Esophageal CA Flashcards
What is the Z line
Juncture of esophageal and gastric mucosa
What is the location of the primary cancer based upon?
It is based upon upper (proximal) edge of the tumor in the esophagus
Which part of the esophagus is Squamous cell and Adenocarcinoma of the esophagus most commonly found ?
SCC = middle third ADC = lower third
What is the Siewert Classification of GOJ adenoCA?
Type I:
- At least 1cm above the GEJ
- usually originates in an area of Barrett’s
- +1cm to +5cm
Type II:
- True carcinomas of the cardia
- arising from cardiac epithelium or Barrett’s at the GEJ
- signet ring histology
- +1cm to -2cm
Type III:
- Subcardial gastric carcinomas
- Infiltrate the GEJ or distal esophagus
- -2cm to -5cm
0 = epicenter = point of reference
Describe the anatomical locations of esophageal CA
1) Cervical 15-20cm = upper third 2) Upper thoracic 20-25cm = middle third 3) Middle 25-30cm = lower third 4) Lower 30-40 cm = overlapping ` Some landmarks: - Cricopharyngeus is located at 15cm - Carina at 25cm - Hiatus at 38cm - GEJ at 40cm
Name me the risk factors for Squamous cell oesophagus
1) Carcinogens
- Smoking
- Chewing tobacco/betel nut
- Alcohol
- Nitrosamines
- Furacin C
- Opiates
- Fungal Toxins
- Spices
2) Nutritional deficiencies
- Vitamins A, C, riboflavin
- Trace elements: Molybdenum, zinc
3) Physical factors
- Thermal trauma
- hot food or dinks
- abrasive material food dye
4) Predisposing factors
- Tylosis
- Plummer-Vinson syndrome
- Achalasia
- Celiac sprue
- Alcohol increases risk of SCC only, is a moderate established RF for adenoCA
- 3-5fold with 3+ drinks/day
- risk remains unchanged even after stopping smoking for several years
- Tobacco increases risk of OSCC by 3-7 fold, adenoCA by 2 fold
Tell me about the T staging of AJCC staging Version 7
T1 = lamina propria, Muscularis mucosae, Submucosae T1a = lamina propria, Muscularis mucosae T1b = Submucosae
T2 = invades muscularis propria
T3 = invades adventitious
T4 = invades adjacent structures T4a = resectable tumor invading pleura, pericardium or diaphragm T4b = Unresectable tumor invading other adjacent structures eg. Aorta, vertebral body, trachea
Tell me about the N staging of the AJCC 7th edition
N1 = 1-2 regional LN N2 = 3-6 regional LN N3 = 7 or more LN
What is the difference between AJCC Staging version 6 and version 7?
T and N staging broken down not more specifics
Nodes from SCF to celiac are regional
Different staging for adeno CA and SqCC
GOJ tumors are staged as esophageal Ca
Pls tell me what are the corresponding stages in each of the following:
N3 disease = Stage?
T4a/b =
N2 =
N3 = At least Stage IIIC T4a/b = at least stage IIIC N2 = At least Stage IIIA
When is bronchoscopy evaluation required?
If tumor is at or above the Carina with no evidence of M1 disease
How will you work up a patient suspected of esophageal CA?
History and physical examination
OGD and biopsy
CT Chest/abdomen
PET/CT if no evidence of M1 disease
Blood tests
EUS +/- FNA if no evidence of M1 disease
Bronchoscopy if tumor is at above the Carina with no evidence of M1 disease
Laparoscopy if no evidence of M1 disease and tumor is at GEJ
Biopsy confirmation of suspected metastatic disease
Her2-Neu testing if Met disease is documented/suspected
Assess Siewert Category
Lung function test
When can we consider endoscopic mucosal resection?
Tis and T1a
If no vascular invasion
No poorly diff histology
No nodal mets
How many number of nodes need to be resected?
At least 15
What are the benefits of CRT?
1) Improved OS
2) Tumor down staging
Evidenced by Meta-analysis of pre-2000 studies published by Fiorica in Gut 2004
- 6 RCTs, only 2 with adenoCA
- Walsh et al with 100% adenoCA
- Urba with 75% AdenoCA
What is the evidence for preop ChemoRT?
CROSS Trial by van Hagen NEJM 2012
Resectable tumors 75% adenoCA, 25% SCC 60% lower esophageal, 20% GEJ 80% T3, 65% N1 N=350
2 arms:
1) Surgery alone
2) Carbo AUC2, Pac (50) weekly with concurrent RT (41Gy in 23#) –> Surgery
RESULTS: R0 resection 90% vs 70% Path CR 30% - pCR 20% in adenoCA, 50% in SCC Post-op complx similar Med OS 50m vs 24m
Any evidence AGAINST pre-op ChemoRT?
