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Background: Both acute and chronic symptoms of oxaliplatin-induced peripheral neuropathy (OIPN) affect patients' treatment dose and duration as well as quality-of-life. Hand/foot-cooling has been shown to reduce taxane-induced peripheral neuropathy but there is unclear evidence in the setting of oxaliplatin., Patients and Methods: In a monocentric, open-label phase II trial, patients with malignancies of the digestive system receiving oxaliplatin-based chemotherapy were randomly assigned to receive either continuous cooling of hands and feet using hilotherapy at 11°C during oxaliplatin infusion compared with usual care (no cooling). The primary endpoint was grade ≥2 neuropathy-free rate in 12 weeks after initiation of chemotherapy. Secondary endpoints included OIPN-related treatment alterations, acute OIPN symptoms and perceived comfort of the intervention., Results: The intention-to-treat population included 39 patients in the hilotherapy group and 38 in the control group. The grade ≥2 neuropathy-free rate at 12 weeks was 100% in the experimental group versus 80.5% in the control group (P = 0.006). This effect was persistent at 24 weeks (66.0% versus 49.2%, respectively) (P = 0.039). Next, treatment alterations-free rate at week 12 was 93.5% in the hilotherapy group compared with 83.3% in the control group (P = 0.131). Patients in the hilotherapy group experienced significantly less acute OIPN symptoms of numbness or tingling [odds ratio (OR) 0.05, 95% confidence interval (CI) 0.02-0.11, P < 0.0001], pain (OR 0.06, 95% CI 0.02-0.15, P < 0.0001) and/or cold sensitivity (OR 0.02, 95% CI 0.01-0.05, P < 0.0001) in fingers or toes as well as less pharyngeal cold sensitivity (OR 0.14, 95% CI 0.05-0.42, P = 0.0005). The majority of patients in the hilotherapy group rated the intervention as neutral, rather comfortable or very comfortable., Conclusions: In this first study on hand/foot-cooling in oxaliplatin alone, hilotherapy significantly reduced the incidence of grade ≥2 OIPN at 12 and 24 weeks. Hilotherapy also reduced acute OIPN symptoms and was generally well tolerated., Competing Interests: Disclosure The authors have declared no conflicts of interest. Data sharing Data are available upon request to the authors (https://doi.org/10.5281/zenodo.7495771)., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Laparoscopic liver resection (LLR) has gained acceptance as an effective treatment for colorectal liver metastases (CRLM) in selected patients, providing similar oncologic outcomes compared to open liver resection (OLR). The aim of this study was to determine prognostic factors for survival outcomes associated with LLR for CRLM., Methods: A single-center retrospective analysis of a prospectively maintained database was performed. The inclusion period ranged from September 2011 until mid-March 2020., Results: Two hundred consecutive LLRs were included. The 5-year overall survival (OS) and disease-free survival (DFS) rates equalled 54.8% and 49%, respectively. A pushing (HR = 5.42, 95% CI 1.56-18.88, p = 0.008), as well as a replacement (3.87, 1.05-14.2, p = 0.04) growth pattern of the CRLM, poor differentiation of the primary colorectal cancer (CRC) (3.72, 1.72-8.07, p < 0.001) and administration of neoadjuvant chemotherapy (NAC) (2.95, 1.28-6.8, p = 0.01) were identified as independent predictors of a worse OS. Requirement of more than 6 cycles of NAC (6.17, 2.37-16.03, p < 0.001), a replacement (4.96, 1.91-12.87, p < 0.001), as well as a pushing (4.3, 1.68-11, p = 0.002) growth pattern of the CRLM and poor differentiation of the primary CRC (2.61, 1.31-5.2, p = 0.006) were identified as independent predictors of a worse DFS., Conclusion: LLR for CRLM offers adequate long-term oncologic outcomes. OS and DFS rates are negatively affected by the administration of NAC and by pathological features, including the differentiation grade of the primary CRC and the histological growth pattern of the CRLM., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: Laparoscopic liver resections (LLR) of bilobar colorectal liver metastases (CRLM) are challenging and the safety and long-term outcomes are unclear. In this study, the short- and long-term outcomes and recurrence patterns of one-stage LLR for bilobar CRLM were compared to single laparoscopic resection for CRLM., Methods: This single-center study consisted of all patients who underwent a parenchymal sparing LLR for CRLM between October 2011 and December 2018. Demographics, perioperative outcomes, short-term outcomes, oncologic outcomes and recurrence patterns were compared. Data were retrieved from a prospectively maintained database., Results: Thirty six patients underwent a LLR for bilobar CRLM and ninety patients underwent