Management of Carcinoma Oesophagus

By – Dr. Satyajeet RathModerator – Prof. Kamal Sahni

Date - 24/01/17

AJCC TNM classification

Staging : Squamous cell carcinoma

Group T N M Grade0 Tis (HGD)

N0

M0

1, XIA T1 1-2, XIB T1 3

T2 1-2, XIIA T2 3IIB T3

Any

T1-2 N1IIIA T1-2 N2

T3 N1T4a N0

IIIB T3 N2IIIC T4a N1-2

T4b AnyAny N3

IV Any Any M1

Staging : Adenocarcinoma

AJCC 8th Edition, TNM 8 Classification

• A tumour the epicenter of which is within 2 cm of the oesophagogastric junction and also extends into the oesophagus is classified and staged using the oesophageal scheme.

• Cancers involving the oesophagogastric junction (OGJ) whose epicenter is within the proximal 2 cm of the cardia (Siewert types I/II) are to be staged as oesophageal

• The AJCC also publish pathological staging for adenocarcinoma and squamous cell carcinoma

Pathological Stage (SCC)Stage 0 Tis N0 M0

Stage IA T1a N0 M0

Stage IB T1b N0 M0

T2 N0 M0

Stage II T3 N0 M0

T1 N1 M0

Stage IIIA T1 N2 M0

T2 N1 M0

Stage IIIB T2 N2 M0

T3 N1, N2 M0

T4a N0, N1 M0

Stage IVA T4a N2 M0

T4b Any N M0

Any T N3 M0

Stage IVB Any T Any N M1

Pathological Stage (Adeno ca)Stage 0 Tis N0 M0

Stage IA T1a N0 M0

Stage IB T1b N0 M0

Stage IIA T2 N0 M0

Stage IIB T1a,T1b N1 M0

Stage IIIA T1 N2 M0

T2 N1 M0

T3, T4a N0 M0

Stage IIIB T2 N2 M0

T3 N1, N2 M0

T4a N1 M0

Stage IVA T4a N2 M0

T4b Any N M0

Any T N3 M0

Stage IVB Any T Any N M1

•

Siewert Classification for GE Junction Adenoca :

• Type I : 5 cm to 1 cm cephalad to above GE junction

• Type II : 1 cm cephalad to 2 cm caudad

• Type III : Below 2 cm from GE junction

Matzinger O, Gerber E, Bernstein Z, et al. EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach. Radiother Oncol 2009;92:164–175

Evolution of treatment

Non surgical treatment• Radiation therapy alone• Combined modality therapy(CT+RT)• Intensification of the radiation dose

Surgical treatment• Sx alone• Sx+adjuvant• Preop CT + Sx

Surgical options

Conservative Esophagectomy

• Mucosal Ablation

• Endoscopic Mucosal resection

• Transthoracic• Transhiatal

• Minimally invasive

Conservative procedures

• Mucosal Ablative techniques• Photodynamic therapy (PDT)• Laser ablation• Multipolar electrocoagulation• Argon plasma coagulation• Radiofrequency ablation (RFA)

Pacifico et al, Surg Oncol Clin North Am 2002

• Endoscopic Mucosal Resection (EMR)• EMR is now considered an essential diagnostic, staging, and therapeutic

option for patients with HGD or superficial disease (T1a). • Involves either

• (a) a submucosal injection of fluid to lift and separate the lesion from the underlying muscular layer or

• (b) the use of suction to trap the lesion into a cylinder. This then allows a full resection and tissue retrieval.

• These results and similar findings in smaller series1 examining EMR confirm that use of this technique is feasible for the treatment of high-grade dysplasia and carcinoma limited to the mucosa (T1a) and provides an alternative to esophagectomy.

1. Nijhawan K et al, Gastrointest Endosc 2000

Conservative procedures

• Criteria for EMR• Lesions with

• No ulceration• T1 N0• No LVI• <2 cm• Wd-md

Esophagectomy: Broad Principles

• Depends on• Site of disease• Extent of disease involvement• Co-morbid conditions• Patient preference• (May depend on) Histology

• Mainstay of treatment for all resectable disease

• T4b disease is non resectable disease.

