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Radiation therapy, chemoradiotherapy, and neoadjuvant approaches for localized esophageal cancer

Arlene A Forastiere, MD
Noah C Choi, MD
Michael Gibson, MD

UpToDate performs a continuous review of over 330 journals and other resources. Updates are added as important new information is published. The literature review for version 13.3 is current through August 2005; this topic was last changed on September 9, 2005. The next version of UpToDate (14.1) will be released in February 2006.

INTRODUCTION — Cancer of the esophagus is a highly lethal malignancy. There are approximately 14,520 people diagnosed with esophageal cancer each year in the United States, and 13,570 deaths from the disease [1]. Survival correlates with stage of disease. Five-year survival rates range from 40 to 62 percent for patients treated for localized cancer (stage I and IIA, show table 1), and from 18 to 25 percent for those with involvement of regional nodes (stage IIB and III) [2,3]. According to data from the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) Program, the five-year survival rate for all patients with esophageal cancer improved modestly over the last 30 years, from 5 percent in the years 1974 to 1976, to 13 percent during the period 1992 to 1998 [1]. These dismal figures are indicative of the advanced stage of disease (local-regional or metastatic, stages IIB, III and IV) at diagnosis in most individuals [4].

For patients who undergo a potentially curative resection, histologic tumor type influences the pattern of first recurrence. Those with upper or mid-thoracic squamous cancers tend to demonstrate local-regional recurrence first, while distal esophageal adenocarcinomas more commonly recur with distant dissemination. These recurrence patterns account for the low cure rate that follows locoregional therapy alone, and have prompted the inclusion of systemic chemotherapy in multimodality treatment regimens, to both control distant micrometastatic disease, and enhance local radiation effects [5-10].

The management of local-regional esophageal cancer has undergone a major evolution over the past 15 years. Despite the demonstration of a survival benefit for the addition of cisplatin-based chemotherapy to radiation therapy in non-surgically treated patients [11,12], the optimal therapy for potentially resectable esophageal cancer remains unclear. Only a minority of such patients are cured by multimodality therapy, and distant failure accounts for three-fourths of all recurrences [13].

This topic review will focus on the efficacy of radiation and chemotherapy in the multimodality management of patients with locally advanced cancer involving the thoracic esophagus and gastroesophageal junction (GEJ). The management of cervical esophageal tumors is also considered briefly. Surgical treatment for localized disease, treatment of patients with metastatic disease, and the management of locally advanced unresectable disease are discussed elsewhere. (See "Surgical management of localized esophageal cancer" and see "Chemotherapy for advanced esophageal cancer" and see "Management of locally advanced unresectable esophageal cancer").

SURGERY ALONE — Surgery has been the standard treatment for early stage esophageal cancer, but its utility as monotherapy has been challenged [5,6,14,15]. Only 30 to 40 percent of patients have potentially resectable disease at presentation. Data from contemporary surgical series report five-year survival rates of 15 to 20 percent for patients treated with surgery alone [13,16-18]. 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 management of localized esophageal cancer", section on Techniques and outcome).

RADIATION THERAPY ALONE — Radiation alone can result in long-term survival in a minority of patients. Before the era of modern chemotherapy and combined chemoradiotherapy, radiation alone (60 to 66 Gy in 30 to 33 fractions 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 [9,10,19]. In one review of 49 early series involving more than 8400 patients treated with radiation alone, survival rates at one, two, and five years were 18, 8, and 6 percent, respectively [20].

Better results are reported in later studies from single institutions in well-defined patient populations using specific radiation protocols. As examples:

Three and five-year survival rates of 27 and 21 percent, respectively, were observed in a series that included 101 selected patients with clinically localized esophageal cancer treated with radiation alone (45 to 52.5 Gy in 15 or 16 fractions over three weeks) [19].

In a cohort of 17 patients with clinical stage I esophageal squamous cell cancer (after endoscopic ultrasound and CT) treated with radiation alone (median 60.6 Gy), the five-year overall survival rate was 59 percent [21].

Modern radiation techniques (eg, three-dimensional conformal radiation therapy) are associated with more favorable toxicity profiles than those associated with the lower energy units used in earlier years (see below). More recently, the role of radiation alone has been supplanted by combined chemoradiotherapy in the majority of patients, albeit with a higher rate of treatment-related toxicity.

COMBINED CHEMORADIATION — Combined chemotherapy and radiation has been administered to patients as definitive nonoperative treatment, and in the preoperative (neoadjuvant) setting.

Concurrent chemoradiotherapy as definitive therapy — Concurrent radiation and systemic chemotherapy (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 [22-24].

