March 2004, Volume 54, Issue 3

Review Articles

Esophageal Cancer - a review

A. Alidina  ( Departments of Medicine and Surgery*, The Aga Khan University, Karachi. )
T. Siddiqui  ( Departments of Medicine and Surgery*, The Aga Khan University, Karachi. )
I. Burney  ( Departments of Medicine and Surgery*, The Aga Khan University, Karachi. )
W. Jafri  ( Departments of Medicine and Surgery*, The Aga Khan University, Karachi. )
F. Hussain  ( Departments of Medicine and Surgery*, The Aga Khan University, Karachi. )
M. Ahmed  ( Departments of Medicine and Surgery*, The Aga Khan University, Karachi. )

Introduction


Esophageal cancer is a highly virulent malignancy, where the overall cure rate is <10%. At presentation, systemic disease is found in over 50% of the cases, leading to incurability. Of the patients that present with loco-regional disease, most will relapse with the primary therapy, leaving the cure rate in this group to 12-35%.1-3 The most commonly accepted standard of care for localized disease is surgical resection. Neoadjuvant chemoradiotherapy given as a combined modality therapy leads to pathological responses to 20-40%, which could be the surrogate markers to cure. Newer agents and targeted therapies will have an important role in the care of esophageal cancer.

Epidemiology


World wide, esophageal cancer is the fourth most common malignancy, after gastric, colorectal and hepatocelluar malignancies. It is the 10th most common malignancy (3.9%), but is the 6th leading cause of cancer death (5.9%). World over, 316,000 new cases are diagnosed each year, of which 286,000 die. In the USA, the cure rate does not appear to be any better. Each year 13,000 new cases are diagnosed, of which 12,600 will die.1-3 Data from Karachi showed that it is the 7th most common malignancy in men and 6th most common malignancy in females.4 At AKUH, this was the 10th most common in men (5%)5, while at Cenar, Quetta, this was the 3rd most common malignancy in men, accounting for 11% of all cancers seen.6 This uneven distribution is at least partly because Cenar has radiation therapy, where referrals would be higher. This may also suggest that perhaps there are higher cases of esophageal cancer in that part of Pakistan as compared to Karachi, owing to the meeting of the border of Baluchistan with Iran and Afghanistan, parts of where this disease is endemic. However definitive epidemiological data is lacking. While in the West, adenocarcinoma is the most prevalent histology, world over, including Pakistan; squamous cell carcinoma is the predominant histology.1,2,7 The incidence is as high as 100/100,000 cases in some parts of the world, including parts of Iran, China and USSR. South East Asia has intermediate probability of about 10-50/100,000, and the West, including the USA has low incidence of about <10/100,000.1,2
The median age at presentation in our country is 55 years. Male: female ratio is 1.2:1. Lower esophageal cancers account for 44-60% of cases, mid esophagus 30-54% and upper esophagus 10-25%.

Risk Factors


Tobacco use is strongly associated with esophageal cancer. In one study, 78% of all cases were tobacco users. Niswar and betel nut use is also implicated as a risk factor. It is known that smoking increases the risk of developing squamous cell carcinoma of the esophagus by 5-10 folds, and of developing adenocarcinoma by 2 fold. Molecular changes, including p53 mutation with smoking heralds the development of malignancy. Alcohol has additive and perhaps synergistic effect, where the risk increases to as high as 100 folds.8-11 The raise in the adenocarcinoma of the esophagus in the West may be attributable to the raise in the prevalence of Barrett's Esophagus, a well-recognized risk factor. This may be related to Helicobacter Pylori infection, the incidence of which is decreasing, leading to less atrophic gastritis and higher gastroesophageal reflux disease.12,13 About 1-3% of these patients with Barrett's Esophagus will develop adenocarcinoma, 3% will develop high grade dysplasia, and 15% low grade dysplasia.14,15 Determining flow cytometric and molecular studies in patients with Barrett's and dysplasia appear useful to indicate which patients will develop invasive malignancy.16,17 However, this needs more studies before becoming a standard part of surveillance endoscopy. The American Society of Gastroenterology guidelines for surveillance endoscopy in patients with Barrett's Esophagus calls for endoscopic evaluation every 3-5 years in patients with no dysplasia and every 6-12 months in patients with low grade dysplasia. For patients with high-grade dysplasia, options include intensive surveillance done every 3 months, ablative therapy or esophagectomy.18