Yes. FFCD 9901 trial by Mariette et al JCO 2014
Only Thoracic Esophagus
N=200
80% Stage II
70% SCC, 72%Node negative
2 arms: 1) Surgery 2) ChemoRT --> Surgery CDDP (75) D1/5FU(800) D1-4 Q4w for 2 cycles RT 45Gy in 25#
RESULTS:
R0 resection 94% (CRT) vs 92%
3y OS 47% (CRT) vs 53%
Post-op mortality 11% vs 3%
What about evidence for SCC Oesophagus?
Bosset study NEJM 1997
N=300
Stage I/II SCC
80% Node negative
30% T3
Staging done via CT only
2 arms:
1) Surgery
2) ChemoRT –> Surgery
2# one-week course, RT 18.5 Gy over 5#, CDDP (80) 0 to 2 days before RT
RESULTS:
- No diff in OS 18m
- DFS longer with preop CRT
- lower rate of cancer-related deaths with preop CRT
- higher frequency of curative resection with preop CRT
But more post op deaths.
In early stage SCC, pre-op CRT does NOT improve OS
What is the conclusion in the management of SCC esophagus?
T1N0, surgery alone
T2N0 surgery alone reasonable, but different opinions
T3Nx, CRT– > Surgery
T2N1, data is equivocal:
FFCD 9901 only 30% N+, hence follow CROSS and give pre-op CRT
How about evidence for AdenoCA for CRT?
CALGB9781 Tepper et al JCO 2008 N=56 Closed early Thoracic esophagus, T1/2 GOJ 75% adenoCA, 25% SCC 85% T3, 30% N+, no M1a
2 arms:
1) Surgery alone
2) pre-op CRT –>Surgery
RESULS:
- med survival 4.5y vs 1.8y (surgery)
5y OS 40% vs 16%
What is the POET trial about?
Michael Stahl et al. JCO 2009
N=100
Aim is to evaluate Preop chemo vs preop ChemoRT
Lower esophagus T1-3, GOJ, T3/4
100% AdenoCarcinoma
90% T3, 10% T4, no M1a
2 arms:
1) 2.5# PLF weekly 5FU (2g/m2/day) + LV (500)/m2/2h + biweekly CDDP (50) Q6w –> SurgeRy
2) 2 PLF –> 30Gy in 15# of CDDP (50) 1,8 + Etoposide (80) D3-5 + RT 30Gy –> Surgery
RESULTS:
- increased pCR 15% vs 2%
- tumor-free LN 60% vs 40%
- no difference in RO
- increase in post-op mortality 10% vs 4%
What is the evidence for pre-op chemotherapy?
1) Intergroup 0113 (US)
Operable oesophageal and GOJ, 50% adenoCA
12/52 chemo, CDDP (100) 5FU (1000) D1-5 Q4w
- 3# preop, if R0, then 2# postop
70% completed chemo, 20% in chemo arm did not have surgery.
R0 resection 62% vs 59% (Sx alone arm)
3y OS 20%
2) MRC OEO2 (UK)
Operable Oeso and GOJ, 66% lower. 66% adenoCA
6/52 chemo. CDDP (80)/5FU(1000) D1-4Q3w; 2# preop.
90% completed chemo, 8% in chemo arm did not have surgery
R0 resection 60% vs 54% (Sx arm)
10% had preop RT
3y OS 40%
Tell me about the OEO2 study
Allum et al JCO 2009 (updated after 6y f/u)
N=800
Operable Oeso and GOJ cancers, 66% in lower Oeso. 66% adenoCA
2 arms: Preop Chemo–> Surgery vs Sx alone
Chemo used: CDDP (80)/5FU(1000) D1-4 Q21days for 2 cycles pre-op
6/52 duration
90% completed chemo, with 8% did not go for surgery
R0 resection rate 60% vs 54%
3yOS 40%
5yOS 23% vs 17%
Neoadjuvant chemo reduces R2 14% vs 26%
3y survival by Resection status: R0 40%, R1 20%, R2 10%
Tell me about the Intergroup 0113 study
Operable Oeso and GOJ cancers
54% adenoCA
Chemo:
3# pre op and if R0 resection, followed by 2 more # postop
Chemo CDDP (100)/5FU(1000) D1-5 Q28days
Over 12 week period
70% completed chemo and 20% did not make it to surgery
R0 resection 62% vs 59%
3yOS 20%
What are the advantages of pre-op chemo?