• A 5 cm margin cranio-caudally should be obtained to ensure negative final microscopic margins.

• Thus not performed for cervical esophagus.

• May be performed for primaries of the upper-third thoracic esophagus depending on location.

• The stomach is considered by the replacement conduit of choice for the resected esophagus.

Esophagectomy: Broad Principles

• An abdominal and a cervical incision with blunt mediastinal dissection through the esophageal hiatus (i.e. Transhiatal esophagectomy [THE])

• An abdominal and a thoracic incision (i.e. Transthoracic esophagectomy [TTE])

Open Esophagectomy

Approaches TTE McKneown

Approaches TTE Ivor Lewis

Transhiatal Esophagectomy (THE)• 2 incisions:

• Upper midline• Left side of neck (6cms)

• Disadvantages of the transhiatal approach• Poor visualization of upper and middle

thoracic esophageal tumors• Increased anastomotic leak rate with

subsequent stricture formation• Possibility of chylothorax, recurrent

laryngeal nerve injury

Transthoracic Esophagectomy(TTE)• 2 incisions:

• Upper midline• Right posterolateral (5th or 6th ICS)

• The greatest advantage of the transthoracic approach is that it provides direct visualization and exposure of the intrathoracic esophagus, allowing wider dissection to achieve adequate margins around the primary tumor, and more thorough lymph node dissection.

• Its disadvantages (reasons for the emergence of transhiatal approach)

• The combined effects of an abdominal and thoracic incision may compromise cardiorespiratory function.

• An intrathoracic anastomotic leak can lead to mediastinitis and sepsis.

• More perioperative pain• Longer duration of surgery

Meta analyses comparing TTE and THE

Rindani et al, Aust N Z J Surg 1999

• Other meta analyses have found similar outcomes with both procedures while showing variable outcomes in terms of patient morbidity.

• Chemotherapy• Regimens• Perioperative / NACT / ACT

• Radiotherapy (with or without chemotherapy)• Neoadjuvant• Postoperative• Definitive• Palliative

Non-Surgical treatmentRadiotherapy and/or Chemotherapy

Rationale of neo-adjuvant treatment

• Downstage the disease:- Enhances resectability • Drugs enhances radiosensitivity• Reduced dissemination of tumor cells during surgery :- Hence reduces distant

metastasis• Remove microscopic persistent disease

RT alone

• No randomized studies comparing surgery alone with radiation alone, and radiation therapy alone has been usually delivered when lesions are deemed inoperable because of tumor extent, medical contraindications, and/or palliative treatment is indicated

Pre-op RT - Cochrane Review 2005

• Median follow-up 9 years

• Mostly squamous carcinomas

• Hazard ratio (HR) of 0.89 (95% CI 0.78-1.01)

• Overall reduction in the risk of death of 11%

• Absolute survival benefit of 3% at 2 years and 4% at 5 years. (p-0.06)

Post-op RT

• 3 studies• French• Hong Kong• Xiao

• Postoperative radiation therapy may decrease local recurrence, particularly in the setting of involved margins, although the impact of this adjuvant treatment on overall survival remains less clear.

• Platinum doublet is preferred over single agents• Cisplatin plus 5-FU are commonly used combinations

Regimens:• Paclitaxel and carboplatin• Cisplatin and 5-FU or capecitabine• Oxaliplatin and 5-FU or capecitabine• Paclitaxel or docetaxel and cisplatin• Carboplatin and 5-FU• Irinotecan and cisplatin• Oxaliplatin, docetaxel and capecitabine• Epirubicin, cisplatin and 5-FU (Only for adenocarcinoma)

