Αρχές χημειοθεραπείας στην θεραπεία του NSCLC και του SCLC Καραχάλιος Δημήτριος Ογκολόγος Επιμελητής Ογκολογικής Κλινικής, 424 ΓΣΝΕ Υπεύθυνος Ογκολογικού Τμήματος Κλινική «Ευαγγελισμός», Θεσσαλονίκη
NSCLC Stage IA Stage IB Stage II Stage IIB Operable Medically inoperable XRT
Stage IIIA R0 chemo+rt (T1-3,N2) T3>7cm,N1) Rx chemoxrt+chemo
N3 (-) I-IIIA treatment Stage IIIB chemoxrt N3 (+) Concurrent T1-3, N3 +chemo Metastatic Stage IV treatment
Adjuvant NSCLC At surgery Stage IA (T1ab, N0) Adjuvant treatment Observe Stage IB (T2a, N0) Observe OR Stage IIA (T2b, N0) Chemo high risk Stage IIA (T1ab-T2a, N1) Chemo RT Stage IIB (T3, N0 T2b, N1) Stage IIIA (T1-3, N2) Chemo RT
High risk IB, IIA Poorly differentiated tumors Vascular invasion Wedge resection Tumors>4cm Visceral pleural involvement Nx
Adjuvant regimens Cis 50 d1, 8 Cis 75 d1 Vinorelbine 25 d1,8,15 Gemcitabine 1250 d1,8 Cis 100 d1 Cis 75 Vinorelbine 30 d1,8,15, 22 Docetaxel 75 Cis 25-80 d1 Cis 75 Vinorelbine 25 d1,8 Pem 500 Cis 100 d1 Paclitaxel 200 Etoposide 100 d1-3 Carboplatin AUC 6 Cis 80 d1 Vinblastine 4 d1,8,15, 22
Adjuvant chemotherapy Pignon et al LACE Collaborative Group JCO 2008 Winton et al N Engl J.M 2005 Arriagada et al N Engl J.M 2004 Scagliotti et al J N C I 2003 Hotta et al JCO 2004 Edell et al Chest 1992
Lace meta analysis survival ALPI Cis/MVd - BLT Cis/4 - IALT Cis/Vinca VP16 + NCIC Cis/Vin + ANITA Cis/Vin +
Pignon et al LACE Collaborative Group JCO 2008 analysis from the five largest trials 4,584 patients cisplatin-based chemotherapy in patients with completely resected NSCLC 5-year absolute benefit of 5.4% from chemotherapy.
Adjuvant chemotherapy Two trials FRE-IALT and ANITA significant OS benefits associated with postoperative chemotherapy in stage IIIA disease. For the subgroup of stage IIIA patients in ANITA (n = 325), the HR was 0.69 (95% CI, 0.53 0.90), and the result for the FRE- IALT trial (n = 728) was HR = 0.79 (95% CI, 0.66 0.95). Chemotherapy effect was higher in patients with a better performance status (PS). Douillard et al ANITA Lancet 2006 Arriagada et al N Engl. J M 2004
TREAT Adjuvant cis+pem vs cis+vinorelbine Ο συνδυασμός Cisplatin+ Pemetrexed στην επικουρική θεραπεία είναι καλύτερα ανεκτός λιγότερο τοξικός επιτρέπει χορήγηση μεγαλύτερης συνολικής δόσης και βέλτιστης έντασης δόσης (dose density) H δυσανεξία του συνδυασμού Cisplatin+ Vinorelbine οφείλεται κυρίως σε αιματολογική τοξικότητα Αποτελέσματα πολύ πρώϊμα για έλεγχο δραστικότητας (υψηλό ποσοστό squamous-45%)
DFS = OS? Surgery + adjuvant CT versus Surgery alone Median follow-up: 5.7 years Surgery + RT + adjuvant CT versus Surgery + RT Median follow-up: 6.4 years DFS and OS effects are highly/strongly correlated
CALGB 9633 NSCLC IB Adjuvant carbo/taxol observation Τάση για βελτιωμένη συνολική επιβίωση υπέρ ΧΜΘ: ΗR=0.82, 95%CI 0.65-1.04, p=0.084 6% όφελος στην 8ετή επιβίωση (51% vs 45%, p=0.38)
CALGB 9633 T>4cm: ΗR=0.78, 95%CI 0.57-1.05, p=0.079 10% όφελος στην 8ετή επιβίωση (54% vs 44%, p=0.064) Τα δεδομένα υποστηρίζουν τη χορήγηση επικουρικής ΧΜΘ σε ασθενείς με όγκους ΙΒ με Τ>4 cm Το θεραπευτικό όφελος καθίσταται μέγιστο σε όγκους με Τ>7cm, που πλέον ταξινομούνται ως Τ3 (ΙΙΑ) στο ΑJCCC 7
Treatment of Stage IIIA N2 NSCLC Surgery Radiotherapy Chemotherapy Combinations
