Chemo-Radiotherapy for Resectable Esophageal Cancer — Unresolved Problems Remain

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 (http://info.cancerresearchuk.org/ cancerstats/types/oesophagus/survival/), and less than 10% in most parts of Europe (Keighley 2003). In Japan, an updated nationwide survey (http://ganjoho.jp/public/statistics/backnum‐ ber/2011_en.html) 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 chemoradiotherapy (CRT) (neoadjuvant CRT) has been developed and proved promising; nonethe‐ less, 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.


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 (http://info.cancerresearchuk.org/cancerstats/types/oesophagus/survival/), and less than 10% in most parts of Europe (Keighley 2003).In Japan, an updated nationwide survey (http://ganjoho.jp/public/statistics/backnumber/2011_en.html) 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 chemoradiotherapy (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 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).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.

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 radiationinduced 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.).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.

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 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.(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  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.

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 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. 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.
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 EUSbased 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%,  Cancer Treatment -Conventional and Innovative Approaches 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.

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  ).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

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 (http:// clinicaltrials.gov).
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.

Figure 1 .
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.

Table 1 .
Treatment results of definitive chemo-radiotherapy for far advanced esophageal cancer in Japan.

Table 3 .
Mortality and late morbidity of definitive chemo-radiotherapy.
(Hernando et al., 2001)M Yamada et al., 1998)radio-therapy 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 (Fujita et al., 2010)02)ison 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)andKazui et al.

Table 4 .
Overall and local recurrence rates among CR patients undergoing dCRT.
SCC; squamous cell cancer.ADC; adenocarcinoma ND; not described, CR; complete response (Chao et al., 2009;Tomimaru et al., 2006;Oki et al., 2007;Swisher et al., 2002;Tachimori et al., 2009;Tomimaru et al., 2006)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 (Minsky et al., 2002; 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).