Oesophageal cancer

By

Osama Elzaafarany, MDAssistant lecturer of clinical oncology

Medical Research Institute, Alexandria University

Jan 2015

Introduction: Esophageal cancer is the 8th most common cancer worldwide.

Esophageal cancer is the 7th leading cause of cancer deaths.

At USA, in 2014 estimated ≈ 18.000 cases and ≈ 15.500 deaths from esophageal cancer.

The crude incidence of oesophageal cancer in the European Union (EU) is about 4.5 cases/100 000/year (43 700 cases)

accounts for 1% of all malignancy & 6% of all GI malignancy.

Most common in China, Iran, South Africa, India and the former Soviet Union.

The incidence rises steadily with age, reaching a peak in the 6th to 7th decade of life.

Male : Female = 3.5 : 1

African-American males : White males = 5:1

Pathological Classification

• Esophageal intraepithelial neoplasia

• Glandular epithelial dysplasia/adenocarcinomain situ in Barrett's mucosa

PreinvasiveNeoplasia

• Squamous cell carcinoma

• Adenocarcinoma,

• Adenoid cystic carcinoma

• Mucoepidermoid carcinoma

• Adenosquamous carcinoma

• Small cell carcinoma

• Carcinoid tumor

• Malignant melanoma

• Sarcomas

Invasive Malignant Neoplasia

95%

Worldwide squamous cell carcinoma (SCC) responsible for most of the cases.

SCC usually occurs in the middle 3rd of the esophagus (the ratio of upper : middle : lower is 15 : 50 : 35).

Adenocarcinoma (AC) is most common in the lower 3rd of the esophagus, accounting for over 65% of cases.

Risk Factors : Squamous Cell Carcinoma

Smoking and alcohol (80% - 90%)

Dietary factors:

N-nitroso compounds (animal carcinogens)

Pickled vegetables and other food-products

Toxin-producing fungi

Betel nut chewing

Ingestion of very hot foods and beverages (such as tea).

Underlying esophageal disease: (such as achalasia and

caustic strictures, Tylosis)

Genetic abnormalities: p53 mutation, loss of 3p and 9q alleli,

amp. Cyclin D1 & amp. EGFR

Risk Factors:

Adenocarcinoma

Associated with Barretts’s esophagus, GERD

& hiatal hernia.

Obesity (3 to 4 fold risk)

Smoking (2 to 3 fold risk)

Increased esophageal acid exposure such as

Zollinger-Ellison syndrome.

Site-wise nodal involvement

Site-wise nodal involvement

Staging

Diagnostic work-up:(according to ESMO-guidelines)

The diagnosis should be made from an endoscopic biopsy with the histology to be classified according to the World Health Organization criteria.

Should include:1) Cinical examination.2) Bood count, liver-, pulmonary- and renal function tests.3) Endoscopy: (including upper-aerodigestive tract endoscopy in

case of tumours at or above the tracheal bifurcation).4) Computed tomography (CT) scan of chest and

abdomen. 5) In candidates for surgical resection endoscopic

ultrasound and positron emission tomography (PET)-CT should be added in order to evaluate the T- and N-category of the tumour. Nevertheless, the accuracy of clinical N-staging does not exceed 80%.

Treatment

Surgery

= Limited disease

= Locally advanced disease

Treatment overview

Contraindications to surgery:

1) Metastasis to N2 nodes (ie, cervical or supraclavicular lymph nodes) or solid organs (eg, liver, lungs); the treatment of patients with celiac lymph node involvement remains controversial.

2) Invasion of adjacent structures (eg, the recurrent laryngeal nerve, tracheobronchial tree, aorta, pericardium)

In addition, the presence of severe, associated comorbidconditions (eg, cardiovascular disease, respiratory disease) can decrease a patient's chances of surviving an esophageal resection. Consequently, cardiac and respiratory function must be carefully evaluated preoperatively

The optimal surgical procedure is controversial. One approach advocates transhiatal esophagectomy with anastomosis of the stomach to the cervical esophagus.

A second approach advocates abdominal mobilization of the stomach and transthoracic excision of the esophagus with anastomosis of the stomach to the upper thoracic esophagus or the cervical esophagus.

