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Management of Colorectal Cancer Metastatic Disease
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Management of Colorectal Cancer Metastatic Disease

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 50344

Special Issue Editor

Prof. Dr. Constantinos T. Sofocleous

E-Mail Website
Guest Editor
Weill-Cornell Medical College, Attending Physician Interventional Oncology IR Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Interests: metastatic colorectal cancer; liver tumor ablation; lung tumor ablation; intra-arterial hepatic therapies; radioembolization; debiri tace
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Interventional oncology is a subspecialty of interventional radiology that is dedicated to the management of cancer through the use of image-guided therapies. In this Special Issue, we will review image-guided therapies used in the management of hepatic and pulmonary metastases. Thermal ablation is a minimally invasive, image-guided therapy that can offer a local cure in selected patients with limited metastatic disease in the liver and lungs. Within the last 5 years, several publications have shown that limited hepatic metastases ablated with margins offer excellent local tumor control with a low morbidity rate. The indications and outcomes of the use of thermal ablation in the setting of oligometastatic disease will be presented in detail. A randomized controlled trial in initially unresectable patients indicated that the combination of thermal ablation with standard-of care-chemotherapy resulted in a survival benefit when compared to patients treated with chemotherapy alone. Discussions include comparisons to other image-guided therapies, such as image-guided radiotherapy. Image-guided therapies are also used in the management of advanced disease, especially chemorefractory hepatic metastases. These are hepatic-directed intra-arterial therapies including the use of Yttrium 90 radioembolization as well as chemotherapy (irinotecan) eluding beads (DEBIRI-TACE). The outcomes of image guided therapies are influenced by tumor genetics. For example, the negative impact of KRAS mutations on both disease control and patient survival after image-guided therapies has been shown. The indications, outcomes, and evolution of image-guided therapies are discussed in detail.

This Special Issue solicits review and original papers on the use of interventional oncology and image-guided therapies in the management of liver and pulmonary metastases associated with colorectal cancer.

Prof. Dr. Constantinos T. Sofocleous
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Interventional Oncology in Metastatic Colorectal Cancer
  • Metastatic Colorectal cancer
  • Metastatic Colorectal Cancer Liver Tumor Ablation
  • Metastatic Colorectal Cancer Lung Tumor Ablation
  • Metastatic Colorectal Cancer Liver Intrarterial hepatic Therapies
  • Metastatic Colorectal Cancer Liver Radioembolization
  • Metastatic Colorectal Cancer DEBIRI TACE

Published Papers (18 papers)

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Research

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13 pages, 6082 KiB  
Article
Real-Time Split-Dose PET/CT-Guided Ablation Improves Colorectal Liver Metastasis Detection and Ablation Zone Margin Assessments without the Need for Repeated Contrast Injection
by Mahdi Zirakchian Zadeh, Randy Yeh, Henry S. Kunin, Assen S. Kirov, Elena N. Petre, Mithat Gönen, Mikhail Silk, Francois H. Cornelis, Kevin C. Soares, Etay Ziv, Stephen B. Solomon, Vlasios S. Sotirchos and Constantinos T. Sofocleous
Cancers 2022, 14(24), 6253; https://doi.org/10.3390/cancers14246253 - 19 Dec 2022
Cited by 8 | Viewed by 2167
Abstract
Background: Real-time split-dose PET can identify the targeted colorectal liver metastasis (CLM) and eliminate the need for repeated contrast administration before and during thermal ablation (TA). This study aimed to assess the added value of pre-ablation real-time split-dose PET when combined with non-contract [...] Read more.
Background: Real-time split-dose PET can identify the targeted colorectal liver metastasis (CLM) and eliminate the need for repeated contrast administration before and during thermal ablation (TA). This study aimed to assess the added value of pre-ablation real-time split-dose PET when combined with non-contract CT in the detection of CLM for ablation and the evaluation of the ablation zone and margins. Methods: A total of 190 CLMs/125 participants from two IRB-approved prospective clinical trials using PET/CT-guided TA were analyzed. Based on detection on pre-TA imaging, CLMs were categorized as detectable, non-detectable, and of poor conspicuity on CT alone, and detectable, non-detectable, and low FDG-avidity on PET/CT after the initial dose. Ablation margins around the targeted CLM were evaluated using a 3D volumetric approach. Results: We found that 129/190 (67.9%) CLMs were detectable on CT alone, and 61/190 CLMs (32.1%) were undetectable or of poor conspicuity, not allowing accurate depiction and targeting by CT alone. Thus, the theoretical 5- and 10-mm margins could not be defined in these tumors (32.1%) using CT alone. When TA intraprocedural PET/CT images are obtained and inspected (fused PET/CT), only 4 CLM (2.1%) remained undetectable or had a low FDG avidity. Conclusions: The addition of PET to non-contrast CT improved CLM detection for ablation targeting, margin assessments, and continuous depiction of the FDG avid CLMs during the ablation without the need for multiple intravenous contrast injections pre- and intra-procedurally. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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16 pages, 1682 KiB  
Article
Comparative Effectiveness of Bevacizumab versus Cetuximab in Metastatic Colorectal Cancer Patients without Primary Tumor Resection
by Yi-Chia Su, Chih-Chien Wu, Chien-Chou Su, Meng-Che Hsieh, Ching-Lan Cheng and Yea-Huei Kao Yang
Cancers 2022, 14(9), 2118; https://doi.org/10.3390/cancers14092118 - 24 Apr 2022
Cited by 4 | Viewed by 2028
Abstract
Primary tumor resection may be unfeasible in metastatic colorectal cancer. We determined the effects of bevacizumab and cetuximab therapies on survival or conversion surgery in patients with metastatic colorectal cancer who did not undergo primary tumor resection. This retrospective cohort study enrolled 8466 [...] Read more.
