Cancer de Esofago. Abeloff

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13  78 Cancer of the Esophagus Lawrence R. Kleinberg, Malcolm V. Brock, Sanjay B. Jagannath, and Arlene A. Forastiere SUMMARY OF KEY POINTS Classification • Esophageal cancer is subdivided into the following four groups: epithelial tumors, metastatic tumors, lymphomas, and sarcomas. • Cancers of epithelial origin, predom- inantly squamous cell carcinomas and adenocarcinomas, are the most com- mon; other histologic types are rare. Incidence • Within the United States, the incidence of esophageal cancer in people younger than 80 years is 3.2 per 100,000 persons. • Historically and internationally, squamous cell tumors are the most common histologic type; however, a dramatic increase in the incidence of adenocarcinoma has been documented in the United States, the United Kingdom, and western Europe. Pathogenesis • Exact etiology is unknown. • The data support the hypothesis that epithelial tumors arise as a result of chronic irritation from a wide variety of sources, including gastric contents in chronic reflux and known carcinogens. • A strong association of Barrett’s esophagus and adenocarcinoma is seen, but a benefit to screening endoscopy for those who are at risk for or have known Barrett’s esophagus is unknown, as the overall risk of cancer-related mortality is low. Studies with longer- term follow-up are needed to clarify this issue. Other identified risk factors are gastroesophageal reflux disease, obesity, and smoking. • Squamous cell carcinoma is associated with smoking as well as alcohol use, and the declining incidence has paralleled the decline in smoking. • Point mutations, increased copy number, and promoter region hypermethylation all appear to be important in the progression to malignancy. Diagnosis and Staging • Symptoms and demographics will strongly suggest the diagnosis. • Endoscopy is the best screening examination, but esophagram may also be utilized. • Diagnosis is made by endoscopy with cytology and biopsy of tumor. • Transesophageal ultrasound should be used to assess T and N stage to guide optimal definitive therapy. • Computed tomography (CT) of the chest and abdomen is useful in screening for metastatic disease. • Positron emission tomography (PET) scan is useful to detect additional cases of metastatic disease before costly and toxic definitive therapy. PET may be superior to endoscopic ultrasonography in detecting intra-abdominal lymph nodes but not periesophageal nodes adjacent to the primary tumor. • Additional studies include laparoscopy, thoracoscopy, bone scan, and CT of the brain when indicated by clinical circumstances. Treatment • Treatment of premalignant dysplasia is guided by grade of histology. Low-grade dysplasia should be closely followed by endoscopy. High-grade dysplasia is treated with esophagectomy, although close follow-up or endoscopic treatments might be appropriate for selected patients. • Selection of appropriate treatment for carcinoma depends on tumor stage and patient performance status. • Surgery is an accepted single-modality therapy for patients with localized disease (T1 to 3 N0 to 1 M01a). The selection of surgical approach depends on location and experience, but no approach has been demonstrated to lead to superior cure rates. • Combined chemoradiation leads to prolonged median survival and long- term survival compared with radiation alone, at the price of increased toxicity This represents a potentially curative alternative to surgery for squamous cel cancers and is appropriate for most unresectable T4 N(any) M0 lesions of either histology. As most patients treated on prospective chemoradiation trials had squamous cell carcinomas, the benefits of nonoperative management for adenocarcinoma are not known. • Randomized trials have not confirmed a survival benefit with surgery added to chemoradiation in squamous cell carcinoma, but there was a significant local control benefit. • Accumulating evidence, including multiple modestly powered randomized trials and meta-analyses, suggests that combination therapy with preoperative chemoradiation followed by surgery improves local control and may increase survival compared with surgery alone. • Postoperative adjuvant chemotherapy or chemoradiation is less well studied in esophageal cancer, but trials in gastric cancer, including gastroesophageal  junction adenocarcinoma, have demonstrated a benefit. • Combined modality chemotherapy regimens frequently include 5- fluorouracil and cisplatin agents; other commonly used regimens include taxanes and irinotecan. • Endoscopic palliative therapy includes laser or electrical fulguration, photodynamic therapy, or stenting. Except for very superficial lesions, these therapies are not alternatives to surgery, as they do not address deeper disease or lymphatic spread. • Radiation therapy, with or without chemotherapy, may be used to palliate local symptoms. • Chemotherapy may be used for metastatic disease, but response rates and duration of response are modest for most patients. Clinical trials are recommended.

Transcript of Cancer de Esofago. Abeloff

  • 1399

    78 Cancer of the EsophagusLawrence R. Kleinberg, Malcolm V. Brock, Sanjay B. Jagannath, and Arlene A. Forastiere

    S U M M A R Y O F K E Y P O I N T S

    Classi cation Esophageal cancer is subdivided into

    the following four groups: epithelial tumors, metastatic tumors, lymphomas, and sarcomas.

    Cancers of epithelial origin, predom-inantly squamous cell carcinomas and adenocarcinomas, are the most com-mon; other histologic types are rare.

    Incidence Within the United States, the incidence

    of esophageal cancer in people younger than 80 years is 3.2 per 100,000 persons.

    Historically and internationally, squamous cell tumors are the most common histologic type; however, a dramatic increase in the incidence of adenocarcinoma has been documented in the United States, the United Kingdom, and western Europe.

    Pathogenesis Exact etiology is unknown. The data support the hypothesis that

    epithelial tumors arise as a result of chronic irritation from a wide variety of sources, including gastric contents in chronic re ux and known carcinogens.

    A strong association of Barretts esophagus and adenocarcinoma is seen, but a bene t to screening endoscopy for those who are at risk for or have known Barretts esophagus is unknown, as the overall risk of cancer-related mortality is low. Studies with longer-term follow-up are needed to clarify this issue. Other identi ed risk factors are gastroesophageal re ux disease, obesity, and smoking.

    Squamous cell carcinoma is associated with smoking as well as alcohol use, and the declining incidence has paralleled the decline in smoking.

    Point mutations, increased copy number, and promoter region hypermethylation all appear to be important in the progression to malignancy.

    Diagnosis and Staging Symptoms and demographics will

    strongly suggest the diagnosis. Endoscopy is the best screening

    examination, but esophagram may also be utilized.

    Diagnosis is made by endoscopy with cytology and biopsy of tumor.

    Transesophageal ultrasound should be used to assess T and N stage to guide optimal de nitive therapy.

    Computed tomography (CT) of the chest and abdomen is useful in screening for metastatic disease.

    Positron emission tomography (PET) scan is useful to detect additional cases of metastatic disease before costly and toxic de nitive therapy. PET may be superior to endoscopic ultrasonography in detecting intra-abdominal lymph nodes but not periesophageal nodes adjacent to the primary tumor.

    Additional studies include laparoscopy, thoracoscopy, bone scan, and CT of the brain when indicated by clinical circumstances.

    Treatment Treatment of premalignant dysplasia is

    guided by grade of histology. Low-grade dysplasia should be closely followed by endoscopy. High-grade dysplasia is treated with esophagectomy, although close follow-up or endoscopic treatments might be appropriate for selected patients.

    Selection of appropriate treatment for carcinoma depends on tumor stage and patient performance status.

    Surgery is an accepted single-modality therapy for patients with localized disease (T1 to 3 N0 to 1 M01a). The selection of surgical approach depends on location and experience, but no approach has been demonstrated to lead to superior cure rates.

    Combined chemoradiation leads to prolonged median survival and long-term survival compared with radiation

    alone, at the price of increased toxicity. This represents a potentially curative alternative to surgery for squamous cell cancers and is appropriate for most unresectable T4 N(any) M0 lesions of either histology. As most patients treated on prospective chemoradiation trials had squamous cell carcinomas, the bene ts of nonoperative management for adenocarcinoma are not known.

    Randomized trials have not con rmed a survival bene t with surgery added to chemoradiation in squamous cell carcinoma, but there was a signi cant local control bene t.

    Accumulating evidence, including multiple modestly powered randomized trials and meta-analyses, suggests that combination therapy with preoperative chemoradiation followed by surgery improves local control and may increase survival compared with surgery alone.

    Postoperative adjuvant chemotherapy or chemoradiation is less well studied in esophageal cancer, but trials in gastric cancer, including gastroesophageal junction adenocarcinoma, have demonstrated a bene t.

    Combined modality chemotherapy regimens frequently include 5- uorouracil and cisplatin agents; other commonly used regimens include taxanes and irinotecan.

    Endoscopic palliative therapy includes laser or electrical fulguration, photodynamic therapy, or stenting. Except for very super cial lesions, these therapies are not alternatives to surgery, as they do not address deeper disease or lymphatic spread.

    Radiation therapy, with or without chemotherapy, may be used to palliate local symptoms.

    Chemotherapy may be used for metastatic disease, but response rates and duration of response are modest for most patients. Clinical trials are recommended.

  • 1400 Part III: Speci c Malignancies

    INTRODUCTIONCarcinoma of the esophagus is a devastating disease associated with poor survival outcome and with adverse affects on swallowing and quality of life. Although esophageal cancer is an aggressive malig-nancy that usually presents in a locally advanced stage, signi cant progress has been made in the treatment of this disease, including expanded treatment options, decreased surgical morbidity and mor-tality, and improvements in identifying patients who are at risk. These advances are resulting in incremental improvements in outcome, but there remains considerable controversy over the optimal management under individual scenarios. The emphasis of this chapter is on selecting the appropriate options in the curative and palliative management of esophageal cancer.

    CLASSIFICATION AND LOCATIONEsophageal cancer (Table 78-1) is classi ed on the basis of histologic appearance and cell of origin, as follows: (1) epithelial tumors, (2) metastatic tumors, (3) lymphomas, and (4) sarcomas. Cancers of epithelial cell origin, predominantly squamous cell carcinoma and adenocarcinoma, are the most common.

    Squamous cell cancer usually occurs in the middle third of the esophagus. In a collective review of over 28,000 cases of squamous cell cancers, Postlethwait1 estimated the ratio of upper, middle, and lower cancers to be 15 : 50 : 35, respectively. Adenocarcinoma, on the other hand, is most common in the lower third of the esophagus. In a collective review of 4783 cases of esophageal adenocarcinoma, Ming2 noted an upper esophageal location in 4%, middle in 18%, and lower in 67%. Of the rare primary histologic types, 95% of small cell cancers occur in the middle and lower thirds; both malignant melanoma and choriocarcinoma tend to occur in the lower third. Esophageal sarcomas may occur anywhere along the esophagus, as is the case for esophageal lymphomas or metastases from other primary cancers.

