- Email: [email protected]
II nonsmall cell lung cancer (NSCLC): Initial report of Japan Clinical Oncology Group trial (JCOG 0204)
$17
Oral Sessions / Early detection~Prevention ~What
Is the meaning of local-regional control alter chsmoradlatlon for locally advanced NSCLC? An RTOG analysis
M Machtay I . S Swarm 2. R Komaki 3. R Byherdt 4. R Paulus 2. W. Sause ~. W. Curran ~. K. Albain. B. Moves. ~thomas Jefferson Untvarstty
Hosptal Phlladelphta, Pennsylvanta, USA: 2RTOG Headquarters, USA: 3M B Anderson Cancer Center, USA, SMedcal Col/age or Wisconsin, USA, ~LDS Hospital, USA: ~Loyo/a Umverslty, USA: 7 WaJme State Untvarstty, USA Background: We studied several different definitions of local-regional COntTol (LRC) and the factors that predict LRC after definilJve chemoradiatlon (without surgery) for locally advanced (LA) non-small cell lung cancer (NSCLC) Methods: This secondary analysis combined data from seven RTOG thals in which chemoradiotherapy was used for LA NSCLC These thals were: RTOG 88-08 (chome-RT arm only). 80-15. 9 1 - 0 6 . 9 2 - 0 4 . 9 3 - 0 9 (nonoperatlve arm only). 94-10. and 98-01. Three different defmqltions of LRC were studied: 1. Freedom from local prregression (FFLP). the tradtlonal RTOG methodology. in which a local regional failure is int]'athoraclc tumor progression by WHO cntena; 2. Complete local cont]-ol (CLC). in which any patient not achieving complete response was considered to have local regional failure at Day 0; and 3. Partial local control (PLC). in which any patient net achieving at least partial response was considered to have local-regional failure at Day 0 Response and prregression were based upon institutional repo~ng: pathologic assessment of intrathoracic control was rarely performed and central review of scans was not done Testing for associations between LRC and survival was performed using a Cox multivariate model that included other potential precictive factors Results: A total of 1290 patients were analyzed The 2-year and `5-year actuarial rates of LRC when analyzed as FFLP were 46% and 33% When analyzed as CLC. these rates were 7% and 4%. When analyzed as PLC. these rates were 17% and 8%. Regardless of the definition of LRC stuc|ed. there was a sb'ong association betwcon LRC and overall sur-vlval CO<0.0001). However. this association was weakest when FFLP was used as the definition of LRC; paradoxically for the frst 12 months after treatment. FFLP was inversely correlated with overall survival. On mult]vanate analysis, in addition to LRC. several other factors were statistically significantly associated with survival Regarcless of which defini'don of LRC was used. pretreatment Kamofsk'y Performance status (90/100 vs 70/80) was highly predictive of survival (,o<0004) When FFLP was used as the definilJon of LRC. age (~<70 vs >70) and stage (II/IIIA vs IIIB) were also significant predictors of survival (p <0 0001) When CLC was used. gender (females did better than males) and histology (non-squamous was better than squamous) but not age or stage were sigrtficent predictors of survival CO 0 0005 and p 0 004 respectwely). When PLC was used. ilstology but not age. gender or stage was significant CO<0.0001). Rac|etherspy dose intensity, as defined via the Biologically Equivalent Dose (BED) model, was net assec~ated wtth local regional oonb'ol for any of these three definitions. Conclusions: LRC is suboptimal after definitive chemoradiotherapy alone for locally advanced NSCLC. The results from analyses of LRC clffer considerably with different definitions of LRC. A consensus definition of LRC. perhaps incorporating functional imaging and/or central review, is needed [ ~
Overall trealznant time dudng concurrent chemoradlotharapy and outcomes: An RTOG secondary analysis
M. Machtay I . S. Swann2. R. Komaki ~. W. Sause 4. C. Langer ~. R. Byhardt 6. W. Curran ~. ~1homas Jefferson Untversrty HospttaJ, Philadelphia,
