2. MANAGEMENT OF ESOPHAGEAL CANCER Elshami Elamin, MD Medical Oncologist Central Care Cancer Center www.cccancer.com Newton, KS - USA

3. ESOPHAGEAL CANCER  Risk factors  Alcohol / Tobacco  Head / neck cancer  High fat, low protein & calories  Barrett’s  Tylosis  Plummer Vinson syndrome (Paterson-Brown- kelly Synd)  Achalasia

4. Symptoms & Signs  Dysphagia  Wt. Loss  Cough  Pain  Hoarseness  Malig pleural effusion, Ascites  Hypercalcemia

5. Work-UpH&PEGD CBC, CMP CT chest/abd No Mets: Bronchoscopy Bronchoscopy *Tumor at or above Carina *Tumor at or above Carina EUS EUS Laparoscopy (GEJ) Laparoscopy (GEJ) PET/CT PET/CT Locoregional I-III/IVA IVB

6. INTRODUCTION  Surgery has been the raditional management of patients with localised esophageal cancer  Survival is poor, and many pts develop mets or locoregional recurrence soon after surgery

7. Treatment modalities  Esophagectomy:  Resectable esophageal cancer:  >5 cm from cricopharyngeus  Cervical and cervicothoracic cancer i.e <5 cm from cricopharyngeus should be treated with definitive chemoradiation.  R.T.  Chemotherapy  BSC

8. Locoregional I-III/IVA IVB Salvage Therapy Medically Fit Resectable (>5cm from cricopharyngeus) Inresectable: T4 Medically unfit MultidisiplinaryMultidisiplinaryMultidisiplinary Eval NutritionalNutritionalNutritional Assessment (NGT, J-Tube, PEG (NGT, J-Tube, PEG not recommended) not recommended)

9.  GEJ: Celiac nodal involvement may not exclude combined modality therapy  Resectable stage IVA:  Distal esophageal cancer with resectable celiac node  No involvement of aorta or other organ  No involvement of celiac artery  ReseInvctable T4:  Involvement of  Pericardium  Pleura  Diaphragm

10. Medically Fit Resectable disease

11. Esophagectomy (preferred for noncervical) Tis, T1aTis, T1a Medically Fit Resectable T1b,N0-1T1b,N0-1 T1b, N1 T2-4, N0-1,Nx M1a (IVA) Endoscopic mucosal resection OR Esophagectomy

12. T1b, N1 T2-4, N0-1,Nx M1a (IVA) Preop Chemo for adeno of distal Esoph or GEJ (ECF) Preop ChemoRT RT 50-50.4 Gy Definitive ChemoRT

13. Preop Chemo for adeno of distal Esoph or GEJ Preop ChemoRT RT 50-50.4 Gy Definitive ChemoRT PET-CT/CT*EGD Salvage esophagectomy for local residual disease Esophagectomy PET-CT/CT*EGD See Surgical outcome *EGD > 5 wks with biopsy or brushings*EGD > 5 wks with biopsy or brushings

14. Preop ChemoRT RT 50-50.4 Gy Persistent local dis NED unresectableMets See Surgical outcome PET-CT/CTPET-CT/CT *EGD*EGD Esophagectomy (preferred)Esophagectomy (preferred) ObserveObserve EsophagectomyEsophagectomy(preferred) paliative/ (chemo)paliative/ (chemo) *EGD > 5 wks with biopsy or brushings*EGD > 5 wks with biopsy or brushings

15. R0 Surgical outcomes R1 R2 N -N - N+N+ adenoadeno Tis, T1, N0: observeTis, T1, N0: observe T2,N0: observe or chemoRT *ECF if given preop (categ 1)T2,N0: observe or chemoRT *ECF if given preop (categ 1) T3,N0: chemoRT * ECF if given preop (categ 1)T3,N0: chemoRT * ECF if given preop (categ 1) Observe or chemoRTObserve or chemoRT SquamousSquamous ObserveObserve Adeno prox or midAdeno prox or mid Adeno distal or GEJAdeno distal or GEJ chemoRT * ECF if given preop (categ 1)chemoRT * ECF if given preop (categ 1) chemoRTchemoRT chemoRT or palliativechemoRT or palliative

16. Medically Unfit Unresectable dis.

17. ChemoRT Chemo RT BSC Tis, T1aTis, T1a Medically unfit unresectable Medically unfit Chemo is tolerable Unresectable: T4/IVA Endoscopic mucosal resection OR ChemoRT Medically unfit Chemo is not tolerable Palliative RTPalliative RT BSCBSC

18. ANY SCEINTIFIC EVIDENCE TO SUPPORT THE USE OF CHEMOTHERAPY/R.T. IN LOCALLY ADVANCED OPERABLE ESOPHAGEAL/GASTRIC CANCER ?