The addition of cisplatin-based chemotherapy to radiation has been shown to provide a significant survival benefit compared to treatment with radiotherapy alone [11,25]. However, the available randomized trial data are almost exclusively in squamous cell esophageal cancer, 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 studies.

RTOG protocol 85-01 — A landmark study from the Radiation Therapy Oncology Group (RTOG) compared radiation therapy alone (64 Gy in 32 fractions over 6.5 weeks) and concurrent chemoradiotherapy (four cycles of 5-FU [1000 mg/m2 by continuous infusion for the first 4 days of weeks 1, 5, 8, and 11] plus cisplatin [75 mg/m2 day 1, every four weeks] and radiation therapy [50 Gy in 25 fractions over five weeks]) in patients with locoregional thoracic esophageal cancer (ie, no evidence of spread beyond mediastinal and supraclavicular lymph nodes) [11]. Ninety percent of the trial participants had squamous cell carcinoma. The trial was closed prematurely, after 121 patients had been enrolled, when an interim analysis showed a significant survival advantage in the chemoradiotherapy arm. In the most recent update of this study, combined treatment was associated with a significantly better median survival (14 versus 9.3 months) and five year survival (27 versus 0 percent) [12]. Analysis of patterns of failure showed a significant reduction in both local-regional and distant failure for the chemoradiotherapy arm. Despite this apparent benefit, 46 percent of patients in the experimental treatment group had recurrence or persistence of disease in the esophagus at 12 months.

As a result of this trial, combined 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 American Intergroup Study 0123 (INT 0123), all 236 enrolled patients received concurrent chemotherapy with cisplatin and 5-FU (as in RTOG 85-01), but they were randomly assigned to one of two different radiation doses: 50.4 Gy (28 fractions of 1.8 Gy each, 5 fractions per week) or 64.8 Gy (36 fractions of 1.8 Gy each, 5 fractions per week) [26]. Patients without evidence of distant metastatic squamous cell carcinoma or adenocarcinoma of the thoracic esophagus were eligible for the study. The use of higher radiation doses was not associated with a higher median survival (13 versus 18 months), two year survival rate (31 versus 40 percent), or incidence of local-regional persistent or recurrent disease (56 versus 52 percent for the high dose and control groups, respectively. In addition, the high radiation dose arm was also associated with significantly more toxicity.

The reason for the failure to demonstrate improved survival or local-regional control with higher radiation doses is unclear. At present, 50 Gy of radiation therapy plus four courses of concurrent cisplatin and 5-FU (as in RTOG 85-10) remains the standard of care.

Newer regimens — More recent studies are investigating the role of newer chemotherapy drugs combined with radiation. As an example, in a French phase I study, 33 patients with inoperable, locally advanced squamous cell carcinoma and adenocarcinoma were treated with escalating doses of oxaliplatin combined with infusional 5-FU and folinic acid (FOLFOX) plus radiation therapy (50 Gy) followed by three additional cycles of FOLFOX [27]. Oxaliplatin doses of 85 mg/m2 were well tolerated and this regimen resulted in a median time to progression of 5 months (95% CI 3-6 months) and an overall survival of 9 months (95% CI 5-13 months).

Preoperative chemoradiotherapy — The poor long-term survival associated with surgery alone, and the radiosensitizing effect of concurrent administration of chemotherapy and radiation provided the impetus to evaluate chemoradiotherapy prior to resection, both to improve local-regional control and affect distant micrometastatic disease. At least six trials have directly compared preoperative (neoadjuvant) chemoradiotherapy followed by surgery and surgery alone for patients with potentially resectable esophageal carcinoma, five of which have been published [16,28-32]; only one demonstrated a significant survival benefit from combined modality therapy [32]. Two general approaches have been used: concurrent and sequential chemoradiotherapy.

Concurrent chemoradiotherapy — Two completed randomized trials have compared preoperative concurrent chemoradiotherapy with surgery alone. In a trial conducted in Ireland, 113 patients with esophageal adenocarcinoma were randomly assigned to surgery alone or surgery preceded by chemoradiotherapy [32]. Preoperative treatment consisted of two courses of 5-FU (15 mg/kg by bolus days 1 to 5), and cisplatin (75 mg/m2, on day 7 of each cycle), both administered during weeks one and six of concurrent radiotherapy (40 Gy in 15 fractions over three weeks). A complete pathologic response (pCR) was noted in 25 percent of patients treated with preoperative chemoradiotherapy, and when the surgical specimens were compared, regional nodal involvement was less frequent in this group (42 versus 82 percent). Combined modality therapy was associated with significantly longer median survival (16 versus 11 months) and three year survival (32 versus 6 percent). However, the results of surgery alone in this trial were inferior to other contemporary series [13,16].

