- Email: [email protected]
Combination chemotherapy without cisplatin in the treatment of advanced non-small cell lung cancer
Lung Cancer 38 (2002) S57 /S60 www.elsevier.com/locate/lungcan
Combination chemotherapy without cisplatin in the treatment of advanced non-small cell lung cancer Jean-Louis Pujol , Xavier Quantin, Didier Choma, William Jacot, Farid Khial Montpellier University Academic Hospital, Unite´ d’Oncologie Thoracique, Hoˆpital Arnaud de Villeneuve, Avenue du doyen Giraud, 34295 Montpellier cedex 5, France
Abstract Cisplatin-based combinations are standard regimens in the treatment of advanced non-small cell lung cancer. Survival improvement has been achieved using this therapy. However, the high toxicity induced by cisplatin-based doublets urges the research of alternate treatments. Newest cytotoxic compounds yield a better efficacy /toxicity ratio. Platinum-free doublet regimens based on new drugs are expected to offer the patient an improved survival without decreasing his quality of life. Treatment-allocated time and period with high grade toxicity could be considered as wasted from the patient point of view. QUALY methods based on time without symptoms and toxicity allow the accurate evaluation of this end-point. This brief state-of-the-art deals with methodological statements highlighted by the first publications of randomized studies comparing non-platinum-based doublets with either single-drug chemotherapy or standard cisplatin-based doublets. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Chemotherapy; Non-small cell lung cancer; Non-platinum combinations; New drugs
1. Introduction Advanced non-small cell lung cancer (NSCLC) is referred to as the group of patients affected by a disease eligible for neither surgery nor radiotherapy. This definition belongs to stage IV disease or stage IIIb with pleural or pericardium effusion. Chemotherapy improves survival of patients affected by advanced NSCLC [1]. Randomized studies comparing best supportive care (BSC) versus BSC plus chemotherapy have suggested a moderate outcome improvement for patients receiving cytotoxic agents [2]. Meta-analyses concluded positively in favour of chemotherapy in this setting [1,3]. However, one can stress the fact that the magnitude of survival improvement is not precisely known and remains probably low. In addition, evidence of usefulness of chemotherapy mainly arose from cisplatin-containing regimens [4].
Corresponding author. Tel.: /33-4-67-33-61-36; fax: /33-4-6733-61-48 E-mail address: [email protected] (J.-L. Pujol).
World-wide, standard NSCLC chemotherapy is therefore based on this alkylating agent. Insofar as this molecule yields notable toxicities, including ototoxicity, peripheral neuropathy and renal insufficiency, search for alternative combinations is needed. Among the different new anti-cancer agents, gemcitabine (difluorodeoxycytidine), a new pyrimidine analogue [5,6], paclitaxel [7], the prototypical taxane, docetaxel, a semi-synthetic taxane analogue [8 /10] and vinorelbine, a semi-synthetic vinca-alkaloid [11], share promising levels of anti-tumour activity as single-agent chemotherapy in patients with advanced NSCLC. It is noteworthy that patients receiving one of these drugs as a single-drug chemotherapy benefited from a longer survival when compared with patients receiving BSC alone according to four different studies performed in previously untreated populations [6,7,9,11] The aforementioned drugs share a better efficacy: toxicity profile when compared with the older ones. That makes it possible to test the hypothesis that nonplatinum containing regimens can be an alternative therapy to the classical platinum-based combinations in advanced NSCLC.
0169-5002/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 2 ) 0 0 2 7 1 - 4
J.-L. Pujol et al. / Lung Cancer 38 (2002) S57 /S60
S58
Table 1 Design of the study comparing gemcitabine /cisplatin versus gemcitabine /cisplatin /vinorelbine versus gemcitabine /vinorelbine followed by vinorelbine /ifosfamide in non-small cell lung cancer n 562 (518 analyzed) Gem 1250 mg/m2, D1&8 Cis 100 mg/m2, D1
Gem 1250 mg/m2, D1 & 8 Vnr 30 mg/m2, D1&8 Cis 80 mg/m2, D1
Vnr 30 mg/m2, D1&8 Gem 1250 mg/m2, D1&8 Then Ifo, 3 g/m2, DI Vnr 30 mg/m2, D1&8
Abbreviations used : Gem, gemcitabine; Vnr, vinorelbine; Cis, cisplatin; Ifo, ifosfamide [17]. q3w.
