Neoadjuvant chemotherapy including bevacizumab in potentially curable metastatic colorectal cancer

3546 Background: the addition of targeting therapies to combination chemotherapy have dramatically improved outcome in metastatic colorectal cancer (mCRC). Special issues have been raised regarding the sequence of bevacizumab (bev) administration and surgery in mCRC. Methods: a pilot series of non-optimal resectable mCRC patients was initiated including a neoadjuvant protocol with bevacizumab 5mg/kg every two weeks plus XELOX (capecitabine 3500mg/m2/day days 1–7 plus oxaliplatin 85mg/m2 day 1 of a 2-week cycle) for six cycles (3 months). The sixth cycle did not include bev resulting in a gap of 5 weeks between last bev and surgery. Additional 6 cycles were started 5 weeks after surgery. Primary end points were feasibility of the regimen, possibility of curative surgical approach and morbidity of the surgical procedure including liver resection. Results: we have enrolled 22 patients of whom 12 are evaluable for all primary endpoints today. Median age of the patients was 61.5 years (± 8.8), 83% had a lymph node positive primary, 67% had synchronous liver metastases (LM), 33% had bilobar LM. The neoadjuvant treatment regimen was safely administered resulting in 2 CR, 8 PR and 2 SD; XELOX was dose reduced to 75% due to HFS, diarrhoe or PNP ≥ 3 in 3 patients (25%). Potentially curative surgery was performed in all but one patient (92%) including liver resection in 11 patients, involving additional resection of the primary in 3 patients. No patient required perioperative blood transfusions, morbidity consisted of one bile leak from the resection edge and one wound infection. No patient experienced bleeding complications or showed postoperative liver dysfunction. Median postoperative hospital stay was 7 days (± 1.7). All patients started adjuvant treatment within 5 weeks. Liver regeneration as evaluated during staging CTs confirmed no abnormalities. Conclusions: these data suggest that bevacizumab can be administered prior and after potentially curative surgery including liver resection without appearing to adversely effect surgical wound healing, bleeding or liver regeneration. However we would like to emphasize that patients need to be treated by an experienced multidisciplinary team including a liver surgeon qualified in dealing with chemotherapy altered livers. [Table: see text]

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Association of marked thrombocytopenia at postoperative day 1 with incidence of liver dysfunction, morbidity, and mortality in metastatic colorectal cancer patients undergoing liver resection.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e14095 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e14095-e14095

Author(s):

Thomas Gruenberger ◽

Beata Perisanidis ◽

Dietmar Tamandl ◽

Stefan Stremitzer ◽

Christine Brostjan ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Resection ◽

Liver Regeneration ◽

Metastatic Colorectal Cancer ◽

Liver Dysfunction ◽

Morbidity And Mortality ◽

Pivotal Role ◽

Function Parameter ◽

Hepatic Regeneration ◽

Remnant Liver

e14095 Background: After major liver resection, the most significant factor determining postoperative morbidity and mortality is the ability of the remnant liver to regenerate. Liver regeneration is a tightly regulated process involving various different growth factors. Recently, platelets have been shown to play a pivotal role in liver regeneration after partial hepatectomy. Methods: Patients treated with liver resection for metastatic colorectal cancer (mCRC) between January 2000 and December 2010 were eligible. Liver dysfunction (LD) was defined as bilirubin > 5 mg/dL or prothrombin time <50% within the first postoperative week. The association of marked immediate postoperative thrombocytopenia with LD, morbidity and mortality was analyzed. Results: 518 patients with mCRC were treated for liver metastasis, of whom 476 underwent liver resection. 67.9% of these had received preoperative CTx. 20.1% of all patients developed LD. Postoperative complications occurred in 39%. 7 patients died within 90 days after liver resection (1.5%). Postoperative platelets < 100 x 103/ml on the first postoperative day were the only liver function parameter predicting postoperative LD in multivariate analyses (p = 0.015). Furthermore, reduced platelets were significantly associated with increased morbidity (p = 0.014) and mortality (platelets < 100 x 103/ml – 4.1%, platelets > 100 x 103/ml – 1.5%, p = n.s.). Conclusions: Platelets < 100 x 103/ml on the first postoperative day seem to be an early marker to predict postoperative LD, increased morbidity and mortality in patients after liver resection. Using this cut-off, it might be possible to identify patients at high risk for developing postoperative LD and complications already on the first day after liver resection. Furthermore, this data suggests a pivotal role of platelets in hepatic regeneration.

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Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

Gastroenterology Research and Practice ◽

10.1155/2016/9189483 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

R.-D. Hofheinz ◽

U. Ronellenfitsch ◽

S. Kubicka ◽

A. Falcone ◽

I. Burkholder ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Kinase Inhibitors ◽

Meta Analysis ◽

Progression Free Survival ◽

Optimal Sequence ◽

Primary Endpoints ◽

Disease Stabilization ◽

Antiangiogenic Drugs ◽

The Impact

Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis.Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression.Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75) and OS (HR 0.83; 95%-CI, 0.76–0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58).Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs.

