Ca Gastro "Radiation Therapy, Chemoradiotherapy, Neoadjuvant Approaches, and Postoperative Adjuvant Therapy For Localized Cancers of The Esophagus"

Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus
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Official reprint from UpToDate www.uptodate.com 2013 UpToDate
Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus Authors Noah C Choi, MD Michael K Gibson, MD, PhD, FACP Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Dec 2012. | This topic last updated: dic 6, 2012. INTRODUCTION Cancer of the esophagus is a highly lethal malignancy. There are approximately 17,460 people diagnosed with esophageal cancer each year in the United States and 15,070 deaths from the disease [1]. Data on global incidence and mortality are available from the World Health Organization GLOBOCAN database. According to data from the US Surveillance, Epidemiology and End Results (SEER) Program, the five-year survival for all patients with esophageal cancer improved only modestly over the last 30 years, from 5 percent in the years 1975 to 1977, to 19 percent during the period 2001 to 2007 [1]. These sobering figures are indicative of the advanced stage of disease (local-regional or metastatic) at diagnosis in most patients [2]. The management of local-regional esophageal cancer has undergone a major evolution over the past 15 years. The low cure rates after locoregional therapy alone prompted the inclusion of systemic chemotherapy in multimodality treatment regimens, to control distant micrometastatic disease and enhance local radiation effects. The seminal RTOG 85-01 trial demonstrated a survival benefit for the addition of cisplatin-based chemotherapy to radiation therapy (RT) in nonsurgically treated patients [3,4]; whether induction chemoradiotherapy adds benefit to surgery for potentially resectable disease remains a controversial area. Fewer than one-third of all patients are cured by multimodality therapy, and distant failure accounts for three-fourths of all recurrences [5]. Classification and management of esophagogastric junction (EGJ) tumors has also evolved over time. In the latest edition of the TNM staging manual, tumors arising at the EGJ or in the cardia of the stomach within 5 cm of the EGJ that extend into the EGJ or esophagus are staged as esophageal rather than stomach cancers, while those that arise within 5 cm of the EGJ but without extension into the esophagus are still staged as gastric cancers [6]. (See "Diagnosis and staging of esophageal cancer", section on 'TNM staging criteria' and "Clinical features, diagnosis, and staging of gastric cancer", section on 'TNM staging criteria'.) Most clinicians now treat EGJ and proximal gastric (ie, cardia, (figure 1)) cancers as esophageal cancers, using preoperative chemoradiotherapy. However, these tumors have been included in many of the trials examining the benefit of adjuvant and neoadjuvant chemotherapy for gastric cancer, and institutional practice varies. Management of EGJ and gastric cardia tumors is discussed in detail separately. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas".) This topic review will focus on the efficacy of RT and chemotherapy and multimodality management of localized and locoregional cancer involving the thoracic esophagus. Management of cervical esophageal tumors is also considered briefly. Multimodality approaches to cancer of the esophagogastric junction (EGJ), neoadjuvant and adjuvant approaches for true gastric tumors, principles of surgical treatment for localized esophageal and EGJ cancer, nutritional support during
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Section Editors Richard M Goldberg, MD Christopher G Willett, MD
Deputy Editor Diane MF Savarese, MD
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multimodality therapy, endoscopic methods for palliation of dysphagia during neoadjuvant treatment, issues specific to superficial and locally advanced unresectable disease, and treatment of metastatic disease are discussed elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas".) (See "Adjuvant and neoadjuvant treatment of gastric cancer".) (See "Surgical oncologic principles for management of resectable esophageal cancer".) (See "The role of parenteral and enteral/oral nutritional support in patients with cancer".) (See "Expandable stents in the treatment of esophageal obstruction", section on 'Self-expandable plastic stents'.) (See "Endoscopic palliation of esophageal cancer".) (See "Management of superficial esophageal cancer".) (See "Management of locally advanced unresectable esophageal cancer".) (See "Chemotherapy for locally advanced unresectable and metastatic esophageal and gastric cancer".) SQUAMOUS CELL VERSUS ADENOCARCINOMA There are two major histologies of esophageal cancer: squamous cell cancer (SCC) and adenocarcinoma. Although most clinical studies have not differentiated between the two histologies, an increasing amount of evidence supports the view that they differ in terms of pathogenesis, epidemiology, tumor biology, and prognosis: The incidence of SCC is declining in the US while that of adenocarcinoma has increased markedly over the last 20 years, suggesting underlying etiologic differences. SCC is almost always the result of tobacco and/or alcohol abuse while adenocarcinomas are associated with gastroesophageal reflux disease (GERD) and high body mass [7-9]. (See "Epidemiology, pathobiology, and clinical manifestations of esophageal cancer".) The precursor lesion of SCC is epithelial dysplasia, which progresses in sequence to carcinoma in situ, and finally to invasive carcinoma [10]. In contrast, adenocarcinomas usually arise as a consequence of persistent GERD, in which the mucosa of the distal esophagus undergoes intestinal metaplasia. Carcinogenesis begins with genetic alterations which endow the metaplastic cells with a growth advantage, permitting them to hyperproliferate. As the cells progressively acquire DNA damage, they become morphologically dysplastic, and eventually, frankly malignant. (See "Pathogenesis of Barrett's esophagus and its malignant transformation", section on 'Adenocarcinoma arising from Barrett's'.) Although SCCs tend to arise 10 years earlier, on average, than adenocarcinomas, perioperative mortality is higher for SCC than for a Barrett's adenocarcinoma, likely related to associated comorbidity and tumor location [9,11]. The sequelae of GERD involve mostly the distal esophagus/EGJ, and 94 percent of cancers associated with Barrett's esophagus are located below the tracheal bifurcation. In contrast, 65 percent of SCCs are located above this location [12]. Tumors located in the upper third of the esophagus have significantly higher rates of postoperative death. (See "Surgical oncologic principles for management of resectable esophageal cancer" and "Epidemiology, pathobiology, and clinical manifestations of esophageal cancer" and "Pathogenesis of Barrett's esophagus and its malignant transformation".) Histology also influences the pattern of first recurrence after resection. Upper or mid-thoracic SCCs (figure 2) tend to recur locoregionally first, while distal esophageal adenocarcinomas more commonly recur with distant dissemination. Despite these data, many (but not all [13]) contemporary series suggest that the prognosis of adenocarcinoma is better than that of SCC, particularly in early stage disease [7,8,13-17]. One reason may be the lower prevalence of lymphatic spread for Barrett's-associated cancer than for SCCs [7,13].
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It has been proposed that the difference in tumor location also has implications for the choice of therapy. Some suggest that induction chemotherapy alone may suffice for adenocarcinomas, while results are superior with chemoradiotherapy for SCCs because of the greater need for tumor downsizing to achieve a complete radical resection [7]. However, there are few data to support this viewpoint and little agreement as to whether histologic type should be used as a factor in selecting the treatment strategy. A major area where data are lacking is nonsurgical management for adenocarcinomas. (See 'Necessity for surgery' below.) Summary In summary, there seems little doubt that esophageal SCC and adenocarcinoma represent two different diseases with characteristic pathogenesis, epidemiology, tumor biology, and outcomes. In acknowledgement of these differences, the most recent 2010 TNM staging system provides separate stage groupings (but similar definitions for T, N, M and grade [G] categories) for SCCs and adenocarcinomas of the esophagus and EGJ (table 1 and table 2) [6]. In addition, tumor location (for SCCs only) was incorporated into stage grouping. (See "Diagnosis and staging of esophageal cancer".) However, it remains unclear as to whether and how histology should dictate the therapeutic approach. Future studies in esophageal cancer should analyze and report separately the results of therapeutic strategies according to histology. THORACIC ESOPHAGUS TUMORS Surgery alone Although only 30 to 40 percent of patients have potentially resectable disease at presentation, surgery has been the standard treatment for early stage esophageal cancer. Its utility as monotherapy has been challenged [18,19]. Data from contemporary surgical series report five-year survival rates of 15 to 20 percent for surgery alone [5,20-23]. In an analysis of 4627 patients with esophageal cancer who were treated with surgery alone without adjuvant or neoadjuvant therapy, five-year survival rates were <50 percent for all disease stages except stage I (T1N0 according to the 6th edition of the AJCC TNM staging system), and they were 15 percent for any patient with node-positive disease [24]. This poor long-term outcome has prompted an evaluation of neoadjuvant (preoperative), adjuvant (postoperative), and nonoperative strategies aimed at improving survival in patients with apparently localized disease. (See "Surgical oncologic principles for management of resectable esophageal cancer", section on 'Thoracic cancer resection'.) RT alone Before the era of modern chemotherapy and combined chemoradiotherapy, RT alone (60 to 66 Gy over a period of 6 to 6.6 weeks) was associated with five-year survival rates of 5 to 20 percent, depending upon tumor extent [25-27]. In a review of 49 early series involving more than 8400 patients treated with RT alone, survival rates at one, two, and five years were 18, 8, and 6 percent, respectively [28]. Better results are reported in later studies from single institutions in well-defined patient populations using modern RT protocols. As examples: Three- and five-year survival rates of 27 and 21 percent, respectively, were observed in a series of 101 selected patients (11 adenocarcinomas) with clinically localized disease treated with RT alone (45 to 52.5 Gy in 15 or 16 fractions over three weeks) [27]. In a cohort of 17 patients with clinical stage I esophageal SCC (after endoscopic ultrasound [EUS] and CT) treated with RT alone (median 60.6 Gy), the five-year survival rate was 59 percent [29]. Modern techniques (eg, three-dimensional conformal RT [3D-CRT], intensity modulated RT [IMRT]) are associated with more favorable toxicity profiles than those associated with the lower energy units used in earlier years. The success of advanced radiation technology can be illustrated by a preliminary report of a Chinese trial in which surgery was compared to RT alone in 269 patients with esophageal SCC [30]. RT was planned using 3D-CRT technique, and 69 Gy were delivered in 41 fractions over 45 days (45 Gy in 25 fractions over five weeks followed by 24 Gy in twice daily 1.5 Gy