One study concluded that transhiatal esophagectomy was associated with lower morbidity than transthoracic esophagectomywith extended en bloc lymphadenectomy; however, median overall disease-free and quality-adjusted survival did not differ significantly.[Hulscher JB, et al. NEGM 2002]

Dysphagia: In patients with partial esophageal obstruction, dysphagia may, at times, be relieved by placement of an expandable metallic stent or by radiation therapy if the patient has disseminated disease or is not a candidate for surgery. Alternative methods of relieving dysphagia have been reported, including laser therapy and electrocoagulation to destroy intraluminal tumor.

Minimally invasive techniques have been introduced to

reduce postoperative complication rates and recovery times.

Debates continue as to whether these challenging techniques

decrease morbidity and whether the oncological outcome is

compromised. Part of this answer is given in a recent

randomised trial [Biere SS, et al. Lancet 2012], showing a 3 fold

decrease in post-operative pulmonary infection rate after

totally mini-invasive oesophagectomy compared with open

transthoracic surgery. However, Open surgery remains the

standard of care.

Surgical treatment of resectable esophageal cancers results in

5year survival rates of 5% to 30%, with higher survival rates

in patients with early stage cancers. This is associated with a

less than 10% operative mortality rate.

In an attempt to avoid this perioperative mortality and

to relieve dysphagia, definitive radiation therapy in combination with chemotherapy has been studied.

RTOG8501 trial (Cooper JS, et al. JAMA 1999) of chemotherapy and radiation therapy VS radiation therapy alone in (T1-3, N0-1, M0) (SCC or AC) resulted in an improvement in 5-year survival for the combined modality group (27% vs. 0%).

An 8-years follow up of this trial demonstrated an overall survival (OS) rate of 22% for patients receiving chemo-radiation therapy.

An Eastern Cooperative Oncology Group trial (EST1282) of 135 patients showed that chemo plus radiation provided a better 2ys survival than radiation therapy alone,[Smith TJ, et al. Int J

Radiat Oncol Biol Phys. 1998] which was similar to that shown in the Intergroup trial.

In an attempt to improve upon the results of RTOG8501, Intergroup-0123 (RTOG9405, JCO-2002) randomly assigned 236 patients with localized esophageal tumors to chemoradiation with highdose radiation therapy (64.8 Gy) and four monthly cycles of fluorouracil (5FU) and cisplatin VS conventional dose radiation therapy (50.4 Gy) and the same chemotherapy schedule.

Although originally designed to accrue 298 patients, this trial was closed in 1999 after a planned interim analysis showed that it was statistically unlikely that there would be any advantage to using highdose radiation.

At 2 years' median follow-up, no statistical differences were observed between the high dose and conventional dose radiation therapy arms in median survival (13 months VS 18 months), 2-year survival (31% vs. 40%), or local/regional failures (56% vs. 52%).

Pre-operative Chemo-radiation Therapy

CROSS study:

Randomly assigned 366 patients with resectable esophageal or junctional cancers.

surgery alone VS pre-op.CCRTx: weekly carboplatin (AUC 2

mg/mL/minute) + paclitaxel (50 mg/m of BSA ) + concurrent radiation therapy (41.4 Gy/23 Fx) administered over 5 weeks.

The majority of the patients enrolled in the study have adenocarcinoma (75%).

With a median followup of 45 months, preoperative chemo-radiation improves median OS from 24 ms to 49.4 ms(P = .003).

preoperative chemoradiation improved the rate of R0 resections, with complete pathologic response was achieved in 29% of pts.

Postoperative complications and in hospital mortality were equivalent in both groups.

The most common hematologic side effects in the chemoradiation group were

leukopenia (6%) and neutropenia (2%).

Van Hagen P, Hulshof MC, van Lanschot JJ, et al.: Preoperative chemoradiotherapy foresophageal or junctional cancer. N Engl J Med 366 (22): 207484, 2012.

Survival in CROSS study

A phase III German trial by Stahl M, et al. in 2005 also compared induction chemotherapy (three courses of bolus 5FU, leucovorin, etoposide, and

cisplatin) followed by chemoradiation therapy (cisplatin, etoposide, and 40 Gy) followed by surgery (arm A), VS the same induction chemotherapy followed by chemo-radiation therapy (at least 65 Gy) without surgery (arm B).

for patients with T3 or T4 squamous cell carcinoma of the esophagus.

