Highlites in NSCLC: Combined modality treatment in stage III disease Lucio Trodella Cattedra di...

Highlites in NSCLC:Combined modality

treatment in stage III disease

Lucio TrodellaCattedra di Radioterapia Oncologica

Università Campus Bio-MedicoRoma

Chemoradiotherapy: Chemoradiotherapy: QuestionsQuestions

Sequential Chemotherapy Sequential Chemotherapy Radiotherapy Radiotherapy X X X

Concurrent Chemoradiotherapy Concurrent Chemoradiotherapy Consolidation Chemotherapy Consolidation Chemotherapy

(x) (x) (x) X X X

Concurrent Chemoradiotherapy Concurrent Chemoradiotherapy Surgery Surgery

Concurrent Chemoradiotherapy Concurrent Chemoradiotherapy (x) (x) (x)

Induction Chemotherapy Induction Chemotherapy Concurrent Chemoradiotherapy Concurrent Chemoradiotherapy

X X X (x) (x) (x)

20042004

Overall survival

0,86 [0,78-0,95]0,86 [0,78-0,95]

711 pts711 pts

Rowell 2004 Cochrane Review

60-66Gy once daily60-66Gy once daily

RTOG 9410

NPC 9501

CT+RT CT+RT vs vs

CTCTRTRT

Favours SequentialFavours Concurrent

Treatment-related toxicity

Rowell 2004 Cochrane Review

RTOG 9410

NPC 9501

Favours SequentialFavours Concurrent

Concurrent CT-RT vs CTConcurrent CT-RT vs CTRTRTRowell, The Cochrane Meta-analysis, 2004Rowell, The Cochrane Meta-analysis, 2004

A 14% reduction in risk of death at 2 years with concurrent treatment (RR 0.86; 95% CI 0.78 to 0.95; p = 0.003), but at the expense of toxicity (acute esophageal toxicity)

20042004

20072007

Total dose 144 mg/m2

189 death events were expected 189 death events were expected for each armfor each arm. The study . The study was was interrupted at 158 accrued patients, due to difficulties in accrualinterrupted at 158 accrued patients, due to difficulties in accrual..(62 deaths –arm Sequential & 58 deaths arm Concurrent)(62 deaths –arm Sequential & 58 deaths arm Concurrent)

2007

Metanalisi di Rowell 2004 -Conclusioni Conc.

CT-RT (C) vs Sequential CTRT (S)

S 2y

Trial N. Conc Conc SeqSeq RT

Curran 2003* 402 37% 31% 60/30fr

Zatloukal 2004*102 34% 14% 60/30fr

Fournel 2005* 205 35% 23% 66/33fr

*Citati nella metanalisi di Rowell 2004 Cochrane

2004

2007

EORTC EORTC

08972-22973 08972-22973 158 158 39%39% 34% 34% 66/66/24fr24fr

Combined Modality in Stage III NSCLC

Meta-analyses evaluating optimal chemoRT strategy

Strategy#

trial

#

pts

Absolute Benefit @

3 yrs (%)

HR for survival (95 %

CI)

p

Seq ChemoRT

vs RT alone 22 3839 2.60.88

(0.92-

0.94)

0.0001

Conc

ChemoRT vs

RT alone

16 2910 3.20.88

(0.81-

0.95)

0.0008

Conc

ChemoRT vs

Seq ChemoRT

6 1199 6.6

0.83

(0.73-

0.94)

0.0026

Rolland E et al. J Thor Oncol 2 (8): S309, 2007, abstract

Auperin A et al. J Thor Oncol 2 (8): S310, 2007, abstract

Take Home Message

“Concurrent treatment is better and feasible”

Studio randomizzato di fase III con Docetaxel, e cisplatino versus

mitomicina, vindesina e cisplatino associati a Radioterapia nel NSCLC:

OLCSG 0007

Kiura K (200 pz)




(x) (x) (x) X X X




X X X (x) (x) (x

http://images.google.it/imgres?imgurl=http://www.associazioneitalianaobesita.it/images/pic_farmaci02.jpg&imgrefurl=http://www.associazioneitalianaobesita.it/farmaci.htm&h=219&w=197&sz=12&hl=it&start=3&tbnid=VjAc8s6BGJSf1M:&tbnh=107&tbnw=96&prev=/images%3Fq%3Dfarmaci%26svnum%3D10%26hl%3Dit%26lr%3D


20072007

Vokes ASCO 04

20072007

CALGB 39801- Vokes ASCO ‘04

Results RTCT CT RTCTMedian survival 11.4 mo 14 mo

Conclusion

“Our results do not support the use of induction chemotherapy followed by CT/RT as evidence based standard of care for patients with unresectable stage III NSCLC”

p=NSp=NS

CALGB 39801- Vokes ASCO ‘04

Induction chemotherapy followed by concurrent radiochemotherapy

(CCRT) versus CCRT alone for locally advanced unresectable

stage III NSCLC:

Randomized phase III trial

Min Kyoung Kim, Woo-Sung Kim

Daegu, Korea

Seul 2007

Study DesignLocally advanced unresectable stage

III NSCLC

Randomization

Arm A

Standard CCRT

Arm B

IC CCRT

Paclitaxel 50 mg/mq IV/1hr/week

Cispaltin 20 mg/mq IV/1hr/week

For a total of 6 cycles

With RT total 66 Gy/30 fraction

Gemcitabine 1000 mg/mq IV/1 hr d1,d8

Cisplatin 70 mg/mq IV/1hr d1 q21 for a total of 2 cyclesPaclitaxel 50 mg/mq IV/1hr/week

and Cispaltin 20 mg/mq IV/1hr/week for a total of 6 cycles

with RT total 66 Gy/30 fraction

Survival

ArmMedian

Survival

time in

months

P-

value

HR

OS

A (CCRT)18.2

0.18 1.36

B (IC CCRT)

12.6

PFS

A (CCRT)11.6

0.04 1.53

B (IC CCRT)

7.5

Take Home Message

Induction chemotherapy does not improves OS and

PFS

In Bulky desease?

Study CT n° of pts ORRCALGB 39801 CBCDA+Paclitaxel 331 65%

68%CALGB 9431 CDDP+Paclitaxel 58 67%CALGB 9534 CBCDA+Paclitaxel 40 58%Jeremic CBCDA+Paclitaxel 64 83%

TAX 206 Docetaxel 43 58%

60%Moriyama CDDP+ Docetaxel 21 60%Mudad CDDP+ Docetaxel 22 60%Segawa CDDP+ Docetaxel 33 60%Nyman CDDP+ Docetaxel 24 64%

Taxanes and concurrent Radiotherapy

RTCT in locally advanced NSCLC

Study CT n° of pts ORR

French trial CDDP + Vinorelbine 93 49%61%

CALGB 9431 CDDP+Vinorelbine 55 73%

Van Putten Gemcitabine 24 63%68%

Trodella Gemcitabine 77 74%

Alabama Univ. Paclitaxel + Gem 57 75%

80%CALGB 9431 CDDP+Gemcitabine 62 74%

Trodella CDDP+Gemcitabine 33 93%

Gemcitabine or Vinorelbine and concurrent RT

RTCT in locally advanced NSCLC

Chemioterapia di induzione con docetaxel e cisplatino seguita da radiochemioterapia con docetaxel settimanale in NSCLC stadio III: Galician Lung Cancer group

G Huidobro, M Amenedo

ASCO 2008, Abstract 7561

71 pazienti inoperabili (66 valutabili)

70% IIIB

Docetaxel 75 mg/mq e Cisplatino 40 mg/mq giorni 1,2 q 21 seguito da RT 60-66 Gy con fx 1.8 Gy/die con docetaxel 30 mg/mq ogni 2 settimane

Risposta RECIST alla Chemio 1 CR e 39 PR ( RR 61%), 28% SD, 8,9 % PD

Induzione con gemcitabina, docetaxel e cisplatino più chemioterapia

concomitante a radioterapia toracica nel NSCLC stadio III

S. De Santis, F. De Marinis

RR 60%

CHIR 44%

pN0 58%

Boost RT-CT 33%

Take Home Message

…in selected Bulky Disease patients INDUCTION CHEMOTHERAPY can be usefull reducing Radiotherapy Target Volume”

“Induction chemotherapy does not improves OS

and PFS

but…




(x) (x) (x) X X X




X X X (x) (x) (x



SWOG 9504, phase II trial

Consolidation docetaxel after

concurrent chemoradiotherapy

in stage IIIB non-small cell

lung cancer: phase II trial

Southwest Oncology Group

Study 9504Gandara, J Clin Oncol 21:2004-

10, 2003

SWOG 9504 Phase II Trialof Consolidation Docetaxel

Gandara et al. Clin Lung Cancer. 2006;8:116-21.

Stage IIIB

Cisplatin/VP16XRT

Docetaxel75 mg/m2 cycle 1 then100 mg/m2 cycles 2-3

83 PatientsMST: 26 months

29

54

29

37

2-y 3-y 4-y 5-y

Percentage of patients

Median follow-up: 71 mo

Conclusion

The core regimen of PE\TRT followed

by docetaxel exhibits favorable survival

and can be considered a standard

treatment option for patients with

unresectable Stage III NSCLC

Chemo-radiotherapy of NSCLCChemo-radiotherapy of NSCLC

Kelly K, ASCO ‘05

HOG LUN 01-24 Phase III Study DesignChemoRT

Cisplatin 50 mg/m2 IV d 1,8,29,36Etoposide 50 mg/m2 IV d 1-5 & 29-33

Concurrent RT 59.4 Gy (1.8 Gy/fr)

Stratificationat randomization

• PS 0-1 vs 2

• IIIA vs IIIB

• CR vs non-CR

Inclusion at baseline

• Unresectable stage IIIA or IIIBNSCLC

• ECOG PS 0-1 at study entry(+PS2 at random)

