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Current Approaches in Chemotherapy of Advanced and Metastatic Non-Small Cell Lung Cancer (NSCLC)

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Current Approaches in Chemotherapy of Advanced and Metastatic Non-Small Cell Lung Cancer (NSCLC) ANTICANCER RESEARCH 25: 1501-1506 (2005) Review Current Approaches in Chemotherapy of Advanced and Metastatic Non-small Cell Lung Cancer (NSCLC) MARTIN RECK Department of Thoracic Oncology, Hospital Grosshansdorf, Center of Pneumology and Thoracic Surgery, Woehrendamm 80, D-22927 Grosshansdorf, Germany Abstract. Several new agents have been introduced in the manipulations have been identified. In conclusion, several new palliative treatment of advanced and metastatic NSCLC in the specific therapeutic options have been developed and applied. recent years. In randomized trials, the new third-generation regimens showed comparable efficacy to each other, but a better Combined chemotherapy response rate and time to progression combined with a remarkably improved tolerability compared to "classic schedules". In patients Several randomized trials have recently been conducted to who are not suitable for platinum-based therapy, monotherapy compare the efficacy of new regimens. In the largest study with could be an attractive opportunity, as shown in randomized trials. 1207 patients, Schiller et al. (4) found no significant difference In second-line therapy, the novel antifolate Pemetrexed showed in survival among the regimens Cisplatin/Paclitaxel, comparable activity to Docetaxel with significantly reduced toxicity. Cisplatin/Gemcitabine, Cisplatin/Docetaxel and Carboplatin/ Among the new oral tyrosine kinase inhibitors, Erlotinib proved to Paclitaxel. With respect to the low rate of toxic effects, the be active in second- and third-line treatments, whereas in first-line ECOG chose Carboplatin/Paclitaxel as its reference regimen treatment, no survival benefit has been observed to date. for future studies (4). In a Southwest Oncology Study group, comparing Non-small cell lung cancer (NSCLC) has become a Cisplatin/Vinorelbine with Carboplatin/Paclitaxel, there was no worldwide health problem. More than 60% of patients with difference between the arms in terms of response, survival and NSCLC are not suitable for curative treatment at the time quality of life, but significantly higher rates of toxic effects in of diagnosis because of advanced or metastatic disease (1). the group of patients who received Cisplatin/Vinorelbine (5). Taking the bad prognosis of these patients into These results were underlined by a study of Scagliotti et al. (6), consideration, each treatment has a palliative intention. comparing Cisplatin/Gemcitabine, Cisplatin/Vinorelbine and After the impact of Cisplatin-based chemotherapy on the Carboplatin/Paclitaxel, who noticed an increased rate of grade survival of patients with NSCLC had been confirmed by the 3/4 neutropenia and nausea/vomiting in the Cisplatin/ NSCLC Collaborative Group and recently by the Big Lung Vinorelbine arm and an increased rate of thrombocytopenia Trial (2, 3), many regimens using new agents like the taxanes, in the Cisplatin/Gemcitabine arm. In agreement with the other the topoisomerase I inhibitors Topotecan and Irinotecan, studies, there were no differences concerning the efficacy Vinorelbine and Gemcitabine have been investigated. between the arms (6). Furthermore, specific pathways of intracellular signal In contrast, Fosella et al. reported a significantly higher transduction in tumor cells and key points for targeted response rate and a significantly longer survival for Docetaxel in combination with Cis-/Carboplatin combined with a improved quality of life compared to Cisplatin/Vinorelbine (7). In the last trial of Alberola et al., Correspondence to: Martin Reck, MD, Department of Thoracic the three-drug combination Gemcitabine,Vinorelbine and Oncology, Hospital Grosshansdorf, Center of Pneumology and Cisplatin failed to show any superiority regarding response Thoracic Surgery, Woehrendamm 80, D-22927 Grosshansdorf, or survival and was associated with a highly significant Germany. Tel: 0049 4102 601188, Fax: 0049 4102 691317, e-mail: increase in toxicity (8) (Table I). [email protected] Targeting the question of the superiority of the new Key Words: Non-small cell lung cancer (NSCLC), chemotherapy, regimens over the old second-generation regimens, a couple targeted therapy. of randomized trials have been published in recent years. Five 0250-7005/2005 $2.00+.40 1501 ANTICANCER RESEARCH 25: 1501-1506 (2005) Table I. Randomized trials in first-line chemotherapy of NSCLC with third-generation agents. Study Regimen ORR TTP (months) Median survival 1-year survival ECOG 15944 Tax / P 21% 3.4 m 7.8 m 31% Gem / P 21% 4.2 m* 8.1 m 36% TXT / P 17% 3.7 m 7.4 m 31% Tax / Carbo 15% 3.1 m 8.1 m 34% *p=0.001 to Tax/P SWOG 95095 Tax / Carbo 26% 4.0 m 8.6 m 38% Nav / P 28% 4.0 m 8.1 m 36% Scagliotti6 Nav / P 30% 4.6 m 9.5 m 37% Tax / Carbo 32% 5.5 m 10.0 m 43% Gem / P 30% 5.3 m 9.8 m 37% Tax 3267 TXT / P 