy of this combination more valid. The evidence of a more than 50% ORR (even in patients with stage IV disease) and of a 50-week median survival (with an almost 20% two-year survival probability) appears to be a good result, although further confirmations are required prior to drawing definite conclusions. These results were achieved at a price of moderate hematologic and even negligible nonhematologic toxicity. Finally, the relevant proportion of patients experiencing substantial and durable symptom relief, associated with a significant improvement of QOL is, in our opinion, a clear confirmation that the adoption of a more aggressive approach may result in an improvement rather than an impairment of QOL, especially when an accurate selection of the study population has been performed, excluding elderly or unfit patients.

The results of the phase I-II study, which tested the cisplatin-GEM-paclitaxel regimen, deserve some considerations as well. The split of administration of both cisplatin and paclitaxel on days 1 and 8 permitted delivery of these two drugs at the cumulative doses of 100 mg/m² and 250 mg/m² every three weeks in combination with full doses of GEM, at a price of mild hematologic and nonhematologic toxicities. The 61% ORR observed in the 64 chemo-naive patients looks very promising, especially if we take into account that four different paclitaxel doses were employed and that a relevant proportion of patients had poor prognostic features at diagnosis (stage IV, poor performance status, brain involvement). Also worth noting is the evidence of a clear improvement of QOL in about 70% of the patients. This means that in the majority of advanced NSCLC patients, the use of new "aggressive" regimens substantially improves rather than impairs QOL.

It is too soon to draw definite conclusions about the impact of this regimen on survival, since the median follow-up is too short (seven months), and too few patients have a longer than one-year potential follow-up. However, the evidence of a six-month death risk of 14% (with 20/39 patients at risk at that time) is very promising and suggests that this new approach could at least substantially reduce the risk of death within the first six months.

The above reported results of the interim analysis of our three-arm phase III study also require some comments. This trial was aimed at clarifying whether a substantial difference in antitumor activity existed between GEM and VNR when added to cisplatin and whether the combination of both drugs with CDDP was of any advantage if compared with the addition of only one of them.

The analysis of the survival outcomes of the first 199 randomized patients permits us to provide a first answer to these questions. The triplet regimen of cisplatin-GEM-VNR strongly improves the prognosis of advanced NSCLC patients when compared with the standard Le Chevalier treatment, resulting in an approximate four-month prolongation of the median survival time. The relevance of this survival gain is confirmed by the fact that the p level was less than 0.01, in spite of the small number of patients included in the analysis. This result seems important if we consider that the cisplatin-VNR combination is still considered among the most active in the treatment of advanced NSCLC patients. Besides, it deserves to be pointed out that such a wide difference in median survival has not been commonly observed in the previous phase III trials. Moreover, this difference was not due to an underestimation of the activity of the cisplatin-VNR combination, since the median survival time observed in this arm (34 weeks) was similar to that reported in the Southwest Oncology Group study [5]. The achievement of an almost one-year median survival with our triplet combination represents, in our opinion, an important goal, since in the most recent randomized trials involving the newest combinations, the median survival times had always remained far below this threshold value.

The present study continues in order to address another important issue: whether the addition of a third drug to cisplatin and GEM can provide a substantial advantage in QOL or overall survival. In view of that, we are now continuing the inclusion of patients in the cisplatin-GEM and cisplatin-GEM-VNR arms. Besides, in view of the very promising results obtained in phase II with the cisplatin-GEM-paclitaxel regimen, we have decided to include this combination in the study as a third arm.

Even if the final results of this phase III trial should conclude that the use of a triplet combination (cisplatin-GEM-VNR or cisplatin-GEM-paclitaxel) does not provide a substantial therapeutic advantage in patients with locally advanced or metastatic disease when compared with the use of the cisplatin-GEM regimen, the role of such an aggressive approach in other NSCLC patient subgroups deserves to be addressed. On this proposal, it could be interesting to test these new regimens as adjuvant or neoadjuvant treatment in stage I-IIIAN2 disease, or as an induction chemotherapy followed by concomitant chemoradiotherapy in stage IIIB disease.

In conclusion, the use of triplet cisplatin-based combinations including two of the following three molecules—GEM, VNR, and paclitaxel—seems able to positively affect the prognosis of advanced NSCLC patients. Both cisplatin-GEM-VNR and cisplatin-GEM-paclitaxel produce a major objective response and a QOL improvement in more than half of patients. It is not yet proved whether one or both of these regimens substantially prolong survival in advanced NSCLC patients, although our preliminary results confirm that the cisplatin-GEM-VNR regimen yields a relevant survival advantage over the classical Le Chevalier treatment.

	Appendix

Top Abstract Introduction Cisplatin-GEM-VNR: Phase I... Cisplatin-GEM-VNR: Phase II... Cisplatin-GEM-Paclitaxel: Phase... Cisplatin-GEM-VNR Versus... Discussion Appendix References

 
Institutions (and investigators) of the Southern Italy Cooperative Oncology Group involved in the NSCLC trials reported in this overview are the following:

• Division of Medical Oncology A (Giuseppe Comella, Adriano Gravina, John Perchard, Pasquale Comella), National Tumor Institute, Naples.
  
• Department of Oncohematology (Nicola Panza, Gianpaolo Nicolella, Carmen Pacilio, Giovannni Pacilio), and Division of Pneumology (Michele Natale), Cardarelli Hospital, Naples.
  
• Division of Medical Oncology (Luigi Manzione, Domenico Bilancia) San Carlo Hospital, Potenza.
  
• Division of Medical Oncology (Vito Lorusso, Mario De Lena), Oncology Institute, Bari.
  
• Division of Thoracic Surgery (Franco Carpagnano, Gaetano Di Rienzo), San Paolo Hospital, Bari.
  
