Continuation of fluoropyrimidine treatment with S-1 after cardiotoxicity on capecitabine- or 5-fluorouracil-based therapy in patients with solid tumours: a multicentre retrospective observational cohort study.

BACKGROUND: Capecitabine- or 5-fluorouracil (5-FU)-based chemotherapy is widely used in many solid tumours, but is associated with cardiotoxicity. S-1 is a fluoropyrimidine with low rates of cardiotoxicity, but evidence regarding the safety of switching to S-1 after 5-FU- or capecitabine-associated cardiotoxicity is scarce. PATIENTS AND METHODS: This retrospective study (NCT04260269) was conducted at 13 centres in 6 countries. The primary endpoint was recurrence of cardiotoxicity after switch to S-1-based treatment due to 5-FU- or capecitabine-related cardiotoxicity: clinically meaningful if the upper boundary of the 95% confidence interval (CI; by competing risk) is not including 15%. Secondary endpoints included cardiac risk factors, diagnostic work-up, treatments, outcomes, and timelines of cardiotoxicity. RESULTS: Per protocol, 200 patients, treated between 2011 and 2020 [median age 66 years (range 19-86); 118 (59%) males], were included. Treatment intent was curative in 145 (73%). Initial cardiotoxicity was due to capecitabine (n = 170), continuous infusion 5-FU (n = 22), or bolus 5-FU (n = 8), which was administered in combination with other chemotherapy, targeted agents, or radiotherapy in 133 patients. Previous cardiovascular comorbidities were present in 99 (50%) patients. Cardiotoxic events (n = 228/200) included chest pain (n = 125), coronary syndrome/infarction (n = 69), arrhythmia (n = 22), heart failure/cardiomyopathy (n = 7), cardiac arrest (n = 4), and malignant hypertension (n = 1). Cardiotoxicity was severe or life-threatening in 112 (56%) patients and led to permanent capecitabine/5-FU discontinuation in 192 (96%). After switch to S-1, recurrent cardiotoxicity was observed in eight (4%) patients (95% CI 2.02-7.89, primary endpoint met). Events were limited to grade 1-2 and occurred at a median of 16 days (interquartile range 7-67) from therapy switch. Baseline ischemic heart disease was a risk factor for recurrent cardiotoxicity (odds ratio 6.18, 95% CI 1.36-28.11). CONCLUSION: Switching to S-1-based therapy is safe and feasible after development of cardiotoxicity on 5-FU- or capecitabine-based therapy and allows patients to continue their pivotal fluoropyrimidine-based treatment.

Treatment response of colorectal cancer liver metastases to neoadjuvant or conversion therapy: a prospective multicentre follow-up study using MRI, diffusion-weighted imaging and 1H-MR spectroscopy compared with histology (subgroup in the RAXO trial).

BACKGROUND: Colorectal cancer liver metastases respond to chemotherapy and targeted agents not only by shrinking, but also by morphologic and metabolic changes. The aim of this study was to evaluate the value of advanced magnetic resonance imaging (MRI) methods in predicting treatment response and survival. PATIENTS AND METHODS: We investigated contrast-enhanced MRI, apparent diffusion coefficient (ADC) in diffusion-weighted imaging and 1H-magnetic resonance spectroscopy (1H-MRS) in detecting early morphologic and metabolic changes in borderline or resectable liver metastases, as a response to first-line neoadjuvant or conversion therapy in a prospective substudy of the RAXO trial (NCT01531621, EudraCT2011-003158-24). MRI findings were compared with histology of resected liver metastases and Kaplan-Meier estimates of overall survival (OS). RESULTS: In 2012-2018, 52 patients at four Finnish university hospitals were recruited. Forty-seven patients received neoadjuvant or conversion chemotherapy and 40 liver resections were carried out. Low ADC values (below median) of the representative liver metastases, at baseline and after systemic therapy, were associated with partial response according to RECIST criteria, but not with morphologic MRI changes or histology. Decreasing ADC values following systemic therapy were associated with improved OS compared to unchanged or increasing ADC, both in the liver resected subgroup (5-year OS rate 100% and 34%, respectively, P = 0.022) and systemic therapy subgroup (5-year OS rate 62% and 23%, P = 0.049). 1H-MRS revealed steatohepatosis induced by systemic therapy. CONCLUSIONS: Low ADC values at baseline or during systemic therapy were associated with treatment response by RECIST but not with histology, morphologic or detectable metabolic changes. A decreasing ADC during systemic therapy is associated with improved OS both in all patients receiving systemic therapy and in the resected subgroup.