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fractions for eight days using IMRT). Three- and five-year overall survival rates in the RT alone group (61 and 37 percent, respectively) were not significantly different from those in the surgery group (56 and 35 percent, respectively). These results cannot be extrapolated to patients with adenocarcinoma. Although these data are encouraging, the role of RT alone has been supplanted by combined chemoradiotherapy in the majority of patients, despite a higher rate of treatment-related toxicity. Combined IMRT and cisplatin-based chemotherapy is under study. Chemoradiotherapy Concomitant chemotherapy and RT has been studied as definitive nonoperative treatment and in the preoperative (neoadjuvant) setting. The more recent strategy of using chemotherapy alone as induction therapy prior to surgery is discussed below (see 'Neoadjuvant chemotherapy' below). Definitive chemoradiotherapy Concurrent chemoradiotherapy permits maximal tumor control because the combined local antitumor effect is more than additive (a therapeutic advantage termed radiation sensitization), and chemotherapy provides the opportunity for control of micrometastatic disease [31-33]. In randomized trials, the addition of cisplatin-based chemotherapy to RT significantly improves survival over RT alone [3,4,34]. However, the available data are almost exclusively in SCC, and none of the trials have performed adequate pretreatment staging to reliably correlate outcome with locoregional tumor extent (ie, locally advanced unresectable versus potentially operable disease). The following sections will summarize the data for patients with disease confined to the primary and regional nodes based upon radiographic imaging. RTOG 85-01 A landmark RTOG trial compared RT alone (64 Gy in 32 fractions over 6.5 weeks) versus concurrent chemoradiotherapy (two cycles of infusional FU [1000 mg/m2 per day, days 1 to 4, weeks 1 and 5] plus cisplatin [75 mg/m2 day 1 of weeks 1 and 5] and RT [50 Gy in 25 fractions over five weeks]) in patients with locoregional thoracic esophageal cancer [3]. Patients were required to have no evidence of spread beyond mediastinal and supraclavicular lymph nodes; 90 percent had SCC. The chemoradiotherapy group received two additional chemotherapy courses, three weeks apart, after RT. Surgery was not part of the treatment schema. The trial was closed prematurely with 121 patients, when an interim analysis showed a significant survival advantage for chemoradiotherapy (five-year survival 27 versus 0 percent) [4]. Analysis of failure patterns showed a significant reduction in both locoregional and distant failure for chemoradiotherapy. However, despite this benefit, 46 percent of patients in the chemoradiotherapy group had locally recurrent or persistent disease in the esophagus at 12 months. (See 'Necessity for surgery' below.) As a result of this trial, definitive chemoradiotherapy became the standard of care for patients with inoperable disease. (See "Management of locally advanced unresectable esophageal cancer".) The issue of the unacceptably high locoregional failure rate was addressed in a follow-up trial, INT 0123. Intergroup 0123 In the US Intergroup Study 0123 (INT 0123), 236 patients with nonmetastatic esophageal SCC or adenocarcinoma received concurrent cisplatin and FU (as in RTOG 85-01), but they were randomly assigned to one of two different RT doses: 50.4 Gy (28 fractions of 1.8 Gy each, five fractions per week) or 64.8 Gy (36 fractions of 1.8 Gy each, five fractions per week) [35]. Higher RT doses were not associated with a higher median (13 versus 18 months) or two-year survival (31 versus 40 percent), or the incidence of locoregional persistent or recurrent disease (56 versus 52 percent for the high dose and control groups, respectively). High-dose RT was significantly more toxic. The reason for the failure to demonstrate better survival or locoregional control with higher RT doses is unclear. At present, 50 Gy of RT plus concurrent cisplatin and FU remains a standard approach. More recent studies are investigating the role of newer chemotherapy drugs combined with RT. Many of these trials are discussed elsewhere. (See "Management of locally advanced unresectable esophageal cancer", section on
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'Chemotherapy intensification'.) Elderly patients Few data are available on the safety and efficacy of chemoradiotherapy in the elderly. However, at least one report suggests that patients over age 70 tolerate cisplatin-based chemoradiotherapy without a major increase in adverse events and with outcomes that seem comparable to those achieved in younger individuals [36]. However, patients with significant comorbidity (ie, Charlson score !1, (table 3)) experienced more severe toxicity and chemotherapy delays/dose reductions than those without comorbidity. (See "Comprehensive geriatric assessment for patients with cancer".) Whether results with definitive chemoradiotherapy are as good as can be obtained with esophagectomy in elderly patients with early stage esophageal cancer is unclear [37]. Preoperative chemoradiotherapy The poor long-term survival associated with surgery alone and the radiosensitizing effect of concurrent chemotherapy provided the impetus to evaluate preoperative chemoradiotherapy. At least seven trials have directly compared surgery with or without preoperative chemoradiotherapy for patients with potentially resectable esophageal carcinoma [20,38-43]. Two demonstrate a significant survival benefit from combined modality therapy, both using a concurrent rather than sequential approach [42,43]. Concurrent chemoradiotherapy Of the five completed randomized trials compared preoperative concurrent chemoradiotherapy versus surgery alone, only two show a statistically significant survival benefit for chemoradiotherapy [42,44], three others do not, two of which were underpowered [38,43,45]. Of these, the two most important are the Dutch CROSS trial and CALGB 9781. CROSS trial Dutch investigators randomly assigned 363 patients with potentially resectable esophageal or EGJ cancer (86 SCC, 273 adenocarcinoma, four other; majority distal esophageal, 11 percent EGJ) to preoperative chemoradiotherapy using weekly paclitaxel 50 mg/m2 plus carboplatin (area under the curve of concentration X time [AUC] of 2) plus concurrent RT (41.4 Gy over five weeks) or surgery alone [46]. Preoperative chemoradiotherapy was well tolerated, with grade 3 or worse hematologic toxicity in 7 percent, and grade 3 or higher non-hematologic toxicity in <13 percent; there were also no differences in postoperative morbidity or mortality between the two groups. The complete (R0) resection rate was higher with chemoradiotherapy (92 versus 69 percent), and 29 percent of those treated with chemoradiotherapy had a pCR. At a median follow-up of 32 months, median overall survival was significantly better with preoperative chemoradiotherapy (hazard ratio for death 0.657, 95% CI 0.495-0.871, three-year survival rate 58 versus 44 percent). CALGB 9781 CALGB 9781 was originally designed as a randomized Intergroup trial of trimodality therapy versus surgery in 500 patients with stages I-III esophageal or EGJ cancer, staged with esophagogastroduodenoscopy, barium esophagram, and CT. Staging EUS and thoracoscopy/laparoscopy were encouraged. Due to poor accrual, the study was closed prematurely with only 56 patients enrolled (42 adenocarcinomas, 14 SCC). A pCR was achieved in 10 of 25 assessable patients in the trimodality arm (40 percent), and neither perioperative morbidity nor mortality were increased compared to surgery alone [43]. Five-year survival was 39 versus 16 percent in favor of trimodality therapy, although the difference was not statistically significant. Early stage disease Trimodality treatment should not be used for stage I esophageal cancer, as it is best assessed by endoscopic ultrasound. (See "Diagnosis and staging of esophageal cancer", section on 'Locoregional staging with EUS'.) The benefit of preoperative chemoradiotherapy in smaller resectable tumors was addressed in the French FFCD 9901 trial, which randomly assigned 195 patients with stage I or II esophageal or EGJ cancer (T1N0/N+, T2 N0/N+, or T3N0, (table 1)) to preoperative chemoradiotherapy (two courses of infusional fluorouracil 800 mg/m2 daily days 1 to 4 and 29
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to 32 plus cisplatin 75 mg/m2 on day 1 or 2 of each course and concurrent RT [45 Gy]) versus surgery alone [45]. In a preliminary report of an interim analysis, at a median followup of 69 months, neoadjuvant chemoradiotherapy did not improve median overall survival (32 versus 44 months with surgery alone), and it was associated with significantly more serious adverse events (65 versus 35 percent) and a significantly higher rate of perioperative mortality (7.3 versus 1.1 percent). Sequential chemoradiotherapy In contrast to the data on concurrent chemoradiotherapy, at least three trials comparing sequentially administered chemotherapy and RT followed by surgery to surgery alone have failed to show any survival advantage to combined modality therapy [20,39,40]. Meta-analyses Several meta-analyses have addressed the benefit of trimodality therapy over surgery alone for esophageal cancer. The most recent and largest of these included 12 randomized comparisons of neoadjuvant chemoradiotherapy (either concurrent or sequential) versus surgery alone for esophageal or EGJ cancer, including the FFCD 9901, CALGB 9781, and CROSS trials [47]. The hazard ratio (HR) for all-cause mortality for neoadjuvant chemoradiotherapy was 0.78 (95% CI 0.70-0.88), and this translated into an absolute survival benefit of 8.7 percent at two years and a number needed to treat to prevent one death of 11. The benefit was similar across histologic subtypes (for SCC, the HR was 0.80, 95% CI 0.68-0.93; for adenocarcinomas, the HR was 0.75, 95% CI 0.59-0.95). The potential benefit of neoadjuvant therapy was not offset by a higher postoperative mortality (in-hospital or 30-day postoperative death). Summary With several trials and at meta-analyses demonstrating better survival with preoperative concurrent chemoradiation, combined modality therapy for potentially resectable stage II or III localized cancer of the thoracic esophagus is generally preferred over local therapy alone. However, for patients who do undergo preoperative concurrent chemoradiotherapy, the optimal regimen is not established. Intensification of preoperative therapy A consistent finding in many studies is that response to preoperative therapy, particularly the absence of residual disease in the surgical specimen, is an indicator of better disease-free and overall survival [38,48-58]. In a comprehensive literature review of 22 studies in which patients with esophageal or GEJ cancer underwent esophagectomy after neoadjuvant chemoradiotherapy, patients with a pCR were two- to threefold more likely to survive as were those with residual disease in the esophagectomy specimen [58]. These benefits translate into a 33 to 36 percent mean absolute survival benefit when a pCR is achieved than when it is not. These results provide the rationale for intensification of preoperative treatment through adding several cycles of induction chemotherapy prior to preoperative chemoradiation [59-64], or increasing the number of cytotoxic agents administered concurrent with RT [59,60,65-79]. Several groups have reported their experience with sequential induction chemotherapy followed by chemoradiotherapy [60-64]. While no randomized trials have compared this sequential induction chemotherapy followed by chemoradiotherapy to standard chemoradiotherapy, there are two trials comparing this approach to surgery alone or induction chemotherapy followed by surgery: A Swedish trial compared one course of preoperative induction chemotherapy followed by concurrent chemoradiotherapy versus surgery alone in 91 patients with resectable esophageal cancer (50 percent SCC) [64]. Patients randomized to preoperative treatment received three cycles of chemotherapy (cisplatin 100 mg/m2 on day 1 plus infusional FU 750 mg/m2 daily, days 1 to 5), with the first course given prior to and the next two concurrent with RT (64 Gy). In a preliminary report, at a median follow-up of 52 months, median survival was 13 months for the chemoradiotherapy group and 16 months for the surgery alone group, and four- year survival was not significantly better in the chemoradiotherapy group (29 versus 23 percent). The RT dose was much higher than that established in RTOG 85-01 (see 'RTOG 85-01' above).
