1. Management of Locally Advanced NSCLC
Shilpen Patel MD FACRO
Department of Radiation Oncology,
University of Washington, Seattle, WA 1

2. Roadmap Background Evolution of therapy Radiation alone
Sequential chemotherapy and radiation
Concurrent chemotherapy and radiation
Trimodality versus bimodality
Superior Sulcus Tumors
Imaging

3. Survival Improvement in Stage III NSCLC since 1980’s
17.7
13.8
9.8

4. Evolution: Radiation Alone
In the 1970’s stage III NSCLC was an unresectable disease
Standard of care was radiation alone

6. Evolution: Sequential chemotherapy and radiation

7. Cisplatin + vinorelbine
Dillman et al. Improved Survival in Stage III NSCLC: 7yr f/u of CALGB # JNCI Vol 88, No 17: , 1990 & 1996
165 Pts w/ stage III NSCLC randomized to:
Cisplatin + vinorelbine
Radiation--60Gy
Radiation--60Gy

8. Median survival improved with chemotherapy
Dillman et al. Improved Survival in Stage III NSCLC: 7yr f/u of CALGB # JNCI Vol 88, No 17: , 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

9. Evolution: Concurrent Chemoradiation
Improvements in Overall Survival and Median Survivals encouraging with sequential therapy
Better radiation targeting and improved supportive care for patients allowed investigators to ask if concurrent therapy would be better than sequential

10. RTOG 94-10: Curran, et al, J Natl Cancer Inst
RTOG 94-10: Curran, et al, J Natl Cancer Inst Oct 5;103(19): R A N D O M I Z T
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
CON- QD
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
595 patients with unresected stage IIIa and IIIb or medically inoperable stage II disease
CON- BID
cDDP 50 mg/m2 d1, 8, 29, 36
VP mg/m2 d1-5, 8-12, 29-33, 36-40
Hyperfractionated RT (69.6 Gy) d1

11. RTOG 94-10: Curran, et al, J Natl Cancer Inst
RTOG 94-10: Curran, et al, J Natl Cancer Inst Oct 5;103(19):
Courtesy of Walter Curran, MD

12. RTOG 94-10: Curran, et al, J Natl Cancer Inst
RTOG 94-10: Curran, et al, J Natl Cancer Inst Oct 5;103(19):
Courtesy of Walter Curran, MD

13. RTOG 94-10: Curran, et al, J Natl Cancer Inst
RTOG 94-10: Curran, et al, J Natl Cancer Inst Oct 5;103(19):
In Field failure rates
Sequential: 38%
Concurrent: 33%
Hyperfractionated: 25%

14. Local Control
65%
65%
65%

15. Evolution: Trimodality
With improving survivals despite little or no improvement in local control over the last 30 years, the stage was set for trimodality therapy
Improved radiation techniques, improved supportive care and improved surgical techniques made this approach seem feasible

16. Intergroup 0139- Albain, et al., 2009
Median F/U 81 months
Re-evaluate 2 to 4 weeks post RT; if no PD R A N D O M I Z E
Cis/VP16
x 2 cycles
w/concurrent
XRT 45Gy
Stage IIIA (T1-3, pN2, M0)
NSCLC
N = 429 (396 eligible)
Considered Resectable
Cis/VP16
x 2 cycles
Surgery
Cis/VP16
x 2 cycles
w/concurrent
XRT 45Gy
Cis/VP16
x 2 cycles
Continue RT to 61GY
Re-evaluate 7 days prior to RT completion; if no PD

17. Results: Intergroup 0139
Courtesy of Kathy Albain, MD

18. Intergroup 0139/RTOG 9309 Progression-Free Survival by Treatment Arms
100
Trimodality ( n=201)
Median 12.8 months
5-year 22.4% / / / 80 / 60 /
Chemoradiation (n=191)
Median 10.5 months
5-year 11.1% / / / / / / / /
Percent Alive / / 40 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / 20 / / / / / / /
Log rank p = 0.017 / / / / / 6 12 18 24 30 36 42 48
Months

