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Definitive Chemo-Radiotherapy for Resectable Esophageal Cancer — Unresolved Problems Remain

Written By

Shouji Shimoyama

Submitted: 30 April 2012 Published: 09 May 2013

DOI: 10.5772/55501

From the Edited Volume

Cancer Treatment - Conventional and Innovative Approaches

Edited by Letícia Rangel

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1. Introduction

Esophageal cancer, the 8th most common cancer and 6th leading cause of cancer deaths worldwide (Jemal et al., 2010), remains an invasive disease with 5-year overall survival rates (SRs) of only 20% in the USA (Daly, et al., 1996), 13% in UK (, and less than 10% in most parts of Europe (Keighley 2003). In Japan, an updated nationwide survey ( has demonstrated 5-year SRs of 33% for all esophageal cancers and 43% for resected cases, while in the USA, the survivals have improved to 42% in the past decade (Rice et al., 2009). Still, these statistics consistently confirm that survival remains disappointing, with less than half of all patients surviving at 5 years. Where the disease appears resectable and patients are sufficiently fit, surgery remains the mainstay of curative therapy. However, the overall poor prognosis with esophagectomies has led to the investigation of multimodal therapies in order to improve the treatment results. Among these, preoperative chemo-radiotherapy (CRT) (neoadjuvant CRT) has been developed and proved promising; nonetheless, morbidity and mortality have increased. What this means is that any improvement in survival rates of complete resection or local disease control by neoadjuvant CRT happens at the expense of greater toxicity. Several meta-analysis have elucidated that preoperative CRT significantly (Fiorica et al., 2004) or at least non-significantly increased (Kranzfelder et al., 2011; Urschel et al., 2003) postoperative in-hospital mortality.

On the other hand, evidence for CRT as a curative intent (definitive CRT: dCRT) has been established for patients with esophageal cancer who otherwise do not qualify for surgery due to disease extent and/or medical comorbidity. In Japan, dCRT for T4/M1(lymph) squamous cell cancer (SCC) achieved 1-, 2-, and 3-year SRs of 41%, 27-32%, and 22-23%, respectively, which compared well with SRs of T4 SCC undergoing resection (Ishida, et al., 2004; Japanese Society of Esophageal Diseases, 2005; Y Nishimura et al., 2002; Ohtsu, et al., 1999; Kumekawa et al., 2006) [Table 1], although they were not a nonrandomized comparison. Subsequently, three pivotal RCTs demonstrated that survival results were similar between dCRT and neoadjuvant CRT followed by surgery or surgery only. A German trial revealed that dCRT with at least 65Gy for T3-4/N0-1/M0 SCC offered similar survival results with less likelihood of treatment-related mortality as compared with neoadjuvant CRT with 40Gy radiation (Stahl, et al., 2005). A French FFCD trial recruiting T3/N0-1/M0 SCC patients found no benefit of subsequent surgery following CRT for those responding to CRT (Bedenne et al., 2007). This study has established a rationale that the response to neoadjuvant CRT is a favorable prognostic sign which allows the selection of patients most likely to benefit from dCRT, thereby indicating the potential of dCRT for organ-sparing treatments. A CURE trial conducted in China compared T2-3/N1 SCC patients undergoing standard esophagectomy with those undergoing dCRT with 50-60Gy radiation and observed no survival differences between these two treatments (Chiu et al., 2005). Consequently, a very recent meta-analysis has also elucidated that there is no trend regarding differences in overall survival between surgery and dCRT (Pöttgen et al., 2012).

Author Tumor stage Radiation dose Chemotherapy Histology Number of patients Complete response rate Median survival time (months) Survival Tretment-related death
Ohtsu, 1999 T4 and/or M1 lymph 60 Gy Fluorouracil Cisplatin SCC 54 33% 9 1YSR=41% 3YSR=23% 6.8%
Nishimura, 2002 T4 N0-1 M0-1 60 Gy Fluorouracil Cisplatin SCC 28 32% stage III=12 stage IV=5 2YSR=27% NA
Ishida, 2004 (JCOG9516) T4 and/or M1 lymph 60 Gy Fluorouracil Cisplatin SCC 60 15% 10 2YSR=32% 1.7%
Kumekawa, 2006 T1-4 and M1lymph 60 Gy Fluorouracil Cisplatin SCC 81 42% 14 1YSR=62% 3YSR=22% 11.8%

Table 1.

Treatment results of definitive chemo-radiotherapy for far advanced esophageal cancer in Japan.

YSR; year survival rate

Against these backgrounds and considering that surgery for esophageal cancer is a formidable procedure with significant morbidity and mortality (as discussed in section3.1) which raises concerns about its applicability in most patients, dCRT, at first investigated with palliative intent, has been further extended to resectable cases. While there was much initial enthusiasm for dCRT, notes of caution have been raised in interpreting the accumulated dCRT experience. These should be resolved for the further advancement of multimodal approaches for esophageal cancer. This chapter introduces current problems to be taken into account when performing dCRT, especially for patients with potentially resectable esophageal cancer.


2. Definitive CRT for resectable esophageal cancer is promising and could be an alternative to esophagectomy

Many chemotherapeutic agents are potential candidates that could be combined with radiation (Kleinberg et al., 2007). Among these, the most frequently used agents are fluorouracil and cisplatin, both act as radiosensitizers. Fluorouracil inhibits DNA and RNA synthesis resulting in decreasing radiation-induced DNA injury repair, which eventually enhances radiation-induced cytotoxicity. Cisplatin forms inter- and intrastrand cross-links to DNA that impede repair. This action also leads to decrease in cellular repair in response to radiation-induced damage. Therefore, besides a direct action of fluorouracil and cisplatin to DNA, these two agents and radiation act synergistically.

Several nonrandomized comparisons have been conducted to investigate whether dCRT could achieve the same impact on survival as esophagectomy for those patients deemed suitable for surgery. More important are the encouraging results of dCRT for patients with operable rather than inoperable esophageal cancer. Table 2 lists the results of dCRT for each stage of esophageal cancer; these studies of dCRT with at least 60Gy radiation have shown consistent favorable SRs, which compare favorably with the Japan nationwide 3-year SR (44%) of surgery only (Japanese Society of Esophageal diseases, 2005). Ishikura et al. (Ishikura, et al., 2003) and Hironaka et al. (Hironaka et al., 2003) respectively recruited T1-3 (70% T3) and T2-3 SCC patients, and dCRT yielded 3-year and 5-year SRs of 49-55% and 46-49%, respectively. Three other dCRT studies revealed promising 3-year SRs which were 80% for patients with stage II SCC (Morota et al., 2009), 45% for those with stage II and III SCC (K Kato et al., 2011), and 72% for those with stage 0-III SCC (Murakami et al., 1998). These results motivated the researchers to conduct dCRT studies for less progressed esophageal SCC. For T1N0M0 stage I esophageal SCC, dCRT resulted in 1-, 2-, 3-, 4-, and 5-year SRs of 98%, 93%, 79-89%, 81%, and 66-67%, respectively, which could be compared favorably with survivals of surgical cases (H Kato et al., 2009; Minashi et al., 2006; K Yamada et al., 2006; Yamamoto et al., 2011). These findings are indeed encouraging and dCRT could be an alternative to esophagectomy. In addition, since dCRT can preserve the esophagus, it could theoretically offer better posttreatment quality of life than that for patients treated by surgery. Indeed, esophagectomy resulted in worse functional, symptomatic, and global quality of life scores at 6 weeks postoperatively than before surgery (Blazeby et al., 2000). However, the recently accumulated data on dCRT has raised several issues of concern.