    INCIDENCETumors of the esophagus other than squamous cell carcinoma and adenocarcinoma are very rare. This chapter therefore focuses on

    esophageal squamous cell carcinoma and adenocarcinoma. Epide-miologic data show that the incidence of esophageal cancer varies considerably from one country to another and often within a single country. The geographic diversity of esophageal cancer worldwide, of which over 90% are squamous cell cancers, underscores the mul-tifactorial etiologies of this group of diseases. In the United States and other Western industrialized countries,38 however, there has been a slight decline in squamous cell esophageal cancer over the past three decades and a dramatic rise in adenocarcinoma of the distal esophagus and gastroesophageal (GE) junction. This histology has increased in incidence approximately sixfold and, since the mid-1990s, has been the predominant esophageal cancer in Caucasians.7 The absolute incidence in the United States has increased from 3.8 per million in 19731975 to 23.3 per million in 2001, according to the National Cancer Institutes Surveillance, Epidemiology and End Results database.7 This rate of increase exceeds that of all other cancers, including lung, breast, prostate, and melanoma. Adenocar-cinoma is much less common in African Americans but has increased from 0.4 per 100,000 to 0.9 per 100,000, and 0 to 0.2 per 100,000 in females. Obesity and gastroesophageal re ux disease (GERD) appear to contribute to this rise in adenocarcinoma incidence. In contrast, the incidence of squamous cell carcinoma decreased in all of these groups during this period, perhaps owing to a decline in the prevalence of smoking and increased consumption of fresh fruits and vegetables.9

    PATHOGENESISData support the hypothesis that epithelial esophageal tumors arise as a result of chronic irritation and in ammation of the esophagus leading to a sequence of genetic alterations in the damaged epithe-lium and histologic changes of dysplasia to carcinoma. The geo-graphic and demographic distributions of esophageal cancer vary widely. Whether this variance can be explained solely by environ-mental factors or whether a genetic component exists as well is conjectural. The most commonly reported irritants include tobacco, alcohol, dietary factors, lye, radiation, and re uxed bile salts and gastric contents. There are important differences between the risk factors, histologic progression, and molecular events that support the concept that squamous cell carcinoma and adenocarcinoma should be considered as separate entities with potential to respond differently to newer treatment approaches. These differences are highlighted in the following sections.

    Clinical Risk Factors

    Tobacco smoking is a proven etiologic factor in the development of squamous cell esophageal cancer for both men and women according to epidemiologic studies from various countries worldwide. This relationship is dose-dependent, and the risk of esophageal cancer decreases with smoking cessation. Smokeless tobacco products have also been shown to correlate with an increased risk of cancers of the mouth, larynx, throat, and esophagus.10 There is also a multiplicative interaction of alcohol intake and tobacco use.1114 In a study from Taiwan, the strongest risk for squamous esophageal cancer was alcohol consumption, with a 13.9-fold increased risk, while com-bined exposure with smoking increased the risk to nearly 20-fold.11

    A prospective study of tobacco, alcohol, and risk of esophageal squamous cell carcinoma and adenocarcinoma in the United States found an increased risk of squamous cell carcinoma among current smokers compared with nonsmokers (hazard ratio (HR): 9.27, 95% con dence interval (CI): 4.04, 21.29) and also an increased risk for adenocarcinoma (HR: 3.70, 95% CI: 2.20, 6.22). For people who drink more than three alcoholic beverages a day compared to one drink, there was increased risk of esophageal squamous cell carcinoma but not adenocarcinoma of the esophagus, GE junction, or cardia.13 The association of adenocarcinoma with smoking, though much less

    Table 78-1 Classi cation of Esophageal Cancer

    EPITHELIAL

    Squamous cell carcinoma

    Ordinary squamous cell

    Verrucous squamous cell

    Spindle cell (carcinosarcoma)

    Adenocarcinoma

    Ordinary

    Adenoacanthoma

    Mucoepidermoid

    Adenoid cystic

    Small cell

    Melanoma

    Choriocarcinoma

    METASTATIC DISEASE

    Lymphoma

    Sarcoma

  • 1401Cancer of the Esophagus CHAPTER 78

    striking than that of squamous cell carcinoma, appears to remain elevated for more than 30 years after smoking cessation.15

    Other factors that are associated with an increased risk of squa-mous cell esophageal cancer are lye ingestion, radiation therapy (RT), achalasia, Plummer-Vinson syndrome, and previous head and neck squamous cell cancer. The interval between injury and the develop-ment of cancer may be considerable in patients who sustain lye ingestion or are irradiated.

    Nutritional and dietary factors have been evaluated in an attempt to explain the worldwide variability in the incidence of squamous esophageal cancer. Ghadirian and colleagues16 reported that the pop-ulations with the highest incidence of esophageal cancer shared dietary characteristics, including a rapidly consumed high-starch diet with few or no fruits and vegetables. Many dishes consist of granular foods or foods that are served quite hot, both of which irritate the esophagus.16 Associations between fruit and vegetable intake and esophageal cancer risk have been found for both squamous cell car-cinomas and adenocarcinomas of the esophagus and aerodigestive tract cancers in general,17,18 some data suggesting that this relation-ship might vary according to histologic type.19 For example, risk factors for esophageal, gastric cardia, and noncardia gastric cancers in Linxian, China, which has one of the highest rates of these cancers in the world, were prospectively evaluated in a population-based study of over 25,000 adults performed by the National Cancer Insti-tute.20 After 15 years of follow-up, improved socioeconomic status seemed to be a common factor for lowering risks for all three sites. Protective factors for esophageal squamous cell cancer included formal education; water piped into the home; and increased consumption of meat, eggs, and fresh fruits. A study in Sweden that controlled for other risk factors assessed the importance of three diets as a risk factor: healthy diet (high in vegetables, tomatoes, fruits, sh, and poultry), Western diet (high in processed meat, red meat, sweets, high-fat dairy, and high-fat gravy), and alcohol drinker (high in intakes of beer, liquor, and French fries). A Western diet was associated with increased risks of gastric cardia adenocarcinoma (high third tertile versus low rst quartile, odds ratio [OR]: 1.8, 95% CI: 1.1 to 2.9, P for trend: 0.04) and esophageal adenocarcinoma (high third tertile versus low rst tertile, OR: 1.6, 95% CI: 0.9 to 3.1, P for trend: 0.13), whereas a dietary pattern characterized by high beer and liquor intake (alcohol drinker) signi cantly increased the risk of squamous cell carcinoma of the esophagus (third tertile versus low rst tertile, OR: 3.5, 95% CI: 1.9 to 6.3, P for trend:

  • 1402 Part III: Speci c Malignancies

    progression to esophageal adenocarcinoma is estimated as 1 per 250 patient-years, or 0.4% per year. These uncertainties are in part due to the problem of sampling error when biopsies are performed during endoscopy and to a high degree of interobserver variability in dyspla-sia grading.34 Thus, the current method for detecting esophageal cancer early in at-risk individuals through endoscopic screening and biopsy has low sensitivity and is controversial.

    Approximately two thirds of patients who develop adenocarci-noma have histologic evidence of BE3537; however, an estimated 40% will give no clear-cut history of GERD. Thus, screening endoscopy of individuals with symptomatic GERD will still miss the substantial proportion of individuals who do not report re ux symptoms.38

    Although there has been much progress in unraveling the relation-ship between Barretts mucosa, dysplasia, and esophageal adenocar-cinoma, there are still many unanswered questions, such as why Barretts mucosa is seen in such a speci c demographic pattern, and what is the trigger to initiate the progression to dysplasia and carcinoma.

    Molecular Progression to Adenocarcinoma

    Molecular genetic data support the histologic observation that there is a progression from normal epithelium to BE to dysplasia to adeno-carcinoma.39,40 Although a clearly de ned sequence of genetic alterations leading to adenocarcinoma has not been de ned, an accumulation of abnormalities has been identi ed in a wide range of genes that regulate proliferation, apoptosis, invasion, metastasis, angiogenesis, growth, and cell cycle regulation. Tumor suppressor genes such as p53 and p16 have been implicated as early events, as loss of cell cycle checkpoints may be permissive for genetic instability, allowing later transformation in the metaplasia-dysplasia-adenocarci-noma sequence.39,41,42 Moskaluk and colleagues43 performed immu-nohistochemical staining for p53, an important regulatory gene in cell cycle control and apoptosis, and p21/WAF1, a cyclin-dependent kinase inhibitor, in 98 adenocarcinoma esophagectomy specimens. They found similar p53 and p21 WAF1 expression in adenocarci-noma specimens with and without associated Barretts mucosa, and they concluded that the molecular mechanism of carcinogenesis for these two groups is the same. Wu and colleagues44 investigated DNA replication errors and allelic losses of chromosomes 17p, 18q, and 5q in esophageal adenocarcinoma (without associated Barretts mucosa), Barretts adenocarcinoma, and Barretts mucosa with dysplasia. More recently, Barrett and colleagues45 have reported that alteration in p53 and p16 are generally seen throughout an area of Barretts abnormal-ity, suggesting that these abnormalities were inherent in the original clonal development of BE. Additional mutations involving loss of heterozygosity at 5q, 13q, or 18q occurring in no particular order appeared to be important in the bifurcation into aneuploidy and onto progression into neoplasm.45 Wong and colleagues46 focused on the role of p16 inactivation and found that more than 85% of BE clones had inactivation of one or both p16 alleles by loss of heterozygosity (53%), hypermethylation (61%), and point mutation (15%). The loss of cell cycle regulation from these early changes may promote DNA instability, leading to additional changes required for progres-sion to malignancy. Interestingly, in patients with Barretts mucosa that harbor p16 +/ or p16 / alterations, the prevalence of other abnormalities, including 17p (p53) LOH, aneuploidy, or tetraploidy, can be 44% higher than that in patients without any p16 loss in their esophageal mucosae. In addition, the median length of Barretts mucosa increased from 1.5 in patients without p16 loss to 6.0 to 8.0 cm in those with p16 abnormalities. This again suggests that p16 might be an important step in the eld change leading to Barretts epithelium and invasive cancer.46

