multidisciplinary management of squamous cell esophageal cancers

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 29-

35cm from the incisors• Polypoid lesion• Normal gastric exam• Histology: squamous cell

carcinoma

Case 1: (cont.) EndosonographyRemoval of all layers of esophageal wall. Enlarged regional lymph nodes

Bronchoscopy

No infiltration or impression of the tracheo-bronchial tree

21.2 mm

15.4 mm

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)

1. Neo-adjuvant chemoradiotherapy planned Surgery (three field lymphadenectomy)

2. Induction chemotherapy Chemoradiotherapy Surgery only in case of tumor response

3. Definitive chemoradiotherapy including cervical nodes

4. Palliative chemoradiotherapy of primary esophageal tumor

5. Surgery Chemo-RT

What is your recommendation for initial treatment of this 66 year old patient with a T3N2M1 (cervical lymph node metastasis) SCC of mid esophagus?


Answers from the audience to question 1


1. Surgery with three field lymphadenectomy

2. Increasing radiation dose to 66 Gy, including the cervical nodes

3. Completion of chemotherapy up to 4 - 6 courses

4. Wait and see

After radiochemotherapy (50.4 Gy + weekly cisplatin-based chemotherapy) with almost complete response what would be your next recommended step

IS CONCURRENT CHEMORADIATION A VALID ALTERNATIVE TO SURGICAL MANAGEMENT?

Randomized Trials Have Established Trimodality Therapy as a Standard

Compared with Surgery Alone

RADIOTHERAPY QUESTION

Chemoradiotherapy Alone Valid Option for Squamous Cell Carcinomas

Squamous Cell SitesEffective Organ Preserving Curative Therapy for Squamous Cell

• Oropharynx• Larynx• Oral Cavity• Anal• Esophagus?

AdenocarcinomaChemoRT 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% --

Bedenne FCD 1993-2000 40%(responders only)

--

RTOG 04362008-present

??? ???

Why Consider Adding Surgery?Responders to chemoradiation

Randomized +/- surgeryAll Enrolled Patients

Randomized +/- Surgery

Bedenne L et al. JCO 2007;25:1160-1168 Stahl M et al. JCO 2005;23:2310-2317

2 Year Local Control 66% vs. 57%Stent Placement 5% vs. 32% 3 month death 9.3% vs 0.8%

2 year Local PFS 64% vs. 41%Treatment Death 12.8% vs. 3.5%

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: 6% 30 day post-op mortality– ECOG 1201: 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


• 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


• Radiation Oncology Perspective:


Rice TW, Cancer 116:3763, 2010

Stage IV

Data-driven stagingfor the seventh editionof the AJCC / UICCstaging manuals


• 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



What is your recommended treatment for this 66 year old patient with a T3N2M1 (cervical lymph node metastasis) SCC of mid esophagus?

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 alive38 and 46 months

Liu (2011) 30 cervical paraesophageal;78 other cervical

Cisplatin /5FU/RT 60-70 Gy 3 year33% paresoph15% other cervical


What actually happened?


CT scan: After Induction Chemotherapy

The patient received 2 cycles of 6 weeks of induction chemotherapy (cisplatin, 5-FU, folinic acid)

Esophageal tumor regressing (lenght 4 cm)Thickend esophageal wall upto 12.3 mm


• 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


CT scan: After Radio-Chemotherapy

The patient received Radiochemotherapy of the esophagus (66 Gy + weekly application of cisplatin / irinotecan, 50 Gy to the cervical nodes)

Esophageal tumor at and belowthe bifurcation (6 cm in length)Thickend esophageal wall upto 16.7 mm.No more enlarged lymph nodes(also in cervical region). No mets


CT scan: After Radio-Chemotherapy

Rapidly progressive dyspnoeover the last days.Diffuse interstitial opacities in all lobes, suggesting atypical pneumonia


Endoscopy: After Radio-Chemotherapy

Was not performed due to severe dyspnoe.Instead patient was admitted to the hospital andAntibiotic + antimykotic therapy was initiated


1. X-ray and abdominal ultrasound only

2. CT-scan every 3 – 6 months3. PET-scan every 3 – 6 months4. No follow-up, just wait for

symptoms

After having completed definitive radiochemotherapy how do you follow-up the patient?