In a second study from Michigan, 100 patients with locoregional esophageal cancer (25 squamous cell, 75 adenocarcinoma) were randomly assigned to transhiatal esophagectomy with or without preoperative chemoradiotherapy [28]. Neoadjuvant treatment consisted of cisplatin (20 mg/m2 per day, by continuous infusion days 1 to 5, and 17 to 21), 5-FU (300 mg/m2 per day by continuous infusion on days 1 to 4 and 17 to 20), and vinblastine (1 mg/m2 per day, by IV bolus, on days 1 to 4, and 17 to 20) plus concurrent radiotherapy (45 Gy in 1.5 Gy fractions, given twice daily for three weeks). Radiation was administered using a three-dimensional (3D) conformal treatment planning technique. Surgery was performed on day 42, after a three week rest from completion of the chemoradiotherapy.

A pCR was observed in 28 percent of patients receiving neoadjuvant treatment. Despite this, at a median follow-up of 8.2 years, the median survival was similar with both treatments (16.9 versus 17.6 months for multimodality therapy and surgery respectively), and there was nearly a two-fold higher, but nonstatistically significant, improvement in three year survival for the combined treatment group (30 versus 16 percent). Patients achieving a pCR had a significantly improved three-year survival compared to those with residual tumor in the resected specimen (64 versus 19 percent, respectively). Although the combined therapy group had a significantly lower locoregional recurrence rate (19 versus 42 percent) preoperative chemoradiotherapy had no effect on the distant metastatic rate (65 versus 60 percent). The study was statistically powered to detect a doubling of median survival from 12 to 26 months. Thus, although this was a negative study, it was insufficiently powered to detect a lesser survival difference.

Sequential chemoradiotherapy — Two other completed trials compared sequentially administered chemotherapy and radiation followed by surgery to surgery alone [29,30].

A Scandinavian trial randomly assigned 187 patients with potentially resectable squamous cell esophageal cancer to one of four arms: surgery alone, preoperative chemotherapy (cisplatin and bleomycin), preoperative radiotherapy, or preoperative chemotherapy followed by radiotherapy and then surgery [29]. Three year survival was significantly higher in the two pooled groups receiving radiotherapy compared to those treated without radiation. However, when compared to the surgery alone arm, there was no difference in survival with sequential chemoradiotherapy followed by surgery.

Similar outcomes were noted in a trial from French investigators, in which 86 patients with localized esophageal squamous cell carcinoma were randomly assigned to sequential cisplatin plus 5-FU followed by radiation therapy and surgery, or surgery alone [30]. Although the median survival was no different between the groups, the dose of radiation was only 20 Gy, less than one-half of current standard doses.

A third study, sponsored by the EORTC, included 282 patients with stage I or II esophageal squamous cell carcinoma who were randomly assigned to surgery alone or surgery preceded by chemoradiotherapy [16]. Preoperative treatment consisted of cisplatin (80 mg/m2) administered 0 to 2 days prior to each course of split course radiation (18.5 Gy in 5 fractions of 3.7 Gy each, 5 fractions per week, administered during weeks one and four). Surgery was performed two to four weeks after the completion of the preoperative therapy.

After a median follow-up of 55 months, preoperative treatment was associated with a higher frequency of curative resection, a significantly longer disease-free survival, time to local failure, and a lower rate of cancer-related deaths. However, the median survival (18.6 months in both groups) and the three-year survival rates were identical. Combined modality therapy was also associated with significantly higher postoperative mortality (12.3 versus 4 percent). Limitations of this study included the inadequate radiation dose-fractionation schedule, and the use of single agent cisplatin rather than multiagent chemotherapy.

Meta-analysis — A meta-analysis of randomized controlled trials comparing neoadjuvant chemoradiation followed by surgery with surgery alone included 1,116 patients enrolled on 9 trials [33]. When compared to surgery alone, the odds ratios showed a nonsignificant trend towards improved survival with neoadjuvant chemoradiotherapy (0.79, 0.77, and 0.66 for one, two, and three-year survival, respectively); however, the improvement in three-year survival reached the level of statistical significance only when the analysis was restricted to those trials using concurrent chemotherapy and radiation (OR 0.45, 95 % CI, 0.26 to 0.79). Although patients treated with surgery alone were significantly more likely to undergo resection, those receiving preoperative chemoradiotherapy were more likely to undergo complete (R0) resection (OR 0.53, 95 % CI 0.33 to 0.84).

