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      Accuracy of Detecting Residual Disease After Cross Neoadjuvant Chemoradiotherapy for Esophageal Cancer (preSANO Trial): Rationale and Protocol


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          Results from the recent CROSS trial showed that neoadjuvant chemoradiotherapy (nCRT) significantly increased survival as compared to surgery alone in patients with potentially curable esophageal cancer. Furthermore, in the nCRT arm 49% of patients with a squamous cell carcinoma (SCC) and 23% of patients with an adenocarcinoma (AC) had a pathologically complete response in the resection specimen. These results provide a rationale to reconsider and study the timing and necessity of esophagectomy in (all) patients after application of the CROSS regimen.


          We propose a “surgery as needed” approach after completion of nCRT. In this approach, patients will undergo active surveillance after completion of nCRT. Surgical resection would be offered only to those patients in whom residual disease or a locoregional recurrence is highly suspected or proven. However, before a surgery as needed approach in oesophageal cancer patients (SANO) can be tested in a randomized controlled trial, we aim to determine the accuracy of detecting the presence or absence of residual disease after nCRT (preSANO trial).


          This study is set up as a prospective, single arm, multicenter, diagnostic trial. Operable patients with potentially curable SCC or AC of the esophagus or esophagogastric junction will be included. Approximately 4-6 weeks after completion of nCRT all included patients will undergo a first clinical response evaluation (CRE-I) including endoscopy with (random) conventional mucosal biopsies of the primary tumor site and of any other suspected lesions in the esophagus and radial endo-ultrasonography (EUS) for measurement of tumor thickness and area. Patients in whom no locoregional or disseminated disease can be proven by cytohistology will be offered a postponed surgical resection 6-8 weeks after CRE-I (ie, approximately 12-14 weeks after completion of nCRT). In the week preceding the postponed surgical resection, a second clinical response evaluation (CRE-II) will be planned that will include a whole body PET-CT, followed again by endoscopy with (random) conventional mucosal biopsies of the primary tumor site and any other suspected lesions in the esophagus, radial EUS for measurement of tumor thickness and area, and linear EUS plus fine needle aspiration of PET-positive lesions and/or suspected lymph nodes. The main study parameter is the correlation between the clinical response assessment during CRE-I and CRE-II and the final pathological response in the resection specimen.


          The first patient was enrolled on July 23, 2013, and results are expected in January 2016.


          If this preSANO trial shows that the presence or absence of residual tumor can be predicted reliably 6 or 12 weeks after completion of nCRT, a randomized trial comparing nCRT plus standard surgery versus chemoradiotherapy plus “surgery as needed” will be conducted (SANO trial).

          Trial Registration

          Netherlands Trial Register: NTR4834; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4834 (archived by Webcite at http://www.webcitation.org/6Ze7mn67B).

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          Most cited references30

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          Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial.

          After curative resection, the prognosis of gastroesophageal adenocarcinoma is poor. This phase III trial was designed to evaluate the benefit in overall survival (OS) of perioperative fluorouracil plus cisplatin in resectable gastroesophageal adenocarcinoma. Overall, 224 patients with resectable adenocarcinoma of the lower esophagus, gastroesophageal junction (GEJ), or stomach were randomly assigned to either perioperative chemotherapy and surgery (CS group; n = 113) or surgery alone (S group; n = 111). Chemotherapy consisted of two or three preoperative cycles of intravenous cisplatin (100 mg/m(2)) on day 1, and a continuous intravenous infusion of fluorouracil (800 mg/m(2)/d) for 5 consecutive days (days 1 to 5) every 28 days and three or four postoperative cycles of the same regimen. The primary end point was OS. Compared with the S group, the CS group had a better OS (5-year rate 38% v 24%; hazard ratio [HR] for death: 0.69; 95% CI, 0.50 to 0.95; P = .02); and a better disease-free survival (5-year rate: 34% v 19%; HR, 0.65; 95% CI, 0.48 to 0.89; P = .003). In the multivariable analysis, the favorable prognostic factors for survival were perioperative chemotherapy (P = .01) and stomach tumor localization (P < .01). Perioperative chemotherapy significantly improved the curative resection rate (84% v 73%; P = .04). Grade 3 to 4 toxicity occurred in 38% of CS patients (mainly neutropenia) but postoperative morbidity was similar in the two groups. In patients with resectable adenocarcinoma of the lower esophagus, GEJ, or stomach, perioperative chemotherapy using fluorouracil plus cisplatin significantly increased the curative resection rate, disease-free survival, and OS.
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            Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation.

