Sequential FDG-PET and Induction Chemotherapy in Locally Advanced Adenocarcinoma of the

Esophagogastric Junction (AEG): Implementation of a Response-guided Treatment Algorithm at the

National Center for Tumor Diseases (NCT)

1 National Center for Tumor Diseases (NCT)2 Department of Surgery

3 Department of Nuclear Medicine4 Department of Pathology, University of Heidelberg, Germany

Poster Session ASCO GI, San Franciso, CA, 15 January 2009

F.Lordick1, K. Ott2, I. Buchmann3, C. Kahlert2, C. von Gall3, H. Bläker4,P. Schirmacher4, Weitz J2, Haberkorn U3, Jäger D1

Background

• MUNICON-1 showed a superior R0 resection rate and superior survival in patients with early response to preoperative chemotherapy.

• Continuation of neoadjuvant chemotherapy in metabolic non- responders may even deteriorate the outcome compared to early resection of resectable AEG.

• But these results have not yet been reproduced at other centers.

• Therefore, we implented sequential FDG-PET assessments and an early response-guided treatment algorithm at the National Center for Tumor Diseases (Heidelberg).

Treatment Plan

AEGtype I-II

AEGtype I-II

CTx

ResectionResection

ResectionResection

Non-Responder

Responder

CTx: 3 monthsCTx: 3 monthsPET d0PET d0

PET d14PET d14

Response definition: Decrease of the SUVmean PETd14 / PETbaseline > 35% Weber et al. J Clin Oncol 2001;19:3058-65 Ott et al. J Clin Oncol 2006;24:4692-8

Response definition: Decrease of the SUVmean PETd14 / PETbaseline > 35% Weber et al. J Clin Oncol 2001;19:3058-65 Ott et al. J Clin Oncol 2006;24:4692-8

SUV Definition

Region of interest (ROI)1 cm around maximal SUV(corresponding to 10 pixel)

Standard uptake value (SUV)

SUVBW =Qtumor [MBq/l] x W [kg]

Qinjected [MBq/l]

Study Population

• Histologically proven adenocarcinoma of the esophagus or cardia (AEG type I or II according to Siewert‘s classification)

• Staged uT3/4 Nx M0 (EUS, CT and PET)

• Adequate 18-FDG-uptake (tumor) in baseline-PET (> 1.35 x liver-SUV + 2 x SA of the liver-SUV)

• Medically fit for chemotherapy and esophagectomy

• > 18 years

• Written informed consent

Capecitabine 1250 mg/mCapecitabine 1250 mg/m22

/d p.o./d p.o.Capecitabine 1250 mg/mCapecitabine 1250 mg/m22

/d p.o./d p.o.

Chemotherapy

EpirubicinEpirubicin

50 mg/m50 mg/m22

OxaliplatinOxaliplatin

130130 mg/m mg/m22

OxaliplatinOxaliplatin

130130 mg/m mg/m22

3 weeks

EOX: Epirubicin d1, Oxaliplatin d1, Capecitabine d1-14, 3 cycles

Surgery

AEG Siewert type IAbdomino-thoracic esophagectomy (Ivor-Lewis operation)

AEG Siewert type IITotal gastrectomy with transhiatal distal esophagectomy

Patients‘ Characteristics

Evaluable patients (enrolled 8/2007-8/2008) n = 24

Age (years) median 62 (39-81)

Gender female 1 (4 %)male 23 (96 %)

Tumor localization AEG type 1 14 (58 %)AEG type 2 10 (42 %)

Stage uT3 24 (100 %)cN0 1 (4 %)cN+ 23 (96 %)cM0 22 (92 %)cM1b (lymph nodes) 2 (8 %)

Resection

n = 24

Resection 22 (92%)Not resected 2 (8%)(reasons: M1b disease and consent withdrawal)

Type of resection

Subtotal abdomino-thoracic esophagectomy 15 (68%)Extended transhiatal gastrectomy 7 (32%)

Residual tumor

R0 16 (72%)R1 6 (28%)

Postoperative course

Relevant complications 7 (32%)Mortality (hospital) 0 (0%)