Primary tumor resection may be unfeasible in metastatic colorectal cancer. We determined the effects of bevacizumab and cetuximab therapies on survival or conversion surgery in patients with metastatic colorectal cancer who did not undergo primary tumor resection. This retrospective cohort study enrolled 8466 patients who underwent first-line bevacizumab- or cetuximab-based therapy. We analyzed the data of both therapies in patients who did not undergo primary tumor resection. Overall survival after targeted therapy plus chemotherapy was assessed. The groups were matched using propensity score matching and weighting. Cetuximab resulted in lower mortality than bevacizumab (hazard ratio (HR) = 0.75); however, it did not have the same effect in patients that underwent primary tumor resection (HR = 0.95) after propensity score weighting. Among patients treated with targeted agents, primary tumor resection was associated with lower mortality among those who received both bevacizumab (HR = 0.60) and cetuximab (HR = 0.75). Among patients that did not undergo primary tumor resection, multivariable analysis for conversion surgery showed that the cetuximab group (HR = 1.82) had a significantly higher metastasectomy rate. In these patients, cetuximab-based therapy was associated with significantly better survival compared with bevacizumab-based therapy. Cetuximab also yielded a higher conversion surgery rate. These findings demonstrate the importance of stratification by primary tumor resection in the application of current treatment guidelines and initiation of future clinical trials. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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21 pages, 1802 KiB  
Article
Health-Related Quality of Life in Metastatic Colorectal Cancer Patients Treated with Curative Resection and/or Local Ablative Therapy or Systemic Therapy in the Finnish RAXO-Study
by Kaisa Lehtomäki, Hanna P. Stedt, Emerik Osterlund, Timo Muhonen, Leena-Maija Soveri, Päivi Halonen, Tapio K. Salminen, Juha Kononen, Raija Kallio, Annika Ålgars, Eetu Heervä, Annamarja Lamminmäki, Aki Uutela, Arno Nordin, Juho Lehto, Tiina Saarto, Harri Sintonen, Pirkko-Liisa Kellokumpu-Lehtinen, Raija Ristamäki, Bengt Glimelius, Helena Isoniemi and Pia Osterlundadd Show full author list remove Hide full author list
Cancers 2022, 14(7), 1713; https://doi.org/10.3390/cancers14071713 - 28 Mar 2022
Cited by 8 | Viewed by 2507
Abstract
Metastasectomy and/or local ablative therapy in metastatic colorectal cancer (mCRC) patients often provide long-term survival. Health-related quality of life (HRQoL) data in curatively treated mCRC are limited. In the RAXO-study that evaluated repeated resectability, a multi-cross-sectional HRQoL substudy with 15D, EQ-5D-3L, QLQ-C30, and [...] Read more.
Metastasectomy and/or local ablative therapy in metastatic colorectal cancer (mCRC) patients often provide long-term survival. Health-related quality of life (HRQoL) data in curatively treated mCRC are limited. In the RAXO-study that evaluated repeated resectability, a multi-cross-sectional HRQoL substudy with 15D, EQ-5D-3L, QLQ-C30, and QLQ-CR29 questionnaires was conducted. Mean values of patients in different treatment groups were compared with age- and gender-standardized general Finnish populations. The questionnaire completion rate was 444/477 patients (93%, 1751 questionnaires). Mean HRQoL was 0.89–0.91 with the 15D, 0.85–0.87 with the EQ-5D, 68–80 with the EQ-5D-VAS, and 68–79 for global health status during curative treatment phases, with improvements in the remission phase (disease-free >18 months). In the remission phase, mean EQ-5D and 15D scores were similar to the general population. HRQoL remained stable during first- to later-line treatments, when the aim was no longer cure, and declined notably when tumour-controlling therapy was no longer meaningful. The symptom burden affecting mCRC survivors’ well-being included insomnia, impotence, urinary frequency, and fatigue. Symptom burden was lower after treatment and slightly higher, though stable, through all phases of systemic therapy. HRQoL was high in curative treatment phases, further emphasizing the strategy of metastasectomy in mCRC when clinically meaningful. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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14 pages, 1441 KiB  
Article
Biopsy and Margins Optimize Outcomes after Thermal Ablation of Colorectal Liver Metastases
by Nikiforos Vasiniotis Kamarinos, Efsevia Vakiani, Mithat Gonen, Nancy E. Kemeny, Carlie Sigel, Leonard B. Saltz, Karen T. Brown, Anne M. Covey, Joseph P. Erinjeri, Lynn A. Brody, Etay Ziv, Hooman Yarmohammadi, Henry Kunin, Afsar Barlas, Elena N. Petre, Peter T. Kingham, Michael I. D’Angelica, Katia Manova-Todorova, Stephen B. Solomon and Constantinos T. Sofocleous
Cancers 2022, 14(3), 693; https://doi.org/10.3390/cancers14030693 - 29 Jan 2022
Cited by 14 | Viewed by 2085
Abstract
Background: Thermal ablation is a definitive local treatment for selected colorectal liver metastases (CLM) that can be ablated with adequate margins. A critical limitation has been local tumor progression (LTP). Methods: This prospective, single-group, phase 2 study enrolled patients with CLM < 5 [...] Read more.
