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Editorial |
Division of Surgical Oncology, Department of Surgery, Temple University School of Medicine, The Western Pennsylvania Hospital, Suite 4600N, 4800 Friendship Avenue, Pittsburgh, Pennsylvania 15224
Correspondence: Address correspondence and reprint requests to: Carmine Volpe, MD, FACS; E-mail: cvolpe{at}wpahs.org.
In this issue of the Annals of Surgical Oncology, Gaca et al.1 from Duke University Medical Center present a retrospective analysis of 101 patients receiving neoadjuvant chemoradiation followed by surgical resection for gastroesophageal junction (GEJ) carcinoma. The purpose of the study was to identify factors affecting the overall survival and disease-free survival (DFS) in patients receiving multimodality therapy for GEJ tumors. Almost 90% of the tumors were located in the distal esophagus, and all but five were adenocarcinoma. All patients underwent pretreatment staging with computed tomographic scanning of the chest and abdomen, and endoscopic ultrasonography (EUS) was performed in 39 patients. The predominant chemotherapy regimen consisted of continuous-infusion 5-fluorouracil (225 mg/m2) and cisplatinum (20 mg/m2) for three cycles. Radiation therapy began the first day of chemotherapy and was delivered to a total dose of 45 Gy. Surgical resection was performed 4 to 8 weeks after completion of neoadjuvant chemoradiation. The median overall survival was 25 months, and the median DFS was 16 months. Apathologic complete response (pCR) was achieved in 28 patients (27%) with a median survival of 50 months. Patients with node-negative tumors experienced a median DFS of 24 months compared with 9 months for patients with node-positive tumors. Pathologic N status was the only variable found to be statistically significant by both univariate and multivariate analysis. The authors concluded from their study that the identification of lymph node metastases in patients with GEJ/esophageal tumors receiving neoadjuvant therapy followed by resection portends a poor prognosis. They also suggest that patients enrolled in neoadjuvant protocols undergo posttreatment nodal restaging and that consideration be given to curtailing or modifying future surgical management if positive lymph nodes are detected.
It is well known that pathologically involved lymph nodes in patients with GEJ cancer are a strongly adverse prognostic factor, and its importance has been demonstrated in the literature on many occasions. The clinical significance of neoadjuvant studies is partly related to how well they treat locally advanced, i.e., node-positive, tumors. Gaca et al. from the study cited above, make no claim as to the effectiveness of their treatment and do not clearly express how many patients were deemed node positive prior to neoadjuvant therapy and how many were actually downstaged from N1 to N0 with treatment. The pretreatment staging was based solely on T staging and lymph node size since fine-needle aspiration was not performed. The size of the lymph node has been determined to be an inaccurate indicator of lymph node metastasis.2 Nonetheless, the investigators identified 23 patients with locally advanced GEJ carcinoma, 2 patients with stage IIb disease (T1/T2N1M0), and 21 patients with stage III (T3N1M0 and T4N0M0) prior to therapy. Final pathologic staging after multimodality therapy and resection revealed 36 patients with locally advanced disease, 15 with stage IIb, and 21 with stage III. Although by the numbers it appears that treatment was less than optimal, the results are difficult to interpret because of what is considered by today’s standard a lack of sophisticated pretreatment staging.
Mallery et al.3 from Brigham and Women’s Hospital, reported a 43% pCR rate in patients with N1 disease using a regimen similar to the one employed by Gaca et al. Mallery et al. also found that posttreatment restaging with EUS after chemoradiation was unreliable as a result of postneoadjuvant fibrosis. Prior to administration of neoadjuvant therapy, the extent of disease must be accurately assessed. The determination of T, N, and M status is essential. EUS, computed tomographic scanning, and positron emission tomography can predict T and M status, respectively; however, N status cannot be reliably predicted by these techniques. Diagnostic laparoscopy, video-assisted thoracoscopy, and EUS/fine-needle aspiration are the most accurate lymph node staging techniques available today.2 Knowledge of pretreatment lymph node status confers many advantages toward maximizing patient outcome. Radiation treatment fields can be modified or altered to include involved lymph nodes; similarly, the surgeon may expand the lymph node dissection either above or below the diaphragm to encompass lymph node metastases. Finally, it permits assessment of treatment efficacy and quantifies the protocol’s capability of converting locally advanced disease to a pCR.
