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Cancer of the Esophago-Gastric Junction (EGJ): The Role of Radiotherapy

Cancer of the Esophago-Gastric Junction (EGJ): The Role of Radiotherapy. A . Kuten Dept. of Oncology, Rambam Med Ctr. Males cases ASR 1980 34 1.69 1990 39 1.75 2000 71 2.18. Females

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Cancer of the Esophago-Gastric Junction (EGJ): The Role of Radiotherapy

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  1. Cancer of the Esophago-Gastric Junction (EGJ):The Role of Radiotherapy A. Kuten Dept. of Oncology, Rambam Med Ctr

  2. Males cases ASR 1980 34 1.69 1990 39 1.75 2000 71 2.18 Females cases ASR 35 1.5 38 1.31 45 0.93 Israel Cancer Registry 1980 – 2000Esophageal Cancer, Jews

  3. Males Feamles cases ASR cases ASR 1980 315 16.75 185 8.91 1990 323 13.63 178 6.67 2000 352 11.20 233 5.51 Israel Cancer Registry 1980 – 2000Gastric Cancer, Jews

  4. AEGJ: Shares both similarities and differences with gastric and esophageal cancer Proximal gastric tumors are associated with worse prognosis than distal tumors

  5. SCC and ADC of Lower Esophagus and Cardia: • Different entities ? • Long term prognosis – conflicting reports. • Stage of disease is a much more important determinant of treatment strategy and survival than cell type. Alexandrou et al, dis esophagus, 2002 (Hong Kong)

  6. Assessment of Extent of Disease:Clinical Staging Still Deficient ! • CT+US+EUS (Nishimaki et al, 1999) Accuracy: 72% Sensitivity: 78% Specificity: 60% • EUS (Flamen et al, 2000) Sensitivity: 81% Specificity: 67% • FDG-PET Sensitivity: 43% Specificity: 98% • Diagnostic laparoscopy + US ?

  7. Sentinel node detection in Barrett`s and Cardia Cancer Burian et al. Ann Surg Oncol 204 (Munich)

  8. Overall 5 yr survival Resection “2 field” lymphadenectomy Less extensive lymphadenectomy Median survival Best supportive care Palliatve care Exploratory surgery Resection Conclusion: Major Surgery Confers Long Term Survival 12.5% 29% 50% 23.2% 36.5 d (0 – 68.1 mos) 116.5 d (0 – 59.5 mos) 211 d (113 – 26.6 mos) 17.6 mos (0 – 101.1 mos) Finish Cancer Registry, 1990-1998# pts: 402 Shivo et al Am J Gastroenterol 2004 (Finland)

  9. Locoregional Hematogenous Hematogenous + local Peritoneal (type II+III only) All pts with > 6 positive LNs recurred within 2 yrs De Manzoni et al, EJSO 2003 (Verona) 33% 40% 9% 18% AEGJ: Patterns of Recurrence After Surgery

  10. AEGJ: Risk of Lymph Node Mets • Tumors limited to the mucosa (pT1a): rare • Tumors limited to the submucosa (pT1b): uncommon • More advanced tumors: Paracardial Posterior lower mediastinum Lesser & greater curvature of stomach Left gastric artery Celiac axis Splenic artery (superior border of pancreas) – splenic hilum Left adrenal and left renal vein

  11. Mediastinum Middle Lower Abdomen Superior gastric Splenic artery & hilum Celiac trunk Common Hepatic Nigro et al 1999 DistalesophagusGEJ 8.3% 13% 33% 50% 78% 50% 6% 13% 14% 25% 3% 0% Transmural Adenocarcinoma of the Distal Esophagus & GEJ:Frequency of LN Mets by Nodal Location (44 pts)

  12. AEGJ: Lymphatic Pathways • Type I (distal esophagus): upward: mediastinal LN downward: celiac axis • Type II+III (cardia & subcardia): celiac axis, splenic hilum, para-aortic LN

  13. Treatment Strategies Surgery: Resection of primary tumor & lymphatic drainage • Route and extent of resection (extended vs limited) – controversial ! • Extent of lymphadenectomy (extended “3 field” vs limited) – controversial ! The role of adjuvant/neoadjuvant therapy controversial !

  14. Dent et al (1979) Gunderson et al (1983) Cohen et al (1981) Gez et al (1986) Moertel et al (1984) Bleiberg et al (1989) Regine et al (1992) Henning et al (2000) Macdonald et al (2001) Yao et al sem surg oncol 2003 5FU+20Gy vs S NS 5FU+45Gy vs 5FU/ADM NS 5FU + 30Gy 5FU + 50Gy 5FU+37.5Gy vs S p<0.024 55Gy vs 5FU+55Gy p<0.041 5FU or FAM vs 40-60Gy p<0.05 40-60Gy + 5FU 5FU+45Gy vs Sp<0.03 Adjuvant Chemo-radiotherapy for Gastric/EGJ Cancer