Background: Thermal ablation is a definitive local treatment for selected colorectal liver metastases (CLM) that can be ablated with adequate margins. A critical limitation has been local tumor progression (LTP). Methods: This prospective, single-group, phase 2 study enrolled patients with CLM < 5 cm in maximum diameter, at a tertiary cancer center between November 2009 and February 2019. Biopsy of the ablation zone center and margin was performed immediately after ablation. Viable tumor in tissue biopsy and ablation margins < 5 mm were assessed as predictors of 12-month LTP. Results: We enrolled 107 patients with 182 CLMs. Mean tumor size was 2.0 (range, 0.6–4.6) cm. Microwave ablation was used in 51% and radiofrequency ablation in 49% of tumors. The 12- and 24-month cumulative incidence of LTP was 22% (95% confidence interval [CI]: 17, 29) and 29% (95% CI: 23, 36), respectively. LTP at 12 months was 7% (95% CI: 3, 14) for the biopsy tumor-negative ablation zone with margins ≥ 5 mm vs. 63% (95% CI: 35, 85) for the biopsy-positive ablation zone with margins < 5 mm (p < 0.001). Conclusions: Biopsy-proven complete tumor ablation with margins of at least 5 mm achieves optimal local tumor control for CLM, regardless of the ablation modality used. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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23 pages, 4623 KiB  
Article
Repeat Local Treatment of Recurrent Colorectal Liver Metastases, the Role of Neoadjuvant Chemotherapy: An Amsterdam Colorectal Liver Met Registry (AmCORE) Based Study
by Madelon Dijkstra, Sanne Nieuwenhuizen, Robbert S. Puijk, Florentine E. F. Timmer, Bart Geboers, Evelien A. C. Schouten, Jip Opperman, Hester J. Scheffer, Jan J. J. de Vries, Kathelijn S. Versteeg, Birgit I. Lissenberg-Witte, Martijn R. Meijerink and Monique Petrousjka van den Tol
Cancers 2021, 13(19), 4997; https://doi.org/10.3390/cancers13194997 - 05 Oct 2021
Cited by 7 | Viewed by 2582
Abstract
This cohort study aimed to evaluate efficacy, safety, and survival outcomes of neoadjuvant chemotherapy (NAC) followed by repeat local treatment compared to upfront repeat local treatment of recurrent colorectal liver metastases (CRLM). A total of 152 patients with 267 tumors from the prospective [...] Read more.
This cohort study aimed to evaluate efficacy, safety, and survival outcomes of neoadjuvant chemotherapy (NAC) followed by repeat local treatment compared to upfront repeat local treatment of recurrent colorectal liver metastases (CRLM). A total of 152 patients with 267 tumors from the prospective Amsterdam Colorectal Liver Met Registry (AmCORE) met the inclusion criteria. Two cohorts of patients with recurrent CRLM were compared: patients who received chemotherapy prior to repeat local treatment (32 patients) versus upfront repeat local treatment (120 patients). Data from May 2002 to December 2020 were collected. Results on the primary endpoint overall survival (OS) and secondary endpoints local tumor progression-free survival (LTPFS) and distant progression-free survival (DPFS) were reviewed using the Kaplan–Meier method. Subsequently, uni- and multivariable Cox proportional hazard regression models, accounting for potential confounders, were estimated. Additionally, subgroup analyses, according to patient, initial and repeat local treatment characteristics, were conducted. Procedure-related complications and length of hospital stay were compared using chi-square test and Fisher’s exact test. The 1-, 3-, and 5-year OS from date of diagnosis of recurrent disease was 98.6%, 72.5%, and 47.7% for both cohorts combined. The crude survival analysis did not reveal a significant difference in OS between the two cohorts (p = 0.834), with 1-, 3-, and 5-year OS of 100.0%, 73.2%, and 57.5% for the NAC group and 98.2%, 72.3%, and 45.3% for the upfront repeat local treatment group, respectively. After adjusting for two confounders, comorbidities (p = 0.010) and primary tumor location (p = 0.023), the corrected HR in multivariable analysis was 0.839 (95% CI, 0.416–1.691; p = 0.624). No differences between the two cohorts were found with regards to LTPFS (HR = 0.662; 95% CI, 0.249–1.756; p = 0.407) and DPFS (HR = 0.798; 95% CI, 0.483–1.318; p = 0.378). No heterogeneous treatment effects were detected in subgroup analyses according to patient, disease, and treatment characteristics. No significant difference was found in periprocedural complications (p = 0.843) and median length of hospital stay (p = 0.600) between the two cohorts. Chemotherapy-related toxicity was reported in 46.7% of patients. Adding NAC prior to repeat local treatment did not improve OS, LTPFS, or DPFS, nor did it affect periprocedural morbidity or length of hospital stay. The results of this comparative assessment do not substantiate the routine use of NAC prior to repeat local treatment of CRLM. Because the exact role of NAC (in different subgroups) remains inconclusive, we are currently designing a phase III randomized controlled trial (RCT), COLLISION RELAPSE trial, directly comparing upfront repeat local treatment (control) to neoadjuvant systemic therapy followed by repeat local treatment (intervention). Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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17 pages, 3012 KiB  
Article
Role of Resin Microsphere Y90 Dosimetry in Predicting Objective Tumor Response, Survival and Treatment Related Toxicity in Surgically Unresectable Colorectal Liver Metastasis: A Retrospective Single Institution Study
by Tina Sankhla, Bernard Cheng, Nariman Nezami, Minzhi Xing, Ila Sethi, Zachary Bercu, David Brandon, Bill Majdalany, David M. Schuster and Nima Kokabi
Cancers 2021, 13(19), 4908; https://doi.org/10.3390/cancers13194908 - 29 Sep 2021
Cited by 10 | Viewed by 2897
Abstract
Purpose: To Evaluate the correlation between tumor dosimetric parameters with objective tumor response (OR) and overall survival (OS) in patients with surgically unresectable colorectal liver metastasis (CRLM) undergoing resin-based Ytrrium-90 selective internal radiation therapy (Y90 SIRT). Materials and Methods: 45 consecutive patients with [...] Read more.