Pennsylvania, USA, 2RTOG Headquarters, USA, 3M D Anderson Cancer Center, USA, "~LDS Hosptal, USA, 5Fox Chase Canoar Center, USA, ~MeStcal College of Wisconsin, USA Background: With radiotherapy alone, there is a StTOng relationship between overall treatment time and outcomes The purpose of this analysis was to determine if overall treatment time is associated with outcomes after definitive concurrent chemoradiotherapy for locally advanced non-small call lung carcinoma (NSCLC). Methods: Data were analyzed from three prospective RTOG thals (RTOG 91-06. 92-04. and 94-10) in which immediate concurrent chemoradation (clsplatln4~ased) was the pnmary therapy for gcod~erformanca status Stage III (and selected inoperable Stage II) NSCLC. Protocol specified radiotherapy was 63-69.6 Gy over approximately 6.,5 weeks. Treatment time was analyzed in two ways: 1. First. It was analyzed as a dichotomous variable ("long" treatment time >5 day interruption versus "short" tTeatment time) and 2 Treatment time was analyzed as a continuous variable 0n days) in a multlvanate model The Cox multivariate model also incorporated histology, performance status, gender, age. stage, radiotherapy fractionation, and radiotherapy dose Endpuints studied were overall survival, progression free survival (PFS). localregional contTol and toxicity Results: A total of 474 patients were analyzed Median followup for surviving patients was 6.1 years. The multrvanate model showed that prolonged treatment time was highly significantly assoaated with worsening overall sur.qval (p=0.Ol) and PFS (!o=0.02). The hazard ratio was 1.02 (95% confidence interval 1.00-1.03). reflecting an estimated 2% increase in the nsk of death for each day of proloeged treatment. Histology and performance status
were also significant prognestlcators in this model Co= 0.02 and p = 0.03 for survival, respectively) A total of 8/" patients (18.%) had a tTeatment time that was prolonged >`5 days beyond protocol specification: these patients had a median survival of 14 8 months, versus 19 `5 months for other patients (p 01`5 by log rank) Although detailed data on the causes of tTeatment interruptions ware net available, prolonged tTeatment time was strengly associated with high grade acute esephagitls (p < 0 0001) Conclusions: This retrospective analysis demonstrates a negative asseciatlon between prolonged overall treatment time and survival in patients t]-eated with conourrent chemoradiatlon. Tils is s~milar to the results when this topic is studied with radetherspy alone, though the magnitude of the association is net as large in the setting of concurrent chemoradiation. Improvements in radetherspy dose intens~ are probably needed in future tnals.
IONIA
randomized phase II trial of pre-operatlve docetaxel and clsplaUn (DP) or docetaxsl alone (I)) In clinical (c-) stage IB/II nonsrnall cell lung cancer (NSCLC): Initial report of Japan Clinical Oncelogy Group trial (JCOG 0204)
H. Tada ~. H. Katoh. H. Kunltoh. M. Tsuboi. H. Asamura. K. Nagai. £ Mltsudomi. T Koike. N Ishizuka. N Saljoh ~Osaka OtyGenera/Hosp/ta/, Osaka, Japan,
2Nattonal Canoar Center, Tokyo, Japan, 3 Tokyo MeStca/ College, Tokyo, Japan: 4Tokyo Mecica/ Co//ede, Tokyo, Japan, 5Nabona/ Cancer Center, Tokyo, Japan, °Nattonal Canoar Center East, Kashtwa, Japan; 7N/tgata Cancer Center, Niigata, Japan eAichi Cancer Center, Nagoya, Japan, g/ntemabona/ Medica/ Center of Japan, Tokyo, Japan, 1oNabone~ Cancer Center East, Kashiwa, Japan Background: There are few data on optimal pre-operative chemotherapy (Cx) in early c-stage NSCLC We conducted a randomized phase II thai in order to evaluate the safety and efficacy of the preoperative platlnum~ased doublet Cx and D monetherapy in o-stage IB/II. resectable NSCLC Methods: Patients Cots) with pathologically documented ~stage IB/II NSCLC. performance status (PS) 0-1 and ample organ functions were eligible. Mediastlnal nodes >lcm on CT scan must be biops~ed and proved to be negative via mec|astinescopo. Pts were randomized to receive either two cycles of DP given q4 (q3 allowed) weeks: P 80mgim 2 and D 60mgim 2 on day 1. or. three cycles of D 70mg/m 2 q3weeks. Pts went on to thoracotomy 4-5 weeks (DP) or 3-4 weeks (D) after completion of the Cx. Preoperattve Cx could be stopped and switched to surgery when tumor size increased >10% in diameter Primary endpolnt was 1-year disease-free survival (DFS) rate Results: From Oct]02 to Nov/03. 