a single LLR. Demographics were similar among groups. More patients received neoadjuvant chemotherapy in the bilobar group (55.6% vs 34.4%, P = 0.03). There was no difference in conversion rate, R0 resection and transfusion rate. Blood loss and operative time were higher in the bilobar group (250 ml (IQR 150-450) vs 100 ml (IQR 50-250), P < 0.001 and 200 min (IQR 170-230) vs 130 min (IQR 100-165), P < 0.001) and hospital stay was longer (5 days (IQR 4-7) vs 4 days (IQR 3-6), P = 0.015). The bilobar group had more technically major resections (88.9% vs 56.7%, P < 0.001). Mortality was nil in both groups and major morbidity was similar (2.8% vs 3.3%, P = 1.0). There was no difference in recurrence pattern. Overall survival (OS) was similar (1 yr: 96% in both groups and 5 yr 76% vs 66%, P = 0.49), as was recurrence-free survival (RFS) (1 yr: 64% vs 73%, 3 yr: 38 vs 42%, 5 yr: 38% vs 28%, P = 0.62)., Conclusion: In experienced hands, LLR for bilobar CRLM can be performed safely with similar oncologic outcomes as patients who underwent a single LLR for CRLM., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: With growing popularity and experience in laparoscopic liver surgery, the options for more difficult procedures increase. Only small case series have been published regarding laparoscopic liver resection (LLR) for tumours in proximity to major vessels (MVs). The aim was to compare outcomes of LLR for tumours located less or more than 15 mm from MVs., Methods: This was a retrospective analysis of a prospectively collected database of consecutive LLR (October 2011-August 2017). Proximity to MVs (PMV) was defined as lesions located within 15 mm to the caval vein, hepatic veins and portal vein (main trunk and first branches). The control group were all lesions located more than 15 mm from MVs., Results: Some 60/235 LLR were performed for lesions in proximity to major vasculature (24%). In the PMV group, median IWATE Difficulty Score was higher (8.5 (IQR: 6.0-9.0) VS 5.0 (IQR: 3.0-6.0), p < 0.001) as was the use of CUSA® (45.0% VS 8.6%, p < 0.001) and Pringle manoeuvre (8.3% VS 1.7%; p = 0.028). Operative time was longer (180min (IQR: 140-210) VS 120min (IQR: 75-150), p < 0.001) and blood loss was higher (190 ml (IQR: 100-325) VS 75 ml (IQR: 50-220), p < 0.001) in the PMV group. There was no difference in perioperative blood transfusion (3.3% VS 1.7%, p = 0.60) or postoperative morbidity (15.0% VS 14.3%, p = 0.89). There was no mortality in both groups. On mean follow-up of 21 months, no significant differences could be found in disease free (p = 0.77) and overall survival (p = 0.12)., Conclusion: In experienced hands, LLR of lesions in proximity to MVs is safe and feasible with acceptable short and long-term results., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: The purpose of this study was to retrospectively assess the technical and clinical outcomes, overall survival and prognostic factors for prolonged survival after yttrium-90 ((90)Y) radioembolization as a salvage therapy for patients with chemorefractory liver-only or liver-dominant colorectal metastases., Material and Methods: From January 2005 to January 2014, all the patients selected for (90)Y radioembolization to treat chemorefractory colorectal liver metastases were identified. Demographic, laboratory, imaging and dosimetry data were collected. Post-treatment technical and clinical outcomes were analyzed as well as overall survival; finally several factors potentially influencing survival were analyzed., Results: In total 88 patients were selected for angiographic workup; 71 patients (81%) finally underwent catheter-directed (90)Y microsphere infusion into the hepatic artery 25 days (standard deviation 13 days) after angiographic workup. Median infused activity was 1809 MBq; 30-day toxicity included: fatigue (n = 39; 55%), abdominal discomfort (n = 33; 47%), nausea (n = 5; 7%), fever (n = 14; 20%), diarrhea (n = 6; 9%), liver function abnormalities and elevated bilirubin (transient) (n = 3; 4%). Gastric ulcer was found in five patients (7%). A late complication was radioembolization-induced portal hypertension (REIPH) in three patients (4%). Median time to progression in the liver was 4.4 months. Estimated survival at six and 12 months was 65% and 30%, respectively, with a 50% estimated survival after 8.0 months in this group of chemorefractory patients. Prognostic factors for worse survival were high preprocedural bilirubin, alkaline phosphatase and tumor volume levels., Conclusion: (90)Y microsphere radioembolization for chemorefractory colorectal liver metastases has an acceptable safety profile with a 50% estimated survival after 8.0 months. Pretreatment high bilirubin, alkaline phosphatase and tumor volume levels were associated with early death.