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The only trial to directly compare induction chemotherapy followed by concurrent chemoradiotherapy versus induction chemotherapy alone was the German POET trial, in which 126 patients with EGJ adenocarcinoma were randomly assigned to 16 weeks of chemotherapy alone (cisplatin plus short-term infusional leucovorin-modulated FU) versus 12 weeks of the same chemotherapy regimen followed by low-dose RT concurrent with cisplatin and etoposide; both groups underwent subsequent surgical resection [63]. The pathologic complete response (pCR) rate was significantly higher after induction chemotherapy followed by chemoradiotherapy, and there was a nonsignificant trend towards better median and three-year survival (47 versus 28 percent, p = 0.07) in this group as well. Whether these results can be extrapolated to SCC of the thoracic esophagus is uncertain. This trial and the implication of its findings for treatment of EGJ cancers are discussed in detail elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas", section on 'German POET trial'.) Although early results from many trials evaluating intensified chemotherapy during RT are encouraging, whether the added toxicity of any of these approaches is counterbalanced by substantial survival gains is unclear. Phase III trials are needed to confirm the benefit of these more toxic approaches over concurrent cisplatin/FU. Necessity for surgery The necessity of resection in patients undergoing chemoradiotherapy is controversial. A survival benefit for post-chemoradiotherapy esophagectomy has been suggested in national surveys of patients with thoracic adenocarcinoma or squamous cell cancer (SCC) who were treated in the 1990s [80-82] and in an analyses of data from a Surveillance, Epidemiology and End Results (SEER) regional database of patients with esophageal cancer who were treated between 1988 and 2006 [83]. However, others have questioned the necessity of surgery [18,19]. In contemporary series, definitive chemoradiotherapy provides long-term survival in up to 27 percent of patients with SCC [3,35,84,85], a result that is not dissimilar to that achieved with preoperative chemoradiotherapy followed by surgery [18,38,42], neoadjuvant chemotherapy and surgery (see 'Neoadjuvant chemotherapy' below) [5,86], and surgery alone [5,20]. Nearly all reports note a higher rate of locally persistent/recurrent disease when surgery is not a component of treatment [3,85]. In general, there is a lack of data on nonsurgical management for patients with adenocarcinoma, and at least some retrospective series suggest inferior outcomes in this group with nonsurgical therapy [87]. At least two randomized trials directly comparing chemoradiotherapy alone to chemoradiotherapy followed by surgery have failed to demonstrate better survival, although both show better locoregional control and a lesser need for palliative procedures when surgery is a component of multimodality treatment [88,89]. The patient populations in both were either exclusively or predominantly SCC: In one trial, 172 patients (all with esophageal SCC) were randomly assigned to three cycles of induction 5-FU, leucovorin, etoposide, and cisplatin followed by concomitant chemoradiotherapy (cisplatin plus etoposide on days 2 and 8 only, and 40 Gy external beam RT) and then resection, or the same chemotherapy followed by concomitant chemoradiotherapy (chemotherapy on days 2 and 8 only) with an additional 20 Gy of RT added instead of surgery [88]. Treatment-related mortality was higher in the trimodality arm (12.8 versus 3.5 percent). The surgically treated patients had significantly better local control (two-year local progression-free survival 64 versus 41 percent), but this did not translate into significantly better overall survival at three (31 versus 24 percent), five (28 versus 17 percent), or ten years (19 versus 12 percent) [90]. Of note, in comparison to other trials using concomitant chemoradiotherapy alone [3] or followed by surgery [38], RT doses and the intensity of chemotherapy were lower in this study. This may in part explain the lower survival rate in the nonsurgically treated patients, when compared to the results of RTOG 85-01 (see 'RTOG 8501' above). In the French trial FFCD 9102, 444 patients with potentially resectable T3, N0-1, M0 esophageal SCC (89
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percent) or adenocarcinoma (11 percent) received induction chemoradiotherapy with either protracted (46 Gy in 4.5 weeks) or split course (2 X 15 Gy, days 1 to 5 and 22 to 26) RT concurrent with two courses of FU and cisplatin chemotherapy [89]. Patients with at least a partial response and who had no contraindication to surgery (n = 259) were then randomly assigned to continue chemoradiotherapy (three more cycles of chemotherapy with either 30 Gy [protracted] or 15 Gy [split course] RT) or to undergo surgery. At a median follow-up of 47 months, the surgically treated patients had similar two-year (34 versus 40 percent) and median survival (17.7 versus 19.3 months) as compared to those assigned to continue chemoradiotherapy. Surgically treated patients had significantly lower rates of locoregional recurrence (34 versus 43 percent) and were significantly less likely to require palliative intervention for dysphagia (24 versus 46 percent). There were no differences in longitudinal quality of life among survivors with two years of follow-up [91]. Some of the only data on nonsurgical management of adenocarcinoma come from a retrospective analysis of 239 patients treated with definitive chemoradiotherapy at MD Anderson for unresectable esophageal cancer, 181 of whom had adenocarcinoma [92]. RT was planned and delivered using modern techniques (four-dimensional CT and intensity-modulated RT), and a moderate-dose (50.4 Gy in 28 fractions) was combined with chemotherapy. The majority of patients had T3 (81 percent), N1 (67 percent), and M0 (79 percent) disease. Nearly all (99 percent) received concurrent chemotherapy, and 46 percent also received induction chemotherapy. At a median follow-up of 44 months, 119 (50 percent) had experienced a local recurrence, 107 of whom failed within the gross tumor volume while 116 (48 percent) encountered distant failure and 74 (31 percent) had no evidence of disease at last follow-up. Taken together, these data suggest that patients who undergo surgery after chemoradiotherapy appear to have better locoregional control and similar quality of life. Thus, inclusion of surgery remains the preferred treatment approach for clinically resectable esophageal cancer, particularly for adenocarcinoma since there are few data on nonsurgical management, and the rate of pathologic complete response is relatively low as compared to SCC. For patients with SCC who have an endoscopic complete response, nonoperative management is an option balancing the risks of surgical mortality versus improved locoregional control. Utility of postinduction therapy PET scans Postinduction therapy FDG PET provides information about metabolic response in the primary tumor that may be clinically useful for selection of subsequent therapy. In particular, some retrospective data suggest that post-chemoradiotherapy FDG-PET scanning may serve to identify those patients for whom surgery might be avoided. One series included 105 patients with stage I to IVA esophageal cancer (75 percent adenocarcinoma) who were evaluable for a post-chemoradiotherapy PET response, 50 of whom received chemoradiotherapy alone [93]. In this cohort, those whose PET response was characterized by a posttreatment standard uptake value (SUV) "3 in the tumor (n = 19, 38 percent) had an excellent outcome without resection (two-year overall survival 71 versus 11 percent for those with a posttreatment tumoral SUV !3.1; the corresponding two-year rates of freedom from local failure were 75 versus 28 percent). In contrast, those patients undergoing trimodality therapy (n = 55) showed no difference in outcome according to the post-chemoradiotherapy PET findings, probably because those patients who had residual disease underwent resection. These data need to be confirmed and validated in a prospective trial before PET-directed therapy for esophageal cancer can be considered a standard approach. Furthermore, the best method to quantify FDG PET for clinical use in esophageal cancer remains to be determined. The main use of PET in esophageal cancer may be to recognize which patients are not responding to induction chemotherapy [94,95]. Tailoring treatment based upon postinduction chemotherapy PET scanning is being directly studied in CALGB 80302 [96]. These and other data on the utility of postinduction therapy PET scans are presented
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elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas", section on 'Use of PET and PET-CT during treatment'.) Neoadjuvant chemotherapy Multiple randomized trials have evaluated the benefit of chemotherapy administered prior to resection in patients with esophageal cancer limited to the primary and regional nodes by clinical assessment [5,49,86,97-100]. Four trials with a surgery alone control arm are negative, including the US Intergroup 0113 trial, [5,49,97,101] while three others (the MRC OE2 trial, the UK MAGIC trial, and a preliminary report of the French FNLCC/FFCD trial), demonstrate a survival benefit compared to resection alone [86,98,99,102]. Meta-analyses A survival benefit for neoadjuvant chemotherapy relative to surgery alone was shown in a year 2011 meta-analysis that included nine randomized comparisons of neoadjuvant chemotherapy versus surgery alone for esophageal or EGJ cancers [47]. The hazard ratio (HR) for all-cause mortality for neoadjuvant chemotherapy was 0.87 (95% CI 0.70-0.88), and this translated into an absolute survival benefit at two years of 5.1 percent and a number needed to treat to prevent one death of 19. The potential benefit of neoadjuvant therapy was not offset by a higher postoperative mortality (in-hospital or 30-day postoperative death). Subgroup analysis by histologic type, for those studies where histology data were available gave an HR for SCC of 0.80 (95% CI 0.68-0.93), while for adenocarcinomas the HR was 0.75 (95% CI 0.59-0.95). Neoadjuvant chemotherapy versus chemoradiotherapy Chemotherapy was directly compared to chemoradiotherapy in a randomized phase II Australian trial involving 75 patients with adenocarcinoma of the esophagus or EGJ [103]. Although the histopathologic response rate and rate of margin-negative resections favored chemoradiotherapy, median overall survival was not significantly better (32 versus 29 months). The only phase III trial to directly compare induction chemoradiotherapy versus chemotherapy was the multicenter German POET trial, in which 126 patients with EGJ adenocarcinoma were randomly assigned to 16 weeks of chemotherapy alone (cisplatin plus short-term infusional FU plus leucovorin) versus 12 weeks of the same chemotherapy regimen followed by low-dose RT concurrent with cisplatin and etoposide; both groups underwent subsequent surgical resection [63]. The pathologic complete response (pCR) rate was significantly higher after induction chemotherapy followed by chemoradiotherapy (16 versus 2 percent), and there was a nonsignificant trend towards better median and three-year survival in this group as well (47 versus 28 percent, p = 0.07). These data, which are discussed in more detail elsewhere, support the view that chemoradiotherapy is a preferred strategy rather than induction chemotherapy alone for patients with EGJ adenocarcinomas. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas", section on 'German POET trial'.) Of note, both of these trials were closed prematurely, and therefore, underpowered to show a survival advantage; neither enrolled patients with SCC. Meta-analysis These two trials were subjected to a meta-analysis, and the HR for all-cause mortality was 0.77 in favor of chemoradiotherapy, but this was not statistically significant (95% CI 0.53-1.12) [47]. Neoadjuvant chemotherapy versus postoperative chemotherapy The superiority of neoadjuvant as compared to postoperative adjuvant chemotherapy was shown in a Japanese trial (JCOG9907) in which 330 patients with clinical stage II or III SCC of the thoracic esophagus were randomly assigned to surgery preceded or followed by two 21-day courses of cisplatin (80 mg/m2 on day 1) plus infusional FU (800 mg/m2 daily for five days) [100]. Five-year overall survival was significantly higher in the group receiving preoperative chemotherapy (55 versus 43 percent, p = 0.04). Impact of preoperative treatment on local control Although most trials focus upon survival as a primary endpoint, local-regional control is also important when selecting among treatment options. Local failures can be defined as recurrent local disease following margin-negative esophagectomy or positive resection margins. Using this definition, the frequency of local failure appears to be higher in trials in which patients were treated with surgery alone or
