Comprehensive overview of esophageal carcinoma: diagnosis, staging and treatment

1. Esophageal Caner
Ahmed Zeeneldin
Ass. Prof Medical Oncology
NCI-
NCI-Cairo
2009
1

2. Case Scenario
n Male
n 65 years
n CO: dysphagia
n How will you proceed?
2

3. n What are the causes of dysphagia?
dysphagia?
n What about male 65 y?
3

4. Esophageal Anatomy
Upper Esophageal
Sphincter (UES)
Esophageal Body 18 to 24 cm
(cervical & thoracic)
Lower Esophageal
Sphincter (LES)
4

5. Tumor as seen via endoscope
endosonography
5

6. Histology of esophagus
6

7. 7

8. Epidemiology
Worldwide
Worldwide estimates for 2000
n Eight most common cancer
with 412,000 new cases
412,
n Sixth most common cause of
cancer death with 338,000
338,
deaths
n 2002 update
462,
462,000 new cases
386,
386,000 deaths
Parkin DM, Lancet Oncol 2001; 2: 533-543
Parkin DM, CA Cancer J Clin. 2005;55:74-108 8

9. Epidemiology
US
US estimates for 2005
• 14,520 new cases
- 11,220 male
- 3,300 female
• 13,570 deaths
9
Jemal A CA Cancer J Clin. 2005;55:10-30

10. Incidence in Egypt
year 2002
n 0.8% of all cancers
n 19th in males and 22nd in females
n Male to female: 1.9:1
n Median age 60 years
n Site: U (10%), M (20%), L (61%), ?
(10%), (20%), (61%),
n Pathology:
n SCC: 65%
65%
n Adeno: 22%
22%
GPCR (2007)
(2007)
10

11. NCI Cairo
n 1.3 % of all cancers
n Male: female: 1.7:1
n Median age 60 y
NCI report (2002, 2003)
(2002, 2003)
11

12. LNs along the esophagus
12

13. Staging
n T:
n 1:
n 1a: Lamina Propria or
n 1b: submucosa
n 2: Musclaris
n 3: Adventitia
n 4: adjacent
n N:
n 1: regional LN
n M:
n 1a: cervical LN in upper
thoracic esoph,
esoph,
celiac LN in lower thoracic eso
n 1b: other distant sites
13

14. 14

15. Stage grouping
T1 T2 T3 T4 M1
(a/b)
N0 I IIA IIA III IV (a/b)
N1 IIB IIB III III IV (a/b)
IV (a/b) IV (a/b) IV (a/b) IV (a/b) IV (a/b)
M1
(a/b)
5y OS 1: 80 2a: 40 3: 10 4a: <5
<5
2b: 20 4b: <1
<1
15

16. Prognostic factors
n Definition:
n Stage: TNM
n Weight loss
n C-reactive protein* [Ikeda, Ann surg, 2003, 238: 179]
2003, 238: 179]
n Others:
n PS
n Age
n Comorbidities
n Sex
n others
16

17. Work-
Work-up
n H&P
n EGD (+Bx)
(+Bx)
n CT Chest and Abdomen e contrast
n CBCD and chemistry
n Barium swallow (optional)
n If no M1:
M1
n Bronchoscopy (T at/above carina)
n EUS
n Laparoscopy (T at EG junction)
n PET
n Biopsy of suspected M1 disease
M1
17

18. Treatment
n Multidisciplinary evaluation:
n Surgeon
n Medical oncologist
n Radiation oncologist
n Radiologist
n Gastroenterologist
n pathologist
18

19. Outcome of initial assessment
n Metastatic (Stage IV B) = M1b
M1
n Very early (stage I): T1 & N0/Nx & M0
N0 M0
n loco-
loco-regionally advanced (Stage II, III,IVA)
(Stage
M1a or N1 or T2-T4)
N1 T2
Factors that govern decision
• Tumor extent: resectable or not
• Patient:
• Choice
• Fitness for radical surgery
• Fitness for chemoradiation
• Clinical setting:
• Surgical expertise and facilities
• Medical and radiation oncology
expertise and facilities
19