A second meta-analysis identified six randomized controlled trials totaling 764 patients, all of which were included in the above analysis, that compared preoperative chemoradiotherapy plus surgery versus surgery alone [34]. Most patients had squamous cell carcinoma, and in at least four of the six trials, radiation and chemotherapy were given concurrently. When compared to surgery alone, preoperative chemoradiotherapy again significantly improved three-year survival (OR 0.53, 95 % CI 0.31-0.93).

In the absence of a definitive trial but with two small trials [28,32] demonstrating better survival with neoadjuvant concurrent chemoradiation, investigators have more recently focused on ways to intensify treatment. This has consisted of adding several cycles of induction chemotherapy prior to preoperative chemoradiation [35-38], increasing the number of cytotoxic agents administered concurrent with radiation therapy [35,36,39], and adding adjuvant chemotherapy [40].

Sequential plus concurrent chemoradiotherapy — Three groups of investigators have published their institutional experience, although no randomized trials compare these approaches to the standard regimen (four courses of cisplatin and 5-FU plus concurrent radiation (50 Gy) [35-38].

Induction chemotherapy followed by concomitant chemoradiotherapy has been explored at the MD Anderson Cancer Center (MDACC). In one trial, 38 patients with resectable cancer of the esophagus or GEJ received induction chemotherapy, consisting of one or two courses of 5-FU (750 mg/m2 daily by continuous infusion days 1 to 5) plus cisplatin (15 mg/m2 daily bolus, days 1 to 5) and paclitaxel (200 mg/m2 over 24 hours on day 1), repeated on day 28 [37,38]. This was followed by radiotherapy (45 Gy in 25 fractions) and concurrent 5-FU (300 mg/m2 daily by continuous infusion days 1 to 5 every week) plus cisplatin (20 mg/m2 on days 1 to 5 of radiation), and then surgery. In the most recent update of this study, potentially curative resection was possible in 35, and a complete pathologic response rate (pCR) was noted in 8 (23 percent) [37]. With a median follow-up of 58 months, three and five year survival estimates were 63 and 39 percent, respectively.

In two other trials, one from MDACC and the other from Memorial Sloan Kettering Cancer Center (MSKCC), induction chemotherapy with cisplatin plus irinotecan has been followed by either 5-FU with paclitaxel and concurrent radiation (MDACC), or cisplatin with irinotecan and radiation (MSKCC) [35,36]. In an early report of the dose escalation portion of MSKCC study, a pCR rate of 27 percent was found in the 15 patients who underwent surgery [36]. The final analysis of the MDACC study reported a pCR rate of 26 percent, and a median survival of 22.1 months in patients followed for a minimum of 28 months.

Intensification of preoperative chemoradiotherapy — Intensification of preoperative systemic treatment has been explored in several studies.

A Minnie Pearl Cancer Research Network trial treated 129 patients with localized esophageal squamous cell carcinoma or adenocarcinoma with concurrent radiation (45 Gy in daily 1.8 Gy fractions) plus paclitaxel (200 mg/m2 over one hour day 1 and 22), carboplatin (area under the concentration X time curve [AUC] 6.0, on days 1 and 22), and 5-FU (225 mg/m2 per day by continuous infusion, days 1 to 42) [39], followed by resection. Grade 3 or 4 treatment-related leukopenia and esophagitis developed in 73 and 43 percent respectively, and 57 percent required hospitalization. The pCR rate was 36 percent (47/129) overall, with microscopic residual disease only in 23 percent (30/129). At a median follow-up of 45 months, the three-year estimated survival rate was 41 percent. These results indicate added toxicity without substantial incremental survival improvement.

In another series from MSKCC, weekly infusional paclitaxel was dose- escalated in combination with weekly fixed-dose cisplatin (30 mg/m2) and concomitant radiotherapy (to 50.4 Gy), and followed by resection [41]. Of the 34 patients enrolled, four were treated at the maximally tolerated dose (MTD) of paclitaxel (60 mg/m2 per week). Of the 17 who received higher doses (80 mg/m2 per week), eight had grade 3 or 4 hematologic toxicity. Four of the 22 patients who underwent surgery achieved a pCR. With a median follow-up of 47 months, three-year survival was 43 percent.

Paclitaxel (50 mg/m2 on days 1,8,15,22,29), carboplatin (AUC 5 on days 1 and 29) and 5-FU (225 mg/m2 daily, five days per week during RT) was administered concurrent with radiation therapy (45Gy), and followed by surgery in 36 patients with esophageal or gastric cancer [42]. In a preliminary report, the pCR rate was 30 percent among the 33 who underwent surgery. This intensified three-drug regiment was well-tolerated; however, survival data were not reported.