Chemotherapy agents

Pre-op Chemotherapy

• 4 RCTs Study Authors/

YearPtsNo

HPE/Site Treatment arms Results

US Intergroup trial/INT 133

Kelsen et al.1998

440 53% adenoca47% SCC

3 5FU/Cis -> Sx ->3 5FU/Cis vs. Sx alone

3 yr OS - 26% vs 23%

MRC MRC 2002 802 66% adenoca31% scc

2 Cis/5FU -> Sx vs Sx alone

2 yr OS - 43% vs 34% 5 yr OS - 23% vs 17%

MAGIC Cunningham2008

503 Lower esophagGEJStomach

3 ECF -> Sx -> 3ECF vs Sx alone

5 yr OS - 36% vs 23%(p-0.009)PFS – (P – 0.001)

FNCLCC/FFCD YchouJCO 2011

224 Lower esophagGEJStomach

2 Cis/5FU -> Sx ->3 5FU/Cis vs Sx alone

5 yr OS 38% vs 24%(p – 0.02)5 yr DFS 34% vs 19%(p – 0.003)

• N = 503 (Chemotherapy 250, Surgery 253; 26% esophageal tumors)• Chemotherapy: epirubicin (50 mg) and cisplatin (60 mg/m2) on d1, and a 5FU CI (200 mg/m2/day for 21 days): 3

cycles each pre and post operatively.• Surgery: 3-6 weeks after NACT/within 6 weeks for controls. ACT was started 6-12 weeks after surgery.

• The primary end point was overall survival.

• ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in both arms (46% and 45% respectively), as was the postop 1 month mortality. The resected tumors were significantly smaller and less advanced in the chemotherapy group.

Cunningham et al. N Engl J Med. 2005;355(1):877–89.

MAGIC Trial

• At a median follow-up of 4 years, 149 patients in the chemotherapy group and 170 in the surgery group had died.

• Adjusted HR for death, 0.74; 95% CI 0.59 to 0.93; p = 0.008• HR for progression 0.66; 95% CI 0.53 to 0.81; p<0.001)• 5-year survival 36% vs. 23%

• Limitations:• Only 42% of patients in the test group completed all protocol treatment.• 5 year survival data with a median survival of 4 years is questionable.

• Conclusion: Perioperative chemotherapy with a regimen of ECF improves OS and PFS among patients with resectable adenocarcinoma of the stomach, lower esophagus, or GE junction, as compared with surgery alone.

Cunningham et al. N Engl J Med. 2005;355(1):877–89.

AUTHOR MEDIAN FOLLOW UP

REGIMEN NO OF PTS

Ro resection/Dist Met

PATH CR LOCOREG FAILURE 3-Yr

SurvivalSURVIVAL DIFF

Urba et al 8.2 5fu+cddp+Vbl+RT+SS

50

50

90 60%90 65%

28-

19%42%P=0.02

30

16

p=0.15

Boset et al 4.6 Cddp+RT+SS

143138

81 69

26---

3436

NS

Walsh et al 1.5 5fu+cddp+RT+SS

58

58

NR NR

25 32

6

P=0.01

Burmeister et al

5.4 5fu+cddp+RT+SS

128

128

80 59

16

---

35

30

NS

Tepper et al(CALGB 9781)

6.0 5fu+cddp+RT+SS

30

26

NRNR

33 13

15

39

16

P=0.008

Pre op CRT f/b Sx vs Sx alone

Cross Trial – Hagen,2012

• Esophagus or esophago-gastric junction• 368 pts , Median FU -45 mnths• 5 cycles of neoadjuvant chemoradiotherapy (intravenous

carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m2 of body-surface area]) with concurrent radiotherapy

• RT - 41·4 Gy, given in 23 fractions of 1·8 Gy • Median overall survival was 49.4 months in the CRT– Sx

group versus 24.0 months in the Sx group. • Overall survival was significantly better in the CRT– Sx

group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P=0.003).

