1. Advances in esophageal cancer: Current and future strategies
Yelena Y. Janjigian, MD
Assistant Attending Physician
Gastrointestinal Oncology Service
Memorial Sloan-Kettering Cancer Center
18th Annual Perspectives in Thoracic Oncology
November 15, 2013

2. Esophageal and GEJ US Incidence in 2013
Esophagus and GEJ: 17,900 cases
7th leading cause of cancer death in men
Decline in Gastric Cancer Incidence
Increase in Esophageal , GE JX, cardia adenocarcinoma (not squamous)
Increases in obesity  GERD, smoking
OS improvement, , ,
Esophageal: 5%  10%  19%
Siegel et al, CA 63: ; 2013

3. New AJCC Staging: Survival in over 4600 pts with esophageal and GEJ cancer
T3 or N+
T3N+, N2-3
Rice Cancer 2010

4. Gastroesophageal Junction Tumors: Classification and Treatment
Siewart Classification1
Type I: lesions with center 1-5 cm proximal to the GE junction
Type II: lesions with center 1 cm proximal to and 2 cm distal to the GE junction
Type III: lesions with center 2-5 cm distal to the GE junction
AJCC Staging
Siewert I-III considered esophageal cancers
1. Siewert et al. Ann Surg : Stahl. Onkologie :33.

5. Preop therapy for T2-3 or N+
EMR for T1a
Surgery for T1b

6. PET SCAN: 1) Staging: 15% occult mets 2) Determine Response to Preop Chemo
Supraclavicular LN = Stage IV
Response to Preop Chemo
SUV = 10.6
SUV = 2.2

7. Esophageal GEJ Cancer: Neoadjuvant Therapy
Poor survival with Surgery Alone
Staging should include EUS and PET scan
Preoperative Therapy
Chemo (U.K., Magic)
Chemoradiotherapy (U.S.)
Increasingly validated by randomized trials
Carboplatin + Paclitaxel + RT a new standard option
Chemoradiotherapy Alone
nonoperative management
PET scan to direct preop chemo under study
Targeted Agents

8. Esophageal Adenocarcinoma: Consensus on Adjuvant Therapy
T2-3 or N+: Something more than surgery alone should be done
Preoperative chemo ECF, CF improves overall survival in some but not all trials
MAGIC (ECF): 13% ↑ OS at 5 yr (esophagus and GEJ: 120 pts)
No pathologic CR
No improvement in RO resection
FFCD / FNLC (CF): 14% ↑ OS at 5 yr (esophagus and GEJ: 180 pts)  same as MAGIC, no epirubicin
Improved R0 resection rate by 11%
Cunningham NEJM 355: 11; 2006, Ychou J Clin Oncol 29: 1715; 2011

9. Esophageal Adenocarcinoma: Consensus on Adjuvant Therapy
Trials focusing purely on esophageal and GE junction cancers
Preop chemo CF failed:
U.S. INT 113 (CF): 450 pts
No impact on OS or any endpoint, including R0 rate
MRC 0E0-2 (CF): 800 pts
5 year update: 6% OS increase
No impact on distant recurrence
Impact due to increase in R0 resection
EORTC (CF): 70 pts
No impact on OS, improved R0 resection
Alllum J Clin Oncol 2009, Kelsen NEJM 1988, Schuhmacher J Clin Oncol 278: 5210; 2010

10. Preop Chemo vs Surgery Alone: 2062 patients, 10 Trials
HR favoring Chemo 0.87 (p = 0.005)
Squamous: HR 0.92 (p = 0.18)
Adeno: HR 0.83 (p = 0.01)
Sjoquist Lancet Oncol 12: 681; 2011

11. Paclitaxel 50mg/m2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29
Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy
Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE)
Van Hagen et al NEJM 366: 2074; 2012

12. CROSS: Major Results EUS staged patients T3N0-1 75%, median age 60
74% Adenocarcinoma
93% received all courses chemotherapy
23% had > = grade 3 toxicity from pre-op therapy
Post-operative morbidity and mortality almost identical (mortality %)