1) Downstaging tumor, and improving chance of R0 resection
2) Eliminating micro mets
3) Improve tumor-related symptoms
4) Establishing the sensitivity of tumor to chemotherapy
What is the pivotal trial that established Peri-op chemo as standard of care in UK for oesophageal/gastric CA?
MAGIC trial by David Cunningham NEJM 2006
Aim: establish if addition of peri operative regime of ECF to surgery improves outcomes among patients with potentially curable gastric CA?
Resectable adenoCA of stomach/OGJ or lower esophagus
N=500
70% stomach,
15% lower eso
10% GEJ
2 arms:
1) Surgery within 6 weeks of randomization
2) pre-op ECF 3# –> Surgery within 3-6w –> postop ECF 3# within 6-12w
Chemo:
Day 1 IV Bolus Epiruicin (50)/IV CDDP (60) over 4hr
Day 1-21 IV 5FU CI (2000)
Results: Med OS 24m vs 20m 5yOS 36% vs 23% HR 0.75 Preop chemo well-tolerated with no increase in post-op complications LR: 20% with surgery, 14% with chemo Mets: 37% with surgery, 24% with chemo Resected tumors were significantly smaller and less advanced. Only 40% completed all 6# of chemo
What is the FNLCC/FFCD 9703 French trial on peri-op chemo about?
Ychou et al JCO 2011
N=200
Stomach 25%
GEJ 65%
Lower eso 10%
Lower esophageal, GEJ, stomach adenoCA randomized to:
1) Surgery
2) Preop chemo–>Sx–> post op chemo
Chemo:
CDDP (80) + 5FU (800) D1-5 Q28days for 2-3# followed by surgery.
Then followed by CF for 3-4#
Total CF for 6#
In the chemo arm, 90% received 2-3# pre-op
RESULTS: 5y DFS 35% s 20% HR 0.65 5y OS 40% vs 25% R0 resection 85% vs 75% No increase in post-op mortality
What is the evidence for post-op ChemoRT?
INT 0116 study by MacDonald NEJM 2001
Resected gastric/Type 3 EGJ T1-4/Nx T3/4 70% N+85% Cardia tumors 20% D0 resection 55%, D1 35% and D2 only 10%
Randomized into 2 arms post resection:
1) Observation
2) Chemo –> ChemoRT –> Chemo
Chemo: 5FU (425) D1-5Q28d (1 cycle pre ChemoRT and 2# after)
ChemoRT: 45Gy 25# + 5FU (400) D1-4 and D23-35
RESULTS: Improved RFS 19m vs 30m Improved OS 27m vs 36m 3y PFS 30% vs 50% 3y OS 40% vs 50% D2 with less benefit Diffuse histology also with less benefit
What do you know about definitive ChemoRT?
RTOG 85-01 by Herskovic NEJM, Al-Saraf JCO
T3N0-1 thoracic eso SCF LN allowed 90% SqCC 10% adeno N=120
2 arms:
1) RT (64Gy)
2) ChemoRT
- 2# CDDP(75) D1 + 5FU (1000) D1-4 Q28d
- RT 50Gy/25#
- post-RT, 2 more cycles of CF, but Q3w
RESULTS: Med OS 14m (CRT) vs 9m 5y OS 27% vs 0% Local failure 45% vs 65% RT alone is generally palliative
PIVOTAL trial that showed definitive CRT is a curative option for SqCC or localized Unresectable adenoCA
High local failure rate without surgery
Based on RTOG 85-01, definitive ChemoRT is a possible option for treatment. So, is more RT then therefore better?
NO.
INT 0123, Minsky 2002
N=200
2 arms:
1) 5FU/CDDP 4# + RT 65Gy
2) 5FU/CDDP 4# + RT 50Gy
RESULTS: 2y OS 30% (RT 65) vs 40% (p not sig) Med OS 13m vs 18m Total local recurrence 60%~ Distant failure 10% vs 15%
Higher RT dose did not improve outcome, Many early death seen before 50Gy
?newer conformal RT may overcome increased toxicity
Is Oxaliplatin an option?
Yes
Phase II/III Prodige 5/ACCORD 17
Conroy Tan Lancet Oncol 2014
Unresectable esophageal CA Adeno or Squamous Stage I-IVa Tx-naive No LOW >20% No tracheal invasion or TE fistula N=250
85% Squamous
55% Stage III
10% Stage IV
2 arms:
1) 3#mFOLFOX concurrent with 50Gy RT –> 3#mFOLFOX
2) 2#5FU/CDDP concurrent with 50Gy RT –> 2#5FU/CDDP
RESULTS: (p not sig) Med PFS ~9.5m Med OS 20m vs 17.5m 3y OS 20% vs 27% (CF) Toxicities fairly similar except: - Ox more neuropathy - CDDP more mucositis/alopecia/Creat rise
CONCLUSION: Can substitute mFOLFOX for CF in definitive CRT
Locoregional failure ~40%
What is an option available for frail patient?