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chemoradiotherapy alone as compared to those receiving chemoradiotherapy followed by surgery [5,20,38,85,104]. As an example, in the Michigan study, described above, the rate of local failure as the first site of failure was significantly lower in those randomized to combined modality therapy compared to surgery alone (19 versus 42 percent) [38]. In the previously described meta-analysis of trials comparing preoperative chemoradiotherapy to surgery alone [104], the odds ratio for local-regional recurrences was significantly lower with preoperative therapy (OR for local recurrence 0.38, 95% CI 0.23-0.63). (See 'Concurrent chemoradiotherapy' above.) Whether local recurrence rates are lower in patients treated with neoadjuvant chemotherapy as compared to surgery alone is uncertain. In the MAGIC trial, local failure was confirmed before death in fewer patients in the chemotherapy group as compared to surgery alone (14 versus 20 percent), but the p value for the comparison was not reported [98]. In the MRC trial, the local failure rates were nearly identical in the chemotherapy and surgery groups (12 and 11 percent, respectively) [86]. The meta-analysis of preoperative chemotherapy versus surgery alone did not address the issue of locoregional control [105]. (See 'Meta-analyses' above.) Technique for preoperative RT The degree of response of a tumor and normal tissues/organs to radiation depends upon several radiotherapeutic factors [106-108]: Fraction size (standard fraction size, 1.8 Gy to 2.0 Gy) and interfractional intervals (standard interval, 24 hours) Total dose (standard preoperative dose in once daily schedule, 45 to 50.4 Gy) Duration of treatment (5 to 5.6 weeks for standard fractionation, without a rest during treatment) The arrangement of radiation portals in a manner that achieves the maximum dose differential between tumor and adjacent vital organs Significant deviations from standard techniques should be avoided in a potentially curative setting. Fraction sizes that are larger than 2.5 Gy, treatment breaks of longer than one week, split-course fractionation schedules [85], and suboptimal radiation plans with a potential for increased risk of injury to the lung, heart and spinal cord should be avoided. 3D conformal RT Three-dimensional conformal RT (3D-CRT) is recommended for the best possible coverage of the target volume while protecting the surrounding normal organs from excess RT dose. Target volume The target volume consists of gross tumor volume (GTV) with a margin of clinically uninvolved tissue (clinical target volume, or CTV). The CTV should include 4 to 5 cm margins beyond the radiographic tumor extent (GTV) in the cephalad-caudad direction and 2 to 2.5 cm beyond the radial border of GTV (defined by barium esophagogram or CT scan). For lesions of the lower third of the esophagus and gastroesophageal junction (GEJ), the caudal extension CTV beyond GTV includes a 3 to 4 cm margin of gastric cardia below the lower border of GTV. CTV for regional lymph nodes includes the celiac, gastric, and gastrohepatic Iymph node groups for primary tumors at the GE junction. For primary tumors involving the upper two-thirds of the thoracic or the cervical esophagus, CTV includes both supraclavicular regions. It is necessary to add another 0.7 cm beyond CTV as the PTV (planning target volume) in order to compensate for daily set-up error and respiratory tumor motion. Esophageal cancers that are located at the GE junction can have a significant degree of tumor motion associated with respiration. We reported peak-to-peak motion of the primary tumor in 10 patients (nine near the GE junction with their involved lymph nodes at the celiac region) [108]. The peak-to-peak tumor motion in craniocaudal directions ranged from 0.6 cm to 4.8 cm for the primary tumor and from 1.2 cm to 4.4 cm for the involved lymph nodes. In order to avoid geographic miss in some of these patients when using 3D CRT, four-dimensional (4D) CT treatment planning and delivery of 3D CRT according to the tumor characteristics of individual patients has a significant advantage for optimum
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coverage of the target volume over 3D-CRT planned with the conventional helical CT. Optimal dose and fractionation schedules Tumor size and radiation dose are important considerations for local-regional tumor control. Radiation therapy with curative intent requires a total dose of 60 to 66.6 Gy in 30 to 37 daily fractions using 1.8 to 2.0 Gy daily fractions, five fractions per week. Small daily fractions (ie, 1.8 to 2.0 Gy instead of 2.5 to 3.0 Gy) reduce the likelihood of late toxicity [106,107]. The optimal radiation dose for preoperative chemoradiotherapy regimens is not defined, although a total dose of 41.4 to 50.4 Gy administered in daily 1.8 Gy fractions, five days per week, produces reasonable results with acceptable toxicity [3,46,84,109]. Altered fractionation schedules such as accelerated schedules (45 Gy in 30 fractions over three weeks using twice daily 1.5 Gy fractions) or hybrid schedules using twice daily radiation during chemotherapy and once daily treatment between chemotherapy cycles (45 Gy in 25 fractions over five weeks to CTV, and 58.5 Gy in 34 fractions over five weeks to GTV, respectively) are tolerable, with encouraging tumor response, high pathologic CR rates, and survival [38,110]. Patients judged inoperable because of either poor general condition or the presence of distant metastases can be treated by rapid fractionation schedules. A total dose of 40 to 45 Gy at 2.5 Gy daily fractions five days a week is a reasonable schedule for patients who require palliation of esophageal obstruction. 3D CRT uses four to six beams to conform the distribution of radiation dose to the GTV and PTV, while the surrounding normal structures are spared from excessive radiation dose, to the greatest extent possible. 3D CRT plan provides a dose-volume-histogram for GTV and PTV as well as for normal organs at risk for complications. Thus, it is feasible to formulate a radiation dose schedule for the desired level of tumor control probability that is balanced with an acceptable level of toxicities. Intensity-modulated radiation therapy (IMRT) is an advanced form of 3D CRT. IMRT uses inverse treatment planning to generate optimum treatment plan. IMRT uses dynamic multileaf collimators to conform the radiation beam to the shape of the tumor from any angle, while protecting normal adjacent tissue as much as possible. It may be expected (though not yet proven) that treatment with IMRT will result in fewer side effects [111-113]. Postoperative adjuvant therapy Based upon the data presented above, many patients with esophageal or esophagogastric junction (EGJ) cancer are offered induction therapy with chemotherapy or chemotherapy plus RT prior to attempted surgical resection. Although this is a preferred approach for patients who present with clinically nodepositive or T3/4 disease, some patients will undergo surgery initially. (See 'Chemoradiotherapy' above.) For patients who are found to have node-positive or T4 disease after undergoing surgery alone, the addition of postoperative adjuvant therapy (chemotherapy with or without RT) is reasonable in an effort to improve outcomes [114,115]. Chemoradiotherapy For patients with a node-positive adenocarcinoma of the EGJ, postoperative chemoradiotherapy is a standard approach, at least in the United States, based upon results from the US Intergroup trial. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas", section on 'Adjuvant chemoradiotherapy'.) For other patients, particularly those with an esophageal squamous cell cancer, the optimal approach is uncertain. Some uncontrolled trials and retrospective comparisons of patients treated with and without chemoradiotherapy suggest potential benefit for postoperative chemoradiotherapy. However, others do not, and there are no randomized trials proving benefit as compared to surgery alone: In a retrospective report, outcomes of 38 patients with node-positive disease after esophagectomy alone who received postoperative chemoradiotherapy (concurrent or sequential RT plus cisplatin and FU with or without epirubicin) were compared to 28 similar patients who did not receive further therapy [116]. Local recurrence rates
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were lower in the group receiving postoperative therapy (35 versus 13 percent), and the median overall survival was longer (48 versus 14 months). Mature data from a prospective phase II uncontrolled trial also support benefit for adjuvant chemoradiotherapy in this setting. In this trial, 50 patients with locally advanced esophageal cancer (90 percent T3, 81 percent nodepositive, 13 percent with extraregional nodal metastases) received chemoradiotherapy (RT 50.4 to 59.4 Gy plus concurrent cisplatin and FU) after esophagectomy [117]. At a median follow-up of 47 months, four year projected survival was 51 percent, a rate that is far higher than might be expected for this relatively poor prognosis cohort. The contribution of RT to these results has been questioned. A lack of benefit from RT was suggested by a randomized trial comparing postoperative chemotherapy (five weeks of cisplatin plus FU) alone versus the same chemotherapy regimen with RT (50 Gy over five weeks) in 45 patients undergoing potentially curative resection for squamous cell cancer of the thoracic esophagus who did not receive preoperative therapy [118]. There was no significant benefit from the addition of RT to chemotherapy in terms of five-year survival (50 versus 38 percent), and locoregional control rates were also not better in this group. Chemotherapy alone For patients with esophageal cancer who have not received preoperative chemotherapy or chemoradiotherapy, postoperative chemotherapy alone may be beneficial, although proof of a survival benefit from randomized trials with a surgery alone control group is absent: Benefit for adjuvant chemotherapy alone was suggested in an uncontrolled trial conducted by the Eastern Cooperative Oncology Group that included patients with distal esophageal (n = 9), EG junction (n = 34) or gastric cardia (n = 12) tumors [119]. Eligible patients had either T2N1-2 or T3/4 disease that was completely resected with negative margins; 49 (89 percent) were node-positive. Treatment consisted of four three-week cycles of paclitaxel (175 mg/m2) followed by cisplatin (75 mg/m2). With a median follow-up of four years, the two and threeyear survival rates were 60 and 44 percent, respectively. The lack of a surgery alone control group precludes interpretation of these data. The only randomized trial to compare surgery alone versus surgery followed by adjuvant chemotherapy (two courses of cisplatin 80 mg/m2 on day 1 and FU 800 mg/m2 daily for five days) included 242 patients with esophageal squamous cell cancer recruited from 17 Japanese institutions [120]. The five-year disease-free survival rate (the primary endpoint) was significantly better with chemotherapy (55 versus 45 percent), but overall survival was not significantly different (61 versus 52 percent). The short duration of adjuvant chemotherapy, and the fact that 25 percent of the patients in the chemotherapy group did not receive both full courses of therapy may have compromised the ability to document a survival difference. Summary For patients with completely resected node-positive esophageal cancer who have not received neoadjuvant therapy, we typically recommend some form of postoperative therapy. It is difficult to come to any conclusions as to whether there are specific advantages for adjuvant chemoradiotherapy over chemotherapy alone. In our view, either approach is reasonable. Further confirmatory trials, particularly randomized trials, are necessary before specific recommendations can be made. POSTTREATMENT CANCER SURVEILLANCE The majority of recurrences develop within one year. In a series of 590 patients who underwent esophagectomy for adenocarcinoma, the peak interval for recurrence after esophagectomy alone was six to nine months, and more than 90 percent of the disease recurrences occurred by three years [121]. In contrast, among patients treated with neoadjuvant chemoradiotherapy, the peak time frame for recurrence was the first three months, and >90 percent of recurrences were evident by 21 months. The pattern of recurrence was distant, locoregional, or both in 60, 30, and 10 percent of patients, respectively, and did not differ in patients treated with