Author Tumor stage Radiation dose Chemotherapy Histology Number of patients Complete responders (%) Median survival time (months) Survival
Advanced cancer
Hironaka, 2003 T2-3 N any M0 60Gy Fluorouracil Cisplatin SCC 53 37(70%) 33 3YSR=49% 5YSR=46%
Ishikura, 2003 T1-3,M0 (70% T3) 60Gy Fluorouracil Cisplatin SCC 67 ND 44 3YSR=55% 5YSR=49%
Kato, 2011 (JCOG9906) II and III 60Gy Fluorouracil Cisplatin SCC 76 46(62%) 29 3YSR=45% 5YSR=37%
Morota, 2009 I-IVB 60Gy Fluorouracil Cisplatin SCC 69 36(52.2%) ND stage I 3YSR=80% stage II 3YSR=80% stage III 3YSR=30% stage IV 3YSR=30%
Murakami, 1998 0-III 60-75Gy Fluorouracil Cisplatin SCC 30 16(53.3%) not reached 2YSR=81% 3YSR=72%
T1 cancer
Kato, 2009 (JCOG9708) T1N0M0 30Gy Fluorouracil Cisplatin SCC 72 63(88%) not reached 2YSR=93% 4YSR=81%
Minashi, 2006 T1N0M0 60Gy Fluorouracil Cisplatin SCC 41 36(88%) not reached 1YSR=98% 3YSR=79% 5YSR=67%
Yamada, 2006 T1N0M0 55-66Gy Fluorouracil Cisplatin SCC 63 ND ND 5YSR=66%
Yamamoto, 2011 T1N0M0 60Gy Fluorouracil Cisplatin SCC 54 ND not reached 1YSR=98% 3YSR=89%

Table 2.

Treatment results of definitive chemo-radiotherapy for potentially resectable esophageal cancer.

SCC; squamous cell cancer, YSR; year survival rate

ND; not described


3. Problems remain to be resolved

3.1. Invasiveness of dCRT

When considering dCRT—especially for potentially resectable esophageal cancer, risks from the treatment, i.e., treatment-related complications or death, should be taken into account in evaluating whether dCRT could substitute for surgery. Some patients undergoing dCRT have experienced severe grade 3/4 pericarditis, pleural effusion, and radiation pneumonitis, which respectively developed in 1.4-16% (Hironaka et al., 2003; Ishikura et al., 2003; K Kato et al., 2011; Kumekawa et al., 2006; Minashi et al., 2006; Morota et al., 2009; Sasamoto et al., 2007), 1.4-14% (Hironaka et al., 2003;, Ishihara et al., 2010; Ishikura et al., 2003; K Kato et al., 2011; Kumekawa et al., 2006; Li et al., 2010; Minashi et al., 2006; Morota et al., 2009; Sasamoto et al., 2007), and 1.2-14% (Hironaka et al., 2003;, Ishihara et al., 2010; Ishikura et al., 2003; K Kato et al., 2011; Kumekawa et al., 2006; Morota et al., 2009; Sai et al., 2004; Yamamoto et al., 2011; Yamashita et al., 2008) of the study population. These complications eventually caused treatment-related death at a rate of 3-14% of the study population (K Kato et al., 2011; Morota et al., 2009; Sai et al., 2004; Sasamoto et al., 2007; Yamashita et al., 2008) or 8-12% of the CR patients (Ishihara et al., 2010; Ishikura et al., 2003; Kumekawa et al., 2006; Minashi et al., 2006; Sasamoto et al., 2007) [Table 3]. Especially, 8% of treatment-related death among the CR patients with stage I disease (Minashi et al., 2006) cannot be overlooked because they would be expected to survive by surgery unless fatal complications occurred.

Author Grade 3/4 Toxicities Tretment-related death
Pericarditis Pleural effusion Pneumonitis of all patients of CR patients
Hironaka, 2003 10.8%* 13.5%* 8.1%* 0.0% ND
Ishihara, 2010 NA 0.9%** 2.7%** ND 8.2%
Ishikura, 2003 5.8% 5.8% 2.2% ND 10.3%
Kato, 2011 (JCOG9906) 16.0% 9.0% 4.0% 5.3% ND
Kumekawa, 2006 3.7% 3.7% 1.2% ND 11.8%
Li , 2010 NA 6.8% NA ND ND
Minashi, 2006 2.8%* 11.1%* 0.0% ND 8.3%
Morota, 2009 1.4% 1.4% 1.4% 2.9% ND
Sai, 2004 NA NA 13.8% 13.8% ND
Sasamoto, 2007 8.9% 8.9% NA 7.1% 7.1%
Yamamoto, 2011 0.0% 0.0% 3.7% ND ND
Yamashita, 2008 NA NA 6.1% 6.1% ND

Table 3.

Mortality and late morbidity of definitive chemo-radiotherapy.

*among the complete responders, **death rate

ND; not described, CR; complete response

The heart is susceptible to radiation injury. Pericardial damage is most frequently mentioned, but all structures of the heart are at risk. Mediastinal radiation causes inflammation and progressive fibrosis of all of the structures of this organ. A worsening of clinical severity with increased radiation volume has been suggested. The risk of pericarditis has been found to rise with increased total dose and larger dose per fraction, reaching 3-fold and 2-fold greater relative risks at total doses of 41 Gy or greater, or a dose per fraction of 3.0 Gy or greater, respectively (Cosset et al., 1991). Another study also demonstrated that larger fraction size has a significant relationship with the chance of pericarditis (Martel et al., 1998 ). These observations suggest that dose effect as well as fractionation effect account for the increased risk of pericarditis.

Radiation pneumonitis has been reported in patients who have undergone mediastinal radiation therapy for various diseases. The risks of radiation pneumonitis rise when radiotherapy is combined with chemotherapy (McDonald et al., 1995; M Yamada et al., 1998). The risks of lung toxicity appear to be related to dose-volume parameters such as the irradiated lung volume, mean lung dose (Hernando et al., 2001), total dose (Roach et al., 1995), daily fraction dose (Roach et al., 1995), and number of daily fractions (Roach et al., 1995), —although there are some inconsistencies (Allen et al., 2003). Similarly, the percentage of lungs receiving a specified dose has also been reported to be a predictor of pneumonitis (Madani et al., 2007; Tsujino et al., 2003).

The obstruction of cardiac and mediastinal lymphatic vessels due to radiation fibrosis has been postulated as a possible etiology of radiation-induced pericardial and pleural effusions. As a result, radiation-induced cardiac or lung disease is responsible for a certain fraction of death not directly attributable to esophageal cancer itself in some patients who would survive if they could have undergone surgery without complications. Although nonsurgical approaches are appealing in trying to manage this difficult disease, it is a fact that there is a fine therapeutic window because of the significant toxicities, and the toxicity may outweigh any potential advantages.