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Ninety-Six Five-Year Survivors After Liver Resection for Metastatic Colorectal Cancer

Journal of the American College of Surgeons ◽

10.1016/s1072-7515(97)00103-8 ◽

1997 ◽

Vol 185 (6) ◽

pp. 554-559 ◽

Cited By ~ 79

Author(s):

M DAANGELICAMD ◽

M BRENNANMDFACS ◽

J FORTNERMDFACS ◽

A COHENMDFACS ◽

L BLUMGARTMDFRCSFACS ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Resection ◽

Metastatic Colorectal Cancer

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Socioeconomic differences in selection for liver resection in metastatic colorectal cancer and the impact on survival

European Journal of Surgical Oncology ◽

10.1016/j.ejso.2018.05.024 ◽

2018 ◽

Vol 44 (10) ◽

pp. 1588-1594 ◽

Cited By ~ 3

Author(s):

A.E. Vallance ◽

J. van der Meulen ◽

A. Kuryba ◽

M. Braun ◽

D.G. Jayne ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Resection ◽

Metastatic Colorectal Cancer ◽

Socioeconomic Differences ◽

Impact On Survival ◽

Selection For ◽

The Impact

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The effect of preoperative chemotherapy on liver regeneration after portal vein embolization/ligation or liver resection in patients with colorectal liver metastasis: a systematic review protocol

Systematic Reviews ◽

10.1186/s13643-020-01545-w ◽

2020 ◽

Vol 9 (1) ◽

Author(s):

Mihai-Calin Pavel ◽

Raquel Casanova ◽

Laia Estalella ◽

Robert Memba ◽

Erik Llàcer-Millán ◽

...

Keyword(s):

Colorectal Cancer ◽

Systematic Review ◽

Liver Resection ◽

Liver Metastasis ◽

Neoadjuvant Chemotherapy ◽

Portal Vein ◽

Liver Failure ◽

Liver Regeneration ◽

Meta Analysis ◽

Number Of Cycles

Abstract Introduction Liver resection (LR) in patients with liver metastasis from colorectal cancer remains the only curative treatment. Perioperative chemotherapy improves prognosis of these patients. However, there are concerns regarding the effect of preoperative chemotherapy on liver regeneration, which is a key event in avoiding liver failure after LR. The primary objective of this systematic review is to assess the effect of neoadjuvant chemotherapy on liver regeneration after (LR) or portal vein embolization (PVE) in patients with liver metastasis from colorectal cancer. The secondary objectives are to evaluate the impact of the type of chemotherapy, number of cycles, and time between end of treatment and procedure (LR or PVE) and to investigate whether there is an association between degree of hypertrophy and postoperative liver failure. Methods This meta-analysis will include studies reporting liver regeneration rates in patients submitted to LR or PVE. Pubmed, Scopus, Web of Science, Embase, and Cochrane databases will be searched. Only studies comparing neoadjuvant vs no chemotherapy, or comparing chemotherapy characteristics (bevacizumab administration, number of cycles, and time from finishing chemotherapy until intervention), will be included. We will select studies from 1990 to present. Two researchers will individually screen the identified records, according to a list of inclusion and exclusion criteria. Primary outcome will be future liver remnant regeneration rate. Bias of the studies will be evaluated with the ROBINS-I tool, and quality of evidence for all outcomes will be determined with the GRADE system. The data will be registered in a predesigned database. If selected studies are sufficiently homogeneous, we will perform a meta-analysis of reported results. In the event of a substantial heterogeneity, a qualitative systematic review will be performed. Discussion The results of this systematic review may help to better identify the patients affected by liver metastasis that could present low regeneration rates after neoadjuvant chemotherapy. These patients are at risk to develop liver failure after extended hepatectomies and therefore are not good candidates for such aggressive procedures. Systematic review registration PROSPERO registration number: CRD42020178481 (July 5, 2020).