19. LITRETURE REVIEW

20. ADJUVANT THERAPY  Adj RT, chemo, or chemoRT  Mixed results and disappointing  Because trials were small and lacked statistical power  Adj treatment based on 2 or 3-year survival rates  chemoRT and chemo have similar benefits

21. NEOADJUVANT THERAPY  Due to sig postop complication rate, focus has turned to neoadj treatment.  Currently, there is no evidence to support the use of neoadj RT alone

22. Any role for Chemo/RT  <30% of locally advanced Gastric/GEJ adeno could be cure with surgery alone  Previous adj chemo failed to show clinical benefit

23. INT-0116 (SWOG 9008)  Randomized lll Trial:  Resectable adeno of stomach  GEJ (lB-IVA)  5-FU/LVx5d--> RT+5-FU/LV during first 4d and last 3d of RT --> 2cycles of 5-FU/LVx5d  postop CT/RT improve DFS&OS in R0 (resected locally advanced)  [standard of care] Adj Option Macdonald et al; N Engl J Med. 2001 Sep 6;345(10):725-30.

24. The MAGIC Trial The Medical Research Council Adjuvant Gastric Infusional Chemotherapy  Operable adeno of the stomach, the lower third of the esophagus, and the GEJ ( 74% of pts had tumors in the stomach)  ECFx3->surg->ECFx3 (250 pts) vs Surgery alone (253 pts):  5Y survival: 36% vs 23%  Chemo sig. improves resectability, PFS and OS Periop. option D. Cunningham, et al ; N Engl J Med. 2006 Jul 6;355(1):11-20.

25. Preoperative Chemotherapy vs Surgery Alone  FNLCC ACCORD 07-FFCD 9703, multicenter, randomized trial indicated benefit of preoperative chemotherapy vs surgery alone for resectable adenocarcinoma of stomach and lower esophagus [1]  Higher rate of R0 resection (87% vs 74%; P =.04)  Higher 5-yr OS (38% vs 24%; P =.021)  No increase in postoperative morbidity or mortality Boige V, et al. ASCO 2007; Abstract 4510.

26. Preoperative Chemotherapy vs Surgery Alone  Meta-analysis also demonstrated benefit for preoperative chemotherapy in resectable esophageal cancer [2]  5-yr OS benefit of 4.3% (P =.003)  5-yr DFS benefit of 4.4% (P =.0001) Thirion P, et al. ASCO 2007. Abstract 4512.

27. CALGB 9781  Only 56 pt with stage I-III  Preop-chemo/RT vs surgery alone  MS 4.5y vs 1.8y  Trimodality imroves survival

28. Lancet Oncol 2007; 8: 226–34 Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma (meta-analysis) Val Gebski, Bryan Burmeister, B Mark Smithers, Kerwyn Foo, John Zalcberg, John Simes, for the Australasian Gastro-Intestinal Trials Group

29. Meta-analysis  MEDLINE, Cancerlit, and EMBASE databases from major scientific meetings (1980-2006)  Pts with local operable esophageal ca  10 randomised trials of neoadjuvant chemoRT vs surgery (n=1209)  SCC = 6, adeno =1, both = 3  8 of neoradjuvant chemo vs surgery (n=1724) with comparisons  SCC = 7, both = 2

30. Meta-analysis Findings  The hazard ratio for all-cause mortality with neoadj chemoRT vr surgery  0·81 (95% CI 0·70–0·93; p=0·002)  corresponding to a 13% absolute difference in survival at 2 years  0·84 (0·71–0·99; p=0·04) for SCC  0·75 (0·59–0·95; p=0·02) for adeno  The hazard ratio for neoadj chemo was 0·90 (0·81–1·00;p=0·05)  2-year absolute survival benefit of 7%  No sig effect on all-cause mortality of chemo for SCC (hazard ratio 0·88 [0·75–1·03]; p=0·12)  Sig benefit for adeno (0·78 [0·64–0·95]; p=0·014)

31. NEOADJ CHEMO  For SCC, neoadj chemo did not have a survival benefit  hazard ratio for mortality 0 ・ 88 [0 ・ 75–1 ・ 03]  p = 0 ・ 12  For adeno, neoadj chemo showed sig survival benefit (UK Medical Research Council MRC trial)  hazard ratio for mortality 0 ・ 78 [0 ・ 64–0 ・ 95]  P = 0 ・ 014

32. Long term results of the MRC OEO2 randomized trial of surgery with or without preoperative chemotherapy in resectable esophageal cancer  Conclusions: Long term follow-up confirms that preoperative chemotherapy improves survival in operable esophageal cancer and should be considered as a standard of care.  2002 (Lancet 2002; 359: 1727-33)

33. NEOADJUVANT CHEMO/RT  Neoadj chemoRT vs surgery  sign benefit over surgery for both histological types  0 ・ 84 (0 ・ 71–0 ・ 99); p = 0 ・ 04 for SCC  0 ・ 75 (0 ・ 59–0 ・ 95); p = 0 ・ 02 for adeno

34. Sequential vs Concurrent chemoRT  No survival benefit of sequential chemoRT in SCC  hazard ratio for mortality 0 ・ 90 [0 ・ 72–1 ・ 03]; p=0 ・ 18)  similar to SCC treated with neoadj chemo  Concurrent chemoRT had sig benefit for both histological types  hazard ratios 0 ・ 76 and 0 ・ 75 for SCC and adeno, respectively

35. Meta-analysis Interpretation  A signifi cant survival benefi t was evident for preoperative chemoradiotherapy and, to a lesser extent, for chemotherapy in patients with adenocarcinoma of the oesophagus.

36. THANKS