1411 APLCC AHNYC Tri Bimodality N2

Tri- and Bi-modality Therapy

for N2(+) NSCLC

Yong Chan Ahn, MD/PhD Dept. of Radiation Oncology

Samsung Medical Center, Sungkyunkwan University School of Medicine

Modalities in Treating Cancer

• Loco-regional:

– Surgery

– Radiation therapy

• Systemic:

– Chemotherapy

– Immunotherapy

Radiation and Surgery

Radiation usually fails in tumor center, and

rarely doses at periphery

Surgery usually fails at periphery because of

microscopic tumor cells left behind

Less radical surgery + RT

Organ and function preservation

Improved quality of life

Radiation and Chemotherapy

Synergy/sensitizer/potentiator: drugs directly

modifying radiation survival curve

Hypoxic cell sensitizer: drugs specifically

affecting tumor response

Decreased toxicity: drugs with independent

action or additivity

Theoretic Rationales of Combined Modality

Spatial cooperation

Toxicity independence

Reduction of toxicity

Enhanced tumor response

Prevention of emergence of resistant clones

Treatment Selection Factors

Treatment-related factors

Tumor-related factors

Patient-related factors

Physician-related factors

知彼知己, 百戰百勝

Knowing oneself and one's opponent,

invincibility!

Management of N2(+) NSCLC

N2 disease

• N2 disease is a very heterogenous, and at the

same time, important prognostic factor in

NSCLC.

– Remarkable improvements in diagnosis of N2 disease

(CT, FDG PET-CT, mediastinoscopy, video-assisted

thoracoscopy, and EBUS)

– A few different ways of classifying N2 disease

(clinical vs surgical, minimal vs bulky etc…).

• Still there is no single right answer in treating N2

disease.

Backgrounds

What do they say on role of surgery?

Van Meerbeeck et al (EORTC), JNCI, 2007


Response rate to CDDP-based

Ind CTx = 61%



Resection vs RT after Ind CTx (EORTC)

• In pathologic N2(+) NSCLC and response to Ind

CTx, surgical resection did not improve OS or

PFS compared with RT.

• RT should be considered preferred locoregional

Tx in view of low morbidity and mortality.

• Lobectomy, pN down-staging, R0 resection were

associated with better outcomes!


Albain et al (NCI), Lancet, 2009


45 Gy 61 Gy


45 Gy 61 Gy


RT compliance to protocol:

193 (96%) in Group 1 vs 154 (79%) in Group 2 (p<0.0001)

PFS

CT/RT/S

(N=202)

CT/RT

(N=194)

Median PFS 12.8 mo

(5.3~42.2)

10.5 mo

(4.8~20.6)

HR=0.77

(0.62~0.96)

Dead of progression 159 (79%) 172 (89%) p=0.008

Dead PF 36 (18%) 19 (10%) p=0.02

PF at 5 years 32 (22%) 13 (11%) P=0.017

1st failure site CT/RT/S CT/RT

Local only 21 (10%) 43 (22%)

Primary only 5 (2%) 28 (14%)

N1-3 only 14 (7%) 6 (3%)

Both 2 (1%) 9 (5%)

Brain only 12 (11%) 29 (15%)

Other distant sites 75 (37%) 81 (42%) Albain et al (NCI), Lancet, 2009

OS

CT/RT/S

(N=202)

CT/RT

(N=194)

Median OS 23.6 mo

(9.0~)

22.2 mo

(9.7~52.7)

HR=0.87

(0.70~1.10)

Dead 145 (72%) 155 (80%)

Alive at 5 years 37 (27%) 24 (20%) OR=0.63

(0.36~1.10)


OS matched lobectomy candidates (N=90) OS matched pneumonectomy candidates (N=51)

CT/RT/S CT/RT

Median survival 33.6 mo 21.7 mo p=0.002

Alive at 5 years 21 (36%) 10 (18%)

CT/RT/S CT/RT

Median survival 18.9 mo 29.4 mo

Alive at 3 years 17 (36%) 22 (45%)

Alive at 5 years 7 (22%) 10 (24%)


RT + CTx +/- Surgery (NCT-2550)

• CRT with or without resection (preferably

lobectomy) are options for stage IIIA(N2)

NSCLC.

