Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08)

Ruhstaller, Thomas; Thuss‐Patience, Peter; Hayoz, Stefanie; Schacher, Sabina; Knorrenschild, Jorge Riera; Schnider, Annelies; Plaßwilm, Ludwig; Budach, Wilfried; Eisterer, Wolfgang; Hawle, Hanne; Mariette, C.; Hess, Viviane; Mingrone, Walter; Montemurro, Michael; Girschikofsky, Michael; Schmidt, Sven; Bitzer, Michael; Bedenne, Laurent; Brauchli, Peter; Ståhl, Michael

doi:10.1093/annonc/mdy105

Cited by 84 publications

(87 citation statements)

References 12 publications

(15 reference statements)

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“…The data from our study showed such an intermediate prognostic group for patients with 1–50% VTCs in the Cologne Regression scale and for the Mandard classification combining TRG1 and TRG2, but not for the ypT category. For Mandard classification, such a medium prognostic group for oesophageal cancer patients was not found in two studies . Using the percentage of VTCs compared to the original volume of the tumour, Swisher et al .…”

Section: Discussionmentioning

confidence: 99%

“…For Mandard classification, such a medium prognostic group for oesophageal cancer patients was not found in two studies. 33,34 Using the percentage of VTCs compared to the original volume of the tumour, Swisher et al described such a medium prognostic group for patients with oesophageal cancer after neoadjuvant therapy with 1-50% VTCs. 35 Similar results are described by Langer et al 36 According to our results, the group of patients with <10% VTC has a very good prognosis, comparable with those patients with pCR of the primary tumour, and a better prognosis compared to those with 10-50% VTC.…”

Section: Discussionmentioning

confidence: 99%

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Neoadjuvant chemoradiation for patients with advanced oesophageal cancer – which response grading system best impacts prognostic discrimination?

et al. 2019

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Aims Neoadjuvant chemoradiation reduces tumour volume and improves the R0 resection rate, followed by extended survival for patients with advanced oesophageal cancer. The degree of tumour regression has high prognostic relevance. To date, there is still no generally accepted tumour regression grading system. The aim of this study was to compare the prognostic discrimination power of different histological regression grading systems: (i) the fibrosis/tumour ratio within the primary tumour (Mandard classification), (ii) the percentage of residual vital tumour cells (VTC) compared to the original primary tumour (Cologne Regression) and (iii) the ypT category, in patients with cT3 carcinoma of the oesophagus after neoadjuvant chemoradiation. Methods and results This study included 216 patients with oesophageal cancer clinically staged as cT3NxM0 and treated from 2009 to 2012 with standardised chemoradiation followed by oesophagectomy [median age 62 years, 176 (81%) male and 138 (64%) adenocarcinoma patients]. The subgroup frequencies of the three classification systems were ypT category: ypT0 = 18%, ypT1 = 14%, ypT2 = 23%, ypT3 = 44%, ypT4 = 1%; Mandard classification: TRG1 = 18%, TRG2 = 26%, TRG3 = 24%, TRG4 = 30%, TRG5 = 2%; and Cologne Regression Scale: no tumour = 18%, 1–10% VTC = 27%, 10–50% VTC = 26% and >50% VTC = 29%. The Mandard and Cologne Regression classifications showed better prognostic differentiation for the subgroups than the ypT category. The four‐tiered Cologne Regression system had a good prognostic relevance. Comparing results of the re‐evaluated Cologne Regression classification with the classification by routine pathological report showed very good inter‐rater agreement, with kappa value 0.891. Conclusion Compared to the original primary tumour, the tumour regression grading system using the percentage of residual vital tumour has prognostic relevance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neoadjuvant chemoradiation for patients with advanced oesophageal cancer – which response grading system best impacts prognostic discrimination?

et al. 2019

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“…The two trials that studied SCRT did not show benefit in any of the variables evaluated. This strategy was also re-evaluated with modifications, i.e., induction chemotherapy (docetaxel, infusional FU, cisplatin) followed by neoadjuvant chemoradiation followed by surgery, with or without cetuximab [48]. The addition of cetuximab did improve the locoregional control but did not translate in survival benefit.…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant strategies in resectable carcinoma esophagus: a meta-analysis of randomized trials