  15. # eligible pts: 556 Median OS Median RFS Local relapse Regional relapse Distant relapse However… 54% of pts underwent D0 resection ! 73% of CT/RT pts had Gr 3-4 toxicity ! Sub-optimal CT and RT ! 36 vs 27 mos p=0.003 vs 19 mos p=0.001 19% vs 29% 65% vs 72% 33% vs 18% MacDonald JS et al. NEJM 2001 (Intergroup 0116)CT/RT after S vs S for ADC of the Stomach or GEJ

  16. Extended LN Dissection for Gastric Cancer: Who May Benefit ? Final results of the Randomized Dutch Gastric Cancer Group Trial • 1989-1993: 1078 pts 711/1078 treated with curative intent D1: 380 pts; D2: 331 pts • After 11 yrs: no survival difference (30% vs 35%) higher morbidity + mortality in D2 • D2 resection curative fot N2 pts ? • 5 yr survival rates of the group that received adjuvant CT-RT in the INT 0116 trial resemble those of the Dutch Gastric Cancer trial (with no adjuvant CT/RT)… Hartgrink et al JCO 2004

  17. Patterns of failure in Gastric Carcinoma After D2 Gastrectomy and Chemoradiotherapy: A Radiation Oncologist`s View Study period: 1995 – 1999 Total # pts: 332 Evaluable pts: 291 Median FUP: 48 mos Treatment: • R0 gastrectomy • > D2 dissection (median # dissected LNs: 35) • Adjuvant CT/RT: INT 0116 (“MacDonald”) protocol Lim DH et al, Korea, BJC 2004

  18. Patterns of failure in Gastric Carcinoma After D2 Gastrectomy and Chemoradiotherapy: A Radiation Oncologist`s View 5 yr OS/DFS: 62%/ 58% Relapse: 114 pts (39%) • Local: 7% • Regional: 12% • Distant: 35% Toxicity: • Nausea > Gr 3: 12%; Diarrhoea > Gr 3: 10% • Neutropenia > Gr 3: 31% • Late intestinal obstruction > Gr 3: 20 pts Conclusions: • Postop RT/CT after D2 dissection is feasible • Low locoregional recurrence rate • Phase III study needed • Need for more efficient systemic treatment ?! (AK) Lim DH et al, Korea, BJC 2004

  19. Chemotherapy in gastric cancer:a brief chronicle with emphasis on recent developments Response rates to combination CT in metastatic gastric cancer reach 35%-50% • Doxetaxel • Paclitaxel • Irinotecan • Oral fluoropyrimidines • Oxaliplatin Sulkes A, IMAJ, July 2004

  20. Leidman (2001)…………….. Keller (1998)………………. Ajani (1998)……………….. Komaki (2000)……………... Lowy (2001)……………….. Wilson (2000)……………… Increased morbidity and mortality Improved survival in CRs Increased morbidity Increased pCRs Irinotecan+RT is feasible Increasd pCRs Increased postop morbidity Increased pCRs Increased toxicity Organ preservation possible Neo-adjuvant Chemo-radiotherapy for Gastric, Esophageal and GEJ Cancer

  21. Neoadjuvant therapy in AEGJ: randomized phase III trials • Preop RT (40Gy) + S > S Zhang ZX et al, “Red J” 1998 (Beijing, China) • Preop RT/CT + S > S Walsh et al. NEJM 1996(Dublin, Ireland) But… • Results of surgery were sub-optimal ! • Methodological problems !

  22. Neoadjuvant therapy is associated with morbidity and mortality • Randomized trials are needed to investigate the optimal type of preoperative therapy for particular subgroups of patients, before multimodal therapy for adenocarcinoma of the EGJ can be widely recommended

  23. On going phase III studies Adjuvant/neoadjuvant CT/RT • “MacDonald” vs neoadjuvant CEF-RT+CI 5FU-CEF (NCI sponsored, ASCO 2003) Adjuvant CT studies: • Italian – GISCAD (adjuvant cDDP/VP16/5FU/LCV “PELF” vs 5FU/LCV) • “Magic” – UK (S vs ECF – S – ECF) • EORTC (S +/- cDDP/5FU/LCV)

  24. ISDE/IGCA* Concensus Conference Neoadjuvant therapy is restricted to pts with locally advanced tumors of EGJ Schuhmacher C & Panel of Experts, Diseases of the Esophagus 2000 * Intntl Soc Dis Esoph/Intntl Gastr Cancer Assoc

  25. University of Minnesota Reoperation Sereis (82 pts) Gunderson LL, Sosin H, IJROBP 1982

  26. Anatomy and pathways of tumor spread Surgical considerations Pattern of failure (local, LNs) Treatment planning guidelines Ancillary care Smalley et al, IJROBP 2002 Gastric Surgical Adjuvant RT Concensus Report: Rationale and Treatment Implementation

  27. AEGJ: Guidelines for 3D RT Planning • Adapt surgical guidelines to delineate CTV • Use CT, EUS and FDG-PET to optimize CTV delineation • LN with >10% probability of microscopic involvement should be included in CTV

  28. AEGJ: Neoadjuvant/Adjuvant RT/CT The benfit of including different LN regions should be weighed against the risk of morbidity and surgical complications

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