• Long-term results after a minimum follow-up of 5 years• OS and PFS benefit were confirmed for both histological subtypes • LC and distant disease control also improved

CRT f/b Sx Sx alone P value5-yr OS 58% 33% 0.003

5-yr PFS 44% 27% 0.000217

Cross Trial –updated by Shapiro,2015

Urschel Meta-analysis - 2002

• 9 RCT• 1116 patients• Compared with Sx, NA CTRT

• Improved 3 yr OS• Reduced LRF• Higher R0 rates• pCR in 21% pts

• Survival benefit was most pronounced when CT+RT were given concurrently instead of sequentially

Three-year survival (odds ratio 0.66, 95% confidence interval 0.47to 0.92; P - 0.016).

Rate of complete resection (odds ratio 0.53, 95% confidence interval0.33 to 0.84; P - 0.007).

• 6 RCTs• 764 pts• In resectable oesophageal cancer,

preoperative CRT significantly improves three year survival versus surgery alone (NNT=10)

• Reduction in the rate of advanced oesophageal cancer (stages IIb and III) was observed in almost all trials at the time of surgery (down- staging) (NNT = 5).

Florica Meta-analysis - 2004

OR and CI for the effect of treatment on three year overall mortality

Gebski Meta-analysis 2007, Updated by Sjoquist, 2011

• NA CTRT – 10 trials, 1209 pts• NA Chemo – 8 trials, 1724 pts• Updated analysis – 4188 pts• Local operable oesophageal carcinoma

• Neo adjuvant chemo increases • Absolute 2 yr survival – 7%• Absolute 5 yr survival – 4%

• Neo adjuvant CRT increases • Absolute 2 yr survival – 13%• Absolute 5 yr survival – 6.5%

Provides strong evidence for a survival benefit of neoadjuvant chemoradiotherapy or chemotherapy over surgery alone in patients with oesophageal carcinoma. Clear advantage of neoadjuvant chemoradiotherapy over neoadjuvant chemotherapy has not been established.

SCC AdenocarcinomaHR 95% CI P value HR 95% CI P value

CRT 0.80 0.68 – 0.93 0.004 0.75 0.59 – 0.95 0.02CT 0.92 0.81 – 1.04 0.18 0.83 0.71 – 0.95 0.01

Pre op CRT vs Pre op Chemo

• German Trial , JCO Stahl 2009• IC + Sx vs IC + CRT + Sx• locally advanced (uT3-4NXM0) adenocarcinoma of the lower esophagus or gastric cardia • 46 mnths FU, Study closed prematurely• Preoperative radiation therapy improved 3-year survival rate from 27.7% to 47.4%

RT alone vs CRT as Definitive Therapy

• RTOG 85-01• Herskovic 1992, Al sarraf 1997, Cooper 1999

RANDOMISE

Wk 1

50Gy/25 fractions

Wk 5 Wk 11

CDDP 75mg/m2 Day 1 and 5-FU 1gm/m2 C.I. day 1- 4

CT+RT

RT

Wk 8

64Gy/32 fractions

Comp-liance

Gr III toxicity

Gr IV Gr V Localfailure

Distfailure

Median and 5yr survival

CT+RT (n=61)

54% 44% 20% 3% 43% 22% 12.5 mo, 27%

RT (n=60)

83% 25% 3% 0 64% 38% 8.9 mo, 0%

P-value Sig Sig Sig Sig Sig Sigp<0.0001

All patients who received RT alone were dead of disease by 3 years. Established chemoradiation as the conventional nonsurgical treatment for esophageal cancer

RT dose escalation during Definitive CRT

• RTOG 94-05, INT 0123• Minsky et al , JCO 2002• CRT 50.4 Gy vs • CRT 64.8 Gy (Chemo Cis/5FU x 4

cycles)• The trial was stopped after an

interim analysis. The median follow-up was 16.4 months for all patients and 29.5 months for patients still alive.

No significant difference in survival(p=NS)

MS-18 v/s 13 months2 yr survival—40% v/s 31%

No significant difference in time to first failure(52% v/s 56%)

(local /regional failure or locoregional persistance of cancer)

This trial demonstrated that for patients who receive concurrent chemotherapy with radiation, higher doses of radiation therapy do not offer a local/regional control or survival advantage.