The extent of lymph node dissection remains a debatable issue in patients with GEJ carcinoma, as it is with gastric and esophageal cancers. However, it is generally recommended that at least 15 lymph nodes accompany the operative specimen to ensure that the tumor is indeed node negative. According to the sixth edition of the American Joint Committee on Cancer Cancer Staging Manual,4 regional lymph nodes assigned to GEJ cancer include lymph nodes found in the lower mediastinum and along the diaphragm, left gastric artery, and celiac axis. Because of the heterogeneity of carcinomas found in the area of the GEJ, one might also include lymph nodes residing along the splenic artery and splenic hilum, which typically drain the proximal stomach. In the study by Gaca et al. almost 90% of the cancers were located in the distal esophagus (type I), and the authors chose not to include the celiac axis lymph nodes in their dissection, nor did they disclose the total number of lymph nodes retrieved or the number of positive lymph nodes discovered. I believe that one can safely assume that limited D1 gastroesophageal resections were performed in all patients in this study.
Many investigators now feel that GEJ carcinomas are a separate entity from gastric and esophageal cancers. Stein et al.5 have proposed classifying GEJ cancers into three distinct tumor types, all within 5 cm of the GEJ: type I, adenocarcinoma of the distal esophagus; type II, true cancer of the cardia; and type III, cancers arising from the subcardial area. Arecent Consensus Conference of the International Gastric Cancer Association and the International Society for Diseases of the Esophagus concluded that this classification should form the basis for defining, assessing, and reporting the treatment of patients with adenocarcinoma of the GEJ.6
The study cited above appears to be of modest clinical significance; however, added value may lie within data not revealed in the study. The authors reported a 27% pCR rate, which is consistent with what is reported in the literature and indicates that the treatment employed does have merit. We also know that about a third of patients received a failing grade when tumor was discovered in the lymph nodes included with their surgical specimen. In order to assess the potential of any neoadjuvant protocol, the extent of disease prior to enrollment must be vigorously pursued. A patient who has N1 disease prior to treatment and is declared N1 after resection makes one statement, whereas another downstaged from N1 to N0 after treatment voices an entirely equal but opposing claim. The majority of patients offered neoadjuvant therapy are afflicted with advanced or metastatic disease. After they have appropriately staged and treatment has been instituted, their response to treatment should be closely monitored. Downey et al.7 suggested positron emission tomography scanning after one cycle of neoadjuvant chemotherapy. Early detection of the tumor response will encourage further treatment, while nonresponders can potentially cross over to other modalities.
It is difficult to conduct a valid trial evaluating the management of GEJ carcinomas with so many unresolved variables: neoadjuvant or adjuvant, chemoradiation or chemotherapy alone, extended or limited lymph node dissection, and esophageal or gastric in origin. We have made little progress in the treatment of carcinomas of the GEJ when the standard arm of a phase III trial remains surgery alone. A neoadjuvant trial for GEJ cancer requires meticulous pretreatment staging, including invasive techniques, such as diagnostic laparoscopy and video-assisted thoracoscopy; precise identification of tumor location, confirmed by cytokeratin and adhesion molecule expression, if necessary; and resection including at least 15 lymph nodes (and more when patients are staged as N1 at pretreatment). Nonresponders should be detected early, followed by reassessment and verification of the tumor type or treatment modifications, such as alternative chemotherapy, changes in radiation portals, or early surgery followed by adjuvant therapy.
Received for publication November 2, 2005. Accepted for publication November 8, 2005.
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