Cancer of the EsophagusTreatment Optionswww.aboutcancer.com

NCCN.org

Staging System, T and N for Esophagus Cancer

Tis T1intramucosal

T1submucosal

aorta

T4T3T2

N0N11-2 nodes

Mucosa

N23-6 nodes

N37+nodes

Muscularispropria

Submucosa

Tis

Endoscopic Resection or

Ablation

Esophagectomy

EMR Endoscopic Mucosal Resection

EMR (endoscopic mucosal resection)

EMR

Photodynamic Therapy

Endoscopic Resection

EMR (endoscopic mucosal resection) or ESD (endoscopic submucosal dissection) or ablation (e.g. RFA or radiofrequency ablation or cryoablation or photodynamic therapy)

Goal is the complete removal and eradication of all cancer in early stage disease (Tis or T1a)

One of the largest studies with long-term follow-up included 402 patients with superficial esophageal squamous carcinoma

The patients were treated either with EMR (48 percent) or ESD (52 percent) The overall survival rates was 84 percent.

Survival was highest among patients whose tumors did not invade beyond the lamina propria (five-year survival rate of 91 percent).

The five-year survival rate was 71 percent both for patients with involvement of the muscularis mucosa and for patients with involvement of the submucosa.

Am J Gastroenterol. 2013;108(4):544.

EMR or ESD• A meta-analysis of 15 studies found that ESD,

compared with EMR, had higher en bloc and curative resection rates as well as lower rates of local recurrence for malignant and premalignant lesions of the gastrointestinal tract. Similar results were noted in two other meta-analyses

• In a retrospective study of 300 patients with squamous cell cancer of the esophagus, patients who underwent resection with ESD had significantly higher en bloc resection rates and lower local recurrence rates compared with patients who underwent EMR (100 versus 53 percent and 1 versus 10 percent, respectively)

T1a

Endoscopic Resection plus

Ablation

Esophagectomy

T1bN0 Esophagectomy

For superficial T1b adenocarcinoma consider endoscopic resection

French FFCD 9901 trial, which randomly assigned 195 patients with stage I or II esophageal or EGJ cancer  to preoperative chemoradiotherapy (fluorouracil plus cisplatin and concurrent RT [45 Gy]) versus surgery alone 

Results Chem/Rad/Sug Surgery Alone

Survival 32 mos 44 mosAdverse Events 65% 35%%Mortality 7.3% 1.1%

J Clin Oncol 2010; 28:302s

T1bN+ or T2-T4a

Squamous

PreOp Chemoradiation

then Surgery

Esophagectomylow risk

Chemoradiation

.A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer.Urschel JD, Vasan H Am J Surg.2003 Jun;185(6):538-43

Compared with surgery alone, neoadjuvant chemoradiation and surgery improved 3-year survival and reduced local-regional cancer recurrence.

Preoperative chemoradiotherapy for oesophageal cancer: a systematic review and meta-analysis.Gut.2004 Jul;53(7):925-30.

In patients with resectable oesophageal cancer, chemoradiotherapy plus surgery significantly reduces three year mortality (OR = 0.53) compared with surgery alone. However, postoperative mortality was significantly increased (OR = 2.10) by neoadjuvant chemoradiotherapy.

Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis.Lancet Oncol.2011 Jul;12(7):681-92.

The HR for all-cause mortality for neoadjuvant chemoradiotherapy was 0.78. The HR for the overall indirect comparison of all-cause mortality for neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy was 0.88.

This updated meta-analysis provides strong evidence for a survival benefit of neoadjuvant chemoradiotherapy or chemotherapy over surgery alone in patients with oesophageal carcinoma

157 esophageal cancer patients at the University of Texas M.D. Anderson Cancer Center The treatment approaches included preoperative chemotherapy, n = 76 or preoperative C/RT, n = 81

Preoperative C/RT demonstrated increased pathologic complete response (28% versus 4%) and overall survival (3 years, 48% versus 29%)

Ann Thorac Surg. 2010 Sep;90(3):892-8;

Preoperative Chemoradiotherapy for Esophageal or Junctional CancerP. van Hagen for the CROSS GroupN Engl J Med 2012; 366:2074-2084

randomly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin and paclitaxel for 5 weeks and concurrent radiotherapy (41.4 Gy), followed by surgery.

