Histopathological growth patterns as biomarker for adjuvant systemic chemotherapy in patients with resected colorectal liver metastases

Abstract Adjuvant systemic chemotherapy (CTx) is widely administered in patients with colorectal liver metastases (CRLM). Histopathological growth patterns (HGPs) are an independent prognostic factor for survival after complete resection. This study evaluates whether HGPs can predict the effectiveness of adjuvant CTx in patients with resected CRLM. Two main types of HGPs can be distinguished; the desmoplastic type and the non-desmoplastic type. Uni- and multivariable analyses for overall survival (OS) and disease-free survival (DFS) were performed, in both patients treated with and without preoperative chemotherapy. A total of 1236 patients from two tertiary centers (Memorial Sloan Kettering Cancer Center, New York, USA; Erasmus MC Cancer Institute, Rotterdam, The Netherlands) were included (period 2000–2016). A total of 656 patients (53.1%) patients received preoperative chemotherapy. Adjuvant CTx was only associated with a superior OS in non-desmoplastic patients that had not been pretreated (adjusted hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.37–0.73, p < 0.001), and not in desmoplastic patients (adjusted HR 1.78, 95% CI 0.75–4.21, p = 0.19). In pretreated patients no significant effect of adjuvant CTx was observed, neither in the desmoplastic group (adjusted HR 0.83, 95% CI 0.49–1.42, p = 0.50) nor in the non-desmoplastic group (adjusted HR 0.96, 95% CI 0.71–1.29, p = 0.79). Similar results were found for DFS, with a superior DFS in non-desmoplastic patients treated with adjuvant CTx (HR 0.71, 95% CI 0.55–0.93, p < 0.001) that were not pretreated. Adjuvant CTx seems to improve OS and DFS after resection of non-desmoplastic CRLM. However, this effect was only observed in patients that were not treated with chemotherapy.

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Preoperative systemic chemotherapy alters the histopathological growth patterns of colorectal liver metastases

The Journal of Pathology Clinical Research ◽

10.1002/cjp2.235 ◽

2021 ◽

Author(s):

Pieter MH Nierop ◽

Diederik J Höppener ◽

Florian E Buisman ◽

Eric P Stok ◽

Boris Galjart ◽

...

Keyword(s):

Liver Metastases ◽

Colorectal Liver Metastases ◽

Systemic Chemotherapy ◽

Growth Patterns ◽

Histopathological Growth Patterns

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Histopathological growth patterns as a guide for adjuvant systemic chemotherapy in patients with resected colorectal liver metastases

European Journal of Surgical Oncology ◽

10.1016/j.ejso.2018.10.069 ◽

2019 ◽

Vol 45 (2) ◽

pp. e10

Author(s):

F. Buisman ◽

E. van der Stok ◽

B. Galjart ◽

P. Vermeulen ◽

P. Allen ◽

...

Keyword(s):

Liver Metastases ◽

Colorectal Liver Metastases ◽

Systemic Chemotherapy ◽

Growth Patterns ◽

Histopathological Growth Patterns

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Is Hepatic Resection Justified After Chemotherapy in Patients With Colorectal Liver Metastases and Lymph Node Involvement?

Journal of Clinical Oncology ◽

10.1200/jco.2007.15.7297 ◽

2008 ◽

Vol 26 (22) ◽

pp. 3672-3680 ◽

Cited By ~ 124

Author(s):

René Adam ◽

Robbert J. de Haas ◽

Dennis A. Wicherts ◽

Thomas A. Aloia ◽

Valérie Delvart ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Lymph Node ◽

