LONG-TERM SURGICAL OUTCOMES OF 1018 PATIENTS WITH EARLY STAGE NSCLC IN ACOSOG Z0030 (ALLIANCE) TRIAL Stacey Su, MD; Walter J. Scott, MD; Mark S. Allen, MD; Gail E. Darling, MD; Paul A. Decker, MS; Robert J. McKenna, MD; Rodney J. Landreneau, MD; David R. Jones, MD; Richard I. Inculet, MD; Bryan F. Meyers, MD Fox Chase Cancer Center; Mayo Clinic; University of Toronto; Cedars-Sinai Medical Center; University of Pittsburgh Medical Center; University of Virginia; London Health Science Center; Washington University Disclosures: none
Background Surgical lobectomy is the standard of care for treatment of early stage NSCLC in operable patients Stereotactic body radiotherapy (SBRT) has become the standard for treatment of early stage NSCLC in inoperable patients. In contrast to conventional RT, SBRT offers Higher dose per fraction Limited toxicity profile Improved therapeutic ratio (efficacy/toxicity)
RTOG 0236 set the standard for SBRT in inoperable pts with early NSCLC Multicenter phase II study 55 pts with medically inoperable ct1-2n0 NSCLC 60Gy in 3 fractions Median f/u 2.9 y At 3y Primary tumor control 98% Local (tumor+lobe) control 91% Locoregional control 87% Distant metastasis rate 22% Median OS 48 months Limited toxicity, no deaths from treatment
Is SBRT an effective option in the treatment of high-risk operable ct1-2n0 NSCLC? RTOG 0618, closed accrual 2010 Survival outcomes are not yet available
Comparative studies of SBRT and surgery in high-risk pts Onishi et al (2011) Palma et al (2011) Crabtree et al (2010) Grills et al (2010) 87 operable pts s/p Sample SBRT 60 (SBRT) inoperable 57 (SBRT) inoperable 58 (SBRT) inoperable 60 (surgery) 57 (surgery) 69 (wedge) Dates 1993-2004 2005-7 2000-7 2003-9 19 mo (SBRT); 31 mo Median f/u 55 mo 43 mo (surgery) 2.5y OS 72% (ct1) 5y 42% (SBRT) 3y 54% (surgery) 3y 87% (wedge) 30mo 62% (ct2) 5y 60% (surgery) 3y 38% (SBRT) 3y 72% (SBRT) 30mo p=0.14 p=0.22 p=0.27 p=0.01 Local control 92% (ct1) 5y 88% (surgery) 3y 80% (surgery) 30mo 73% (ct2) 5y 90% (SBRT) 3y 96% (SBRT) 30mo p=0.01 p=0.9 p=0.07
SBRT studies are difficult to compare Differing definitions of treatment response and local failure Primary tumor failure: gross tumor volume Marginal failure: within 1 cm of planning target volume Local failure (+ involved lobe) Regional failure: ipsilateral hilum, mediastinum Distant failure
RCTs: SBRT vs surgery for ct1-2n0 NSCLC ACOSOG Z4099/RTOG 1021: phase III trial of SBRT vs sublobar resection +/- brachytherapy ROSEL (Netherlands) STARS
ACOSOG Z0030 (Alliance) trial 102 different surgeons from 63 institutions, 1999-2004 1023 pts randomized to mediastinal lymph node sampling(498) vs dissection (525) Patients with proven NSCLC underwent a rigorous mediastinal and hilar lymph node sampling per protocol before randomization. For tumors in the right lung, lymph node stations 2R, 4R, 7, and 10R were sampled. For tumors in the left lung, stations 5, 6, 7, and 10L were sampled.
Why is the Z0030 dataset unique? Uniform eligibility criteria Modern staging procedures Rigorous data collection Standardized surgical techniques Audited data
Objectives Assess long-term outcomes of Z0030 cohort Perform subset analysis of VATS vs open lobectomy patients by propensity score matching
Methods Differences between groups on clinical and tumor characteristics were compared using the two-sample rank test or chi-square test as appropriate. Cumulative survival probabilities were estimated using the Kaplan-Meier method. The log rank test and Cox proportional hazards regression were used to compare survival and recurrence across groups.
Methods Propensity scores were developed to estimate the adjusted risks of perioperative outcomes associated with the choice of treatment (VATS versus open lobectomy). Clinical and tumor variables such as age, gender, histology, performance status, tumor location, and clinical stage (T1 or T2) were included in the propensity score model. 752 patients (66 in the VATS group and 686 in the open lobectomy group) were classified into 5 equal-sized propensity score groups (groups 1-5). Proportional hazards regression with 5 strata (propensity score groups 1-5) was used to compare long term outcomes between VATS and open patients.
Definitions of recurrence in Z0030 trial Local failure: adjacent lung parenchyma, bronchial stump, or in the hilum adjacent to the bronchial stump. Regional failure: hilum separate from bronchial stump, in the mediastinum, chest wall, or ipsilateral pleura. Distant failure: separate lobe of ipsilateral lung, contralateral thorax, supraclavicular lymph nodes, or distant organ.
Results
Patient characteristics Median f/u 6.7 y
Patterns of failure
Z0030 vs RTOG 0236 outcomes Long term outcomes in patients with T1 and T2 tumors (Z0030) versus RTOG 0236 T1 (n=578) T2 (n=440) RTOG0236 (n=55) 5 year survival 5 year survival 3 year survival Median (95% CI) Median (95% CI) Median (95% CI) Overall survival 9.1 72 (68-76) 6.5 55 (51-60) 4.0 56 (42-68) Disease free survival Local disease free survival Local/regional disease free survival Distant disease free survival NA 77 (73-81) NA 58 (53-64) 2.9 48 (34-61) NA 95 (93-97) NA 91 (88-94) 91 (76-97) NA 88 (85-91) NA 84 (80-88) 87 (71-95) NA 83 (79-86) NA 66 (61-71) 78 (62-88)
Subset analysis of VATS versus open lobectomy patients in Z0030 cohort
There is no difference in T or N stage between VATS and open lobectomy groups
Summary Median OS was 9.1y (pt1); 6.5y (pt2). 5y disease-free survival was 77% (pt1); 58% (pt2). 5y local disease-free survival was 95% (pt1); 91% (pt2). There was no significant difference in long-term outcomes between VATS and open lobectomy in propensity matched analysis.
Limitations Retrospective analysis of Z0030 cohort Small sample size of VATS cohort (n=66) Loss of follow-up regarding recurrence patterns, new primary tumors
Conclusions Secondary analysis of Z0030 trial provides long-term outcomes against which SBRT outcomes must be compared. Before SBRT is considered a valid alternative to surgery for earlystage NSCLC in operable patients, long-term outcomes must be critically evaluated. Accrual to Z4099 is key to evaluating efficacy of SBRT versus surgery for early stage NSCLC in high-risk operable patients.