20. Stage IVB (metastatic)
n Performance status:
n PS >2: BSC
>2
n PS 0-2: BSC +/- CTh
+/-
20

21. Metastatic EC
21

22. BSC
n Dysphagia:
Dysphagia:
n Restore lumenal passage
n Endoscopic: dilatation, stent, Laser
n Radiotherapy: EBRT, Brachtherapy
n Chemotherapy
n Bypass the obstruction
n Stoma: gastrostomy*, jejenostomy
gastrostomy*,
n Surgery
n Pain
n bleeding
22

23. Chemotherapy
n Primary :
n Metastatic setting, stage IVB
n Regimen: CF
n Pre
n Post
n Peri (pre and post)
23

24. Chemotherapy for metastatic disease
n Compared to adenoCA,
n SCC is more sensitive to chemo, radio, and chemoradiation
n But the long term outcome is the same
n Evolving
n No powered phase III trials
n No survival benefit
n Improves QOL
n No preference of any specific regimen
24

25. Agents
n Cisplatin: 20%
Cisplatin: 20% RR
n Older:
n 5FU Doxo MTX
n Mitomycin Bleomycin
n Newer:
n Docetaxel Paclitaxel Irinotecan
n Oxaliplatin Capecitabine
n Targeted:
n Gefitinib Erlotinib Cetuximab
25

26. Combinations
cisplatin-
cisplatin-containing
n Cisplatin-
Cisplatin- 5FU (CF): RR 20-50%
20-50%
n Paclitaxel- cisplatin-
Paclitaxel- cisplatin- 5FU (PCF): SCC and Adeno
n Irinotecan-cisplatin:
Irinotecan-cisplatin: SCC
n Docetaxel-cisplatin-irinotecan:
Docetaxel-cisplatin-irinotecan: RR 63% (ph II, #16)
63% #16)
n Gemcitabie-cisplatin:
Gemcitabie-cisplatin: RR 45%
45%
n Mitomycin- cisplatin-
Mitomycin- cisplatin- 5FU (MCF) equivalent to
epirubicin-cisplatin-
epirubicin-cisplatin- 5FU (ECF): EG CA, lower QOL
n Capecitabine regimens (ECX)
26

27. Non-
Non-Cisplatin combinations
n Irinotecan- FU-
Irinotecan-5FU-LV: RR 29% in platinum
29%
resistant
n Paclitaxel-
Paclitaxel- carboplatin: RR 43% (neutropenia
43%
G3,4 52%)
52%)
n Oxaliplatin regimens (EOX, EOP)
n Capecitabine
27

28. Phase III trials
n German study group
n Metastatic GE CA
n FLO vs. FLP:
n Overall:
n Less toxicity
n PFS: 5.8 vs. 3.9 m* (trend)
n OS: 10.
10.7 vs. 8.8 (NS)
n Over 65 years:
n RR: 41 vs 17%
17%
n TTF: 5.4 vs 2.3 m
n PFS: 6 vs 3m
n OS: 14 vs 7m
Al-
Al-Batran JCO 26(9). 2008`
26( 2008`
28

29. Phase III trials
n REAL-
REAL-2 trial
n 1002 patients with advanced GE CA (30% E)
(30%
n Adeno,
Adeno, SCC, or undifferentiated
n ECF,
ECF, EOF, ECX, EOX
n RR: 41 42 46 58 %
n 1YOS: 38 40 41 47%
47%
n EOX>>>ECF
n Xeloda=
Xeloda= 5FU
n Oxali = Cisplatin
Cuningham NEJM 358(1). 2008
358(
29

30. Phase IIàIII trial
IIà
n Inoperable E CA
n FOLFOX4
FOLFOX4 vs. CF
n Median OS 22.722. 14.
14.7 m
n Median TTP 15 9.5 m
n Median EFS 11.6
11. 7.8 M
Conory ASCO 2007 # 4532
30

31. Very early (stage I)
T1 & N1/Nx & M0
N1 M0
n Tis and T1a: Lamina propria
T1
n Endoscopic mucosal resection
n Ablation
n Esophagectomy
n (non-
(non-cervical, > 5 cm from cricopharyngeus muscle)
n T1b :
n Esophagectomy ( as above)
31

32. Post-
Post-esophagectomy therapy
n Depends on:
n R (residual): R0= no, R1 = microscopic, R2 =macro
R0 R1 R2
n Histology
n LN status
n Site
n T stage
32