Purpose: To Evaluate the correlation between tumor dosimetric parameters with objective tumor response (OR) and overall survival (OS) in patients with surgically unresectable colorectal liver metastasis (CRLM) undergoing resin-based Ytrrium-90 selective internal radiation therapy (Y90 SIRT). Materials and Methods: 45 consecutive patients with CRLM underwent resin-based Y90 SIRT in one or both hepatic lobes (66 treated lobes total). Dose volume histograms were created with MIM Sureplan® v.6.9 using post-treatment SPECT/CT. Dosimetry analyses were based on the cumulative volume of the five largest tumors in each treatment session and non-tumoral liver (NTL) dose. Receiver operating characteristic (ROC) curve was used to evaluate tumor dosimetric factors in predicting OR by Response Evaluation Criteria for Solid Tumors at 3 months post-Y90. Additionally, ROC curve was used to evaluate non-tumoral liver dose as a predictor of grade ≥ 3 liver toxicity and radioembolization induced liver disease (REILD) 3 months post Y90. To minimize for potential confounding demographic and clinical factors, univariate and multivariate analysis of survival with mean tumor dose as one of the factors were also performed. Kaplan-Meier estimation was used for OS analysis from initial Y90 SIRT. Results: 26 out of 45 patients had OR with a median OS of 17.2 months versus 6.8 months for patients without OR (p < 0.001). Mean tumor dose (TD) of the five largest tumors was the strongest predictor of OR with an area under the curve of 0.73 (p < 0.001). Minimum TD, and TD to 30%, 50%, and 70% of tumor volume also predicted OR (p’s < 0.05). Mean TD ≥ 100 Gy predicted a significantly prolonged median OS of 19 vs. 11 months for those receiving TD < 100 Gy (p = 0.016). On univariate analysis, mean TD < 100 Gy, presence of any genomic mutation, presence of MAPK pathway mutation, bilobar hepatic metastases and diffuse metastatic disease (>10 lesions per liver lobe) were found to be predictors of shorter median OS. On multivariate analysis, mean TD < 100 Gy, presence of any genomic mutation, and diffuse hepatic metastatic disease were found to be independent predictors of shorter OS. Overall, six (13.3%) patients developed grade ≥ 3 liver toxicity post Y90 of whom two (4.4%) patients developed REILD. No dose threshold predicting grade ≥ 3 liver toxicity or REILD was identified. Conclusions: Mean TD ≥ 100 Gy in patients with unresectable CRLM undergoing resin-based Y90 SIRT predicts OR and prolonged OS. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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20 pages, 3629 KiB  
Article
Thermal Ablation versus Stereotactic Ablative Body Radiotherapy to Treat Unresectable Colorectal Liver Metastases: A Comparative Analysis from the Prospective Amsterdam CORE Registry
by Sanne Nieuwenhuizen, Madelon Dijkstra, Robbert S. Puijk, Florentine E. F. Timmer, Irene M. Nota, Jip Opperman, Bente van den Bemd, Bart Geboers, Alette H. Ruarus, Evelien A. C. Schouten, Jan J. J. de Vries, Hester J. Scheffer, Anne M. van Geel, Jan Hein T. M. van Waesberghe, Rutger-Jan Swijnenburg, Kathelijn S. Versteeg, Birgit I. Lissenberg-Witte, M. Petrousjka van den Tol, Cornelis J. A. Haasbeek and Martijn R. Meijerink
Cancers 2021, 13(17), 4303; https://doi.org/10.3390/cancers13174303 - 26 Aug 2021
Cited by 13 | Viewed by 3186
Abstract
Thermal ablation and stereotactic ablative radiotherapy (SABR) are techniques to eradicate colorectal liver metastases (CRLM). This study compares the safety, efficacy and long-term oncological outcomes of these treatment methods. All prospectively registered patients (AmCORE registry) treated with thermal ablation or SABR alone for [...] Read more.
Thermal ablation and stereotactic ablative radiotherapy (SABR) are techniques to eradicate colorectal liver metastases (CRLM). This study compares the safety, efficacy and long-term oncological outcomes of these treatment methods. All prospectively registered patients (AmCORE registry) treated with thermal ablation or SABR alone for unresectable CRLM between 2007 and 2020 were analyzed using multivariate Cox-proportional hazard regression. In total 199 patients were included for analysis: 144 (400 CRLM) thermal ablation; 55 (69 CRLM) SABR. SABR patients were characterized by older age (p = 0.006), extrahepatic disease at diagnosis (p = 0.004) and larger tumors (p < 0.001). Thermal ablation patients were more likely to have synchronous disease, higher clinical risk scores (p = 0.030) and higher numbers of CRLMs treated (p < 0.001). Mortality was zero and morbidity low in both groups: no serious adverse events were recorded following SABR (n = 0/55) and nine (n = 9/144 [6.3%]; all CTCAE grade 3) after thermal ablation. SABR was associated with an inferior overall survival (OS) (median OS 53.0 months vs. 27.4 months; HR = 1.29, 95% CI 1.12–1.49; p = 0.003), local tumor progression-free survival (LTPFS) per-tumor (HR = 1.24, 95% CI 1.01–1.52; p = 0.044) and local control per-patient (HR = 1.57, 95% CI 1.20–2.04; p = 0.001) and per-tumor (HR = 1.89, 95% CI 1.44–2.49; p < 0.001). In this study thermal ablation was superior to SABR with regard to OS, LTPFS and local control, albeit at the cost of a limited risk of serious adverse events. Further studies are required to assess whether the worse outcomes following SABR were the effect of true differences in ablative treatment or a result of residual confounding. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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11 pages, 651 KiB  
Article
Hospitalizations and Clinical Outcome in Metastatic Colorectal Cancer During Regorafenib or TAS-102 Therapy
by Florian Huemer, Gudrun Piringer, Verena Schlintl, Hubert Hackl, Gabriel Rinnerthaler, Josef Thaler, Richard Greil and Lukas Weiss
Cancers 2020, 12(10), 2812; https://doi.org/10.3390/cancers12102812 - 30 Sep 2020
Cited by 3 | Viewed by 2526
Abstract
Current National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO) guidelines recommend regorafenib or trifluridine/tipiracil (TAS-102) for the third-line therapy of metastatic colorectal cancer (mCRC). In this analysis, we evaluated hospitalizations during regorafenib or TAS-102 treatment and the impact of [...] Read more.