2. Gemcitabine /vinorelbine doublets
3. Taxane /gemcitabine doublets
Recent medical literature reported a high number of phase II studies of the gemcitabine /vinorelbine combination [12 /14]. Optimal combination might consist of the delivery of both drugs on days 1 and 8 of a 21-day cycle. Dosages of each drug in the combination are almost similar to the ones used as single-drug chemotherapy. The combination is safe and has been welltolerated in patients with poor conditions such as age older than 70 years. There are three different phase III studies evaluating the gemcitabline /vinorelbine combination. Two of them have compared the doublet with single-drug chemotherapy. The results are conflicting inasmuch as the first study suggested a better outcome for patients receiving the doublet in comparison with vinorelbine alone [15], whereas the second did not demonstrate a difference, although evaluating a nearly similar design [16]. The third one is a comparison with a cisplatincontaining regimen. In this latter study [17], two hypotheses were simultaneously tested; i.e. is a cisplatin-based triplet regimen better than a cisplatin-based doublet, and, is a regimen without cisplatin as efficient as a cisplatin-based doublet? The study design is shown in Table 1. No survival difference has been demonstrated between the three arms of this study. Results are summarized in Table 2.
The combination of taxanes and gemcitabine is a promising way of research insofar as each molecule demonstrated original cellular mechanisms of action and distinct toxicity. The only overlapping toxicity between gemcitabine and taxanes consisted of possible severe interstitial pneumonitis in 3/5% of the patients [18]. This putatively life-threatening effect must be known because its early detection using standard chest X-ray and pulmonary function tests remains possible. The herein presented studies are mainly phase III randomized trials.
3.1. Gemcitabine /paclitaxel doublet Hitherto, there are two reported studies comparing this doublet with cisplatin-based regimen. In the Hellenic study, 329 patients were randomly assigned to receive carboplatin /paclitaxel or gemcitabine /paclitaxel [19]. Twenty six percent and twenty one percent of the patients were not eligible and the analyses were done in fully eligible patients. There was no difference according to conventional statistical tests when survival, response rate, or toxicity were compared (Table 3). The mature results of this study confirmed the aforementioned data. In addition, retrospective analysis of cost did not demonstrate a difference between the two arms
Table 2 Summary of the results of the study comparing gemcitabine /cisplatin versus gemcitabine /cisplatin /vinorelbine versus gemcitabine /vinorelbine followed by vinorelbine /ifosfamide in advanced non-small cell lung cancer Variables
Gem /Cis
Gem /Vnr /Cis
Vnr /Gem /Ifo
P
N Response rate (%) Overall survival (month) 1-year survival (%) Time to prog. (month) Vomiting Thrombocyt. gr 3 /4 (%) Neutropenia gr 3 /4 (%)
166 41 8.7 35 5.7 No difference 18 26
176 40 7.9 31 4.7 No difference 23 30
175 24 8.1 35 4.8 No difference 7 18
NS NS NS NS
Abbreviations used : Gem, gemcitabine; Vnr, vinorelbine; Cis, cisplatin; Ifo, ifosfamide [17].
J.-L. Pujol et al. / Lung Cancer 38 (2002) S57 /S60
S59
Table 3 Summary of the study of gemcitabine /paclitaxel versus carboplatin /paclitaxel in advanced NSCLC (n 165) CBDCA AUC 6, D1 PAC 200 mg/m2, D1 123
P
Evaluable patients
(n 164) Gem 1 g/m2, D1 and 8 PAC 200 mg/m2, D1 130
Object response rate (%) TTP (months) Median survival (months) 1-year survival (%) Netropenia G 3-4 (%) Neurotoxicity (%)
37 7.2 12.3 51 10 6
29 6.9 10.7 41 10 5
0.17 0.47 0.47 NS NS NS
Abbreviations used : Gem, gemcitabine; Pac, paclitaxel; CBDCA, carboplatin; TTP, time to progression [19]. q3wks. Number of evaluable patients at time of intermediate analysis.