    There appears to be a diversity of molecular abnormalities in esophageal cancer that are caused by actual genetic mutations, epi-genetic inactivation, and altered cell regulation. Lagarde and col-leagues have reviewed many of the abnormalities of in gene expression

    in esophageal cancer, which occur in a wide variety of genes, such as cyclin D1, EGFR, Her-2/Neu, APC, TGF-, Endoglin, CTGF, P53, Bcl-2, NF-kappaB, Cox-2, E-cadherin, beta-catenin, uPA, MMP-1,3,7,9, the TIMP family, T( h )1/T( h )2 balance, CRP, and PTHrP.41,47 The method of identifying and codifying alterations in these genes into a clinically useful paradigm has not yet proved supe-rior to standard histology for predicting outcome, but more complex analyses using sophisticated molecular techniques such as genomic arrays could be helpful in the future. In the meantime, new molecu-lar abnormalities continue to be identi ed.48

    In the last decade, epigenetic modi cations have emerged as her-itable and fundamental features of most malignancies.49 The best-studied epigenetic modi cation of the DNA is promoter region hypermethylation, an epigenetic modi cation that is associated with gene inactivation. A meaningful understanding of the molecular events that lead to progression to adenocarcinoma will likely require a greater understanding of this phenomenon as it occurs at least as frequently as point mutation. DNA hypermethylation is biologically important in development where it is associated with the inactivation of genes on the X chromosome. In oncogenesis, hypermethylation is often associated with inactivation of tumor suppressor genes, of genes that suppress metastasis and angiogenesis, as well as of genes that repair DNA. Methylation of DNA occurs mostly at CpG sites in the genome and is catalyzed by a family of three active DNA methyl-transferases that transfer a methyl group from S-adenosyl-methionine to cytosine to form 5-methylcytosine. Because this reaction can be blocked effectively by a drug, 5-azacytidine, which acts as an irrevers-ible inhibitor of the DNA methyltransferases, the therapeutic poten-tial inherent in reversing DNA hypermethylation is signi cant.50

    In esophageal adenocarcinoma, CpG-island methylation at CDKN2A/p16INK4a has been implicated in the progression of BE to malignancy with 38% of premalignant and malignant lesions demonstrating this abnormality. Eads and colleagues51,52 reported results for 31 normal esophagus specimens and 22 adenocarcinoma specimens. The following genes were observed to be methylated in a substantial portion of esophageal cancer specimens but less often in normal esophagus from the same patients (percent tumor versus percent normal specimens): CDKN2a/p16 (41% versus 0%), ESR1 (86% versus 0%), MYOD1 (45% versus 0%), TIMP3 (86% versus 19%), APC (68% versus 3%), and CALCA (50% versus 13%). Others have found that CDH1 is methylated with substantially greater frequency in adenocarcinoma than in normal esophagus, BE, or dysplasia. In contrast to colon cancer, in which point mutations of CDKN2a/p16 are frequent, such mutations are rarely found in esophageal adenocarcinoma, and methylation predominates. Hyper-methylation of various genes is also prevalent in esophageal dysplasia. Of note, APC was found to be methylated in normal stomach in 12 of 12 specimens.52 MGMT was methylated in 55% of normal esoph-agus specimens, 73% of adenocarcinoma specimens, and 25% of stomach specimens. Hypermethylation of nel-like 1 gene53 and DAPK54 is uncommon in normal esophagus but is found in 40% to 60% of BE, dysplasia, and esophageal adenocarcinoma specimens and is associated with poorer prognosis, whereas MGMT hypermeth-ylation has not been associated with prognosis.53,55,56

    A study at Johns Hopkins found methylation57 frequencies of the genes APC (68%), E-cadherin (66%), O6-methylguanine DNA methyltransferase (56%), ER (51%), p16 (39%), DAP-kinase (19%), and TIMP3 (19%).57 Analysis of DNA methylation of these genes individually showed only trends toward diminished survival, whereas patients whose tumors had more than 50% of their gene pro le methylated had both signi cantly poorer survival (P = 0.04) and earlier tumor recurrence (P = 0.05) than those without positive methylation. By multivariate analysis, the hazard ratios (HRs) with positive methylation status were more powerful predictors of survival (HR: 2.7 [1.14 to 6.45, 95% CI]) and tumor recurrence (HR: 2.5 [1.11 to 5.6]) than was age (HR: 2.03 and 1.96, respectively) or stage (HR: 1.48 and 1.67, respectively).

  • 1403Cancer of the Esophagus CHAPTER 78

    Molecular Steps to Squamous Cell Carcinoma

    Gene expression pro ling studies have delineated some important differences between adenocarcinoma and squamous cell carcinoma. A comparison of adenocarcinoma, squamous cell carcinoma, BE, and normal esophagus suggested that both histologies had upregulation of genes commonly involved in carcinogenesis such as cell cycle regulators, extracellular matrix genes, immune response genes, kalli-kreins, and serine protease inhibitors with downregulation of genes related to calcium ion binding and gap junctions.58 Despite these similarities, other aspects of the gene expression pro le of squamous cell carcinoma were more closely related to normal esophagus, whereas adenocarcinoma was more closely related to the pro le identi ed in BE.

    As with adenocarcinoma, there exists great complexity in the molecular events that are involved in progression to squamous cell carcinoma. Loss of heterozygosity of Rb, p53, and CDKN2A/p16INK4a has been identi ed as a common event. Methylation, although less well studied in squamous cell cancer than in adenocar-cinoma, appears to play an important role.59 At Johns Hopkins, Guo and colleagues used a panel of methylation markers, including p16, MGMT, MLH1, APC, BRAC1, RAR, CDH1, and DAPK, to suggest that there was a tendency for each of these genes to be meth-ylated at higher frequencies as the grade of the lesion increased through dysplasia to malignancy.59 The conclusion was that accumu-lation of DNA methylation changes suggests epigenetic progression and that this progression parallels visible histologic changes that are observed as squamous dysplasia progresses to frank carcinoma. In this study, the most commonly methylated gene was p16 (52%). Interest-ingly, the rates of methylation for more than one and two genes was 29% and 0%, respectively, for normal esophagus; 56% and 56%, respectively, for high-grade dysplasia; and 91% and 70%, respec-tively, for carcinoma.59 Wu has extensively reviewed methylation of individual genes in adenocarcinoma and squamous cell carcinoma, but the limitations of the currently available data do not allow for de nitive identi cation of any differences.60 Ischii and colleagues61 have also reported that for a large panel of promoter regions, there was a higher tendency toward methylation of many of the candidate genes in carcinoma and intraepithelial neoplasm than in the adjacent nonepithelial neoplasm. The data from Ishii and colleagues corrobo-rate the ndings of Guo and colleagues of an accumulating progres-sion of DNA methylation changes on top of a background of low-level DNA methylation in nonneoplastic esophageal epithelium.61,62 Interestingly, in the same study, p53 mutations occurred almost exclusively in intraepithelial neoplasm (57%) or carcinoma (63%) and in only 4% of adjacent nonneoplastic mucosa.

    The possibility of detecting hypermethylated DNA in circulating plasma and serum has also been investigated in squamous cell cancer. This ultimately could play a role in early detection and/or following response to therapy. For example, in one study, hypermethylation of the APC gene in tissue occurred in 48 of 52 patients (92%) with esophageal adenocarcinoma, in 16 of 32 patients (50%) with esoph-ageal squamous cell carcinoma, and in 17 of 43 patients (39.5%) with Barretts metaplasia but not in matching normal esophageal tissues.62 In the plasma of these patients, hypermethylated APC DNA was observed in only 13 of 52 adenocarcinoma patients (25%) and in 2 of 32 squamous cell carcinoma patients (6.3%). High plasma levels of methylated APC DNA were statistically signi cantly associ-ated with reduced patient survival in this study (P = 0.016).62 In another study, aberrant promoter methylation of the p16 gene was detected in the tumor tissue of 31 of 38 patients (82%) with esoph-ageal squamous cell cancer.63 In subsequent testing for p16 promoter methylation in the paired serum DNA of 31 patients with a p16 methylated in the primary tumor, only 7 of these 31 patients (23%) had the same methylation changes in the serum DNA.63 In another analysis, preoperative blood samples were obtained from 44 esopha-geal squamous cell cancer patients and were subjected to CEA-

    speci c reverse transcriptase polymerase chain reaction assay and methylation-speci c polymerase chain reaction (MSP) assay for p16, E-cadherin, and RAR- gene methylation. Circulating tumor cells were detected in 12 patients (27%), and 14 patients (32%) had aber-rant methylation in the promoter region of at least one gene (6, 4, and 4 patients for p16, E-cadherin, and RARbeta, respectively). No abnormality was detected by either assay in control plasmas. Alto-gether, 23 patients (53%) had a positive result with either molecular assay.64

    OVERVIEW: THE CHOICE OF THERAPYThe primary goals of therapeutic interventions for esophageal cancer are to relieve symptoms (predominantly dysphagia) and to treat the underlying cancer. An ideal therapy would accomplish both, safely and effectively. Currently, three main treatment strategies exist. The rst utilizes endoscopic palliative techniques to control the tumor locally for the purpose of palliation, the second uses single modalities (e.g., surgery, radiation, or chemotherapy), and the third involves intensive combination therapies aimed at cure. There is substantial controversy about the optimal management of curable (localized) esophageal cancer; the treatment options include surgery alone, chemotherapy followed by surgery or adjuvant chemotherapy after resection, chemoradiation followed by surgery, and de nitive chemoradiation. Radiation alone as de nitive treatment aimed at cure is inferior to combined chemoradiation for locally advanced disease and should be considered only when the other options are not feasible. Similarly, RT used in the adjuvant or neoadjuvant setting has not been shown to improve outcome. These options and the supporting data are summarized in Table 78-2. The survival outcome of patients with localized disease who were enrolled in selected randomized controlled trials is summarized in Table 78-3 according to treatment group. The median survival ranges from 9.0 months for patients in RT-alone control groups to as long as 19 months for those receiving preoperative chemoradiation. A statisti-cally signi cant 10% to 15% improvement in survival rate with any of these approaches would be of major importance. As Table 78-3 shows, the median survival rates with surgery, de nitive chemora-diation, and preoperative chemotherapy or preoperative chemoradia-tion do not clearly differ, although selection factors might have varied substantially among the trials.

