On the Path to Standardizing Esophageal Cancer Treatment in Japan

Esophageal cancer is a commonly found neoplasm and is the seventh most common cause of cancer death in the world. The incidence in the United States is about 5 per 100,000 population, whereas China, Iran, and the Asian Belt have an incidence of approximately 20 per 100,000 population. The overall death rate in the general population in Japan from esophageal cancer has been reported to be 15.7 per 100,000 for men and 2.6 per 100,000 for women. Therefore, esophageal cancer is considered a relatively common type of cancer in Japan. However, several differences in tumor characteristics and treatment strategies for esophageal cancer exist between Japan and Western countries.

ADENOCARCINOMA OF THE ESOPHAGOGASTRIC JUNCTION IN JAPAN AND WESTERN COUNTRIES

The two most common histologic subtypes of esophageal cancer are squamous-cell carcinoma and adenocarcinoma. Squamous-cell tumors comprise 98% of malignancies in the upper and middle third of the esophagus, whereas adenocarcinoma is found predominantly in the lower third. Previously, squamous-cell carcinoma was the most frequent subtype, but over the past 20 years, the incidence of adenocarcinoma has been rapidly increasing in the Western world. The reason for this shift is poorly understood.

In Japan, gastric cancer is the most common tumor arising from the upper gastrointestinal (GI) tract. Recent analysis of a database of upper GI cancers in a high-volume cancer center in Japan revealed the proportion of true esophageal cancer, adenomas of the esophagogastric junction (AEG), and true gastric cancer to be 20.2%, 4.0%, and 75.8%, respectively.¹ These findings confirm a relatively low incidence of AEG in Japan. In Western countries, on the other hand, the proportion of true esophageal cancer, AEG, and true gastric cancer has been reported to be 23.9%, 35.9%, and 40.2%, respectively.¹ Thus, the pattern of GI malignancies between Japan and Western countries appears strikingly different. These differences could be attributable to hereditary factors and risk factors such as gastroesophageal reflux, smoking, heavy alcohol consumption, and obesity.²

Recent trials of esophageal cancer in the United States and Europe have included a strong majority of patients with gastroesophageal junction cancers (approximately 75% in the US studies). Thus, AEG is treated as esophageal cancer in Western countries, whereas most AEGs are treated as gastric cancer in Japan.

ESOPHAGEAL CANCER IN THE MULTIDISCIPLINARY TREATMENT ERA

In this issue of Gastrointestinal Cancer Research, Shitara and Muro eloquently describe the status of chemoradiotherapy as currently employed in the treatment of esophageal cancer in Japan.³ In their review, the authors highlight major differences in treatment strategies between Japan and Western countries regarding treatment of early esophageal carcinoma and preoperative treatment. Noting well the several differences in tumor characteristics and treatment strategies for esophageal cancer between Japan and Western countries, they call for further studies to understand the differences in tumor biology in these regions.

Authors Shitara and Muro affirm that a multimodality approach is required to improve the prognosis for patients with esophageal cancer, suggesting a potential role for more intensive induction chemotherapy prior to surgery, as appropriate, or possibly chemoradiotherapy containing molecular targeting agents.

“TAKUMI’S Technique”

As with most malignancies, thorough assessment, accurate staging, multidisciplinary evaluation, and guideline-oriented stage-specific therapy are critical to optimizing outcomes for patients with esophageal cancer.⁴ These basic principles do not differ in essence between Japan and most Western countries. Why, then, have Japanese physicians adopted a substantially different approach for treating early esophageal carcinoma?

In Japan, endoscopic resection (ER) and endoscopic submucosal dissection (ESD) are well-established alternative treatments to surgery for early gastric carcinoma. ⁵ Having accumulated considerable expertise in treating gastric cancer, Japanese endoscopists have adopted aggressive endoscopic procedures using the so-called “TAKUMI’s technique” or “God’s hands.”

Intraepithelial cancers (m1) and cancers invading the lamina propria (m2) are associated with almost no risk of lymph node metastasis.^6–8 The risk appears to be higher with cancers that have invaded the lamina muscularis propria (m3), in the range of 0%–10%⁶ and cancers invading the submucosa in 50%–55%.⁷ Most interestingly, it was shown that even in m3/sm1 tumors, lymph node metastasis was absent if the resected specimen did not show lymphatic and blood vessel permeation.⁸ Japanese endoscopists believe that ER for mucosal squamous-cell cancer with low risk of lymph node metastasis is safe and effective.

In cases of submucosal invasion, patients should always be treated using surgery or chemoradiotherapy. It remains unclear whether a combination of ER and chemoradiotherapy represents adequate treatment for patients with submucosal invasion or otherwise higher risk of lymph node metastases, and further studies are ongoing in Japan.

Preoperative Chemotherapy Becoming Standard in Japan for Stage II/III Disease

We do have several modalities available to treat this devastating disease. Unfortunately, the results of esophagectomies are still unsatisfactory when compared to the results of surgical treatment for gastric cancer or colon cancer, which means a promising novel strategy for this disease is needed. How do Japanese doctors apply a trimodality approach?