80 pts were randomized Median age 65 (range 30 /.4). M/F 62/18. c-IB/ll 45/3`5. PS 0/1 66/14. histology Ad/Sq/Others 54/211`5 (ineluding 1 ineligible sarcoma) As of Dec,'04 monitoring, all/.9 eligible pts (40 in DP and 39 in D) were reported to be treatment-off and followed up for 1 year Cx to~dcitles were mainly hematologic and well tolerated `5 pts (4 in DP. 1 in D) expeneneed major (>IL) intraoperatlve bleeding. Major post operative morbidity was reported in 2 DP pts. which included empyema and pulmonary edema. There were 2 toxic deaths, beth in DP; 1 intraoperatlve bleeding and 1 empyema. Efficacy endpoints are surnmarlzed in the table. P N2 was documented in 8/'39 (DP) and 9/35 (D) of the operated pts. DP Completed Cx eRR to Cx Resection Complete resection Pathologic CR DFS at 1-yr
D
38/40 (0`5%)
24/3g (62%)
18/40 (45%)
6/39 (15%)
39/40 (08%)
34130(8/.%)
38140 (0,5%) 2/40 (5%) 77%
33/3g (85%) 0/39 (0%) 59%
Conclusions: These results suggest that platinum based doublet is supenor in resection rate and short-term DFS and thus should be selected as optimal preoperative Cx for future phase III trials
Early detection/Prevention E a r l y d e t e c t i o n of lung c a n c e r Tuesday, 5 July 2005 ]o~]
14:30-16:30
Storage of plasma or Isolated plasma DNA affects the results of clroulatlng DNA quanUflcetlon assays
E Andriart D Conte. L Roz. L Madani. U Pestering. G Soz~ tstituto
Naz/onale Tureen, Milan, Italy Background: Analysis of molecular markers in biological fluids is often associated
to spiral CT scan in screening thals for early detection
of
Oral Sessions / Early detection~Prevention ~What
Is the meaning of local-regional control alter chsmoradlatlon for locally advanced NSCLC? An RTOG analysis
M Machtay I . S Swarm 2. R Komaki 3. R Byherdt 4. R Paulus 2. W. Sause ~. W. Curran ~. K. Albain. B. Moves. ~thomas Jefferson Untvarstty
Hosptal Phlladelphta, Pennsylvanta, USA: 2RTOG Headquarters, USA: 3M B Anderson Cancer Center, USA, SMedcal Col/age or Wisconsin, USA, ~LDS Hospital, USA: ~Loyo/a Umverslty, USA: 7 WaJme State Untvarstty, USA Background: We studied several different definitions of local-regional COntTol (LRC) and the factors that predict LRC after definilJve chemoradiatlon (without surgery) for locally advanced (LA) non-small cell lung cancer (NSCLC) Methods: This secondary analysis combined data from seven RTOG thals in which chemoradiotherapy was used for LA NSCLC These thals were: RTOG 88-08 (chome-RT arm only). 80-15. 9 1 - 0 6 . 9 2 - 0 4 . 9 3 - 0 9 (nonoperatlve arm only). 94-10. and 98-01. Three different defmqltions of LRC were studied: 1. Freedom from local prregression (FFLP). the tradtlonal RTOG methodology. in which a local regional failure is int]'athoraclc tumor progression by WHO cntena; 2. Complete local cont]-ol (CLC). in which any patient not achieving complete response was considered to have local regional failure at Day 0; and 3. Partial local control (PLC). in which any patient net achieving at least partial response was considered to have local-regional failure at Day 0 Response and prregression were based upon institutional repo~ng: pathologic assessment of intrathoracic control was rarely performed and central review of scans was not done Testing for associations between LRC and survival was performed using a Cox multivariate model that included other potential precictive factors Results: A total of 1290 patients were analyzed The 2-year and `5-year actuarial rates of LRC when analyzed as FFLP were 46% and 33% When analyzed as CLC. these rates were 7% and 4%. When analyzed as PLC. these rates were 17% and 8%. Regardless of the definition of LRC stuc|ed. there was a sb'ong association betwcon LRC and overall sur-vlval CO<0.0001). However. this association was weakest when FFLP was used as the definition of LRC; paradoxically for the frst 12 months after treatment. FFLP was inversely correlated with overall survival. On mult]vanate analysis, in addition to LRC. several