Current National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO) guidelines recommend regorafenib or trifluridine/tipiracil (TAS-102) for the third-line therapy of metastatic colorectal cancer (mCRC). In this analysis, we evaluated hospitalizations during regorafenib or TAS-102 treatment and the impact of hospitalizations on overall survival (OS). This retrospective analysis was based on unselected, consecutive mCRC patients treated with regorafenib and/or TAS-102 at the tertiary cancer centers in Salzburg and Wels-Grieskirchen, Austria. Between January 2013 and May 2019, 93 patients started third- or fourth-line therapy with regorafenib or TAS-102. Tumor therapy (regorafenib versus TAS-102, HR: 1.95 [95% CI: 1.07–3.54], p = 0.03) and the Eastern Cooperative Oncology Group (ECOG) performance status (2–3 versus 0–1, HR: 4.04 [95% CI: 2.11–7.71], p < 0.001) showed a statistically significant association with hospitalization risk in multivariate analysis. The corresponding hospitalization probability from initiation of third- or fourth-line was 30% with regorafenib versus 18% with TAS-102 at five weeks and 41% versus 28% at ten weeks, respectively. Hospitalizations irrespective of cause during regorafenib or TAS-102 therapy did neither impact median survival in patients undergoing only third-line therapy (never-hospitalized: 5.7 months [95% CI: 3.9–10.5] versus hospitalized: 5.4 months [95% CI: 2.8–9.6], p = 0.45), nor in patients receiving third- and fourth-line therapy (12.2 months [95% CI: 10.6–28.8] versus 18.6 months [95% CI: 6.3-not reached], p = 0.90). In conclusion, apart from poor ECOG performance status, regorafenib therapy was associated with an increased hospitalization probability during palliative systemic third- and fourth-line therapy in mCRC. However, hospitalizations during regorafenib or TAS-102 therapy did not impact OS beyond second-line therapy. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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14 pages, 1116 KiB  
Article
Evaluation of Prognostic Factors for Survival in Transverse Colon Cancer
by Michela Roberto, Giulia Arrivi, Francesca Lo Bianco, Stefano Cascinu, Fabio Gelsomino, Francesco Caputo, Krisida Cerma, Michele Ghidini, Margherita Ratti, Claudio Pizzo, Corrado Ficorella, Alessandro Parisi, Alessio Cortellini, Federica Urbano, Maria Letizia Calandrella, Emanuela Dell’Aquila, Alessandro Minelli, Claudia Angela Maria Fulgenzi, Ludovica Gariazzo, Andrea Montori, Emanuela Pilozzi, Marco Di Girolamo, Paolo Marchetti and Federica Mazzucaadd Show full author list remove Hide full author list
Cancers 2020, 12(9), 2457; https://doi.org/10.3390/cancers12092457 - 30 Aug 2020
Cited by 3 | Viewed by 2766
Abstract
Background: Although most of the analyses included transverse colon cancers (TCC) among right colon cancer (RCC), it is not completely clear if they present total similarities with RCC or if they have their specific features. Therefore, we present an observational study to evaluate [...] Read more.
Background: Although most of the analyses included transverse colon cancers (TCC) among right colon cancer (RCC), it is not completely clear if they present total similarities with RCC or if they have their specific features. Therefore, we present an observational study to evaluate clinicopathological characteristics and survival data of patients with TCC. Methods: We retrospectively reviewed 450 RCC, of whom 97 stages I–IV TCC were included in this multicenter study; clinicopathological and molecular parameters were analyzed to identify prognostic factors for disease-free survival (DFS) and overall survival (OS). Results: Most of TCC cases were male (61%), with ≤70 years old (62%), and good performance status (ECOG PS 0, 68%). According to WHO classification, 41 (49%) and 40 (48%) tumors were classified as well to moderate and poorly/undifferentiated respectively, regardless of mucinous component (30%). About molecular data, 8 (26%), 45 (63%), and 14 (24%) were MSI-H, KRAS wild-type, and BRAF V600E mutant, respectively. With a median follow-up of 34 months, there were 29 and 50 disease recurrences and deaths respectively. Charlson comorbidity index ≥5 was a significant prognostic factor for DFS (HR = 7.67, 95% CI 2.27–25.92). Colon obstruction/perforation (HR = 2.65, 95% CI 1.01–7.01), and BRAF mutant (HR = 3.03, 95% CI 0.97–9.50) cases showed a worst, despite not statistically significant, DFS. Whereas for OS, at the multivariate model, only tumor grade differentiation (HR = 5.26, 95% CI 1.98–14.01) and BRAF mutation status (3.71, 95% CI 1.07–12.89) were independent prognostic factors. Conclusions: Poorly/undifferentiated tumor grade and BRAF V600E mutation are independent prognostic factors for OS in TCC. Further prospective clinical trials are needed to better define TCC treatment in order to improve patient outcome. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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Review

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13 pages, 1363 KiB  
Review
Liquid Biopsies in Colorectal Liver Metastases: Towards the Era of Precision Oncologic Surgery
by Diamantis I. Tsilimigras, Ioannis Ntanasis-Stathopoulos and Timothy M. Pawlik
Cancers 2022, 14(17), 4237; https://doi.org/10.3390/cancers14174237 - 31 Aug 2022
Cited by 3 | Viewed by 1729
Abstract
Tumor mutational analysis has been incorporated into the management of patients with CRLM since it can provide valuable prognostic information as well as guide peri-operative systemic treatment. Unlike tumor biopsy, liquid biopsy has emerged as a promising, non-invasive alternative that can detect cell-derived [...] Read more.