Most current approaches are not considered standard, despite the results of many clinical trials. Patients with stage T12N0 disease are treated with surgical resection alone. An esophagectomy with three-field lymph node dissection is considered standard therapy for esophageal cancer. Indeed, the use of three-field lymph node dissection has improved survival for esophageal cancer patients in many Japanese institutions. Transthoracic esophagectomy with two-field resection is recommended for intrathoracic squamous-cell carcinoma.⁹ Should we employ preoperative chemotherapy or chemoradiotherapy to improve surgical outcomes?

Most patients with T3 or N1/M1a disease should be evaluated for induction therapy followed by surgery.¹⁰ The usefulness of neoadjuvant chemotherapy has been examined in two large-scale randomized clinical trials.^11,12 However, the results of these two studies differed. Other data on preoperative chemotherapy are also conflicting. Thus, the usefulness of preoperative chemotherapy is controversial. One meta-analysis of randomized clinical trials comparing neoadjuvant chemotherapy and surgery to surgery alone failed to demonstrate a survival benefit for the combined modality arm.^13,14

Although the effectiveness of neoadjuvant chemotherapy was not supported by these trials, promising data were reported by the Japanese Clinical Oncology Group (JCOG) in 2008. Patients with locally advanced squamous-cell carcinoma of the esophagus were randomly allocated to surgery followed by chemotherapy or to neoadjuvant chemotherapy with surgery. The pre- and post-chemotherapy regimens used the same protocol, with cisplatin and 5-fluorouracil (5-FU). JCOG reported that preoperative chemotherapy improved overall survival. Accordingly, new randomized clinical trials must be conducted in Japan using neoadjuvant chemotherapy as a standard arm instead of surgery alone.¹⁵

On the other hand, definitive chemoradiotherapy has recently shown promise as a treatment modality for resectable esophageal cancer, with data suggesting potential efficacy of combination therapy with chemoradiotherapy and esophagectomy. In fact, preoperative chemoradiotherapy for resectable esophageal cancer is becoming a common therapy in Europe and North America.^16,17

Randomized trials comparing induction chemotherapy and radiotherapy followed by surgery compared to surgery alone in patients with potentially resectable esophageal cancer demonstrate conflicting results. A meta-analysis of six published randomized trials comparing preoperative chemotherapy and radiation therapy followed by surgery to surgery alone revealed that the pooled estimate of treatment effects was statistically significant in favor of preoperative chemoradiotherapy followed by surgery for overall survival.¹⁸ The authors ackowleded, however, that exclusion of the controversial Walsh trial¹⁹ led to a loss of statistical significance between groups. In addition, the risk of postoperative mortality was higher in the trimodality group.

Another meta-analysis was performed to determine survival and treatment-related mortality associated with preoperative treatment in patients with resectable esophageal cancer.²⁰ Eleven randomized trials involving 2,311 patients were analyzed, demonstrating that preoperative chemotherapy improved 2-year survival compared with surgery alone; the absolute difference was 4.4% (95% confidence interval [CI], 3%–8.5%). For combined chemoradiotherapy, the increase in 2-year survival was 6.4% (95% CI, −1.2%–14.0%). Treatment-related mortality increased by 1.7% with neoadjuvant chemotherapy (95% CI, −.9%–4.3%) and by 3.4% with chemoradiotherapy (95%CI, −.1%–7.3%), compared with surgery alone.

A meta-analysis conducted by Urschel and colleagues assessed nine randomized trials with a total accrual of more than 1,000 patients.²¹ This analysis found that induction chemoradiotherapy followed by surgery was associated with improved 3-year survival and reduced local and regional recurrence compared to surgery alone.

There appears to be an increase in treatment-related mortality for patients who receive induction chemotherapy and radiotherapy. Due to the lack of consensus regarding the use of induction chemotherapy prior to surgery in patients with potentially resectable esophageal cancer, the National Comprehensive Cancer Network (NCCN) treatment guidelines support the use of induction therapy only in established clinical trial protocols (www.nccn.org/professionals/physician_gls/PDF/esophageal.pdf).

In Japan, preoperative chemotherapy or chemoradiotherapy with planned esophagectomy represents one treatment option, while definitive chemoradiotherapy with salvage esophagectomy represents another. Patients who are not considered surgical candidates, for oncologic or physiologic reasons, are considered for chemotherapy and radiotherapy.

FUTURE PERSPECTIVES

In the future, biologic parameters may improve the clinician’s ability to determine which patients would likely benefit from surgical resection,²² and a number of promising biologics are currently under investigation. Several obstacles remain to be overcome on the path to standardizing esophageal cancer treatment in Japan, but Japanese physicians will continue to approach this objective using careful staging with “TAKUMI’s technique” for endoscopy along with multimodality employment of surgery, radiotherapy, and chemotherapy as appropriate. Future standard treatment of esophageal cancer is expected to consist of TAKUMI’s approach and strategic use of genetic biomarkers.