ΘΕΡΑΠΕΙΑ ΜΙΚΡΟΚΥΤΤΑΡΙΚΟΥ ΚΑΡΚΙΝΟΥ ΠΝΕΥΜΟΝΑ Σοφία Παπακάτσικα ειδικευόμενη Ογκολογίας 7.10.2018
ΜΙΚΡΟΚΥΤΤΑΡΙΚΟ CA ΠΝΕΥΜΟΝΑ (SCLC) 15% όλων των περιπτώσεων Ca πνεύμονα νευροενδοκρινική διαφοροποίηση συχνά 70% extensive-stage κατά τη διάγνωση (απουσία συμπτωμάτων, μεθόδων screening) καλή απάντηση στην αρχική θεραπεία ταχεία υποτροπή και αντοχή στις επόμενες γραμμές median OS after relapse: 7-12 mo
SCLC TREATMENT ένδεια μεθόδων έγκαιρης διάγνωσης περιορισμένη διάθεση βιοπτικού υλικού για περαιτέρω έρευνα ταχεία εξέλιξη της νόσου
STAGING 2 συστήματα VALG (veterans administration lung study group) AJCC TNM
STAGING-VALG
STAGING-TNM
STAGING-TNM
TNM-STAGE GROUPING
STAGING-TNM limited-stage: any T, any N that is a confined to a single radiation field extensive-stage: any T, any N than extend beyond a single radiation field, M1a/b/c TNM mainly useful for patients eligible for surgical resection
SCLC-SURGERY ESMO : ct1-2 cn0-1 M0 resectable (no biopsy before surgery) συμπληρωματική (adjuvant) 4 cycles Χ/Θ +/- RT
LIMITED STAGE SCLC limited-stage in excess of St I do not benefit from surgery standard-of-care: concurrent CRT with curative intent (good PS) up to 25% 5-y survival
SCLC-ΑΡΧΕΣ ΘΕΡΑΠΕΊΑΣ Σημαντική η άμεση έναρξη θεραπείας Μονήρης μεταστατική εστία υπό διερεύνηση: έναρξη θεραπείας προ ιστολογικής ταυτοποίησης και επανεκτίμηση μετά 2 κύκλους θεραπείας multimodality treatment for limited-stage
CHEMO FOR LIMITED STAGE Χ/Θ συνδυασμού με βάση την πλατίνα Cisplatin-etoposide η κλασική επιλογή βάσει μελετών Cisplatin 60 mg/m2 d1, etoposide 120 mg/m2 d1-d3 (q21d) 4-6 κύκλοι θεραπείας δεν έχουν ένδειξη dose-dense σχήματα
EXTENSIVE STAGE < 5% over 2-y survival median PFS: 2-6 mo, median OS: 9-10 mo chemotherapy alone (good PS/poor PS due to SCLC) no benefit from consolidation treatment
CHEMO FOR EXTENSIVE STAGE συνδυασμένη θεραπεία με βάση την πλατίνα (carbo-etoposide ή cisplatin-etoposide) όχι μονοθεραπεία ταχεία υποστροφή νόσου (2ο κύκλο) και βελτίωση ποιότητας ζωής
CISPLATIN OR CARBOPLATIN?
m OS: 9,6 vs 9,4 mo m PFS: 5,5 vs 5,3 mo
CISPLATIN OR CARBOPLATIN?
CISPLATIN OR CARBOPLATIN?
IRINOTECAN 1ST LINE irinotecan in 1st line a challenging option median survival: 12,8 vs 9,4 mo (p=0,002)
IRINOTECAN 1ST LINE
IRINOTECAN VS ETOPOSIDE
IRINOTECAN VS ETOPOSIDE IP vs EP: no significant differences in OS, time to progression
IRINOTECAN VS ETOPOSIDE
TARGETED THERAPIES high mutational burden (smoking) tumor heterogeneity at the genetic level no clear targetable oncogenic driver, mostly passenger mutations common TP53, RB mutations cross-institutional effort to achieve better molecular profiling
SECOND-LINE TREATMENT early relapse (<6 weeks) resistant ( platinum-refractory ) disease (<3 months) sensitive disease (>3 months) duration of response to front-line therapy affects response to further treatment BSC is preferred
SECOND-LINE TREATMENT early relapse (6 weeks): BSC or clinical trial resistant disease (relapse <3 mo), PS 0-2: topotecan/irinotecan/paclitaxel/docetaxel/im munotherapy/ CAV no difference in OS oral topotecan is the approved treatment after relapse rechallenge with PE benefits sensitive disease only
IMMUNOTHERAPY FOR SCLC
IMMUNOTHERAPY FOR SCLC low PD-L1 expression in most SCLCs tumor mutational burden (TMB) a possible biomarker high TMB predicts PFS and response-rate after immunotherapy TMB correlates with neo-antigen load in the tumor needs broad panel of sequencing
rrelation between TMB and objective response rate with anti-pd1 or anti-pd-l1 therapy in 27 tumor type
1-y OS 33% nivo 43% nivo+ipi durable responses irrespective of platinum-sensitivity, line of treatment or PD-L1 expression status
OS (%) Checkmate 032: OS in Non-Randomized Cohort 10 09 08 07 06 05 04 03 02 01 0 0 Events/Num ber at Risk Median OS, months (95% CI) Nivolumab 82/98 4.1 (3.0, 6.8) Nivolumab + Ipilimumab 1-yr OS=40% 1-yr OS=27% 47/61 7.8 (3.6, 14.2) 2-yr OS=26% 2-yr OS=14% Minimum Follow-up,* months 19.6 20.2 Number of Patients at Nivolum Risk Nivolumab + Ipilimuma b 0 3 6 9 12 15 18 Time 21 24 27 30 33 36 39 (months) 98 56 39 35 26 21 17 12 7 7 6 4 4 0 61 43 33 28 24 21 19 16 14 7 3 1 1 0 *Between first dose and database lock; follow-up shorter for patients who died prior to database lock. Hellmann M et al. Oral presentation at ASCO 2017. Abstract 8503. Abbreviations can be found in the speaker notes. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES. 69
8/2018 accelerated FDA approval of nivolumab for SCLC which progressed on at least 2 previous lines of treatment
THE ROLE OF RADIOTHERAPY
THE ROLE OF RADIOTHERAPY IN LIMITED STAGE all inoperable with good PS start early (2nd cycle) concurrently with chemo 60 Gy in total (once-daily schedule) in 5 w 45 Gy (BID schedule, 1,5 Gy daily dose)-shorter duration-3w, decreased radiation dose sequential RT for poor PS (3-4) due to SCLC
primary endpoint: m OS 30 mo (bid) vs 25 mo (od)
THE ROLE OF RADIOTHERAPY IN EXTENSIVE STAGE extensive-stage pts that respond well to initial treatment (CR/PR) sequential consolidative thoracic RT improves 2-y survival rate and 6-month PFS mainly benefits low-bulk extrathoracic disease
THE ROLE OF PCI prophylactic cranial irradiation prevents brain mets 5% OS advantage in limited-stage: resected, CR or PR can be considered for extensive-stage with good response to 1st line treatment 25 Gy in 10 daily sessions is the highest dose no difference in OS in extensive-stage
1-y OS rate: 52% vs 38,2% (p=0,007) 1-y PFS: 12,6% vs 5,4% (p=0,02)
CHALLENGES IN SCLC TREATMENT to improve duration of responses to front-line therapy to find active treatment after disease relapse better profiling of tumors (better sampling, need for a biomarker to assess response to treatment)
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