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Esophageal Cancer and Combined Modality Treatment

Esophageal Cancer and Combined Modality Treatment. Dong Xiang, MD Hematology/Oncology JBCC, University of Louisville 7/22/2010. Incidence and Mortality in 2010. Source: American Cancer Society, 2010: http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf.

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Esophageal Cancer and Combined Modality Treatment

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  1. Esophageal Cancer and Combined Modality Treatment Dong Xiang, MD Hematology/Oncology JBCC, University of Louisville 7/22/2010

  2. Incidence and Mortality in 2010 Source: American Cancer Society, 2010: http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf

  3. Incidence and Mortality Source: American Cancer Society, 2010: http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf

  4. For most of the twentieth century, SCC comprised the vast majority of esophageal cancers. Before 1980: Only 15% of all cases were adenocarcinoma In 1994 60% of all esophageal cancers were adenocarcinoma. 1% of all cancers diagnosed. Rapidly fatal. One of the most rapidly increasing cancers. Esophageal Cancer in the U.S.

  5. 5 Year Survival (%) Source: American Cancer Society, 2010: http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf

  6. Tobacco Alcohol Diet Chronic esophagitis Achalasis Age Race Gender Role of HPV? Tylosis Predisposing Factorsfor SCCA Esophagus

  7. Tylosis • Autosomal dominant gene. • 50% incidence of esophageal cancer by age 45. • 95% risk by age 65.

  8. Other Risk Factors • Previous head and neck or lung cancer (annual rate 3-7%). • Plummer-Vinson syndrome (Iron deficiency). • Esophageal diverticulae. • Lye strictures: long latent period. • Radiation injury (therapeutic, atomic bomb). • Non-tropical sprue.

  9. Adenocarcinomaof the Esophagus • Incidence rates increased >350% since the mid 1970s. • Increasing 20% per year in U.S. • 6-8 times higher in men than in women. • 3-4 times higher in whites than in blacks. • White men represent 82% of cases.

  10. Adenocarcinomaof the Esophagus • Obesity • Reflux disease and Barrett's esophagus. • Diet • Smoking • Scleroderma

  11. Barrett's Esophagus • Dysplastic changes in distal esophagus and gastroesophageal junction. • 30-40 fold increase in adenocarcinoma of the esophagus. • 10-15% of Barrett’s patients will develop adenocarcinoma. • Risk of cancer is about 0.5% per year.

  12. Treatment: Surgery Surgical resection is the standard treatment for early esophageal cancer ie Stages I, II and most cases of III During the past decade, outcomes with surgery have improved resulting in a better 5 year survival due to: Better staging techniques Increased rate of curative resection A decreased rate of postoperative death However, the proportion of patients who survive for five years remains low 30 to 50 % - stage I 15 to 30 % - stage IIA 5 to 15 % stage IIB

  13. Surgical Approaches for Esophageal Cancer Ivor-Lewis Esophagectomy (TTE) 3 Field Esophagectomy (TTE) Transhiatal Esophagectomy (THE) The Oncologist 1999; 4:95.

  14. Hulscher et al Perioperative morbidity was higher after TTE No significant difference in in-hospital mortality (P=0.45) After a median follow-up of 4.7 years: 70 % of patients died post THE and 60% after TTE (P=0.12) Median overall and disease-free survival did not differ statistically between the groups. However there was a trend towards improved long-term survival at 5 years with the TTE. Transthoracic Esophagectomy(TTE) N=114 Included 2 field lymphadenectomy 220 patients Adeno Ca Randomize Transhiatal Esophagectomy (THE) N=106 NEJM 2003

  15. Surgery is not enough However, the proportion of patients who survive for five years remains low 30 to 50 % - stage I 15 to 30 % - stage IIA 5 to 15 % stage IIB Needs combined-modality treatment Poor surgical outcome Relatively advanced nature of disease at the time of diagnosis Neo-adjuvant Chemotherapy Neo-adjuvant Radiation Neo-adjuvant Chemo-Radiation Adjuvant Chemotherapy Adjuvant Radiation Adjuvant chemoradiation

  16. Why Neoadjuvant/Adjuvant therapy • In most cases esophageal cancer is a systemic disease at diagnosis. • Surgery alone is curative in a small group of patients. • Patterns of recurrence suggest both local and systemic failure. • Disadvantages: • Only 50 % of patients respond to treatment • Delay in surgery • Possibility of selecting drug resistant clones

  17. Neoadjuvant Chemotherapy MAGIC TrialCunningham ASCO 2005 • Evaluate the efficacy of preoperative and postoperative ECF vs. surgery alone • 503 patients, stage II or greater • Adenocarcinoma stomach/ge junction/distal esophagus • ECF was chosen secondary to high RR in two prior randomized trials for locally advanced and metastatic gastric cancer

