Chemoradiotherapy for Treatment of Esophageal Cancer in Japan: Current Status and Perspectives

Abstract

Radical surgery with extended lymph node dissection has been the main method used for treating patients with resectable esophageal cancer in Japan. Based on data from two phase III studies that compared surgery with or without pre- or postoperative chemotherapy, preoperative chemotherapy followed by surgery emerged as standard treatment for patients with stage II or III disease. Definitive chemoradiotherapy may be an alternative to surgery for those with unresectable as well as resectable esophageal cancer. Recent clinical trials in Japan showed that the survival after definitive chemoradiotherapy was comparable to survival following surgery in stage I disease, with a 5-year survival rate of 75%. However, the 5-year survival rate was worse for chemoradiotherapy (37%) and preoperative chemotherapy followed by radical surgery (60%) for stage II or III disease. In addition, salvage treatment following chemoradiotherapy appeared to be important for patients who did not achieve a complete response or who experienced recurrence. To improve the prognosis for esophageal cancer, a multimodality approach that includes more intensive induction chemotherapy prior to surgery, or possibly chemoradiotherapy containing molecular targeting agents, is preferred. Additional studies are necessary to further elucidate this multimodality approach. Current treatment strategies for esophageal cancer and research initiatives in Japan are reviewed.

In 2006, 11,345 people (including 9,650 men and 1,695 women) died of esophageal cancer in Japan.¹ The number of deaths attributable to esophageal cancer has been slowly increasing, and seems to be correlated with aging of the Japanese population. Esophageal cancer represents 3.4% of all cancer deaths (4.9% in men and 1.3% in woman), and the overall death rate in the general population from esophageal cancer has been reported to be 15.7 per 100,000 for men and 2.6 per 100,000 for women.¹ For Japanese men, this rate was higher than that for men in Western countries, while the rate for Japanese women was similar.¹

In Western countries, the incidence of adenocarcinoma in the lower esophagus has been increasing and is now approximately equal to the incidence of squamous cell carcinoma.² According to cancer incidence data from 1993–2001 (gathered from 15 population-based cancer registries and collected by the Japan Cancer Surveillance Research Group in 2005) the incidence of esophageal adenocarcinoma in Japanese men was 2.6% (125/4,819) from 1993–1995 and 3.0% (192/6,360) from 1999–2001, and the rate for Japanese women was 1.9% (19/990) and 3.5% (41/1,157), respectively.³ In addition, the ratio of squamous cell carcinoma to adenocarcinoma from 1999–2001 was 23:1. These figures indicate that no apparent increase in adenocarcinoma had occurred, and that squamous cell cancer was still the predominant histologic subtype in Japan.

As for the site of disease, according to the Annual Report produced by the Japanese Association for Thoracic Surgery (JATS) in 2006,⁴ which included 9,379 patients with esophageal cancer, the predominant site of occurrence was the thoracic esophagus (83.6%), followed by the abdominal esophagus (6.0%), and then the cervical esophagus (4.8%). This pattern differs from Western countries, where tumors of the abdominal esophagus and gastroesophageal junction are more common.

OVERVIEW OF ESOPHAGEAL CANCER TREATMENT IN WESTERN COUNTRIES

In Western countries and in Japan the main method of treatment for esophageal cancer is surgery. However, several differences exist between Western countries and Japan, not only with regard to tumor biology, such as pathologic type and tumor location, but also surgical methods and survival results. The main surgical treatment for esophageal cancer in Japan is radical esophagectomy with three-field lymph node dissection.^5,6 In contrast, several types of surgery are used in Western countries, including transthoracic or transhiatal enbloc esophagectomy, with less extensive lymph node dissection.⁷ Although results from studies of surgery for esophageal cancer vary greatly, depending on when the study was done and whether it took place in a high-volume center, the 5-year survival rate after surgery alone in Western countries has been reported as 15%–25%, which is lower than that reported in Japan.^8–10

Since 1980, nonsurgical treatment consisting of external-beamradiation and chemotherapy has been used for esophageal cancer in Western countries. The 5-year survival rate of patients with esophageal cancer treated by radiotherapy alone was reported to be 0%–10%.^11–13 Two pivotal studies of definitive chemoradiotherapy have been reported. In the Radiation Therapy Oncology Group (RTOG 85-01) randomized trial comparing radiotherapy alone (64 Gy) with definitive chemoradiotherapy consisting of 5-fluororuracil (5-FU), cisplatin, and concurrent radiotherapy (50 Gy), significantly better survival was reported for the chemoradiotherapy arm (median survival time of 8.9 vs. 12.5 months: 5-year survival rate of 0% vs. 26%).^14,15

In the RTOG 94-05/INT 0123 trial, which compared intensive-dose radiation (64.8 Gy) with a conventional dose (50 Gy) in combination with concurrent 5-FU plus cisplatin, it was found that survival was not prolonged by the higher dose of radiation when measured against the higher incidence of toxicity.¹⁶ Based on these results, in Western countries, definitive chemoradiotherapy has been considered the standard of care for patients who either are not suitable for surgery or who do not wish to undergo surgery.

