STAGE III NONSMALL CELL LUNG CANCER TREATMENT APPROACHES WE LIKE TO PRACTICE... ALMOST UNETHICALLY Branislav Jeremic, MD, PhD Professor and Head Division of Radiation Oncology Stellenbosch University and Tygerberg Hospital Cape Town South Africa 1
CONFLICT OF INTEREST NONE TO DECLARE 2
CONCURRENT RADIOCHEMOTHERAPY STANDARD TREATMENT IN LOCALLY ADVANCED, INOPERABLE (STAGE III) NSCLC Cochrane Database Systematic Review O Rourke et al, 2010 Chinese Meta-Analysis Liang et al, Int J Cancer, 2010 IGR/MRC IPD meta-analysis Auperin et al, JCO, 2010
CONCURRENT RADIOCHEMOTHERAPY IN LOCALLY ADVANCED (STAGE III) NSCLC EXISTING ROOM FOR AN IMPROVEMENT INTENSIFICATION OF TREATMENT IMPROVED OUTCOMES? INCREASED TOXICITY?
RTOG 0617/NCCTG N0628/CALGB 30609 R A N D O M I Z E RT: 60 Gy Paclitaxel Carboplatin +/- Cetuximab RT: 74 Gy Paclitaxel Carboplatin +/- Cetuximab Paclitaxel Carboplatin X 2 +/- Cetuximab
Overall Survival (%) 100 60 Gy arm: 81% 75 50 74 Gy arm: 70% 25 0 HR=1.45 (1.02, 2.05) p*=0.02 0 3 6 9 12 Patients at Risk Months since Randomization 60 Gy 213 190 149 124 104 74 Gy 204 175 137 116 93 *One-sided p-value, left tail 60 Gy 74 Gy Dead 58 70 Total 213 204 The higher dose arm fared worse!
What s THE reason that dose escalation is negative? 1) Dose Threshold? 5) Type of failure? 2) Toxicity? 6) Result is actually TRUE? 3) Table of Characteristics? 7) Totally novel strategies? 4) Technical factors?
RTOG 0617 Definitely, Probably, or Possibly Related to Treatment (using CTCAE Version 3.0) September 2011 Arm A: 60 Gy +/- Cetuximab (n=192) Grade Arm B: 74 Gy +/- Cetuximab (n=183) Grade 3 4 5 3 4 5 Worst non-hematologic 79 (41.1%) 14 (7.3%) 4 (2.1%) 85 (46.4%) 17 (9.3%) 8 (4.4%) Worst overall 84 (43.8%) 45 (23.4%) 4 (2.1%) 78 (42.6%) 52 (28.4%) 8 (4.4%) Grade 5 Events (n=4) (n=8) -As scored by institution -No significant difference 2 Pulmonary 1 Thrombosis 1 Death NOS 2 Pulmonary 1 Thrombosis 1 Upper GI Hemorrhage 1 Pulmonary Hemorrhage 1 Pneumonia NOS 1 Esophageal 1 Death NOS
LOCALLY ADVANCED NSCLC ACUTE HIGH-GRADE (> 3) ESOPHAGITIS Study/author RT (Gy) CHT Sequence Esophagitis RTOG 8808 60 (QD) - - < 5% RTOG 8808 60 (QD) PV induction < 5% RTOG 9204 63 (QD) PE induction 6% RTOG 9015 69.6 (BID) PV concurrent 24% RTOG 9106 69.6 (BID) PE concurrent 53% RTOG 9204 69.6 (BID) PE concurrent 36% LUN-27 60 (QD) T concurrent 17% LUN-56 66 (QD) TC concurrent 25% LUN-63 69.6 (BID) TC concurrent 26% Jeremic et al 69.6 (BID) CE concurrent 10-15% Jeremic et al 67.6 (BID) TC concurrent 17%
CONCURRENT RADIOCHEMOTHERAPY LOCALLY ADVANCED (STAGE III) NSCLC Low-dose daily CHT leads to low toxicity Jeremic et al, 1996; 2001; 2005 Koning CC et al, 2013 Hfx RT offers better LC and OS Jeremic et al, 1995; 1996; 1998; 2001; 2005 Mauguen et al, 2012
CONCURRENT RADIOCHEMOTHERAPY LOCALLY ADVANCED (STAGE III) NSCLC Studies included Stage IIIA and pn2 patients Lower burden (T and/or N) of tumour cells More aggressive approach justified? Better outcome with intensification? Concurrent radiochemo still a standard!