    Surgery is a standard treatment option, and there are substantial data, although not a de nitive randomized controlled trial, support-ing the hypothesis that preoperative chemoradiation (trimodality therapy) improves outcome over that achievable with surgery alone. Preoperative chemotherapy has been evaluated in randomized con-trolled trials with con icting results among U.S. and non-U.S. trials. It is not a standard of care or common practice in the United States. On the other hand, de nitive chemoradiation is a potentially curative alternative to surgery and is indicated for patients with unresectable primary tumors or inoperable disease due to medical comorbidities.

    Given the lack of comparative data to demonstrate the superiority of any of one approach for resectable disease, clinical decision making for optimal management is complex and controversial. Surgery as a single therapeutic modality is the appropriate management for early-stage disease (stages I and IIA); however, for more advanced disease (stages IIB, III, and IVA), combined-modality therapy, speci cally preoperative chemoradiation with its associated risks of toxicity but potential for improved long-term survival, is frequently utilized. (See Table 78-4 for stage de nitions.) The available data from phase II trials, underpowered phase III trials, and meta-analyses indicate improved local control and suggest a survival bene t on the order of 10%. However, an adequately powered, randomized controlled trial has not been conducted to validate the observations from phase II clinical trials, and it is unlikely that such a trial will be performed in the United States. Commonly used preoperative chemoradia-tion regimens are associated with substantial toxicity; therefore,

  • 1404 Part III: Speci c Malignancies

    Table 78-2 Options in the Therapy of Esophageal Carcinoma

    Treatment Recommendation

    SINGLE MODALITY

    Surgery

    Radiotherapy

    Accepted standard for resectable AC and SCCa

    Recommended for high-grade dysplasia and stage I carcinoma

    De nitive treatment of inoperable patients unsuitable for chemoradiation

    Palliation of obstructive symptoms

    COMBINED MODALITY

    De nitive chemoradiation

    Preoperative chemotherapy

    Preoperative chemoradiation

    Inoperable SCCa and selected resectable SCCa

    Inoperable AC

    Investigational

    Preferred approach for resectable SCCa and AC

    POSTOPERATIVE ADJUVANT THERAPY

    Following preoperative chemotherapy or chemoradiation

    Following surgery alone

    No demonstrated bene t

    R0 resection: no demonstrated bene t for adjuvant radiotherapy, chemotherapy, or chemoradiation for SCCa; potential bene t for AC based on gastric trial data

    Microscopic or gross residual tumor: consider chemoradiation in good performance status patients or radiation indicated

    AC, adenocarcinoma of the distal esophagus and gastroesophageal junction; SCCa, squamous cell carcinoma.

    Table 78-3 Results from Treatment Arms from Selected Recent Randomized Trials

    Randomized Trial

    1-Year Survival Rate (%)

    2-Year Survival Rate (%)

    3-Year Survival Rate (%)

    5-Year Survival Rate (%)

    Median Survival (Months)

    Local Failure (%)

    SURGERY

    U.S. Intergroup66,174 60 37 26 16.1 59

    MRC65 34 13.3* 37

    Bosset et al.179 18.6

    Walsh et al.186 42 26 6 11*

    Urba et al.176 58 16 17.6 52*

    RADIOTHERAPY

    RTOG178,208,209 34 10 0 0 9.3* 68*

    ECOG (surgery added in 24/56)210 33 12 8 7 9.2*

    CHEMORADIOTHERAPY

    RTOG178,208,209 52 36 30 26 14* 46*

    RTOG (nonrandomized con rmatory group)178,208,209 62 35 26 14 16.7 58

    ECOG (surgery added in 21/58)210 54 27 13 9 14.8*

    Bedenne et al.214 37 17.7

    Stahl et al.67 35 24 15

    PREOPERATIVE CHEMOTHERAPY

    U.S. Intergroup66,174 35 14.9 58

    MRC65 43 16.8* 27

    PREOPERATIVE CHEMORADIOTHERAPY

    Walsh et al.186 52 37 32 16*

    Bosset et al.179 18.6

    Urba et al.176 72 30 16.9 23*

    Bedenne et al.214 37 19.3

    Stahl et al.67 39 31 16

    *Signi cant difference between respective arms in these trials.

  • 1405Cancer of the Esophagus CHAPTER 78

    trimodality therapy should be used cautiously in patients with poor performance status or comorbid conditions that increase the risk of life-threatening toxicity. There are no data to support the notion that chemoradiation is useful to convert an unresectable lesion into a resectable lesion.

    Preoperative chemotherapy has less associated toxicity than does preoperative chemoradiation and is the favored combined modality approach in the United Kingdom, stemming from a survival bene t that was demonstrated in a randomized controlled trial conducted in the United Kingdom by the Medical Research Council (MRC).65 By contrast, a similarly designed U.S. Intergroup trial found no advan-tage over the surgery control group; hence, this approach is consid-ered experimental in the United States.66

    De nitive chemoradiation eliminates the risk of surgery but at the cost of inferior local control and disease-free survival compared to trials of trimodality therapy.67 In evaluating clinical trial results, though, it is important to consider selection factors that might be at work: chemoradiation may be selected for patients with more advanced lesions, unresectable disease, or with signi cant comorbid disease leading to inoperability, a population that is less likely to achieve long-term survival. De nitive chemoradiation has been studied in patients with esophageal squamous cell carcinoma, a pop-ulation with a high prevalence of cardiopulmonary and hepatic disease from excessive tobacco and alcohol use, which increases oper-ative risks. In contrast, nonsurgical treatment aimed at cure has not been adequately tested in patients with resectable adenocarcinoma and therefore cannot be recommended for this histology.

    The role of adjuvant therapy after complete surgical resection has not been as well studied as preoperative therapies. For patients who are undergoing immediate surgery, data to support adjuvant chemo-radiation is extrapolated from gastric trials that included a minority of patients (about 20%) with GE junction primaries. At best, these data showing signi cant improvement in survival for patients with gastric cancer but not powered to look at site-speci c subsets provide a rationale for additional treatment for resected patients with adeno-carcinoma of the distal esophagus or GE junction, stages IIB, III, or IVA. Adjuvant RT has been studied and shown not to be bene cial, whereas there are insuf cient data on adjuvant chemotherapy to recommend its use. In patients who are undergoing primary surgery with microscopic or gross residual disease, postoperative chemora-diation should be considered if it is tolerable.

    When palliation of obstructive symptoms rather than cure is the goal, several options exist. These include RT with or without che-motherapy and the endoscopic therapies of stent placement, laser therapy, and photodynamic therapy (PDT). The choice of palliative treatment is in uenced by the severity of symptoms, patient perfor-mance status, expected survival time, and physician expertise. When survival expectations exceed a few months, palliation with radiosen-sitizing chemotherapy and concurrent radiation limited to the tumor bulk may provide more durable symptomatic relief. RT may also be added after endoscopic palliation to increase the durability of local palliation for patients who are likely to survive more than 3 to 6 months.

    For metastatic disease, chemotherapy is indicated, with the goal of improving survival and preventing or treating symptoms at all locations. Given the modest response rate and brief duration of response with available regimens, chemotherapy alone has limited ability to effectively palliate obstructive symptoms.

    DEFINITIVE TREATMENT OPTIONS

    Diagnostic Evaluation

    The most common presentation of esophageal carcinoma includes solid food dysphagia and weight loss of several months duration. Other presentations that occur with esophageal adenocarcinoma in particular include chest pain in the absence of myocardial ischemia and anemia from a chronic gastrointestinal (GI) bleed from the mucosal lesion. These clinical signs and symptoms should prompt endoscopic evaluation and diagnostic imaging. The diagnosis is usually evident by the characteristic narrowing of the esophagus on barium esophagram, but endoscopy and biopsy are essential for his-topathologic diagnosis. Endoscopic biopsies and brushings of the lesion will yield the diagnosis in more than 90% of patients. Multiple biopsies might be necessary to obtain the diagnosis of an invasive malignancy that is submucosal or necrotic.68 A diagnosis of in situ carcinoma in the face of a large lesion seen on radiographic studies should not be accepted, and biopsy should be repeated.

    Once the pathologic diagnosis has been established, evaluation to determine the extent of disease should include a computed

    Table 78-4 TNM Staging for Esophagus

    PRIMARY TUMOR (T)

    TX Primary tumor cannot be assessed

    T0 No evidence of primary tumor

    Tis Carcinoma in situ

    T1 Tumor invades lamina propria or submucosa

    T2 Tumor invades muscularis propria

    T3 Tumor invades adventitia

    T4 Tumor invades adjacent structures

    REGIONAL LYMPH NODES (N)

    NX Regional lymph nodes cannot be assessed

    N0 No regional lymph node metastasis

    N1 Regional lymph node metastasis

    DISTANT METASTASIS (M)

    MX Distant metastasis cannot be assessed

    M0 No distant metastasis

    M1 Distant metastasis

    CLASSIFICATION OF DISTANT METASTASES

    Tumors of the lower thoracic esophagus

    M1a Metastasis in celiac lymph nodes

    M1b Other distant metastasis

    Tumors of the midthoracic esophagus

    M1a Not applicable

    M1b Nonregional lymph nodes and/or other distant metastasis

    Tumors of the upper thoracic esophagus

    M1a Metastasis in cervical nodes

    M1b Other distant metastasis

    STAGE GROUPING

    Stage 0 Tis N0 M0

    Stage I T1 N0 M0

    Stage IIA T2

    T3

    N0

    N0

    M0

    M0

    Stage IIB T1

    T2

    N1

    N1

    M0

    M0

    Stage III T3

    T4

    N1

    Any N

    M0

    M0

    Stage IV Any T Any N M1

    Stage IVA Any T Any N M1a

    Stage IVB Any T Any N M1b

  • 1406 Part III: Speci c Malignancies

    tomography (CT) scan of the chest and complete abdomen. The chest CT is useful for evaluating lung parenchyma and mediastinal structures.69 Lymph nodes that are more than 1 cm in diameter or have necrotic centers suggest metastatic involvement. The chest CT also is helpful for assessing aortic or pericardial invasion of tumor that would preclude esophagectomy. In contrast, the actual length of the esophageal lesion is better assessed on the barium esophagram.