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 26-

31cm 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

1. Neo-adjuvant chemoradiotherapy planned Surgery

2. Neoadjuvant chemoradiotherapy Surgery only in case of tumor response

3. Neoadjuvant chemoradiotherapy Salvage Surgery in case of residual tumor

4. Definitive chemoradiotherapy without surgery

What is your recommended treatment for this 61 year old somewhat comorbid patient with a T3N1M0 SCC of upper esophagus?

Audience Question (??)

1. Early salvage surgery with curative intent

2. Increasing radiation dose to 66 Gy to prolong time to local tumor progression

3. Consolidation chemotherapy to prolong time to progression?

4. Wait and see

What if the same patient will not show any tumor response to radiochemotherapy, but still may have localised EC?

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

0 6 12 18 24 30 36 42 48 54 600.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

R1 Resection

p < 0.0001

R0 Resection

Survival

Frac

tion

Aliv

e

Pts at Risk: R0 : 814 539 347 234 182 141

R1 : 65 26 11 7 5 3

0 6 12 18 24 30 36 42 48 54 600.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

No Preop C/RT

p = 0.003

Preop C/RT

Pts at Risk: No C/RT: 685 447 289 205 166 130 C/RT: 194 118 69 36 21 14

Survival

Frac

tion

Aliv

e

Treatment outcomes of resected esophageal cancer. Hofstetter W, et al. Annals of Surgery (2002) 236:376-84


• Radiation Oncology Perspective:


• 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) p = 0.07

Gebski 2007 0.81 (0.70-0.93) p = 0.002

Kranzfelder 2011 0.81 (0.70-0.95) p = 0.008

CRT+S vs S alone Meta-Analysis – 30-day mortality after S

Kranzfelder M, Br J Surg 98:768-83, 2011

HR = 1.46 (0.91 – 2.33)

N = 509 vs 510

Locally advanced SCCWho may benefit from Surgery?

FFCD: Bedenne L, JCO 25:1160,2007

Randomisation prior to treatment (all patients)

Randomisation only of patientswith tumor response after CRTX

GECSG: Stahl M, JCO 23:2311,2005

Prospective non-random. ComparisonS vs. CRT + Salvage-S in case of non-response

Ariga H, Int J Radiat Oncol Biol Phys 75:348, 2009

Informed Decision(n=99)

Patient votes for S(n=48)

Patient votes for CRT*(n=51)

* Cis/FU + 60 Gy

Salvage S(n=13)

Primary Surgery(n=46)

Prospective non-random. ComparisonS vs. CRT + Salvage-S in case of non-responseOverall Survival


5-YSRCRT 75%S 51%p = 0.02

Prospective non-random. ComparisonS vs. CRT + Salvage-S in case of non-responseSurvival stage II and III


5-YSR

CRT 65% (n=36)S 44% (n=38)p = 0.08


Answers from the audience

What is your recommended treatment for this 61 year old somewhat comorbid patient with a T3N1M0 SCC of upper esophagus?


What actually happened?


CT scan: After Induction Chemotherapy

The patient received 1 cycle of 6 weekly applications of induction chemotherapy (cisplatin, 5-FU, folinic acid)

No Change:• No improvement of dysphagia• No tumor shrinkage• Identical size ofenlarged lymph nodesalong the trachea

Case 2: T3 N1 M0 Radiation fields


CT scan: During Radio-Chemotherapy (30 Gy)

After that the patient received Radiochemotherapy of the esophagus (66 Gy intended + weekly application of cisplatin / irinotecan)


Endoscopy: During Radio-Chemotherapy (30 Gy)

After that the patient received Radiochemotherapy of the esophagus (weekly application of cisplatin / irinotecan)


• Pulmonary function test• FEV1: 2,1 l (77% of normal value)

• Echokardiography• Extended left atrium, ejection fraction 60%

Re-Assessment of operability during RCT

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

• 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--

Minsky JCO 2002;20(5):1167-74

INT-0123


• 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


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


Follow-up

• Patient alive without tumor recurrence at 8 months after surgery


Audience questions for panel

multidisciplinary management of squamous cell esophageal cancers

Documents

squamous cell carcinoma

t3n1m0 squamous cell

localised squamous cell

5ut3 n2 m1 lymph case

audience question

johns hopkins university

surgical oncology

management of patients