other factors were statistically significantly associated with survival Regarcless of which defini'don of LRC was used. pretreatment Kamofsk'y Performance status (90/100 vs 70/80) was highly predictive of survival (,o<0004) When FFLP was used as the definilJon of LRC. age (~<70 vs >70) and stage (II/IIIA vs IIIB) were also significant predictors of survival (p <0 0001) When CLC was used. gender (females did better than males) and histology (non-squamous was better than squamous) but not age or stage were sigrtficent predictors of survival CO 0 0005 and p 0 004 respectwely). When PLC was used. ilstology but not age. gender or stage was significant CO<0.0001). Rac|etherspy dose intensity, as defined via the Biologically Equivalent Dose (BED) model, was net assec~ated wtth local regional oonb'ol for any of these three definitions. Conclusions: LRC is suboptimal after definitive chemoradiotherapy alone for locally advanced NSCLC. The results from analyses of LRC clffer considerably with different definitions of LRC. A consensus definition of LRC. perhaps incorporating functional imaging and/or central review, is needed [ ~
Overall trealznant time dudng concurrent chemoradlotharapy and outcomes: An RTOG secondary analysis
M. Machtay I . S. Swann2. R. Komaki ~. W. Sause 4. C. Langer ~. R. Byhardt 6. W. Curran ~. ~1homas Jefferson Untversrty HospttaJ, Philadelphia,
Pennsylvania, USA, 2RTOG Headquarters, USA, 3M D Anderson Cancer Center, USA, "~LDS Hosptal, USA, 5Fox Chase Canoar Center, USA, ~MeStcal College of Wisconsin, USA Background: With radiotherapy alone, there is a StTOng relationship between overall treatment time and outcomes The purpose of this analysis was to determine if overall treatment time is associated with outcomes after definitive concurrent chemoradiotherapy for locally advanced non-small call lung carcinoma (NSCLC). Methods: Data were analyzed from three prospective RTOG thals (RTOG 91-06. 92-04. and 94-10) in which immediate concurrent chemoradation (clsplatln4~ased) was the pnmary therapy for gcod~erformanca status Stage III (and selected inoperable Stage II) NSCLC. Protocol specified radiotherapy was 63-69.6 Gy over approximately 6.,5 weeks. Treatment time was analyzed in two ways: 1. First. It was analyzed as a dichotomous variable ("long" treatment time >5 day interruption versus "short" tTeatment time) and 2 Treatment time was analyzed as a continuous variable 0n days) in a multlvanate model The Cox multivariate model also incorporated histology, performance status, gender, age. stage, radiotherapy fractionation, and radiotherapy dose Endpuints studied were overall survival, progression free survival (PFS). localregional contTol and toxicity Results: A total of 474 patients were analyzed Median followup for surviving patients was 6.1 years. The multrvanate model showed that prolonged treatment time was highly significantly assoaated with worsening overall sur.qval (p=0.Ol) and PFS (!o=0.02). The hazard ratio was 1.02 (95% confidence interval 1.00-1.03). reflecting an estimated 2% increase in the nsk of death for each day of proloeged treatment. Histology and performance status
were also significant prognestlcators in this model Co= 0.02 and p = 0.03 for survival, respectively) A total of 8/" patients (18.%) had a tTeatment time that was prolonged >`5 days beyond protocol specification: these patients had a median survival of 14 8 months, versus 19 `5 months for other patients (p 01`5 by log rank) Although detailed data on the causes of tTeatment interruptions ware net available, prolonged tTeatment time was strengly associated with high grade acute esephagitls (p < 0 0001) Conclusions: This retrospective analysis demonstrates a negative asseciatlon between prolonged overall treatment time and survival in patients t]-eated with conourrent chemoradiatlon. Tils is s~milar to the results when this topic is studied with radetherspy alone, though the magnitude of the association is net as large in the setting of concurrent chemoradiation. Improvements in radetherspy dose intens~ are probably needed in future tnals.