Molecular Analysis


The unfavorable biology of patients with esophageal cancers explains at least partly why these patients do poorly. Targeted therapies against these molecular anomalies show promise in the future of this malignancy. Like any other malignancy, over expression of protooncogenes and suppression of tumor suppressor genes will lead to esophageal cancer. Recognized oncogenes include Epidermal Growth Factor Receptors, Cyclin D1 and Telomerase. Tumor suppressor genes implicated in this malignancy include Rb gene, p53, p16, and 3p (FHIT). The cell cycle progression requires that the growth factors be activated, resulting in the expression and binding of Cyclins and Cyclin Dependent Kinases (CDK). This leads the cell to move from G1 to S to G2 and then to M phase where the cell finally divides. Cyclin D-CDK 4/6 complexes result in the phosphorylation of RB gene product that then cannot bind to and inhibit the Transcription factors. The cycle moves on to the S phase where more Cyclin/CDK complexes cause the cells to go forward.19,20
Tumor suppressor gene p53 product regulates cell-cycle progression, DNA repair, apoptosis and neovascularization. It also inhibits the vascular endothelial growth factor. Approximately 50-80% of esophageal cancers express p53 mutation; here it correlates with disease-free and overall survival. P53 mutation is also an early event in the development of dysplasia.21-24 Epidermal Growth Factor Receptor is a 170-kD tyrosine kinase receptor, activation of which results in overexpression of Cyclins and CDKs. Overexpression is more commonly seen in squamous cell carcinoma and confers unfavorable prognosis.25-27 Overexpression of Cyclin D1 protooncogene is seen in 40-60% of esophageal cancer and is more commonly associated with advanced stage, leading to diminish overall survival. Mutations in Rb and p16 genes are seen in 20-60% of esophageal cancer and again, results in poor prognosis.28-32 Telomerase synthesizes telomeres, which are DNA sequences found at the ends of chromosomes, that then protects the chromosomes from recombination, nuclease attacks, activation of cell-cycle check point, and end-to-end fusion. All these functions of telomeres will protect the malignant cells from breakdown. Overexpression of telomerase is seen in many malignancies including esophageal cancer.33-36

Staging and Survival


In one local study, virtually all patients presented with stages III and IV. Dysphagia and loss of weight are found in 93% and 75% of cases respectively. Other symptoms include anorexia, chest pains and GI bleed. Median duration of symptoms is 3-4 months.
The anatomical location accounts for two unfavorable features resulting in poor survival. Firstly, esophagus has an indistinct serosa. Secondly, this organ has a unique lymphatic anatomy. Much unlike the other GI organs, lymphatic channels in the esophagus are present in the submucosa, just below the muscularis mucosa. Therefore, the probability of lymph node metastasis in the submucosal invasive malignancy is as high as 25%. A T2 lesion has a 50% chance of lymphatic spread. This is the reason, why all but the most superficial esophageal malignancies should be considered a systemic disease.37-39
Patients with dysplasia and Stage I disease involving the mucosa have a cure rate of >80%. However, all other esophageal cancer patients have a cure rate of <50%. Even the Stage I disease involving the submucosa have a cure rate 40-50%. Regional lymph node involvement results in cure rate of <25%.37,38