(Kosmidis PA, personal communication during the 2001 ECCO meeting). During the 2001 ASCO meeting, the EORTC group reported a randomized study comparing the gemcitabine /paclitaxel doublet with two different cisplatin-based doublets [20]. In this trial 480 patients were randomly allocated to receive (a) paclitaxel /cisplatin; (b) gemcitabine /cisplatin; or (c) gemcitabine /paclitaxel. The planned doses and schedules for paclitaxel were identical in arm A and C. Similarly, gemcitabine was delivered according to an identical procedure in arm B and C and cisplatin in arm A and B. There was no statistical difference regarding response rates when the three groups were compared (31, 36 and 27% in arms A, B and C respectively). However, patients randomly assigned in arm C proved to have a shorter overall survival and time to progression (6.9 and 3.9 months) when compared with arm A (8.1 and 4.4 months) or arm B (8.8 and 5.6 months). There was a trend towards a significant difference in overall survival favouring arm A in comparison with arm C (P B/0.1). Table 4 Design of the study comparing gemcitabine /docetaxel versus cisplatin /docetaxel in advanced NSCLC
Abbreviations used : Gem, gemcitabine; DOC, docetaxel; CIS, cisplatin; TTP, time to progression; G-CSF, granulocyte-colony stimulating factor [23].
3.2. Docetaxel /gemcitabine doublet This combination has been particularly developed by the Hellenic Group of Oncology. The feasibility of this combination has been reported extensively [21]. Aside this publication there were numerous other phase I /II studies evaluating different dosages and schedules of the docetaxel /gemcitabine doublet. All schedules shared a similar gemcitabine delivery on days 1 and 8 of a 21-day cycle. However, they differed in the modalities of delivery of docetaxel. Most of the studies favoured delivery of docetaxel on day 8 instead of day 1. The day 8 docetaxel delivery avoided subsequent gemcitabine omission (no overlapping myelo-suppression) and appeared well-tolerated [22]. An Hellenic study aimed at comparing the gemcitabine /docetaxel combination with cisplatin/docetaxel [23] (Table 4). A total of 441 patients were randomly allocated to receive either docetaxel 100 mg/ m2 and cisplatin 80 mg/m2 every 21 days or docetaxel 100 mg/m2 day 1 and gemcitabine 1100 mg/m2 days 1 and 8. Granulocyte colony stimulating factor was given in both groups as a primary prophylaxis of neutropenia. Table 5 Summary of the study comparing gemcitabine /docetaxel versus cisplatin /docetaxel in advanced NSCLC Variables
GEM-DOC
CIS-DOC
P
Evaluable points Object response rate (%) TTP (months) Median survival (months) 1-year survival (%) Netropenia G 3-4 (%) Toxic death Fluid retention (%) Emesis G 3-4 (%)
201 (90%) 32 (26 /39) 8 9.5 39 22 1% (2) 14 2
205 (97%) 30 (24 /36) 8 10 42 33 3% (6) 7 10
0.90 0.77 0.98 0.80 0.01 0.15 0.005 0.01
Abbreviations used : GEM, gemcitabine; DOC, docetaxel; CIS, cisplatin; TTP, time to progression; G-CSF, granulocyte-colony stimulating factor [23].
S60
J.-L. Pujol et al. / Lung Cancer 38 (2002) S57 /S60
The study hypothesis was designed to detect a 15% response rate difference in favour of the docetaxel / gemcitabine arm. Taking into account fully eligible patients, no statistical difference was observed when response rate, time to progression and overall survival were considered (Table 5). It is noteworthy that the main difference between the two regimens lied in the toxicity profile, inasmuch as more patients in the docetaxel /cisplatin arm were affected by a grade 3/4 neutropenia whereas more patients in the docetaxel / gemcitabine arm suffered from oedema and fluid retention.
4. Discussion Different cisplatin-free doublets can be considered as feasible and safe regimens in the setting of advanced NSCLC therapy. However, the clinical applicability of such doublet in the routine practice remains to be established. Hitherto, the clinical benefit for the patient is unclear. Future studies comparing these new doublets with classical cisplatin-based regimen might take into account quality of life and cost of the treatment as important endpoints. In this setting the time without symptom and toxicity estimation [24] could be regarded as a useful tool in analysing the putative benefit of new cisplatin-free regimens.