CONCURRENT RADIOCHEMOTHERAPY LOCALLY ADVANCED (STAGE III) NSCLC DO WE ALWAYS PRACTICE IT? OTHER APPROACHES? EVIDENCE?
CONCURRENT RADIOCHEMOTHERAPY LOCALLY ADVANCED (STAGE III) NSCLC DO WE ALWAYS PRACTICE IT? NO! OTHER APPROACHES? MANY! EVIDENCE? NONE! OTHER APPROACHES STILL ADVOCATED WIDELY!! (NCCN, NICE, SIGN, ESTRO, ESMO, CIA, KGB, MI6 you name it)
LOCALLY ADVANCED (STAGE III) NSCLC TWO MOST TROUBLESOME SITUATIONS SURGERY IN STAGE IIIA/pN2 NSCLC CONSOLIDSATION CHEMO IN STAGE III
STAGE IIIA NSCLC Low disease volume Greater chances for cure? More aggressive treatment justified? Surgery and/or CHT and/or RT
STAGE IIIA NSCLC (prospective studies) Author Phase Stage N Treatment MST (mos) Shepherd III IIIA (N2) 15 16 Johnstone III IIIA 29 32 Van Meerbeeck III III (N2) 167 165 RT CHT+S CHT+S CHT/RT CHT+S CHT/RT Albain III IIIA 429 CHT/RT+S CHT/RT Thomas III IIIA/B 264 260 CHT+RT (bid)/cht+s CHT+S+PORT (qd) 16.2 18.7 19.4 17.4 16.4 17.5 23.6 22.2 15.7 17.6 OS (%) n.r. 0% 70 (1yr) 66 (1yr) 15.7 (5yr) 14 (5yr) 27.2 (5yr) 20.3 (5yr) 21 (5yr) 18 (5yr) Mortality (%) 7% 3% 9% <1% 8% 2% 9% 5% Gottfried III IIB (T3N0) IIIA/B (T4N0) 42 37 CHT+S CHT+S+CHT 32.3 31.8 47 (3yr) 49 (3yr) 3% Sorenson III T1-3N2M0 (pn2) 170 171 CHT + S + RT CHT + RT 17 15 20 (5yr) 16 (5yr) n.r.
STAGE IIIA NSCLC (prospective studies) Author Phase Stage N Treatment MST (mos) Shepherd III IIIA (N2) 15 16 Johnstone III IIIA 29 32 Van Meerbeeck III III (N2) 167 165 RT CHT+S CHT+S CHT/RT CHT+S CHT/RT Albain III IIIA 429 CHT/RT+S CHT/RT Thomas III IIIA/B 264 260 CHT+RT (bid)/cht+s CHT+S+PORT (qd) 16.2 18.7 19.4 17.4 16.4 17.5 23.6 22.2 15.7 17.6 OS (%) n.r. 0% 70 (1yr) 66 (1yr) 15.7 (5yr) 14 (5yr) 27.2 (5yr) 20.3 (5yr) 21 (5yr) 18 (5yr) Mortality (%) 7% 3% 9% <1% 8% 2% 9% 5% Gottfried III IIB (T3N0) IIIA/B (T4N0) 42 37 CHT+S CHT+S+CHT 32.3 31.8 47 (3yr) 49 (3yr) 3% Sorenson III T1-3N2M0 (pn2) 170 171 CHT + S + RT CHT + RT 17 15 20 (5yr) 16 (5yr) n.r.