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induction chemoradiotherapy versus surgery alone. There are no randomized trials to guide the postoperative surveillance strategy, and no data that demonstrate improvement in quality of life or longevity from earlier detection of asymptomatic recurrences. Nevertheless, consensusbased guidelines from the National Comprehensive Cancer Network (NCCN) suggest the following [122]: History and physical examination every three to six months for one to three years, then every six months for years four and five, then annually CBC and chemistry profile, as clinically indicated Radiologic imaging and upper GI endoscopy, as clinically indicated Dilation for anastomotic stenosis Nutritional counseling At our institution, we perform history, physical examination, and targeted blood work (for a symptomatic patient, or if there was a serum tumor marker that was elevated preoperatively) every four months for the first three years and also perform restaging CT scans of the chest and abdomen at four month intervals. We do not carry out surveillance endoscopy unless there was a preoperative history of Barrett's esophagus, a questionable margin at the time of surgery, or if the patient has a recalcitrant stricture that is worrisome for an occult local recurrence. When planning the posttreatment surveillance strategy, care should be taken to limit the number of CT scans, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. (See "Radiation-related risks of imaging studies".) CERVICAL ESOPHAGUS TUMORS Squamous cell cancer (SCC) of the cervical esophagus presents a unique management situation. If surgery is performed, it usually requires removal of portions of the pharynx, the larynx, the thyroid gland, and portions of the proximal esophagus. In addition, radical neck dissections are usually carried out; as such, the management is more closely related to SCC of the head and neck than for malignancies involving the more distal portions of the esophagus. In general, radiation therapy combined with chemotherapy is preferred over surgery for these patients since survival appears to be the same and major morbidity is avoided in most. (See "Surgical oncologic principles for management of resectable esophageal cancer", section on 'Cervical esophageal cancer resection' and "Management of locally advanced unresectable esophageal cancer", section on 'Cervical esophageal tumors'.) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient information: Esophageal cancer (The Basics)") SUMMARY AND RECOMMENDATIONS
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The management of local-regional cancer of the esophagus and esophagogastric junction (EGJ) has undergone a major evolution over the past 15 years. The majority of patients now undergo some form of combined modality therapy rather than local therapy alone. However, the optimal management of these patients remains controversial. (See 'Introduction' above.) There are two major histologies of esophageal cancer: squamous cell cancer (SCC) and adenocarcinoma. Although most clinical studies have not differentiated between these two tumor entities, an increasing amount of evidence supports the view that they differ in terms of their pathogenesis, epidemiology, tumor biology, and prognosis. In recognition of these differences, the 2010 edition of the TNM staging criteria provides separate stage groupings for SCC and adenocarcinomas of the esophagus and EGJ (table 1 and table 2) [6]. However, it remains unclear whether and how histology should be used to select the treatment approach, and largely due to the lack of data on the impact of histology on treatment outcomes, the approach tends to be similar for both histologies. At least two randomized trials directly comparing chemoradiotherapy alone to chemoradiotherapy followed by surgery have failed to demonstrate better survival, although both show better locoregional control and a lesser need for palliative procedures when surgery is a component of multimodality treatment [88,89]. The patient populations in both were either exclusively or predominantly SCC. Thoracic esophageal cancer The following conclusions regarding therapy for thoracic esophageal cancers can be derived from phase III studies comparing definitive chemoradiotherapy to radiotherapy alone, and preoperative chemoradiotherapy or preoperative chemotherapy to surgery alone for patients with esophageal or GEJ cancer that is localized to the primary site and regional nodes: While definitive chemoradiotherapy is a potentially curative option for SCC, there is a high rate of locally persistent/recurrent disease after chemoradiotherapy alone, and a lack of data on nonsurgical management of patients with adenocarcinoma, who have a low rate of pathologic complete response after chemoradiotherapy. Thus, inclusion of surgery is preferred for clinically resectable esophageal cancer, particularly for adenocarcinoma. For patients with SCC who have an endoscopically-documented complete response, nonoperative management is an option balancing the risks of surgical mortality versus improved locoregional control. (See 'Necessity for surgery' above.) Several trials and meta-analyses support the view that a concurrent trimodality approach (concomitant chemoradiotherapy followed by surgery) provides a survival benefit compared to surgery alone. Further, local control appears to be better with preoperative chemoradiotherapy compared to surgery alone. (See 'Concurrent chemoradiotherapy' above.) Induction chemotherapy without RT also provides a significant survival benefit over surgery alone, and this approach has been adopted in the United Kingdom based upon the results of several neoadjuvant trials, including the MAGIC trial. However, whether these results can be extrapolated to the setting of esophageal SCCs is uncertain. (See 'Meta-analyses' above.) Furthermore, local failure rates may be lower in patients treated with chemoradiotherapy followed by surgery compared to those receiving either chemotherapy followed by surgery or surgery alone. (See 'Impact of preoperative treatment on local control' above.) As a result of these issues, we recommend combined modality therapy rather than surgery alone for patients with T2-3N0 stage I, and all patients with stages IIA, IIB, and III thoracic esophageal cancer regardless of histology
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(table 1 and table 2) (Grade 1A). For these patients, we suggest concurrent chemoradiotherapy instead of chemotherapy alone for neoadjuvant therapy (Grade 2B). Definitive chemoradiotherapy is a reasonable approach for patients who are not surgical candidates. The benefit of preoperative chemoradiotherapy for patients with T1N0 esophageal or EGJ adenocarcinoma or SCC is less clear. We recommend surgery alone in these patients (Grade 1B). Definitive chemoradiotherapy is a reasonable approach for patients who are not surgical candidates. Although the optimal type, dose, combination, and schedule of drugs has not been definitively established, we suggest the low-dose weekly carboplatin plus paclitaxel regimen (table 4) as was used in the Dutch CROSS trial rather than two courses of cisplatin plus 5-FU as was used in CALGB 9781 (Grade 2B). (See 'CROSS trial' above and 'CALGB 9781' above and "Treatment protocols for esophagogastric cancer".) Issues related to carboplatin dosing (ie, estimation of GFR, appropriate weight to use in the calculation of drug dose according to the Calvert formula) are discussed elsewhere. (See "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency", section on 'AUC dose calculation'.) The optimal dose-fractionation RT schedule for concurrent chemoradiotherapy regimens remains to be determined. However, 3-D conformal techniques should be used for modern treatment planning to minimize toxicities to adjacent vital organs (ie, heart, lung, spinal cord, or liver). Even though the Dutch CROSS trial used a lower dose (41.4 Gy), the standard dose of RT for patients treated with concurrent chemotherapy remains 50.4 Gy administered in 28 daily fractions, as was used in CALGB 9781 and RTOG 85-01. (See 'Optimal dose and fractionation schedules' above and 'CROSS trial' above and 'CALGB 9781' above.) For patients with completely resected node-positive esophageal cancer who have not received neoadjuvant therapy, we suggest postoperative adjuvant therapy (Grade 2C). Chemotherapy alone or chemoradiotherapy are both reasonable options. (See 'Postoperative adjuvant therapy' above.) EGJ cancers Most clinicians now treat esophagogastric junction (EGJ) and proximal gastric (ie, cardia, (figure 1)) cancers as esophageal cancers with preoperative chemoradiotherapy. However, these tumors have been included in many of the trials examining the benefit of adjuvant and neoadjuvant chemotherapy for gastric cancer, and institutional practice varies. The therapeutic approach to tumors of the EGJ is addressed in detail elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas".) Cervical esophageal cancer Management of carcinoma arising in the cervical esophagus is more closely related to SCC of the head and neck than for malignancies involving the more distal portions of the esophagus. In general, radiation combined with chemotherapy is preferred over surgery for these patients since survival appears to be the same, and major morbidity is avoided in most. (See 'Cervical esophagus tumors' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62:10. 2. Daly JM, Karnell LH, Menck HR. National Cancer Data Base report on esophageal carcinoma. Cancer 1996; 78:1820. 3. Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992; 326:1593.
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after preoperative chemoradiotherapy for carcinoma of the esophagus. Cancer 2005; 104:1349. 49. Ancona E, Ruol A, Santi S, et al. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer 2001; 91:2165. 50. Kleinberg L, Knisely JP, Heitmiller R, et al. Mature survival results with preoperative cisplatin, protracted infusion 5-fluorouracil, and 44-Gy radiotherapy for esophageal cancer. Int J Radiat Oncol Biol Phys 2003; 56:328. 51. Choi N, Park SD, Lynch T, et al. Twice-daily radiotherapy as concurrent boost technique during two chemotherapy cycles in neoadjuvant chemoradiotherapy for resectable esophageal carcinoma: mature results of phase II study. Int J Radiat Oncol Biol Phys 2004; 60:111. 52. Chirieac LR, Swisher SG, Ajani JA, et al. Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation. Cancer 2005; 103:1347. 53. Berger AC, Farma J, Scott WJ, et al. Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival. J Clin Oncol 2005; 23:4330. 54. Lagarde SM, ten Kate FJ, Reitsma JB, et al. Prognostic factors in adenocarcinoma of the esophagus or gastroesophageal junction. J Clin Oncol 2006; 24:4347. 55. Rizk NP, Venkatraman E, Bains MS, et al. American Joint Committee on Cancer staging system does not accurately predict survival in patients receiving multimodality therapy for esophageal adenocarcinoma. J Clin Oncol 2007; 25:507. 56. Rizk NP, Seshan VE, Bains MS, et al. Prognostic factors after combined modality treatment of squamous cell carcinoma of the esophagus. J Thorac Oncol 2007; 2:1117. 57. Kim MK, Kim SB, Ahn JH, et al. Treatment outcome and recursive partitioning analysis-based prognostic factors in patients with esophageal squamous cell carcinoma receiving preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys 2008; 71:725. 58. Scheer RV, Fakiris AJ, Johnstone PA. Quantifying the benefit of a pathologic complete response after neoadjuvant chemoradiotherapy in the treatment of esophageal cancer. Int J Radiat Oncol Biol Phys 2011; 80:996. 59. Ilson DH, Bains M, Kelsen DP, et al. Phase I trial of escalating-dose irinotecan given weekly with cisplatin and concurrent radiotherapy in locally advanced esophageal cancer. J Clin Oncol 2003; 21:2926. 60. Ajani JA, Walsh G, Komaki R, et al. Preoperative induction of CPT-11 and cisplatin chemotherapy followed by chemoradiotherapy in patients with locoregional carcinoma of the esophagus or gastroesophageal junction. Cancer 2004; 100:2347. 61. Swisher SG, Ajani JA, Komaki R, et al. Long-term outcome of phase II trial evaluating chemotherapy, chemoradiotherapy, and surgery for locoregionally advanced esophageal cancer. Int J Radiat Oncol Biol Phys 2003; 57:120. 62. Ajani JA, Komaki R, Putnam JB, et al. A three-step strategy of induction chemotherapy then chemoradiation followed by surgery in patients with potentially resectable carcinoma of the esophagus or gastroesophageal junction. Cancer 2001; 92:279. 63. Stahl M, Walz MK, Stuschke M, et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 2009; 27:851. 64. Carstens H, Albertsson M, Friesland S, et al. A randomized trial of chemoradiotherapy versus surgery alone in patients with resectable esophageal cancer (Abstract). J Clin Oncol 2007; 25:205s. 65. Meluch AA, Greco FA, Gray JR, et al. Preoperative therapy with concurrent paclitaxel/carboplatin/infusional 5-FU and radiation therapy in locoregional esophageal cancer: final results of a Minnie Pearl Cancer Research Network phase II trial. Cancer J 2003; 9:251. 66. Choy H. Combining taxanes with radiation for solid tumors. Int J Cancer 2000; 90:113. 67. Blanke CD, Choy H, Teng M, et al. Concurrent paclitaxel and thoracic irradiation for locally advanced esophageal cancer. Semin Radiat Oncol 1999; 9:43. 68. Adelstein DJ, Rice TW, Rybicki LA, et al. Does paclitaxel improve the chemoradiotherapy of locoregionally advanced esophageal cancer? A nonrandomized comparison with fluorouracil-based therapy. J Clin Oncol 2000;
