Transcript Multidisciplinary Management of Squamous Cell Esophageal

Multidisciplinary
Management of Squamous
Cell Esophageal Cancers
Case presentations & treatment
perspectives from Gastroenterology
Radiation Oncology, Surgical Oncology, and
Medical Oncology
Learning Objectives:
After attending this session, the
participants should be able to:
• Identify current controversies in the management of
patients with localised squamous cell cancer of the
esophagus
• Discuss state-of-the art treatment options for patients
esophageal squamous cell cancers
Session Outline:
• Case 1: T3N2M1 (cervical lymph node)
squamous cell carcinoma
• Case 2: T3N1M0 squamous cell
carcinoma in a comorbid patient
Perspectives:
• Radiation Oncology:
Lawrence R. Kleinberg, Johns Hopkins University
• Surgery:
Joe B. Putnam, Vanderbilt University
• Medical Oncology:
Michael Stahl, Kliniken Essen-Mitte
• Gastroenterology:
Mouen A. Khashab, Johns Hopkins University
Case 1
Case 1:
 66 year old man, still working as a
physician in practice, ECOG 0, peripheral
arterial occlusive disease (recently
stenting of A. iliaca com.), normal liver
and renal function
 EGD:
•
•
•
•
Obstructing tumor 2935cm from the incisors
Polypoid lesion
Normal gastric exam
Histology: squamous cell
carcinoma
Case 1: (cont.)
 Endosonography
Removal of all layers of
esophageal wall. Enlarged
regional lymph nodes
21.2 mm
15.4 mm
 Bronchoscopy
No infiltration or
impression of the
tracheo-bronchial
tree
Case 1: (cont.)
 PET-CT
 primary cancer of the
esophagus, length 7 cm
(SUV 16.5),
 3 nodes in the upper
mediastinum (SUV 3.0 –
6.1)
 Right cervical node of 6.1
cm3 volume (SUV 16.5)
 uT3 N2 M1 (lymph)
Case 1: T3 N2 M1 (cervical lymph node)
• Gastroenterology Perspective on diagnosis:
Audience Question (1)
What is your recommendation for initial treatment of this 66
year old patient with a T3N2M1 (cervical lymph node
metastasis) SCC of mid esophagus?
1.
2.
3.
4.
5.
Neo-adjuvant
chemoradiotherapy  planned
Surgery (three field
lymphadenectomy)
Induction chemotherapy 
Chemoradiotherapy  Surgery
only in case of tumor response
Definitive chemoradiotherapy
including cervical nodes
Palliative chemoradiotherapy
of primary esophageal tumor
Surgery  Chemo-RT
Case 1: T3 N2 M1 (cervical lymph node)
Answers from the audience to question 1
Audience Question (2)
After radiochemotherapy (50.4 Gy + weekly cisplatin-based
chemotherapy) with almost complete response what would
be your next recommended step
1.
2.
3.
4.
Surgery with three field
lymphadenectomy
Increasing radiation dose to 66
Gy, including the cervical
nodes
Completion of chemotherapy
up to 4 - 6 courses
Wait and see
Case 1: T3 N2 M1 (cervical lymph node)
Answers from the audience to question 2
RADIOTHERAPY QUESTION
Randomized Trials Have Established
Trimodality Therapy as a Standard
Compared with Surgery Alone
IS CONCURRENT CHEMORADIATION
A VALID ALTERNATIVE TO SURGICAL
MANAGEMENT?
Chemoradiotherapy Alone Valid
Option for Squamous Cell
Carcinomas
Squamous Cell Sites
Effective Organ Preserving
Curative Therapy for Squamous
Cell
•
•
•
•
•
Oropharynx
Larynx
Oral Cavity
Anal
Esophagus?
Adenocarcinoma
ChemoRT Not Effective Option
for Local Control
•
•
•
•
Parotid
Pancreas
Colon
Rectum
Radiochemotherapy: Curative For
Esophageal Squamous Cell Carcinoma?
Trial
2 Year
5 Year
RTOG (Cooper/Herskovic)
Randomized,1995-1990
36%
26%
RTOG Confirmatory,1990-91
35%
14%
Stahl, 1994-2002
35%
--
40%
(responders only)
--
???