            In patients with locoregional carcinoma of the esophagus or esophagogastric junction who underwent preoperative chemoradiation, it is unclear whether survival was better predicted by pretherapy clinical stage or by posttherapy pathologic stage. The authors studied 235 consecutive patients with pretherapy clinical Stage II, III, or IVA (according to American Joint Committee on Cancer criteria) carcinoma of the esophagus or esophagogastric junction who were treated with chemoradiation followed by esophagectomy. Posttherapy cancer status was classified using pathologic stage and semiquantitative assessment of residual carcinoma. Clinicopathologic features, residual carcinoma status, and pretherapy and posttherapy stage were compared with disease-free and overall survival. Posttherapy pathologic stage was Stage 0 in 29% of patients, Stage I in 11% of patients, Stage II in 34% of patients, Stage III in 20% of patients, and Stage IV in 6% of patients. Cancer downstaging occurred in 56% of patients. In univariate analysis, disease-free and overall survival were predicted by posttherapy pathologic stage (both with P < 0.001), margin status (P = 0.002 and P = 0.01, respectively), extent of residual carcinoma (both with P < 0.001), and downstaging (both with P = 0.001), but not by age, gender, type of cancer, pretherapy clinical stage, or preoperative regimen. However, in multivariate analysis, disease-free and overall survival were independently predicted by posttherapy pathologic stage (both with P = 0.02). Extent of residual carcinoma was a marginally significant predictor of overall survival (P = 0.04). Posttherapy pathologic stage was the best available predictor of outcome for patients with locoregional carcinoma of the esophagus or esophagogastric junction who underwent chemoradiation therapy followed by esophagectomy. The findings in the current study supported the concept of downstaging by preoperative therapy. Copyright 2005 American Cancer Society.
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              The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection.

              Surveillance, Epidemiology and End Results (SEER) data indicate that number of lymph nodes removed impacts survival in gastric cancer. Our aim was to study this relationship in esophageal cancer. The study population included 2303 esophageal cancer patients (1381 adenocarcinoma, 922 squamous) from 9 international centers that had R0 esophagectomy prior to 2002 and were followed at regular intervals for 5 years or until death. Patients treated with neoadjuvant or adjuvant therapy were excluded. Operations consisted of esophagectomy with (1700) and without (603) thoracotomy. Median number of nodes removed was 17 (IQR10-29). There were 508 patients with stage I, 853 stage II, and 942 stage III. Five-year survival was 40%. Cox regression analysis showed that the number of lymph nodes removed was an independent predictor of survival (P < 0.0001). The optimal threshold predicted by Cox regression for this survival benefit was removal of a minimum of 23 nodes. Other independent predictors of survival were the number of involved nodes, depth of invasion, presence of nodal metastasis, and cell type. The number of lymph nodes removed is an independent predictor of survival after esophagectomy for cancer. To maximize this survival benefit a minimum of 23 regional lymph nodes must be removed.

                Author and article information

                JMIR Res Protoc
                JMIR Res Protoc
                JMIR Research Protocols
                JMIR Publications Inc. (Toronto, Canada )
                Apr-Jun 2015
                29 June 2015
                : 4
                : 2
                : e79
                [1] 1Erasmus MC - University Medical Center Rotterdam Department of Surgery RotterdamNetherlands
                [2] 2Erasmus MC - University Medical Center Rotterdam Department of Gastroenterology RotterdamNetherlands
                [3] 3Academic Medical Center Department of Gastroenterology AmsterdamNetherlands
                [4] 4Academic Medical Center Department of Medical Oncology AmsterdamNetherlands
                [5] 5Academic Medical Center Department of Surgery AmsterdamNetherlands
                [6] 6Catharina Cancer Center Department of Surgery EindhovenNetherlands
                [7] 7University Medical Center Department of Surgery UtrechtNetherlands
                [8] 8Atrium Medical Center Department of Surgery HeerlenNetherlands
                [9] 9Erasmus MC - University Medical Center Rotterdam Department of Public Health RotterdamNetherlands
                Author notes
                Corresponding Author: Bo Jan Noordman b.noordman@ 123456erasmusmc.nl
                Author information
                ©Bo Jan Noordman, Joel Shapiro, Manon CW Spaander, Kausilia K Krishnadath, Hanneke WM van Laarhoven, Mark I van Berge Henegouwen, Grard AP Nieuwenhuijzen, Richard van Hillegersberg, Meindert N Sosef, Ewout W Steyerberg, Bas PL Wijnhoven, J Jan B van Lanschot. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 29.06.2015.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on http://www.researchprotocols.org, as well as this copyright and license information must be included.

                : 10 February 2015
                : 27 February 2015
                : 3 April 2015

                esophageal cancer,neoadjuvant chemoradiotherapy,esophagectomy,surgery as needed,active surveillance policy


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