Originally published as JCO Early Release 10.1200/JCO.2008.17.0506 on January 12 2009

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Phase III Comparison of Preoperative Chemotherapy Compared With Chemoradiotherapy in Patients With Locally Advanced Adenocarcinoma of the Esophagogastric Junction

From the Departments of Medical Oncology and Hematology, and Surgery, Kliniken Essen-Mitte; Department of Radiation Oncology, and the Institute for Medical Informatics, Biometry, and Epidemiology, University of Duisburg-Essen Medical School, Essen; Department of Surgery, Klinikum Solingen, Solingen; Departments of Hematology and Oncology, Surgery, and Radiation Oncology, University Clinic, Marburg; and the Department of Gastroenterology, Surgery, and Radiation Oncology, University Clinic, Tübingen, Germany for the German Oesophageal Cancer Study Group.

Corresponding author: Michael Stahl, MD, Department of Medical Oncology and Hematology, Kliniken Essen-Mitte, Henricistr. 92, D-45136 Essen, Germany; e-mail: m.stahl{at}kliniken-essen-mitte.de.

	ABSTRACT

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Purpose Preoperative chemotherapy is an accepted standard in the treatment of localized esophagogastric adenocarcinoma. Adding radiation therapy to preoperative chemotherapy appears promising, but its definitive value remains unknown.

Patients and Methods Patients with locally advanced (uT3-4NXM0) adenocarcinoma of the lower esophagus or gastric cardia were randomly allocated to one of two treatment groups: induction chemotherapy (15 weeks) followed by surgery (arm A); or chemotherapy (12 weeks) followed by chemoradiotherapy (3 weeks) followed by surgery (arm B). Primary outcome was overall survival time. A total of 354 patients were needed to detect a 10% increase in 3-year survival from 25% to 35% by addition of radiation therapy. The study was prematurely closed due to low accrual.

Results The median observation time was 46 months. A total of 126 patients were randomly assigned and 119 eligible patients were evaluated. The number of patients undergoing complete tumor resection was not different between treatment groups (69.5% v 71.5%). Patients in arm B had a significant higher probability of showing pathologic complete response (15.6% v 2.0%) or tumor-free lymph nodes (64.4% v 37.7%) at resection. Preoperative radiation therapy improved 3-year survival rate from 27.7% to 47.4% (log-rank P = .07, hazard ratio adjusted for randomization strata variables 0.67, 95% CI, 0.41 to 1.07). Postoperative mortality was nonsignificantly increased in the chemoradiotherapy group (10.2% v 3.8%; P = .26).

Conclusion Although the study was closed early and statistical significance was not achieved, results point to a survival advantage for preoperative chemoradiotherapy compared with preoperative chemotherapy in adenocarcinomas of the esophagogastric junction.

	INTRODUCTION

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Tumors of the lower esophagus and the proximal stomach are usually summarized as adenocarcinomas of the esophagogastric junction (EGJ). These carcinomas are the most rapidly increasing type of tumor in many Western countries and they represent an aggressive disease with poor prognosis.^1,2 Although surgery is the primary modality that can cure patients, the majority of patients present with recurrences leading to death within 2 years after resection. This is particularly true for high-risk patients with locally advanced tumor stage, where complete resection is impossible in a relevant number of patients and lymph node metastases were observed in almost all the patients.^3–5 Preoperative chemotherapy proved superiority to surgery alone in esophagogastric cancer.^6–8 Preoperative chemoradiotherapy appeared to improve survival even more than chemotherapy in adenocarcinoma of the esophagus, but at the cost of increased operative mortality.^9–11 Based on a phase II experience,¹² our group proceeded to a phase III trial to investigate whether preoperative combined chemoradiotherapy adds to prognosis compared to chemotherapy alone in patients with locally advanced adenocarcinomas of the EGJ.

	PATIENTS AND METHODS

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Eligibility Criteria
Untreated patients up to 70 years of age with histologically proven adenocarcinoma of the esophagogastric junction (type I to III according to Siewert's classification¹³) qualified for the study. Further eligibility criteria were locally advanced disease (eg, T3-T4 NX M0) according to computed tomography scan, endoscopic ultrasound (EUS), and diagnostic laparoscopy, good general condition (WHO performance status grade 0 to 1) allowing major surgery, normal liver, renal and bone marrow function (bilirubin < 1.5 mg/dL, cholinesterase > 3,000 U/L, total protein > 60 g/L, creatinine clearance > 60 mL/min, leukocytes > 4.0 x 10⁹/L, thrombocytes > 150 x 10⁹/L, hemoglobin > 10 g/dL), and written informed consent. The trial was approved by the ethics committee of the Ärztekammer Nordrhein, Düsseldorf, Germany.