References [1] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 1995;311:899 /909. [2] Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non-small cell lung cancer */ report of a Canadian multicenter randomized trial. J Clin Oncol 1988;6:633 /41. [3] Souquet PJ, Chauvin F, Boisesel JP, et al. Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. Lancet 1993;342:19 /21. [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 /7. [5] Abratt R, Bezwoda W, Falkson G, et al. Drug efficacy and safety profile of gemcitabine in non-small cell lung cancer: a phase II study. J Clin Oncol 1994;12:1535 /40. [6] Anderson H, Hopwood P, Stephens RJ, et al. Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer */a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-small cell lung cancer. Br J Cancer 2000;83:447 /53. [7] Ranson M, Davidson N, Nicolson M, et al. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000;92:1074 /80.
[8] Cerny T, Kaplan S, Pavlidis N, et al. Docetaxel (Taxotere) is active in non-small cell lung cancer: a phase II trial of the EORTC-Clinical Trials Group. Br J Cancer 1994;70:384 /7. [9] Roszkowski K, Pluzanska A, Krzakowski M, et al. A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC). Lung Cancer 2000;27:145 /57. [10] Shepherd F, Dancey J, Ramlau R, et al. Prospective randomized trial of Docetaxel versus best supportive care in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095 /103. [11] The Elderly Lung Cancer Vinorelbine Italian Study Group. Effect of vinorelbine on quality of life an survival of elderly patients with advanced non-small cell lung cancer. J Natl Cancer Inst 1999;91:66 /72. [12] Gridelli C, Frontini L, Perrone F. Gemcitabine plus vinorelbine in advanced non-small cell lung cancer: a phase II study of three different doses. Gem Vin Investigators. Br J Cancer 2000;83:707 / 14. [13] Beretta GD, Michetti G, Belometti MO, et al. Gemcitabine plus vinorelbine in elderly or unfit patients with non-small cell lung cancer. Br J Cancer 2000;83:573 /6. [14] Bajetta E, Chiara Stani S, De Candis D, et al. Gemcitabine plus vinorelbine as first-line chemotherapy in advanced nonsmall cell lung carcinoma a phase II trial. Cancer 2000;89:763 /8. [15] Frasci G, Lorusso V, Panza N, et al. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced nonsmall-cell lung cancer. J Clin Oncol 2000;18:2529 /36. [16] Gridelli C, Perrone F, Cigolari S, et al. The MILES (multicenter Italian lung cancer in the elderly study) phase III trial: gemcitabine / vinorelbine versus vinorelbine versus gemcitabine in elderly advanced non-small cell lung cancer patients. Proc Am Assoc Clin Oncol 2001;20:A1230. [17] Alberola V, Camps C, Provencia D, et al. Cisplatin gemcitabine versus cisplatin gemcitabine vinorelbine versus sequential doublets gemcitabine vinorelbine followed by ifosfamide vinorelbine in advanced non-small cell lung cancer: results of a Spanish lung cancer group phase III study. Proc Am Assoc Clin Oncol 2001;20:A1229. [18] Dunsford M, Mead GM, Bateman A, et al. Severe pulmonary toxicity in patients treated with a combination of docetaxel and gemcitabine for metastatic transitional cell carcinoma. Ann Oncol 1999;10:943 /7. [19] Kosmidis PA, Bacoyiannis C, Mylonakis N, et al. A randomized phase III trial of paclitaxel plus carboplatin versus paclitaxel plus gemcitabine in advanced non small cell lung cancer (NSCLC). A preliminary analysis. Proc Am Assoc Clin Oncol 2000;18:A1908. [20] VanMeerbeeck JP, Smit EF, Lianes P, et al. A EORTC randomized phase III trial of three chemotherapy regimens in advanced non-small cell lung cancer. Proc Am Assoc Clin Oncol 2001;20:A1228. [21] Georgoulias, Kouroussis C, Androulakis N, et al. Front-line treatment of advanced non-small-cell lung cancer with docetaxel and gemcitabine: a multicenter phase II trial. J Clin Oncol 1999;17:914 /20. [22] Rebattu P, Quantin X, Ardiet C, et al. Dose-finding, pharmacokinetic and phase II study of docetaxel in combination with gemcitabine in patients with inoperable non-small cell lung cancer. Lung Cancer 2001;33:277 /87. [23] Georgoulias V, Papadakis E, Alexopoulos A, et al. Platinumbased and non-platinum-based chemotherapy in advanced nonsmall-cell lung cancer: a randomized multicentre trial. Lancet 2001:357 /1478. [24] Gelber RD, Goldhisrsh A, Cole BF. Evaluation of effectiveness: Q-TWiST. The Internetional Breast Cancer Study Group. Cancer Treat Rev 1993;19:73 /84.