Bedenne FFCD 9102 JCO 2007

• In patients with locally advanced thoracic esophageal cancers, especially SCC, who respond to chemoradiation, there is no benefit for the addition of surgery after chemoradiation compared with the continuation of additional chemoradiation

Stahl JCO 2005 , 2008

Conclusion• Adding surgery to chemoradiotherapy improves

local tumor control but does not increase survival of patients with locally advanced esophageal SCC.

• Tumor response to induction chemotherapy identifies a favorable prognostic group within these high-risk patients, regardless of the treatment group.

Is Surgery after chemoradiation a must?

• ConclusionSelective surgery after chemoradiation is an evolving concept; effect on ultimate survival is unclear and the standard remains Neoadjuvant CRT followed by surgery.

Bedenne et alJCO 2007

Adding surgery to CRT improves local control but does not increase survival in locally advanced esophageal SCC.

Stahl et alJCO 2005

Improvement in local controls, but similar 3 year survivals in esophageal SCCs.

Berger et al, JCO 2005, Rohatgi et al Cancer 2005:Patients who achieve a pCR had an improvement in survival compared to those who do not. Surgical resection may not be necessary and has led to the concept of selective surgery after preoperative chemoradiation.

Indications for Post-op Chemo RT :• Unfavourable T2 N0• T3/T4• LN +ve• Close/+ve margin

R0 resection Surveillance

R1 resection

Chemoradiation(if no neoadjuvant therapy)

Observation till progression or Chemotherapy + Radiation

R2 resectionChemoradiation (if not given before)orPalliative Management

• For R0 resections, may consider chemotherapy alone as adjuvant treatment if Node positive.

Postoperative Management - SCC

NCCN 2016

Postoperative Management - Adenocarcinomas

R0 resection

R1 resection

R2 resectionChemoradiationorPalliative Management

N0

N+

Upto T1 Surveillance

> T2

SurveillanceorChemotherapy + Radiation

(No neoadjuvant therapy) Chemoradiation

ObservationorChemotherapy + Radiation

ObservationorChemotherapy + Radiation

NCCN 2016

Radiotherapy Techniques

Radiotherapy

CurativeDose-

50.4 Gy/28#41.4 Gy/23#39 Gy/13#25 Gy/5#

ConventionalConformal

• 3 D CRT• IMRT• IGRT• Arc

Respiratory gatingProton

Palliative

EBRTDose-30 Gy/10#

Brachytherapy12 Gy/#15 Gy/3#

Techniques of radiation therapy• External beam radiotherapy• Important considerations for RT

• Nearby vital structures: spinal cord. lungs, heart• Movement in target tissue and vital structures: lungs, heart• Variable density of tissues: lungs

• Dose limitations• Spinal cord Dmax:45 Gy at 1.8 Gy/fx• Lung: Limit 70% of both lungs <20 Gy• Heart: Limit 50% of ventricles <25 Gy

EBRT• Patient Positioning:

• Cervical and upper thoracic Esophagus: Supine, arms by the side• Middle and Lower third:

• Supine with arms above their head if AP – PA portals are being planned• Prone position may be considered if posterior obliques are being included.

Esophagus is pulled anteriorly and spinal cord can be spared.

• Immobilization: • Vertebral column should be as parallel to couch as possible.

• Image acquisition: Preferably with iv contrast; oral contrast may also be used for better visualization of the lumen.

• A 3 cm margin proximally and distally would cover microscopic disease in 94% of all SCCs.

• For GE junction tumors, a 3cm margin proximally and 5cm distally would allow similar coverage.

• Most contemporary radiation trials used margins of 3 to 5 cm cranially and caudally on the GTV, along with a 2-2.5cm radial margin.

