Gastro-Conference Berlin 2005 October 1-2, 2005 Surgical strategies in esophageal cancer J. Rüdiger Siewert Department of Surgery, Klinikum rechts der Isar Technische Universität München
Esophageal Cancer Rate per 1,000,000 35 30 25 20 15 10 5 Incidence (SEER Database 1975-2001) 0 1975 1980 1985 1990 1995 2000 Histology and esophageal cancer incidence (1975-2001). Data from the National Cancer Institute s Surveillance. Epidemiology and End Results program with ageadjustment using the 2000 U.S. standard population. Solid line = adenocarcinoma; dashed line = squamous cell carcinoma; dotted line = not otherwise specified. Pohl and Welch, J Natl Cancer Inst 2005
Relative increase in the prevalence of adenocarcinoma 100% 90% 80% squamous cell carcinoma adenocarcinoma prevalence (%) 70% 60% 50% 40% 30% 20% 10% 30,9 37,5 47,2 52,3 0% 1987-1991 1992-1996 1997-2000 2001-2003 TU München 1982-2003
Adenocarcinoma and Squamous Cell Cancer Affect Different Patient Populations Adenocarcinoma Squamous Cell Cancer Age 65 Reflux Adipositas Coronary Heart Disease Age 55 Alcohol Nicotine COPD Liver Zirrhosis Malnutrition Second Cancers Cooperation
Surgical epidemiology of patients with squamous cell cancer and with adenocancer of the esophagus Squamous cell cancer Adenocancer of the p of the esophagus esophagus Median age 53,4 years 62,6 years p<0,001 Male/female 7:1 8:1 n.s. Occupation (prevalence) Academics 20,8 % 52,9 % p<0,001 White collar worker 27,2 % 27,7 % Blue collar worker 52,2 % 20,2 % Alcohol abuse (prevalence) 69,7 % 42,3 % p<0,001 Nicotine abuse (prevalence) 69,3 % 51,9 % p<0,05 Malnutrition (prevalence) 24,1 % 1,9 % p<0,001 Pulmonary capacity 82,5 % 93,7 % p<0,05 (average FEV % compared to normal) Cardiovascular risk factors 19,5 % 34,8 % p<0,01 (prevalence) Impaired liver functioning 35,3 % 24,9 % p<0,05 (prevalence) TU München 03
Resected Adenocarcinoma and Squamous Cell Cancer Have a Different Prognosis (TU München 1982-2003, n=1285) 1,0 Multivariate Analysis,8,6 Adenocarcinoma, n=494,4 p<0.01,2 Squamous Cell Carcinoma, n=791 0,0 0 24 48 72 96 120
Survival SCC / Barrett-Ca 100 80 B-Ca Survival (%) 60 40 20 pt1 SCC pt1 ADC Stage I SCC Stage I ADC SCC 0 0 12 24 36 48 60 Time (months) pt1 SCC 107 95 76 55 41 28 pt1 ADC 21 21 20 16 10 7 Stage I SCC 114 106 74 55 45 35 Stage I ADC 16 16 12 8 5 3 C. Mariette...J.P. Triboulet, World J. Surg. 2005
Independent Prognostic Factors Histologic Tumor Type 1.0 Early Adenocarcinoma, n=157 0.8 Survival Probability 0.6 0.4 Early Squamous Cell Cancer, n=133 0.2 0.0 0 12 24 36 48 60 Months
Early Esophageal Cancer Prevalence of Lymphatic Spread Squamous Cell Cancer Adeno- Carcinoma Total 41/133 (30.8%) 18/157 (11.5%) HGIEN / pt1a 2/26 (7.7%) 0/70 (0%) pt1b 39/107 (36.4%) 18/87 (20.7%)* *p<0.05 Stein/Sie Ann. Surg 2005
AEG-Early Ca Limited Resection n=64 TU Munich Complete Tumor Resection (R0): 64/64 (100%) Complete Resection of Barrett Mucosa: 62/64 (96.8%) Postop Mortality: 0/64 (0 %) Postop Morbidity: 10/64 (15.6%) Surgical Revisions: 2/64 (3.1%) Median F/U: 43 Months - No Recurrences - No Deaths No Reflux: 58/64 (90.6%) Good Overall Functional Results: 56/64 (87.5%)
Early SCC of the Esophagus needs always subtotal esophagectomy and mediastinal LA (transthoracic approach)
Locally advanced Esophageal Cancer What are the relevant questions with therapeutical consequences in preop. Staging / Diagnostic today? R 0 -Resectability Distant metastases ( CT scan) ( PET-Scan) T-Category for therapeutical Stratification (T 1/2 T 3/4 ) Neoadj. Th.