Treatment of Early Disease


Esophagectomy is the most commonly accepted standard of care for loco-regional disease. Whether a transthoracic approach is undertaken, or a transhiatal esophagectomy is performed, the results are dismal, as the recurrences are high. The overall cure rate with surgery alone is 12-25%. Surgical mortality is less than 10% and the results are the same whether the histology is adenocarcinoma or squamous cell carcinoma.40-42 The Japanese Oncology Group performed three randomized trials in the adjuvant setting. No benefit was seen when radiation therapy was compared with Cisplatin/Vindescine chemotherapy. Again, in the second trial, no benefit was seen when surgery alone was compared with postoperative Cisplatin/Vindescine in node positive patients. In the third study, surgery alone was compared with postoperative Cisplatin/5FU for 2 cycles; there was trend toward improvement in disease free survival in patients with node positive disease.43-45 This suggests that adjuvant chemotherapy might be useful in node positive patients, however 2 cycles may not be enough. Two studies defining the role of the adjuvant radiation therapy showed no benefit in improving survival.46,47
Preoperative chemoradiotherapy in improving the cure rate has been studied. Unfortunately the data is not very impressive. There are four randomized studies comparing preoperative chemoradiotherapy followed by surgery vs. surgery alone.48-51 Three of the four studies are underpowered. Only one study is positive in patients with adenocarcinoma of the esophagus; however the controls with surgery alone had a poor survival of 6% only.51 Another criticism that this study had was that CT scan was not mandated for staging. The randomized multimodality therapy on squamous cell carcinoma was negative.50 However, their use of chemotherapy was sub optimal. What is required is a large randomized, multicenter study testing preoperative chemoradiotherapy with surgery alone. Such a study was initialed by the Intergroup, but was closed because of poor accrual. The reason is physician-bias; despite lack of concrete evidence over 50% of the oncologists in the USA will treat the limited disease with chemoradiotherapy followed by surgery.52
Two large randomized trials in preoperative chemotherapy setting deserve attention. Both these studies compared surgery with preoperative chemotherapy with 5FU/Cisplatin followed by surgery. The RTOG study showed no improvement with addition of chemotherapy.53 The MRC study, which is almost twice as large, is showing a four-year projected survival favoring chemotherapy arm. However, the follow-up so far is short, staging CT scan was optional, and the surgical procedure was not standardized .54 Many randomized trials testing preoperative radiation therapy did not show benefit with addition of radiation therapy to surgery.
Those patients with localized disease who are poor candidates for surgery should be treated with combined chemoradiotherapy, which is superior to radiotherapy alone. Five-year survival in one pivotal study was 26% with chemoradiotherapy vs. 0% with radiotherapy alone.55

Metastatic Disease


One study showed that nearly all cases here are Stages III or IV disease. The most common modality of treatment in that study is radiation therapy with or without Cisplatin based chemotherapy.
Nearly half the patients with esophageal cancer in the West present with disseminated disease. Treatment of advanced disease is largely with chemotherapy. Single agents have a response rate of 20-30%56, while combination chemotherapy respond better, with response rates of 44-55%. Cisplatin/5FU continues to be a commonly used combination chemotherapy.57 Newer agents are active in this disease. Agents like Taxanes, a microtubule inhibitor, and Irinotecan, a Topo-isomerase I inhibitor, are particularly active. Both these agents can be used singly or in combination with Cisplatin. Primary endpoint in treatment of metastatic disease is improvement of quality of life in face of acceptable toxicity profile. Subjective relief of dysphagia is seen in 80-90% of cases with these newer combination chemotherapies.58-61
Targeted therapies are being actively tested in malignancies, including esophageal cancer. Anti-Epidermal Growth Factor Receptors show synergy with both chemotherapy and radiation therapy, and has had responses in head and neck, colorectal and lung cancers.62-64 A study looking at one such agent, Cetuximab (C-225), in combination with chemoradiotherapy is planned in esophageal cancer.

Conclusion


Esophageal Cancer is a challenge to treat for oncologists. Firstly, over 50% of these patients present as advanced disease, and hence are incurable. Secondly, early disease, despite definitive treatment, tends to recur. This is largely due to unfavorable biology and anatomical constraints. The most widely used standard of treatment for early disease is surgical resection. Larger trials are required to answer the role of addition chemotherapy and radiation therapy to surgery in localized disease. Newer chemotherapy and targeted therapy including the anti-epidermal growth factor receptors will continue to impact and define the optimum treatment of this very lethal malignancy.

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