IONIA
randomized phase II trial of pre-operatlve docetaxel and clsplaUn (DP) or docetaxsl alone (I)) In clinical (c-) stage IB/II nonsrnall cell lung cancer (NSCLC): Initial report of Japan Clinical Oncelogy Group trial (JCOG 0204)
H. Tada ~. H. Katoh. H. Kunltoh. M. Tsuboi. H. Asamura. K. Nagai. £ Mltsudomi. T Koike. N Ishizuka. N Saljoh ~Osaka OtyGenera/Hosp/ta/, Osaka, Japan,
2Nattonal Canoar Center, Tokyo, Japan, 3 Tokyo MeStca/ College, Tokyo, Japan: 4Tokyo Mecica/ Co//ede, Tokyo, Japan, 5Nabona/ Cancer Center, Tokyo, Japan, °Nattonal Canoar Center East, Kashtwa, Japan; 7N/tgata Cancer Center, Niigata, Japan eAichi Cancer Center, Nagoya, Japan, g/ntemabona/ Medica/ Center of Japan, Tokyo, Japan, 1oNabone~ Cancer Center East, Kashiwa, Japan Background: There are few data on optimal pre-operative chemotherapy (Cx) in early c-stage NSCLC We conducted a randomized phase II thai in order to evaluate the safety and efficacy of the preoperative platlnum~ased doublet Cx and D monetherapy in o-stage IB/II. resectable NSCLC Methods: Patients Cots) with pathologically documented ~stage IB/II NSCLC. performance status (PS) 0-1 and ample organ functions were eligible. Mediastlnal nodes >lcm on CT scan must be biops~ed and proved to be negative via mec|astinescopo. Pts were randomized to receive either two cycles of DP given q4 (q3 allowed) weeks: P 80mgim 2 and D 60mgim 2 on day 1. or. three cycles of D 70mg/m 2 q3weeks. Pts went on to thoracotomy 4-5 weeks (DP) or 3-4 weeks (D) after completion of the Cx. Preoperattve Cx could be stopped and switched to surgery when tumor size increased >10% in diameter Primary endpolnt was 1-year disease-free survival (DFS) rate Results: From Oct]02 to Nov/03. 80 pts were randomized Median age 65 (range 30 /.4). M/F 62/18. c-IB/ll 45/3`5. PS 0/1 66/14. histology Ad/Sq/Others 54/211`5 (ineluding 1 ineligible sarcoma) As of Dec,'04 monitoring, all/.9 eligible pts (40 in DP and 39 in D) were reported to be treatment-off and followed up for 1 year Cx to~dcitles were mainly hematologic and well tolerated `5 pts (4 in DP. 1 in D) expeneneed major (>IL) intraoperatlve bleeding. Major post operative morbidity was reported in 2 DP pts. which included empyema and pulmonary edema. There were 2 toxic deaths, beth in DP; 1 intraoperatlve bleeding and 1 empyema. Efficacy endpoints are surnmarlzed in the table. P N2 was documented in 8/'39 (DP) and 9/35 (D) of the operated pts. DP Completed Cx eRR to Cx Resection Complete resection Pathologic CR DFS at 1-yr
D
38/40 (0`5%)
24/3g (62%)
18/40 (45%)
6/39 (15%)
39/40 (08%)
34130(8/.%)
38140 (0,5%) 2/40 (5%) 77%
33/3g (85%) 0/39 (0%) 59%
Conclusions: These results suggest that platinum based doublet is supenor in resection rate and short-term DFS and thus should be selected as optimal preoperative Cx for future phase III trials
Early detection/Prevention E a r l y d e t e c t i o n of lung c a n c e r Tuesday, 5 July 2005 ]o~]
14:30-16:30
Storage of plasma or Isolated plasma DNA affects the results of clroulatlng DNA quanUflcetlon assays
E Andriart D Conte. L Roz. L Madani. U Pestering. G Soz~ tstituto
Naz/onale Tureen, Milan, Italy Background: Analysis of molecular markers in biological fluids is often associated
to spiral CT scan in screening thals for early detection
of