Combination chemotherapy without cisplatin in the treatment of advanced non-small cell lung cancer Jean-Louis Pujol , Xavier Quantin, Didier Choma, William Jacot, Farid Khial Montpellier University Academic Hospital, Unite´ d’Oncologie Thoracique, Hoˆpital Arnaud de Villeneuve, Avenue du doyen Giraud, 34295 Montpellier cedex 5, France
Abstract Cisplatin-based combinations are standard regimens in the treatment of advanced non-small cell lung cancer. Survival improvement has been achieved using this therapy. However, the high toxicity induced by cisplatin-based doublets urges the research of alternate treatments. Newest cytotoxic compounds yield a better efficacy /toxicity ratio. Platinum-free doublet regimens based on new drugs are expected to offer the patient an improved survival without decreasing his quality of life. Treatment-allocated time and period with high grade toxicity could be considered as wasted from the patient point of view. QUALY methods based on time without symptoms and toxicity allow the accurate evaluation of this end-point. This brief state-of-the-art deals with methodological statements highlighted by the first publications of randomized studies comparing non-platinum-based doublets with either single-drug chemotherapy or standard cisplatin-based doublets. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Chemotherapy; Non-small cell lung cancer; Non-platinum combinations; New drugs
1. Introduction Advanced non-small cell lung cancer (NSCLC) is referred to as the group of patients affected by a disease eligible for neither surgery nor radiotherapy. This definition belongs to stage IV disease or stage IIIb with pleural or pericardium effusion. Chemotherapy improves survival of patients affected by advanced NSCLC [1]. Randomized studies comparing best supportive care (BSC) versus BSC plus chemotherapy have suggested a moderate outcome improvement for patients receiving cytotoxic agents [2]. Meta-analyses concluded positively in favour of chemotherapy in this setting [1,3]. However, one can stress the fact that the magnitude of survival improvement is not precisely known and remains probably low. In addition, evidence of usefulness of chemotherapy mainly arose from cisplatin-containing regimens [4].
Corresponding author. Tel.: /33-4-67-33-61-36; fax: /33-4-6733-61-48 E-mail address: [email protected] (J.-L. Pujol).
World-wide, standard NSCLC chemotherapy is therefore based on this alkylating agent. Insofar as this molecule yields notable toxicities, including ototoxicity, peripheral neuropathy and renal insufficiency, search for alternative combinations is needed. Among the different new anti-cancer agents, gemcitabine (difluorodeoxycytidine), a new pyrimidine analogue [5,6], paclitaxel [7], the prototypical taxane, docetaxel, a semi-synthetic taxane analogue [8 /10] and vinorelbine, a semi-synthetic vinca-alkaloid [11], share promising levels of anti-tumour activity as single-agent chemotherapy in patients with advanced NSCLC. It is noteworthy that patients receiving one of these drugs as a single-drug chemotherapy benefited from a longer survival when compared with patients receiving BSC alone according to four different studies performed in previously untreated populations [6,7,9,11] The aforementioned drugs share a better efficacy: toxicity profile when compared with the older ones. That makes it possible to test the hypothesis that nonplatinum containing regimens can be an alternative therapy to the classical platinum-based combinations in advanced NSCLC.
0169-5002/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 2 ) 0 0 2 7 1 - 4
J.-L. Pujol et al. / Lung Cancer 38 (2002) S57 /S60
S58
Table 1 Design of the study comparing gemcitabine /cisplatin versus gemcitabine /cisplatin /vinorelbine versus gemcitabine /vinorelbine followed by vinorelbine /ifosfamide in non-small cell lung cancer n 562 (518 analyzed) Gem 1250 mg/m2, D1&8 Cis 100 mg/m2, D1
Gem 1250 mg/m2, D1 & 8 Vnr 30 mg/m2, D1&8 Cis 80 mg/m2, D1
Vnr 30 mg/m2, D1&8 Gem 1250 mg/m2, D1&8 Then Ifo, 3 g/m2, DI Vnr 30 mg/m2, D1&8
Abbreviations used : Gem, gemcitabine; Vnr, vinorelbine; Cis, cisplatin; Ifo, ifosfamide [17]. q3w.