Purpose: Liver dissemination is a major cause of mortality among patients with advanced colorectal cancer. Hepatic intra-arterial injection of the beta-emitting isotope yttrium-90 ((90)Y) bound to resin microspheres (radioembolization) delivers therapeutic radiation doses to liver metastases with minimal damage to adjacent tissues., Patients and Methods: We conducted a prospective, multicenter, randomized phase III trial in patients with unresectable, chemotherapy-refractory liver-limited metastatic CRC (mCRC) comparing arm A (fluorouracil [FU] protracted intravenous infusion 300 mg/m(2) days 1 through 14 every 3 weeks) and arm B (radioembolization plus intravenous FU 225 mg/m(2) days 1 through 14 then 300 mg/m(2) days 1 through 14 every 3 weeks) until hepatic progression. The primary end point was time to liver progression (TTLP). Cross-over to radioembolization was permitted after progression in arm A., Results: Forty-six patients were randomly assigned and 44 were eligible for analysis (arm A, n = 23; arm B, n = 21). Median follow-up was 24.8 months. Median TTLP was 2.1 and 5.5 months in arms A and B, respectively (hazard ratio [HR] = 0.38; 95% CI, 0.20 to 0.72; P = .003). Median time to tumor progression (TTP) was 2.1 and 4.5 months, respectively (HR = 0.51; 95% CI, 0.28 to 0.94; P = .03). Grade 3 or 4 toxicities were recorded in six patients after FU monotherapy and in one patient after radioembolization plus FU treatment (P = .10). Twenty-five of 44 patients received further treatment after progression, including 10 patients in arm A who received radioembolization. Median overall survival was 7.3 and 10.0 months in arms A and B, respectively (HR = 0.92; 95% CI, 0.47 to 1.78; P = .80)., Conclusion: Radioembolization with (90)Y-resin microspheres plus FU is well tolerated and significantly improves TTLP and TTP compared with FU alone. This procedure is a valid therapeutic option for chemotherapy-refractory liver-limited mCRC.

Background: Dysregulation of the epidermal growth factor receptor (HER1/EGFR) has been reported in colorectal cancer (CRC). Erlotinib is a potent inhibitor of HER1/EGFR-mediated signaling. This trial of patients with metastatic CRC (MCRC) examined the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin (XELOX), a regimen with established efficacy., Patients and Methods: Patients previously untreated or treated with one line of 5-fluorouracil and/or irinotecan received escalating oral doses of erlotinib (daily), capecitabine (days 1-14) and i.v. oxaliplatin (day 1 of a 21-day cycle)., Results: The first six patients in cohort 1 (erlotinib 100 mg/day, capecitabine 825 mg/m(2) twice daily, oxaliplatin 130 mg/m(2)) had no dose-limiting toxicities (DLTs). In cohort 2 (capecitabine increased to 1000 mg/m(2) twice daily), two of six patients had DLTs. When cohort 2 was expanded to 11 patients two further DLTs occurred, exceeding the definition of MTD. Cohort 1 was expanded to 12 patients, and no DLTs occurred. The most common adverse events (AEs) were diarrhea and rash. There was a trend for reduced capecitabine concentrations in the presence of erlotinib. While this was not statistically significant, the possibility of an interaction affecting capecitabine PK cannot be excluded. Antitumor activity was observed in both cohorts (one complete and four partial responses, and stable disease in 11 patients)., Conclusion: The MTD for this combination in MCRC is capecitabine 825 mg/m(2) twice daily days 1-14, oxaliplatin 130 mg/m(2) day 1 and erlotinib 100 mg/day of a 21-day cycle. The combination was well tolerated at the MTD, with no unexpected AEs. The use of this combination in MCRC warrants further investigation.