Liver Metastases ◽

Preoperative Chemotherapy ◽

Colorectal Liver Metastases ◽

Regional Lymph Node ◽

Young Patients ◽

Disease Free Survival ◽

High Risk Group

Purpose For patients with colorectal liver metastases (CLM), regional lymph node (RLN) involvement is one of the worst prognostic factors. The objective of this study was to evaluate the ability of a multidisciplinary approach, including preoperative chemotherapy and hepatectomy, to improve patient outcomes. Patients and Methods Outcomes for a consecutively treated group of patients with CLM and simultaneous RLN involvement were compared with a cohort of patients without RLN involvement. Univariate and multivariate analysis of clinical variables was used to identify prognostic factors in this high-risk group. Results Of the 763 patients who underwent resection at our institution for CLM between 1992 and 2006, 47 patients (6%) were treated with hepatectomy and simultaneous lymphadenectomy. All patients had received preoperative chemotherapy. Five-year overall survival (OS) for patients with and without RLN involvement were 18% and 53%, respectively (P < .001). Five-year disease-free survival rates were 11% and 23%, respectively (P = .004). When diagnosed preoperatively, RLN involvement had an increased 5-year OS compared with intraoperative detection, although the difference was not significant (35% v 10%; P = .18). Location of metastatic RLN strongly influenced survival, with observed 5-year OS of 25% for pedicular, 0% for celiac, and 0% for para-aortic RLN (P = .001). At multivariate analysis, celiac RLN involvement and age ≥ 40 years were identified as independent poor prognostic factors. Conclusion Combined liver resection and pedicular lymphadenectomy is justified when RLN metastases respond to or are stabilized by preoperative chemotherapy, particularly in young patients. In contrast, this approach does not benefit patients with celiac and/or para-aortic RLN involvement, even when patients’ disease is responding to preoperative chemotherapy.

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A single-arm, phase II study of intrahepatic chemotherapy in patients with unresectable colorectal liver metastases.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.162 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 162-162

Author(s):

Kate Elenna Besel ◽

Yoo-Joung Ko ◽

Paul Jack Karanicolas ◽

Christina Yiyoung Kim

Keyword(s):

Liver Metastases ◽

Colorectal Liver Metastases ◽

Systemic Chemotherapy ◽

Infusion Pump ◽

Disease Free Survival ◽

The United States ◽

Median Number ◽

Time To Progression ◽

Unresectable Colorectal Liver Metastases ◽

Number Of Cycles

162 Background: In Canada, the standard of care for patients with unresectable colorectal liver metastases (uCRLM) is systemic chemotherapy and/or best supportive care. Intrahepatic chemotherapy using floxuridine (FUDR), in addition to systemic chemotherapy, is available in the United States but its adoption outside major centers has been limited. Methods: A single-center, prospective study of intrahepatic chemotherapy for the treatment of patients with uCRLM was initiated at Sunnybrook Health Sciences Centre in 2014. Patients underwent implantation of a hepatic infusion pump with resection of their primary tumor (if in place). Patients were treated with FUDR in addition to systemic chemotherapy (FOLFIRI or FOLFOX). Study objectives include the rate of conversion to complete resection, time to progression (TTP), disease-free survival (DFS), time to progression in liver, overall survival (OS), andresponse rate (RR). Results: From 2014 to present, 46 patients have been enrolled. Median age at the time of HAIP placement was 51 years (30-72 years). Males accounted for 61% (28/46). All patients received at least one cycle of systemic chemotherapy prior to surgery. 44 patients received a minimum of one cycle of FUDR, with the median number of cycles of FUDR received being 7.5 (0-28 cycles). Only one patient was unable to receive any FUDR after surgery. Response rate was 80% (n = 37/46). Three patients are too early for assessment. Eight (17.4%) patients have undergone liver resection. Median number of cycles of FUDR prior to resection was 7 (4-13 cycles). TTP, DFS, time to progression in liver, OS, and safety will be presented. Conclusions: The addition of intrahepatic chemotherapy to best systemic therapy may provide an increase in the rate of conversion to complete hepatic resection in patients with uCRLM. Clinical trial information: ON1233.

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Distinguishing pure histopathological growth patterns of colorectal liver metastases on CT using deep learning and radiomics: a pilot study

Clinical & Experimental Metastasis ◽

10.1007/s10585-021-10119-6 ◽

2021 ◽

Vol 38 (5) ◽

pp. 483-494

Author(s):

Martijn P. A. Starmans ◽

Florian E. Buisman ◽

Michel Renckens ◽

François E. J. A. Willemssen ◽

Sebastian R. van der Voort ◽

...

Keyword(s):

