Βασικές αρχές χηµειοθεραπείας στην αντιµετώπιση του µικροκυτταρικού καρκίνου (SCLC) Δηµήτρης Διονυσόπουλος MD, PhD Ειδικός Παθολόγος Ογκολόγος Επιµελητής Β Γ.Ν. Παπαγεωργίου Απρίλιος 2014
Progress in the therapy of SCLC has been painfully slow. In fact you could argue that little or no therapeutic advances have been made for extensive- stage SCLC in more than 20 years. Gandara and Lara. J Clin Oncol 2008
ΔΕΔΟΜΕΝΑ ü Η συχνότητα µειώνεται µε το χρόνο (από17.26% το 1986 στο 12.95% το 2002 των περιπτώσεων καρκίνου του πνεύµονα στις ΗΠΑ (Govindan JCO 2006) ü Το 1/3 των ασθενών έχουν περιορισµένη νόσο ü Εξαιρετική χηµειοευαίσθητη και ακτινοευαίσθητη νόσος ü Λίγοι ασθενείς έχουν µακρά επιβίωση ü Υψηλός κίνδυνος τοπικής υποτροπής ü Υψηλός κίνδυνος µεταστάσεων (εγκέφαλος)
limited-stage SCLC stage I to III (T any, N any, M0) that can be safely treated with definitive radiation therapy; Extensive-stage SCLC stage IV (T any, N any, M1a/b) or T3 4 due to multiple lung nodules or tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan. Because of the aggressive nature of SCLC, staging should not delay the onset of treatment for more than 1 week
State of the art treatment of SCLC ØPlatinum-based combination chemotherapy (PE) at full standard doses, x 4-6 as 1st line treatment for both LD and ED patients. ØEarly thoracic irradiation (TRT), 40-50 Gy, added to CT for LD patients. ØProphylactic cranial irradiation (PCI), 25-36 Gy, for patients with either LD or ED and CR/good PR. ØSingle agent CT (Topotecan) as 2nd line treatment for relapsed SCLC. A Ardizzoni, ASCO 2007
CEVcyclophosphamide/epirubicin/vincristine EPetoposide/cisplatin EP 436 patients with LS and ES EP vs CEV Survival 10.2 vs 7.8 p = 0.0004 CEV Sundstrøm et al. J Clin Oncol 2002
Overall survival LSD 14.5m vs 9.7m p = 0.01 Overall survival ESD 8.4m vs 6.5m p = ns
Platinum vs non-platinum 21 phase III trials extensive stage SCLC ü between 1972 and 1990 ü median survival 9.5 vs 7.1 months, p = 0.002 ü cisplatin based therapy independent predictor of survival p = 0.04 Chute et al, J Clin Oncol 1999 Meta-analysis 19 trials 4054 pts ü cisplatin vs no cisplatin ü Cisplatin - 4.4% survival benefit at 1 year Pujol et al Br J Cancer 2000 Cochrane meta-analysis 2008 ü 29 trials, 5530 patients ü No difference in 6, 12 or 24 month survival ü No difference OR rate ü Higher CR rate for platinum ü Higher toxicity rates with platinum Amarasena et al. Cochrane Library 2009
EXPECTATIONS In pts with limited-stage disease, response rates of 70% to 90% are expected after treatment with EP plus thoracic RT, whereas in extensive-stage disease, response rates of 60% to 70% can be achieved with combination chemotherapy alone. Unfortunately, median survival rates are only 14 to 20 months and 9 to 11 months for pts with limited- and extensive-stage disease, respectively. After appropriate treatment, the 2-year survival rate is approximately 40% in pts with limited-stage disease, but less than 5% in those with extensive-stage disease
OTHER STRATEGIES üplatinum + Irinotecan ütriplets (addition of paclitaxel) ümaintenance / Consolidation chemo üalternating / Sequential regimens ühigher doses of standard chemotherapy üantiangiogenic agents (bevacizumab)
Algorithm of first-line treatment for limited disease SCLC1,2 Very limited disease (T1 3, N0 1) Limited disease Surgery Combination chemotherapy (4 6 cycles) based on etoposide platinum or cyclophosphamide doxorubicin Thoracic radiotherapy Start in cycle 1 or 2 during chemotherapy Prophylactic brain irradiation in all patients with CR Figure modified from: 1. Felip E et al. Ann Oncol 2005; 16(S1): i30 i31. 2. Jackman DM, Johnson BE. Lancet 2005; 366: 1385 1396.
SCLC PS 0-2 chemo + concurrent XRT Limited stage PS 3-4 Due to SCLC chemo+ - XRT PS 3-4 Individualized treatment not due to SCLC BSC
Algorithm of first-line treatment for extensive disease SCLC Extensive disease Combination chemotherapy (4 6 cycles) based on etoposide platinum Thoracic radiotherapy in patients with CR or PR Additional chemotherapy for progressive or recurrent disease Prophylactic brain irradiation in all patients with CR SCLC; small cell lung cancer; CR: complete response; PR: partial response Figure modified from: Jackman DM, Johnson BE. Lancet 2005; 366: 1385 1396.
Treatment paradigm for relapsed SCLC1,2 Relapsed disease median survival only 4 to 5 months NO YES Refractory Resistant TFI <90 days Sensitive TFI 90 days BSC or active treatment Non-cross resistant chemotherapy Re-challenge first-line or other chemotherapy regimen SCLC: small cell lung cancer; TFI: treatment-free interval; BSC: best supportive care Figure modified from: 1. Cheng S et al. J Thorac Oncol 2007; 2(4): 348 354. 2. Ferraldeschi R et al. Drugs 2007; 67(15): 2135 2152.
RELAPSED DISEASE Based on phase II trials, active subsequent agents include ü paclitaxel, ü docetaxel, ü topotecan, ü irinotecan, ü vinorelbine, ü gemcitabine, ü ifosfamide, ü temozolomide, and ü oral etoposide
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