  18. Conclusions for Magic Trial • First trial with neoadjuvant chemotherapy to show PFS/OS benefit • Pathologic staging showed improvement in downsizing of primary tumor • Chemotherapy tolerated fairly well • Value of post-operative chemotherapy unknown (only 42% completing tx)

  19. Neo-adjuvant Radiation alone • A meta-analysis of 1147 patients from five randomized trials showed no survival benefit. • Based on existing trials, there is no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. Int J Radiat Oncol Biol Phys 1998 1;41(3):579-83

  20. Neo-adjuvant chemo or XRT are not enough !NeoadjuvantChemo-radiation:Phase III Studies • Walsh et al NEJM 1996 • J ThoracCardiovascSurg 1997 Aug;114(2):205-9

  21. 3 Year survival combined modality Vs Surgery alone • Walsh et al NEJM 1996 • J ThoracCardiovascSurg 1997 Aug;114(2):205-9

  22. Intergroup RTOG 85-01 R A N D O M I S E CRT (50 Gy 25 F; Cis/5FU wks 1+5) Cis/5FU Cis/5FU 61 Localised Oesophageal Cancer RT (64 Gy 32 F) 62 Herskovic et al 1992; Al Sarraf et al 1997; Cooper et al 1999

  23. How about adjuvant treatment? 5 yr survival :44.9% Surgery N=100 Randomize N=205 Surgery & Cis/Vindesinex2 N=105 5 yr survival: 48.1% No significant differences in survival were detected between the two groups, even with lymph node stratification Transthoracic esophagectomy with lymphadenectomy Cisplatin (70 mg/m2) and Vindesine (3 mg/m2) • J Thorac Cardiovasc Surg 1997 Aug;114(2):205-9

  24. Adjuvant Radiation Vs chemotherapy 5 yr survival : 44% Radiation Randomize Post Surgery N=258 Cis/Vindesinex2 5 yr survival: 42% No difference in time to recurrence or sites of recurrence Radiotherapy (50 Gy) 2 courses of chemotherapy consisting of cisplatin (50 mg/m2) and vindesine (3 mg/m2) following curative resection • Chest 1993 Jul;104(1):203-7

  25. Adjuvant Chemotherapy

  26. Not candidates for surgery This study confirms response, survival, and QOL benefits of ECF observed in a previous randomized study. The equivalent efficacy of MCF was demonstrated, but QOL was superior with ECF. ECF remains one of the reference treatments for advanced esophagogastric cancer.

  27. 2 New England Journal of Medicine. 358(1):36-46, January 3, 2008.

  28. Figure 2 . Kaplan-Meier Estimates of OS. Panel A shows OS according to a 2 X 2 comparison in the per-protocol population between the capecitabine and fluorouracil regimens; the HR for death in the capecitabine groups was 0.86 (95% CI, 0.80 to 0.99). The upper limit of the 95% confidence interval for the HR was well below the non inferiority margin of 1.23. The median survival and 1-year survival rate for capecitabine as compared with fluorouracil were 10.9 months versus 9.6 months and 44.6% (95% CI, 40.1 to 49.0) versus 39.4% (95% CI, 35.0 to 44.0). Panel B shows OS according to a 2X 2 comparison in the per-protocol population between the oxaliplatin and cisplatin regimens; the HR for death in the oxaliplatin groups was 0.92 (95% CI, 0.80 to 1.10). The upper limit of the 95% confidence interval was well below the non inferiority margin. The median survival and 1-year survival rate for oxaliplatin as compared with cisplatin were 10.4 months versus 10.0 months and 43.9% (95% CI, 39.4 to 48.4) versus 40.1% (95% CI, 35.7 to 44.4). Panel C shows OS in the intention-to-treat population between the group that received epirubicin and oxaliplatin plus capecitabine (EOX) and the group that received epirubicin and cisplatin plus fluorouracil (ECF). The HR for death in the EOX group, as compared with the ECF group, was 0.80 (95% CI, 0.66 to 0.97; P=0.02) . New England Journal of Medicine. 358(1):36-46, January 3, 2008.

  29. Where are we? • Surgery remains a standard of care for potentially resectable disease. • Definitive chemoradiation is a standard of care for locoregional disease, particularly if a patient is medically unfit for surgery, if a surgeon experienced in esophagectomies is unavailable, or if the patient has cervical disease, which would require very extensive surgery. • Preoperative and Post operative chemotherapy with ECF are standard of care. • Role of post op adjuvant chemotherapy currently undefined

  30. Questions ? thanks

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