Results Chem/Rad/Surg Surgery Alone

R0 Resection92% 69%Path CR 19%Hospital Mortality 4% 4%Median Survival 49.4 mos 24.0 mosSurvival/5y 47% 34%

Months

CRT + Surgery

Surgery

Survival

Surgery Alone Versus Chemoradiotherapy Followed by Surgery for Stage I and II Esophageal Cancer: Final Analysis of Randomized Controlled Phase III Trial FFCD 9901 

Christophe Mariette. J Clin Onc 2014: 2416

randomly assigned to surgery alone or NCRT followed by surgery. CRT protocol was 45 Gy with concomitant chemotherapy composed of fluorouracil and cisplatin

Results Chemo/Rad/Sug Surgery Alone

Survival/3 y 47.5% 53.0%PostOp Mortality 11.1% 3.4%

 Arm A chemotherapy and surgery median survival time 21.1 months, 3-year survival rate 27.7%.

Arm B chemoradiotherapy and surgery): median survival time 33.1 months, 3-year survival rate 47.7%.

JCO February 20, 2009vol. 27 no. 6 851-856

Comparison of Preoperative Chemotherapy Compared With Chemoradiotherapy 

Trial of Preoperative Oxaliplatin, Docetaxel, and Capecitabine With Concurrent Radiation Therapy (45Gy) in Localized Carcinoma of the Esophagus

pCR rate, 49%; Sixty-nine percent of patients underwent surgery. median disease-free survival (DFS) and overall survival (OS) were 16.3 and 24.1 months, respectively. Two-year DFS and OS were 45.1% and 52.2%, respectively. 

Months

Over all Survival

Spigel J Clin Onc 2010:28:2213

T1bN+ or T2-T4a

Squamous

PreOp Chemoradiation

then Surgery

Esophagectomylow risk

Chemoradiation

Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). JAMA.1999 May 5;281(17):1623

Squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0. Combined modality therapy: 50 Gy plus cisplatin and fluorouracil, compared with RT only : 64 Gy in 32 fractions over 6.4 weeks.

Results Chemo-Radiation Radiation

Survival/5Y 14 – 26% 0%

RTOG 94-05J Clin Onc 2002;20:1167

5-FU + cisplatin + radiation (64.8Gy or 50. 4Gy)

Results High Dose Low Dose

Median survival 13.0 mos 18.1 mosSurv/2y 31% 40%Local Failure 56% 52%

Survival from 94-05

50.4Gy

64.8Gy

Months

Randomized Trial of Two Nonoperative Regimens of Induction Chemotherapy Followed by Chemoradiation in Patients With Localized Carcinoma of the Esophagus: RTOG 0113

assigned to receive either induction with fluorouracil, cisplatin, and paclitaxel and then fluorouracil plus paclitaxel with 50.4 Gy of radiation (arm A) or induction with paclitaxel plus cisplatin and then the same chemotherapy with 50.4 Gy of radiation (arm B)

The median survival time was 28.7 months for patients in arm A and 14.9 months for patients in arm B (18.8 months for patients in RTOG 9405). The 2-year survival rate was 56% for arm A and 37% for arm B.

ChemoRadiation Alone, RTOG

Months

Survival

RTOG 0113

RTOG 9405

JCO 2008;28:4551

Survival with ChemoRadiation versus Esophagectomy

Chan. IJROBP ;1999:45:265

10y Survival Chemoradiation with or without Surgery

2 4 6 8 10Years

No Surgery

Surgery

Bidoli. Cancer 2002:94:352

Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus.Stahl. J Clin Oncol. 2005 Apr 1;23(10):2310-7

locally advanced squamous cell carcinoma (SCC) of the esophagus were randomly allocated to either

Induction chemotherapy followed by chemoradiotherapy (40 Gy) followed by surgery (arm A),

or the same induction chemotherapy followed by chemoradiotherapy (at least 65 Gy) without surgery (arm B).

Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus.Stahl. J Clin Oncol. 2005 Apr 1;23(10):2310-7

overall survival to be equivalent between the two treatment groups 

Local progression-free survival was better in the surgery group (2-year progression-free survival, 64.3%) than in the chemoradiotherapy group (2-year progression-free survival 40.7%

Treatment-related mortality was significantly increased in the surgery group than in the chemoradiotherapy group (12.8% v 3.5%)

Years

Survival

Surgery

Radiation

J Clin Oncol. 2005 Apr 1;23(10):2310-7

Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102.Bedenne.

J Clin Oncol. 2007 Apr 1;25(10):1160-8.

Patients received fluorouracil (FU) and cisplatin and either conventional (46 Gy) or split-course (15 Gy X 2) concomitant radiotherapy. Then randomly assigned to surgery (arm A) or continuation of chemoradiation (arm B;FU/cisplatin and either conventional [20 Gy] or split-course [15 Gy] radiotherapy). 

Results Surgery Radiation

Survival/2y 34% 40% Median Surv 17.7 mos 19.3 mos Local Control 66% 57% Stent 5% 32%

Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102.Bedenne.

J Clin Oncol. 2007 Apr 1;25(10):1160-8.

No evidence

of Disease

Surveillance

Esophagectomy

What to Do after PreOp Chemoradiation?

Persistent Disease

Esophagectomy

Palliative Care

What to Do after PreOp Chemoradiation?

PostOperative Therapy

Types of Resection Based on Pathology Findings

R0 = No cancer at Resection MarginsR1 = Microscopic Residual at MarginsR2 = Macroscopic (obvious) residual or Metastases

PostOperative Therapy

Squamous

R0 = SurveillanceR1 = Observation or ChemoradiationR2 = Chemoradiation or Palliation

PostOperative Therapy

Adenocarcinoma

R0 = Surveillance for T1N0consider chemoradiation for others and for all N+R1 = ChemoradiationR2 = Chemoradiation or Palliation

Surgery

Surgery

remove replaced

Esophagus EsophagusEsophagus joined to stomachCancer

Cancer removed

Stomach Stomach

Surgery

Principles of Surgery

All patients who are fit enough to undergo major resection (esophagectomy) should be considered for surgery unless:

Tumor is < 5cm from the cricopharyngeus (too high in the neck)

Superficial (Tis or Ta) enough that endoscopic surgery would be an option

Too locally advanced (inoperable or bulky lymph nodes or metastatic)

T4b

Chemoradiation

Palliative Care

Chemo alone or Radiation alone

Single Agent Chemotherapy

Drug Response Rate

5-FU 17%Doxorubicin 0%Cisplatin 19%Methotrexate 13%Paclitaxel 15-32%Docetaxel 20%Irinotecan 14%

Chemotherapy

Cisplatin-fluorouracil , response rates of 20 – 30% , median survival of 8 months, and 30%/1 year survival

ECF (epirubicin, cisplatin, fluorouracil) ECX (capecitiabine) EOF (oxaliplatin) or EOX response rate was 40 to 48%, survival was 17 to 19 months, and 1 year survival 37 to 47%

N Engl J Med 2008; 358:36-46

Chemotherapy

PreOp ChemoRadiation Protocols

• Paclitaxel (Taxol) and Carboplatin• Cisplatin and Fluorouracil (or

Capecitabine (Xeloda)• Oxaliplatin (Eloxatin) and Fluorouracil

Chemotherapy

Metastatic Protocols

• DCF (docetaxel (Taxotere), cisplatin, fluorouracil

• ECF (epirubicin, oxaliplatin, fluorouracil)• Other drugs: trastuzumab (Herceptin),

irinotecan (Camptosar), Ramucirumab (VEGFR2)

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Cancer of the EsophagusTreatment Options