2. Gemcitabine /vinorelbine doublets
3. Taxane /gemcitabine doublets
Recent medical literature reported a high number of phase II studies of the gemcitabine /vinorelbine combination [12 /14]. Optimal combination might consist of the delivery of both drugs on days 1 and 8 of a 21-day cycle. Dosages of each drug in the combination are almost similar to the ones used as single-drug chemotherapy. The combination is safe and has been welltolerated in patients with poor conditions such as age older than 70 years. There are three different phase III studies evaluating the gemcitabline /vinorelbine combination. Two of them have compared the doublet with single-drug chemotherapy. The results are conflicting inasmuch as the first study suggested a better outcome for patients receiving the doublet in comparison with vinorelbine alone [15], whereas the second did not demonstrate a difference, although evaluating a nearly similar design [16]. The third one is a comparison with a cisplatincontaining regimen. In this latter study [17], two hypotheses were simultaneously tested; i.e. is a cisplatin-based triplet regimen better than a cisplatin-based doublet, and, is a regimen without cisplatin as efficient as a cisplatin-based doublet? The study design is shown in Table 1. No survival difference has been demonstrated between the three arms of this study. Results are summarized in Table 2.
The combination of taxanes and gemcitabine is a promising way of research insofar as each molecule demonstrated original cellular mechanisms of action and distinct toxicity. The only overlapping toxicity between gemcitabine and taxanes consisted of possible severe interstitial pneumonitis in 3/5% of the patients [18]. This putatively life-threatening effect must be known because its early detection using standard chest X-ray and pulmonary function tests remains possible. The herein presented studies are mainly phase III randomized trials.
3.1. Gemcitabine /paclitaxel doublet Hitherto, there are two reported studies comparing this doublet with cisplatin-based regimen. In the Hellenic study, 329 patients were randomly assigned to receive carboplatin /paclitaxel or gemcitabine /paclitaxel [19]. Twenty six percent and twenty one percent of the patients were not eligible and the analyses were done in fully eligible patients. There was no difference according to conventional statistical tests when survival, response rate, or toxicity were compared (Table 3). The mature results of this study confirmed the aforementioned data. In addition, retrospective analysis of cost did not demonstrate a difference between the two arms
Table 2 Summary of the results of the study comparing gemcitabine /cisplatin versus gemcitabine /cisplatin /vinorelbine versus gemcitabine /vinorelbine followed by vinorelbine /ifosfamide in advanced non-small cell lung cancer Variables
Gem /Cis
Gem /Vnr /Cis
Vnr /Gem /Ifo
P
N Response rate (%) Overall survival (month) 1-year survival (%) Time to prog. (month) Vomiting Thrombocyt. gr 3 /4 (%) Neutropenia gr 3 /4 (%)
166 41 8.7 35 5.7 No difference 18 26
176 40 7.9 31 4.7 No difference 23 30
175 24 8.1 35 4.8 No difference 7 18
NS NS NS NS
Abbreviations used : Gem, gemcitabine; Vnr, vinorelbine; Cis, cisplatin; Ifo, ifosfamide [17].
J.-L. Pujol et al. / Lung Cancer 38 (2002) S57 /S60
S59
Table 3 Summary of the study of gemcitabine /paclitaxel versus carboplatin /paclitaxel in advanced NSCLC (n 165) CBDCA AUC 6, D1 PAC 200 mg/m2, D1 123
P
Evaluable patients
(n 164) Gem 1 g/m2, D1 and 8 PAC 200 mg/m2, D1 130
Object response rate (%) TTP (months) Median survival (months) 1-year survival (%) Netropenia G 3-4 (%) Neurotoxicity (%)
37 7.2 12.3 51 10 6
29 6.9 10.7 41 10 5
0.17 0.47 0.47 NS NS NS
Abbreviations used : Gem, gemcitabine; Pac, paclitaxel; CBDCA, carboplatin; TTP, time to progression [19]. q3wks. Number of evaluable patients at time of intermediate analysis.