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Low preoperative platelets to predict postoperative liver dysfunction in patients with metastatic colorectal cancer undergoing liver resection.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.634 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 634-634

Author(s):

Patrick Starlinger ◽

Beata Herberger ◽

Dietmar Tamandl ◽

Stefan Stremitzer ◽

Christine Brostjan ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Resection ◽

High Risk ◽

Postoperative Complications ◽

Metastatic Colorectal Cancer ◽

Liver Dysfunction ◽

Postoperative Mortality ◽

Platelet Counts ◽

The Impact ◽

Selection Of

634 Background: Despite improving median survival of metastatic colorectal cancer (mCRC) patients, chemotherapy (CTx) compromises liver function. Therefore, selection of patients who are of high risk to develop liver dysfunction (LD) after surgery is important. As platelets are of major importance in liver regeneration, we investigated the impact of preoperative platelet counts on the incidence of postoperative LD and its correlation to postoperative morbidity and mortality. Methods: Patients treated with liver resection for mCRC between January 2000 and December 2010 were eligible. LD was defined as bilirubin > 5 mg/dL or prothrombin time <50% within the first postoperative week. The association of preoperative platelets < 150 x 103/ml with LD, 90 days mortality and surgical complications was analyzed. Results: 518 patients with metastatic CRC cancer underwent liver resection, of whom 68% had received neoadjuvant CTx. 21% of all patients developed LD. Postoperative complications occurred in 13.5%. 10 patients died within 90 days after liver resection (1.9%). The incidence of LD and complications was significantly higher in patients with preoperative platelets < 150 x 103/ml (P=0.010, P=0.047). 90 days mortality was nearly 3 times higher in patients with reduced preoperative platelets (9.8% vs. 3.7%). Neoadjuvant CTx was associated with an increased rate of platelets < 150 x 103/ml (with CTx 25%, without CTx 17%; P=0.051), LD (with CTx 23%, without CTx 15%; P=0.029) and postoperative mortality (with CTx 5.3%, without CTx 2.5%). Conclusions: Patients with platelets < 150 x 103/ml have an increased incidence of postoperative LD, major complications and 90 days mortality. Using this simple routine parameter, it might be possible to select patients that could be better served with alternative treatments such as radiofrequency ablation. Furthermore, reduced platelet counts and the incidence of LD were more frequent in patients after neoadjuvant CTx resulting in an increased 90 days mortality. This suggests that patients after extensive CTx accompanied by low platelets are of high risk to suffer from postoperative complications and surgical treatment should be reconsidered.

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A phase I study of sorafenib with FOLFIRI as first-line therapy for metastatic colorectal cancer (mCRC): Safety and efficacy results.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3633 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3633-3633

Author(s):

Jean Alfred Maroun ◽

Derek J. Jonker ◽

M. Christine Cripps ◽

Timothy R. Asmis ◽

Rakesh Goel ◽

...

Keyword(s):

Colorectal Cancer ◽

Phase I ◽

Metastatic Colorectal Cancer ◽

Objective Response ◽

Progression Free Survival ◽

Response Duration ◽

Maximum Tolerated Dose ◽

Future Research ◽

Curative Surgery ◽

First Line Therapy

3633 Background: Phase I dose escalation to a maximum planned dose (MPD) o determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended-phase-II-dose (RP2D) and preliminary efficacy of sorafenib and FOLFIRI (irinotecan reduced-dose) in metastatic colorectal cancer (mCRC) patients. Methods: Starting doses: irinotecan 80 mg/m2 iv d1, sorafenib 400 mg po twice daily (bid, continuous), starting day 2. Escalations based on toxicity observed at the previous dose level (DL) up to: irinotecan 100 mg/m2 and sorafenib 800 mg bid. DLT was evaluated within the 1st study cycle (1 cycle = 2 FOLFIRI treatments). Results: 5 cohorts were concluded. All 16 ECOG PS 0-1 patients (9/7 men/women; 2/14 rectal/colon) with median age of 64, discontinued study: 10 (62%) disease progression, 4 (25%) toxicity, 1 curative surgery, 1 comorbidities. The dose levels of irinotecan (mg/m2, day1) and sorafenib (mg/day, bid, day 2-28) studied were DL1-80/400, DL2-80/600, DL3-90/600, DL4-100/600 and DL5-100/800, repeated every 4 weeks, 3 patients/DL. No DLT was observed. The MTD was not reached at the MPD (DL5). The most common ≥Gr2 treatment related adverse events (AEs) were: neutropenia 81%, HFS 69%, leucopenia 50%, fatigue 38%, anemia 31%, constipation 31%, nausea/vomiting 31%, mucositis 31%, diarrhea 25%, hypophosphatemia 25%. The most severe treatment related AEs were: Gr4: neutropenia 2 (12.5%); pulmonary embolism 1 (6%); Gr3: HFS 9 (56%), neutropenia 3 (19%), leucopenia 3 (19%), hypophosphatemia 3 (19%). Objective response rate was 56% (9 of 16 patients, 95%CI; 33-77%). Response duration was 13 months (95%CI; 5-17). Median progression-free survival and overall survival were 11 months (95%CI; 6-17) and 25 months (95%CI; 15-34), respectively. Conclusions: Combination therapy with S and modified FOLFIRI in these patients is well tolerated and demonstrates clinical efficacy at the MPD. The MTD was not reached at the MPD. Future research of this combination is warranted. Supported by Bayer Healthcare Pharmaceuticals. Clinical trial information: NCT00780169.

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