???
Bedenne FCD 1993-2000
RTOG 0436
2008-present
Why Consider Adding Surgery?
Responders to chemoradiation
Randomized +/- surgery
2 Year Local Control 66% vs. 57%
Stent Placement
5% vs. 32%
3 month death
9.3% vs 0.8%
Bedenne L et al. JCO 2007;25:1160-1168
All Enrolled Patients
Randomized +/- Surgery
2 year Local PFS 64% vs. 41%
Treatment Death 12.8% vs. 3.5%
Stahl M et al. JCO 2005;23:2310-2317
Is data for chemoradiation as a viable alternative
still valid today?
Questions Exist
– The competing risks that prevent a benefit may
be less important in current area
• Only those who survive surgery: Mortality decreased
in recent trials.
– “CROSS” Trial:
– ECOG 1201:
6% 30 day post-op mortality
3% 30 day post-op mortality
• Only those without metastasis at time of treatment can
benefit. Better staging today with PET, CT scanning.
• More successful systemic therapy may increase
importance of local control for survival.
• Better ability to select responders may be important.
When Should Surgery be Added?
Issue Remains Controversial.
• All appropriate surgical candidates for local control
benefit?
• All appropriate surgical candidates as benefits may be
greater now with decreased mortality and more accurate
staging?
• In clinical trials to better assess new systemic therapies
with reduced competing risk of local progression?
• PET Guided Assessment of Response to ChemoRT in
Future?
–
–
–
–
–
SUV decline >51% after PET 4-5 weeks/6-7 weeks RT
Hazard ratio for death 0.331
Median Survival 37 vs. 19 months
5 Year survival 40% vs. 0%
Yang Clin Nucl Med 2011;36: 860–866
• CT Scan/EUS Unreliable at assessing response
Case 1: T3 N2 M1 (cervical lymph node)
• Surgery Perspective: Joe B. Putnam, MD; Vanderbilt University,
Nashville, Tennessee
• Esophagectomy in the presence of extrathoracic nodal metastases is
not standard.
• If palliation of dysphagia has occurred, then the role of surgery would be
supportive only.
• If recurrence, endoscopy and stent placement could be considered
Case 1: T3 N2 M1 (cervical lymph node)
• Radiation Oncology Perspective:
Case 1: T3 N2 M1 (cervical lymph node)
Data-driven staging
for the seventh edition
of the AJCC / UICC
staging manuals
Stage IV
Rice TW, Cancer 116:3763, 2010
Case 1: T3 N2 M1 (cervical lymph node)
• Medical Oncology Perspective: M. Stahl, Kliniken Essen-Mitte, Essen,
Germany
• We must reflect that patients with distant lymph node
metastases can only be treated with palliative intent
• So, palliative chemotherapy and best supportive care are
indicated
• Special focus should be kept on sustaining the capability to
swallow
Case 1: T3 N2 M1 (cervical lymph node)
What is your recommended treatment for this 66 year old
patient with a T3N2M1 (cervical lymph node metastasis)
SCC of mid esophagus?
Answers from the audience to question 2
Radiotherapy Question
Should patients with cervical and
supraclavicular disease be treated
for cure?
Should Deep Cervical/Supraclivicular
Nodes be Irradiated?
Lymph Flow Esophageal
Cancer
Incidence of Cervical Nodes
• Squamous cell clinical and
imaging positive cervical
nodes*, 1017 pts
– Upper third 17%
– Middle third 4%
– Lower third 2%
• Subclinical Cervical Nodes**
• Aggregate analysis 18,415 pts.
• 3 Field dissection
– Upper third 30%
– Middle third 17%
– Lower third 11%
Nishira, Surg Today (1995) 25:307-317
*Huang, Rad and Oncol 95: 2010; 229–233
**Ding, Br J Radiol. 2012 85: 1110-9
Cervical (Deep Cervical and
Supraclavicular) Nodes Curable?
Selected cases; Some example reports
Series
Number of Pts.