et al. 2020

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Background: The survival benefit of neoadjuvant therapy in resectable carcinoma esophagus has been elucidated. We performed a meta-analysis in light of new studies and long-term results of past trials. The search strategy was refined to include only "neoadjuvant" so that any bias by adjuvant treatment is eliminated. Methods: A detailed search of MEDLINE, Embase, and Cochrane Library was done. Only published randomized English language trials were included. Data were categorized as neoadjuvant concurrent chemoradiation (NACRT), neoadjuvant chemotherapy (NACT), neoadjuvant radiotherapy (NART), and neoadjuvant sequential chemoradiotherapy (SCRT). Meta-analysis was done using odds ratio (OR) and 95% CI using fixed/random effects model. Heterogeneity was tested by chi-square and I 2 test. Z probability calculated significant difference across subgroups. Outcomes assessed were overall survival (OS) and disease-free survival (DFS) at 3 and 5 years, respectively, mortality (30/90 day) and failures (local/systemic). Results: Twenty-five randomized trials involving 5272 patients were included for quantitative analysis. NACRT was evaluated in 12 studies (2676 patients). Superior 3-year OS (OR = 0.68 CI 0.52-0.90, p = 0.007), 3-year DFS (OR = 0.55 CI 0.45-0.68, p = 0.00001), and 5-year DFS (OR = 0.59 CI 0.47-0.74, p = 0.00001), with lower failures (OR = 0.52 CI 0.37-0.73, p = 0.0001), were seen in favor of NACRT at the cost of increased perioperative mortality (OR = 1.79 CI 1.15-2.80, p = .01). However, 5-year OS (OR = 0.78 CI 0.60-0.1.01, p = 0.06) was not found to be significantly superior. NACT, NART, and SCRT were not found to have any benefit over surgery alone. Conclusion: This meta-analysis presents strong evidence favoring NACRT over upfront surgery. It also shows no survival advantage of neoadjuvant chemotherapy.

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“…This additional analysis was planned after initiation of the study but before primary analysis. The study design and clinical efficacy endpoints have been published in detail [8].…”

Section: Methodsmentioning

confidence: 99%

“…Patients with locally advanced and resectable oesophageal cancer are treated with multimodal therapy in curative intention with 5-year overall survival rates of at least 50% and platinum-based chemotherapy is an established part of the treatment [8][9][10]. Due to the paucity of prospective data on VTEs in resectable oesophageal cancer the aim of this analysis was to describe the rate and pattern as well as potential risk factors of VTEs (such as histologic subtype and the "Khorana risk factors" listed above) in patients with resectable oesophageal cancer with multidisciplinary treatment within an international phase lll trial.…”

Section: Introductionmentioning

confidence: 99%

High thromboembolic event rate in patients with locally advanced oesophageal cancer during neoadjuvant therapy. An exploratory analysis of the prospective, randomised intergroup phase III trial SAKK 75/08

et al. 2020

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Background: High rates of venous thromboembolic events (VTEs), mainly in advanced disease, are reported for patients with cancer of the upper gastrointestinal tract (stomach, pancreas) and for treatment with cisplatin. Methods: Exploratory analysis of VTEs reported as adverse events and serious adverse events in a prospective, randomised, multicentre, multimodal phase III trial according to VTEs reported as adverse events and severe adverse events. Patients with resectable oesophageal cancer (T2N1-3, T3-4aNx) were randomized to 2 cycles of chemotherapy with docetaxel 75 mg/m 2 , cisplatin 75 mg/m 2 followed by chemo-radiotherapy (CRT) and subsequent surgery (control arm) or the same treatment with addition of cetuximab (investigational arm). Results: VTEs occurred in 26 of 300 patients included in the trial, resulting in an incidence rate (IR) of 8.7% [95% CI 5.7-12.4%]. A total of 29 VTEs were reported:13 (45%) VTEs were grade 2, 13 (45%) grade 3 and three (10%) fatal grade 5 events. 72% (21/29) of all VTEs occurred preoperatively (IR 6.7%): 14% (4/29) during chemotherapy and 59% (17/29) during CRT. In multivariable logistic regression only adenocarcinoma (IR 11.1%, 21/189 patients) compared to squamous cell cancer (IR 4.5%, 5/111 patients) was significantly associated with VTE-risk during treatment, OR 2.9 [95%CI 1.0-8.4], p = 0.046. Baseline Khorana risk score was 0 in 73% (19/26), 1-2 in 23% (6/26) and 3 in only 4% (1/ 26) of patients with VTEs.

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Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08)

Abstract: NCT01107639.

Cited by 84 publications

References 12 publications

Neoadjuvant chemoradiation for patients with advanced oesophageal cancer – which response grading system best impacts prognostic discrimination?

Neoadjuvant chemoradiation for patients with advanced oesophageal cancer – which response grading system best impacts prognostic discrimination?

Neoadjuvant strategies in resectable carcinoma esophagus: a meta-analysis of randomized trials

High thromboembolic event rate in patients with locally advanced oesophageal cancer during neoadjuvant therapy. An exploratory analysis of the prospective, randomised intergroup phase III trial SAKK 75/08

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