Adjuvant chemotherapy Patients with completely resected stage IIIA NSCLC may benefit from postoperative cisplatin-based chemotherapy
Unresectable Stage IIIA Concurrent chemo-rt chemo Stage IIIB Concurrent chemo-rt chemo
Chemoradiation therapy A meta-analysis of patient data from 11 trials Lung Cancer Collaborative Group BMJ 1995 Cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone. A meta-analysis of 13 trials 2,214 patients Rowell et al Cochrane Database 2004 The addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years A meta-analysis from 1,764 patients 9 trials Auperin et al Ann Oncol 2006 radiation therapy and chemotherapy compared with radiation therapy alone benefit of chemotherapy of 4% at 2 years. platinum with etoposide more effective than platinum alone.
Concurrent versus sequential chemoradiation therapy The results from two randomized trials (including RTOG-9410) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy may provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy
Concurrent versus sequential chemoradiation therapy 610 patients sequential chemotherapy with cisplatin and vinblastine followed by 60 Gy of radiation therapy, concurrent chemotherapy, or concurrent chemotherapy with cisplatin and vinblastine with twice-daily radiation therapy Median and 4-year survival were superior in the concurrent chemotherapy with daily radiation therapy arm (17 mo vs. 14.6 mo and 21% vs. 12% for sequential regimen) Curran et al ASCO 2003
Concurrent versus sequential chemoradiation therapy A meta-analysis of three trials evaluated concurrent versus sequential treatment (711 patients) The analysis indicated a significant benefit of concurrent over sequential treatment (RR = 0.86; 95% CI, 0.78 0.95; P =.003). All studies used cisplatin-based regimens and once-daily radiation therapy More deaths (3% OS rate) were reported in the concurrent arm, not statistical significant There was more acute esophagitis (grade 3 or worse) with concurrent treatment compared with sequential treatment Rowell et al Cochrane Database 2004
Concurrent Chemotherapy/RT followed by chemo Cisplatin 50mg/m on D 1,8,29,36 Etoposide 50mg/m D 1-5, 29-33 Concurrent thoracic RT followed by cisplatin 50 mg/m and etoposide 50 mg/mx2 additional cycles Paclitaxel 45-50mg/m weekly Carboplatin AUC 2, concurrent thoracic RT Followed by 2 cycles of paclitaxel 200 mg/m and carboplatin AUC 6
Concurrent chemotherapy/rt regimens Cisplatin 50mg/m D1,8,29,36 Etoposide 50mg/m D 1-5, 29-33 Concurrent thoracic RT (preferred) Cisplatin 100mg/mD1,29 Vinblastin 5mg/m/weeklyX5 Concurrent thoracic RT (preferred) Paclitaxel45-50mg/mweekly over 1 hour Carboplatin AUC=2 mg/ml/min over 30 min weekly Concurrent thoracic RT
Chemo-RT Cis 50 D 1, 8, 29, 36 Etoposide 50 D 1-5, 29-36 Cis 100 D 1, 29 Vinblastine 5 weekly 5 Concurrent Paclitaxel 50 w Carboplatin AUC2 w
Sequential chemotherapy/rt regimens Cisplatin 100 mg/m on D 1, 29 Vinblastin 5 mg/m/weekly on D 1, 8, 22,29 Followed by RT Paclitaxel 200mg/m every 3 weeks 2 cycles Crboplatin AUC 6, 2 cycles followed by thoracic RT
Chemo-RT Cis 100 D1,29 Vinbl. 5 w Paclitaxel 200 Carboplatin AUC 6 sequential
GEMCAP (neoadjuvant) Induction chemo IIIA IIIB gemcitabine+carboplatin+paclitaxel αρχικό ΙΙΙΑ (εξαιρεσιμότητα: 44%) Διάμεσο PFS:10.5 μήνες Διάμεσος OS: 21.1 μήνες