Therapy
Survival
Shim (2005)
24 M1a
Resection
24% 5 year
Tong (2008)
17 M1a, selected
after neoadjuvant tx
Preop 5FU/Cisplatin/RT
20% 5 Year
Chao (2010)
14 M1a
Preop 5FU/Cisplatin/ 30
GyRT
42% 5 year
Ruhstaller (2010) Propsective
“beyond hope”
5 Squamous M1a
Docetaxel/Cisplatin/59.4
Gy RT
2/5 alive
38 and 46 months
Liu (2011)
Cisplatin /5FU/RT 60-70 Gy
3 year
33% paresoph
15% other
cervical
30 cervical
paraesophageal;
78 other cervical
Case 1: T3 N2 M1 (cervical lymph node)
What actually happened?
Case 1: T3 N2 M1 (cervical lymph node)
The patient received 2 cycles of 6 weeks of
induction chemotherapy (cisplatin, 5-FU, folinic acid)
CT scan: After Induction Chemotherapy
Esophageal tumor regressing
(lenght 4 cm)
Thickend esophageal wall up
to 12.3 mm
Case 1: T3 N2 M1 (cervical lymph node)
• Combined radiochemotherapy was initiated
• The patient (orthopedic surgeon) demanded
surgery
• In our center we advised him against surgery
• The patient was sent to a surgical high volume
center in Germany
• There surgery was also regarded as not
indicated
• The patient decided to complete definitive
radiochemotherapy as planned
Case 1: T3 N2 M1 (cervical lymph node)
The patient received Radiochemotherapy of the
esophagus (66 Gy + weekly application of
cisplatin / irinotecan, 50 Gy to the cervical nodes)
CT scan: After Radio-Chemotherapy
Esophageal tumor at and below
the bifurcation (6 cm in length)
Thickend esophageal wall up
to 16.7 mm.
No more enlarged lymph nodes
(also in cervical region). No mets
Case 1: T3 N2 M1 (cervical lymph node)
CT scan: After Radio-Chemotherapy
Rapidly progressive dyspnoe
over the last days.
Diffuse interstitial opacities in all
lobes, suggesting atypical pneumonia
Case 1: T3 N2 M1 (cervical lymph node)
Endoscopy: After Radio-Chemotherapy
Was not performed due to severe dyspnoe.
Instead patient was admitted to the hospital and
Antibiotic + antimykotic therapy was initiated
Audience Question (3)
After having completed definitive
radiochemotherapy how do you follow-up
the patient?
1.
2.
3.
4.
X-ray and abdominal
ultrasound only
CT-scan every 3 – 6 months
PET-scan every 3 – 6 months
No follow-up, just wait for
symptoms
Case 1: T3 N2 M1 (cervical lymph node)
Answers from the audience to question 3
Case 1: T3 N2 M1 (cervical lymph node)
Audience questions for panel
Case 2
Case 2:
 61 year old patient, ECOG 1, COPD, GOLD
group B (pink puffer), coronary heart disease
without cardiac infarction, normal liver and
renal function
 EGD:
•
•
•
•
Obstructing tumor 2631cm from the incisors
ulcerous lesion
Normal gastric exam
Histology: squamous cell
carcinoma
Case 1: (cont.)
 Endosonography
•
Removal of all layers of
esophageal wall. At lease 3
enlarged regional lymph nodes
 Bronchoscopy
• Impression of
dorsal wall of
trachea without
infiltration
Case 1: (cont.)
 PET-CT
• primary cancer of the
esophagus, length 6 cm
(SUV 12.5)
• 2 regional lymph nodes
(SUV 4.0 – 7.0)
• uT3 N1 M0
Case 2: T3 N1 M0
• Gastroenterology Perspective on diagnosis:
Audience Question
What is your recommended treatment for this 61 year old
somewhat comorbid patient with a T3N1M0 SCC of upper
esophagus?
1.
2.
3.
4.
Neo-adjuvant
chemoradiotherapy  planned
Surgery
Neoadjuvant
chemoradiotherapy  Surgery
only in case of tumor response
Neoadjuvant
chemoradiotherapy  Salvage
Surgery in case of residual
tumor
Definitive chemoradiotherapy
without surgery
Audience Question (??)
What if the same patient will not show any tumor response
to radiochemotherapy, but still may have localised EC?
1.
2.
3.