Random Assignment
This was an unblinded, prospectively randomized phase III trial looking for an improvement of 10% in 3-year survival rate (from 25% to 35%) by adding radiation therapy to preoperative chemotherapy. After evaluation of eligibility patients were stratified according to five criteria (center, sex, extent of weight loss within the last 8 weeks, T stage, and tumor localization according to Siewert type I to III). Allocation to treatment groups was performed at the Institute for Medical Informatics, Biometry and Epidemiology, Medical Faculty, University of Duisburg-Essen, using a computerized randomization program.

Treatment
Induction chemotherapy. Treatment in arm A consisted of induction chemotherapy with 2.5 courses of cisplatin, fluorouracil, leucovorin (PLF).¹⁴ One course comprised a 6-week schedule of weekly fluorouracil (2 g/m², 24-hour infusion) and leucovorin (500 mg/m², 2-hour infusion) as well as biweekly cisplatin (50 mg/m², 1-hour infusion). Treatment of arm B consisted of 2.0 courses of the same induction chemotherapy. This was followed by 3 weeks of combined chemoradiotherapy. Surgery was performed 3 to 4 weeks after the end of chemotherapy (arm A) or chemoradiotherapy (arm B). Tumor specimens were carefully analyzed according to the pTNM system.¹⁵ Application of erythropoietin alpha 10,000 U three times per week subcutaneously was recommended to keep the hemoglobin level between 10.5 and 12.5 g/dL.

Combined chemoradiotherapy in arm B. Treatment in arm B consisted of two courses of the PLF regimen, followed by the concurrent radiochemotherapy phase that started 2 weeks after the last day of PFL chemotherapy. Concurrent chemotherapy consisted of cisplatin (50 mg/m², 1-hour infusion IV), day 1 + 8 and etoposide (80 mg/m², 1-hour infusion IV) days 3 to 5. Radiation therapy was performed with photons from a linear accelerator with an energy 5 MeV. Three-dimensional planning was recommended. The mean dose to each kidney and the mean dose to liver had to be kept below 15 and 17 Gy, respectively. The clinical target volume included the primary tumor in its pretreatment extensions with a margin of 5 cm in the oral and 3 cm in the aboral and all circumferencial mucosal directions. The transversal margins around the macroscopic primary tumor were 2 cm but not across bony borders. All macroscopically involved lymph nodes were included with a margin of 1 cm and the following elective lymph nodes stations were irradiated: the left and right cardiac lymph nodes, the lymph nodes along the left gastric artery and the lesser curvature, the celic axis lymph nodes, and the nodes along the splenic artery and hepatic artery. The planning target volume (PTV) contained the clinical target volume together with a margin of 8 mm to account for set up errors and organ motion. A total dose of 30 Gy was given at 2.0 Gy per fraction, 5 fractions per week. The dose was prescribed to a reference point within the PTV according to International Commission on Radiation Units and Measurements 50. The minimum dose within the PTV was more than 1.9 Gy per fraction.

Surgery
Centers had to define before the study which approach each one would use for patients with type I or type II/III adenocarcinoma, respectively. For type I carcinomas, transthoracic esophagectomy (TTE) by a separated right thoracal and abdominal approach as well as transhiatal esophagectomy (THE) by a limited mediastinal approach was allowed. In TTE, resection of the esophagus and the proximal stomach included excision of the paraesophageal, paracardial, left gastric, and celiac lymph nodes (two-field lymphadenectomy). The resected esophagus was usually replaced by the stomach, with a cervical or intrathoracal esophagogastric anastomosis. For type II to III carcinomas, extended total gastrectomy with resection of the lower esophagus was recommended, including paraesophageal as well as perigastric lymph nodes and those of the upper edge of the pancreas (D2-lymphadenectomy). The reconstruction was usually done by a Roux-Y esophago-jejunostomy.

Follow-Up
Patients were seen for the first follow-up 8 to 12 weeks after the end of treatment, and thereafter every 3 months up to 2 years. Afterward, follow-up was planned every 6 months up to 5 years.