33. Post-
Post-esophagectomy therapy
n R2:
n chemoradiation (fluoropyrimidine based) or
n palliative therapy
n R1:
n chemoradiation (FPB)
n R0:
n Squamous (N+, N-): observe
N-
n Adenocarcinoma:
Adenocarcinoma:
n N+:
n proximal or mid E: observe or chemoradiation
n distal E or EGJ : chemoradiation or chemo (ECF if given preoperative)
n N-:
n Tis /T1: observe
/T1
n T3/4: chemoradiation
n T2: observe or chemoradiation
33

34. Stage II-IVA
II-
(Loco-
(Loco-regionally advanced, M1a, N1, T2-T4)
M1 N1 T2
n Site and histology
n Distal E/EG junction AND adenocarcinoma:
adenocarcinoma:
n Neo-
Neo-adjuvant chemo therapy
n ECF x 3 ->Surgery -> ECF x 3
n Other sites or squamous histology:
n Neo-
Neo-adjuvant or definitive Chemo-radiation
Chemo-
n Definitive:
Definitive: followed by observation or palliative surgery
n Neo-adjuvant:
Neo-adjuvant: to be followed by radical surgery if CR or PR
or palliative therapy/ BSC if SD or PD
34

35. Some scenarios
n Irresectable:
Irresectable: chemoradiation then assess
resectability
n Unfit for surgery or Refused surgery
n Chemoradiation (FPB)
n Unfit for chemoradiation: radiotherapy alone
chemoradiation:
n Unfit for radiotherapy: chemo
n Unfit for any thing: BSC
35

36. Stage II-VIA, resectable and fit
II-
36

37. Stage II-IVA
II-
(Loco-
(Loco-regionally advanced, M1a, N1, T2-T4)
M1 N1 T2
n Applicable to resectable:
resectable:
n T: Tis- T4 (some T4 are unresectable)
Tis- T4 unresectable)
n N: 0,1,X
n M1a: cervial and celiac LN (some M1 celiac are
M1
unresectable )
37

38. Surgery
n Gold standard
n All patients should be assessed for respectability
n Considered for
n ALL
n FIT
n RESECTABLE
n Abdominal and thoracic (> 5 cm from cricopharyngyeus m)
n NB: cervical and thoracic < 5cm CPM: definitive CRT
38

39. Surgery
n Type of surgery:
n Tumor location
n Surgeon: experience and preference
n Patient preference
n Indications:
n Tis T1a (mucosa): EMR, ablation, surgery
n T1b, T2, T3: surgery
T2 T3
n T4 (pericardium, pleura or diaphragm): resectable
n NB: irresectable T4 (heart, great vessels, trachea, liver, spleen, pancreas, lung):
: CRT
n N1: resectable (LN#=15)
(LN#=15)
n M1a lower esophagus and resectable celiac LN
n NB: M1b: systemic treatment
M1
39

40. Limitations of surgery
n Resection of tumor and nodes
n Margin: circuferential and longitudinal
n Anatomic location
n Restoration of continuity
40

41. Radiotherapy
n Definitive and palliative
n Pre- post-
Pre- or post-operative
n Types:
n External beam (EB)
n Brachytherapy (BT):
n Palliation
n Not superior to EB
41

42. Combined modality treatment
42

43. Peri-
Peri-operative CT
43

44. MAGIC trial
44

45. n MRC (MAGIC trial)
n Resectable gastric (74%) , lower esophagus (14%),
(74%) (14%),
EGJ (11%)
(11%)
n S vs ECFx3àSàECFx3
ECFx3 ECFx3
n # 253 250
n 5y OS 23 36%
36%
n PFS HR 0.66
n Down-
Down-staging
Cunningham N Engl J M 355(1). 2006
355(
45