4.
Early salvage surgery with
curative intent
Increasing radiation dose to 66
Gy to prolong time to local
tumor progression
Consolidation chemotherapy
to prolong time to
progression?
Wait and see
Case 2: T3 N1 M0 (mid esophagus)
• Surgery Perspective: Joe B. Putnam, MD; Vanderbilt University,
Nashville, Tennessee
• Staging of middle third esophageal tumors must include bronchoscopy
• Esophagectomy can be performed safely following neoadjuvant
chemoradiotherapy. Typical dose in the United States is 50.4 Gy
• Neoadjuvant chemoradiotherapy is associated with R0 resection
• R0 resection is associated with improved survival.
• The decision for resection is made by the surgeon based on a
multidisciplinary group discussion, and prior to the initiation of any
therapy.
• Resection is not performed if extra-regional metastases are confirmed.
Locally Advanced Disease
• Dedicated multidisciplinary esophageal conference
– Esophageal cancer
– Benign esophageal diseases
– Clinical services involved include:
• Thoracic Surgery
• General Surgery
• GI Medical Oncology (specialist in GI, esophageal
cancer)
• GI Radiation Oncology
• Pathology
• Gastroenterology (experts in esophageal diseases,
EUS with FNA, ablation techniques, GERD and
motility studies)
• Speech pathology
Long-term survival improves with
R0 resection and preop chemoradiotherapy
1.0
1.0
0.9
0.9
p < 0.0001
p = 0.003
0.8
Fraction Alive
Fraction Alive
0.8
0.7
0.6
R0 Resection
0.5
0.4
0.3
0.7
Preop C/RT
0.6
0.5
0.4
0.3
R1 Resection
0.2
No Preop C/RT
0.2
0.1
0.1
0.0
0.0
0
6
12
18
24
30
36
42
48
54
60
0
6
12
Survival
Pts at Risk:
R0 : 814
R1 : 65
539
26
347
11
234
7
18
24
30
36
42
48
54
60
Survival
182
5
141
3
Pts at Risk:
No C/RT: 685
C/RT: 194
447
118
289
69
205
36
166
21
130
14
Treatment outcomes of resected esophageal cancer. Hofstetter W, et al. Annals of Surgery (2002) 236:376-84
Case 2: T3 N1 M0 (mid esophagus)
• Radiation Oncology Perspective:
Case 2: T3 N1 M0 (mid esophagus)
• Medical Oncology Perspective: M. Stahl, Kliniken Essen-Mitte, Essen,
Germany
• Based on a couple of meta-analyses trimodal therapy is
regarded as standard treatment for locally advanced
esophageal cancer
• Patient selection is crucial due to high probability of
postoperative mortality after radiochemotherapy
• Definitive radiochemotherapy is an option for patients with
increased operative risk
• Early salvage surgery should be included in the treatment
plan for patients with incomplete tumor response
Esophageal Cancer (SCC/AC)
Meta-analysis RCT+S vs S alone
Autor / Jahr
Hazard Ratio
Log rank
p
Urschel 2003
0.66 (0.47-0.92)
p = 0.02
Fiorica 2004
0.53 (0.31-0.89)
P = 0.03
Malthaner 2004
0.87 (0.80-0.96)
p < 0.05
Stuschke 2004
0.63 (0.47-0.85) p = 0.002
Greer 2005
0.86 (0.74-1.01)
Gebski 2007
0.81 (0.70-0.93) p = 0.002
Kranzfelder 2011
0.81 (0.70-0.95) p = 0.008
p = 0.07
CRT+S vs S alone
Meta-Analysis – 30-day mortality after S
N = 509 vs 510
HR = 1.46 (0.91 – 2.33)
Kranzfelder M, Br J Surg 98:768-83, 2011
Locally advanced SCC
Who may benefit from Surgery?