13. Resection rate and resection margins
Resection rate of all randomized patients
Surgery alone CRT + surgery
186/188 (99%) 168/178 (95%)
Resection margins
R0 111/161 (69%) 148/161 (92%) p<0.002
R0 = no tumor within 1 mm of the resection margins
CROSS study

14. CROSS: Overall Survival
HR % CI ( )
5-year survival 47% vs 34%
Median survival 49 vs 24 months, HR 0.66, p = 0.003)
Squamous HR 0.453, Adeno HR 0.732
Squamous path CR 49%, Adeno 23% (p = 0.008) 18

15. Subgroups: Impact on OS with Chemo RT

16. Preop Chemo vs ChemoRT
Stahl J Clin Oncol: 27: 836; 2009

17. Preop Chemo vs Chemo RT: Stahl
EUS, laparoscopy staged pts
Siewert I-III, T3-4 adenocarcinoma
Arm N R0
pCR N0
Median Survival
3 yr OS
Local Control
Chemo 59
70% 2%
37%
21 mos
28%
59%
Chemo RT 60
72%
16%
64%
33 mos
47%
P = 0.07
77%
P = 0.06
Stahl J Clin Oncol: 27: 836; 2009

18. Sjoquist Lancet Oncol 12: 681; 2011
Preop Chemo RT vs Surgery Alone: 1932 patients, 13 trials –All cause mortality
HR favoring Chemo RT: 0.78 (p < )
Squamous HR 0.8 (p = 0.004)
Adeno HR 0.75 ( p = 0.02)
Sjoquist Lancet Oncol 12: 681; 2011

19. Esophageal and GEJ Cancer: Preop Chemo, RT, or Both? Conclusions
Something more than surgery alone should be done for T2-T3 or N+ disease
Preop Chemo, Cisplatin + 5-FU based improves survival and is feasible
Toxicity of chemo backbone may limit the addition of targeted agents
RT + Chemo, Carbo + Paclitaxel: potentially superior OS, more path CR’s
Low toxicity of therapy makes this regimen an ideal backbone for targeted therapy

22. Esophageal and GEJ Cancer and the Role of Surgery?
Low rate of pathologic complete response after chemo RT (23% CROSS trial)
Surgery considered for most patients
Chemo RT alone: Elderly, co morbidities
Delay surgery in responders, use as a salvage procedure

23. Esophageal Cancer: Predictive Accuracy of post ChemoRT Endoscopy
137 pts: Cisplatin based chemo RT  surgery
 EGD and biopsy  Surgery
104 pts (76%) negative biopsy post therapy
Poor Predictor: Only 35% had pathologic CR at surgery
A negative biopsy better predictor for squamous cell carcinoma (p <0.001)
More accurate assessment to predict Path CR
Sarkaria JCO 24: Abs 4024, 182, 2006

24. PET Scan and Path CR: Esophageal Cancer
493 pts preop chemoRT, 87% cisplatin based chemort
PET scan prior, after chemort
80% Adeno
Path CR 27%
PET response not associated with pCR
In squamous cancer patients: SUV response correlated with pCR
SUV reduction < 50%, 50-75%: : pCR 29-44%
SUV reduction > 75%: pCR 85%
Rizk J Clin Oncol 27: Abstr 4552; 2009

25. Esophageal Cancer: PET scan response to Induction / Preop Chemo
Weber: Preop chemo in esophageal and GEJ cancers
5-FU, cisplatin based for 3 months
PET scan performed at day 14
PET responders: SUV decline > = 35%
PET responders 2 yr survival 60% vs 37% for non responders
Weber J Clin Oncol 19:3058;2001

26. Treatment Plan: MUNICON-1 trial Lordick
Non-Responder
Resection
CTx
AEG type I-II
PET d14
PET d0
CTx: 3 months
Responder
Resection
Response definition: Decrease of the SUVmean PETd14 / PETbaseline > 35%
Weber et al. J Clin Oncol 2001;19: Ott et al. J Clin Oncol 2006;24:4692-8

27. Comparison with historic cohort
Ott et al. J Clin Oncol 2006;24:4692-8
CTx for 12 weeks in all patients
MUNICON-1 study; 2007
CTx stopped after 2wks in Non-Responders
PET-Responder
Survival
PET-Non-Responder
Survival time [months]
Survival (median)
Responders: not reached
Non-Responders: 18 months
Survival (median)
Responders: not reached
Non-Responders: 26 months

28. Esophageal Cancer: PET scan trials
It is unlikely that nonresponding pts will gain from continuing the same chemo
Discontinuing inactive chemo did not adversely affect outcome
Will changing chemo improve outcome?