Various combined modalities such as surgery followed by chemotherapy or chemoradiotherapy, preoperative chemotherapy, or chemoradiotherapy followed by surgery, have been performed to improve treatment outcomes of esophageal cancer. Although there has been some controversy surrounding the optimal treatment for esophageal cancer, neoadjuvant chemoradiotherapy followed by surgery is favored in Western countries, where esophagogastric junction adenocarcinoma is prevalent.^7,17

Recently, a French group reported on a randomized trial for operable esophageal cancer (T3) that compared chemoradiotherapy followed by surgery or definitive chemoradiotherapy (FFCD 9102) in responders. ¹⁸ Another trial in Germany compared chemoradiotherapy (40 Gy) followed by surgery and definitive chemoradiotherapy for patients with localized esophageal cancer (T3–4).¹⁹ These two studies, in which approximately 90% of the cases were squamous cell cancer, showed no significant difference in survival between treatment arms in patients who responded to initial chemoradiotherapy. These results suggested that additional surgery has little effect on survival if patients achieve an adequate response to chemoradiotherapy, especially those with squamous cell carcinoma. Currently, preoperative chemoradiotherapy followed by surgery is considered standard care for esophageal cancer in Western countries, especially for adenocarcinoma. Another option is definitive chemoradiotherapy, especially for patients with squamous cell cancer who obtain a good response.

OVERVIEW OF TREATMENT OF ESOPHAGEAL CANCER IN JAPAN

Radical surgery with extended lymph node dissection has been the main method of treatment for patients with esophageal cancer in Japan. Chemoradiotherapy has been used in Japan since 1990, especially for patients with locally advanced disease and/or distant lymph node metastases, or for those who were not fit to undergo surgery. A retrospective survival analysis of patients treated with definitive chemoradiotherapy for stage I, II, and III (non T4) disease at the National Cancer Center East Hospital showed almost similar 5-year survival rates and median survival times for each stage.²⁰ Thus, it was hoped that chemoradiotherapy would be equivalent to surgery, and several clinical trials were conducted. Currently, definitive chemoradiotherapy is considered optional treatment for each stage (Figure 1). In contrast to Western countries, preoperative chemoradiotherapy using more low-intensity radiotherapy than definitive chemoradiotherapy is not common in Japan. In addition, increasing numbers of patients with early stage disease undergo endoscopic resection, which is not performed in Western Countries.

Figure 1.

Current standard treatment for esophageal cancer and ongoing trial

Abbreviations: CRT = chemoradiotherapy; CT = chemotherapy; ER = endoscopic resection; JCOG = Japan Clinical Oncology Group; BSC = best supportive care

According to the Comprehensive Registry of Esophageal Cancer in Japan,²¹ among 2,953 patients who registered in 1999, there were 1,817 (61.5%) who underwent esophagectomy, 840 (28.4%) who received chemotherapy and/or radiotherapy, and 231 (7.8%) who underwent endoscopic resection. According to the 2006 annual report by JATS, of 9,379 patients with esophageal cancer, 5,236 (55.8%) underwent esophagectomy, 1,312 (14%) underwent endoscopic resection, and 2,831 (30.1%) received nonsurgical therapy.⁴ These two large data summaries showed almost similar rates of treatment. However, the information was primarily collected from surgical departments, and data from esophageal patients who were treated through nonsurgical methods and not registered. As expected, in our institution, 582 patients with esophageal cancer were treated between 2001 and 2005; stage IV disease represented approximately one third of patients, and only 35% of cases underwent esophagectomy. Therefore, more than half of patients with esophageal cancer underwent nonsurgical treatment in general practice in Japan.

In this review, we summarize the results of a pivotal study and treatment strategy for patients with esophageal cancer in Japan according to disease stage based on the International Union Against Cancer (UICC) classification.