The analysis of 172 eligible, randomly assigned patients showed that OS at 2 years was not statistically significantly different between the two treatment groups (P < .007).

Local progressionfree survival (PFS) was higher in the surgery group (2-year PFS, 64.3%; 95% CI, 52.1%–76.5%) than in the chemoradiation therapy group (2year PFS, 40.7%; 95% CI, 28.9%–52.5%; HR for arm B vs. arm A, 2.1; 95% CI,

1.3–3.5; P < .003).

Treatment related mortality was higher in the surgery group compared with the chemoradiation therapy group (12.8% vs. 3.5%,

respectively; P < .03).

• Of 444 eligible patients, 259 were

randomly assigned; 230 patients (88.8%) had epidermoid cancer, and 29 (11.2%) had glandular carcinoma.

• Two-year survival rate was 34% in arm A versus 40% in arm B (adjusted P .44).

• Median survival time was 17.7 months in arm A compared with 19.3 months in arm B.

• Two-year local control rate was 66.4% in arm A compared with 57.0% in arm B, and stents were less required in the surgery arm (5% in arm A v 32% in arm B; P .001).

• The 3-month mortality rate was 9.3% in arm A compared with 0.8% in arm B (P .002).

• Cumulative hospital stay was 68 days in arm A compared with 52 days in arm B (P .02).

Conclusion of French study:

Locally advanced thoracic esophageal cancers, especially epidermoid, who respond to chemoradiation, there is no benefit for the addition of surgery after chemoradiation compared with the continuation of additional chemoradiation

Preoperative Chemotherapy Alone

The effects of preoperative chemotherapy are being evaluated in randomized trials, as was done in the NCT00525785 trial. (NEGM, 1998)

An Intergroup trial randomly assigned 440 patients with operable esophageal cancer of any cell type to three cycles of preoperative 5-FU+cisplatin followed by surgery and two additional cycles of chemotherapy VSsurgery alone.

After a median follow-up of 55 months, there were no significant differences between the chemotherapy/surgery and surgery alone groups in median survival (14.9 months and 16.1 months, respectively) or 2year survival (35% and 37%, respectively).

The addition of chemotherapy did not increase the morbidity associated with surgery.

The Medical Research Council Oesophageal Cancer Working Party (Lancet 2002) randomly assigned 802 patients with resectableesophageal cancer also of any cell type to two cycles of preoperative 5FU and cisplatin followed by surgery VS surgery alone.

At a median follow-up of 37 months, median survival was significantly improved in the preoperative chemotherapy arm (16.8 months vs. 13.3 months with surgery alone; difference 3.5 months; 95% CI, 1–6.5 months), as was 2year OS (43% and 34% respectively; difference 9%; 95% CI, 3–14 months).

The Japanese Clinical Oncology Group (Ann Surg Oncol 2012)

randomly assigned 330 patients with clinical stage II or III, excluding T4, squamous cell carcinomas to receive either two cycles of preoperative cisplatin+5FU followed by surgery VS surgery followed by postoperative chemotherapy of the same regimen 5-ys OS was 55% with preoperative chemotherapy VS 43% with postoperative chemotherapy (P = .04).

Conclusion

Surgery alone is regarded as standard

treatment only in carefully selected operable patients with localized SCC (T1-2 N0-3 M0).

Preoperative or post-operative radiation alone (without

chemotherapy) does not add any survival benefit to

surgery alone, so this treatment is not recommended for

curative intent in localized tumors.

Evidence for clinical benefit from preoperative

chemotherapy exists for all types of oesophageal

cancer, though it is stronger for adenocarcinoma

(AC).

Patients with AC of the lower oesophagus or OGJ should be managed with pre- and post-operative chemotherapy (or chemoradiation).

A couple of meta-analyses and two recent phase III trials suggested that preoperative chemoradiationconfers a survival benefit and it appears that patients benefit with increased tumour down-staging from preoperative chemoradiation. [N.B, post-operative mortality may be increased].

Data on adjuvant chemo(radio)therapy is limited, except for lower oesophageal/OGJ AC after limited surgery (lymph node dissection D1 and less). Therefore, adjuvant therapy is not recommended.

NCCN guidelines