(Kosmidis PA, personal communication during the 2001 ECCO meeting). During the 2001 ASCO meeting, the EORTC group reported a randomized study comparing the gemcitabine /paclitaxel doublet with two different cisplatin-based doublets [20]. In this trial 480 patients were randomly allocated to receive (a) paclitaxel /cisplatin; (b) gemcitabine /cisplatin; or (c) gemcitabine /paclitaxel. The planned doses and schedules for paclitaxel were identical in arm A and C. Similarly, gemcitabine was delivered according to an identical procedure in arm B and C and cisplatin in arm A and B. There was no statistical difference regarding response rates when the three groups were compared (31, 36 and 27% in arms A, B and C respectively). However, patients randomly assigned in arm C proved to have a shorter overall survival and time to progression (6.9 and 3.9 months) when compared with arm A (8.1 and 4.4 months) or arm B (8.8 and 5.6 months). There was a trend towards a significant difference in overall survival favouring arm A in comparison with arm C (P B/0.1). Table 4 Design of the study comparing gemcitabine /docetaxel versus cisplatin /docetaxel in advanced NSCLC
Abbreviations used : Gem, gemcitabine; DOC, docetaxel; CIS, cisplatin; TTP, time to progression; G-CSF, granulocyte-colony stimulating factor [23].
3.2. Docetaxel /gemcitabine doublet This combination has been particularly developed by the Hellenic Group of Oncology. The feasibility of this combination has been reported extensively [21]. Aside this publication there were numerous other phase I /II studies evaluating different dosages and schedules of the docetaxel /gemcitabine doublet. All schedules shared a similar gemcitabine delivery on days 1 and 8 of a 21-day cycle. However, they differed in the modalities of delivery of docetaxel. Most of the studies favoured delivery of docetaxel on day 8 instead of day 1. The day 8 docetaxel delivery avoided subsequent gemcitabine omission (no overlapping myelo-suppression) and appeared well-tolerated [22]. An Hellenic study aimed at comparing the gemcitabine /docetaxel combination with cisplatin/docetaxel [23] (Table 4). A total of 441 patients were randomly allocated to receive either docetaxel 100 mg/ m2 and cisplatin 80 mg/m2 every 21 days or docetaxel 100 mg/m2 day 1 and gemcitabine 1100 mg/m2 days 1 and 8. Granulocyte colony stimulating factor was given in both groups as a primary prophylaxis of neutropenia. Table 5 Summary of the study comparing gemcitabine /docetaxel versus cisplatin /docetaxel in advanced NSCLC Variables
GEM-DOC
CIS-DOC
P
Evaluable points Object response rate (%) TTP (months) Median survival (months) 1-year survival (%) Netropenia G 3-4 (%) Toxic death Fluid retention (%) Emesis G 3-4 (%)
201 (90%) 32 (26 /39) 8 9.5 39 22 1% (2) 14 2
205 (97%) 30 (24 /36) 8 10 42 33 3% (6) 7 10
0.90 0.77 0.98 0.80 0.01 0.15 0.005 0.01
Abbreviations used : GEM, gemcitabine; DOC, docetaxel; CIS, cisplatin; TTP, time to progression; G-CSF, granulocyte-colony stimulating factor [23].
S60
J.-L. Pujol et al. / Lung Cancer 38 (2002) S57 /S60
The study hypothesis was designed to detect a 15% response rate difference in favour of the docetaxel / gemcitabine arm. Taking into account fully eligible patients, no statistical difference was observed when response rate, time to progression and overall survival were considered (Table 5). It is noteworthy that the main difference between the two regimens lied in the toxicity profile, inasmuch as more patients in the docetaxel /cisplatin arm were affected by a grade 3/4 neutropenia whereas more patients in the docetaxel / gemcitabine arm suffered from oedema and fluid retention.
4. Discussion Different cisplatin-free doublets can be considered as feasible and safe regimens in the setting of advanced NSCLC therapy. However, the clinical applicability of such doublet in the routine practice remains to be established. Hitherto, the clinical benefit for the patient is unclear. Future studies comparing these new doublets with classical cisplatin-based regimen might take into account quality of life and cost of the treatment as important endpoints. In this setting the time without symptom and toxicity estimation [24] could be regarded as a useful tool in analysing the putative benefit of new cisplatin-free regimens.
References [1] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 1995;311:899 /909. [2] Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non-small cell lung cancer */ report of a Canadian multicenter randomized trial. J Clin Oncol 1988;6:633 /41. [3] Souquet PJ, Chauvin F, Boisesel JP, et al. Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. Lancet 1993;342:19 /21. [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 /7. [5] Abratt R, Bezwoda W, Falkson G, et al. Drug efficacy and safety profile of gemcitabine in non-small cell lung cancer: a phase II study. J Clin Oncol 1994;12:1535 /40. [6] Anderson H, Hopwood P, Stephens RJ, et al. Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer */a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-small cell lung cancer. Br J Cancer 2000;83:447 /53. [7] Ranson M, Davidson N, Nicolson M, et al. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000;92:1074 /80.