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18:2032. 69. Kleinberg L, Powell ME, Forastiere A, et al. E1201: An Eastern Cooperative Oncology Group (ECOG) randomized phase II trial of neoadjuvant preoperative paclitaxel/cisplatin/RT or irinotecan/cisplatin/RT in endoscopy with ultrasound (EUS) staged adenocarcinoma of the esophagus (Abstract). J Clin Oncol 2007; 25:205s. 70. Brenner B, Ilson DH, Minsky BD, et al. Phase I trial of combined-modality therapy for localized esophageal cancer: escalating doses of continuous-infusion paclitaxel with cisplatin and concurrent radiation therapy. J Clin Oncol 2004; 22:45. 71. Anne PR, Axelrod R, Rosato E, et al. A phase II trial of preoperative paclitaxel, carboplatin, 5-FU and radiation in patients with resectable esophageal or gastric cancer (abstract). Proc Am Soc Clin Oncol 2004; 23:320a. 72. Urba S, Hayman J, Iannettonni M, et al. Preoperative chemoradiotherapy with cisplatin, 5-FU and paclitaxel followed by surgery and adjuvant chemotherapy, for loco-regional esophageal carcinoma (abstract). Proc Am Soc Clin Oncol 2004; 23:319a. 73. Khushalani NI, Leichman CG, Proulx G, et al. Oxaliplatin in combination with protracted-infusion fluorouracil and radiation: report of a clinical trial for patients with esophageal cancer. J Clin Oncol 2002; 20:2844. 74. Cagol M, Ruol A, Sileni VC, et al. [Multimodal treatment in locally advanced esophageal cancer: a multicenter phase II study with neoadjuvant oxaliplatin, 5-fluorouracil, leucovorin and neoadjuvant radiotherapy: preliminary results]. Chir Ital 2006; 58:433. 75. Kleinberg L, Gibson MK, Forastiere AA. Chemoradiotherapy for localized esophageal cancer: regimen selection and molecular mechanisms of radiosensitization. Nat Clin Pract Oncol 2007; 4:282. 76. van de Schoot L, Romme EA, van der Sangen MJ, et al. A highly active and tolerable neoadjuvant regimen combining paclitaxel, carboplatin, 5-FU, and radiation therapy in patients with stage II and III esophageal cancer. Ann Surg Oncol 2008; 15:88. 77. Jatoi A, Martenson JA, Foster NR, et al. Paclitaxel, carboplatin, 5-fluorouracil, and radiation for locally advanced esophageal cancer: phase II results of preliminary pharmacologic and molecular efforts to mitigate toxicity and predict outcomes: North Central Cancer Treatment Group (N0044). Am J Clin Oncol 2007; 30:507. 78. Chiarion-Sileni V, Innocente R, Cavina R, et al. Multi-center phase II trial of chemo-radiotherapy with 5-fluorouracil, leucovorin and oxaliplatin in locally advanced esophageal cancer. Cancer Chemother Pharmacol 2009; 63:1111. 79. Conroy T, Yataghne Y, Etienne PL, et al. Phase II randomised trial of chemoradiotherapy with FOLFOX4 or cisplatin plus fluorouracil in oesophageal cancer. Br J Cancer 2010; 103:1349. 80. Coia LR, Minsky BD, Berkey BA, et al. Outcome of patients receiving radiation for cancer of the esophagus: results of the 1992-1994 Patterns of Care Study. J Clin Oncol 2000; 18:455. 81. Suntharalingam M, Moughan J, Coia LR, et al. The national practice for patients receiving radiation therapy for carcinoma of the esophagus: results of the 1996-1999 Patterns of Care Study. Int J Radiat Oncol Biol Phys 2003; 56:981. 82. Suntharalingam M, Moughan J, Coia LR, et al. Outcome results of the 1996-1999 patterns of care survey of the national practice for patients receiving radiation therapy for carcinoma of the esophagus. J Clin Oncol 2005; 23:2325. 83. McKenzie S, Mailey B, Artinyan A, et al. Improved outcomes in the management of esophageal cancer with the addition of surgical resection to chemoradiation therapy. Ann Surg Oncol 2011; 18:551. 84. al-Sarraf M, Martz K, Herskovic A, et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol 1997; 15:277. 85. Crehange G, Maingon P, Peignaux K, et al. Phase III trial of protracted compared with split-course chemoradiation for esophageal carcinoma: Federation Francophone de Cancerologie Digestive 9102. J Clin Oncol 2007; 25:4895. 86. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 2002; 359:1727. 87. Tougeron D, Scott M, Hamidou H, et al. Definitive chemoradiotherapy in patients with esophageal adenocarcinoma: an alternative to surgery? J Surg Oncol 2012; 105:761. 88. Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 2005; 23:2310.
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89. Bedenne L, Michel P, Bouch O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol 2007; 25:1160. 90. Stahl M, Wilke H, Lehmann N, et al. Long-term results of a phgase III study investigating chemoradiation with and without surgery in locally advanced squamous cell carcinoma (LA-SCC) of the esophagus (abstract). J Clin Oncol 2008; 26:220s. 91. Bonnetain F, Bouch O, Michel P, et al. A comparative longitudinal quality of life study using the Spitzer quality of life index in a randomized multicenter phase III trial (FFCD 9102): chemoradiation followed by surgery compared with chemoradiation alone in locally advanced squamous resectable thoracic esophageal cancer. Ann Oncol 2006; 17:827. 92. Welsh J, Settle SH, Amini A, et al. Failure patterns in patients with esophageal cancer treated with definitive chemoradiation. Cancer 2012; 118:2632. 93. Monjazeb AM, Riedlinger G, Aklilu M, et al. Outcomes of patients with esophageal cancer staged with [#!F]fluorodeoxyglucose positron emission tomography (FDG-PET): can postchemoradiotherapy FDG-PET predict the utility of resection? J Clin Oncol 2010; 28:4714. 94. Lordick F, Ott K, Krause BJ, et al. PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial. Lancet Oncol 2007; 8:797. 95. Ott K, Herrmann K, Lordick F, et al. Early metabolic response evaluation by fluorine-18 fluorodeoxyglucose positron emission tomography allows in vivo testing of chemosensitivity in gastric cancer: long-term results of a prospective study. Clin Cancer Res 2008; 14:2012. 96. http://clinicaltrials.gov/ct2/show/NCT00316862. 97. Roth JA, Pass HI, Flanagan MM, et al. Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg 1988; 96:242. 98. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006; 355:11. 99. Allum WH, Stenning SP, Bancewicz J, et al. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol 2009; 27:5062. 100. Ando N, Kato H, Igaki H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol 2012; 19:68. 101. Schuhmacher C, Schlag P, Lordick F, et al. Neoadjuvant chemotherapy versus surgery alone for locally advanced adenocarcinoma of the stomach and cardia: Randomized EORTC phase III trial #40954) (Abstract #4510). J Clin Oncol 2009; 27:204s. 102. Boige V, Pignon J, Saint-Aubert B, et al. Final results of a randomized trial comparing preoperative 5fluorouracil/cisplatin to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial (abstract). J Clin Oncol 2007; 25:200s. 103. Burmeister BH, Thomas JM, Burmeister EA, et al. Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial. Eur J Cancer 2011; 47:354. 104. Urschel JD, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg 2003; 185:538. 105. Gebski V, Burmeister B, Smithers BM, et al. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol 2007; 8:226. 106. Thames HD Jr, Peters LJ, Withers HR, Fletcher GH. Accelerated fractionation vs hyperfractionation: rationales for several treatments per day. Int J Radiat Oncol Biol Phys 1983; 9:127. 107. Withers HR. Biologic basis for altered fractionation schemes. Cancer 1985; 55:2086. 108. Patel A, Wolfgang J, Niemierko A, et al. Implications of respiratory motion as measured by 4D CT for radiation treatment planning of esophageal tumors (abstract). Int J Radiat Oncol Biol Phys 2006; 66:S607.
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109. Leichman L, Herskovic A, Leichman CG, et al. Nonoperative therapy for squamous-cell cancer of the esophagus. J Clin Oncol 1987; 5:365. 110. Wright CD, Wain JC, Lynch TJ, et al. Induction therapy for esophageal cancer with paclitaxel and hyperfractionated radiotherapy: a phase I and II study. J Thorac Cardiovasc Surg 1997; 114:811. 111. Liu HH, Wang X, Dong L, et al. Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004; 58:1268. 112. Murshed H, Liu HH, Liao Z, et al. Dose and volume reduction for normal lung using intensity-modulated radiotherapy for advanced-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004; 58:1258. 113. Schwarz M, Alber M, Lebesque JV, et al. Dose heterogeneity in the target volume and intensity-modulated radiotherapy to escalate the dose in the treatment of non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2005; 62:561. 114. Minsky BD. Carcinoma of the esophagus. Part 2: Adjuvant therapy. Oncology (Williston Park) 1999; 13:1415. 115. Kosugi S, Ichikawa H, Kanda T, et al. Clinicopathological characteristics and prognosis of patients with esophageal carcinoma invading adjacent structures found during esophagectomy. J Surg Oncol 2012; 105:767. 116. Bdard EL, Inculet RI, Malthaner RA, et al. The role of surgery and postoperative chemoradiation therapy in patients with lymph node positive esophageal carcinoma. Cancer 2001; 91:2423. 117. Adelstein DJ, Rice TW, Rybicki LA, et al. Mature results from a phase II trial of postoperative concurrent chemoradiotherapy for poor prognosis cancer of the esophagus and gastroesophageal junction. J Thorac Oncol 2009; 4:1264. 118. Tachibana M, Yoshimura H, Kinugasa S, et al. Postoperative chemotherapy vs chemoradiotherapy for thoracic esophageal cancer: a prospective randomized clinical trial. Eur J Surg Oncol 2003; 29:580. 119. Armanios M, Xu R, Forastiere AA, et al. Adjuvant chemotherapy for resected adenocarcinoma of the esophagus, gastro-esophageal junction, and cardia: phase II trial (E8296) of the Eastern Cooperative Oncology Group. J Clin Oncol 2004; 22:4495. 120. Ando N, Iizuka T, Ide H, et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study--JCOG9204. J Clin Oncol 2003; 21:4592. 121. Abate E, DeMeester SR, Zehetner J, et al. Recurrence after esophagectomy for adenocarcinoma: defining optimal follow-up intervals and testing. J Am Coll Surg 2010; 210:428. 122. National Comprehensive Cancer Network (NCCN) guidelines. Available at: www.nccn.org (Accessed on May 15, 2012). Topic 2478 Version 27.0
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GRAPHICS
Anatomy of the stomach
This figure depicts the anatomy of the stomach and the adjacent structures. The short gastric arteries are divided to increase the mobilization of the stomach for exposure of the gastroesophageal junction.
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AJCC regions of the esophagus
The American Joint Committee on Cancer (AJCC) divides the esophagus into four areas. The cervical esophagus extends from the lower border of the cricoid cartilage to the thoracic inlet. The upper thoracic esophagus extends from the thoracic inlet to the tracheal bifurcation. The mid-thoracic esophagus extends from the tracheal bifurcation to a level approximately 32 cm from the incisors. The lower thoracic and abdominal esophagus extends from the mid-thoracic esophagus to the EG junction,
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approximately 40 cm from the incisors.
Data from: Esophagus. In: AJCC Cancer Staging Manual, 6th edition, 2002.
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TNM staging of esophageal squamous cell cancer (SCC)