A similar three-drug regimen of neoadjuvant chemoradiotherapy was combined with two cycles of adjuvant chemotherapy in a trial from the University of Michigan of 65 patients with esophageal squamous cell cancer or adenocarcinoma [43]. Preoperative treatment consisted of 5-FU (200 mg/m2/day CI), cisplatin (30 mg/m2 on days 3,10,17,24) and paclitaxel (45 mg/m2 on days 3,10,17,24) administered concurrent with radiation therapy (45 Gy); following surgery, each of two adjuvant chemotherapy cycles consisted of 5-FU (750 mg/m2 on days 1 to 5), cisplatin (50 mg/m2 on days 1 and 2) and paclitaxel (135 mg/m2 on day 1). Sixty patients were able to undergo surgery but only 40 percent tolerated both cycles of adjuvant chemotherapy at the planned dose. The pCR rate was only 17 percent, and at an average follow-up of 2.2 years, estimated three-year and median survival was 50 percent, and 2.8 years, respectively.

Necessity for surgery — A survival benefit for the addition of esophagectomy was suggested in a national survey involving 400 patients with thoracic adenocarcinoma or squamous cell carcinoma who were treated between 1992 and 1994 [44]. Preoperative chemoradiotherapy was associated with a higher two-year survival rate compared to definitive chemoradiotherapy without surgery (63 versus 39 percent), although the difference was not statistically significant. Trimodality therapy was also associated with a significant reduction in locoregional failure at two years (22 versus 30 percent).

A later Patterns of Care Study reviewed findings in 414 patients who were treated between 1996 and 1999 [45]. Compared to the earlier findings from 1992 to 1994, this study found that more patients underwent staging with endoscopic ultrasound (18 versus <2 percent), a significantly higher percentage received preoperative chemoradiotherapy (27 versus 10 percent), and a greater number received paclitaxel as a component of the induction regimen (22 versus <1 percent). In a later analysis, patients treated with chemoradiotherapy followed by surgery had a significantly lower risk of death as compared to those undergoing chemoradiotherapy alone (HR 0.32, p<0.0001) [46].

On the other hand, the benefit of surgery following chemoradiotherapy has been questioned [14,15]. Contemporary series suggest that chemoradiotherapy as a nonsurgical approach may provide long-term survival in up to 27 percent of patients with squamous cell carcinoma [11,26,47], a result that is not dissimilar to that achieved with preoperative chemoradiotherapy and surgery [14,28,32], preoperative chemotherapy and surgery (see below) [13,48], and surgery alone [13,16]. However, there is a high rate of locally persistent/recurrent disease after chemoradiotherapy alone, and a lack of data for nonsurgical management of patients with adenocarcinoma. Thus, inclusion of surgery remains the preferred treatment approach for clinically resectable esophageal cancer.

At least two randomized trials directly comparing chemoradiotherapy alone to chemoradiotherapy followed by surgery have failed to demonstrate better survival in the surgically treated patients [49,50]. Nevertheless, local-regional control is better in patients who undergo surgery as a component of multimodality management:

In one trial, 172 patients with esophageal squamous cell cancer 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 irradiation) 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 [49]. 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 the three-year overall survival (31 versus 24 percent) and median survival durations (16 versus 15 months, respectively) were not different.

Of note, in comparison to other trials using concomitant chemoradiotherapy [11] or CRT followed by surgery [28], 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 above) [11].

In the second study, 455 patients with T3-4, N0-1, M0 esophageal squamous cell or adenocarcinoma received induction chemoradiotherapy with either protracted (46 Gy in 4.5 weeks) or split course (2 X 15 Gy, days 1-5 and 22-26) radiation plus two courses of 5-FU and cisplatin chemotherapy [50]. Patients with at least a partial response and who lacked a 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] radiation) or to undergo surgery. In a preliminary report, continued chemoradiotherapy was associated with similar two year survival (40 versus 340 percent) and median survival (19.3 versus 17.7 months), although surgically treated patients were significantly less likely to require esophageal stents (13 versus 27 percent, p = 0.005), or repeated dilation (22 versus 32 percent, p = 0.07).

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 [13,29,48,51-54]. Only two of these studies, one of which has been reported in preliminary form only, demonstrate a survival benefit [48,51].

Intergroup 0113 — In the United States Intergroup trial 0113, 467 patients with potentially resectable esophageal cancer were randomly assigned to surgery alone, or three cycles of preoperative chemotherapy consisting of cisplatin (100 mg/m2, on days 1, 29 and 58), and 5- fluorouracil (5-FU, 1000 mg/m2 by continuous infusion, days 1 to 5 of each cycle), followed by surgery [13]. Patients with chemotherapy-responsive disease (stable or objective response with preoperative chemotherapy) who underwent potentially curative resection received an additional two courses of postoperative chemotherapy with a reduced dose of cisplatin (75 mg/m2) plus 5-FU.