Power Issues and Statistical Analysis
The study was planned according a two-stage adaptive design.¹⁶ The alternative hypothesis was superiority of 10% in 3-year survival of the chemoradiotherapy arm compared with the chemotherapy arm to be assessed using a one-sided log-rank test at a significance level of 5%. Based on the results of a preceding phase II study¹² and reported experiences from different phase III trials testing neoadjuvant chemo(radio)therapy in adenocarcinomas of the esophagus or esophagogastric junction,^17,18,19 we expected a 3-year overall survival of 25% in the control arm and an increase of 10% (to 35%) in the experimental arm. In the first stage, analysis of 100 patients per arm was planned, and the number of patients required in the second stage to achieve a power of 80% was to be calculated. As the recruitment rate was low, an amendment to the protocol was adopted allowing first stage analysis 5 years after start of the study, when 125 patients were recruited. From the results of first stage analysis an additional 163 patients per arm would have been required. This led to the decision to close the study. Allocated patients were observed for another 1.5 years. With the acquired number of patients (59/60 patients eligible in arm A/B), the power of the one-sided log-rank test to detect the hypothesized 10% difference in 3-year survival is low (40%). Thus, caution is due when drawing conclusions from nonsignificance of results.

Survival curves are calculated employing the Kaplan-Meier method and compared using the log-rank test. In addition, Cox proportional hazard regression models were calculated, adjusting the treatment effect for stratification variables used in the randomization procedure (ie, sex, extent of weight loss within the last 8 weeks, T stage, tumor localization), and for center size. Continuous data were compared using the Mann-Whitney u statistic, categoric data using Fisher's exact test. In this exploratory analysis of the data acquired despite early closure of the trial, all statistical tests reported are two sided. Statistical significance was assumed when a P value fell below .05.

	RESULTS

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Patients
From November 2000 until December 2005, 126 patients from 19 German centers were registered. Twelve centers included fewer than five patients. After assessment of eligibility, seven patients proved uneligible (five for metastatic disease, one for contraindication to cisplatin, and one for poor performance status). Thus, 59 patients were assigned chemotherapy and surgery (arm A) and 60 patients chemoradiotherapy and surgery (arm B), respectively. Patients in arm B were older than those in arm A (Table 1). Other patients' characteristics were well balanced between the two treatment groups.

View larger version (49K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig. 1. Trial profile.

Hospital mortality was increased by adding preoperative radiation therapy (two of 52 patients undergoing surgery [3.8%] v five of 49 patients undergoing surgery [10.2%] in arm A and B, respectively; Fisher's exact P = .26). Causes for death were pneumonia (one v two), anastomotic leakage (one v two), and decompensated cardiac disease (zero v one). One of two deaths in arm A and three of five deaths in arm B were observed after a TTE had been performed. Overall, the median time on respirator, the median days on intensive care ward, and of total stay in the hospital did not differ between treatment groups (Table 2).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival (intent to treat). Arm A, n = 59 (chemotherapy and surgery): median survival time 21.1 months, 3-year survival rate 27.7%. Arm B, n = 60 (chemoradiotherapy and surgery): median survival time 33.1 months, 3-year survival rate 47.7%.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig. 3. Survival after complete tumor resection by pN stage (patients with complete resection of distant metastases were excluded): pN0: patients with tumor-free resected lymph nodes after preoperative therapy (n = 45); pN+: patients with tumor cells in resected lymph nodes after preoperative therapy (n = 34).

	DISCUSSION

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In the Medical Research Council (MRC) Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial⁶ the comparison of surgery to perioperative cisplatin-based chemotherapy plus surgery resulted in a significant survival improvement of 13% at 5 years with multimodal treatment (23% v 36%). Patients had to have localized tumors (stage II or higher) and approximately 75% of the primaries were located in the stomach. Similar results had been reported from a former MRC trial²¹ in esophageal cancer, where 66% of the patients had adenocarcinomas. These data was recently confirmed by a French Intergroup trial⁷ also investigating pre- and postoperative chemotherapy in localized adenocarcinomas with approximately 75% of the tumors located in the esophagogastric junction. The results of long-term survival were almost identical with an increase of 5-year survival rate from 24% to 38% by perioperative chemotherapy. In both trials, the majority of patients tolerated chemotherapy in the preoperative phase, whereas only less than half of the patients completed the planned postoperative treatment. A significant downsizing effect of preoperative chemotherapy was observed supporting the value of this treatment. However, the role of postoperative therapy remains unclear as it is true for adjuvant chemotherapy alone which did not prove to benefit patients in Western trials.²¹ So one can suggest that the preoperative therapy adds most to the impressive survival advantage of almost 15%.^6,7