Primary tumor (T)*
TX T0 Tis T1
T1a T1b
Primary tumor cannot be assessed No evidence of primary tumor High-grade dysplasia Tumor invades lamina propria, muscularis mucosae, or submucosa
Tumor invades lamina propria or muscularis mucosae Tumor invades submucosa
T2 T3 T4
T4a T4b
Tumor invades muscularis propria Tumor invades adventitia Tumor invades adjacent structures
Resectable tumor invading pleura, pericardium, or diaphragm Unresectable tumor invading other adjacent structures, such as aorta, vertebral body, trachea, etc.
Regional lymph nodes (N)!

NX N0 N1 N2 N3 Regional lymph node(s) cannot be assessed No regional lymph node metastasis Metastasis in 1-2 regional lymph nodes Metastasis in 3-6 regional lymph nodes Metastasis in seven or more regional lymph nodes
Distant metastasis (M)

M0 M1 No distant metastasis Distant metastasis
Histologic grade (G)

GX G1 G2 G3 G4 Grade cannot be assessed - stage grouping as G1 Well differentiated Moderately differentiated Poorly differentiated Undifferentiated - stage grouping as G3 squamous
Anatomic stage/prognostic groups

Squamous cell carcinoma"
Stage T N M Grade Tumor location
Tis (HGD)
N0
M0
1, X
Any
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IA IB
T1 T1 T2-3
N0 N0 N0 N0 N0 N0 N1 N2 N1 N0 N2 N1-2 Any N3 Any
M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1
1, X 2-3 1, X 1, X 2-3 2-3 Any Any Any Any Any Any Any Any Any
Any Any Lower, X Upper, middle Lower, X Upper, middle Any Any Any Any Any Any Any Any Any
IIA
T2-3 T2-3
IIB
T2-3 T1-2
IIIA
T1-2 T3 T4a
IIIB IIIC
T3 T4a T4b Any
IV
Any
Note: cTNM is the clinical classification, pTNM is the pathologic classification.