Randomisation prior to
treatment (all patients)
GECSG: Stahl M, JCO 23:2311,2005
Randomisation only of patients
with tumor response after CRTX
FFCD: Bedenne L, JCO 25:1160,2007
Prospective non-random. Comparison
S vs. CRT + Salvage-S in case of non-response
Informed Decision
(n=99)
Patient votes for
CRT*
(n=51)
Patient votes for S
(n=48)
Primary Surgery
(n=46)
Salvage S
(n=13)
Ariga H, Int J Radiat Oncol Biol Phys 75:348, 2009
* Cis/FU + 60 Gy
Prospective non-random. Comparison
S vs. CRT + Salvage-S in case of non-response
Overall Survival
5-YSR
CRT 75%
S
51%
p = 0.02
Ariga H, Int J Radiat Oncol Biol Phys 75:348, 2009
Prospective non-random. Comparison
S vs. CRT + Salvage-S in case of non-response
Survival stage II and III
5-YSR
CRT 65% (n=36)
S
44% (n=38)
p = 0.08
Ariga H, Int J Radiat Oncol Biol Phys 75:348, 2009
Case 2: T3 N1 M0 (mid esophagus)
What is your recommended treatment for this 61 year old
somewhat comorbid patient with a T3N1M0 SCC of upper
esophagus?
Answers from the audience
Case 2: T3 N1 M0 (mid esophagus)
What actually happened?
Case 2: T3 N1 M0 (mid esophagus)
The patient received 1 cycle of 6 weekly
applications of induction chemotherapy (cisplatin,
5-FU, folinic acid)
CT scan: After Induction Chemotherapy
No Change:
• No improvement of dysphagia
• No tumor shrinkage
• Identical size of
enlarged lymph nodes
along the trachea
Case 2: T3 N1 M0 Radiation fields
Case 2: T3 N1 M0 (mid esophagus)
After that the patient received Radiochemotherapy
of the esophagus (66 Gy intended + weekly
application of cisplatin / irinotecan)
CT scan: During Radio-Chemotherapy (30
Gy)
Case 2: T3 N1 M0 (mid esophagus)
After that the patient received Radiochemotherapy
of the esophagus (weekly application of cisplatin /
irinotecan)
Endoscopy:
During Radio-Chemotherapy
(30 Gy)
Case 2: T3 N1 M0 (mid esophagus)
Re-Assessment of operability during RCT
• Pulmonary function test
•FEV1: 2,1 l (77% of normal value)
• Echokardiography
•Extended left atrium, ejection fraction 60%
RADIOTHERAPY QUESTION?
What Radiotherapy Dose to Use?
NCCN Guidelines
• Preoperative Therapy 41.4-50.4 Gy (1.8-2
Gy/day)
• Postoperative Therapy: 45-50.4 Gy (1.8-2
Gy/day)
• Definitive Therapy: 50-50.4 Gy (1.8-2
Gy/day)
– Higher doses may be appropriate for tumors
of the cervical esophagus, especially when
surgery is not planned
Optimal Radiation Dose
in the past, under current
circumstances, and for
the future
INT-0123
Minsky JCO 2002;20(5):1167-74
• Do the results of Int-0123 apply today?
• Improved systemic control may increase survival benefit to
improved local control
• Better planning technologies may allow safer dose escalation.
• Better initial staging to r/o distant metastasis unaddressed by local
radiation.
• Better imaging to plan treatment: Beams eye view of target and
normal tissues to allow better targeting and avoidance of possible
underdosage in part of tumor.
50.4 accepted in US, surgery at Hopkins, Japan.Europe---NCCN--
Case 2: T3 N1 M0 (mid esophagus)
• Tumor board decision for early salvage
surgery
• Transthoracic esophagectomy with
cervical anastomosis of pulled-up
stomach
• Path: ypT3yN2Mx, R0 – invasive poorly
differentiated SCC.
• Regression grade 2 according to Dworak
• 5/12 paraesophageal LNs
• 0/15 para-gastric LNs
Case 2: T3 N1 M0 (mid esophagus)
 Outcome after surgery
• 16 days on intensive care unit
• Need for prolonged mechanical
ventilation due to pneumonia and
intermittent arrhythmia absoluta
• Leak of cervical anastomosis, handled
by conservative treatment
• Hospital stay for 32 days
Case 2: T3 N1 M0 (mid esophagus)
 Follow-up
• Patient alive without tumor recurrence
at 8 months after surgery
Case 2: T3 N1 M0 (mid esophagus)
Audience questions for panel