If treatment-related morbidity and mortality of dCRT exceed those of surgery, the benefits of dCRT may be cancelled. Therefore, the risk balance between dCRT and surgery should be taken into account in consideration of dCRT; however, one should remember that the morbidity and mortality of esophagectomy differ considerably between countries. Surgical mortality was 2-4% in Japan (Fujita et al., 2010; Suzuki et al., 2011; Tachimori et al., 2009), while 4.2-7.6% in Taiwan (Lin et al., 2006), 6% in Italy (Ruol et al., 2009), 4-13% in the Netherlands (Steyerberg et al., 2006; Wouters et al., 2008), and 6-23% in the USA (Atkins et al., 2004; Bailey et al., 2003; Birkmeyer et al., 2002; Dimick et al., 2005; Finks et al., 2011; Rentz et al., 2003), suggesting that differences in surgical mortality between countries can be more than doubled or quadrupled.

However, the risk comparison between dCRT and surgery should require considerations of the hospital volume, surgeon volume, specialization, study period, and country, i.e., when and where the studies of dCRT are conducted, as well as the number of esphagectomies that each surgeon performs. With regard to hospital volume, even in the USA —where surgical mortality is generally high, hospital mortality after esophagectomy varied from 23% for institutions undertaking <2 cases per annum to 8% for those undertaking 20 or more cases per annum (Birkmeyer et al., 2002). In Japan, the average mortality was 1.8% when >51 esophagectomies per annum were undertaken, compared with 4.6% if 20 or fewer esophagectomies were performed per annum (Suzuki et al., 2011). Fujita et al. (Fujita et al., 2010) and Kazui et al. (Kazui et al., 2007) also reported a larger hospital volume with a lower 30-day or in-hospital mortality rates. The same volume-outcome relationship was also observed in Taiwan (Lin et al., 2006) and the Netherlands (Wouters et al., 2008). In addition, high volume surgeons experienced a 4.2% mortality rate, which was one-quarter of that of low volume surgeons, approaching the average in-hospital mortality in Japan (Migliore et al., 2007). Also in Japan, risk of morbidity by low volume surgeons is twice that of high volume surgeons (Yasunaga et al., 2009). Collectively, a larger experience of esophagectomies could significantly reduce the 30-day or in-hospital mortality from 18% to 5% (Metzger et al., 2004).

The study period is also a determinant. Single institutions in the USA (Orringer et al., 2007) or Italy (Ruol et al., 2009) experienced consistently decreased hospital mortality from 4% to 1% (Orringer et al., 2007) or from 8.2% to 2.6% (Ruol et al., 2009). Taking into account the various determinants of hospital mortality, the treatment-related death rates of 8-12% among CR patients of dCRT are undoubtedly higher than those of surgical mortality in Japan, but equal to or lower than in some countries. Considering the balance between the risks of dCRT and those of surgery, dCRT is regarded as a risky treatment as compared with surgery in some countries or in some institutions where surgery can be performed more safely.

3.2. Response evaluation is not necessarily perfect

The lack of any definitive diagnostic methods currently available for the response evaluation after dCRT remain pressing issues following dCRT. Strikingly, some segments of patients who underwent surgery following dCRT due to persistent disease proved to be complete responders postoperatively. The rates of such seemingly unnecessary salvage surgery are 10-50% (Ariga, et al., 2009; Beseth et al., 2000; Lim et al., 2003; Murakami et al., 1998; M Nishimura et al., 2007; Tachimori et al., 2009; Wilson et al., 2002). On the other hand, clinically diagnosed CR patients sometimes prove to have residual diseases and eventually exhibit relapse. The rates of overall recurrence or local recurrence after CR are substantial, being respectively 19-67% and 14-40% (Di Fiore et al., 2006; Ishihara et al., 2010; Kumekawa et al., 2006; Minashi et al., 2006; Morota et al., 2009; Murakami et al., 1998; Takeuchi et al., 2007; Tougeron et al., 2008; Wilson et al., 2000) [Table 4], suggesting that patients whose tumor response is deemed complete after dCRT could have residual diseases and that clinically CR is not always a reason to preclude further additional treatment. Such local recurrence rates do not depend on the initial tumor stage or depth. These discrepancies may be ascribed to the limitations of current imaging methods.

Author Tumor stage Radiation dose Histology Number of patients Complete responders (%) Overall recurrence rate after CR Local recurrence rate after CR
Di Fiore, 2006 T1-4/N0-1/M0 50 Gy or 60 Gy SCC 116 86 (74.1%) ND 40%
Ishihara, 2010 I-IVA 60 Gy ND 173 110 (63.6%) 26% 12%
Kumekawa, 2006 T1-4 and M1lymph 60 Gy SCC 81 34(42.0%) ND 25%
Minashi, 2006 T1N0M0 60 Gy SCC 41 36(88%) 39% 14%
Morota, 2009 I-IVB 60 Gy SCC 69 36(52.2%) ND 17%
Murakami, 1998 0-III 60-75 Gy SCC 30 16(53.3%) 19% ND
Takeuchi,2007 II-III 60 Gy SCC 178 113 (63.5%) 36% ND
Tougeron, 2008 I-IV 50-55 Gy SCC+ADC 109 63(58%) 52% 33%
Wilson, 2000 anyT, anyN, M0 50 Gy SCC+ADC 31 24 (77.4%) 67% 21%

Table 4.

Overall and local recurrence rates among CR patients undergoing dCRT.

SCC; squamous cell cancer. ADC; adenocarcinoma

ND; not described, CR; complete response

There are several diagnostic tools for evaluating responses to CRT. Endoscopy is an easily available means of investigation, but its accuracy is low as recurrent or residual tumors often lie beneath the mucosa [Figure 1]. Negative endoscopy findings have sometimes included microscopic foci of a residual tumor in the resected esophagus specimens. Moreover, the differentiation between tumor and radiation changes is not easy. A false negative rate of 48% for biopsy by endoscopy (Jones et al., 1997) suggests a poor correlation between endoscopic findings and pathologic status.

Figure 1.

Low and high magnifications of a patient who was considered CR after CRT. Histological specimens revealed small foci of a residual tumor in the esophageal wall which could not be detected by endoscopically obtained biopsy specimens preoperatively.

Endoscopic ultrasonography (EUS) also cannot reliably distinguish a residual tumor from postinflammatory changes, which is, on the other hand, a characteristic of the efficacy of dCRT. Even in earlier reports demonstrating the efficacy of EUS, (Hirata et al., 1997; Willis et al., 2002), it should be noted that a perfect discrimination between T0 and T1 tumors was not a consideration) since a certain degree of remaining tumor (<50-70%) was considered an EUS-based response, or a scattered or even a remaining degree of 1/3< viable cells was considered a pathological response. Such a cut-off value is less useful for deciding the need for salvage surgery following dCRT because only patients with no viable cells could theoretically be escaped from salvage surgery. EUS T staging accuracy after neoadjuvant CRT was only 43%, a rate ascribed to significant fibrosis and inflammation caused by CRT (Isenberg et al., 1998). Consequently, EUS had a tendency to overstage lower pathological T stages. On the other hand, 79% of pathologically complete responders were diagnosed as having T+ disease (Zuccaro et al., 1999). These T+ patients underwent immediate post CRT surgery, but this could deem unnecessary because of pathological CR. Similarly, EUS could not detect microscopic disease, while 27% of patients with positive EUS findings proved to have no residual tumor in the resected specimens (Beseth et al., 2000). Furthermore, EUS may be suboptimal when the sonography probe cannot pass the tumor.