Centralized repeated resectability assessment of patients with colorectal liver metastases during first-line treatment: prospective study.

BACKGROUND: Metastasectomy is probably underused in metastatic colorectal cancer. The aim of this study was to investigate the effect of centralized repeated assessment on resectability rate of liver metastases. METHODS: The prospective RAXO study was a nationwide study in Finland. Patients with treatable metastatic colorectal cancer at any site were eligible. This planned substudy included patients with baseline liver metastases between 2012 and 2018. Resectability was reassessed by the multidisciplinary team at Helsinki tertiary referral centre upfront and twice during first-line systemic therapy. Outcomes were resectability rates, management changes, and survival. RESULTS: Of 812 patients included, 301 (37.1 per cent) had liver-only metastases. Of these, tumours were categorized as upfront resectable in 161 (53.5 per cent), and became amenable to surgery during systemic treatment in 63 (20.9 per cent). Some 207 patients (68.7 per cent) eventually underwent liver resection or ablation. At baseline, a discrepancy in resectability between central and local judgement was noted for 102 patients (33.9 per cent). Median disease-free survival (DFS) after first resection was 20 months and overall survival (OS) 79 months. Median OS after diagnosis of metastatic colorectal cancer was 80, 32, and 21 months in R0-1 resection, R2/ablation, and non-resected groups, and 5-year OS rates were 68, 37, and 9 per cent, respectively. Liver and extrahepatic metastases were present in 511 patients. Of these, tumours in 72 patients (14.1 per cent) were categorized as upfront resectable, and 53 patients (10.4 per cent) became eligible for surgery. Eventually 110 patients (21.5 per cent) underwent liver resection or ablation. At baseline, a discrepancy between local and central resectability was noted for 116 patients (22.7 per cent). Median DFS from first resection was 7 months and median OS 55 months. Median OS after diagnosis of metastatic colorectal cancer was 79, 42, and 17 months in R0-1 resection, R2/ablation, and non-resected groups, with 5-year OS rates of 65, 39, and 2 per cent, respectively. CONCLUSION: Repeated centralized resectability assessment in patients with colorectal liver metastases improved resection and survival rates.

Long-term neuropathy and quality of life in colorectal cancer patients treated with oxaliplatin containing adjuvant chemotherapy.

BACKGROUND: Oxaliplatin, combined with capecitabine (CAPOX) or infused 5-fluorouracil (FOLFOX), is standard of care in the adjuvant treatment of colorectal cancer (CRC). Prospective data on prevalence of oxaliplatin induced acute and long-term neuropathy in a real-life patient population and its effects on quality of life (QOL) and survival is limited, and scarce in CAPOX versus FOLFOX treated, especially in a subarctic climate. METHODS: One hundred forty-four adjuvant CRC patients (all 72 CAPOX cases and 72 matched FOLFOX controls) were analyzed regarding oxaliplatin induced sensory neuropathy, which was graded according to NCI-CTCAEv3.0. Ninety-two long-term survivors responded to the QOL (EORTC QLQ-C30) and Chemotherapy-Induced Peripheral Neuropathy (EORTC CIPN20) questionnaires and were interviewed regarding long-term neuropathy. RESULTS: Acute neurotoxicity was present in 94% (136/144) during adjuvant therapy and there was a significant association between acute neurotoxicity and long-term neuropathy (p < .001). Long-term neuropathy was present in 69% (grade 1/2/3/4 in 36/24/8/1%) at median 4.2 years. Neuropathy grades 2-4 did not influence global health status, but it was associated with decreased physical functioning (p = .031), decreased role functioning (p = .040), and more diarrhea (p = .021) in QLQ-C30 items. There were no differences in acute neurotoxicity, long-term neuropathy, or in QOL between CAPOX and FOLFOX treated. Neuropathy showed no pattern of variation according to starting and stopping month or treatment during winter. CONCLUSIONS: Neuropathy following oxaliplatin containing adjuvant chemotherapy is present in two-thirds, years after cessation, and impairs some QOL scales. There is no difference in severity of acute or long-term neuropathy between CAPOX and FOLFOX treated and QOL is similar. No seasonal variation in neuropathy was noted.

