management of locally advanced nsclc shilpen patel md facro department of radiation oncology,...
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Management of Management of Locally Advanced Locally Advanced
NSCLCNSCLC
Management of Management of Locally Advanced Locally Advanced
NSCLCNSCLCShilpen Patel MD FACRO
Department of Radiation Oncology, University of Washington, Seattle, WA
Roadmap• Background
•Evolution of therapy
•Radiation alone
•Sequential chemotherapy and radiation
•Concurrent chemotherapy and radiation
•Trimodality versus bimodality
•Superior Sulcus Tumors
•Imaging
Survival Improvement in Stage III NSCLC since 1980’s
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1980's 1990's 2000's
me
dia
n s
urv
iva
l
CALBG
Finish
IGR
NCCTG
WJLCG
GLOT
CZECH
LAMP
RTOG 9410
MUNICH
ECOG 2597
9.89.8
13.813.8
17.717.7
Evolution: Radiation Alone
• In the 1970’s stage III NSCLC was an unresectable disease
• Standard of care was radiation alone
RTOG 73RTOG 73--0101----Perez, et alPerez, et alCancer 45: 2744, 1980. Update Cancer 59: 1874, 1987.Cancer 45: 2744, 1980. Update Cancer 59: 1874, 1987.
Dose escalation trial of 365 pts w/ T3 Dose escalation trial of 365 pts w/ T3 or N2 NSCLC randomized to 4 arms, or N2 NSCLC randomized to 4 arms, each utilizing radiotherapy alone:each utilizing radiotherapy alone:Dose In-field
recurrenceMediansurvival
3 yearsurvival
40Gy split course 53% 37wks 6%40Gy conventional 58% 45wks 6%50Gy 49% 41wks 10%60Gy 35% 47wks 15%
Evolution: Sequential chemotherapy and radiation
Dillman et al. Improved Survival in Stage III NSCLC: 7yr f/u of CALGB #8433. JNCI Vol 88,
No 17: 1210-14, 1990 & 1996
• 165 Pts w/ stage III NSCLC randomized to:
Cisplatin + vinorelbine
Radiation--60Gy
Radiation--60Gy
Dillman et al. Improved Survival in Stage III NSCLC: 7yr f/u of CALGB #8433. JNCI Vol 88,
No 17: 1210-14, 1990 & 1996
• Median survival improved with chemotherapy– 9.7 months with radiation alone– 13.8 months with chemotherapy and radiation
• OS improved at 7 years:– 6% with radiation alone– 13% with chemotherapy and radiation
Evolution: Concurrent Chemoradiation
RTOG 94-10: Curran, et al, J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60
RANDOMIZATION
cDDP 100 mg/m2 d1, 29Vlb 5 mg/m2 Q wk X 5 (d1, 8, 15, 22, 29)Standard fractionated RT (60 Gy) d 50
cDDP 100 mg/m2 d1, 29Vlb 5 mg/m2 Q wk X 5 (d1, 8, 15, 22, 29)Standard fractionated RT(60 Gy) d1
cDDP 50 mg/m2 d1, 8, 29, 36VP-16 50 mg/m2 d1-5, 8-12, 29-33, 36-40Hyperfractionated RT (69.6 Gy) d1
CON- QD
CON- BID
SEQ
RTOG 94-10: Curran, et al, J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60
Courtesy of Walter Curran, MD
RTOG 94-10: Curran, et al, J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60
Courtesy of Walter Curran, MD
RTOG 94-10: Curran, et al, J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60
In Field failure rates
– Sequential: 38%
– Concurrent: 33%
– Hyperfractionated: 25%
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100
1980's 1990's 2000's
Lo
ca
l C
on
tro
lLocal ControlLocal Control
65% 65% 65%
Evolution: Trimodality
Intergroup 0139- Albain, et al., 2009
Stage IIIA (T1-3, pN2,
M0)NSCLCN = 429
(396 eligible)
Considered Resectable
RANDOMIZE
Cis/VP16 x 2 cycles
w/concurrent XRT 45Gy
Cis/VP16 x 2 cycles
w/concurrent XRT 45Gy
Surgery
Cis/VP16 x 2 cycles
Cis/VP16 x 2 cycles
Re-evaluate 2 to 4 weeks post RT; if no PD
Re-evaluate 7 days prior to RT completion; if no PD
Continue RT to 61GY
Median F/U 81 months
Results: Intergroup 0139
Courtesy of Kathy Albain, MD
Intergroup 0139/RTOG 9309 Progression-Free Survival by Treatment Arms
Per
cen
t A
live
Months
Trimodality ( n=201)Median 12.8 months5-year 22.4%
Chemoradiation (n=191)Median 10.5 months5-year 11.1%
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48
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Log rank p = 0.017
Intergroup 0139/RTOG 9309 Lancet 8/1/09
Independent Favorable Survival Predictors •Female
•No weight loss
•Trimodality Arm–pN0 OS=41%–pN1-3 OS=24%–No SurgeryOS=8%
Joshua Sonett, MD, et al Pulmonary Resection after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy in NSCLC. Ann Thor Surg 2004;78(4)•40 consecutive patients who received high dose radiotherapy and concurrent platinum based chemotherapy between January 1994-May 2000 who then went on to undergo a lung resection.