Neoadjuvant therapy is recommended in selected patients Which patients should be operated on after induction chemo for N2 nsclc? analysis of 175 patients 7 year experience Those who respond to induction chemo In patients with stage IIIA-N2 disease and PS<2, induction chemoradiotherapy with cisplatin-etoposide followed by either surgical resection or thoracic radiotherapy are both valid options with comparable outcomes. Stefani A J Thor Cardiovasc Surg 2010
Metastatic NSCLC
Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy Advanced-Stage NSCLC and PS 0-1 EGFR mutation positive ELM4-ALK positive EFGR mutation and ALK negative and nonsquamous histology EFGR mutation and ALK negative and squamous histology Bevacizumab appropriate Bevacizumab inappropriate Erlotinib or gefitinib first line Consider crizotinib first or second line Consider carboplatin/paclitaxel + bevacizumab Or cisplatin/pemetrexed ± Bevacizumab Consider cisplatin or carboplatin combined with pemetrexed, docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbine ± cetuximab Consider cisplatin or carboplatin combined with docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbine ± cetuximab
Metastatic NSCLC TKI vs Chemo (platinum based) PFS? OS? TKI > Chemo EURTAC TKI vs chemo 10 vs 6months OPTIMAL TKI vs chemo 11 vs 6months NEJ002 TKI vs chemo 9.7 vs 6.7months WJTOG 3405 TKI vs chemo 12.5 vs 7months
Συμπεράσματα Οι ΤΚΙs ΠΡΕΠΕΙ να αποτελούν την θεραπευτική επιλογή έναντι της ΧΜΘ σε ασθενείς με μεταλλάξεις του EGFR Απαραίτητος ο ιστολογικός έλεγχος και η δημιουργία υποδομών για τον έλεγχο ύπαρξης μεταλλάξεων Δεν είναι ξεκάθαρο αν κάποιος αναστολέας υπερέχει ξεκάθαρα των άλλων
EGFR TKI Gefitinib Erlotinib Afatinib Icotinib? BIBW 2992 PF 299804
Crizotinib ΤΚ αναστολέας της ALK και Met κινάσης Crizotinib ALK-Positive Το crizotinib φαίνεται να αυξάνει σημαντικά την επιβίωση σε ασθενείς ALK+ που λαμβάνουν θεραπεία, έναντι ασθενών ALK+ που δεν λαμβάνουν θεραπεία H θετικότητα ALK αποτελεί αρνητικό προγνωστικό παράγοντα
INNOVATIONS Cis+Gem+Bev vs Erlotini+Bev Median 10months 17 months Should E+B be used in an unselected population NO Does the addition of B to E improves outcomes for EGFR mutated patients May Be
PARAMOUNT (Maintenance for Pem) Pem+Cis Pem+BSC Placebo+BSC PFS
PARAMOUNT Σημαντική παράταση του PFS με pemetrexed ως θεραπεία συντήρησης (HR:0.62) Ευνοϊκό profile τοξικότητας για τους ασθενείς στο σκέλος θεραπείας συντήρησης
State of the art treatment of SCLC P-based combination chemotherapy (PE) at full standard doses, x 4-6 as 1st line treatment for both LD and ED patients. Early thoracic irradiation (TRT), 40-50 Gy, added to CT for LD patients. Prophylactic cranial irradiation (PCI), 25-36 Gy, for patients with either LD or ED and CR/good PR. Single agent CT (Topotecan) as 2nd line treatment for relapsed SCLC. Amrubicin? A Ardizzoni, ASCO 2007
Algorithm of first-line treatment for limited disease SCLC 1,2 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 SCLC: small cell lung cancer; CR: complete response 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.
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 SCLC 1,2 Relapsed disease 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.
MDTs (multidisciplinary meeting) ΠΝΕΥΜΟΝΟΛΟΓΟΣ ΘΩΡΑΚΟΧΕΙΡΟΥΡΓΟΣ ΑΚΤΙΝΟΘΕΡΑΠΕΥΤΗΣ ΟΓΚΟΛΟΓΟΣ ΠΑΘΟΛΟΓΟΑΝΑΤΟΜΟΣ