46. Neoadjuvant chemotherapy
46

47. Neoadjuvant chemotherapy
Randomized Trials
Study (year) Patients Chemotherapy pCR (%) Median 5-year P value
Survival (mo) Survival (%)
Roth (1988)
(1988) C + S 19 Neo: C,Vin, Bleo NA 9 NA NS
S 20 Adjuvant: C, Vin 9 NA
Nygaard (1992)
(1992) C + S 50 C, Bleo NA 8 3-y 3 NS
S 41 8 9
Ancona (2001)
(2001) C + S 47 CF X 2 or 3 13%
13% 25 34 NS
S 47 24 22
Schlag (1992)
(1992) C + S 22 CF X 3 NA 10 NA NS
S 24 10
INT 0113 (1998)
1998) C + S 213 Neo CF X 3 2.5% 14.
14.9 2 y 35 NS
S 227 Adj CF X 2 16.
16.1 37
MRC (2002)
(2002) C + S 400 CF X 2 4% 16.
16.8 2 y 43 P = 0.004
S 402 13.
13.3 34
47

48. Preoperative CT
n RTOG 8911 (INT 0113)
0113)
n Potentailly resctable E CA
n S vs CT (CF)àS
(CF)à
n OS same
n R0 59 63 %
n R1 15 4 %
48

49. Preoperative CT
n MRC OEO2 (INT 0113)
OEO2 0113)
n 802 Potentially resctable E CA
n S vs CT (CFx2 )àS
(CFx2
n Median OS 13.3 16.8 m
13. 16.
n 6yOS 17 23 %
49

50. Preoperative CT
n French study group (FFCD 9703)
9703)
n 244 Potentially resectable lower E & G CA
n S vs CT (CF )àS
)à
n 5y PFS 21 34 %
n 5yOS 24 38 %
50

51. Neoadjuvant chemotherapy
Meta-
Meta-analysis
Cochrane Database 2003
n 11 Randomized trials involving 2051 patients
n Clinical relevance based on median survival and 1 to
5 year survival
n When specific survival was not available, it was
calculated from the published survival curves
- Pooled response rate to chemotherapy was about
36%
36% with 3% pCR
- No difference in survival at 1 and 2 years
- Survival advantage starts at 3 years and reaches
statistical significance at 5 years
Cochrane Database Syst Rev 2003; 4: CD001556
2003; CD001556
51

52. Neoadjuvant Chemoradiotherapy
52

53. Non-
Non-Randomized Trials
n 46 trials from 1981 to 1999
n 2704 patients – 69% SCC, 31% Adenocarcinoma
69% 31%
n RT dose from 30 to 60 Gy
n Majority of studies used 5-FU and cisplatin
n Resection rate 74%
74%
n Pathologic CR: 24% (32% surgical patients)
24% (32%
n Patterns of recurrence after surgical resection
- Locoregional 9%
- Distant 31%
31%
- Both 6%
Geh JI, Br J Surg 2001; 88:338-356. 53

54. Randomized Trials
Study Patients Histology Chemotherapy Surgical pCR (%) Median 3-year survival (%) P value
RT mortality (%) Survival (mo)
Nygaard (1992)
(1992) S 41 S Cis + Bleo 13 NA 7.5 9 NS
CS 47 35 Gy 24 7.5 17
Le Prise (1994)
(1994) S 45 S Cis + 5-FU 7 10 10 14 NS
CS 41 20 Gy 8.5 10 19
Apinop (1994)
(1994) S 34 S Cis + 5-FU 15 7 20 NS
CS 35 40 Gy 14 10 26
Walsh (1996)
(1996) S 55 A Cis + FU 4 22 11 6 P = 0.01
CS 58 40 Gy 8 16 32
Law (1998)
(1998) S 30 S Cis + 5-FU 0 25 27 NA NS
CS 30 40 Gy 0 26 NA
Bosset (1997)
(1997) S 139 S Cis 4 26 19 37 NS
CS 143 37 Gy 12.
12.3 19 39
Urba (2001)
(2001) S 50 S (25%)
(25%) Cis + 5-Fu + Vin 2 28 18 16 NS
CS 50 A (75%)
(75%) 45 Gy 7 17 30
Burmeister S 128 S (36%)
(36%) Cis + 5-FU NA 15%
15% 22 NA NS
(2002)
2002) CS 128 A (61%)
(61%) 35 Gy 19 NA
54