Researchers have reported a low accuracy of CT for the assessment of responses in patients with esophageal cancer; this accuracy was substantially worse than that of EUS and FDG-PET (fluorine18-labelled deoxyglucose in positron emission tomography). This is most likely owing to the difficulty in the differentiation between viable tumors and reactive changes, including edema, fibrosis, and inflammation at CT. CT tumor volume change was poorly correlated with pathological tumor response (Griffith et al., 1999). Some tumors exhibited marked volume regression with a poor histological response, while some tumors showed little volume regression with a considerable histological response. This means that CT by itself represents an inadequate tool in assessing those who have residual disease and those who should undergo surgery following CRT. Jones et al. reported the same results (Jones, et al., 1999).

On the other hand, PET is a useful noninvasive tool in discriminating responders from nonresponders, with the colleration between PET-based response assessment and pathology being 78% (Flamen et al., 2002). The sensitivity and specificity of PET ranged from 71-100% and 55-95%, respectively (Brücher et al., 2001; Flamen et a., 2002; Weber et al., 2001). Any false positive results are attributable to the metabolically active leukocytes or macrophages associated with post CRT inflammation. False negative phenomena can occur because PET is unable to detect perfectly the residual viable disease in the primary tumor.

3.3. Salvage surgery is highly invasive

Patients who have received dCRT should undergo subsequent surgery if the tumors exhibit strictures or subsequent relapse. Salvage surgery is a surgery for residual or recurrent disease following dCRT, but it is technically more difficult and highly invasive than primary surgery, leading to increased morbidity (50-79%) and in-hospital mortality (7-22%) due to the adverse events of predominantly respiratory complications and anastomotic leakage (Chao et al., 2009; Nakamura et al., 2004; M. Nishimura et al., 2007; Oki et al., 2007; Smithers et al., 2007; Swisher et al., 2002; Tachimori et al., 2009; Tomimaru et al., 2006). These complications are attributable to the radiation-induced injury in the thoracic cavity that causes an increase in bleeding, fibrotic masses around the tumor due to the fibrogenic pathway that makes surgical technique more difficult, and an increasingly fragile stomach, esophagus, and trachea arising from the impaired blood supply that eventually causes anastomotic leakage or conduit necrosis. Even in Japan, these hospital mortality rates are obviously higher than those for primary esophagectomy reported from specialized centers or in a nationwide survey (2-4%) (Fujita et al., 2010; Suzuki et al., 2011; Tachimori et al., 2009). Reserving surgery for patients not already cured by CRT should always be taken into account in performing dCRT, and efforts should be continuously made to reduce mortality and to select patients who stand to benefit most from this invasive treatment.

First, invasiveness undoubtedly depends on surgical procedure. The most common surgical approaches which are applicable to cancers of the upper, middle and lower esophagus are the Ivor-Lewis or McKeown esophagectomy. The Ivor-Lewis esophagectomy involves right thoracotomy with midline laparotomy and an anastomosis of the gastric conduit to the proximal mediastinal esophagus (at or above the azygos vein). The McKeown technique involves right thoracotomy, laparotomy, and cervical anastomosis, which facilitates precise surgical staging and enables more local control (van de Ven et al., 1999). The extent of lymphadenectomy is three-field (cervial thoracic, abdominal), which has traditionally been more prevalent in Japan, measuring the prevalence of positive cervical nodes (Akiyama et al., 1994; Nishihira et al., 1995). The survival benefit of three-field lymphadenectomy was suggeted in Japanese (Nishihira et al., 1998) and Western series (Altorki et al., 2002). Importantly, the risks of positive cervical nodes are substantial even at an earlier stage (Stein et al., 2005), and are seemingly independent of histological types (SCC or adenocarcinoma) or independent of tumor location within the esophagus (Akiyama et al., 1994; van de Ven et al., 1999). The McKeown technique enables this dissection to be performed under direct vision, allowing more precise dissection in cases where the tumor is large, lymphadenopathy is present, or the tumor is located in proximity to the airway (upper or middle thoracic esophagus). However, in salvage surgery, attempts have been made to reduce surgical morbidity and mortality with preservation of the blood supply to the trachea or to the main bronchus as well as to the reconstruction conduit. These include a reduced scope of lymphadenectomy with avoidance of cervical lymph node dissection or the preservation of right and left bronchial arteries (Tachimori et al., 2009).

Second, an accurate prediction of resection status prior to surgery is important at the time of completion of dCRT since resection status is one of the significant factors that affect survival after salvage surgery. Long term survivors after salvage surgery were those undergoing R0 resection, while no patients left with gross or microscopic residual tumors after salvage surgery (R1/R2 resections) survived more than 24 months in any series (Chao et al., 2009; Nakamura et al., 2004; Oki et al., 2007; Swisher et al., 2002; Tachimori et al., 2009; Tomimaru et al., 2006). Multivariate analysis also confirmed resection status correlation with patient survival (Chao et al., 2009; Tomimaru et al., 2006). However, the resection status cannot be confidently predicted before surgery or even during surgery because of the indistinct planes between a tumor and fibrotic masses within the irradiated mediastinum. In this regard, PET, which has a relatively high specificity, could identify non-responders for dCRT and may be a more useful imaging modality than CT or EUS (Swisher et al., 2004) to select patients who are absolutely unfit for salvage surgery, allowing for early modifications of the treatment strategy of such selected patients.

Third, it is imaginable that larger, more advanced cancers are more difficult to control than smaller ones and require longer doses of RT; however, higher radiation doses are associated with increased morbidity. A dose of 60Gy of radiation has been used for dCRT in Japan (Kenjo et al., 2009). In this regard, the possibility of reducing total radiation volume from 64.8Gy to 50.4Gy (Minsky et al., 2002; Nakajima et al., 2009) has recently prompted a phase II study of dCRT with a radiation dose of 50.4Gy for stage II/III esophageal SCC (JCOG0909).


4. Future perspectives

The combination of conventional CRT with molecular targeting therapies has been developing. This combination is encouraged by the findings that radiotherapy plus cetuximab, a monoclonal antibody against epidermal growth factor receptor, for loco-regionally advanced SCC of the head and neck resulted in the prolonged duration of loco-regional control, progression free survival, and overall survival as compared with radiotherapy alone (Bonner et al., 2006; Bonner et al., 2010). The feasibility of adding cetuximab to CRT for esophageal cancer is supported by the safety profiles of this combination without any increase in esophagitis or other radiation-enhanced toxicity (Safran et al., 2008). The ongoing phase III trials (NCT 00655876, NCT01107639, NCT00509561) will provide evidence whether cetuximab in combination with CRT is effective in locally advanced or resectable esophageal cancer (

A gain in survival with a substantial increase in toxicity necessitates considerable caution that immediately draws the attention of clinicians. Diagnostic tools which can accurately evaluate tumor response early in the course of dCRT can facilitate decisions about whether this toxic therapy should be continued in responders, or stopped in non-responders. However, there are currently no modalities that can definitively confirm CR. The reason for this problem is that the tools to estimate individual patient prognosis or tumor response are unreliable, and a diagnosis of CR is possibly merely by resected specimens. This means that negative findings by these imaging methods do not rule out residual disease. Clearly, patients with residual disease would no longer be long term survivors without undergoing resection. Therefore, efforts should continue to establish diagnostic tools for the detection of residual diseases after CRT.