STAGE IIIA NSCLC (retrospective studies) Author Phase Stage N Treatment MST (mos) OS (%) Mortality (%) Uy retrospective IIIA (N2) 40 CHT/RT+S+CHT 40 52 (3yr) 7% Yap retrospective IIIA/B 33 CHT/RT+S 29.9 74 (2 yr) <1% Taylor retrospective ciiia 107 CHT +S (+ PORT) RT-CHT 31 27 33 (5yr) 30 (5yr) n.r. Mac Manus retrospective IIIA 25 RT-CHT 26 32 (4yr) n.r. Seder retrospective IIIA 56 88 CHT/RT + S RT-CHT n.r. n.r. 2% 2% Jeremic retrospective ciiia 222 RT-CHT 38 41 (5yr) 0
STAGE IIIA NSCLC (retrospective studies) Author Phase Stage N Treatment MST (mos) OS (%) Mortality (%) Uy retrospective IIIA (N2) 40 CHT/RT+S+CHT 40 52 (3yr) 7% Yap retrospective IIIA/B 33 CHT/RT+S 29.9 74 (2 yr) <1% Taylor retrospective ciiia 107 CHT +S (+ PORT) RT-CHT 31 27 33 (5yr) 30 (5yr) n.r. Mac Manus retrospective IIIA 25 RT-CHT 26 32 (4yr) n.r. Seder retrospective IIIA 56 88 CHT/RT + S RT-CHT n.r. n.r. 2% 2% Jeremic retrospective ciiia 222 RT-CHT 38 41 (5yr) 0
STAGE IIIA NSCLC Author Study/ phase Stage N Treatment MST (mos) OS (%) Mortality (%) Remarks Shepherd III IIIA (N2) 15 16 RT CHT+S 16.2 18.7 n.r. 0% Johnstone III IIIA 29 32 CHT+S CHT/RT 19.4 17.4 70 (1yr) 66 (1yr) 7% 3% bulky N2 in 54% pts Van Meerbeeck III III (N2) 167 165 CHT+S** CHT/RT 16.4 17.5 15.7 (5yr) 14 (5yr) 9% <1% ** PORT in 40% pts Albain III IIIA 429 CHT/RT+S CHT/RT 23.6 22.2 27.2 (5yr) 20.3 (5yr) 8% 2% 26% mortality in 54 patients undergoing pneumonectomy Thomas III IIIA/B 264 260 CHT+RT (bid)/cht+s CHT+S+PORT (qd) 15.7 17.6 21 (5yr) 18 (5yr) 9% 5% Gottfried III IIB (T3N0) IIIA/B (T4N0) 42 37 CHT+S CHT+S+CHT 32.3 31.8 47 (3yr) 49 (3yr) 3% Sorenson III T1-3N2M0 (pn2) 170 171 CHT + S + RT CHT + RT 17 15 20 (5yr) 16 (5yr) n.r. Uy retrospective IIIA (N2) 40 CHT/RT+S+CHT 40 52 (3yr) 7% Yap retrospective IIIA/B 33 CHT/RT+S 29.9 74 (2 yr) <1% Taylor retrospective ciiia 107 CHT +S (+ PORT) RT-CHT 31 27 33 (5yr) 30 (5yr) n.r. KPS < 70 in 2% pts W. loss > 5% in 10% pts Jeremic retrospective ciiia 177 RT-CHT 38 41 (5yr) 0 All pts had KPS 70-100 and weight loss < 5%
STAGE IIIA NSCLC NO EVIDENCE FOR ROLE OF SURGERY EVIDENCE ABOUT TOXICITY/MORTALITY MYRIAD OF POTENTIAL PROGNOSTICATORS A LOT OF PATIENTS STILL BLEED (volunteer needed to inform NCCN, ESTRO, ESMO, CIA, KGB, MI6..)
