Standards for neoadjuvant Treatment

Standards for neoadjuvant Treatment

Rudolf M. Huber

PneumologyUniversity of Munich

Istanbul, 7. 5. 2010

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Neoadjuvant chemotherapy

‘‘Neoadjuvant’’ chemotherapy means treatment given prior to surgery

Rationale:– shrink the tumour to facilitate and simplify surgery– treat occult micrometastases– inhibit tumour growth factor release during

surgery Does not intend to make an inoperable

tumour operable (“downstaging chemo-therapy”)

Istanbul, 7. 5. 2010 Huber

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Expected Outcome After Surgical Resection in Operable NSCLC

Surgical Stage5-Yr Survival

(%)Relapse (%)

Local Distant

IA T1N0M0 67 10 15

IB T2N0M0 57 10 30

IIA T1N1M0 55

IIB T2N1M0 39 12 40

T3N0M0 38

IIIA T3N1M0 25 15 60

T1-3N2M0 23Pisters and Le Chevalier. J Clin Oncol. 2005;23:3270-3278


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André F ea. JCO 18 (2000)

N = 562

N2 Subgroups and survivalResected NSCLC

Huber

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Accuracy of stagingNSCLC – N2 disease

Weder W. Ann Oncol 19 (Supplement 7): vii28–vii30, 2008

TechniqueSensiti-vity %

Specificity %

NPV %

PPV %

CT 57 82 83 56

PET 84 89 93 79

Blind TBNA 76 96 71 100

EUS-FNA 88 91 77 98

Mediastinoscopy 81 100 91 100


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NSCLC: IIIA N2 – subsets

IIIA1 incidental nodal metastases found on final surgical

pathology IIIA2 single nodal metastasis,

recognized intraoperatively

IIIA3 Mediastinal nodal metastases, detected preoperatively by

mediastinoscopy or PET

IIIA4 „Bulky“, multi-station

Adapted from ACCP Guideline. Chest 2003


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NSCLC Stage III

Treatment Modalities

Surgery

Chemotherapy RT

Surgery + Chemo

Surgery + RT

Chemo + RT

Tri-modality

Balance between local and systemic control


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LA CE

CT effect & stage

CT may be detrimental for stage IA, but stage IA patients were generally not given the potentially best combination cisplatin + vinorelbine (13% of stage IA patients versus ~43% for other stages)

META

Stage IA 102 / 347 1.41 [0.96;2.09]

Stage IB 509 / 1371 0.92 [0.78;1.10]

Stage II 880 / 1616 0.83 [0.73;0.95]

Stage III 865 / 1247 0.83 [0.73;0.95]

CategoryNo. Deaths

/ No. EnteredHazard ratio

(Chemotherapy / Control) HR [95% CI]

Test for trend: p = 0.051Chemotherapy better | Control better

0.5 1.0 1.5 2.0 2.5

Stage IA 102 / 347 1.41 [0.96;2.09]

Stage IB 509 / 1371 0.92 [0.78;1.10]

Stage II 880 / 1616 0.83 [0.73;0.95]

Stage III 865 / 1247 0.83 [0.73;0.95]

CategoryNo. Deaths

/ No. EnteredHazard ratio

(Chemotherapy / Control) HR [95% CI]

Test for trend: p = 0.051Chemotherapy better | Control better

0.5 1.0 1.5 2.0 2.5


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NSCLC Stage IIIACT + OP (+ RT) vs. OP (+ RT)

Design Pat. pN2 Survival(median)

Pass et al. 2 x PE - OP - 4 x PE 27 27 29

1992 OP - RT 16 p = 0.1

Roth et al. 3 x PEC - OP - (3 x PEC) 60 54 64

1994 OP 11 p = 0.008

Rosell et al. 3 x MIC - OP - RT 60 44 26

1994 OP - RT 8 p = 0.001


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Neoadjuvant Chemotherapy – French Trial

Randomized trial comparing perioperative chemotherapy (PCT) to primary surgery (PRS):– Preoperative CT: two cycles of mitomycin (6

mg/m2, d 1), ifosfamide (1.5 g/m2, d 1 to 3) and cisplatin (30 mg/m2, d 1 to 3)

– Postoperative CT (responders): two additional cycles

Thoracic radiotherapy for all pT3 or pN2 pts Benefit confined to N0 to N1 disease (RR

0.68; 95% CI, .49 to .96; P = .027)

HuberIstanbul, 7. 5. 2010

Depierre A ea. J Clin Oncol; 20:247-253 2002

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Overall survival by treatment arm: arm A, PRS; arm B, PCT + surgery