Liver Metastases ◽

Colorectal Liver Metastases ◽

Cross Validation ◽

Area Under The Curve ◽

Growth Patterns ◽

Learning Approaches ◽

Intra Class Correlation ◽

Preoperative Prediction ◽

Intra Class Correlation Coefficient ◽

Histopathological Growth Patterns

AbstractHistopathological growth patterns (HGPs) are independent prognosticators for colorectal liver metastases (CRLM). Currently, HGPs are determined postoperatively. In this study, we evaluated radiomics for preoperative prediction of HGPs on computed tomography (CT), and its robustness to segmentation and acquisition variations. Patients with pure HGPs [i.e. 100% desmoplastic (dHGP) or 100% replacement (rHGP)] and a CT-scan who were surgically treated at the Erasmus MC between 2003–2015 were included retrospectively. Each lesion was segmented by three clinicians and a convolutional neural network (CNN). A prediction model was created using 564 radiomics features and a combination of machine learning approaches by training on the clinician’s and testing on the unseen CNN segmentations. The intra-class correlation coefficient (ICC) was used to select features robust to segmentation variations; ComBat was used to harmonize for acquisition variations. Evaluation was performed through a 100 × random-split cross-validation. The study included 93 CRLM in 76 patients (48% dHGP; 52% rHGP). Despite substantial differences between the segmentations of the three clinicians and the CNN, the radiomics model had a mean area under the curve of 0.69. ICC-based feature selection or ComBat yielded no improvement. Concluding, the combination of a CNN for segmentation and radiomics for classification has potential for automatically distinguishing dHGPs from rHGP, and is robust to segmentation and acquisition variations. Pending further optimization, including extension to mixed HGPs, our model may serve as a preoperative addition to postoperative HGP assessment, enabling further exploitation of HGPs as a biomarker.

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Histopathological growth patterns and positive margins after resection of colorectal liver metastases

HPB ◽

10.1016/j.hpb.2018.06.114 ◽

2018 ◽

Vol 20 ◽

pp. S223-S224 ◽

Cited By ~ 1

Author(s):

P.M.H. Nierop ◽

E.P. van der Stok ◽

B. Groot Koerkamp ◽

P.J. Allen ◽

W.R. Jarnagin ◽

...

Keyword(s):

Liver Metastases ◽

Colorectal Liver Metastases ◽

Growth Patterns ◽

Positive Margins ◽

Histopathological Growth Patterns

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LiverMetSurvey: Analysis of clinicopathologic factors associated with the efficacy of preoperative chemotherapy in 2,122 patients with colorectal liver metastases

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3521 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3521-3521 ◽

Cited By ~ 2

Author(s):

R. Adam ◽

T. Aloia ◽

J. Figueras ◽

L. Capussotti ◽

G. Poston ◽

...

Keyword(s):

Liver Metastases ◽

Preoperative Chemotherapy ◽

Primary Tumor ◽

Colorectal Liver Metastases ◽

Systemic Chemotherapy ◽

Treatment Options ◽

Treatment Strategies ◽

Multimodality Treatment ◽

Primary Tumor Site ◽

Number Of Patients

3521 Background: LiverMetSurvey is an international, internet-based registry designed to assess the efficacy of multimodality treatment options for colorectal liver metastases (CLM) by analyzing outcomes following hepatic resection (HR) in a large number of patients. Methods: Data were analyzed for the 2,122 patients entered into LiverMetSurvey by six hepatobiliary centers from inception to August 2004 (HR: 1974 to 2004; 1,306 men: 816 women; mean age: 61 years). The distributions of potential prognostic factors including age, sex, primary tumor site, timing of metastasis diagnosis, tumor number, diameter of the largest metastasis, bilaterality, and treatment with chemotherapy were compared to survivals using univariate and multivariate statistics. Results: Metastases originated in the colon in 69% of patients and were synchronous (diagnosed within 3 mo of primary tumor treatment) in 49% of patients. 34% of patients had ≥ 3 metastases and tumors were distributed bilaterally in 43% of cases. The mean size of the largest metastasis was 41.8 mm. 55% of patients were treated with preoperative systemic chemotherapy. Following resection, 60-day mortality was 1.2% and median, 5-year, and 10-year overall survivals (OS) were 46 mo, 42%, and 26%, respectively. Variables independently associated with poor prognosis included number of metastases > 3 (p<0.0001), bilateral metastases (p=0.0002), and size of the largest metastasis > 5 cm (p=0.03). Preoperative chemotherapy (PC) did not appear to benefit patients with solitary CLM (5-yr OS: PC 45% vs. no PC 58%), but was associated with improved survival in patients with > 5 metastases (5-yr OS: PC 22% vs. no PC 12%). Conclusions: Assessment of outcomes for the first 2,122 registrants to LiverMetSurvey not only confirms the prognostic importance of intrahepatic tumor burden, but also indicates that the ability of preoperative systemic chemotherapy to improve survivals is limited to patients with multiple (> 5) metastases. In addition, this analysis demonstrates the potential for LiverMetSurvey, which is now prospectively enrolling patients from over 40 centers, to determine the therapeutic value of current and future treatment strategies. No significant financial relationships to disclose.

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