The high rates of local or regional recurrence in esophagogastric cancer have prompted groups to investigate additional radiation therapy in adenocarcinomas of the upper GI tract. Both an Irish trial¹⁷ and a US study at the Michigan University¹⁸ proved chemoradiotherapy before surgery to influence long-term prognosis of patients with (predominantly) adenocarcinoma of the esophagus. Although the Irish results may have been biased by limited staging procedures and by not giving an intent-to-treat analysis, whereas the US trial just missed statistical significance due to low number of patients included, both trials added important numbers to several meta-analyses that proved preoperative chemoradiotherapy to increase survival in esophageal adenocarcinomas.^9–11 The study of the Southwest Oncology Group²³ was the first to show that postoperative chemoradiotherapy is able to significantly improve survival in localized gastric and EGJ cancer (increase of 3-year survival rate from 41% to 50%). Although this trial was criticized for the limited surgery with most of the patients, it confirmed the hypothesis that improving local therapy will not only reduce locoregional recurrences but moreover may have impact on overall survival.

From our preceeding phase II trial we set up the hypotheses that adding radiation therapy to preoperative chemotherapy may provide a higher rate of R0 resections in locally advanced tumors, as well as may increase the number of patients with pathCR or with tumor-free lymph nodes in the resected specimen. Since complete tumor resection and pN0 status are accepted prognostic factors in primary surgery of esophageal cancer^3–5,25 and pathohistologic response to chemoradiotherapy is very likely to determine patients prognosis in multimodal therapy,^25–27 we consequently anticipated an improvement of long-term survival by adding radiation therapy. Although the R0 resection rate in operated patients was increased from 79% to 88% by chemoradiotherapy, the intent-to-treat probability of complete resection was not different between treatment arms. Compared with other groups that used induction chemotherapy followed by chemoradiotherapy,^25,26 we applied a relatively low radiation dose of 30 Gy. This was done to keep low the risk of radiation therapy–related complications after surgery. Nevertheless, pathCR and the rate of tumor-free lymph nodes were significantly increased by chemoradiotherapy compared with chemotherapy alone. Interestingly, tumor-free lymph nodes after preoperative therapy resulted in a survival benefit in subgroup analysis (Fig 3). This issue was obviously not due to downstaging, because the rate of complete resection was comparable between groups and disease-free survival after macroscopic complete resection still favored combined chemoradiotherapy (24.9% v 41.3% at 3 years). From that, preoperative chemoradiotherapy resulted in a 20% increase of 3-year survival. Although its superiority was not proven (P = .07), our data provide evidence that preoperative chemoradiotherapy may improve survival and should be further investigated. It is unlikely that this difference was biased on the extent of surgery, since the lymphadenectomy was even more extended in the chemotherapy group. Moreover, operative procedures were predefined accordingly to the tumor location and more than 90% of resections were performed in accordance with the study protocol. Interestingly, the survival benefit was achieved although the postoperative mortality was more than doubled (10.2% v 3.8%) by adding radiation therapy. Because of the low total radiation dose applied, it is likely that other factors than radiation therapy contributed to postoperative mortality which appears increased compared with what should be observed after primary surgery.²⁸ Moreover, we suggest this to be rather a result of a patient selection bias than of low center experience, because four of five deaths occurred in centers with the highest case load.

Although our trial did not meet its accrual goals and could not provide statistical significance, the improvement in both local tumor-free and overall survival adds to the knowledge that preoperative chemoradiotherapy appears most valuable to cure patients with localized esophagogastric adenocarcinoma. As it is more than evident that major response to preoperative treatment is an important prognostic factor future trials should aim to optimize preoperative treatment by combining all treatment modalities including chemotherapy, targeted therapy, and also radiation therapy.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Hansjochen Wilke, Merck KGaA (C), Pfizer (C) Stock Ownership: None Honoraria: Michael Stahl, Roche, Pfizer, Ortho Biotech; Hans-Joachim Meyer, Merck Pharma GmbH, Pfizer Pharma GmbH Research Funding: None Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Michael Stahl, Martin Stuschke, Nils Lehmann, Hans-Joachim Meyer, Wilfried Budach, Hansjochen Wilke

Administrative support: Michael Stahl

Provision of study materials or patients: Michael Stahl, Martin K. Walz, Martin Stuschke, Hans-Joachim Meyer, Jorge Riera-Knorrenschild, Peter Langer, Rita Engenhart-Cabillic, Michael Bitzer, Alfred Königsrainer, Wilfried Budach