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Overall survival by treatment arm and by nodal status




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Operable NSCLC: Neoadjuvant CT– MRC LU22/NVALT2/EORTC08012

Gilligan D ea. Lancet 2007; 369: 1929–37


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Operable NSCLC: Neoadjuvant CT


MRC LU22/NVALT2/ EORTC08012

PFS

OS

CT … 3 cycles of platinum based chemotherapy


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Operable NSCLC Neoadjuvant Chemotherapy


Test for heterogeneity: Chi-squared 3.04, 7 degrees of freedom, p=0.88, I2=0%. Test for overall effect: Z=1.78, p=0.07.


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S9900: A phase III trial of surgery alone or surgery plus preoperative paclitaxel/ carboplatin (PC) in early stage NSCLC

P:225 mg/m2 in 3 hours, C:AUC=6 3 cycles, q 3 weeks PS 0-1, postop. FEV1 ≥1 L

Pisters K ea. ASCO 2005, LBA7012

Arm A: C + S (+RT)Stage IB - IIIA NSCLC

n = 353 (of planned 600)

Arm B: S

R


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Neoadjuvant Chemotherapy S9900


Overall survival by treatment arm (median follow-up, 64 months)

Pisters KMW ea. J Clin Oncol; 28:1843-1849 2010

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NATCH – Stages at Surgery, SurvivalSurgeryn = 200

Adj. CTn = 201

Preop. CTn = 181

pCR - - 19 (10 %)

p-stage I 96 (48 %) 105 (52 %) 89 (49 %)p-stage II 43 (21 %) 45 (22 %) 37 (20 %)p-stage T3 N1 3 (1.5 %) 5 (3 %) 1 (0.5 %)p-stage ≥ IIIA N2 58 (29 %)* 46 (23 %)* 35 (19 %)**clinical stage III T3 N1

2 % 0.5 % 3 %

Median OS months49 50 55

5-year survival %44 46 47

Huber

Felip E ea. ASCO 2009 Abstract # 7500, mod. from Wakelee H, discussionIstanbul, 7. 5. 2010 Huber

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Neoadjuvant Chemotherapy - Operable: surgery vs. no surgery

Arm A: CT/RT (45 Gy) + S + CT

Arm B: CT/RT (61 Gy) +CT

Stage IIIA-N2 NSCLC

PS 0-1

n = 396

R

North American Intergroup 0139 (RTOG 9309) K. Albain et al. Proc Am Soc Clin Oncol 2003;22:2497(abstr) und 2005 abstr. 7014

n CT: Cisplatin 50 mg/m2 d1,8; Etoposid 50 mg/m2 d1-5n TRD: 6,9% (14) arm A vs. 1,6% (3) Arm B


Albain KS ea. Lancet 2009; 374: 379–86

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North American Intergroup 0139 (RTOG 9309)

* albumin was ≥ 85% of the normal value with <10% weight loss within 3 months

Reevaluate (n = 396 evaluable)2 – 4 weeks after completion of RT 7 days before completion of RT

Induction CT/RT

Cisplatin 50 mg/m² d1,8, 29, 36; Etoposide 50 mg/m² d 1 -5, 29 – 33Thoracic RT 45 Gy (1,8 Gy/d), begin d1

Randomize (n = 429)

Stratify

KPS 70 – 80* vs. 90 – 100, T1 vs. T2 vs. T3, Contralateral mediastinal nodal sampling yes vs. no

NSCLC Stage IIIA-pN2

FEV1 postop. pred. ≥ 0.8 l

Mod. from K. Albain ea. Proc Am Soc Clin Oncol 2005 abstr. 7014Huber

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K. Albain et al. Proc Am Soc Clin Oncol 2005 abstr. 7014

The primary endpoint was overall survival


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Overall survival

The primary endpoint was overall survival

Median survival

23.6 mo

22.2 mo ns

5-yr-survival

27.2 % 20.3 % ns

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Overall survival pneumonectomy

subset of post-pneumonectomy patients from the intention-to-treat population in group 1 vs. matched cohort in group 2

Huber

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Radical surgery vs. thoracic radiotherapy in IIIA-N2 NSCLC after response to induction chemotherapy (EORTC 08941)

3 cycles of platinum-based chemotherapy Response randomisation In the radiotherapy arm at least 60 Gy + 40 Gy

to the mediastinum

van Meerbeeck JP ea. ASCO 2005, LBA7015J. Natl. Cancer Inst. 2007 99:442-450; doi:10.1093/jnci/djk093

Arm A: S (+RT)Stage IIIA-N2 NSCLCInduction chemotherapy

n = 572Arm B: RT

R


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Radical surgery vs. thoracic radiotherapy in IIIA-N2 NSCLC after response to induction chemotherapy (EORTC 08941)

572 patients induction chemotherapy, 61,5 % response

Radical resection 51 %, mortality 4 % (pneum-ectomy!)