Tumor mutational analysis has been incorporated into the management of patients with CRLM since it can provide valuable prognostic information as well as guide peri-operative systemic treatment. Unlike tumor biopsy, liquid biopsy has emerged as a promising, non-invasive alternative that can detect cell-derived markers from a variety of body fluids and might better characterize all subclones present at a specific time point and allow sequential monitoring of disease evolution. Although not currently considered standard of care, an increasing number of cancer centers are nowadays routinely using liquid biopsies in the treatment of CRLM patients with promising results. The current review provides an overview of liquid biopsies in cancer therapeutics and focuses on the application of this relatively new approach on patients with CRLM. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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11 pages, 589 KiB  
Review
The Role of Conventional TACE (cTACE) and DEBIRI-TACE in Colorectal Cancer Liver Metastases
by Thomas J. Vogl and Maximilian Lahrsow
Cancers 2022, 14(6), 1503; https://doi.org/10.3390/cancers14061503 - 15 Mar 2022
Cited by 13 | Viewed by 3805
Abstract
Colorectal cancer (CRC) is one of the most common tumor entities worldwide and a common cause of cancer-associated death. Colorectal cancer liver metastases (CRLM) thereby constitute a severe life-limiting factor. The therapy of CRLM presents a major challenge and surgical resection as well [...] Read more.
Colorectal cancer (CRC) is one of the most common tumor entities worldwide and a common cause of cancer-associated death. Colorectal cancer liver metastases (CRLM) thereby constitute a severe life-limiting factor. The therapy of CRLM presents a major challenge and surgical resection as well as systemic chemotherapy remain the first-line treatment options. Over the years several locoregional, vascular- and image-based treatments offered by interventional radiologists have emerged when conventional therapies fail, or metastases recurrence occurs. Among such options is the conventional/traditional transarterial chemoembolization (cTACE) by local injection of a combination of chemotherapeutic- and embolic-agents. A similar treatment is the more recent irinotecan-loaded drug-eluting beads TACE (DEBIRI-TACE), which are administered using the same approach. Numerous studies have shown that these different types of chemoembolization can be applied in different clinical settings safely. Furthermore, such treatments can also be combined with other local or systemic therapies. Unfortunately, due to the incoherent patient populations of studies investigating TACE in CRLM, critics state that the definite evidence supporting positive patient outcomes is still lacking. In the following article we review studies on conventional and DEBIRI-TACE. Although highly dependent on the clinical setting, prior therapies and generally the study population, cTACE and DEBIRI-TACE show comparable results. We present the most representative studies on the different chemoembolization procedures and compare the results. Although there is compelling evidence for both approaches, further studies are necessary to determine which patients profit most from these therapies. In conclusion, we determine TACE to be a viable option in CRLM in different clinical settings. Nevertheless, a multidisciplinary approach is desired to offer patients the best possible care. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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37 pages, 1011 KiB  
Review
Local Treatments in the Unresectable Patient with Colorectal Cancer Metastasis: A Review from the Point of View of the Medical Oncologist
by Javier Torres-Jiménez, Jorge Esteban-Villarrubia, Reyes Ferreiro-Monteagudo and Alfredo Carrato
Cancers 2021, 13(23), 5938; https://doi.org/10.3390/cancers13235938 - 25 Nov 2021
Cited by 10 | Viewed by 3318
Abstract
For patients with isolated liver metastases from colorectal cancer who are not candidates for potentially curative resections, non-surgical local treatments may be useful. Non-surgical local treatments are classified according to how the treatment is administered. Local treatments are applied directly on hepatic parenchyma, [...] Read more.
For patients with isolated liver metastases from colorectal cancer who are not candidates for potentially curative resections, non-surgical local treatments may be useful. Non-surgical local treatments are classified according to how the treatment is administered. Local treatments are applied directly on hepatic parenchyma, such as radiofrequency, microwave hyperthermia and cryotherapy. Locoregional therapies are delivered through the hepatic artery, such as chemoinfusion, chemoembolization or selective internal radiation with Yttrium 90 radioembolization. The purpose of this review is to describe the different interventional therapies that are available for these patients in routine clinical practice, the most important clinical trials that have tried to demonstrate the effectiveness of each therapy and recommendations from principal medical oncologic societies. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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21 pages, 1654 KiB  
Review
Image-Guided Ablation for Colorectal Liver Metastasis: Principles, Current Evidence, and the Path Forward
by Yuan-Mao Lin, Iwan Paolucci, Kristy K. Brock and Bruno C. Odisio
Cancers 2021, 13(16), 3926; https://doi.org/10.3390/cancers13163926 - 04 Aug 2021
Cited by 24 | Viewed by 3099
Abstract
Image-guided ablation can provide effective local tumor control in selected patients with CLM. A randomized controlled trial suggested that radiofrequency ablation combined with systemic chemotherapy resulted in a survival benefit for patients with unresectable CLM, compared to systemic chemotherapy alone. For small tumors, [...] Read more.