PET Staging of Esophageal Cancer Distant LN Metastases Primary Tumor May identify distant lymph node metastases Increases Detection of Distant Solid Organ Metastases (+20%)
Esophageal Cancer - Surgical treatment - TU Munich 1982-2004 n=1367 SCC B-Ca 59% 41% n=807 n=560 Primary Res. Neoadj. Th. Primary Res. Neoadj. Th. 54% 46% 66% n=435 n=372 n=370 n=190 34%
Esophagectomy 30 day Mortality - Morbidity TU Munich % 100 90 80 70 60 50 40 30 29,2 28,1 29,6 29,6 15,6 18,1 27,9 22,4 20,7 25 20 10 0 1,4 1,1 0 2,4 1,3 0 1,1 1 0,9 1,6 Morbidity 30 day mortality 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 Years
Barrett-Ca / SCC below Bifurcation Procedure of Choice Abdomino-right thoracic Resection Transthoracic Esophagectomy (Ivor-Lewis) High located intrathoracic Anastomosis Transabdominal Gastric Tube preparation Abdominal LA
Cumulative Overall Survival (%) 100 80 60 40 20 Surgery Choice of Procedure Barrett-Ca Survival Hulscher et al. N. Engl. J. 2002 Transthoracic esophagectomy Transhiatal esophagectomy 0 No. at risk 0 1 2 3 4 5 6 7 8 Transhiatal esophagectomy 106 74 53 35 25 16 11 4 Transthoracic esophagectomy 114 76 57 42 31 20 14 7 Years
Advantages of Intrathoracic Anastomosis Anastomosis-Healing safer (in case of leakage - stent) swallowing function better more adequate LA N. Recurrence paralysis fewer
Locally advanced Esophageal - SCCa Location more frequent above the bifurcation R 0 -Res. from the anatomical point of view more difficult ( RCTx) Cervical Anastomosis more frequent necessary OP-Risk higher
Esophageal-Ca Multiple logistic regression analysis of the effects on operative death Adjusted odds ratio p Age (Years) 0.009 < 59.5 1 59.5-67.8 2.06 (0.52, 8.22) 67.9-73.2 1.55 (0.36, 6.72) > 73.2 4.87 (1.35, 17.55) FEV1 (% predicted) 0.018 110-150 1 97-109 2.32 (0.44, 12.25) 82-96 5.49 (1.20, 25.22) 26-81 4.72 (1.01, 21.99) Position 0.041 Upper third 4.23 (1.06, 16.86) Other 1 H. Abunasra et al. Brit. J. Surg. 2005
What s new in Neoadj. Therapy? with surgical consequences FDG-PET: Response evaluation after therapy with sufficient accuracy is possible FDG-PET: Good correlation between metabolic response and survival Stratification of responders and non-responders in different treatment concepts to improve prognosis and avoid postoperative morbidity individualized therapy
Early Response Evaluation - Barrett-Ca Before therapy After 14 days of chemotherapy (PLF)
Early Response Evaluation - using FDG-PET Change in metabolic activity during RCTx and CTx 14 12 10 10-30% 9-35% 8 8 7 N = 12 SUV 6 4 2 0 Before therapy after 14days after 28days before surgery SUV 6 5 4 3 2 Pre CTx 14 Days 100 Days Squamous Cell Carcinoma Adenocarcinoma
Barrett-Ca / Municon Trial Treatment flowchart Non-Responder Surgery d21 AEG ut3 Nx PET d0 CTx PET d14 Responder CTx 3 Months Surgery d120