    The accuracy of identifying metastases to the liver and celiac axis by abdominal CT depends on the bulk of the disease. Small liver metastases, peritoneal studding, and abdominal nodes will often be undetectable.6975 For squamous cell lesions of the upper and mid-thoracic esophagus, a CT scan of the upper abdomen that includes the liver and adrenals is suf cient. For the patient with an adenocar-cinoma of the distal esophagus, GE junction or cardia, a complete abdominal-pelvic CT is necessary to visualize potential areas of nodal metastases. Cancers of this histologic type are more likely to metas-tasize early to periaortic lymph nodes. A complaint of back pain might signal the presence of enlarged retroperitoneal nodes.

    Positron emission tomography (PET) scanning enables the iden-ti cation of metastatic disease in patients who might otherwise inap-propriately receive de nitive local therapy and therefore is now considered a standard if not mandatory staging test. Prospective studies 76,77 demonstrated that PET will detect unsuspected metastatic disease in approximately 15% of patients after all other staging tests are completed, although it is not as useful as other techniques in identifying involved regional nodes. A prospective study of 79 patients76 found that the speci city and sensitivity of PET for iden-tifying stage IV disease was 90% and 74% versus 47% and 78% for the combination of CT and endoscopic ultrasonography (EUS), with an overall accuracy of identi cation of stage IV disease of 82% versus 64% (P = 0.004). Furthermore, when PET was added to CT and EUS, 22% of patients had a change in stage that altered their planned treatment (15% upstaged to incurable stage IV disease, and 7% downstaged to a stage at which curative therapy would be appropri-ate). Other investigators have con rmed that PET scanning will change management from curative to palliative in 10% to 20% of patients while also occasionally demonstrating that suspicious nd-ings on other staging tests did not represent metastatic disease.7880 Combined PET and CT imaging allows viewing of both sets of images in register and is optimal for accurate identi cation of smaller-volume metastatic tumor.81,82

    A bone scan is recommended for patients with an elevated alkaline phosphatase level or symptomatic painful areas, although this might not be necessary when a PET scan is performed. Bone metastases are infrequent as the initial site of metastases, but they do occur, more commonly in patients with adenocarcinoma. Evaluation for tracheal involvement with bronchoscopy is necessary for all lesions located at or above the carina.

    Accurate determination of the extent of disease has a major impact on therapeutic decision making for single-modality versus multimo-dality treatment or curative versus palliative intent; therefore, it is essential that comprehensive staging be performed. A substantial literature now exists regarding transesophageal ultrasound (EUS), laparoscopy, and thoracoscopy. The largest and earliest experience was with EUS.8387 Recent surveys of the literature indicate an accu-racy for T stage of approximately 85% and an accuracy of approxi-mately 75% for N stage. The accuracy for N stage is increased to 85% if ne-needle aspiration biopsy is included.88,89 EUS is not a reliable technique for diagnosing liver and peritoneal metastases because of the limited depth of penetration of ultrasound.89

    The indications for minimally invasive staging techniques are not yet fully de ned. Laparoscopic evaluation of abdominal lymph nodes can be achieved with minimal risks when high-yield staging informa-tion is not obtainable with standard imaging studies. The staging accuracy of laparoscopy for nodal involvement exceeds 95%.7275,9092 Unsuspected ndings such as liver metastases or peritoneal studding that alter treatment occur in 12% to 17% of patients studied.7274,90,93

    Laparoscopy appears to be most useful for evaluating intra-abdominal spread of disease in patients with a bulky distal third or GE junction primary and/or celiac adenopathy. Small hepatic metastases and peri-toneal carcinomatosis that are below the limit of resolution of CT and PET imaging may be detected. Laparoscopy is commonly per-formed at the time of jejunostomy tube placement for patients who are planning to receive preoperative chemoradiation. Thoracoscopy also has a high level of accuracy: 95% in detecting regional nodal involvement compared with surgical staging.71,90,94

    Surgery Alone

    Esophagectomy with reconstruction has a clear goal of both achieving local tumor control and restoring swallowing function. Esophageal surgical intraoperative risks, postoperative complications, and length of hospitalization have all decreased over the past decade to acceptable levels that are now compatible with those of other major oncologic resections.95100 Whether surgical resection is performed as the sole therapy or as part of a combined approach, the surgical principles and techniques are the same. A combination of concurrent chemo-therapy and radiation without surgery is a potentially curative alterna-tive for patients who refuse surgery, who are at high risk for surgery, who have unresectable tumors, or who have upper esophageal lesions for which resection might also require laryngectomy. A so-called pal-liative esophagectomy to restore swallowing function but with little or no change of long-term survival due to the extent of disease is rarely acceptable treatment and usually should not be contemplated. The standard operation in the United States to resect an esophageal cancer includes resecting the involved portion of esophagus, the proximal stomach, and the regional lymph nodes, as illustrated in Figure 78-1. The surgical resection is therefore properly termed a

    Figure 78-1 Regardless of the surgical approach used, a partial esopha-gogastrectomy is performed to resect esophageal tumors. Depending on the approach, different lengths of esophagus are removed.

    Transhiatal

    Left thoracoabdominal

    Ivor-Lewis

  • 1407Cancer of the Esophagus CHAPTER 78

    partial esophagogastrectomy with regional (or one eld) lymphade-nectomy. The resected esophagus is replaced with a conduit, usually the stomach or segments of the small or large intestine, which are in turn mobilized as a vascularized pedicle and anastomosed to the remaining proximal esophagus.

    A number of incisional approaches are used to perform a partial esophagogastrectomy, including the transhiatal, Ivor-Lewis, left tho-racoabdominal, and three-incision techniques (Fig. 78-2). The spe-ci c incisional approach that is used generally determines how much esophagus is removed and where the esophageal anastomosis will be located (see Fig. 78-1). In the past, various surgeons have argued in support of their preferred techniques, giving the impression that all of these approaches were uniquely different procedures. It is now appreciated, however, that all of these incisional techniques use partial esophagogastrectomy (except segmental esophagectomy with free jejunal grafting, which is discussed separately), and the patient outcome results that have been reported are similar in terms of surgi-cal morbidity and mortality. Long-term disease-speci c survival after esophagectomy is related to pathologic tumor stage. Prospective studies do not demonstrate a survival advantage related to the surgi-cal esophagectomy technique.101,102 The data continue to demonstrate no difference in morbidity, mortality, or survival between transtho-racic and transhiatal esophagectomy approaches.103 The main vari-ables in performing a partial esophagogastrectomy are which incision(s) to use, the length of esophagus to resect, what to use to replace the esophagus, and which route through the chest this conduit will take.

    Transhiatal ApproachThe transhiatal esophagectomy (THE) is a frequently used approach, rediscovered in 1976 by Dr. Mark Orringer, in which the intra-

    thoracic esophagus is mobilized distally through the esophageal hiatus and proximally through a cervical incision. The increased prevalence of adenocarcinoma of the distal esophagus and GE junction has largely been responsible for the widespread popularity among sur-geons of the transhiatal approach. Because of their distal esophageal location, these tumors are invariably near the esophagogastric junc-tion and readily accessible for direct-vision dissection through the hiatus. Moreover, the regional lymph nodes for these distal tumors are in the parahiatal and proximal lesser curvature regions, both accessible via laparotomy. The resected esophagus is then recon-structed by using stomach or long-segment colon, which are passed up into the neck as vascularized grafts to be anastomosed to the proximal cervical esophagus.99,104106 Although reports exist on the use of jejunum for long-segment esophageal replacement, small bowel is generally not an option for esophageal replacement because of its mesenteric vascular anatomy unless specialized techniques with vas-cular augmentation are used.107 The esophageal replacement conduit is passed through the chest into the neck by one of three routes: subcutaneous, substernal, or posterior mediastinum. The posterior mediastinum is the preferred route when possible. The advantages of the THE include avoiding post-thoracotomy discomfort, wide prox-imal esophageal margins to ensure complete resection of tumor and Barretts mucosa, cervical anastomosis in which the consequences of anastomotic leak are minimized, and an esophageal reconstruction that results in an excellent quality of swallowing. It is well docu-mented that the approach is acceptable for both benign and malig-nant esophageal disease.108,109 The disadvantages include inability to visualize middle or proximal third tumors, inability to perform exten-sive intrathoracic regional lymphadenectomy, potential for injury to intrathoracic structures, and the need for long-segment esophageal replacement. The technique is safe, well tolerated, and associated with infrequent major complications in experienced hands.110 In large series, late functional results have been good or excellent in 73% of surgeries, and mortality rates as low as none to 3% have been reported.106,110,111 Recently, Orringer and colleagues reported a series of over 2000 patients who underwent a THE with a mortality rate of only 1% in the patients who underwent surgery since 1998, an anastomotic leak rate of 9%, and 2% pulmonary complications.110

    Ivor-Lewis ApproachPartial esophagogastrectomy with an abdominal and right thoracot-omy approach, also known as the Ivor-Lewis approach, was designed to optimize exposure of the intrathoracic esophagus, which passes through the upper two thirds of the chest along the right posterior mediastinum.111 Once the involved intrathoracic esophagus is mobi-lized, a partial esophagogastrectomy is performed, and the esophagus is replaced by stomach, colon, or (less frequently) jejunum, which is passed into the chest along the esophageal bed and anastomosed to the proximal esophagus, usually at or above the level of the azygos arch. The advantages of the technique are the excellent exposure of the middle to upper intrathoracic esophagus, and the disadvantages are related to the use of a thoracotomy, with limits on the proximal resection margin and the potential for an intrathoracic esophageal anastomotic leak, which is a more dif cult management problem than a cervical anastomotic leak. Reported complications include respiratory problems in 11% to 20%, anastomotic leak in 3% to 7%, and wound infection in 5%. Operative mortality ranges from none to 4%.95,98,112,113

    Left Thoracoabdominal ApproachThe left thoracoabdominal approach uses a single incision extending from the left chest onto the abdomen; it provides excellent exposure of the lower third of the esophagus and left upper quadrant of the abdomen.114 This technique is ideal for patients with tumors near the GE junction, especially when the extent of gastric invasion is unclear, because it yields superb exposure and maximizes recons-tructive options of the lower third of the esophagus. Respiratory

    Transhiatal approach Ivor-Lewis approach

    Three-incision approachLeft thoracoabdominalapproach

    Figure 78-2 The different incisions used to perform partial esophago-gastrectomy are depicted.