The majority of patients had adenocarcinoma (55 percent) and outcomes were similar for both histologies. The clinical response rate to preoperative chemotherapy (as assessed by barium-contrast study) was 19 percent. A complete pathologic response (pCR) was noted at resection in only five (2.5 percent) of 202 patients who received at least one cycle of chemotherapy. There were no differences between the groups in rate of complete resection (65 versus 66 percent), treatment-related mortality (6.4 versus 4.0 percent), median survival (14.9 versus 16.1 months), or survival at one, two, or three years (59, 35, and 23 versus 60, 37, and 26 percent), respectively. Pretreatment weight loss of >10 percent was a significant predictor of poor outcome.

MD Anderson trial — Similar results were noted in an earlier single institution American trial, in which 39 patients with potentially resectable mid to lower esophageal cancer were randomly assigned to surgery with or without preoperative plus postoperative chemotherapy (cisplatin, vindesine, bleomycin) [52]. There were no differences in resectability rates, postoperative complication rates, or survival between the two groups. As in Intergroup 0113, pretreatment weight loss >10 percent was associated with poor outcome.

Italian trial — Comparable results were noted in a trial from Italy, in which 96 patients with potentially resectable squamous cell esophageal cancer were randomly assigned to surgery alone or surgery preceded by chemotherapy (two or three courses of cisplatin 100 mg/m2 on day 1 and 5-FU 1000 mg/m2 by continuous infusion days 1 to 4, every three weeks) [53]. Neoadjuvant chemotherapy was not associated with significant differences in three-year (44 versus 41 percent) or five-year overall survival (34 versus 22 percent) when all patients were considered. A subset of 19 patients who responded to preoperative chemotherapy and were completely resected had significantly better three- and five-year survival rates (74 and 60 percent, respectively) than patients in the surgery alone arm who underwent complete resection (46 and 26 percent, respectively).

Rotterdam and United Kingdom trials — In contrast to the above studies, at least two reports suggest a survival benefit for preoperative chemotherapy compared to surgery alone:

In a multicenter trial from the Medical Research Council in the United Kingdom, 802 patients with operable esophageal cancer (two-thirds adenocarcinoma) were randomly assigned to resection alone, or resection preceded by two courses of cisplatin (80 mg/m2 on day 1) and 5-FU (1000 mg/m2 by continuous infusion days 1 to 4) given three weeks apart [48]. Preoperative radiation, administered at the discretion of the treating clinician, was received by 9 percent of the patients in each group. The percentage of patients undergoing surgery was similar for the two groups, 92 versus 97 percent, as was the curative resection rate (ie, R0 resection), 60 versus 54 percent.

Preoperative chemotherapy was associated with significantly greater overall survival (hazard ratio 0.79, 95 percent confidence interval, 0.67 to 0.93), two year survival (43 versus 34 percent) and median survival (16.8 versus 13.3 months). The frequency of postoperative deaths and nonfatal complications were similar in the two groups. On examination of the resected specimen, tumors in the chemotherapy group were significantly smaller, extended less frequently into surrounding tissue, and showed less lymph node involvement. The frequency of local recurrence as a component of failure was similar in patients undergoing chemotherapy compared to surgery alone (12 versus 11 percent).

Similar benefit was suggested a multicenter study, sponsored by the Rotterdam Oesophageal Study Group, in which 160 patients with operable esophageal squamous cell carcinoma were randomly assigned to surgery alone, or surgery preceded by two or four cycles of cisplatin (80 mg/m2 on day 1) and etoposide (100 mg IV on days 1 and 2 and 200 mg/m2 orally on days 3 and 5) [51]. Patients with a major tumor response received four cycles of chemotherapy before surgery, while nonresponders underwent surgery after two courses. In a preliminary report, the clinical response rate in those receiving preoperative chemotherapy was 36 percent (25 of 69). Multimodality therapy was associated with a significantly longer median survival (18.5 versus 11 months). However, average follow-up was only 15 months, and the study has never been published in final form.

United Kingdom MAGIC trial — Investigators with the Medical Research Council (MRC) conducted a second study of preoperative chemotherapy, which, in contrast to the previous MRC study, included patients with resectable gastric (74 percent), gastroesophageal junction (GEJ,15 percent) and distal esophageal (11 percent) adenocarcinomas [54]. Patients were randomly assigned to surgery with or without perioperative chemotherapy (consisting of three preoperative plus three postoperative cycles of ECF [epirubicin 50 mg/m2 day 1, cisplatin 60 mg/m2 day 1 and infusional 5-FU 200 mg/m2/day days 1-21]). (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on Chemotherapy).