Purpose: This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor-expressing metastatic colorectal cancer (mCRC)., Patients and Methods: The activity of cetuximab plus oxaliplatin was investigated in colon cancer cell lines and xenograft models. In the clinical study, patients with mCRC received on day 1 of a 14 day cycle, cetuximab (initial dose 400 mg/m(2) during week 1, then 250 mg/m(2) weekly) followed by FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1; leucovorin 200 mg/m(2) on days 1 and 2, followed by fluorouracil 400 mg/m(2) bolus then 600 mg/m(2) intravenous infusion during 22 hours on days 1 and 2)., Results: The preclinical studies confirmed the supra-additive activity of cetuximab to oxaliplatin. In the clinical study, 43 patients were included, with a median age of 65 years (range, 43 to 78 years). Response rates (RRs) were 79% (unconfirmed) and 72% (confirmed), with 95% disease control. Median progression-free survival (mPFS) and median duration of response were 12.3 and 10.8 months, respectively. Ten patients (23%) underwent resection with curative intent of previously unresectable metastases. After a median follow-up of 30.5 months, median overall survival (mOS) was 30.0 months. Cetuximab did not increase the characteristic toxicity of FOLFOX-4 and was generally well tolerated., Conclusion: Cetuximab in combination with FOLFOX-4 is a highly active first-line treatment for mCRC, showing encouraging RR, mPFS, and mOS values. The treatment resulted in a high resectability rate, which could potentially result in an improved cure rate. This combination is under phase III development.

Background: Preliminary evidence suggests that magnesium wasting occurs in patients who are treated with epidermal-growth-factor receptor (EGFR)-targeting antibodies for colorectal cancer. The mechanism of this side-effect is unknown, and if all or a subset of patients are affected is also unclear. We aimed to assess the incidence, characteristics, and predictive factors of magnesium wasting during treatment with EGFR-targeting antibodies, and to study the pathophysiology of this phenomenon., Methods: We measured prospectively magnesium concentrations in a cohort of 98 patients with colorectal cancer treated with EGFR-targeting antibodies with or without combined chemotherapy. The primary outcome measure was the slope of the serum magnesium concentrations over time. In 35 patients, 24-h urinary magnesium excretion was measured. In a subset of patients (n=5), an intravenous magnesium load test was done. 16 patients who had chemotherapy alone acted as controls. A clinical protocol was written before initiation of the study, but because this was a non-interventional study, the protocol was not formally registered., Findings: 95 (97%) patients had decreasing serum magnesium concentrations during EGFR-targeting treatment compared with baseline measurements. The mean serum magnesium slope during EGFR-targeting treatment (with or without combined chemotherapy) was significantly lower compared with chemotherapy alone (-0.00157 mmol/L/day, SD 0.00162 [95% CI -0.00191 to -0.00123] vs 0.00014 mmol/L/day, SD -00076 [-0.00026 to 0.00055]; (t test, p < 0.0001). 24-h urine analysis and intravenous magnesium load tests showed a defect in renal magnesium reabsorption., Interpretation: EGFR-inhibiting antibodies compromised the renal magnesium retention capacity, leading to hypomagnesaemia in most patients. Future studies should address the effects of exposure and target affinity. Our study suggests a pivotal role of the EGFR-signalling pathway in regulating magnesium homoeostasis.