29. PET Scan Directed Therapy Trial Design: CALGB 80803
PET-responders: ≥ 35% SUV decrease: continue same chemo + concurrent RT (5040cGy in 180cGy fx)
T3/4 or N1 Esophageal Adenoca
PET/CT: Induction Chemo: modified FOLFOX6 days 1,15, 22 or Carbo/Taxol days 1,8,22,29
Surgical resection 6 weeks post-RT
PET Scan day 29-35
PET- nonresponders: < 35% SUV decrease: Cross over to alternate chemo + RT (5040cGy in 180cGy fx)
Hypothesis: changing chemo in PET non responding patients will improve pCR during chemo + RT

30. Adding a Targeted Agent to Chemo, Chemo RT Neoadjuvant Therapy
Validation of agent in advanced disease trials
Specific targeting of an over expressed or activated target
Biomarker enrich selection of treatment population
Potential for agent to have systemic activity and reduce or suppress systemic micrometasases
Potential for agent to enhance radiotherapy or overcome radiotherapy resistance
Non overlapping toxicity with chemotherapy
Less of an issue with 5-FU, capecitabine, oxaliplatin
Clearly an issue with ECF and variants

31. Molecular Targets: Esophageal and Gastric Cancer
KRAS mutation: < 5%
BRAF mutation: < 5%
EGFr over expression: %
Over expression may be prognostic
EGFr mutation: < 5% , amplification in 15%
VEGF over expression
Correlates with advanced stage, worse prognosis
HER2 over expression: %, not prognostic in local disease
CMET amplification:
IHC over expression 40%, poorer prognosis in metastatic disease
Amplification in 10%
Galizia W J Surg 31: 1458; 2007 Mammano Anticancer Res 26: 3547; 2006 Lee Oncogene 22: 6942; Yano Oncol Rep 15: 65; Gold GI CA Symp 2008 Abs 96

32. Targeted Agents: Neoadjuvant Therapy
Only validated Biomarker Selected Targeted Agent is Trastuzumab, HER2+ pts
Ongoing RTOG Trial 1010 of Trastuzumab + ChemoRT in HER2+ Esophageal and GEJ Cancers
Negative phase II, phase III trials for Bevacizumab and Cetuximab + chemo RT
Ongoing trial of Bevacizumab + EOX in Gastric Cancer
CMET and other pathways under active investigation in early phase trials
Biomarker for selection for over expression or activation of a target remains a key component of trial design

33. Management of Residual Disease
After chemo RT and surgery, observation alone is standard therapy.
Any preop therapy has a modest benefit: 60-80% of pts still die
Survival improvements 6-14%
Pts with no treatment effect, N + residual disease post surgery: poor outcome

34. After preop therapy and surgery, should chemo be continued post op?
Does continuing same chemo even benefit responding patients?
Timing of therapy months after diagnosis
Similar survival outcomes with short duration vs protracted chemo
OS increases in trials of chemo only during RT, CROSS Trial
= to MAGIC, FFCD trials (3 pre 3 post op cycles)
Unlikely that non responding patients will gain from more of the same treatment

35. Targeted Therapy Post Op?
Maintenance therapy with a novel targeted agent , high risk residual disease pts
Suppress rather than eradicate micro metastatic disease
CALGB/Alliance, GEJ cancer
High risk N+ pts post chemort and surgery
1 year Regorafenib (Anti VEGF TKI) vs Placebo
Based on phase II activity for Sorafenib (MSKCC)