Transcript Trimodality Therapy in stage IIIA and IIIB NSCLC

Management of Locally
Advanced NSCLC
Shilpen 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
17.7
19
Finish
IGR
median survival
17
13.8
15
CALBG
NCCTG
WJLCG
13
11
GLOT
CZECH
9.8
LAMP
9
RTOG 9410
7
MUNICH
ECOG 2597
5
1980's
1990's
2000's
Evolution: Radiation Alone
• In the 1970’s stage III NSCLC was an
unresectable disease
• Standard of care was radiation alone
Dose
In-field
recurrence
40Gy split course 53%
40Gy conventional 58%
50Gy
49%
60Gy
35%
Median
survival
37wks
45wks
41wks
47wks
3 year
survival
6%
6%
10%
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
R
A
N
D
O
M
I
Z
A
T
I
O
N
SEQ
cDDP 100 mg/m2 d1, 29
Vlb 5 mg/m2 Q wk X 5 (d1, 8, 15, 22, 29)
Standard fractionated RT (60 Gy) d 50
CONQD
cDDP 100 mg/m2 d1, 29
Vlb 5 mg/m2 Q wk X 5 (d1, 8, 15, 22, 29)
Standard fractionated RT(60 Gy) d1
CONBID
cDDP 50 mg/m2 d1, 8, 29, 36
VP-16 50 mg/m2 d1-5, 8-12, 29-33, 36-40
Hyperfractionated RT (69.6 Gy) d1
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%
Local Control
100
90
Local Control
80
70
65%
65%
65%
1980's
1990's
2000's
60
50
40
30
20
10
0
Evolution: Trimodality
Intergroup 0139- Albain, et al., 2009
Median F/U 81 months
Stage IIIA
(T1-3, pN2,
M0)
NSCLC
N = 429
(396
eligible)
Considered
Resectable
R
A
N
D
O
M
I
Z
E
Cis/VP16
x 2 cycles
w/concurrent
XRT 45Gy
Cis/VP16
x 2 cycles
w/concurrent
XRT 45Gy
Re-evaluate 2 to 4 weeks
post RT; if no PD
Surgery
Continue
RT to
61GY
Cis/VP16
x 2 cycles
Cis/VP16
x 2 cycles
Re-evaluate 7 days prior to
RT completion; if no PD
Results: Intergroup 0139
Courtesy of Kathy Albain, MD
Percent Alive
Intergroup 0139/RTOG 9309 Progression-Free Survival by
Treatment Arms
100 /
Trimodality ( n=201)
/
Median 12.8 months
/
5-year 22.4%
80
/
/ //
/ // /
/
60
40
Chemoradiation (n=191)
Median 10.5 months
5-year 11.1%
/
/
//
//
20
Log rank p = 0.017
// /
/ ///
/ / //// // / / /
// / //
// /
/ / / /
0
0
6
12
18
24
30
Months
36
42
48
Intergroup 0139/RTOG 9309
Lancet 8/1/09
Independent Favorable Survival Predictors
•Female
•No weight loss
•Trimodality Arm
–pN0
–pN1-3
–No Surgery
OS=41%
OS=24%
OS=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
(pathologic
ally 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
Re-evaluate 2 to 4 weeks
post RT; if no PD
Surgery
CBDCA
AUC =6,
paclitaxel
200 mg/m2
q 21d x 2.
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 German
Lung 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
Re-evaluate 2 to 4 weeks
post RT; if no PD
Pancoast
tumors
(n=83)
Cis/Etoposide
+ XRT 45 Gy
Surgery
2 cycles
of chemo
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, 3070.2 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
Kwong KF, et al . J Thorac Cardiovasc
Surg. 2005 Jun;129(6):1250-7
• 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
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 Cancer
Assessing Gross Tumor Volume
CT-then-PET Registration
PET-CT
Staging – PET/CT
What Respiratory 4D PET/CT Will Show
…
…
}
3D PET (today)
4D PET (tomorrow)
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 preoperatively may improve outcomes
• Imaging will grow in importance in
oncology