* At least maximal dimension of the tumor must be recorded and multiple tumors require the T(m) suffix. High-grade dysplasia (HGD) includes all noninvasive neoplastic epithelia that was formerly called carcinoma in situ, a diagnosis that is no longer used for columnar mucosae anywhere in the gastrointestinal tract. ! Number must be recorded for total number of regional nodes sampled and total number of reported nodes with metastasis. " Or mixed histology including a squamous component or NOS. Location of the primary cancer site is defined by the position of the upper (proximal) edge of the tumor in the esophagus. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.
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TNM staging of esophageal and esophagogastric junction (EGJ) adenocarcinoma

Primary tumor (T)*
TX T0 Tis T1
T1a T1b
Primary tumor cannot be assessed No evidence of primary tumor High-grade dysplasia Tumor invades lamina propria, muscularis mucosae, or submucosa
Tumor invades lamina propria or muscularis mucosae Tumor invades submucosa
T2 T3 T4
T4a T4b
Tumor invades muscularis propria Tumor invades adventitia Tumor invades adjacent structures
Resectable tumor invading pleura, pericardium, or diaphragm Unresectable tumor invading other adjacent structures, such as aorta, vertebral body, trachea, etc.
Regional lymph nodes (N)!

NX N0 N1 N2 N3 Regional lymph node(s) cannot be assessed No regional lymph node metastasis Metastasis in 1-2 regional lymph nodes Metastasis in 3-6 regional lymph nodes Metastasis in seven or more regional lymph nodes
Distant metastasis (M)

M0 M1 No distant metastasis Distant metastasis
Histologic grade (G)

GX G1 G2 G3 G4 Grade cannot be assessed - stage grouping as G1 Well differentiated Moderately differentiated Poorly differentiated Undifferentiated - stage grouping as G3 squamous
Anatomic stage/prognostic groups

Adenocarcinoma carcinoma
Stage T N M Grade
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0 IA IB
Tis (HGD) T1 T1 T2
N0 N0 N0 N0 N0 N0 N1 N2 N1 N0 N2 N1-2 Any N3 Any
M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1
1, X 1-2, X 3 1-2, X 3 Any Any Any Any Any Any Any Any Any Any
IIA IIB
T2 T3 T1-2
IIIA
T1-2 T3 T4a
IIIB IIIC
T3 T4a T4b Any
IV
Any
Note: cTNM is the clinical classification, pTNM is the pathologic classification.

* At least maximal dimension of the tumor must be recorded and multiple tumors require the T(m) suffix. High-grade dysplasia (HGD) includes all noninvasive neoplastic epithelia that was formerly called carcinoma in situ, a diagnosis that is no longer used for columnar mucosae anywhere in the gastrointestinal tract. ! Number must be recorded for total number of regional nodes sampled and total number of reported nodes with metastasis. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.
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Charlson risk index

Condition
Myocardial infarct Heart failure Peripheral vascular disease Cerebrovascular disease Dementia Chronic pulmonary disease Connective tissue disease Ulcer disease Mild liver disease Diabetes Hemiplegia Moderate or severe renal disease Diabetes with end organ damage Any tumor Leukemia Lymphoma Moderate or severe liver disease Metastatic solid tumor AIDS 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 3 6 6
Assigned weights for diseases
Weighted comorbidity classes

Low Medium High Very high 0 points 1 to 2 points 3 to 4 points #5 points
Adapted from: Charlson ME, Pompei P, Ales KL, et al. J Chron Dis 1987; 40:373.
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Weekly carboplatin and paclitaxel chemotherapy with concurrent radiotherapy for esophageal and esophagogastric junction (EGJ) cancer[1]
Carboplatin and paclitaxel are each given weekly for five weeks with concurrent radiotherapy (RT) followed by surgery.
Drug
Paclitaxel
Dose and route

50 mg/m2 IV
Administration
Dilute in 250 mL normal saline (NS)* and administer over one hour; special tubing needed. Dilute in 250 mL NS" and administer over 30 minutes after paclitaxel.
Given on days
Days 1, 8, 15, 22, and 29
Carboplatin
AUC! = 2 mg/mL x min IV
Days 1, 8, 15, 22, and 29
Pretreatment considerations:
Emesis risk: MODERATE (30 to 90 percent frequency of emesis). We recommend prophylaxis with a combination of a 5-HT3 receptor antagonist plus dexamethasone on days 1, 8, 15, 22, and 29, and with a 5-HT3 antagonist on days when radiation alone is given. Refer to UpToDate topics on "Prevention and treatment of chemotherapy-induced nausea and vomiting" and "Radiotherapyinduced nausea and vomiting: Prophylaxis and treatment". Prophylaxis for infusion reactions: Premedicate with dexamethasone plus both an H1 and an H2 receptor antagonist prior to paclitaxel administration. Refer to UpToDate topic on "Infusion reactions to systemic chemotherapy". Vesicant/irritant properties: Carboplatin is an irritant. Paclitaxel can cause significant tissue damage; avoid extravasation. Refer to UpToDate topic on "Chemotherapy extravasation injury". Infection prophylaxis: Primary prophylaxis with G-CSF is not justified (incidence of neutropenic fever <1 percent[1]). Refer to UpToDate topic on "Use of granulocyte colony stimulating factors in patients with chemotherapy-induced neutropenia". Dose adjustment for baseline liver or renal dysfunction: A lower starting dose of paclitaxel may be needed for liver impairment[2]. Carboplatin dose is calculated based upon renal function by use of the Calvert formula![3]. Refer to UpToDate topics on "Chemotherapy hepatotoxicity and dose modification in patients with liver disease" and "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency".
Monitoring parameters:
CBC with differential and platelet count weekly during treatment. Assess electrolytes, renal, and liver function weekly during treatment. Assess changes in neurologic function weekly during treatment.
Suggested dose alterations for toxicity:

Myelotoxicity/neurologic toxicity: Weekly doses of paclitaxel and carboplatin should not be repeated unless the ANC is at least 1500 cells/mm3 and the platelet count is at least
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100,000/mm3. Reduce paclitaxel dose by 20 percent for ANC <500 cells/mm3 for a week or longer, or severe peripheral neuropathy[2]. Renal toxicity: Alterations in renal function during therapy require a recalculation of the carboplatin dose. Refer to UpToDate topic on "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency". If there is a change in body weight of at least 10 percent, dose should be recalculated.
IV: intravenous; G-CSF: granulocyte colony stimulating factor: CBC: complete blood count; ANC: absolute neutrophil count; GFR: glomerular filtration rate. $ * For paclitaxel administration, use glass or polypropylene bottles or polypropylene or polyolefin plastic bags, and administer through a polyethylene-lined administration sets with a microporous membrane 0.22 microns or less. $ ! AUC (area under the concentration X time curve) is converted to a patient-specific carboplatin dose (in mg) according to renal function by using the Calvert formula: total dose (mg) = (target AUC) x (GFR + 25). If using measured creatinine, limit the maximal GFR for the calculation to 125 mL/min. Refer to UpToDate topic on "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency. " Diluent solutions should not be modified without consulting a detailed reference due to potential incompatibility(ies). References: 1. Gaast AV, et al. Effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable esophageal or esophagogastric cancer: Results from a multinational randomized phase III study (abstract 4004). J Clin Oncol 2010; 28:302s. 2. Taxol (paclitaxel) injection. US FDA-approved manufacturer's package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on November 5, 2011). 3. Paraplatin (carboplatin) injection. US FDA-approved manufacturer's package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on November 5, 2011).
This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen must be administered by a clinician trained in the use of chemotherapy. The clinician is expected to use his or her independent medical judgment in the context of individual circumstances to make adjustments, as necessary.
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Ca Gastro "Radiation Therapy, Chemoradiotherapy, Neoadjuvant Approaches, and Postoperative Adjuvant Therapy For Localized Cancers of The Esophagus"

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Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus

Official reprint from UpToDate www.uptodate.com 2013 UpToDate

Section Editors Richard M Goldberg, MD Christopher G Willett, MD

Deputy Editor Diane MF Savarese, MD

AJCC regions of the esophagus

approximately 40 cm from the incisors.

TNM staging of esophageal squamous cell cancer (SCC)

Regional lymph nodes (N)!

Distant metastasis (M)

Histologic grade (G)

Anatomic stage/prognostic groups

N0 N0 N0 N0 N0 N0 N1 N2 N1 N0 N2 N1-2 Any N3 Any

T3 T4a T4b Any

Note: cTNM is the clinical classification, pTNM is the pathologic classification.

TNM staging of esophageal and esophagogastric junction (EGJ) adenocarcinoma

Regional lymph nodes (N)!

Distant metastasis (M)

Histologic grade (G)

Anatomic stage/prognostic groups

N0 N0 N0 N0 N0 N0 N1 N2 N1 N0 N2 N1-2 Any N3 Any

T3 T4a T4b Any

Note: cTNM is the clinical classification, pTNM is the pathologic classification.

Charlson risk index

Assigned weights for diseases

Weighted comorbidity classes

Dose and route

AUC! = 2 mg/mL x min IV

Days 1, 8, 15, 22, and 29

Suggested dose alterations for toxicity:

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