Evaluable patients 23

Response assessed by PET Responder 14 (60%)Non-Responder 9 (40%)

One patient was not evaluable due to insufficient baseline tumor 18-FDG uptake

Metabolic Response

Postoperative Course

PET-Responder

(n = 12)

PET-Non-Responder

(n = 9)

Complications

42%(n=5)

Anast. insufficiency (x 2)Biliary leakage

Necrosis of the gastric pull-up

Pneumonia

25%(n=2)

Pneumonia (x 2)

Mortality 0%(n=0)

0%(n=0)

Histological Remissions

PET-Responder

(n = 14)

PET-Non-Responder

(n = 9)

Complete remission (1a)0% residual tumor

7%(n=1)

0%(n=0)

Subtotal remission (1b)< 10% residual tumor

7%(n=1)

0%(n=0)

Moderate remission (2)10-50% residual tumor

15%(n=2)

0%(n=0)

No remission (3)> 50% residual tumor

68%(n=8)

0%(n=0)

Not evaluable 15%(n=2)

-

Major remission (1a + 1b)0 - 10% residual tumor

15%(n=2)

0%(n=0)

Remissions scored according toBecker et al. Cancer 2003; 98: 1521-30

ypT-Category

PET-Responder

(n = 14)

PET-Non-Responder

(n = 9)

ypT0 7%(n=1)

15%(n=2)

7%(n=1)

0%(n=0)

0%(n=1)

7%(n=1)

ypT1

ypT2

ypT2b/3 58%(n=8)

93%(n=9)

ypT4 0%(n=0)

0%(n=0)

Not evaluable (n=2) -

29% 7%

ypN-category

PET-Responder

(n = 14)

PET-Non-responder

(n = 9)

ypN0 21%(n=3)

22%(n=2)

ypN+ 64%(n=9)

78%(n=7)

Not evaluable (n=2) -

Resectability

PET-Responder

(n = 14)

PET-Non-Responder

(n = 9)

R0 71%(n=10)

55%(n=5)

R1 15%(n=2)

44%(n=4)

R2 0%(n=0)

0%(n=0)

No resection 15%(n=2)

0%(n=0)

Conclusions

These results confirm the feasibility of an early metabolic response (PET)-guided treatment algorithm for locally advanced AEG.

R0 resectability in pts with early metabolic non-response remains dismal.

Therefore, we started to investigate alternative CTx combined with radiation as salvage treatment in early metabolic non-responders

Future Perspective

PETd 14

ResectResect

Non-Responder

Responder

Rando-mize

Resect immediatelyResect immediately

ResectResectRadio-CTx

CTxCTx CTxCTx CTxCTx

CTxCTx

IMAGE study designR-CTx vs S in PET non-responders

References

1. Weber WA, Ott K, Becker K, et al. Prediction of response topreoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging.J Clin Oncol 2001; 19:3058–3065.

2. Ott K, Weber WA, Lordick F, et al. Metabolic imaging predicts response, survival, and recurrence in adenocarcinomas of the esophagogastric junction. J Clin Oncol 2006; 24:4692–4698.

3. Wieder HA, Beer AJ, Lordick F, et al. Comparison of changes in tumor metabolic activity and tumor size during chemotherapy of adenocarcinomas of the esophagogastric junction. J Nucl Med 2005; 46:2029–2034.

4. Lordick F, Ott K, Krause BJ, et al. Use of PET to assess early metabolic response and guide treatment of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction: a feasibility study. Lancet Oncology 2007; 8: 797-805

5. Siewert JR, Lordick F, Ott K, et al. Induction chemotherapy in Barrett Cancer. Influence on Surgical Risk and Outcome. Ann Surg 2007; 246: 624-631

6. Lordick F, Ruers T, Aust DE, et al; European Organisation of Research and Treatment of Cancer Gastrointestinal Group. European Organisation of Research and Treatment of Cancer (EORTC) Gastrointestinal Group: Workshop on the role of metabolic imaging in the neoadjuvant treatment of gastrointestinal cancer. Eur J Cancer. 2008; 44: 1807-19