In a preliminary report with a median follow-up of three years, both progression-free survival (hazard ratio [HR] 0.66, 95% CI 0.53-0.81) and overall survival (HR 0.75, 95% CI 0.6-0.93) were significantly better in the chemotherapy group [55], This 25 percent reduction in the risk of death translated into a four month improvement in median survival. Effective downstaging was suggested by the fact that more chemotherapy-treated patients had T1/2 tumors (52 versus 38 percent) and N0/N1 disease (84 versus 76 percent). While 219 patients underwent surgery, only 104 (42 percent) completed all three cycles of postoperative chemotherapy. Generalizing these data to esophageal cancer is limited given that only 26 percent of the patients enrolled on this trial had distal esophageal or GEJ adenocarcinomas.

Cochrane database review — In a review of seven randomized trials that included 1653 patients (any histology, excluding cervical esophageal cancers) who were randomly assigned to either surgery alone or chemotherapy followed by surgery, the odds ratio for survival at 1, 2, 3, 4, and 5 years slightly favored chemotherapy followed by surgery [56]. However, the reviewers concluded that the results were not robust, and as such, they did not come out in favor of preoperative chemotherapy.

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 patients treated with surgery alone or chemotherapy followed by surgery compared to those receiving chemoradiotherapy followed by surgery [13,28,33]. As an example, in the Michigan study, 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) [28]. Similar conclusions were drawn in the previously described meta-analysis of trials comparing preoperative chemoradiotherapy to surgery alone [33]; 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).

CONCLUSIONS AND RECOMMENDATIONS — The optimal management of localized esophageal cancer is controversial. The following conclusions are derived from phase III studies comparing definitive chemoradiotherapy to radiotherapy alone, and preoperative chemoradiotherapy or preoperative chemotherapy to surgery alone for patients with esophageal cancer that is localized to the primary and regional nodes:

Radiation therapy alone is suboptimal. In addition, there is a high rate of locally persistent/recurrent disease after chemoradiotherapy alone, and a lack of data for nonsurgical management of patients with adenocarcinoma. Thus, inclusion of surgery remains the preferred treatment approach for clinically resectable esophageal cancer.

Contemporary series suggest that preoperative concurrent chemoradiotherapy appears to provide a survival benefit compared to surgery alone, and is a reasonable alternative to surgery alone. This conclusion is supported by two randomized studies [28,32], and a meta-analysis [33], even though the survival benefit in one of the randomized trials did not reach statistical significance, probably because it was underpowered [28]. Further, local control appears to be better with preoperative chemoradiotherapy compared to surgery alone [28,33].

Therefore, combined modality therapy with preoperative chemoradiotherapy followed by surgery appears to be acceptable management for patients with stages IIB, III, and possibly stage IVa disease (show table 1). The benefit of induction therapy for patients with early stage, localized disease (ie, stages I and IIA) is less clear so surgery alone is a reasonable option. The most recent National Patterns of Care survey noted a significant greater use of concurrent chemoradiation before planned surgery during 1996 and 1999 compared with 1992 to 1994 (27 versus 10 percent) [45].

Although the optimal type, dose, combination, and schedule of drugs is unclear, multiagent chemotherapy appears to be better than single agent cisplatin. We recommend preoperative concurrent treatment with two courses of cisplatin and 5-FU plus radiation therapy (50 Gy), as per the RTOG 85-01 trial [11]. While taxane and irinotecan-containing regimens are under investigation, the results published thus far do not consistently indicate a superior toxicity profile, or higher response rates compared to standard 5-FU and cisplatin.

Preoperative chemotherapy without radiation also provides a gain in median and two year survival compared to surgery alone. This is the standard of care in the United Kingdom based upon the MRC trials [48,54]. However, the data are insufficient to conclude that preoperative chemotherapy is preferable to preoperative chemoradiotherapy. Further, the frequency of local failure may be lower in patients treated with chemoradiotherapy followed by surgery compared to those receiving chemotherapy followed by surgery [28,57]. Better control of locoregional disease by the addition of preoperative radiotherapy to chemotherapy may provide some gain in overall survival based upon the view that uncontrolled locoregional cancer is a theoretical source of ongoing distant seeding.

