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TERAPIA SEQUENZIALE E/O DI MANTENIMENTO DOPO UNA PRIMA LINEA: ANCORA UN TRATTAMENTO SPERIMENTALE?
Paolo Bidoli S.C. Oncologia Medica A.O. San Gerardo Monza
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Sequential & Maintenance chemotherapy
Sequential administration of non–cross-resistant chemotherapy for a defined number of cycles. In a sequential regimen, the switch from one treatment to another does not require documented progression. Maintenance/consolidation is prolongation of CT duration with administration of additional drugs at the end of a defined number of initial CT cycles, after maximum response
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Maintenance, consolidation and sequential chemotherapy
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Rationale for maintenance/sequential chemotherapy
In view of the Goldie & Coldman hypothesis, sequential non-cross-resistant agents increase the probability of killing more cancer cells before resistance arises Patients who achieved a CR/PR/SD could benefit from additional therapy with one of drugs included in induction regimen
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Sequential chemotherapy: Randomized phase II study
Bidoli P. Ann Oncol 2007
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Sequential chemotherapy: ITT results
Bidoli P. Ann Oncol 2007
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Sequential chemotherapy: OS
Bidoli P. Ann Oncol 2007
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Single agent followed by a single agent
The sequential addministration of non-cross resistant single agent may theoretically reduce toxicity while potentially killing tumor cells subsets due to different sensitivity of CT agents Grossi F, The Oncologist 2007
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Consolidation Docetaxel 75 mg/m2 D1, Q21D, until PD or max. 6 cycles
Consolidation vs delayed docetaxel in advanced NSCLC N=145 CR PR SD Consolidation Docetaxel 75 mg/m2 D1, Q21D, until PD or max. 6 cycles Patient Eligibility Stage IIIB/IV Chemonaive ECOG PS 0-2 CNS metastases allowed GC Phase: Gemcitabine 1,000 mg/m2 D 1,8 Carboplatin AUC=5 D1 Q21D x 4 cycles Delayed BSC, then start at PD, Docetaxel 75 mg/m2 D1, Q21D, until PD or max. 6 cycles N=566 N=309 I: 153 D: 156 Endpoints: N=98 Primary: OS Secondary: Response, PFS, Toxicity, QoL Fidias P, JCO 2008 10
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Overall Survival (from randomization) Progression-Free Survival
Consolidation vs delayed docetaxel: PFS and Survival Overall Survival (from randomization) Progression-Free Survival 2 4 6 8 10 12 14 16 18 20 22 24 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Survival PFS, mo 153 72 27 11 5 154 28 C : D : Consolidation (n=153) 5.7 (4.4, 7.2) 20% (13, 26) Median PFS, mo (95% CI) 1-y PFS (95% CI) Delayed D (n=156) 2.6 (2.6, 3.4) 9% (5, 14) Log-Rank p-value <0.001 52 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Survival 4 8 12 16 20 24 28 32 36 44 48 OS, mo 153 111 56 27 5 2 154 98 45 22 9 3 62 IC: D : 40 Consolidation (n=153) 12.5 (10, 13.7) 51.1% (39.9, 57.1) Delayed D (n=156) 9.7 (8, 11.2) 38.3% (30, 4.5) Log-Rank p-value 0.0853 Median survival, mo (95% CI) 1-y OS (95% CI) Fidias P, JCO 2008 11
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Consolidation vs delayed docetaxel:
Toxicity Grade 3/4 Toxicity Consolidation Delayed Thrombocytopenia 1.4 Neutropenia 26.1 28.6 Febrile neutropenia 2.8 1.1 Anemia 0.7 Fatigue 9.2 3.3 Diarrhea 4.4 Fidias P, JCO 2008 12
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Consolidation vs delayed docetaxel:
Conclusions Immediate use of docetaxel following CBDCA+GEM: Significantly improved PFS: mo Allowed a trend toward improved survival: mo Did not compromise quality of life Did not lead to increased toxicity Increased feasibility: 50% more patients than delayed Fidias P, JCO 2008 13
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Hanna JCO 2008
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NSCLC stage III (inoperable): Docetaxel consolidation
Conclusions: consolidation docetaxel after PE/RT results in increased toxicities but does not further improved survival compared with PE/RT alone Hanna JCO 2008