• FEV-1 > 1 liter at study entry

203 patients

147 patients73 patients 74 patients

Taxotere75 mg/m2 q 3 wk 3

Observation

Primary endpoint: OSSecondary endpoints: PFS, toxicity Hanna et al. WCLC 2007

HOG LUN 01-24: OS (ITT)Randomized Patients (n=147)

Months Since Registration

0 10 20 30 40 50 60

Perc

ent

of

pati

ents

surv

ivin

g

0%

25%

50%

75%

100%

P-value: 0.940

Median 3 yearsurvival rate

Observation 18.0-34.2 27.6%

Taxotere 17-34.8 27.2%

Hanna et al. WCLC 2007

Grade 3/4 Non-Hematological Toxicities

Toxicity PE/XRT Taxotere OBS *p-value

Esophagitis 17.2% ------------- ------- -----------

Nausea 8.9% 2.7% 0.0% 0.245

Vomiting 6.9% 2.7% 0.0% 0.245

Dehydration 9.4% 2.7% 0.0% 0.245

Fatigue 9.9% 3.4% 0.0% 0.120

Dyspnea 5.4% 5.5% 1.4% 0.209

Infections 8.9% 11.0% 0.0% 0.003

Pneumonitis -------------- 8.2% 1.4% <0.001

Related death 1.5% 5.5% 0.0% 0.058

Hanna et al. WCLC 2007

Take Home Message

Consolidation chemotherapy does not improves OS




(x) (x) (x) X X X




X X X (x) (x) (x

IIIA

IIIB

NEOADIUVANT RT RADICAL RT

TStation 7

Station 4R

Marginally resectable disease

Martini N,. Preoperativechemotherapy for stage IIIa (N2) lung cancer: the Sloan–Kettering experience with 136 patients. Ann Thorac Surg1993;55:1365–74.

SurgeryThe 5-year SVV tends to be less

than 5%

Has the surgery any

role?

988 pts

La Chemioterapia neoadiuvante

493 CT+ S

495 S

Dautzenberg 1990, Roth 1998, Rosell 1999, Depierre 2002, JCOG 9209 Nagai 2003, Sorensen ASCO 2006, SWOG 9900 Pisters ASCO 2007


Take Home Message

Induction chemotherapy is better than surgery alone

Stages: IIIA: Evidences

Surgery Surgery vsvs RTRT

EORTC 0894108941

CtCtindind OROR RandomRandom 20072007

months12 24 36 48 60 72 84 96 1080

20

40

60

80

100

SurgeryRadiotherapy

Logrank p > 0.05

Hazard ratio = 1,06 (0.84, 1.35)

“In NSCLC patients with N2 disease identifiedPreoperatively, platinum-based combination chemoradiotherapy is recommended as primary treatment”

“In NSCLC patients with cN2 disease neoadiuvant chemotherapy is standard treatment”

Ulteriore Opzione Terapeutica:

La Radiochemioterapia

Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II study(SAKK study) D C Betticher

75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m-2 (day 1) plus cisplatin 40 or 50 mg m-2 Overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological OS and EFS times were 35 and 15 months, At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free.

At 5-year follow-up, 60% and 65% of patients had local relapse and distant metastases, respectively. Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and pathologic response, mediastinal downstaging).

British Journal of Cancer (2006) 94, 1099-1106

Marginally resectable NSCLC“Chemo Surgery”Path CR rate are rare to find (<10%) except in Swiss Trial, where local failure is 60 %Chemo Pneumonectomy mortality is 20-25% i.e. it’s not RT causing the problem

Standard induction therapy is chemoradiotherapy, whose complete response is 20-30%”

Putnam JB, Treatment of IIIA NSCLC, Overview. Seoul September 6 2007

Albain ’05 INT0139

Uy ’07- Toronto University

Park, Lung Cancer’06 Choi ’97

Author pCR pN0

ESSEN ’98 25.5% 27.8%

Machtay ‘04 16% 28.3%

Trodella ’04 17.4% 28.3%

Park ’06 4.8% 38%

Uy ‘07 17.7% /

Trodella ’08 28% 50%

Mean 14.5% 32.1%

Author pCR pN0

Van Zandwijk’00

2.1% 19.1%

Betticher ’03 15.5% 25.6%

Migliorino ’02 2.9% 10%

De Marinis ’03 14.3% 34.7%

Cappuzzo ’03 7.2% NR

Leon ’03 2.2% NR

Burkes ’05 4.6% 18.5%

Ramnath ’05 1.5% 3%

Mean 6.2% 18.4%

CT CT NeoadiuvanteNeoadiuvante

RT-CT NeoadiuvanteRT-CT Neoadiuvante

Downstaging

RTOG 0412/SWOG 0332

Highlites in NSCLC: Combined modality treatment in stage III disease Lucio Trodella Cattedra di...

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