One challenge in this regard lies in the detection of histologic markers—such as p53, Ki67, and EGF-R—for the prediction of therapeutic response; however, neither a single marker nor a combination of markers can correctly be used to predict the response with sufficient accuracy. The small number of patients or small number of genes investigated in this field is a further limitation. In the future, gene profiling may help identify markers that can be used in combination with conventional imaging methods for the prediction of the response to dCRT.


  1. 1. Akiyama H Tsurumaru M Udagawa H Kajiyama Y 1994Radical lymph node dissection for cancer of the thoracic esophagus. Ann Surg. 220 3
  2. 2. Allen A. M Henning G. T Ten Haken, R.K., Hayman, J.A., & Martel, M.K. (2003Do dose-volume metrics predict pulmonary function changes in lung irradiation? Int J Radiat Oncol Biol Phys. 55 4 921 929
  3. 3. Altorki N Kent M Ferrara C Port J 2002Three-field lymph node dissection for squamous cell and adenocarcinoma of the esophagus. Ann Surg. 236 2
  4. 4. Ariga H Nemoto K Miyazaki S Yoshioka T Ogawa Y Sakayauchi T Jingu K Miyata G Onodera K Ichikawa H Kamei T Kato S Ishioka C Satomi S Yamada S 2009Prospective comparison of surgery alone and chemo-radiotherapy with selective surgery in resectable squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys. 75 2 348 356
  5. 5. Atkins B. Z Shah A. S Hutcheson K. A Mangum J. H Pappas T. N Harpole D. H Jr, & D’Amico, T.A. (2004Reducing hospital morbidity and mortality following esophagectomy. Ann Thorac Surg. 78 4 1170 1176
  6. 6. Bailey S. H Bull D. A Harpole D. H Rentz J. J Neumayer L. A Pappas T. N Daley J Henderson W. G Krasnicka B Khuri S. F 2003Outcomes after esophagectomy: a ten-year prospective cohort. Ann Thorac Surg. 75 1 217 222
  7. 7. Bedenne L Michel P Bouché O Milan C Mariette C Conroy T Pezet D Roullet B Seitz J. F Herr J. P Paillot B Arveux P Bonnetain F Binquet C 2007Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 25 10 1160 1168
  8. 8. Beseth B. D Bedford R Isacoff W. H Holmes E. C Cameron R. B 2000Endoscopic ultrasound does not accurately assess pathologic stage of esophageal cancer after neoadjuvant chemo-radiotherapy. Am Surg. 66 9 827 831
  9. 9. Birkmeyer J. D Siewers A. E Finlayson E. V Stukel T. A Lucas F. L Batista I Welch H. G Wennberg D. E 2002Hospital volume and surgical mortality in the United States. N Engl J Med. 346 15 1128 1137
  10. 10. Blazeby J. M Farndon J. R Donovan J Alderson D 2000A prospective longitudinal study examining the quality of life of patients with esophageal carcinoma. Cancer. 88 8 1781 1787
  11. 11. Bonner J. A Harari P. M Giralt J Azarnia N Shin D. M Cohen R. B Jones C. U Sur R Raben D Jassem J Ove R Kies M. S Baselga J Youssoufian H Amellal N Rowinsky E. K Ang K. K 2006Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 354 6 567 578
  12. 12. Bonner J. A Harari P. M Giralt J Cohen R. B Jones C. U Sur R. K Raben D Baselga J Spencer S. A Zhu J Youssoufian H Rowinsky E. K Ang K. K 2010Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 11 1 21 28
  13. 13. Brücher B. L Weber W Bauer M Fink U Avril N Stein H. J Werner M Zimmerman F Siewert J. R Schwaiger M 2001Neoadjuvant therapy of esophageal squamous cell carcinoma: response evaluation by positron emission tomography. Ann Surg. 233 3 300 309
  14. 14. Chao Y. K Chan S. C Chang H. K Liu Y. H Wu Y. C Hsieh M. J Tseng C. K Liu H. P 2009Salvage surgery after failed chemo-radiotherapy in squamous cell carcinoma of the esophagus. Eur J Surg Oncol. 35 3 289 294
  15. 15. Chiu P. W Chan A. C Leung S. F Leong H. T Kwong K. H Li M. K Au-yeung A. C Chung S. C Ng E. K 2005Multicenter prospective randomized trial comparing standard esophagectomy with chemo-radiotherapy for treatment of squamous esophageal cancer: early results from the Chinese University Research Group for Esophageal Cancer (CURE). J Gastrointest Surg. 9 6 794 802
  16. 16. http://clinicaltrialsgov
  17. 17. Cosset J. M Henry-amar M Pellae-cosset B Carde P Girinski T Tubiana M Hayat M 1991Pericarditis and myocardial infarctions after Hodgkin’s disease therapy. Int J Radiat Oncol Biol Phys. 21 2 447 449
  18. 18. Daly J. M Karnell L. H Menck H. R 1996National Cancer Data Base report on esophageal carcinoma. Cancer. 78 8 1820 1828
  19. 19. Di FioreF., Lecleire, S., Rigal, O., Galais, M.P., Ben Soussan, E., David, I., Paillot, B., Jacob, J.H., & Michel, P. (2006Predictive factors of survival in patients treated with definitive chemo-radiotherapy for squamous cell esophageal carcinoma. World J Gastroenterol. 12 26 4185 4190
  20. 20. Dimick J. B Wainess R. M Upchurch G. R Jr, Iannettoni, M.D., & Orringer, M.B. (2005National trends in outcomes for esophageal resection. Ann Thorac Surg. 79 1 212 216
  21. 21. Finks J. F Osborne N. H Birkmeyer J. D 2011Trends in hospital volume and operative mortality for high-risk surgery. N Engl J Med. 364 22 2128 2137
  22. 22. Fiorica F Di Bona, D., Schepis, F., Licata, A., Shahied, L., Venturi, A., Falchi, A.M., Craxì, A., & Cammà, C. (2004Preoperative chemo-radiotherapy for oesophageal cancer: a systematic review and meta-analysis. Gut. 53 7 925 930
  23. 23. Flamen P Van Cutsem E Lerut A Cambier J. P Haustermans K Bormans G De Leyn P Van Raemdonck D De Wever W Ectors N Maes A Mortelmans L 2002Positron emission tomography for assessment of the response to induction radiochemotherapy in locally advanced oesophageal cancer. Ann Oncol. 13 3 361 368
  24. 24. Fujita H Ozawa S Kuwano H Ueda Y Hattori S Yanagawa T 2010Esophagectomy for cancer: clinical concerns support centralizing operations within the larger hospitals. Dis Esophagus. 23 2 145 152
  25. 25. http://ganjohojp/public/statistics/backnumber/2011en.html