Image-guided ablation can provide effective local tumor control in selected patients with CLM. A randomized controlled trial suggested that radiofrequency ablation combined with systemic chemotherapy resulted in a survival benefit for patients with unresectable CLM, compared to systemic chemotherapy alone. For small tumors, ablation with adequate margins can be considered as an alternative to resection. The improvement of ablation technologies can allow the treatment of tumors close to major vascular structures or bile ducts, on which the applicability of thermal ablation modalities is challenging. Several factors affect the outcomes of ablation, including but not limited to tumor size, number, location, minimal ablation margin, RAS mutation status, prior hepatectomy, and extrahepatic disease. Further understanding of the impact of tumor biology and advanced imaging guidance on overall patient outcomes might help to tailor its application, and improve outcomes of image-guided ablation. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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15 pages, 4086 KiB  
Review
Magnetic Resonance Imaging-Guided Adaptive Radiotherapy for Colorectal Liver Metastases
by Paul B. Romesser, Neelam Tyagi and Christopher H. Crane
Cancers 2021, 13(7), 1636; https://doi.org/10.3390/cancers13071636 - 01 Apr 2021
Cited by 12 | Viewed by 3262
Abstract
Technological advances have enabled well tolerated and effective radiation treatment for small liver metastases. Stereotactic ablative radiation therapy (SABR) refers to ablative dose delivery (>100 Gy BED) in five fractions or fewer. For larger tumors, the safe delivery of SABR can be challenging [...] Read more.
Technological advances have enabled well tolerated and effective radiation treatment for small liver metastases. Stereotactic ablative radiation therapy (SABR) refers to ablative dose delivery (>100 Gy BED) in five fractions or fewer. For larger tumors, the safe delivery of SABR can be challenging due to a more limited volume of healthy normal liver parenchyma and the proximity of the tumor to radiosensitive organs such as the stomach, duodenum, and large intestine. In addition to stereotactic treatment delivery, controlling respiratory motion, the use of image guidance, adaptive planning and increasing the number of radiation fractions are sometimes necessary for the safe delivery of SABR in these situations. Magnetic Resonance (MR) image-guided adaptive radiation therapy (MRgART) is a new and rapidly evolving treatment paradigm. MR imaging before, during and after treatment delivery facilitates direct visualization of both the tumor target and the adjacent normal healthy organs as well as potential intrafraction motion. Real time MR imaging facilitates non-invasive tumor tracking and treatment gating. While daily adaptive re-planning permits treatment plans to be adjusted based on the anatomy of the day. MRgART therapy is a promising radiation technology advance that can overcome many of the challenges of liver SABR and may facilitate the safe tumor dose escalation of colorectal liver metastases. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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27 pages, 386 KiB  
Review
Review of Intra-Arterial Therapies for Colorectal Cancer Liver Metastasis
by Justin Kwan and Uei Pua
Cancers 2021, 13(6), 1371; https://doi.org/10.3390/cancers13061371 - 18 Mar 2021
Cited by 11 | Viewed by 2872
Abstract
The liver is frequently the most common site of metastasis in patients with colorectal cancer, occurring in more than 50% of patients. While surgical resection remains the only potential curative option, it is only eligible in 15–20% of patients at presentation. In the [...] Read more.
The liver is frequently the most common site of metastasis in patients with colorectal cancer, occurring in more than 50% of patients. While surgical resection remains the only potential curative option, it is only eligible in 15–20% of patients at presentation. In the past two decades, major advances in modern chemotherapy and personalized biological agents have improved overall survival in patients with unresectable liver metastasis. For patients with dominant liver metastatic disease or limited extrahepatic disease, liver-directed intra-arterial therapies such as hepatic arterial chemotherapy infusion, chemoembolization and radioembolization are treatment strategies which are increasingly being considered to improve local tumor response and to reduce systemic side effects. Currently, these therapies are mostly used in the salvage setting in patients with chemo-refractory disease. However, their use in the first-line setting in conjunction with systemic chemotherapy as well as to a lesser degree, in a neoadjuvant setting, for downstaging to resection have also been investigated. Furthermore, some clinicians have considered these therapies as a temporizing tool for local disease control in patients undergoing a chemotherapy ‘holiday’ or acting as a bridge in patients between different lines of systemic treatment. This review aims to provide an update on the current evidence regarding liver-directed intra-arterial treatment strategies and to discuss potential trends for the future. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
12 pages, 533 KiB  
Review
Role of Thermal Ablation in Colorectal Cancer Lung Metastases
by Alexandre Delpla, Thierry de Baere, Eloi Varin, Frederic Deschamps, Charles Roux and Lambros Tselikas
Cancers 2021, 13(4), 908; https://doi.org/10.3390/cancers13040908 - 22 Feb 2021
Cited by 22 | Viewed by 2624
Abstract
Background: Consensus guidelines of the European Society for Medical Oncology (ESMO) (2016) provided recommendations for the management of lung metastases. Thermal ablation appears as a tool in the management of these secondary pulmonary lesions, in the same manner as surgical resection or [...] Read more.