•Patients–Stage IIB – 7 patients
–Stage IIIA – 21 patients
–Stage IIIB – 10 patients
–Stage IV – 2 patients
Surgery •Median time to surgical resection 52.5 days (20-258 days)
•Surgeries
–29 lobectomies
–11 pneumonectomies
•No post-operative deaths
•Median ICU time = 2 days
•Overall length of stay = 6 days
•One patient developed post pneumonectomy pulmonary edema
•One patient developed a BP fistula
Results
•34/40 patients (85%) were downstaged pathologically
•33/40 patients (82.5%) had no residual lymphadenopathy
•18/40 patients (45%) exhibited a complete pathologic response
•22/26 patients (85%) with N2 disease exhibited pathologic confirmed sterilization of their mediastinal disease
Results
•Median follow-up was 2.8 years
•Overall survival at 1,2, and 5 years is 92%, 67%, 46% respectively. Median overall survival 53 months.
•Disease free survival at 1, 2, and 5 years is 73%, 67%, 56%. Median disease free survival not reached
•Failure Pattern–14% Local and distant
–29% Brain only
–29% Distant only
–29% Local only
RTOG 0229, Suntharalingam IJROBP 2012
Stage III (pathologically proven N2 or N3)NSCLC
N = 60 (57 eligible)
CBDCA AUC =2.0,
paclitaxel 50 mg/m2 q week x 6, 50.4 Gy to
the mediastinum and primary tumor and
boost of 10.8 Gy to gross
dz
Surgery
CBDCA AUC =6,
paclitaxel 200 mg/m2 q 21d x 2.
Re-evaluate 2 to 4 weeks post RT; if no PD
Median follow-up is 20 months.
RTOG 0229, Suntharalingam IJROBP 2012
• Grade 3/4 toxicities: heme 35%, GI 14%, pulmonary 23%.
• 43 pts (75%) were evaluable for the primary endpoint; 36 pts underwent resection. 7 pts had residual mediastinal dz. 27/43 (63%) achieved mediastinal clearance.
• There was a 14% (5/37) incidence of grade 3 postoperative pulmonary complications. There was only one postop grade 5 toxicity (3%).
RTOG 0229, Suntharalingam IJROBP 2012
• With a median follow-up of 24 months for all patients, the 2-year overall survival rate was 54%, and the 2-year progression-free survival rate was 33%. The 2 year survival rate was 75% for those who achieved nodal clearance.
• Next steps? RTOG 0839
Thomas M, Macha HN, Ukena D, et al. Cisplatin/etoposide followed by twice daily chemoradiation versus cisplatin/etoposide alone before surgery in Stage III
NSCLC: A randomized Phase III trial of the GermanLung Cancer Cooperative Group. Lancet Oncology 2008
Thomas M, Macha Et al. Lancet Oncology 2008.• Only 54-57% of Stage IIIA patients in either arm
underwent a complete resection (R0)• MST was not different between the arms (15.5 mo.
in chemoradiotherapy and 16.8 mo. in chemotherapy only arm, p=0.97)
• Radiation was delivered in a non standard form (and we know from RTOG 9410 that BID is inferior!)
• Pneumonectomy contributed to mortality (14% versus 6%)
Van Meerbeeck et al JNCI 99(6) p 442-450 EORTC 08941
• 579 pts stage IIIA N2 NSCLC randomized:Platinum based
chemo
Radiation--60Gy
Surgical Resection
Radiation
Van Meerbeeck et al JNCI 99(6) p 442-450 EORTC 08941
• In the XRT arm, g 3/4 acute and late esophageal and pulmonary toxicity was 4% and 7%
• Median and 5 y Overall survival (resection versus XRT) was 16.4 versus 17.5 mo and 15.7% versus 14%
Is long term survival predicted by pathologic response?/Does mediastinal clearance matter?