UICC Stage 0–I

Patients with early stage esophageal cancer involving the epithelium (m1: carcinoma in situ) or the lamina propria (m2) are candidates for endoscopic resection, since lymph node metastases are rare at this stage.²³ For esophageal cancer that invades the muscularis mucosa (m3), the rate of lymph node metastasis is reported to be 9%, and for cancer with minute submucosal invasion (< 200 micrometers below the muscularis mucosa; sm1) the rate is 19%.²⁴ The rate of lymph node metastasis of m3 or sm1 cancer without lymphovascular infiltration of the tumor is reported to be 4.7%. Therefore, for patients unwilling to undergo esophagectomy or patients with comorbid diseases who are not fit for surgery, endoscopic resection is considered to be a relative indication for m3/sm1 cancer.²

Lesions that spread over more than three quarters of the circumference of the esophagus are considered a relative indication for endoscopic resection due to the high incidence of post endoscopic resection stricture.²³ In cases with a pathologic result of sm2–3 after endoscopic resection, additional surgery is standard therapy, and chemoradiotherapy is considered another option. There is currently an ongoing phase II study evaluating endoscopic resection followed by adjuvant chemoradiotherapy (two cycles of 5-FU/cisplatin with 45 Gy radiation) for m3/sm1 (Japan Clinical Oncology Group; JCOG 0508).

For stage I esophageal cancer, which is not an indication for endoscopic resection, surgery is the standard treatment, but chemoradiotherapy is another option. In a retrospective analysis of 73 patients with stage I disease, a complete response was achieved in 68 patients (93%), and the remaining 5 patients with residual tumors were successfully treated with salvage endoscopic resection or surgery.²⁵ Salvage endoscopic resection or surgery was also safely performed for local recurrence, and the 3-year and 5-year survival rates were 80% and 77%, respectively, which were almost comparable to that for surgery.

To confirm these results, a phase-II study of definitive chemoradiotherapy for stage-I disease was conducted (JCOG 9708).²⁶ The treatment schedule was as follows: 5-FU 700 mg/m² on days 1–4 and 29–32, cisplatin 70 mg/m² on days 1 and 29, and radiation 60 Gy delivered in 30 fractions weeks 1–3 and 5–7. A total of 72 patients were treated, with a complete response rate of 88% (Table 1). Recurrent or new lesions were seen in 41 patients after complete response, of which 87% were successfully treated by salvage endoscopic resection or surgery. The 2-year and 5-year survival rates were 93% and 76%, respectively, which were comparable to past surgical results in stage-I disease.²⁷ These results indicated that chemoradiotherapy followed by salvage endoscopic resection or surgery may be useful as a standard treatment option. A randomized trial comparing definitive chemoradiotherapy with surgery for patients with stage I disease and who are not candidates for endoscopic resection is ongoing (JCOG 0502).

Table 1.

Treatment results of definitive chemoradiotherapy in Japan

Study/Author	Treatment	Stage	N	CR rate	2-or 3-year survival	5-year survival
JCOG 970826	FP+RT (60 Gy)	I	72	88%	93%	76%
JCOG 990631	FP+RT (60 Gy)	II/III	76	62%	47%	37%
Ohtsu et al37	FP+RT (60 Gy)	IV (T4 or M1 LYM)	54	33%	23%	17%
JCOG 951638	FP+RT (60 Gy)	IV (T4 or M1 LYM)	60	15%	31%	NR

Abbreviations: JCOG = Japan Clinical Oncology Group; FP = 5-fluorouracil+cisplatin; CR = complete response; NR = not reported

UICC Stage II–III (non T4)

Surgery With or Without Chemotherapy

In Japan, radical surgery with three-field lymph node dissection is commonly indicated for UICC stage II–III.²⁸ In the JCOG 9204 study (N=242) which compared surgery alone with surgery plus adjuvant chemotherapy consisting of two cycles of 5-FU plus cisplatin (5-FU 800 mg/m² on days 1–5, cisplatin 80 mg/m² on day 1, every 3 weeks), better 5-year disease-free survival as a primary end point was observed in the combined modality arm (55% vs. 45%; one-sided log-rank, P = .037) (Table 2).²⁹ In the subgroups with pathologically negative lymph nodes, 5-year disease-free survival was 77% for surgery alone and 82% for surgery plus adjuvant chemotherapy (P = .3). In the subgroups with positive lymph nodes, the rates were 38% and 52%, respectively (P = .041). The 5-year survival rate was favorable in the surgery plus adjuvant chemotherapy group, but was not statistically significant (61% vs. 52%; P = .13). This study was conducted with postoperative registration, which accounted for some selection bias since patients who died, or were in poor condition after surgery, were excluded from analysis. Still, the results were better than the retrospective results examining definitive chemoradiotherapy in Japan.