  • 1408 Part III: Speci c Malignancies

    complications are the most common with this approach. At least some degree of atelectasis, usually involving the left lower lung, occurs in most patients. Pneumonia is reported to occur in up to 24% of cases. Anastomotic leaks occur in as many as 12% (mean: 3.7%) of cases. Other complications include atrial brillation in 10%, wound infection in 1.5% to 5.2%, and, infrequently, empyema and sub-phrenic abscess. The reported operative mortality is none to 6.2%.115,116

    Multiple IncisionsMultiple-incision surgical approaches combine the incisional strate-gies of the standard techniques. Of these, the three-incision approach using a cervical incision (right or left), right thoracotomy, and midline laparotomy, as described by McKeown,117 is the most common and is also referred to as the three-incision, three-hole, total esophagec-tomy or modi ed McKeown approach. It combines the exposure of the thoracotomy approach for esophageal mobilization or nodal dis-section with the advantages of a cervical esophageal anastomosis. Patient outcome results with this technique are similar to those of other approaches, with reported mortality rates of 3% to 4% and esophageal anastomotic leak rates of 5% or less.118120

    Radical ResectionsThe majority of patients with esophageal cancer are rst seen with locally advanced (stage II and III) disease. In these patients, survival results are poor with surgery alone. Two approaches attempt to improve survival in these patients. One involves the use of combina-tion therapies, such as preoperative chemoradiation followed by surgery (to be discussed later); the second involves adding an en bloc, wide- eld lymphadenectomy to the standard esophagectomy tech-nique. The esophagus has an extensive regional lymphatic drainage. Arbitrarily, the lymphatic drainage has been divided into three zones or elds: cervical, intrathoracic, and abdominal. Standard esophagec-tomy techniques involve regional, or one- eld, lymphadenectomy. Radical approaches advocate two- or three- eld lymphadenectomy in conjunction with esophageal resection and replacement. Hagen and colleagues121 believe that proximal hemigastrectomy should also be included as part of an en bloc approach, using colon to replace the resected esophagus. Radical esophagectomy is more complex surgery than standard techniques. This is re ected in morbidity rates as high as 58%.122 Nonetheless, 30-day mortality rates as low as 1.6% to 4.3% have been reported.121124 Survival data using radical esopha-gectomy techniques are con icting; therefore, it is unknown whether there is suf cient bene t to outweigh the increased operative morbid-ity. Hagen and associates121 reported an improved survival in early-stage tumors using en bloc esophagectomy compared with a standard transhiatal technique. Although prospective, their trial was not ran-domized. Also, earlier-stage patients were selected for the en bloc approach and therefore biased the results and conclusions. A more recent update of their results continues to suggest excellent local tumor control and improved survival.125

    In another nonrandomized series, Altorki and coworkers124 reported improved survival in patients with stage III disease with radical esophagectomy compared with standard surgical techniques. Nishimaki and colleagues122 reported an overall 5-year survival rate of 41% with extended radical esophagectomy for thoracic esophageal cancer. Their results are supported by more recent publications.126,127 In contrast, Bumm and coworkers123 demonstrated no difference in overall survival between standard transhiatal and radical THE in which two- eld lymphadenectomy is added. Despite the wide surgi-cal dissection with radical techniques, Bhansali and colleagues128 still documented a 21% locoregional cancer recurrence rate. The deter-mination of which cell type and tumor stage, if any, will bene t from radical surgical techniques has yet to be made.

    Free Jejunal InterpositionFree jejunal interposition permits proximal segmental esophageal resection and replacement without the need to resect distal esopha-

    gus. For technical reasons related to the microvascular anastomosis that is necessary to support the jejunal interposition, this technique has been limited to replacement of the cervical esophagus for either esophageal, laryngeal, or hypopharyngeal cancers or benign strictures (e.g., lye, radiation). Contraindications include factors that would jeopardize the proposed blood supply to the free intestinal segment, such as advanced age, previous carotid surgery, and cervical radiation, or factors that would interfere with the ability to harvest a suitable jejunal segment, such as peritoneal adhesions or in ammatory bowel disease. In resection of the cervical esophageal segment, the branches of the external carotid artery and external jugular veins are preserved as potential host vessels. A segment of jejunum is selected at least 15 to 20 cm distal to the ligament of Treitz. The speci c jejunal segment that is chosen should have a mesenteric arcade supplied by an ade-quate size artery and vein. Approximately 20 to 25 cm of jejunum can be resected, although 10 to 15 cm is usually suf cient. The free jejunal segment is then transferred to the neck, where in an isoperi-staltic fashion, the proximal esophageal anastomosis is performed, the arterial and venous microvascular anastomosis is carried out to the selected host vessels, and then the distal anastomosis is completed.

    With this technique, the reported graft survival rate is 85% to 95%, and the operative mortality rate is 5%. For patients with suc-cessful grafting, 90% are reported to have an adequate swallowing quality. If graft failure occurs, a second attempt will be successful in 50% to 75% of cases.129131

    Minimally Invasive EsophagectomyWith the advent of minimally invasive surgical techniques, an inter-est has been shown in applying thoracoscopic and laparoscopic tech-niques to esophagectomy.132 Certainly, the techniques of gastric and esophageal mobilization have been well established for other complex minimally invasive surgeries. Minimally invasive esophagectomy required that these individual techniques be spliced together. Approaches that have been used have included laparoscopic trans-hiatal resection, combined laparoscopic-thoroscopic procedures, and laparoscopic creation of gastric tube with thoracotomy and other combinations. The need to convert to an open surgery has been uncommon. The number of lymph nodes that are removed also appears similar to that achieved with open surgery.133

    A steep learning curve exists for these surgeries. The total length of hospitalization may be shortened somewhat. However, equipment costs and length of operative procedure can negate cost savings with this approach. Mortality rates of 40% to 70% in experienced hands are extensively reported.133135

    Survival with Surgery AloneSurvival after surgical resection is discussed separately from the description of individual techniques to emphasize the fact that post-esophagectomy survival is a function of stage and not of surgical approach. Several points concerning postesophagectomy survival have now become quite clear. The rst is that regardless of whether a thoracotomy or nonthoracotomy technique is used, cumulative postoperative survival is the same, approximately 20% to 25%. This has been underscored most graphically by Muller and associates,136 who reviewed the world literature to compare overall postesophagec-tomy survival by technique and showed no signi cant difference. Hulscher and coworkers137 performed a meta-analysis of the English language literature of transthoracic and transhiatal resection of esoph-ageal cancer and found a higher risk of pulmonary morbidity and mortality with the transthoracic procedure but a similar 5-year sur-vival rate of approximately 20%. These investigators also compared limited transhiatal resection with THE with extended en bloc lymph-adenectomy in 220 patients with adenocarcinoma of the esopha-gus.137 No signi cant difference was found in survival or operative mortality. More recent large retrospective series suggest a modest improvement in long-term outlook in recent years, probably the result of lower operative mortality.138140 Gockel and colleagues found

  • 1409Cancer of the Esophagus CHAPTER 78

    that for the periods 1985 to 1995 and 1995 to 2005, the 5-year survival rate increased from 15% to 25%, and the 30-day surgical mortality rate improved from 8.3% to 3.1%.139 In addition, better patient selection could play an important role in improved outcome. For example, Steyerberg and colleagues have proposed a simple scale based on important comorbidities, age, neoadjuvant therapies, and esophagectomy volume at the treating hospital that divides patients into groups with predicted 30-day mortality of under 4% to approx-imately 20%.141 It is also expected that more accurate preoperative staging with PET scanning and esophageal ultrasound could improve surgical outcome by removing some patients who have existing gross metastatic disease.

    The second fact is that postoperative survival is stage related. Notably, the majority of patients who are considered for surgery are found to have stage III disease, and the survival rate for these patients, even with surgery, is poor (approximately 10% to 15%). Hofstetter and associates142 reported results for 1097 consecutive patients under-going resection and compared outcome by stage from 1970 through 1985, 1986 through 1996, and 1997 through 2001. Although median survival increased from 7 to 34 months, the surgical mortal-ity rate decreased from 12% to 6%, and the R0 resection rate increased from 78% to 94%; no difference was found in survival according to stage. Three-year survival rates through this period were 63%, 52%, and 44% for pathologic stage IIA and 10%, 18%, and 6% for pathologic stage III. Multivariate analysis showed that survival was associated with complete resection and thorough preoperative staging and that preoperative chemotherapy used in the later years was associated with increased complete resection. For T1 N0 M0 adenocarcinoma of the esophagus,143 survival rates at 5 and 10 years may be closer to 77% and 68% after surgical resection.

    New methods of pathologic staging could improve our ability to predict surgical outcome. Immunohistochemical staining may detect lymph node micrometastasis. In one study,144 62% of patients (ade-nocarcinoma and squamous cell carcinoma) with pathologic node-negative stage by conventional criteria had nodal disease, detected by using monoclonal antibody Ber-EP4. This monoclonal antibody binds to certain glycoproteins found on epithelial tissues. The iden-ti cation of micrometastatic nodal disease had a signi cant impact on survival. A somewhat lower incidence of micrometastatic disease was found by using anticytokeratin antibodies,145148 and there is some suggestion that patients who are upstaged from node-negative disease do have inferior long-term survival.149,150 These novel tech-niques require validation in prospective trials and could provide valuable prognostic information as well as allowing optimal selection of patients for adjuvant therapy.

    The third point is that postsurgical survival is little in uenced by whether the patients esophageal cancer has a squamous cell carci-noma or adenocarcinoma histology. Holscher and coworkers151 doc-umented a postresection survival advantage only for patients with stage I adenocarcinoma. Salazar and colleagues152 reported no differ-ence in cumulative postoperative survival for patients with squamous cell carcinoma and adenocarcinoma. Finally, despite advances in surgical techniques and results, postesophagectomy survival has remained remarkably stable over time. Wilkins153 made this same point almost a decade ago after reviewing postoperative survival gures for the years 1952 and 1986. On the basis of his review, he queried whether surgery had gone as far as it could go and speculated that further improvement in survival statistics would require combi-nation therapy regimens that included systemic chemotherapy. As new systemic agents are developed, a differential response may be seen in adenocarcinoma and squamous cell carcinoma, which sug-gests that new agents will need to be evaluated separately in each histologic type.