32% 5.5 m 11.3 m* 46% TXT / Carbo 24% 5.75 m 10.0 m 38% Nav / P 25% 5.0 m 10.1 m 41% *p=0.044 to Nav/P Alberola8 Gem / P 42%* 6.3 m 9.3 m 38% Gem / Nav / P 41% 6.7 m 8.2 m 33% Gem / Nav Ifo / Nav 27% 8.1 m 34% *p=0.003 to Gem / Nav Abbreviations: Tax: Paclitaxel, P: Cisplatin, G: Gemcitabine, TXT: Docetaxel, Carbo: Carboplatin, Nav: Vinorelbine, Ifo: Ifosfamide. studies compared the combination Gemcitabine/Cis- Monotherapy (Carboplatin) with the MIC regimen (9-11) Cisplatin/ Vindesine (12) or Cisplatin/Etoposide (13). In most studies, a Despite the superiority of combination therapy versus significant improvement in response (9, 10, 12, 13) and time to monotherapy regarding survival, which has been underlined by progression was achieved in the Gemcitabine/Platin arm (9, two meta-analyses and several randomized trials for the 12, 13). Some studies even reported a significant increase in combinations Carboplatin/Paclitaxel, Carboplatin/ Gemcitabine, survival for the experimental arm (9, 12, 13). Hematotoxicity, Cisplatin/Docetaxel, Cisplatin/ Vinorelbine and Cisplatin/ especially thrombocytopenia, was pronounced in the Irinotecan (19-23, 16-18), many patients with NSCLC are not Gemcitabine/Platin group, whereas non hematological side- suitable for combination therapy because of age, bad effects appeared more frequently in the "classic" arms (9-13). performance status or comorbidity. An attractive alternative Comparing Paclitaxel/Cis-(Carboplatin) with Etoposide with a significantly reduced toxicity is monotherapy with one of (Teniposide)/Cis-(Carboplatin), Giaccone et al. observed a the new agents. Gridelli observed no difference in survival significant increase in response rate and quality of life for comparing Gemcitabine/Navelbine with Gemcitabine or the Paclitaxel arm (14), and Bonomi et al. a significantly Navelbine in patients who were at least 70 years old (24). Other superior survival with comparable quality of life data (15). randomized studies suggested that monotherapy with Paclitaxel, Le Chevalier et al. showed a significantly better response Docetaxel, Vinorelbine or Gemcitabine might be a convenient rate and survival for Cisplatin/Vinorelbine compared to alternative for patients with a bad performance status, leading Cisplatin/Vindesine (16, 17). Finally, Negoro et al. reported to a significant increase in survival compared to best supportive a clear trend in survival for Cisplatin/Irinotecan versus care (BSC) (25-27) and to a better control of tumor-related Cisplatin/Vindesine, without reaching a significant level symptoms combined with an improvement of quality of life (25- (18). Analyzing the toxicity, there was a high rate CTC 28). Another attractive prospective for palliative treatment is Grade 4 neutropenia in the Vindesine arm, but also a the new oral application of Vinorelbine, which was active in remarkably high rate of CTC 3/4 diarrhea in the Irinotecan stage IV NSCLC and showed comparable efficacy to arm (18) (Table II). intravenous Vinorelbine in a randomized trial (29, 30). 1502 Reck: Chemotherapy in NSCLC Table II. Randomized trials of “old” versus “new” combinations in first-line chemotherapy of NSCLC. Author Regimen ORR Median survival 1-year survival Toxicity Rudd9 Gem / Carbo 41% 10.2 m* 38% Nausea/Vomiting + in MIC (p<0.0001) MIC 41% 6.9 m 28% Hospital admission + in MIC (p<0.0001) *p<0.004 Thrombopenia + in Gem/Carbo (p<0.0001) Crino10 Gem / P 38%* 8.6 m 33% Thrombopenia + in Gem/Carbo (p<0.001) MIC 26% 9.6 m 34% Alopecia + in MIC (p<0.001) *p=0.029 Danson11 Gem / Carbo 30% 7.9 m 33.2% No significant difference MIC MVP 33% 8.3 m 32.5% Grigorescu12 Gem / Carbo 27%* 11.6 m*+ 36% No significant difference VDS / P 15% 7.9 m* 13% *p<0.05 *mean survival +p=0.0001 Cardenal13 Gem / P 40.6%* 8.7 m 32% Grade 4 Neutropenia + in VP/P (p=0.0009) VP / P 21.9% 7.2 m 26% Grade 3/4 Thrombopenia + in Gem/P (p=0.046) *p=0.02 Giaccone14 Tax / P 41%* 9.7 m 43% Neutropenia, Thrombopenia + in Teni / P Tenip / P 28% 9.9 m 41% Neurotoxicity, arthralgia, myalgia, *p=0.018 hypersensitivity reactions + in Tax/P Bonomi15 Tax 250 / P 27.7%* 10.0 m* 40.3% No significant differences Tax 135 / P 25.3%+ 9.5 m* 37.4% VP / P 12.4% 7.6 m 31.8% *p<0.001 *p=0.048 +p=0.002 Le Chevalier16,17 Nav / P 30%*,+ 10.0 m*+ 34% Neutropenia + in Nav/P (p<0.001) VDS / P 19% 8.0 m 27% Neurotoxicity + in VDS/P (p<0.004) Nav 14% 7.75 m 19% *p=0.02 to VDS/P *p=0.04 to VDS/P +p<0.001 to Nav +p=0.01 to Nav Negoro18 CPT-11 / P 43.7% 12.5 m 46.5% Neutropenia + in VDS/P (p<0.001) VDS / P 31.7% 11.4 m 38.3% Diarrhoea + in CPT/P and CPT (p<0.001) CPT-11 20.5% 11.5 m 41.8% Nausea/Vomiting + in CPT/P and VDS/P (p<0.001) Neurotoxicity + in VDS/P (p<0.001) Abbreviations: Gem: Gemcitabine, P: Cisplatin, MIC: Mitomycin, Ifosfamide, Cisplatin, Carbo: Carboplatin, MVP: Mitomycin, Vinblastine, Cisplatin, VDS: Vindesine, Tax: Paclitaxel, Ten: Teniposide, VP: Etoposide, Nav: Vinorelbine, CPT-11: Irinotecan Second-line therapy toxicity profiles were observed especially with low hematotoxic side-effects (32-34).
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