Association of adverse events and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil and leucovorin: Is efficacy an impact of toxicity?

BACKGROUND: Adverse events associated with 5-fluorouracil (5FU) based adjuvant therapy in colorectal cancer (CRC) patients may predict survival. We studied whether haematological (leucopenia, neutropenia, thrombocytopenia) or non-haematological (mucositis, diarrhoea, nausea/vomiting, hand-foot syndrome or other toxicity) adverse events were associated with disease-free survival (DFS) or overall survival (OS) in a large patient material treated with 5-fluorouracil based adjuvant chemotherapy. PATIENTS AND METHODS: Data from two prospective randomised adjuvant trials were combined to achieve a dataset of 1033 radically operated stage II and III CRC patients treated with either monthly 5FU and leucovorin (LV) as bolus injections (Mayo or modified Mayo) or bi-monthly with bolus and continuous infusion (LV5FU2 or simplified LV5FU2). Toxicities were recorded at each treatment cycle according to NCI-C CTC (the Common Toxicity Criteria of the National Cancer Institute of Canada). The worst toxicity grade was taken into account. The median follow-up time of patients was 6.05 years. RESULTS: 47% of patients developed neutropenia, 54% nausea/vomiting and 43% mucositis. Any grade neutropenia was associated with improved DFS (hazard ratio (HR) 0.81), any grade nausea/vomiting with improved DFS (HR 0.79) and OS (HR 0.62) and mucositis with improved DFS (HR 0.74) and OS (HR 0.72). Patients experiencing no predefined toxicity had the worst outcome. CONCLUSION: Specific adverse events related to adjuvant fluorouracil chemotherapy are associated with improved DFS and OS in early stage CRC patients.

Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.

BACKGROUND: As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. PATIENTS AND METHODS: Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals. RESULTS: The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. CONCLUSIONS: Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.

Hypertension and overall survival in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy.

BACKGROUND: Hypertension (HTN) is a common toxicity of anti-VEGF (vascular endothelial growth factor) antibody treatment. It may be a marker of VEGF signalling pathway inhibition and therefore represent a cancer biomarker in metastatic colorectal cancer (mCRC) patients treated with chemotherapy and bevacizumab. METHODS: A total of 101 consecutive patients with mCRC were treated with standard chemotherapy combined with bevacizumab at dose of 2.5 mg kg(-1) per week in a single centre. The median follow-up time of the patients alive was 64 months. Blood pressure was measured before each bevacizumab infusion, and HTN was graded according to common toxicity criteria for adverse events version 3.0. RESULTS: Overall, 57 patients (56%) developed ≥grade 1 HTN (median blood pressure 168/97 mm Hg), whereas 44 (44%) remained normotensive when treated with bevacizumab-containing chemotherapy regimen. Overall response rate was higher among patients with HTN (30 vs 20%; P=0.025). Hypertension was associated with improved progression-free survival (10.5 vs 5.3 months; P=0.008) and overall survival (25.8 vs 11.7 months; P<0.001), and development of HTN within 3 months had an independent, prognostic influence in a multivariate landmark survival analysis together with other known mCRC prognostic factors (P=0.007). There was no association between HTN and development of thromboembolic complications. CONCLUSION: Hypertension may predict outcome of bevacizumab-containing chemotherapy in mCRC. These data require confirmation in prospective studies including pharmacodynamic and pharmacokinetic analyses.