5-Fluorouracil (5-FU) plus leucovorin (LV) has been the mainstay of treatment for colorectal cancer (CRC), with infused schedules more widely adopted in Europe and bolus schedules preferred in North America. However, the effective, oral fluoropyrimidine capecitabine is increasingly replacing intravenous (IV) 5-FU/LV on both sides of the Atlantic. Capecitabine generates 5-FU preferentially in tumor and is a well-established, first-line treatment for metastatic CRC. In this setting, capecitabine achieves a superior response rate, at least equivalent time to disease progression (TTP) and overall survival, and favorable safety compared with bolus 5-FU/LV. The benefits of capecitabine have been transfered into the adjuvant setting. Recent data from a large, international, randomized trial (Xeloda Adjuvant Chemotherapy Trial [X-ACT]) confirm that capecitabine (Xeloda, Roche Laboratories, Nutley, NJ) achieves favorable safety versus 5-FU/LV (Mayo Clinic regimen) and is at least as effective as IV 5-FU/LV in the adjuvant treatment of patients with resected stage III colon cancer. Capecitabine is also an effective and well-tolerated combination partner for oxaliplatin (XELOX) and irinotecan (XELIRI), achieving high efficacy with a good safety profile. An extensive phase III clinical trial program is further establishing the potential of the simplified capecitabine combinations to improve outcomes and unify treatment practices in the metastatic and adjuvant settings. New combinations with novel agents such as capecitabine/oxaliplatin plus erlotinib or bevacizumab are currently under investigation. Capecitabine has also shown promising activity and good tolerability in combination with radiotherapy in rectal cancer.

Background: The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan., Methods: We randomly assigned 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment., Results: The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P<0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P=0.48). Toxic effects were more frequent in the combination-therapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone., Conclusions: Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer., (Copyright 2004 Massachusetts Medical Society)

The treatment of patients with metastatic colorectal cancer has changed dramatically over recent years. The more optimal use of 5-fluorouracil (5-FU) in association with folinic acid (FA), the development of new drugs such as irinotecan and oxaliplatin and of the oral fluoropyrimidines, capecitabine and UFT, have contributed to increased therapeutic options and to the improved outcome of patients with metastatic colorectal cancer. It is shown that combination therapy with 5-FU/FA and irinotecan or oxaliplatin is more active than 5-FU/FA in the first-line treatment of advanced colorectal cancer. Irinotecan and oxaliplatin are also active in the second-line treatment of colorectal cancer. The oral fluoropyrimidines seem to have an activity comparable to that of intravenous 5-FU/FA in the first-line treatment of metastatic colorectal cancer. New agents acting on novel targets are under development: epidermal growth factor inhibitors, vascular endothelial growth inhibitors, COX-2 inhibitors and farnesyl transferase inhibitors might play a role in the future in the treatment of colon cancer., (Copyright 2002 Elsevier Science Ltd.)

Colorectal cancer is one of the most frequent malignancies and one of the greatest causes of cancer death in the Western world. The prognosis is determined by the stage at diagnosis. Patients with metastatic colon cancer have a bad prognosis. Chemotherapeutic treatment with 5-Fluorouracil (5-FU) and folinic acid is actually considered as the standard treatment in patients with metastatic disease. Although the survival benefit is relatively small, many patients can benefit from this treatment in terms of tumor regression or symptom improvement. Several new drugs are actually in development and create hope for improved tumor or symptom control and longer survival. Thymidylate synthase inhibitors (raltitrexed), topoisomerase I inhibitors (irinotecan), the oral 5-FU prodrugs (capecitabine, UFT), ethynyluracil, and oxaliplatin are promising new drugs. The challenge will be to determine the best combination of these new drugs and the exact sequence in which these drugs will be used. Adjuvant post-operative chemotherapy in colon cancer is one of the most important advances in oncology that has been introduced into the clinic during the last years. For rectal cancer, an adjuvant treatment should consist of a combined chemo-radiotherapy. The search for better prognostic factors for recurrence should help to focus on a better adjuvant treatment for patients with the highest risk for recurrence.