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Study XRP6976B2506 R A N D O M I S E Doc 75 mg/m2 Gem 1200 mg/m2
Cis 75 mg/m2 d 1 q 21 3 cycles Gem 1200 mg/m2 d 1,8 q 21 3 cycles 84 NSCLC Stratification: stage IIIB vs IV Doc 25 mg/m2 Cis 25 mg/m2 d 1,8,15 q 28 3 cycles Gem 1200 mg/m2 d 1,8 q 21 3 cycles Grossi F, ELCC 2008
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Best response at EOT Grossi F, ELCC 2008
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Overall Survival B (qw)= 7.7 months (95%CI: 6.3-10.4)
A (q3w)= 12.1 months (95%CI: ) B (qw)= 7.7 months (95%CI: ) Grossi F, ELCC 2008
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Vinorelbine maintenance
Maintenance VNR 25 mg/mq weekly x 6 months plus BSC N=573 N=90 Patient Eligibility Stage IV NSCLC CR/PR/SD after MIC x 2-4 cycles (N: 227) BSC only N=91 Primary endpoint: Median TTP Westeel JNCI 2005 19
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Vinorelbine maintenance:
PFS p = 0.32
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Vinorelbine maintenance:
OS p = 0.48
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Gemcitabine maintenance
Maintenance GEM 1250 mg/mq 1-8 q21 plus BSC N=352 N=138 Patient Eligibility Stage IV NSCLC CR/PR/SD after CDDP/GEM (N: 206) BSC only N=68 Primary endpoint: Median TTP Brodowicz Lung Cancer 2006 22
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Pemetrexed sequential/maintenance
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R Phase III Trial: Lilly H3E-EW-S124
1st line treatment for advanced NSCLC (non squamous) Pemetrexed 500 mg/m2 Q 3 weeks until to PD CDDP + PEM 4 cycles OR or SD R Placebo N= 600 Random 2:1 Primary endpoint: PFS Secondary endpoints: OS, RR, QoL, Tox
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Systematic review on optimal duration of CT in NSCLC
13 RCTs including 2416 pts Results: continuing CT for more then 3-4 cycles induces delayed disease progression, not statistically significant improvement in overall survival, increase adverse events, and may impare QoL Further trials should determine if extended treatment with targeted agents rather than CT can improve PFS and OS without increasing toxicity Soon YY et al, ASCO 2008
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Not designed to address the maintenance role
Maintenance with targeted agents: agent already present in the induction phase Author Phase Regimen Results Sandler 2007 III CBDCA and TAX plus bevacizumab until progression (vs chemotherapy alone) Bevacizumab prolonged survival Manegold 2008 CDDP and GEM plus bevacizumab until progression (vs chemotherapy alone) Bevacizumab prolonged progression-free survival Pirker 2008 CDDP and VNR plus cetuximab until progression (vs chemotherapy alone) Cetuximab prolonged survival Giaccone 2004 CDDP and GEM plus concurrent gefitinib followed by gefitinib until progression (vs placebo) No survival and progression-free survival improvement Gatzmeier 2004 CDDP and GEM plus concurrent erlotinib followed by erlotinib until progression (versus placebo) Not designed to address the maintenance role
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Maintenance with a biological agent
SWOG S0023 Maintenance with a biological agent N=571 N=429 CR PR SD Patient Eligibility Selected Stage IIIA (N2) Stage IIIB CDDP+VP-16 with concurrent chemoradiation Consolidation Docetaxel 1 q 21 x 3 cycles CR,PR,SD N=118 N=125 Maintenance GEFITINIB PLACEBO Kelly JCO 2008 31
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SWOG S0023: OS p = 0.013 Kelly JCO 2008
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Sequential/ Maintenance
conclusions Future strategies seem to be based on prolungation of treatment until to disease progression Targeted therapies or CT agents (i.e. pemetrexed) with good safety are the best option for manteinance treatment In my opinion further phase III randomized trials are warranted before the sequential/maintenance therapy will become standard therapy
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LEV NIKOLAEVIC TOLSTOJ
“Benchè i dottori lo curassero, gli cavassero sangue e gli facessero prendere molte medicine, tuttavia guarì”. LEV NIKOLAEVIC TOLSTOJ
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