19. 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 Surgery OS=8%

20. 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
Stage 4 patients – isolated brain mets, 13 patients had pancoast tumors
16/26 with N2 proven by med and 10/26 seen on CT
Chemotherapy-platinum based
30/40 used carbo/taxol
5/40 cis/etoposide
4/40 cis/navelobine
1/40 carbo alone

21. 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
Intercoastal muscle flaps were used prophylactically (not in the patient who developed a BP fistula

22. 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

23. 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
Not prospective but retrospective
Single institution
Chemotherapy given at various institutions which made the population heterogeneous
Most patient got substandard chemotherapy

25. RTOG 0229, Suntharalingam IJROBP 2012
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
Stage III (pathologically proven N2 or N3)
NSCLC
N = 60 (57 eligible)
CBDCA
AUC =6,
paclitaxel
200 mg/m2
q 21d x 2.
Surgery
Median follow-up is 20 months.

26. 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%).
Median age: 59 , 61% M, PS =0: 77%, N2: 98% N3: 2%. Histology: 51% adeno, 19% SCC, 28% NSCLC-NOS. 95% received RT per protocol; 91% received induction chemoXRT as per protocol, 49% with dose modifications.

27. 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
Median age: 59 , 61% M, PS =0: 77%, N2: 98% N3: 2%. Histology: 51% adeno, 19% SCC, 28% NSCLC-NOS. 95% received RT per protocol; 91% received induction chemoXRT as per protocol, 49% with dose modifications.

28. Thomas M, Macha HN, Ukena D, et al
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

34. 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%)

37. Van Meerbeeck et al JNCI 99(6) p 442-450 EORTC 08941
579 pts stage IIIA N2 NSCLC randomized:
Platinum based chemo
Surgical Resection
Radiation--60Gy
Post op radiation to 40%
Radiation

38. 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%

39. Is long term survival predicted by pathologic response
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 A multiinstitutional phase II trimodality trial for Stage IIIA NSCLC. J Thorac Cardiovasc Surg 1995; 109;
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:
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:

40. What about superior sulcus tumors?

41. Re-evaluate 2 to 4 weeks post RT; if no PD
SWOG 9416
Re-evaluate 2 to 4 weeks post RT; if no PD
2 cycles
of chemo
Pancoast tumors (n=83)
Cis/Etoposide + XRT 45 Gy
Surgery
Rusch et al. Induction chemoradiation and surgical resection for non–small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg Mar;121(3): eligible patients
(92%) had a complete resection
The 2-year survival was 55% for all eligible patients and 70% for patients who had a complete resection

44. 36 patients with Pancoast tumor Stage IIB-IV
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 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, Gy) was successfully tolerated in all but 1 patient
Pathologic complete response was found in 40.5% (n = 15) of patients

45. 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

46. 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%)

47. Kwong KF, et al . J Thorac Cardiovasc Surg. 2005 Jun;129(6):1250-7

48. 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!

49. What about PET?

50. Assessing Gross Tumor Volume
PET/CT shows that tumor clearly progresses into the chest wall

51. Imaging in Lung Cancer Assessing Gross Tumor Volume
Fused CT/PET shows tumor versus collapsed lung

52. CT-then-PET Registration

53. PET-CT

54. Staging – PET/CT Focal brown fat mimicking supraclavicular node,
CT correlation is critical for this diagnosis – I hope this convinces you of the value of the fused image - may mention the time spent looking for abnormality on a CT ordered because of a PET abnormality

55. What Respiratory 4D PET/CT Will Show… }
3D PET (today)
4D PET (tomorrow)

56. Imaging Questions

57. Imaging Questions How does the tumor change shape during Rx?
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

58. Benefits of Cone Beam CT

59. 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?

60. Should we incorporate SPECT?

61. Voxel-by-voxel ventilation
Thomas Guerrero, M.D., Ph.D.

62. Ventilation

63. Ventilation

64. 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?

65. 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

66. 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