Background: Consensus guidelines of the European Society for Medical Oncology (ESMO) (2016) provided recommendations for the management of lung metastases. Thermal ablation appears as a tool in the management of these secondary pulmonary lesions, in the same manner as surgical resection or stereotactic ablative radiotherapy (SABR). Methods: Indications, technical considerations, oncological outcomes such as survival (OS) or local control (LC), prognostic factors and complications of thermal ablation in colorectal cancer lung metastases were reviewed and put into perspective with results of surgery and SABR. Results: LC rates varied from 62 to 91%, with size of the metastasis (<2 cm), proximity to the bronchi or vessels, and size of ablation margins (>5 mm) as predictive factors of LC. Median OS varied between 33 and 68 months. Pulmonary free disease interval <12 months, positive carcinoembryonic antigen, absence of neoadjuvant chemotherapy and uncontrolled extra-pulmonary metastases were poor prognostic factors for OS. While chest drainage for less than 48 h was required in 13 to 47% of treatments, major complications were rare. Conclusions: Thermal ablation of a selected subpopulation of patients with colorectal cancer lung metastases is safe and can provide excellent LC and delay systemic chemotherapy. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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9 pages, 807 KiB  
Commentary
How Compatible Are Immune Checkpoint Inhibitors and Thermal Ablation for Liver Metastases?
by Yasunori Minami, Haruyuki Takaki, Koichiro Yamakado and Masatoshi Kudo
Cancers 2022, 14(9), 2206; https://doi.org/10.3390/cancers14092206 - 28 Apr 2022
Cited by 4 | Viewed by 1674
Abstract
Cancer immunotherapy, which reactivates the weakened immune cells of cancer patients, has achieved great success, and several immune checkpoint inhibitors (ICIs) are now available in clinical practice. Despite promising clinical outcomes, favorable responses are only observed in a fraction of patients, and resistance [...] Read more.
Cancer immunotherapy, which reactivates the weakened immune cells of cancer patients, has achieved great success, and several immune checkpoint inhibitors (ICIs) are now available in clinical practice. Despite promising clinical outcomes, favorable responses are only observed in a fraction of patients, and resistance mechanisms, including the absence of tumor antigens, have been reported. Thermal ablation involves the induction of irreversible damage to cancer cells by localized heat and may result in the release of tumor antigens. The combination of immunotherapy and thermal ablation is an emerging therapeutic option with enhanced efficacy. Since thermal ablation-induced inflammation and increases in tumor antigens have been suggested to promote the cancer-immunity cycle, the combination of immuno-oncology (IO) therapy and thermal ablation may be mutually beneficial. In preclinical and clinical studies, the combination of ICI and thermal ablation significantly inhibited tumor growth, and synergistic antitumor effects appeared to prolong the survival of patients with secondary liver cancer. However, evidence for the efficacy of ICI monotherapy combined with thermal ablation is currently insufficient. Therefore, the clinical feasibility of immune response activation by ICI monotherapy combined with thermal ablation may be limited, and thermal ablation may be more compatible with dual ICIs (the IO–IO combination) to induce strong immune responses. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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22 pages, 1692 KiB  
Systematic Review
The Role of Neoadjuvant Chemotherapy in Repeat Local Treatment of Recurrent Colorectal Liver Metastases: A Systematic Review and Meta-Analysis
by Madelon Dijkstra, Sanne Nieuwenhuizen, Robbert S. Puijk, Bart Geboers, Florentine E. F. Timmer, Evelien A. C. Schouten, Hester J. Scheffer, Jan J. J. de Vries, Johannes C. F. Ket, Kathelijn S. Versteeg, Martijn R. Meijerink and M. Petrousjka van den Tol
Cancers 2021, 13(3), 378; https://doi.org/10.3390/cancers13030378 - 20 Jan 2021
Cited by 11 | Viewed by 2794
Abstract
The additive value of neoadjuvant chemotherapy (NAC) prior to repeat local treatment of patients with recurrent colorectal liver metastases (CRLM) is unclear. A systematic search was performed in PubMed, Embase, Web of Science, and an additional search in Google Scholar to find articles [...] Read more.
The additive value of neoadjuvant chemotherapy (NAC) prior to repeat local treatment of patients with recurrent colorectal liver metastases (CRLM) is unclear. A systematic search was performed in PubMed, Embase, Web of Science, and an additional search in Google Scholar to find articles comparing repeat local treatment by partial hepatectomy and/or thermal ablation with versus without NAC. The search included randomized trials and comparative observational studies with univariate/multivariate analysis and/or matching as well as (inter)national guidelines assessed using the AGREE II instrument. The search identified 21,832 records; 172 were selected for full-text review; 20 were included: 20 comparative observational studies were evaluated. Literature to evaluate the additive value of NAC prior to repeat local treatment was limited. Outcomes of NAC were often reported as subgroup analyses and reporting of results was frequently unclear. Assessment of the seven studies that qualified for inclusion in the meta-analysis showed conflicting results. Only one study reported a significant difference in overall survival (OS) favoring NAC prior to repeat local treatment. However, further analysis revealed a high risk for residual bias, because only a selected group of chemo-responders qualified for repeat local treatment, disregarding the non-responders who did not qualify. All guidelines that specifically mention recurrent disease (3/3) recommend repeat local treatment; none provide recommendations about the role of NAC. The inconclusive findings of this meta-analysis do not support recommendations to routinely favor NAC prior to repeat local treatment. This emphasizes the need to investigate the additive value of NAC prior to repeat local treatment of patients with recurrent CRLM in a future phase 3 randomized controlled trial (RCT). Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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