  26. 26. Griffith J. F Chan A. C Chow L. T Leung S. F Lam Y. H Liang E. Y Chung S. C Metreweli C 1999Assessing chemotherapy response of squamous cell oesophageal carcinoma with spiral CT. Br J Radiol. 72 859 678 684
  27. 27. Hernando M. L Marks L. B Bentel G. C Zhou S. M Hollis D Das S. K Fan M Munley M. T Shafman T. D Anscher M. S Lind P. A 2001Radiation-induced pulmonary toxicity: a dose-volume histogram analysis in 201 patients with lung cancer. Int J Radiat Oncol Biol Phys. 51 3 650 659
  28. 28. Hirata N Kawamoto K Ueyama T Masuda K Utsunomiya T Kuwano H 1997Using endosonography to assess the effects of neoadjuvant therapy in patients with advanced esophageal cancer. AJR Am J Roentgenol. 169 2 485 491
  29. 29. Hironaka S Ohtsu A Boku N Muto M Nagashima F Saito H Yoshida S Nishimura M Haruno M Ishikura S Ogino T Yamamoto S Ochiai A 2003Nonrandomized comparison between definitive chemo-radiotherapy and radical surgery in patients with T(2-3)N(any) M(0) squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys. 57 2 425 433
  30. 30.
  31. 31. Isenberg G Chak A Canto M. I Levitan N Clayman J Pollack B. J Sivak M. V Jr. (1998Endoscopic ultrasound in restaging of esophageal cancer after neoadjuvant chemoradiation. Gastrointest Endosc. 48 2 158 163
  32. 32. Ishida K Ando N Yamamoto S Ide H Shinoda M 2004Phase II study of cisplatin and 5-fluorouracil with concurrent radiotherapy in advanced squamous cell carcinoma of the esophagus: a Japan Esophageal Oncology Group (JEOG)/Japan Clinical Oncology Group trial (JCOG9516). Jpn J Clin Oncol. 34 10 615 619
  33. 33. Ishihara R Yamamoto S Iishi H Takeuchi Y Sugimoto N Higashino K Uedo N Tatsuta M Yano M Imai A Nishiyama K 2010Factors predictive of tumor recurrence and survival after initial complete response of esophageal squamous cell carcinoma to definitive chemo-radiotherapy. Int J Radiat Oncol Biol Phys. 76 1 123 129
  34. 34. Ishikura S Nihei K Ohtsu A Boku N Hironaka S Mera K Muto M Ogino T Yoshida S 2003Long-term toxicity after definitive chemo-radiotherapy for squamous cell carcinoma of the thoracic esophagus. J Clin Oncol. 21 14 2697 2702
  35. 35. Japanese Society of Esophageal diseasesComprehensive registry of esophageal cancer in Japan, 1999. (2005Esophagus, 2 2 43 69
  36. 36. Jemal A Center M. M Desantis C Ward E. M 2010Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 19 8 1893 1907
  37. 37. Jones D. R Detterbeck F. C Egan T. M Parker L. A Jr, Bernard, S.A., & Tepper, J.E. (1997Induction chemo-radiotherapy followed by esophagectomy in patients with carcinoma of the esophagus. Ann Thorac Surg. 64 1 185 191
  38. 38. Jones D. R Parker L. A Jr, Detterbeck, F.C., & Egan, T.M. (1999Inadequacy of computed tomography in assessing patients with esophageal carcinoma after induction chemo-radiotherapy. Cancer. 85 5
  39. 39. Kato H Sato A Fukuda H Kagami Y Udagawa H Togo A Ando N Tanaka O Shinoda M Yamana H Ishikura S 2009 A Phase II trial of chemo-radiotherapy for stage I esophageal squamous cell carcinoma: Japan Clinical Oncology Group Study (JCOG9708). Jpn J Clin Oncol. 39 10 638 643
  40. 40. Kato K Muro K Minashi K Ohtsu A Ishikura S Boku N Takiuchi H Komatsu Y Miyata Y Fukuda H Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group (JCOG). (2011Phase II Study of Chemo-radiotherapy with 5-Fluorouracil and Cisplatin for Stage II-III Esophageal Squamous Cell Carcinoma: JCOG Trial (JCOG 9906). Int J Radiat Oncol Biol Phys. 81 3 684 690
  41. 41. Kazui T Osada H Fujita H Committee for Scientific Affairs. (2007An attempt to analyze the relation between hospital surgical volume and clinical outcome. Gen Thorac Cardiovasc Surg. 55 12 483 492
  42. 42. Keighley M. R 2003Gastrointestinal cancers in Europe. Aliment Pharmacol Ther. 18Suppl 3, 7 30
  43. 43. Kenjo M Uno T Murakami Y Nagata Y Oguchi M Saito S Numasaki H Teshima T Mitsumori M 2009Radiation therapy for esophageal cancer in Japan: results of the Patterns of Care Study 1999-2001. Int J Radiat Oncol Biol Phys. 75 2 357 363
  44. 44. Kleinberg L Gibson M K Forastiere A. A 2007 Chemo-radiotherapy for localized esophageal cancer: regimen selection and molecular mechanisms of radiosensitization. Nat Clin Pract Oncol. 4 5 282 294
  45. 45. Kranzfelder M Schuster T Geinitz H Friess H Büchler P 2011Meta-analysis of neoadjuvant treatment modalities and definitive non-surgical therapy for oesophageal squamous cell cancer. Br J Surg. 98 6 768 783
  46. 46. Kumekawa Y Kaneko K Ito H Kurahashi T Konishi K Katagiri A Yamamoto T Kuwahara M Kubota Y Muramoto T Mizutani Y Imawari M 2006Late toxicity in complete response cases after definitive chemo-radiotherapy for esophageal squamous cell carcinoma. J Gastroenterol. 41 5 425 432
  47. 47. Li Q. Q Liu M. Z Hu Y. H Liu H He Z. Y Lin H. X 2010Definitive concomitant chemo-radiotherapy with docetaxel and cisplatin in squamous esophageal carcinoma. Dis Esophagus. 23 3 253 259
  48. 48. Lim J. T Truong P. T Berthelet E Pai H Joe H Wai E Larsson S Kader H. A Weinerman B Wilson K Olivotto I. A 2003Endoscopic response predicts for survival and organ preservation after primary chemo-radiotherapy for esophageal cancer. Int J Radiat Oncol Biol Phys. 57 5 1328 1335
  49. 49. Lin H. C Xirasagar S Lee H. C Chai C. Y 2006Hospital volume and inpatient mortality after cancer-related gastrointestinal resections: the experience of an Asian country. Ann Surg Oncol. 13 9 1182 1188
  50. 50. Madani I De Ruyck K Goeminne H De Neve W Thierens H Van Meerbeeck J 2007Predicting risk of radiation-induced lung injury. J Thorac Oncol. 2 9 864 874
  51. 51. Martel M. K Sahijdak W. M Ten Haken, R.K., Kessler, M.L., & Turrisi, A.T. (1998
  52. 52. Fraction size and dose parameters related to the incidence of pericardial effusionsInt J Radiat Oncol Biol Phys. 40 1 155 161
  53. 53. Mcdonald S Rubin P Phillips T. L Marks L. B 1995Injury to the lung from cancer therapy: clinical syndromes, measurable endpoints, and potential scoring systems. Int J Radiat Oncol Biol Phys. 31 5 1187 1203