– Similar OS, improved PFS in trimodality arm.

– Better OS by trimodality in lobectomy candidates, but

not in pneumonectomy candidates.


Comparison ERTOC NCI

Study

- period

- No. of pts.

1994-2002

582

1994-2001

429

Scheme ind. CT RT

ind. CT S

def. CCRT

ind. CCRT S

CTx CDDP (80 mg/m2)

Gemzar or Taxane

CDDP (50 mg/m2)

Etoposide (50 mg/m2)

TRT 60-62.5 Gy/30-32 Fx’s

none

61 Gy/33 Fx’s

45 Gy/25 Fx’s

Surgery

- % pneumonectomy

- % R0 resection

- Tx-related death

47%

50%

2%

31%

71%

8%

Comparison

ERTOC NCI

C+RT vs. C+S CRT vs. CRT+S

OS

- median (mo)

- 5-year

17.5 vs 16.4

14.0% vs 15.7%

22.2 vs 23.6

20.0% vs 27.0%

PFS

- median (mo)

- 2-/5-year

11.3 vs 9.0

(2-year) 24.0% vs 27.0%

10.5 < 12.8

(5-year) 11.0% < 22.0%

Site of 1st relapse

- Locoregional

- Distant

55% < 32%

39% vs 61%

22% < 10%

57% vs 48%

Summary RT is safer than surgery Better OS by trimodality

in lobectomy candidates

Based on the same data, different interpretations are possible!

What have we experienced at SMC?

Therapeutic Decision at SMC

• Work-up’s:

– Standard: Chest CT, PET-CT, PFT, Bronchoscopy…

– Optional: Brain MR (especially if AD)

– Mediastinoscopy and/or EBUS for all potential surgical candidates

• Staging:

– Localized vs loco-regionally advanced vs metastatic

– Operable vs inoperable

– Resectable vs potentially resectable vs unresectable

Tx Scheme at SMC (since mid-90’s)

T

T1 T2 T3 T4

N

N0 IA-IIB

1. Op ± RT/CTx/CRT

2. Def. RT IIIB

1. Def. CCRT

2. RT alone

3. Seq CTx + RT

N1 IIIA (T3N1)

N2

IIIA

1. Preop. CCRT + Op ± RT

2. Def. CCRT

3. RT alone

N3

Trimodality for N2(+) NSCLC at SMC

• TRT

– 45 Gy/25 Fx’s (’97~Sep ’09)

– 44 Gy/22 Fx’s (Oct ’09~)

• CTx

– EP #2 q 4 weeks (’97~Apr ’01)

– Weekly DP #5 (Mar ’01~)

• Surgery in 3-4 weeks

• Optional postop TRT (18 or 20 Gy/2 weeks)

• Optional CTx (usually sequential)

Ann Surg Oncol, 2014

Patients (May ’97~Aug ’11)

Patients’ Characteristics (N=355)

Preop Tx

TRT 45 Gy in 25 Fx’s (1997’ ~ Oct 2009’)

44 Gy in 22 Fx’s (Sep 2009’ ~ )

258 (72.7%)

97 (27.3%)

CTx EP q 3 weeks (1997’ ~ Jul 2001’)

Weekly DP (Jul 2001’ ~ )

38 (10.7%)

317 (89.3%)

Surgery

Sublobar resection

(Bi-)Lobectomy

Pneumonectomy

2 ( 0.6%)

301 (84.8%)

52 (14.6%)

Postop Tx

TRT No or incomplete

Yes (18-20 Gy in 10 Fx’s)

144 (40.6%)

211 (59.4%)

CTx No

Yes

271 (76.3%)

84 (23.7%)

Treatment Characteristics (N=355)

Pathologic Findings (N=355)

Median 3-year 5-year

OS 45.5 (34.6-56.3) mo 56.7% 43.3%

PFS 16.3 (13.2-16.4) mo 32.0% 26.0%

Survival Outcomes (N=355) Median F/U = 35.3 (5.4-67.7) months

Prognostic Factors

Summary • Current study strongly supports that trimodality Tx can

provide remarkable survival benefit in IIIA-N2 NSCLC

patients.