55. Primary CRT
n RTOG 85-01
85-
n Esophageal squamous or adenocarcinoma
n T1-3 N0-1 M0
n RT (64Gy 2x32): # 62
(64Gy 32):
n CRT: # 134 RT (50 Gy 2x25)+ CF (Cd1 F d1-4 q 4w x 3)
(50 25)+ (Cd1 d1
n Cis:
Cis: 100 mg/m2/d2 (cis 50mg/m2 d1 and d8)
mg/m2/d2 50mg/m2 d8
n FU: 800 mg/m2/d1-4 CI
mg/m2/d1
n Q 4 or 3 wks
n For 2-3 cycles
55

56. n RTOG 85-01 results
85-
CRT RT
n 5yOS 26 0 %
n Residual 26 37 %
n Life-
Life-threatening toxicity
n 10 2 %
n acute tox High low
n Late tox same same
56

57. INT 0123 trial
n Follow up of RTOG 85-01
85-
n CF+
n LD RT: 50 Gy
n HD RT: 64 Gy
n No difference in OS or treatment failure
57

58. Preoperative CRT
n Resectable CA and fit patient:
n Most common
n Still investigational
n Unresectable
n May facilitate resection
n Resectable but unfit: definitive CRT
58

59. Surgery vs. CRTà Surgery
CRTà
CALGB 9781
n Stage I-III
I-
n # 56
n CRTS S
n Median OS 4.5 1.8 y
n 5yOS 39 16 %
Tepper JCO 26(7). 2008
26(
59

60. Post-
Post-operative CRT
n Resectable adeno CA of stomach and GEJ
n #556
n S vs S+CRT (FU/LV)
n Median OS 27 36 m
n 3yOS 41 50 %
n 3yRFS 31 48 %
n Significant in high recurrence risk
60

61. Neoadjuvant CRT Meta-analyses
Meta-
Urschel J, Am J Surg 2003; 185: 538-543
2003; 185: 538-
- - Neoadjuvant chemoradiation improves 3-year survival, with
more significant benefit in the concurrent studies (OR 0.45,
45,
95%
95% CI 0.26 to 0.79, p = 0.005)
79, 005)
- - Decrease LR but not distant recurrences
Fiorica F, Gut 2004;53: 925-930
2004;53: 925-
- - Neoadjuvant chemoradiotherapy significantly reduces the 3-
year mortality rate (OR 0.53, 95% CI 0.26 to 0.72, p = 0.03)
53, 95% 72, 03)
- - Risk of postoperative mortality is higher in the neoadjuvant
group ( OR 2.10, 95% CI 1.18-3.73, p = 0.01)
10, 95% 18- 73, 01)
Greer SE, Surgery 2005; 137: 172-177
2005; 137: 172-
- - Neoadjuvant chemoradiotherapy is associated with a small,
non-
non-statistically significant improvement in overall survival
(RR of death in neoadjuvant group 0.86, 95% CI 0.74 to 1.01, p
86, 95% 01,
= 0.07)
07)
Malthaner RA, BMC Med 2004; 2: 35
2004;
- A significant difference in the risk of mortality at 3-years favors
neoadjuvant chemoradiation (RR 0.87, 95% CI 0.80-0.96, p
87, 95% 80- 96,
=0.004)
004)
*None of the meta-analysis included Burmeister’s
study, which has been recently published (Lancet Oncol
2005) and at that time was available only in abstract
form 61

62. The Role of Surgery after Chemoradiotherapy
OS
GOCSG Stahl M, J Clin Oncol 2005; 23:: 2310--2317
2005; 23 2310
FLEP X 3 → EP + 40 Gy → surgery (89 patients)
(89
FLEP X 3 → EP + > 66Gy
66Gy (88 patients)
S
CRT
S CRT
3-year OS 31.
31.3% 24.
24.4%
Median survival 16.
16.4 m 14.
14.9 m
FLRP
- CRT resulted in equivalent survival with preserved esophagus
- Surgery significantly increased local control S
- Survival curves appear to spread after 3 years but without
reaching statistical significance
- Patients responding to induction therapy appear to have good CRT
prognosis regardless of surgical intervention
62

63. Initial management
63

64. 64

65. Conclusions
65

66. n EC is a rare disease
n Male predominance
n Old age
n Poor outcome
n Surgical constrains and secondary tumor effects
n CT in met disease has little survival benefit (CF, EOX, FOLFOX)
n Multimodality therapy is very essential
n CCRT supersedes C and RT alone and can be used as
definitive, preoperative or post operative modality
n BSC is important
66