Control of distant disease remains a problem with both preoperative chemotherapy and preoperative chemoradiotherapy. Both the Michigan (neoadjuvant chemoradiotherapy) and the Sloan Kettering series (neoadjuvant chemotherapy) found no difference in the rate of distant failure between the study and control arms, underscoring the need for better systemic therapies [13,28].

A response to preoperative therapy may be an indicator of better survival. As an example, in the Michigan study, patients with a complete pathologic response had significantly longer median, one year, and three year survival rates (49.7 months, 86 and 64 percent respectively), compared to those with residual disease in the resected specimen (12 months, 52 and 19 percent respectively) [28]. Similar conclusions have been reached by others [53,57-60].

The optimal dose-fractionation schedule of radiation 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). The standard dose of radiation for patients treated with concurrent 5-FU and cisplatin is 50.4 Gy.

TECHNIQUE FOR PREOPERATIVE RADIATION THERAPY — The degree of response of a tumor and normal tissues/organs to radiation depends upon several radiotherapeutic factors [9,61,62]:

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 52 Gy)

Duration of treatment (5 to 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, and suboptimal radiation plans with a potential for increased risk of injury to the lung, heart and spinal cord should be avoided. Three-dimensional (3-D) conformal techniques provide for optimal treatment planning.

Target volume — The target volume consists of gross tumor volume (GTV) with a surrounding margin of clinically uninvolved tissue (the clinical target volume, or CTV). The CTV should include margins of at least 5 cm beyond the radiographic tumor extent in the cephalad-caudad direction, and 2.5 to 3.0 cm beyond the lateral tumor borders (defined by barium esophagogram or CT scan). For lesions of the lower third of the esophagus and gastroesophageal junction (GEJ), the CTV is extended into the lower border of the first lumbar vertebra to include the celiac, gastric, and gastrohepatic Iymph nodes. CT of the upper abdomen is necessary to localize these lymph nodes. For lesions involving the upper two-thirds of the thoracic or the cervical esophagus, both supraclavicular regions are included in the CTV.

Optimal dose and fractionation schedules — Tumor size and radiation dose are important considerations for local control. Curative intent therapy with radiation alone requires a total dose of 60 to 66.6 Gy in 30 to 37 daily fractions of 1.8 to 2.0 Gy, administered five days 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 [61,62].

The optimal radiation dose for preoperative chemoradiotherapy regimens is not defined, although a total dose of 45 to 50.4 Gy administered in daily 1.8 Gy fractions, 5 days per week, produces reasonable results with acceptable toxicity [11,47,63]. 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 and survival [28,64].

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 malignant dysphagia.

Radiation portal arrangements — The arrangement of the radiation portals depends upon the planned total dose and region of involvement. For a two-dimensional (2-D) treatment plan, an arrangement of two parallel-opposed fields, applied anteriorly (AP) and posteriorly (PA) to the mediastinum, is simple and accurate with the least risk of a geographical miss. However, this approach needs to be combined with oblique and/or lateral portals to spare the spinal cord and heart [8,9]. For cervical and upper thoracic esophageal cancer, the technique used by the author (NC) uses a sequential combination of AP-PA fields for the initial dose (36 Gy in 20 fractions over four weeks) and a three-field (AP plus oblique) arrangement for the subsequent dose (27 Gy in 15 fractions over three weeks). Radiation dose to CTV is limited to 45 Gy.

For patients with esophageal carcinoma involving the lower third of the thoracic esophagus and the GEJ, the radiation dose to the heart should be kept below the tolerance limit (ie, 40 Gy to the ventricles, especially when administered with concurrent chemotherapy). The arrangement of radiation portals used by the author includes AP-PA portals for the initial dose (30.6 Gy in 17 fractions over 3.4 weeks), and three fields (AP plus oblique) for a subsequent dose (25.2 Gy in 14 fractions over 2.8 weeks), and right lateral and left lateral parallel opposed fields for an additional dose (7.2 Gy in 4 fractions in one week), for a total dose of 63 Gy in 35 fractions over 7 weeks. The radiation dose to CTV is again limited to 45 Gy.

With the advent of 3-D conformal radiation therapy (3-D CRT) techniques, multiple portals are applied using beam's eye view for each fractional dose aiming for the maximum differential in radiation dose distribution between the target volume and normal organs. 3-D CRT plan provides a dose-volume-histogram for tumor volume as well as for normal organs at risk for complications. Thus, it is feasible to formulate radiation dose schedule for desired level of tumor control probability which 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. As a unique feature, it 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 is expected (though not yet proven) that treatment with IMRT will result in fewer side effects [65-67].

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. Radiation combined with chemotherapy is often preferred over surgery for these patients since survival appears to be the same, and major morbidity is avoided in most.

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