Power point presentation talking about treatment of oesophageal cancer based on recent international guidelines and evidence-based medicine.

1. Oesophageal cancer
By
Osama Elzaafarany, MD
Assistant lecturer of clinical oncology
Medical Research Institute, Alexandria University
Jan 2015

2. 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

3. Pathological Classification
• Esophageal intraepithelial neoplasia
• Glandular epithelial dysplasia/adenocarcinoma
in situ in Barrett's mucosa
Preinvasive
Neoplasia
• Squamous cell carcinoma
• Adenocarcinoma,
• Adenoid cystic carcinoma
• Mucoepidermoid carcinoma
• Adenosquamous carcinoma
• Small cell carcinoma
• Carcinoid tumor
• Malignant melanoma
• Sarcomas
Invasive Malignant
Neoplasia
95
%

4.  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.

5. 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

6. 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.

7. Site-wise nodal involvement
Site-wise nodal involvement

8. Staging

9. 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%.

10. Treatment

11. Surgery
= Limited disease

12. = Locally advanced disease

13. Treatment overview

14. 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 comorbid
conditions (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

15.  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 esophagectomy
with 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.

16. 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.

17.  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.

18. 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.

19.  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%).

20. Pre-operative Chemo-radiation Therapy

21. 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 for
esophageal or junctional cancer. N Engl J Med 366 (22): 207484, 2012.

22. Survival in CROSS study

24.  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).

26. • 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).

27. 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

28. Preoperative Chemotherapy Alone

29.  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 VS
surgery 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.

30.  The Medical Research Council Oesophageal Cancer Working
Party (Lancet 2002) randomly assigned 802 patients with resectable
esophageal 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).

31. Conclusion

32.  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).

33.  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 chemoradiation
confers 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.

34. NCCN guidelines