Table 2.

Randomized trials of surgery with or without chemotherapy in Japan

Study	Treatment	Stage	n	5-year DFS	P value	5-year survival	P value
JCOG 920429	Surgery	II/III	122	45%		52%
	Surgery followed FP	II/III	120	55%	0.03	61%	0.13
JCOG 990730	Surgery followed FP	II/III	166	PFS 2year		38%
	FP followed surgery	II/III	164	PFS 3year	0.04	60%	0.01

Abbreviations: JCOG = Japan Clinical Oncology Group; FP = 5-fluorouracil+cisplatin; DFS = disease free survival

The JCOG 9907 study was a randomized study of preoperative chemotherapy followed by radical surgery and radical surgery plus adjuvant chemotherapy (Table 2).³⁰ This study randomized 330 patients with stage II–III squamous cell carcinoma of the thoracic esophagus to two cycles of chemotherapy with 5-FU plus cisplatin (same regimen as JCOG 9204) followed by surgery, or to surgery followed by the same regimen of chemotherapy. At a planned interim analysis in March 2007 (median follow-up time 23 months), the median progression-free survival (a primary end point of the study) was 3 years for the preoperative chemotherapy arm and 2 years for the postoperative chemotherapy arm, representing a 24% reduction in risk (P = .044), which did not meet the criteria for halting the trial. However, there was an unexpectedly large difference in 5-year overall survival (a secondary end point) of 60% and 38%, for the pre- and postoperative arms, respectively, for a 36% reduction in risk with preoperative treatment (hazard ratio 0.64; 95% confidence interval [CI] 0.446–0.913; P = .013).

Based on these findings, the Data and Safety Monitoring Committee recommended early termination of the study and publication of the results. Subgroup analysis showed that the survival benefit mainly occurred in patients with stage II disease; the 5-year survival rate of the preoperative vs. postoperative arm was 69.7% vs. 49.3% for stage II, and 52.1% vs. 36.5% for stage III. Due to the results of JCOG 9204 and JCOG 9907, preoperative chemotherapy followed by radical surgical resection is considered to be standard care in Japan for patients with stage II or III disease.

There were several confounding factors identified in JCOG 9907. First, a disproportionate number of patients per arm completed their assigned treatments: 89.6% for the postoperative arm vs. 71.7% for the preoperative arm. In addition, 39 patients in the postoperative arm with negative lymph nodes did not receive chemotherapy, since no benefit of adjuvant chemotherapy was observed in the JCOG 9204 study.^28,30 These treatment results supposed that a small number of patients who received chemotherapy in the postoperative arm accounted for a worse survival rate in that group. However, subset analysis of JCOG 9907 showed that the preoperative group had significantly superior survival among lymph-node–positive patients, which suggests that this factor may not be significant.

Second, the survival rate in the postoperative chemotherapy arm in JCOG 9907 was worse than that of JCOG 9204. However, this was probably due to a difference in registration criteria (clinical stage prior to surgery in JCOG 9907 vs. pathologic stage in JCOG 9204). Third, the study was discontinued after interim analysis, before meeting the stopping criteria. The possibility remains that the survival difference was diminished after further followup time. Further study of stage II and III esophageal cancer in Japan is necessary, using neoadjuvant chemotherapy followed by surgery as the reference arm.

Definitive Chemoradiotherapy

After the introduction of chemoradiotherapy in practice, a retrospective comparison of surgical resection and definitive chemoradiotherapy showed survival rates that were comparable to surgical results, suggesting that chemoradiotherapy was useful as an alternative treatment.²⁰

JCOG 9906 was a phase II trial that included 76 patients with UICC clinical stage II/III esophageal carcinoma (excluding those with T4 tumors), and evaluated definitive chemoradiotherapy for this stage (Table 1).³¹ Patients received chemoradiotherapy with 5-FU 400 mg/m² on days 1–5, 8–12, 36–40, and 43–46, with cisplatin at 40 mg/m² on days 1, 8, 36, and 43, plus concurrent radiotherapy of 60 Gy with 2 weeks planned interruption. The complete response rate, and 3-year and 5-year survival rates were 62%, 47%, and 37%, respectively. Acute toxic effects were manageable. However, late toxicity was prevalent and needed to be reduced (grade 3 pericardial effusion, 16%; grade 3 dysphagia/stenosis or fistula of the esophagus, 13%; grade 3 pleural effusion, 9%).