•Rusch VW, Albain KS, Crowley JJ, et al Surgical Resection of Stage IIIA/IIIB NSCLC after induction chemoradiotherapy. J. Thorac Cardiovasc Surgery 1993;105:96-106
•Sugarbaker DJ, Herdon J, Kohman LJ, Krasna MJ, Green MR, CALGB Thoracic Surgery Group. Results of CALGB 8935. A multiinstitutional phase II trimodality trial for Stage IIIA NSCLC. J Thorac Cardiovasc Surg 1995; 109; 473-83
•Voltoni L, Luca L, Ghiribelli C, Paladini P, Di Bisceglie M, Gotti G. Results of induction chemotherapy followed by surgical resection in patients with stage IIIA NSCLC; the importance of nodal down staging after chemotherapy. Eur J Cardiothoracic Surg 2001;20:1106-12.
•Betticher DC, Schmitts S, Totsch M, et al Mediastinal lymph node clearance after docetaxol-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 NSCLC:a multicenter phase II trial JCO 21:1752-9.
What about superior sulcus tumors?
SWOG 9416
Pancoast tumors (n=83)
Cis/Etoposide + XRT 45 Gy
Surgery 2 cycles
of chemo
Re-evaluate 2 to 4 weeks post RT; if no PD
Kwong KF, et al High-dose radiotherapy in trimodality treatment of Pancoast tumors results in high pathologic complete response rates and excellent long-term survival. J Thorac Cardiovasc Surg. 2005
Jun;129(6):1250-7
• 36 patients with Pancoast tumor• Stage IIB-IV • R0 resection was achieved in 36 (97.3%) patients• High-dose radiotherapy (mean 56.9Gy; range, 30-
70.2 Gy) was successfully tolerated in all but 1 patient
• Pathologic complete response was found in 40.5% (n = 15) of patients
Kwong KF, et al . J Thorac Cardiovasc Surg. 2005 Jun;129(6):1250-7
• Operative mortality rate was 2.7% (n=1/37).
• Significant morbidities occurred in 10 patients (n=10/37, 27% patients) but were variable and without a dominant pattern
• Recurrences occurred in 50% of patients
• Distant recurrence accounted for the majority of recurrences (13 patients / 36.1%)
• Local recurrences in the lung-mediastinum occurred in 5 patients (13.8%)
Kwong KF, et al . J Thorac Cardiovasc Surg. 2005 Jun;129(6):1250-7
Kwong KF, et al . J Thorac Cardiovasc Surg. 2005 Jun;129(6):1250-7
New technology requires careful planning
• Treatment planning cannot make up for drawing the wrong volumes
• The most radioresistant tumor cell is the one that’s not in the field!
What about PET?
Assessing Gross Tumor Volume
Imaging in Lung CancerAssessing Gross Tumor Volume
CT-then-PET Registration
PET-CT
Staging – PET/CT
What Respiratory 4D PET/CT Will Show
…
…
4D PET (tomorrow)3D PET (today)
}
Imaging Questions
Imaging Questions• When is the tumor within my fields?
– Tumor motion, mostly respiratory– 4D CT– Does motion change during Rx?
• Infection• Response to Rx• How often should we re-measure motion?
– Who would most benefit?
• How does the tumor change shape during Rx?– Second-to-second– Day-to-day
Benefits of Cone Beam CT
Imaging Questions for Radiation Oncology
– Normal tissue function/risk?• Interpatient differences
– Radiosensitivity– Underlying disease– Pretreatment vs. post treatment imaging
• Can Dose/function histograms be developed?
Should we incorporate SPECT?
Voxel-by-voxel ventilation
Ventilation
Ventilation
Imaging Questions for Radiation Oncology
– How do you account for these changes with IMRT or protons?
– How do doses add together? – How do we image biology?
• Tumor?
– SUV?– MR Spectroscopy?– Hypoxia, other markers?
Take Home Points• Current standard of care for stage
IIIA/IIIB NSCLC continues to be defined• Trimodality is reasonable option on
study and/or with well informed patients– Role of surgery should be based
• Nodal Status
• Performance Status
• Surgeon experience
Take Home Points
• Success of trimodality depends on:– Good radiotherapy techniques– Good surgical techniques
• Higher doses of radiation pre-operatively may improve outcomes
• Imaging will grow in importance in oncology