Collection and assembly of data: Michael Stahl, Martin K. Walz, Hans-Joachim Meyer, Jorge Riera-Knorrenschild, Peter Langer, Michael Bitzer, Alfred Königsrainer

Data analysis and interpretation: Michael Stahl, Nils Lehmann, Hansjochen Wilke

Manuscript writing: Michael Stahl, Martin Stuschke, Nils Lehmann, Hansjochen Wilke

Final approval of manuscript: Michael Stahl, Martin K. Walz, Martin Stuschke, Nils Lehmann, Hans-Joachim Meyer, Jorge Riera-Knorrenschild, Peter Langer, Rita Engenhart-Cabillic, Michael Bitzer, Alfred Königsrainer, Wilfried Budach, Hansjochen Wilke

	Appendix

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The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe® Reader®).

The members of the German Esophageal Cancer Study Group were as follows: data center: M. Stahl (principal investigator); N. Lehmann (biostatistician); S. Hanisch, U. Roggenbuck (data manager); steering committee: H. Wilke (medical oncology); H.-J. Meyer, MK. Walz (surgery); M. Stuschke (radiation oncology); investigating centers: Kliniken Essen-Mitte: M. Stahl, H. Wilke (medical oncology), M.K. Walz (surgery), S. Draia, A. Koziorowski (radiation oncology at Ambulantes Tumorzentrum Essen); Universitätsklinikum Marburg: A. Riera, A. Neubauer (medical oncology), R. Engenhart-Cabilic (radiation oncology), M. Rothmund (surgery); Universitätsklinikum Tübingen: M. Bitzer, (gastroenterology), C. Bokemeyer, T. Hartmann (medical oncology), W. Budach (radiation oncology), A. Königsrainer (surgery); Universitätsklinikum Dresden: G. Folprecht (medical oncology), M. Baumann (radiation oncology), H.-D. Saeger (surgery); Alfried-Krupp-Krankenhaus Essen: H. Knipp (medical oncology), M.H. Seegenschmiedt (radiation oncology), M. Betzler (surgery); Universitätsklinikum Essen (Westdeutsches Tumorzentrum): U. Vanhoefer, S. Seeber (medical oncology), C. Poettgen, M. Stuschke (radiation oncology), Klinikum Solingen: HJ. Meyer (surgery); Universitätsklinikum Bonn: I. Schmidt-Wolf, (medical oncology), H. Schueller (radiation oncology), A. Hirner (surgery); Universitätsklinikum Düsseldorf: M. Schmitt, D. Häussinger (gastroenterology), G. Schmitt (radiation oncology), C. Franke (surgery); Klinikum Krefeld: T. Frieling (gastroenterology), U. Schulz (radiation oncology), P.R. Verreet (surgery); Krankenhaus St. Geort, Leipzig: L. Mantovani (medical oncology), A. Friedrich (radiation oncology), A. Weimann (surgery); Florence Nightingale Krankenhaus Düsseldorf: A. Winter (medical oncology); Krankenhaus Benrath, Düsseldorf: K.-H. Schultheis (surgery); Klinikum Nürnberg Nord: K. Weigang-Köhler (medical oncology), Ch. Germer (surgery), Katholische Kliniken im Kreis Kleve, Goch/Kleve: V. Runde (medical oncology); B. Reers (surgery); Knappschaftkrankenhaus Bottrop: G. Trenn (medical oncology); Klinikum Kassel: J. Pausch (gastroenterology), H. Kops, P. Schneider (radiation oncology), J. Faß (surgery); Klinikum Oldenburg: H. Koehne (medical oncology); H.-R. Raab (surgery); Phillippusstift Essen: R. Kath (medical oncology); Asklepios Klinik Bad Oldesloe: H. Fink (medical oncology).

	Acknowledgment

 
We cordially thank S. Hanisch, Department of Medical Oncology, Kliniken Essen-Mitte, for data management and coordination of the data center, and U. Roggenbuck for data report and analysis.

	NOTES

 
Supported by grants of Ortho-Biotech (Neuss, Germany) and Baxter Deutschland GmbH (Unterschleißheim, Germany).

Presented in part at the 43rd annual meeting of the American Society of Clinical Oncology Chicago, IL, June 1-5, 2007.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted March 5, 2008; accepted October 10, 2008.

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