Sixteen patients underwent salvage surgery and endoscopic resection, which might have contributed to survival; however, the survival rates were worse than those seen in JCOG 9907. Although a direct comparison was difficult, data suggested that preoperative chemotherapy followed by surgery should be considered standard treatment for this stage, and definitive chemoradiotherapy may be another option, especially for patients who are not fit for surgery or who do not want to undergo surgery. Since the complete response rate remained approximately 60%, and the recurrence rate was high after complete response, salvage surgery or endoscopic resection may be necessary to improve prognosis after definitive chemoradiotherapy. Future studies should examine optimal timing and modes of salvage treatment.

Currently, a phase I/II study of definitive chemoradiotherapy using S-1 plus cisplatin and concurrent irradiation is under way. S-1 is a novel oral compound of tegafur, gimeracil, and oteracil in a molar ratio of 1:0.4:1.³² Gimeracil is a reversible competitive inhibitor of dihydropyrimidine dehydrogenase (DPD), and is approximately 180 times more potent than uracil in inhibiting DPD. Thus, gimeracil maintains a higher concentration of 5-FU in the blood. Oteracil inhibits the phosphorylation of 5-FU, thereby attenuating the toxic effects of 5-FU on the gastrointestinal tract. S-1 showed favorable results when compared with infusional 5-FU in gastric cancer, and was approved in Japan not only for gastric cancer but also for colorectal cancer, non–small-cell lung cancer, head and neck cancer, and breast cancer.

UICC Stage III (T4) or M1 LYM (Cervical Lymph Node Metastasis)

Outcomes after radical surgery for T4 disease are poor, with a median survival time of just 6 months and a 5-year survival rate of less than 10% with high morbidity.³³ Although some reports have suggested the usefulness of surgery for patients with pathological M1 LYM, the 5-year survival rate remains just 14%–25%, and the surgical benefit in clinically apparent M1 LYM is unknown.^34–36

Ohtsu et al reported on the use of definitive chemoradiotherapy using 5-FU, cisplatin, and concurrent radiotherapy (60 Gy) for patients with T4 and/or M1 LYM esophageal cancer (36 pts with T4 and 18 pts with non-T4 but M1 LYM).³⁷ Out of 54 patients, 18 (33%) achieved complete response (Table 1). Of those, 9 patients had T4 disease and 9 had non-T4 disease. Although there were 4 (7.4%) treatmentrelated deaths, the median survival time was 9 months, and the 3-year survival rate was 23%. An updated report gave a 5-year survival rate of 17% (9/54).³⁶

JCOG 9516 was a phase II study of chemoradiotherapy for T4 and/or M1 LYM, with a complete response rate of 15% and an objective response rate of 68.3%, as well as a median survival time of 10 months, and 2-year survival of 31.5% (Table 1).³⁸ Another prospective trial that employed definitive chemoradiotherapy consisting of 5-FU, cisplatin, and concurrent external-beam radiotherapy (60 Gy) in 28 patients with T4 esophageal cancer with or without fistulae showed similar survival results.³⁹ This study had a complete response rate of 32%, and 2- year survival of 27% in patients with T4 disease, which was comparable to the results seen in other studies. These prospective and other retrospective data reported similar survival results, with a 2- or 3-year survival rate of about 20%– 30%,^36–40 which was superior to outcomes associated with palliative therapies.

Although a randomized study comparing surgery and definitive chemoradiotherapy has not been conducted, these results suggest that definitive chemoradiotherapy is the best treatment for T4 and/or M1 LYM esophageal cancer. Currently, a randomized phase II/III study (JCOG 0303) is under way, comparing standard chemoradiotherapy (5-FU 700 mg/m² on days 1–4 and 29–32, cisplatin 70 mg/m² on day 1 and 29, 60 Gy radiation) to daily lowdose chemotherapy with radiotherapy (5- FU 200 mg/m² days 1–5 each week for 6 weeks, cisplatin 4 mg/m² days 1–5 each week for 6 weeks, 60 Gy radiation).

Stage IV Patients With Distant Metastases (Non Lymph Node)

There is no standard therapy for stage-IV patients with distant metastases. Chemotherapy, chemoradiotherapy, esophageal stent, and/or palliative chemotherapy may be selected for each patient according to disease status and general status.