    Optimizing Surgical OutcomeEvidence-based surgery uses the treatment outcomes of cost, morbid-ity, mortality, and quality of life to help physicians, health care

    administrators, and hospitals determine the most appropriate setting and speci c management of patients. Data consistently show that increased provider experience improves patient outcome, lowers com-plication rates, and reduces cost for complex surgeries. In terms of technical dif culty, length of stay, morbidity, and mortality, esopha-geal surgery is classi ed as a complex GI operation. Gordon and associates154 reported reduced hospital mortality, length of stay, and cost for a wide range of complex GI procedures, including esopha-gectomy. The institution of standardized patient care pathways, a product of the evidence-based surgery approach, reduced hospital cost for esophagectomies while keeping surgical mortality low (1.3%).155 Indeed, the use of clinical protocols for postoperative care has the potential to substantially reduce operative mortality resulting from a variety of surgical approaches, perhaps to 1% or less.140

    Dimick and colleagues156,157 documented the importance of surgi-cal volume, hospital experience, and intensive care staf ng in opti-mizing outcome after esophagectomy. These studies underscore the fact that even complex surgical procedures, such as esophagectomy, can be both effective therapy and cost-effective.

    In an important multi-institutional analysis158 of outcome in Medicare patients, a substantial difference in operative mortality was found to exist on the basis of the number of esophagectomies per year at the institution. This varied from 23% for centers doing fewer than 2 of these procedures per year to 8.1% for high-volume centers performing more than 19 per year. The operative mortality rates that were reported in this series are higher than those reported in clinical trials, and this might relate not only to particular expertise of the study centers in esophageal cancer treatment but also to patient selec-tion for clinical research. A subsequent analysis suggested that the variation among hospitals was explained, in part, by lower mortality of individual high volume surgeons with adjusted operative mortality among Medicare patients of 18% for surgeons performing fewer than two esophagectomies per year and 9% for those performing more than six.159 Other studies have since con rmed this nding.160,161

    Chemotherapy Followed by Surgery

    Promising results for survival improvement that were reported from numerous phase II trials of preoperative chemotherapy regimens tested in newly diagnosed patients162173 prompted two large random-ized trials with differing results.66,174 These data are summarized fol-lowing. Although preoperative chemotherapy can be justi ed on the basis of an advantage that was demonstrated in the MRC trial, it is considered an investigational approach in the United States. The U.S. Intergroup trial was well conducted and adequately powered. It failed to demonstrate either improved local control or improved survival with preoperative chemotherapy compared to surgery alone. By con-trast, there are data indicating survival bene t and improved local control when RT is added to chemotherapy in a concurrent fashion prior to surgery. Hence, trimodality therapy is favored in the United States over the preoperative chemotherapy approach that is preferred in the United Kingdom.

    The U.S. G-I Intergroup trial included 467 who were patients randomized to receive either three courses of cisplatin 100 mg/m2 plus infusional 5- uorouracil (5-FU) 1000 mg/m2/day from days 1 to 5 before surgery and two courses after surgery (total: ve courses) or immediate surgery.174 No bene t was demonstrated for the addi-tion of chemotherapy in this trial (see Table 78-3), in which 45% of patients had squamous cell carcinoma and 55% had adenocarcinoma. There were no differences in resectability or median 1-, 2-, or 3-year survival rates between treatment groups and between histologic types. The pathologic complete response (pCR) rate was 2.5%. The median survival and 2-year survival rate were 14.9 months and 35%, respec-tively, with chemotherapy versus 16.1 months and 37%, respectively, without chemotherapy. In both arms, approximately 60% of enrolled patients underwent a gross total resection (R0), and 17% of those patients had a subsequent local recurrence, for an ultimate 57%

  • 1410 Part III: Speci c Malignancies

    failure to control local disease. There were no differences in surgical morbidity and mortality rates (6% for both arms). Most patients did not receive the planned two cycles of postoperative chemotherapy; 52% received one cycle, and 38% received both cycles. A recent update reported a 32% disease-free 5-year survival rate for patients who had complete resection and negative margins (R0), whereas only 5% of those with a lesser resection (R1 or R2) were alive at 5 years.67

    The MRC65 conducted a randomized trial involving 802 patients, testing two cycles of cisplatin 80 mg/m2 and 5-FU 1000 mg/m2/day continuous infusion for 4 days given prior to resection of squamous cell carcinoma or adenocarcinoma of the esophagus (see Table 78-3). Patients were required to have resectable tumor, although the staging evaluation was not prescribed by the study. Two thirds of patients had adenocarcinoma. Median survival was signi cantly improved from 13.3 to 16.8 months, with 2-year survival rates improved from 34% to 43%. No information about patterns of failure was reported, but, similar to the results of the U.S. Intergroup trial, 57% had a complete resection with negative margins (R0). There is no immedi-ate explanation for the difference between the results of this trial and the U.S. Intergroup trial, but these con icting results may relate to the greater power or the less rigorous staging in the British study, to chance, or to unknown differences between the populations in the two studies. Another trial conducted by the MRC, Adjuvant Gastric Cancer Infusional Chemotherapy, demonstrated a survival bene t for three cycles of preoperative epirubicin, cisplatin, and 5-FU (ECF) and three cycles of postoperative ECF compared with surgery alone. This trial enrolled patients with gastric, GE junction, and distal esophageal adenocarcinoma (26% of patients). Although not powered for subsite analysis, there did not appear to be heterogeneity in treat-ment effect for distal esophageal lesions or gastric lesions.

    A meta-analysis175 was performed of eight trials of preoperative chemotherapy or chemoradiation compared with immediate surgery to explore the value of chemotherapy. With all-cause mortality as an endpoint, there was not a signi cant bene t to preoperative chemo-therapy alone. When analyzed by histologic type, there was no bene t for squamous cell carcinoma, but the hazard ratio for adenocarci-noma was 0.78 (0.64 to 0.95); however, this estimate was based on only the MRC trial described previously, as outcome by histology was not available from other trials. A greater bene t was seen with preoperative chemoradiation, with a 13% versus 7% absolute 2-year survival bene t for chemotherapy alone.

    There has been only one trial directly comparing preoperative chemotherapy and preoperative chemoradiation, and the preliminary results were reported in abstract form. This trial, conducted by inves-tigators in Germany, compared preoperative chemoradiation using cisplatin, folinic acid, and 5-FU to the same chemotherapy without radiation followed by surgery. The trial was closed early because of poor accrual after 126 of 394 planned patients were enrolled. The results favored preoperative chemoradiation but did not reach statis-tical signi cance; the pCR rate was 17% versus 2.5%, the complete resection (R0) rate was 85% versus 77%, the 3-year survival rate was 43% versus 27%, and median survival was 33 versus 21 months. These results, albeit limited by inadequate accrual and hence an underpowered study, provide additional support for the concept of preoperative chemoradiation over chemotherapy alone.67

    Concomitant Chemotherapy and Radiation Therapy Followed by Surgery

    The rationale for neoadjuvant chemoradiation or trimodality therapy is the high rate of both local and distant failure that is seen with surgery alone, such that intensi ed local and systemic therapies are needed to improve survival outcome. For example, data from the surgery-alone control arm of the U.S. Intergroup trial (1990 to 1995) showed a 57% failure to control local disease (including 41% failure to resect all local disease) and 50% distant failure rate in patients who

    did have complete resection.174 A single-institution randomized trial that was conducted at the University of Michigan176 demonstrated similar survival, local control, and distant rst failure rates with surgery alone. Another single-institution study of adenocarcinoma of the distal esophagus and GE junction examined patterns of failure after surgery alone. Thirty-four percent of patients had distant failure, 19% had local failure, 14% had locoregional nodal failure, and 6% had peritoneal seeding.177 These studies show that the rate of com-plete resection with negative margins and ultimate local control is not improved by the addition of chemotherapy alone prior to surgery. Similarly, the local recurrence rate is high (nearly 50%) after de ni-tive chemoradiation.178 However, the trimodality approach of chemo-radiation followed by surgery results in a signi cant improvement in local control compared to surgery alone in trials of patients with squamous cell carcinoma and adenocarcinoma.176,179

    A number of randomized controlled trials of chemoradiation compared to surgery alone have been conducted, with con icting results. Those that either were limited to adenocarcinoma or included both histologies have been criticized for being underpowered or having a worse than expected outcome for the surgery control arm. However, the combined weight of multiple underpowered or other-wise limited trials supports a local control and survival bene t when compared with the outcome of surgery alone. A number of meta-analyses of randomized controlled trials are now in the literature to evaluate the effect of chemotherapy or chemoradiation prior to surgery.175,180183 The most comprehensive analysis was recently reported by Gebski and colleagues.175 A total of 10 trials and 1209 patients from the period 19832006 were identi ed that compared preoperative chemoradiation with immediate surgery; individual patient data were available for two of the trials. The analysis found a bene t for concomitant chemoradiation followed by surgery com-pared with surgery alone; the hazard ratio for death by any cause was 0.81 (0.70 to 0.93), which corresponded to a 13% reduction in mortality at 2 years. The bene t was similar for both histologies, but no bene t was identi ed in trials that gave chemotherapy and radia-tion sequentially rather than concurrently. Another smaller meta-analysis found improved 3-year survival when the analysis was restricted to trials that used concurrent chemotherapy and radiation (OR: 0.45, 95 % CI: 0.26 to 0.79) but no bene t with sequential regimens.181 Additionally, patients who received preoperative chemo-radiotherapy were more likely to undergo complete resection (R0) (OR: 0.53, 95 % CI: 0.33 to 0.84). In this latter analysis, use of a reduced radiation dose was associated with higher mortality, which might be a design weakness of some of the randomized trials described in the following sections.