Gao et al, IJROBP 2007

Treatment Fields

Treatment volume• The radiation field should include • the primary tumor • 5-cm cranial • 5 cm caudal margins • 2-cm lateral margins. Lymph nodes• The primary local/regional lymph nodes should receive the same dose. For

cervical (proximal) primary tumors (defined as at or proximal to the carina) the treatment volume includes the bilateral supraclavicular nodes

• GE junction (distal) primaries the celiac axis nodes need to be included.

EBRT – Cervical Esophagus

• 2 anterior obliques and 1 posterior OR• 2 posterior obliques and 1 anterior field• AP – PA followed by opposed oblique pair.

• T-shaped AP-PA Field :• Superior Border: C7• Inferior Border: T4 (carina)• 2 cm lateral margins.• Supraclavivular nodes irradiated electively; can be boosted by

a separate field if required.

EBRT – Middle and Lower Third

• Superior Border: 5 cm proximal to superior extent of disease.

• Inferior Border:• Middle third - GEJ as visualised by Barium swallow• Lower third - Coeliac plexus (L1) to be included.

• AP - PA followed by 1 Anterior and 2 Posterior oblique pairs• 4 Field: AP - PA & opposed laterals – for mid 1/3rd lesions. May

consider prone position.• AP - PA to deliver 36-44 Gy followed by posterior obliques to reach

the full dose.

Initial phase (39.6-41.4 Gy)

Parallel opposed AP-PA fields

- 5cm prox and distal margins

- 2 cm lateral margins

Off cord Boost: After 40-44Gy3 field technique -- one direct anterior and two lateral/ posterior oblique Advantages

- Homogeneous dose distribution- Tumor better covered - Critical organs are out of the field

Current approach

• EBRT using 3D-CRT to a total dose of 50.4 Gy (1.8 Gy per daily fraction) is standard.

• IMRT is often utilized to minimize exposure to adjacent structures.• Proton beam in combination with chemotherapy is being explored.• Targeted biologic agents added to standard cytotoxic chemotherapy is

being explored

Brachytherapy

• Gaspar, 2000• RTOG 9207

• The cumulative incidence of fistula was 18%/year and the crude incidence was 14%. • Esophageal fistulas were treatment-related rather than tumor-related of the six treatment-related

fistulas, three were fatal .• Occurred in the region of the brachytherapy.• Five of the six patients developing fistulas received 15 Gy brachytherapy dose. (median-3.9 months)• The other patient received just one fraction of 5 Gy and developed a fistula within 0.5 months.

American Brachytherapy Society Guidelines

• Active length: visible tumor by UGIE + 1 - 2 cm margins both ways.

• External diameter of applicator must be 6 – 10 mm.• Dose is prescribed 1 cm from mid source or mid dwell

position.

Staging

Upto T1a N0

Upto T4N0

or T3N+

Stage IV

Surgcal candidate?

Surgical candidate?Yes

Yes

No

1. EMR2. Esophagectomy

(?MIE ?Open)3. Ablative procedures

Early stage?

Palliative management• Chemotherapy• Radiotherapy• Stenting/dilatation

No

SurgeryYes

CRT

CRT Surgery

Post opHPE

Adj if locallyadvanced

NoRT

Summary :-

• Stg I – IIIA resectable medically fit :• Pre-op CRT (Cis/5FU + 50 Gy) f/b Sx• Definitive CRT (Definitive mngmt for Cervical Oesophagus)• Sx alone – preferred for non-cervical T1 N0

• Inoperable I – IIIA :• Definitive CRT (Cis/5FU + 50 Gy) [RTOG 85-01, INT 0123]

• Stg IV Palliative :• CRT (Cis/5FU + 50 Gy)• RT alone• Stenting for obstruction

Site-wise management :

• Cervical Oesophagus SCC : • Definitive CRT (Cis/5FU + 50 Gy)

• Thoracic Oesophagus SCC/Adenoca: • Pre op CRT(Cis/5FU + 50 Gy) f/b Sx • Definitive CRT

• Lower esophagus and GE Junction Adenoca : • Peri op Chemo with Sx• Pre op Chemo f/b Sx f/b Post op RT

Thank You