JCOG 8807 is a phase II study of chemotherapy using 5-FU plus cisplatin (5-FU 700 mg/m² days 1–5, cisplatin 70 mg/m² on day 1, every 4 weeks) for metastatic esophageal cancer.⁴¹ A total of 40 patients were treated, with a response rate of 36% and a median survival time of 9.5 months for responders and 5.6 months for nonresponders. JCOG 9407 was another phase II study of 5-FU plus cisplatin for patients with metastatic disease (N=42), in which cisplatin 20 mg/m² was administered days 1–5.⁴² However, this regimen did not show the expected superior results in efficacy (response rate of 33.3%, median survival time of 6.7 months), or less toxicity, compared with JCOG 8807.

In JCOG 9905,⁴³ combination chemotherapy using 5-FU plus nedaplatin (a third-generation platinum) was evaluated (5-FU 800 mg/m² days 1–5, nedaplatin 90 mg/m² day 1, every 4 weeks). The response rate was 39.5% and median survival time was 267 days. Since no randomized study has been performed, a standard regimen for metastatic disease has not yet been established, although 5-FU plus cisplatin is commonly used as a first-line defense.

It is difficult to treat progressive or recurrent disease after chemotherapy or chemoradiotherapy containing 5-FU plus cisplatin. Salvage surgery or endoscopic resection might be indicated in some cases. Although there is no evidence to suggest that second-line treatment prolongs survival, docetaxel is commonly used in this setting. A phase-II study of docetaxel for esophageal cancer in Japan showed a response rate of 36% (4/11) for first-line treatment, and 16% (6/38) in the second-line setting.⁴⁴) A recent Japanese phase II study of weekly paclitaxel as second-line treatment for metastatic esophageal cancer showed a very promising response rate of 44.2% (23/52), progression- free survival of 3.9 months, and overall survival of 10.4 months.⁴⁵ It is hoped that paclitaxel will be effective in this setting. Since it has been reported that patients who recurred after a treatmentfree interval of more than 6 months showed sensitivity to the same regimen with a response rate of 30%, 5-FU–based therapy might be indicated for patients who experience relatively long treatmentfree survival.⁴⁶

FUTURE PERSPECTIVES

Although it was hoped that chemoradiotherapy would be equivalent to surgery for localized esophageal cancer, it seemed to have a limited effect, as suggested by the slightly low survival rate (especially in stage II or III disease), late toxicity, and necessity of salvage surgery. It would also be difficult to improve the surgical results technically. Therefore, it is hoped that a multimodality approach that includes more intense induction chemotherapy prior to surgery, or chemoradiotherapy and chemoradiotherapy containing new agents, will improve survival for patients with esophageal cancer.

In Western countries, a large phase-III study of the esophagogastric junction and gastric cancer showed that docetaxel plus 5-FU and cisplatin gave a superior response rate, longer progression-free survival, and better overall survival time compared with 5-FU and cisplatin alone.⁴⁷ Additionally, in cases of head and neck tumors, most of which are squamous cell cancer, induction chemotherapy with docetaxel-cisplatin- 5–FU (DCF) therapy prior to chemoradiotherapy or radiotherapy has shown a superior overall survival rate compared with 5-FU plus cisplatin.^48,49 Similarly, it is hoped that a three-drug combination as neoadjuvant or induction chemotherapy prior to surgery or chemoradiotherapy will be effective for esophageal cancer. We are conducting a feasibility study examining modified DCF as neoadjuvant chemotherapy for resectable esophageal cancer.

Recently, molecular targeting agents have been proven to prolong the survival of several types of cancers. Cetuximab, a monoclonal antibody that targets the epidermal growth factor receptor, in combination with radiotherapy, was shown to prolong survival in head and neck tumors.⁵⁰ Similarly, several phase-II studies have shown promising results in combination for esophageal cancer and gastric cancer.^51–53 Combination chemotherapy containing molecular targeting agents is expected to improve survival after definitive chemoradiotherapy and be comparable in efficacy to surgery.

As noted in this review, several differences in esophageal cancer tumor characteristics and treatment strategies exist between Japan and Western countries. Further investigation is required to understand the differences in tumor biology of esophageal cancer that are peculiar to these different regions. It is hoped that the development of targeted therapies will allow the delivery of tailored treatment more adequate for individual patients through molecular profiling of their tumors.