  54. 54. Metzger R Bollschweiler E Vallböhmer D Maish M Demeester T. R Hölscher A. H 2004High volume centers for esophagectomy: what is the number needed to achieve low postoperative mortality? Dis Esophagus. 17 4 310 314
  55. 55. Migliore M Choong C. K Lim E Goldsmith K. A Ritchie A Wells F. C 2007 A Surgeon s case volume of oesophagectomy for cancer strongly influences the operative mortality rate. Eur J Cardiothorac Surg. 32 2 375 380
  56. 56. Minashi K Doi T Muto M Mera K Yano T Ohtsu A 2006chemo-radiotherapy for superficial esophageal squamous cell carcinoma. Stomach and Intestine. 41 1467 1474
  57. 57. Minsky B. D Pajak T. F Ginsberg R. J Pisansky T. M Martenson J Komaki R Okawara G Rosenthal S. A Kelsen D. P 2002INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 20 5 1167 1174
  58. 58. Morota M Gomi K Kozuka T Chin K Matsuura M Oguchi M Ito H Yamashita T 2009Late toxicity after definitive concurrent chemo-radiotherapy for thoracic esophageal carcinoma. Int J Radiat Oncol Biol Phys. 75 1 122 128
  59. 59. Murakami M Kuroda Y Okamoto Y Kono K Yoden E Kusumi F Hajiro K Matsusue S Takeda H 1998Neoadjuvant concurrent chemo-radiotherapy followed by definitive high-dose radiotherapy or surgery for operable thoracic esophageal carcinoma. Int J Radiat Oncol Biol Phys. 40 5 1049 1059
  60. 60. Nakajima T. E Ura T Ito Y Kato K Minashi K Nihei K Hironaka S Boku N Kagami Y Muro K 2009 A Phase I trial of 5-fluorouracil with cisplatin and concurrent standard-dose radiotherapy in Japanese patients with stage II/III esophageal cancer. Jpn J Clin Oncol. 39 1 37 42
  61. 61. Nakamura T Hayashi K Ota M Eguchi R Ide H Takasaki K Mitsuhashi N 2004Salvage esophagectomy after definitive chemotherapy and radiotherapy for advanced esophageal cancer. Am J Surg. 188 3 261 266
  62. 62. Nishihira T Hirayama K Mori S 1998A prospective randomized trial of extended cervical and superior mediastinal lymphadenectomy for carcinoma of the thoracic esophagus. Am J Surg. 175 1
  63. 63. Nishihira T Sayama J Ueda H Sugawara K Takano R Sagawa J Katayama M Shineha R Hirayama K Mori S 1995Lymph flow and lymph node metastasis in esophageal cancer. Surg Today. 25 4
  64. 64. Nishimura M Daiko H Yoshida J Nagai K 2007Salvage esophagectomy following definitive chemo-radiotherapy. Gen Thorac Cardiovasc Surg. 55 11 461 464
  65. 65. Nishimura Y Suzuki M Nakamatsu K Kanamori S Yagyu Y Shigeoka H 2002Prospective trial of concurrent chemo-radiotherapy with protracted infusion of 5-fluorouracil and cisplatin for T4 esophageal cancer with or without fistula. Int J Radiat Oncol Biol Phys. 53 1 134 139
  66. 66. Ohtsu A Boku N Muro K Chin K Muto M Yoshida S Satake M Ishikura S Ogino T Miyata Y Seki S Kaneko K Nakamura A 1999Definitive chemo-radiotherapy for T4 and/or M1 lymph node squamous cell carcinoma of the esophagus. J Clin Oncol. 17 9 2915 2921
  67. 67. Oki E Morita M Kakeji Y Ikebe M Sadanaga N Egasira A Nishida K Koga T Ohata M Honboh T Yamamoto M Baba H Maehara Y 2007Salvage esophagectomy after definitive chemo-radiotherapy for esophageal cancer. Dis Esophagus. 20 4 301 304
  68. 68. Orringer M. B Marshall B Chang A. C Lee J Pickens A 2007 Lau C. L Two thousand transhiatal esophagectomies: changing trends, lessons learned. Ann Surg. 246 3 363 372
  69. 69. Pöttgen C Stuschke M 2012Radiotherapy versus surgery within multimodality protocols for esophageal cancer- A meta-analysis of the randomized trials. Cancer Treat Rev. 38 6 599 604
  70. 70. Rentz J Bull D Harpole D Bailey S Neumayer L Pappas T Krasnicka B Henderson W Daley J Khuri S 2003Transthoracic versus transhiatal esophagectomy: a prospective study of 945 patients. J Thorac Cardiovasc Surg. 125 5 1114 1120
  71. 71. Rice T. W Rusch V. W Apperson-hansen C Allen M. S Chen L. Q Hunter J. G Kesler K. A Law S Lerut T. E Reed C. E Salo J. A Scott W. J Swisher S. G Watson T. J Blackstone E. H Worldwide esophageal cancer collaboration. (2009Dis Esophagus. 22 1 1 8
  72. 72. Roach M rd,. Gandara, D.R., You, H.S., Swift, P.S., Kroll, S., Shrieve, D.C., Wara, W.M., Margolis, L., & Phillips, T.L. (1995Radiation pneumonitis following combined modality therapy for lung cancer: analysis of prognostic factors. J Clin Oncol. 13 10 2606 2612
  73. 73. Ruol A Castoro C Portale G Cavallin F Sileni V. C Cagol M Alfieri R Corti L Boso C Zaninotto G Peracchia A Ancona E 2009Trends in management and prognosis for esophageal cancer surgery: twenty-five years of experience at a single institution. Arch Surg. 144 3 247 254
  74. 74. Safran H Suntharalingam M Dipetrillo T Ng T Doyle L. A Krasna M Plette A Evans D Wanebo H Akerman P Spector J Kennedy N Kennedy T 2008Cetuximab with concurrent chemoradiation for esophagogastric cancer: assessment of toxicity. Int J Radiat Oncol Biol Phys. 70 2 391 395
  75. 75. Sai H Mitsumori M Yamauchi C Araki N Okumura S Nagata Y Nishimura Y Hiraoka M 2004Concurrent chemo-radiotherapy for esophageal cancer: comparison between intermittent standard-dose cisplatin with 5-fluorouracil and daily low-dose cisplatin with continuous infusion of 5-fluorouracil. Int J Clin Oncol. 9 3 149 153
  76. 76. Sasamoto R Sakai K Inakoshi H Sueyama H Saito M Sugita T Tsuchida E Ito T Matsumoto Y Yamanoi T Abe E Yamana N Sasai K 2007Long-term results of chemo-radiotherapy for locally advanced esophageal cancer, using daily low-dose 5-fluorouracil and cis-diammine-dichloro-platinum (CDDP). Int J Clin Oncol. 12 1 25 30
  77. 77. Smithers B. M Cullinan M Thomas J. M Martin I Barbour A. P Burmeister B. H Harvey J. A Thomson D. B Walpole E. T Gotley D. C 2007Outcomes from salvage esophagectomy post definitive chemo-radiotherapy compared with resection following preoperative neoadjuvant chemo-radiotherapy. Dis Esophagus. 20 6 471 477