Barrett-Ca (Municon Trial) Post-operative morbidity and mortality, R 0 -Resektionsrate Complications Hospital R0 mortality (30 day) Metabolic responder 16 1 90% (n=47) (36 %) (2%) 52% Metabolic 16 0 61% Non-responder (38 %) (%) n.s. s. (n=44) 47%
AEG Typ I n=511 1,0 TU München 1982-2003 n=511,8 Primary resected pt1/2 n=219,6,4 Neoadj. ypt0-4 n=154 Responder / R0-Res.,2 Primary resected pt3/4 n=138 0,0 0 24 48 72 96 120
SCC Postoperative Results Histopathol. Histopathol. Total Response Non- p-value Response < 10 % > 10 % 30-day 3,5 % 1,2 % 6 % 0.02 (n=11) (n=2) (n=9) Hospital 6,1 % 3,7 % 8,7 % 0.06 (n=19) (n=6) (n=13) R 0 n=152 n=95 93.8% 63.8% <0.0001
Response Prediction / Neoadjuvant Therapy 2005 - Consequences for Surgery - ONLY RESPONDERS have a benefit! - RESPONSE PREDICTION (?) Molecular marker? - Early Response evaluation is now possible. (!) There is a difference in SURGICAL RISK following RCTX or CTX (Immunosuppression following RCTx) Relevant for surgical consequences OPEN QUESTIONS: If second line Surgery Who are the candidates for surgery - Responders or Non-Responders?
Neoadjuvant Therapy: Candidates for Surgery? Responders! Residual tumor evaluation needs a surgical specimen (for histopathological examination) Histopathological Response independent Progn. Factor! Only (~10%) Complete Responders (residual tumor free) Low surgical risk in responders Very good prognosis! Non-Responders? High surgical risk Few R0 resections Also following Surgery bad prognosis
Esophageal-Ca / (SCC; T 3/4 ) Survival curves for nonresponders to chemoradiotherapy 100 NS (p=0.168) Survival Rate (%) 50 64% 20% 33% 20% Surgery (n=11) No-surgery (n=5) 0 1 2 3 years after therapy Fujita, H. et al. World J. Surg. 2005 short time improvement
Surgery for T 3/4 SCC-Esophageal-Ca following Neoadj. RCTx Postoperative complications Complication Esophagectomy (n=26) Recurrent nerve paralysis 13 (50%) Aspiration pneumonia 9 (35%) Tracheal ischemia 6 (23%) (ulcer, erosion) Pyothorax 6 (23%) Anastomotic leak 5(19%) Ileus 3 (12%) Severe arrhythmia 2 (8%) Pulmonary infarction 1 a (4%) MRSA enteritis 1 (4%) Brain abscess 1 a (4%) Morbidity 22 (85%) Mortality 2 (8%) Fujita, H. et al World J. Surg 2005
Strategies to overcome Esophageal Cancer 2005 ( Munich Experiences ) Separate concepts for adenocarcinoma and squamous cell carcinoma! Patient selection (staging; risk analysis) Standardisation of surgery Complication-management safety surgery in high risk patient to avoid p.op. mortality Neoadjuvant therapy and early response evaluation for locally advanced tumors Different strategy for Responder vs. Nonresponder Limited procedures for early cancer! High Volume Centers
TU Munich / Germany (1982-2003, n=1285) Surgery for Esophageal Cancer has Improved Markedly 1,0,8 98-03 n=511,6 91-97 n=432,4,2 82-90 n=342 0,0 0 12 24 36 48 60 Improved prognosis of resected esophageal cancer over a twenty year period at TU München Stein / Siewert: World J Surg 2004