Median, 2- and 5-year OS: surgery vs. TRT 16.4 vs.17.5 months, 35 vs. 41% and 16 vs. 13%

Median and 2-year PFS are 9.0 vs.11.4 months and 27 vs. 24%, (p= 0.6)

no advantage from surgeryvan Meerbeeck JP ea. ASCO 2005, LBA7015


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Overall survival rates estimated from time of randomization

van Meerbeeck JP ea. J. Natl. Cancer Inst. 2007 99:442-450; doi:10.1093/jnci/djk093

Resection Vs Radiotherapy After Induction Chemotherapy in Stage IIIA-N2 NSCLC


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Neoadjuvant Chemo- vs. RCT

Thomas M ea. JCO 22 (2004), 14S, 704. Lancet Oncol, July 1, 2008; 9(7): 636-48

Phase III in stage III NSCLC

In both arms, a similar percentage could be sent to surgery (even in stage IIIB)

Bimodality induction: • trend toward better

resection rates (R0) • higher complication

rate, especially bronchial stump insufficiency

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Neoadjuvant therapy: Chemo- vs. Chemoradio-Therapy In patients with stage III NSCLC

amenable to surgery, preoperative chemoradiation in addition to chemotherapy increases pathological response and mediastinal downstaging, but does not improve survival.

After induction with chemoradiation, pneumonectomy should be avoided.

Thomas M ea. Lancet Oncol, July 1, 2008; 9(7): 636-48Istanbul, 7. 5. 2010 Huber

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Andre ea., J Clin Oncol 18: 2981 (2000)

n 5 Y. – Surv.[%]

cN2 237 5

cN2 + neoadjuvant CTh 95 18

cN2 + neoadjuvant CTh 69 26with response + R0

Survival with/without neoadjuvant chemotherapy (n = 332)

NSCLC cN2-Status and Resection


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Cisplatin vs. Carboplatin Meta-Analysis: Survival

Ardizzoni A ea. J Natl Cancer Inst 2007;99: 847 – 57

HR = 1.12, 95 % CI 1.01-1,23


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Betticher et al., J Clin Oncol 21: 1752 (2003)

Cisplatin 50 mg / m2 d 1, 2Docetaxel 85 mg / m2 d 13 x OP *

* If R1/2: RTX (60 Gy; 2 Gy/d)

NSCLC Stage IIIA (N2): CT + OP 90 patients ECOG 0/1, median age 60 yrs T 1-3 N2 (mediastinoscopy) N2-2L (20/62)


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RR PD OP R0 TL RTX pCR pN0/1

66 % 10 % 87 % 48 % 3 % 37 % 16 % 50 %

All Pts pN0/1 pN2

Median 28 Mo. 53 Mo. 16 Mo.

3 Yr. Survival 36 % 61 % 11 %

Survival

Betticher et al., J Clin Oncol 21: 1752 (2003)

NSCLC Stage IIIA (N2): CT + OP


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ACCP 2007

Stage IIIA3: Induction therapy followed by surgery is not recommended except as part of a clinical trial. Grade 1A

Stage IIIB NSCLC as a result of N3 disease: treatment with neoadjuvant (induction) chemotherapy or chemoradiotherapy followed by surgery is not recommended. Grade 1C

Neoadjuvant Treatment - ACCP


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Neoadjuvant Treatment - Germany

Stage I: outside of clinical trials not recommended (grade B).

Stage II: outside of clinical trials not recommended (grade B).

Stage III A: interdisciplinary individual decision in centres possible (grade B)


German Society of Pneumology. Pneumologie 2010; 64, Supp.2: e1– e164

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Standards for neoadjuvant treatment

Thorough preoperative evaluation Interdisciplinary discussion 3 cycles of cisplatin plus „modern“ doublet No preoperative radiotherapy Efficacy is relevant Proper reevaluation, especially of the

mediastinum Radiotherapy postoperatively if necessary


36HuberMünchen,17.9. 2008

Adjuvante Therapie des NSCLC

Thank you for your attention


Standards for neoadjuvant Treatment

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