    A series of randomized trials tested chemoradiation with 5-FU/cisplatin followed by surgery compared with surgery alone. Most of these trials were underpowered, and the results were con icting. The results of these trials are summarized in Table 78-5. Two trials, those of Nygaard and colleagues184 and Le Prise and colleagues,185 utilized a sequential chemotherapy and RT design followed by surgery and failed to demonstrate any signi cant difference in median, disease-free, or overall survival. These trials will not be further discussed. Notably, the studies published by Walsh and colleagues,186 Urba and colleagues,176 and Tepper and colleagues187 included patients with adenocarcinoma. Those of Bosset and colleagues,179 Burmeister and colleagues,188 Walsh and colleagues,186 Urba and colleagues,176 and Tepper and colleagues187 compared concomitant cisplatin-based che-motherapy and RT followed by surgery to immediate surgery. Walsh and colleagues186 and Tepper and colleagues187 demonstrated a sig-ni cant survival bene t, while Urba and colleagues reported a sig-ni cant improvement in local control, but survival differences were not signi cant. Bosset and colleagues179 showed an improvement in disease-free survival and fewer deaths from esophageal cancer but not improvement in overall survival. The trial of Burmeister and col-leagues did not demonstrate a survival bene t, but the chemotherapy and RT were suboptimal. All trials (see Table 78-3) reported similar

  • 1411Cancer of the Esophagus CHAPTER 78

    3- to 5-year survival rates of 32% to 39% for the investigational combined treatment (trimodality) groups, while the survival rate of patients in the surgery control arms varied from 6% to 16%. This probably re ects differences in the patients who were enrolled in each trial and the rigor of baseline staging. The details of these trials are described following.

    The trial reported by Walsh and colleagues186 was limited to adenocarcinoma of the distal esophagus-GE junction and demon-strated signi cantly improved survival with concurrent 5-FU 15 mg/kg on days 1 to 5 and days 30 to 35, cisplatin 75 mg/m2 on days 7 and 37, and RT 40 Gy in 15 fractions on days 1 to 19. The three-year survival rate was 32% versus 6%, and median survival was 16 months versus 11 months (P = 0.01). The complete response rate for all patients who were enrolled in the preoperative chemoradiation arm was 22%, and there was evidence of nodal downstaging with 82% node-positive in the surgery arm versus 25% after neoadjuvant therapy (P < 0.001). This study has been criticized for the relatively small sample size (it closed when an early stopping rule was met), for unexpectedly poor results in the surgery-alone arm, and for lack of uniform preoperative staging.

    The trial reported by Urba and colleagues176 randomized 100 patients to surgery (transhiatal esophagectomy) with or without pre-operative chemoradiation (cisplatin 20 mg/m2 on days 1 to 5 and days 17 to 21, vinblastine 1 mg/m2 on days 1 to 4 and days 17 to 20, 5-FU 300 mg/m2 on days 1 to 21, RT 1.5 Gy twice a day to 45 Gy). Median survival was 17.6 months with neoadjuvant therapy and 16.9 months with surgery alone, and the 3-year survival rate was 30% versus 16%, respectively (P = 0.18). Survival of patients in the trimodality arm was consistent with the Walsh study. The gross total resection rate was in excess of 90% in both arms. The pCR rate was 28% and did not differ by histology, but the number of patients was small (75 adenocarcinoma, 25 squamous cell carcinoma). Preopera-tive therapy reduced the incidence of locoregional failure as the site of rst failure from 42% in the surgery control arm to 19% (P = 0.0002). Distant failure was not affected; it was approximately 60% in both arms. While the improvement in the overall survival rate from 16% to 30% is in an expected range of 10% to 15%, the study was

    powered to show a much larger difference on the basis of the results of prior phase II trials from this group.

    Bosset and colleagues179 reported the results of a multicenter trial that was limited to squamous cell carcinoma, stages I and II. These investigators found no difference in overall survival with preoperative therapy, although there was a signi cant improvement in disease-free survival and local recurrence-free survival. The regimen was cisplatin 80 mg/m2 given 0 to 2 days prior to each set of RT treatments, and the RT consisted of two 1-week courses of 18.5 Gy in ve 3.7-Gy fractions beginning on days 1 and 22. Postoperative mortality was signi cantly higher, 12% versus 4% in the combined treatment arm. This trial has been criticized because chemotherapy was often not administered on the same day as RT, the chemotherapy was less intensive than that in the other trials, and an unusual hypofraction-ated and split-course regimen of RT was utilized.

    The Trans-Tasman Radiation Oncology Group and the Austral-asian Gastro-Intestinal Trials Group randomized 256 patients to surgery alone or to one cycle of preoperative cisplatin 80 mg/m2 on day 1 and 5-FU 800 mg/m2 on days 1 to 4, with concurrent RT, 35 Gy given in 15 fractions.188 Sixty-two percent of patients had adenocarcinoma. No survival bene t was identi ed, but treatment was less intensive with only one cycle of chemotherapy given and a lower radiation dose, although there was a suggestion of bene t for patients with squamous cell carcinoma.

    An adequately powered U.S. Intergroup trial was initiated to de nitively assess survival outcome with preoperative cisplatin and 5-FU chemotherapy and concurrent radiation in comparison with surgery alone. Unfortunately, this trial was closed early as a result of poor accrual likely because of the existence of a strong bias among physicians about the bene ts of preoperative chemoradiation, lack of consensus about an optimal preoperative regimen, and patient resis-tance to randomization. The long-term outcome for the 56 enrolled patients has been reported in abstract form.187 The 5-year survival rate was 39% (21%, 57%) versus 16% (5%, 33%; P = 0.005). There was no appreciable difference in surgical complications. In that this attempt at a de nitive intergroup trial failed to accrue enough patients, it is unlikely that such a trial will be mounted again in the

    Table 78-5 Preoperative Chemotherapy and Radiotherapy: Randomized Trials

    Author Treatment Arms Median (mos.)

    SURVIVAL RATE (%)

    1-Year 2-Year 3-Year

    Nygaard et al.184 S 13 9

    Cisplatin/bleomycin + 35 Gy + surgery 23 17

    Le Prise et al.185 S 10 47 14

    Cisplatin/5-FU + 35 Gy + surgery 10 46 19

    Bosset et al.179 S 18.6 67 42 34

    Cisplatin + 37 Gy + surgery 18.6 69 48 37

    Walsh et al.186 S 11 44 26 6

    Cisplatin/5-FU + 40 Gy + surgery 16 52 37 32

    P = 0.01 P = 0.01

    Urba et al.176 S 17.5 58 39 16

    Cisplatin/5-FU/VBL + 45 Gy + surgery 16.3 70 42 32

    Burmeister et al.188 S 19.3 P = 0.07

    Cisplatin/5-FU +35 Gy + Surgery 22

    Tepper et al.187 S 22 16 (5 year)

    Cisplatin/5-FU + 50.4 Gy + Surgery 48 39 (5 Year)

    P = 0.02

    5-FU, 5- uorouracil; S, squamous cell carcinoma; VBL, vinblastine.

  • 1412 Part III: Speci c Malignancies

    United States, and treatment guidelines will be formulated on the basis of the aggregated existing data.

    On the basis of these data and the results of published series with long-term follow-up (Table 78-6), the use of preoperative chemora-diation is a rational strategy that signi cantly improves local control and might improve survival. Cisplatin and 5-FU concurrent with standard fractionation RT, total dose 44 to 50 Gy, is most commonly used. Other platinum-based regimens containing paclitaxel, docetaxel, oxaliplatin, or irinotecan have been tested in phase II trials, and pCR rates, preliminary survival outcome, and toxicity do not appear to be improved over those of cisplatin and 5-FU. For example, the Eastern Cooperative Oncology Group conducted trial E1201 to evaluate the potential for improved outcome with two alternative regimens in a randomized phase II design.189 The pCR rate was the primary end-point. The regimens that were tested were cisplatin 30 mg/m2 and irinotecan 50 mg/m2 on days 1, 8, 22, and 29 of 45 Gy RT/5 weeks and cisplatin 30 mg/m2 and paclitaxel 50 mg/m2 1-hour infusion on days 1, 8, 15, 22, and 29 with RT. The trial was limited to patients with resectable adenocarcinoma of the distal esophagus, GE junction, and cardia (stages II, III and IVA); the staging evaluation included esophageal endoscopic ultrasound. Of all eligible randomized patients, 83% (38 of 46) and 70% (31 of 44) had a complete resection with negative margins, and 6 of 46 (15%) (95% CI: 5%, 26%) and 7 of 44 (16%) (95% CI: 7%, 30%) had pCR with preoperative cisplatin, irinotecan CI + RT and cisplatin, paclitaxel + RT, respectively. These pCR rates were lower than those observed with standard 5-FU and cisplatin in other multicenter trials, but survival and pattern of failure are not yet available.

    The results of phase II and III preoperative chemoradiation trials demonstrate that pathologic stage based on the resected esophageal specimen and nodes is an important predictor of survival. Patients who are found to have no residual tumor in the resected esophagus and nodes or minimal residual tumor (stage I) have the best progno-sis with overall survival rates of 60% to 70% at 5 years. This ability to downstage patients with locally advanced disease and improve survival is a powerful rationale for utilizing preoperative chemora-diation and a reason that it has become common practice. Surgical stage may also be useful in selecting patients for trials of novel adju-vant therapies, given that the rate of distant metastases is high and that they are the predominant cause of death from disease.

    Safety of Esophagectomy after Chemoradiation

    The question of whether preoperative chemoradiation increases sur-gical morbidity and mortality is an area of controversy but appears to be less relevant in the modern era. The majority of randomized trials discussed previously reported no signi cant increase in surgical mortality when trimodality therapy was compared to surgery alone. The results of 120 patients who were treated at Johns Hopkins with preoperative chemoradiation were analyzed for surgical morbidity and mortality to evaluate the overall complication rate.190 The surgi-cal mortality rate was 1%. The complication rate was 59% for squa-mous cell carcinoma and 31.6% for adenocarcinoma. The higher complication rate that was observed for squamous cell carcinoma, relative to patients with adenocarcinoma, was attributed to an increased risk of pulmonary complications due to the more proximal location of the primary and potential increased prevalence of chronic lung disease in this population. These results are comparable to the mortality rate (2.2% to 9.0%) and morbidity rate (22% to 74%) that were reported after surgery alone and suggest that with careful tech-nique and attention to postoperative management, preoperative therapy does decrease surgical morbidity. The operative mortality rate when transhiatal esophagectomy was performed was 4% with surgery alone and 2% after preoperative therapy. Similar mortality rates have been reported from recent multicenter trials of patients with adeno-carcinoma only or including both histologies.187,189 A retrospective comparison of squamous cell carcinoma patients who had neoadju-

    vant chemoradiation or surgery alone demonstrated an operative mortality rate of 6.3% versus 9% and a morbidity rate of 40.3% and 41%, respectively.191 In contrast, the trial reported by Bosset and colleagues including only patients with squamous cell histology had an operative mortality rate of 12% operative after chemoradiation and 4% after surgery alone.179

    Assessment of Response to Preoperative Therapy Ma