• Division of Pneumology (Riccardo Cioffi), City Hospital, Caserta.
  
• Unit of Medical Oncology (Giuseppe De Cataldis) Da Procida Hospital, Salerno.
  
• Unit of Medical Oncology (Luigi Maiorino), San Gennaro Hospital, Naples.
  
• Chair of Respiratory Diseases (Enrico Micillo, Paolo Marcatili), and Chair of Medical Oncology, (Giuseppe Catalano), School of Medicine, 2nd University of Naples.
  
• Unit of Medical Oncology (Mario Belli, Filomena Del Gaizo), City Hospital, Avellino.
  

	References

Top Abstract Introduction Cisplatin-GEM-VNR: Phase I... Cisplatin-GEM-VNR: Phase II... Cisplatin-GEM-Paclitaxel: Phase... Cisplatin-GEM-VNR Versus... Discussion Appendix References

 

1. Gralla R. New directions in non-small cell lung cancer. Semin Oncol 1990;17(suppl 7):20-29.[Medline]
2. Non-Small Cell Lung Cancer Cooperative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patient data from 52 randomised clinical trials. Br Med J 1995;311:899-909.[Abstract/Free Full Text]
3. Lilenbaum RC, Green MR. Novel chemotherapeutic agents in the treatment of non-small cell lung cancer. J Clin Oncol 1993;11:1391-1402.[Abstract/Free Full Text]
4. Le Chevalier T, Brisgand D, Douillard JY et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small cell lung cancer: results of a European Multicenter Trial including 612 patients. J Clin Oncol 1994;12:360-366.[Abstract]
5. Wozniak AJ, Crowley JJ, Balcezark SP et al. Randomized phase III trial of cisplatin (CDDP) versus CDDP plus Navelbine (NVB) in treatment of advanced non-small cell lung cancer (NSCLC): report of a SouthWest Oncology Group study (SWOG-9308). Proc Am Soc Clin Oncol 1996;15:374a.
6. Klastersky J, Sculier JP. Dose-finding of paclitaxel (Taxol) plus cisplatin in patients with non-small cell lung cancer. Lung Cancer 1995;12(suppl 2):S117-S125.
7. Langer CJ, Leighton JC, Comis RL et al. Paclitaxel and carboplatin in combination in the treatment of advanced non-small cell lung cancer. A phase II toxicity, response, and survival analysis. J Clin Oncol 1995;13:1860-1870.[Abstract/Free Full Text]
8. Bonomi P, Kim K, Kluger J et al. Comparison of survival for stage IIIB versus IV non-small cell lung cancer patients treated with etoposide-cisplatin versus Taxol-cisplatin: an Eastern Cooperative Group trial. Proc Am Soc Clin Oncol 1997;16:454a.
9. Giaccone G, Splinter TA, Debruyne C et al. Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non-small-cell lung cancer. The European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1998;16:2133-2141.[Abstract]
10. Millward MJ, Zalcberg J, Bishop JF et al. Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small cell lung cancer. J Clin Oncol 1997;15:750-758.[Abstract/Free Full Text]
11. Crino L, Scagliotti G, Marangolo M et al. Cisplatin-gemcitabine combination in advanced non-small cell lung cancer. A phase II study. J Clin Oncol 1997;15:297-303.[Abstract/Free Full Text]
12. Abratt RP, Bezwoda WR, Goedhals L et al. Weekly GEM with monthly cisplatin: effective chemotherapy for advanced non-small cell lung cancer. J Clin Oncol 1997;15:744-750.[Abstract/Free Full Text]
13. Gatzemeier U, von Pawel J, Gottfried M et al. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 1998;17:454a.
14. Cardenal F, Rosell R, Anton A et al. Gemcitabine + cisplatin versus etoposide + cisplatin in advanced NSCLC patients: preliminary randomized phase III results. Proc Am Soc Clin Oncol 1997;16:458a.
15. Crino L, Conte P, De Marinis F et al. A randomised trial of gemcitabine, cisplatin versus mitomycin, ifosfamide and cisplatin in advanced non-small cell lung cancer. A multicenter phase III study. Proc Am Soc Clin Oncol 1998;17:455a.
16. Frasci G, Panza N, Comella P et al. Cisplatin, gemcitabine and vinorelbine in locally advanced or metastatic non-small cell lung cancer. Ann Oncol 1997;8:1045-1048.[Abstract/Free Full Text]
17. Ianniello G, De Cataldis G, Comella P et al. Cisplatin, epirubicin, and vindesine with or without lonidamine in the treatment of inoperable non-small cell lung carcinoma. A multicenter randomized clinical trial. Cancer 1996;78:63-69.[Medline]
18. Simon R, Wittes RE, Ellenberg SS. Randomised phase II clinical trials. Cancer Treat Rep 1985;69:1375-1381.[Medline]
19. Comella P, Frasci G, Panza N et al. Cisplatin, gemcitabine, and vinorelbine combination in advanced non-small cell lung cancer: a phase II randomized study of the Southern Italy Cooperative Oncology Group. J Clin Oncol 1999;17:1526-1534.[Abstract/Free Full Text]
20. Frasci G, Panza N, Comella P et al. Cisplatin, gemcitabine and paclitaxel in locally advanced or metastatic NSCLC. A Phase I-II study. J Clin Oncol 1999;8:2316-2325.
21. Belani CP, Natale RB, Lee JS et al. Randomized phase III trial comparing cisplatin/etoposide versus carboplatin/paclitaxel in advanced and metastatic non-small cell lung cancer. Proc Am Soc Clin Oncol 1998;17:455a.

This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Frasci, G. Articles by Pacilio, G. Search for Related Content PubMed PubMed Citation Articles by Frasci, G. Articles by Pacilio, G.