[8] Cerny T, Kaplan S, Pavlidis N, et al. Docetaxel (Taxotere) is active in non-small cell lung cancer: a phase II trial of the EORTC-Clinical Trials Group. Br J Cancer 1994;70:384 /7. [9] Roszkowski K, Pluzanska A, Krzakowski M, et al. A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC). Lung Cancer 2000;27:145 /57. [10] Shepherd F, Dancey J, Ramlau R, et al. Prospective randomized trial of Docetaxel versus best supportive care in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095 /103. [11] The Elderly Lung Cancer Vinorelbine Italian Study Group. Effect of vinorelbine on quality of life an survival of elderly patients with advanced non-small cell lung cancer. J Natl Cancer Inst 1999;91:66 /72. [12] Gridelli C, Frontini L, Perrone F. Gemcitabine plus vinorelbine in advanced non-small cell lung cancer: a phase II study of three different doses. Gem Vin Investigators. Br J Cancer 2000;83:707 / 14. [13] Beretta GD, Michetti G, Belometti MO, et al. Gemcitabine plus vinorelbine in elderly or unfit patients with non-small cell lung cancer. Br J Cancer 2000;83:573 /6. [14] Bajetta E, Chiara Stani S, De Candis D, et al. Gemcitabine plus vinorelbine as first-line chemotherapy in advanced nonsmall cell lung carcinoma a phase II trial. Cancer 2000;89:763 /8. [15] Frasci G, Lorusso V, Panza N, et al. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced nonsmall-cell lung cancer. J Clin Oncol 2000;18:2529 /36. [16] Gridelli C, Perrone F, Cigolari S, et al. The MILES (multicenter Italian lung cancer in the elderly study) phase III trial: gemcitabine / vinorelbine versus vinorelbine versus gemcitabine in elderly advanced non-small cell lung cancer patients. Proc Am Assoc Clin Oncol 2001;20:A1230. [17] Alberola V, Camps C, Provencia D, et al. Cisplatin gemcitabine versus cisplatin gemcitabine vinorelbine versus sequential doublets gemcitabine vinorelbine followed by ifosfamide vinorelbine in advanced non-small cell lung cancer: results of a Spanish lung cancer group phase III study. Proc Am Assoc Clin Oncol 2001;20:A1229. [18] Dunsford M, Mead GM, Bateman A, et al. Severe pulmonary toxicity in patients treated with a combination of docetaxel and gemcitabine for metastatic transitional cell carcinoma. Ann Oncol 1999;10:943 /7. [19] Kosmidis PA, Bacoyiannis C, Mylonakis N, et al. A randomized phase III trial of paclitaxel plus carboplatin versus paclitaxel plus gemcitabine in advanced non small cell lung cancer (NSCLC). A preliminary analysis. Proc Am Assoc Clin Oncol 2000;18:A1908. [20] VanMeerbeeck JP, Smit EF, Lianes P, et al. A EORTC randomized phase III trial of three chemotherapy regimens in advanced non-small cell lung cancer. Proc Am Assoc Clin Oncol 2001;20:A1228. [21] Georgoulias, Kouroussis C, Androulakis N, et al. Front-line treatment of advanced non-small-cell lung cancer with docetaxel and gemcitabine: a multicenter phase II trial. J Clin Oncol 1999;17:914 /20. [22] Rebattu P, Quantin X, Ardiet C, et al. Dose-finding, pharmacokinetic and phase II study of docetaxel in combination with gemcitabine in patients with inoperable non-small cell lung cancer. Lung Cancer 2001;33:277 /87. [23] Georgoulias V, Papadakis E, Alexopoulos A, et al. Platinumbased and non-platinum-based chemotherapy in advanced nonsmall-cell lung cancer: a randomized multicentre trial. Lancet 2001:357 /1478. [24] Gelber RD, Goldhisrsh A, Cole BF. Evaluation of effectiveness: Q-TWiST. The Internetional Breast Cancer Study Group. Cancer Treat Rev 1993;19:73 /84.