Tumor Regression Grading After Preoperative Chemoradiotherapy as a Prognostic Factor and Individual-Level Surrogate for Disease-Free Survival in Rectal Cancer

Fokas, Emmanouil; Ströbel, Philipp; Fietkau, Rainer; Ghadimi, Michael; Liersch, Torsten; Grabenbauer, Gerhard G.; Hartmann, Arndt; Kaufmann, Marco; Sauer, Rolf; Graeven, Ullrich; Hoffmanns, Hans; Raab, Hans-Rudolf; Hothorn, Torsten; Wittekind, Christian; Rödel, Claus

doi:10.1093/jnci/djx095

Cited by 115 publications

(98 citation statements)

References 29 publications

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“…Of note, neutrophilia, leukocytosis, thrombocytosis and high CEA levels also showed significant correlation with lower TRG and higher NAR score that reflect poor response to preoperative CRT and strongly predict for worse DFS, further supporting their clinical relevance. In multivariable analysis, leukocytosis ( p = 0.001) had a stronger prognostic impact on the primary clinical endpoint of our trial, DFS, compared to neutrophilia ( p = 0.007), and thus, might be clinically more important to predict patient outcome.…”

Section: Discussionmentioning

confidence: 67%

Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO‐04 randomized phase 3 rectal cancer trial

Diefenhardt

Hofheinz

Martin

et al. 2019

Intl Journal of Cancer

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Peripheral blood leukocytosis and neutrophilia reflect cancer inflammation and have been proposed as prognostic immunological biomarkers in various malignancies. However, previous studies were limited by their retrospective nature and small patient numbers. Baseline peripheral blood leukocytes, neutrophils, hemoglobin, platelets, lactate dehydrogenase and carcinoembryonic antigen (CEA) were correlated with clinicopathologic characteristics, and clinical outcome in 1236 patients with rectal cancer treated with 5‐FU‐based preoperative chemoradiotherapy (CRT) alone or with oxaliplatin followed by surgery and adjuvant chemotherapy within the CAO/ARO/AIO‐04 randomized phase 3 trial. Multivariable analyses were performed using Cox regression models. After a median follow‐up of 50 months, baseline leukocytosis remained an independent adverse prognostic factor for disease‐free survival (DFS; HR 1.457; 95% CI 1.163–1.825; p = 0.001), distant metastasis (HR 1.696; 95% CI 1.266–2.273; p < 0.001) and overall survival (OS; HR 1.716; 95% CI 1.264–2.329; p = 0.001) in multivariable analysis. Similar significant findings were observed for neutrophilia and high CEA levels. Conversely, treatment‐induced leukopenia correlated with favorable DFS (p = 0.037), distant metastasis (p = 0.028) and OS (p = 0.012). Intriguingly, addition of oxaliplatin to 5‐FU CRT resulted in a significant DFS improvement only in patients with neutrophilia and leukocytosis (p = 0.028 and p = 0.002). Our findings have important clinical implications and provide high‐level evidence on the adverse prognostic role of leukocytes and neutrophils, and the impact of chemotherapy in the context of these biomarkers. These data could help guide patient stratification and should be further validated within prospective studies.

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Section: Discussionmentioning

confidence: 67%

Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO‐04 randomized phase 3 rectal cancer trial

Diefenhardt

Hofheinz

Martin

et al. 2019

Intl Journal of Cancer

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“…Other studies have also shown a prognostic effect of response to neoadjuvant treatment. 196,197 In addition to its prognostic value, there is some initial evidence of predictive value to neoadjuvant treatment response. Subgroup analysis of the EORTC 22921 trial showed that patients downstaged to ypT0-2 were more likely to benefit from adjuvant chemotherapy than those with ypT3-4 staging.…”

Section: Preoperative Chemotherapy Without Chemortmentioning

confidence: 99%

Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology

Benson¹,

Venook²,

Al-Hawary³

et al. 2018

J Natl Compr Canc Netw

809

670

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The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Rectal Cancer address diagnosis, staging, surgical management, perioperative treatment, management of recurrent and metastatic disease, disease surveillance, and survivorship in patients with rectal cancer. This portion of the guidelines focuses on the management of localized disease, which involves careful patient selection for curative-intent treatment options that sequence multimodality therapy usually comprised of chemotherapy, radiation, and surgical resection.

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“…97 Other studies found a more stepwise relationship in all TRG-grades, with better survival in higher TRG. 91,291 Further, one study with focus on the near pCR patients concluded that these patients have at a higher risk for recurrence than expected. 95 The results from the Stockholm III trial indicates that patients with TRG 3 does not have the same excellent outcomes as patients with TRG 4/pCR.…”

Section: Tumour Regressionmentioning

confidence: 99%

Tumour regression after radiotherapy for rectal cancer – Results from the randomised Stockholm III trial

Erlandsson

Lörinc

Ahlberg

et al. 2019

Radiotherapy and Oncology

109

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Tumor Regression Grading After Preoperative Chemoradiotherapy as a Prognostic Factor and Individual-Level Surrogate for Disease-Free Survival in Rectal Cancer

Abstract: Higher TRG after preoperative CRT predicted a favorable long-term outcome. At the individual patient level, TRG was a surrogate marker for DFS. Further phase III trials are needed to validate TRG as a surrogate at trial level.

Cited by 115 publications

References 29 publications

Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO‐04 randomized phase 3 rectal cancer trial

Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO‐04 randomized phase 3 rectal cancer trial

Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology

Tumour regression after radiotherapy for rectal cancer – Results from the randomised Stockholm III trial

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