• Initial bulk and extent of N2 node involvement do not

influence prognosis.

• Sterilization of mediastinal LN remains the most important

factor for prognosis.

• Well-designed prospective clinical trials may be required.

SWOG 8805 RTOG 0229 INT 0139 SMC

Median 13 months 26.6 months 23.6 months 45.5 months

OS 27% (3-Yr) 54% (2-Yr) 27% (5-Yr) 43.3% (5-Yr)

Conclusions

• There definitely is positive role of surgical

resection following CCRT in cN2 disease.

• Benefit of surgery is summarized as improved

loco-regional control at no excess morbidity.

• Without loco-regional control,

“real cure” cannot be

expected, and surgery should

remain essential under multi-

disciplinary spirit.

Bimodality Tx for N2(+) IIIA NSCLC (May ’97~Dec ’12)

Cancer Res Treat (in press)

• Thoracic RT:

– Median 66 Gy in 33 fractions in all

– Median 72 Gy in 13 patients in Group I who had

median 36 days’ Tx break d/t delayed decision on

resectability

• Chemotherapy:

– Weekly Taxane + Platinum in 54 (83.1%)

– Cisplatin + etoposide q 3 weeks in 11 (16.9%)

• Median F/U = 18.8 (1.6~173.1) months

Treatment

• Phase III trial by NCI (Lancet 2009):

– CCRT+Surgery vs. Definitive CCRT

– Survival benefit was observed following lobectomy

• Lobectomy is better than pneumonectomy following CCRT

– National Cancer Database (J Thoracic Oncol 2013)

– SMC trimodality experience (Ann Surg Oncol 2014)

• Bimodality therapy should be primary treatment in

unresectable lesion or probable pneumonectomy

candidates.

Discussion/Conclusion

’97 may~’11 Nov ’97 may~’12 Dec

Pt number 355 65

OS @ 5Y (Med) 43.3% (45.4 M) 33.3% (28.6 M)

Heavily biased by “selection”

• Thoracic RT concurrent with weekly TP chemo is

better than 3-weekly EP.

• Surgery, if in retrospective nature, has played a key

role in terms of local control and survival at SMC.

• Surgery (<pneumonectomy) is an essential

component for “survival with cure”.

• ypN down-staging following CCRT has proved a

key prognostic factor.

Summary (or Bias @ SMC)?

Evidence-based Pride vs Observational Prejudice

• What was known to be “true” sometimes turns

out to be “false”.

• “Religious belief” might be simple bias if not

based on “scientific evidence”.

• Randomized controlled trial is necessary to

discriminate “prejudice” from “pride”!

Evidence-based Medicine?

BMJ 2003

Natural history of gravitational challenge

• Use of parachutes is associated with morbidity

and mortality.

• Survival has been reported after gravitation

challenges of more than 10,000 meters.

• Are studies required to calculate balance of

risks and benefits of parachute use?

Parachute and healthy cohort effect

• Possibility of selection and reporting bias:

– Jumping from aircraft without parachute

likely to have psychiatric morbidity

– Using parachutes less likely to have

psychiatric morbidity

Apparent protective effect may be “healthy

cohort” effect?.

• It is unclear whether results of industry

sponsored trials are reliable.

• In addition to quantitative parameters (disease

control, survival, Tx duration, cost…), qualitative

impacts following Tx need to be evaluated.

• Development of practical and optimal mediastinal

re-staging tool following CCRT would be desired

to select out ideal surgical candidates.

• Intimate multidisciplinary collaboration is

important.

Future Directions

They are all different! Which weapon do

you need babies?

Give me a knife!

I will irradiate!

I will wait/see!

I need toxin!

Factors affecting treatment selection

Modality-

related

Disease-

related

Patient-

related

Physician-

related

Multidisciplinary

spirit!

Lung Cancer Center @ SMC

Thank you for attention!

Health & Medicine

1411 APLCC AHNYC Tri Bimodality N2