SELECTED CONSOLIDATION CHEMOTHERAPY STUDIES IN LOCALLY ADVANCED NSCLC Study Year Concurrent RT-CHT Consolidation CHT MST (months) Survival Lau et al 2001 RT/TC TC x 2 17 40% (2 yr) Ratanatharathorn et al 2001 RT/TC TC x 4 14.5 27% ( 1 yr) Albain et al 2002 RT/PE PE x 2 15 17% (5 yr) Gandara et al 2003 RT/PE D x 3 26 29% (5 yr) Park et al 2003 RT/PoE PoE x 4 15 16% (5 yr) Sakai et al 2004 RT/DC DC x 2 27 61% (2 yr) Sekine et al 2006 RT/PV D x 3 30 43% (3 yr) Iwasaki et al 2006 RT/PD PD X 3 19 40% (2 yr) Jain et al 2009 RT/DC DC x 2 12 20% (2 yr) Ohyanagi et al 2009 RT/PS-1 PS-1 x 2 33 56% (2 yr) Oshita et al 2010 RT/NI NI x 2 36 40% (5 yr) Bastos et al 2010 RT/IrC D x 3 15 19% (3 yr) 22 Ramalingam et a 2013 RT/Cet CetTC/weekly 19 64% (1 yr)
CONSOLIDATION CHT STUDIES PROMISING RESULTS ACCEPTABLE TOXICITY (?) FURTHER VERIFICATION (PHASE III) (?)
CONSOLIDATION CHT STUDIES PROBLEM (I) LACK OF DOCUMENTED PATTERN OF FAILURE IN CR/ PR AFTER CONCURRENT RT/CHT
CONSOLIDATION CHT STUDIES PROBLEM (II) UNEXPLAINED WHERE CONSOLIDATION CHT IS ACTING
CONSOLIDATION CHT STUDIES PROBLEM (III) SAME/DIFFERENT DRUGS MAY HAVE EXERTED DIFFERENT ACTIVITY ON LOCORGIONAL AND/OR DISTANT LEVEL
CONSOLIDATION CHT STUDIES PROBLEM (IV) SOME PATIENTS (SD) MAY HAVE UNNECESSARILY BEEN EXPOSED TO TOXIC TREATMENT
RANDOMIZED STUDIES ON CONSOLIDATION THERAPY IN LOCALLY ADVANCED NSCLC STUDY YEAR CONCURRENT RT-CHT CONSOLDIATION CHT MST (months) OS Hanna et al 2008 RT/PE no 23.2 26% (3yrs) RT/PE DOC x 3 21.2 27% (3yrs) Kelly et al 2008 RT/PE DOC x 3 35 59% (2 yrs) RT/PE DOC x 3 + Gefitinib 23 46% (2yrs) Hoang et al 2012 RT/TC Pre-RT : PC x 2 15 25% (3yrs) RT/TC Pre-RT : PC x 2 Post-RT : Thalidomide 16 23% (3yrs) 28
CONCURRENT RT-CHT +/- CONSOLIDATION CHT Tsujino et al, JTO, 2013 ENDPOINT CCT+ CCT- SIGNIFICANCE No. studies 25 20 No. pts 1707 1772 Pooled 3yr 27% 24.8% Pooled MST 19 (months) (95% CI, 16. 1 19.9) 17.9 (months) (95% CI, 17.3 21.0) Predicted HR 0.94 (95% CI, 0.81-1.09) P = 0.40 Grade 3-5 toxicity 29 pneumonitis esophagitis neutropenia leukopenia deaths n.s. n.s. n.s. n.s. n.s.
CONCURRENT RT-CHT and CONSOLIDATION THERAPY DATA FROM RANDOMZIED TRIALS DIFFER MORE TOXICIITY IN CONSOLIDATION ARMS POORER QUALITY OF LIFE IN CONSOLIDATION ARMS TOXIC DEATHS 2-6% IN CONSOLIDATION ARMS 30
FOR THOSE WHO MAY WISH TO TEST IT FURTHER
CONSOLIDATION CHT SAME STORY AS WITH SURGERY NO EVIDENCE AT ALL PATIENTS STILL SERIOUSLY POISONED ANOTHER VOLUNTEER NEEDED
CONCLUSION (I) EBO CLEAR WITH FACTS AND FIGURES CONCURRENT RT-CHT STANDARD IN ALL STAGE III NSCLC LESS MORTALITY AND HIGH-GRADE TOXICITY THERAPEUTIC BENEFIT CLEARLY FAVOURS IT!
CONCLUSION (II) MANY PEOPLE AND ORG/INC/LTD ALMOST.. UNETHICALLY (?) TREAT PATIENTS DO WE NEED AN ORCHESTRATED ACTION?
Cape Point
A view from Chapman s peak Gracias!