  78. 78. Stahl M Stuschke M Lehmann N Meyer H. J Walz M. K Seeber S Klump B Budach W Teichmann R Schmitt M Schmitt G Franke C Wilke H 2005Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol. 23 10 2310 2317
  79. 79. Stein H. J Feith M Bruecher B. L Naehrig J Sarbia M Siewert J. R 2005Early esophageal cancer: pattern of lymphatic spread and prognostic factors for long-term survival after surgical resection. Ann Surg. 242 4
  80. 80. Steyerberg E. W Neville B. A Koppert L. B Lemmens V. E Tilanus H W Coebergh J. W Weeks J. C Earle C.C. (2006Surgical mortality in patients with esophageal cancer: development and validation of a simple risk score. J Clin Oncol. 24 26 4277 4284
  81. 81. Suzuki H Gotoh M Sugihara K Kitagawa Y Kimura W Kondo S Shimada M Tomita N Nakagoe T Hashimoto H Baba H Miyata H Motomura N 2011Nationwide survey and establishment of a clinical database for gastrointestinal surgery in Japan: Targeting integration of a cancer registration system and improving the outcome of cancer treatment. Cancer Sci. 102 1 226 230
  82. 82. Swisher S. G Maish M Erasmus J. J Correa A. M Ajani J. A Bresalier R Komaki R Macapinlac H Munden R. F Putnam J. B Rice D Smythe W. R Vaporciyan A. A Walsh G. L Wu T. T Roth J. A 2004Utility of PET, CT, and EUS to identify pathologic responders in esophageal cancer. Ann Thorac Surg. 78 4 1152 1160
  83. 83. Swisher S. G Wynn P Putnam J. B Mosheim M. B Correa A. M Komaki R. R Ajani J. A Smythe W. R Vaporciyan A. A Roth J. A Walsh G. L 2002Salvage esophagectomy for recurrent tumors after definitive chemotherapy and radiotherapy. J Thorac Cardiovasc Surg. 123 1 175 183
  84. 84. Tachimori Y Kanamori N Uemura N Hokamura N Igaki H Kato H 2009Salvage esophagectomy after high-dose chemo-radiotherapy for esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg. 137 1 49 54
  85. 85. Takeuchi S Ohtsu A Doi T Kojima T Minashi K Mera K Yano T Tahara M Muto M Nihei K 2007A retrospective study of definitive chemo-radiotherapy for elderly patients with esophageal cancer. Am J Clin Oncol. 30 6 607 611
  86. 86. Tomimaru Y Yano M Takachi K Miyashiro I Ishihara R Nishiyama K Sasaki Y Ishikawa O Doki Y Imaoka S 2006Factors affecting the prognosis of patients with esophageal cancer undergoing salvage surgery after definitive chemo-radiotherapy. J Surg Oncol. 93 5 422 428
  87. 87. Tougeron D Di Fiore, F., Thureau, S., Berbera, N., Iwanicki-Caron, I., Hamidou, H., Paillot, B., & Michel, P. (2008Safety and outcome of definitive chemo-radiotherapy in elderly patients with oesophageal cancer. Br J Cancer. 99 10 1586 1592
  88. 88. Tsujino K Hirota S Endo M Obayashi K Kotani Y Satouchi M Kado T Takada Y 2003Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer. Int J Radiat Oncol Biol Phys. 55 1 110 115
  89. 89. Urschel J. D Vasan H 2003 A Meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg. 185 6 538 543
  90. 90. van de VenC., De Leyn, P., Coosemans, W., Van Raemdonck, D., Lerut, T. (1999Three-field lymphadenectomy and pattern of lymph node spread in T3 adenocarcinoma of the distal esophagus and the gastro-esophageal junction. Eur J Cardiothorac Surg. 15 6 769 773
  91. 91. Weber W. A Ott K Becker K Dittler H. J Helmberger H Avril N. E Meisetschläger G Busch R Siewert J. R Schwaiger M Fink U 2001Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol. 19 12 3058 3065
  92. 92. Willis J Cooper G. S Isenberg G Sivak M. V Jr, Levitan, N., Clayman, J., & Chak, A. (2002Correlation of EUS measurement with pathologic assessment of neoadjuvant therapy response in esophageal carcinoma. Gastrointest Endosc. 55 6 655 661
  93. 93. Wilson K. S Lim J. T 2000Primary chemo-radiotherapy and selective oesophagectomy for oesophageal cancer: goal of cure with organ preservation. Radiother Oncol. 54 2 129 134
  94. 94. Wilson K. S Wilson A. G Dewar G. J 2002Curative treatment for esophageal cancer: Vancouver Island Cancer Centre experience from 1993 to 1998. Can J Gastroenterol. 16 6 361 368
  95. 95. Wouters M. W Wijnhoven B. P Karim-kos H. E Blaauwgeers H. G Stassen L. P Steup W. H Tilanus H. W Tollenaar R. A 2008High-volume versus low-volume for esophageal resections for cancer: the essential role of case-mix adjustments based on clinical data. Ann Surg Oncol. 15 1 80 87
  96. 96. Yamada K Murakami M Okamoto Y Okuno Y Nakajima T Kusumi F Takakuwa H Matsusue S 2006Treatment results of chemo-radiotherapy for clinical stage I (T1N0M0) esophageal carcinoma. Int J Radiat Oncol Biol Phys. 64 4 1106 1111
  97. 97. Yamada M Kudoh S Hirata K Nakajima T Yoshikawa J 1998Risk factors of pneumonitis following chemo-radiotherapy for lung cancer. Eur J Cancer. 34 1 71 75
  98. 98. Yamamoto S Ishihara R Motoori M Kawaguchi Y Uedo N Takeuchi Y Higashino K Yano M Nakamura S Iishi H 2011Comparison between definitive chemo-radiotherapy and esophagectomy in patients with clinical stage I esophageal squamous cell carcinoma. Am J Gastroenterol. 106 6 1048 1054
  99. 99. Yamashita H Nakagawa K Yamada K Kaminishi M Mafune K Ohtomo K 2008A single institutional non-randomized retrospective comparison between definitive chemo-radiotherapy and radical surgery in 82 Japanese patients with resectable esophageal squamous cell carcinoma. Dis Esophagus. 21 5 430 436
  100. 100. Yasunaga H Matsuyama Y Ohe K Japan Surgical Society. (2009Effects of hospital and surgeon case-volumes on postoperative complications and length of stay after esophagectomy in Japan. Surg Today. 39 7 566 571
  101. 101. Zuccaro G Jr, Rice, T.W., Goldblum, J., Medendorp, S.V., Becker, M., Pimentel, R., Gitlin, L., & Adelstein, D.J. (1999Endoscopic ultrasound cannot determine suitability for esophagectomy after aggressive chemo-radiotherapy for esophageal cancer. Am J Gastroenterol. 94 4 906 912

Written By

Shouji Shimoyama

Submitted: 30 April 2012 Published: 09 May 2013