Tell me about “modified CROSS”
Horning Ann Onc 2014
Retrospective series
Unresectable Oeso CA
RTOG 8501 vs weekly carbotaxol 6# + 50Gy RT
Similar efficacy. Pac/Carbo only 6/52
Better compliance
Less haem and non-haem tox
But cannot be used for ALL definitive CRT
- small study
- not well-balanced a CDDP/5FU arm had more N+, M1a and GEJ tumors and fewer SqCC (40% vs 60%)
Is surgery needed?
1) FFCD 9102 Bendenne JCO 2007
T3N0-1 Thoracic Eso 90% SqCC 10% adeno Given CRT and those responding randomized to 2 arms: 1) Surgery 2) CRT 20 Gy/1#CF + 2#CF
CRT:
45Gy
2# CDDP (15) D1-5 + 5FU(*00) D1-5
RESULTS:
2y Recurrence rate 57% vs 60% (CRT)
Locoregional prob 30% vs 40%
Met prob 40% vs 30%
Surgery reduces LR failure by about 10% and dysphasia by about 20%
In patients with good response to CRT, OS appears to be similar
=========== 2) German Oeso Cancer Study Group Stahl JCO 2005 SqCC Upper and mid eso T3-4N0-1 n=150 2 arms: 1) Chemo C --> CRT A--> surgery 2) Chemo C--> CRT B
Chemo C = 3# 5FU/Etoposide/Leucovorin/CDDP
CRT A = RT 40Gy/20# + 1#Etoposide/CDDP
CRT B = RT 65Gy/30# + 1#Etoposide/CDDP
Only 66% underwent surgery
If patient has esophageal SqCC what is the method of treatment?
1) T1Nany
2) T2N0
3) T2N+
1) T1 Nany = surgery alone
2) T2 N0 = surgery alone
3) T2 N+ = CROSS, though surgery alone may be ok
In the treatment of Esophageal AdenoCA, what is the preferred treatment method?
1) T1N0
2) T2N0
3) T1-2 N+
1) T1N0 = Surgery alone
2) T2N0 = Surgery alone if
In the treatment of Unresectable SqCC or Adeno Oeso, what should we do?
1) Definitive CRT
- 5yOS 30%
- Fit patients: RTOG 0801 or similar
- not so fit CROSS x6
2) palliative chemo
3) BSC
What is the benefit of adding Cetuximab to the treatment of esophageal cancer treated without surgery?
RTOG 0436
C225 has no benefit in definitive CRT
N=350
6# weekly CDDP (25)/Paclitaxel (50) + C225 weekly + RT 50.4
2y OS 43.5%(Cetuximab) vs 42% (p not sig)
What are the strategies that we can help with dyshagia?
1) Dilatation without Stenting
2) Stents
- Plastic
- Metal
3) Phototherapy
4) Laser ablation
Any role for palliative ChemoRT?
Not really
TOG NCIC study
N=200
Advanced, mostly Met disease (75%)
ECOG 1/2 = 80%
2 arms:
1) Palliative RT
- 35Gy/15# or 30Gy/10#
2) Same RT + CDDP/5FU D1-4 for 1 cycle only
Results:
No difference and OS or PFS
Has better local control with CRT, but will require higher doses of RT and 4# of chemo.
But more toxicities
Conclusion: palliative RT for dyshagia remains Standard of care
- 70% will respond, with median response duration to be 3 months
What are the preop CRT trials?
1) CROSS
2) FFCD 9901
3) Bosset
What are the pre-op Chemo trials?
Intergroup 0113
MRC OEO2
What are the peri-op chemo trials?
MAGIC
FFCD 9703
What are the post-op ChemoRT trials
INT 0116 by MacDonald in NEJM 2001
What are the definitive ChemoRT trials?
RTOG 85-01
INT 0123
PRODIGE 5 /ACCORD 17
What are the trials evaluating if surgery can be omitted?
FFCD 9102
German Oeso Cancer Study Group, Stahl et al JCO 2005
For cervical Oesophagus SCC, what is the preferred modality of treatment?
CRT
What is the preferred modality of treatment for GOJ AdenoCA?
Peri-op chemo with EOX
- if not as fit, XELOX
