Capecitabine plus Irinotecan (XELIRI regimen) compared to 5-FU/LV plus Irinotecan (FOLFIRI regimen) as neoadjuvant treatment for patients with unresectable liver-only metastases of metastatic colorectal cancer: a randomised prospective phase II trial

<p>Abstract</p> <p>Background</p> <p>Phase II studies have shown that the combination of capecitabine and irinotecan (the XELIRI regimen) is active in metastatic colorectal cancer (MCRC). There are, however, no data about the use of the XELIRI regimen in the neoadjuvant treatment.</p> <p>Methods</p> <p>Patients with unresectable liver-only metastases of MCRC with ≤ 75 years of age were randomised to either the XELIRI (irinotecan 250 mg/m²given on day one and capecitabine 1000 mg/m²twice daily from day 2–15, every 21 days) or the FOLFIRI arm (irinotecan 180 mg/m², 5-FU 400 mg/m², LV 200 mg/m², 5-FU 2400 mg/m²(46-h infusion) – all given on day one, every 14 days). Primary end points were objective response rate (ORR) and rate of radical (R0) surgical resection. Secondary end points were progression-free survival (PFS), overall survival (OS) and safety.</p> <p>Results</p> <p>Altogether 87 patients were enrolled (41 pts in the XELIRI and 46 pts in the FOLFIRI arm). The median age was 63 years (63 years in the XELIRI and 62 years in the FOLFIRI arm) (p = 0.33). ORR was 49% in the XELIRI and 48% in the FOLFIRI arm (p = 0.76). The rate of radical R0 resection was 24% in both arms of patients. At the end of treatment, 37% of patients in the XELIRI and 26% of patients in the FOLFIRI arm were without evidence of the disease (CR+R0 resection) (p = 0.56). There were no statistical differences in grade 3 or 4 adverse events between both arms: diarrhoea 7% vs. 6%, neutropenia 5% vs. 13%, ischemic stroke 0 vs. 2%, acute coronary syndrome 2% vs. 4%, respectively. At the median follow up of 17 (range 1–39) months, the median PFS was 10.3 months in the XELIRI and 9.3 months in the FOLFIRI arm (p = 0.78), the median OS was 30.7 months in the XELIRI arm and 16.6 months in the FOLFIRI arm (p = 0.16).</p> <p>Conclusion</p> <p>The XELIRI regimen showed similar ORR as the FOLFIRI regimen in the neoadjuvant treatment of patients with MCRC. In addition, the XELIRI regimen showed similar PFS and OS with acceptable toxicity compared to the FOLFIRI regimen.</p> <p>Trial Registration</p> <p>Current Controlled Trials ISRCTN19912492</p

Diffusion-Weighted MRI for Verification of Electroporation-Based Treatments

Clinical electroporation (EP) is a rapidly advancing treatment modality that uses electric pulses to introduce drugs or genes into, e.g., cancer cells. The indication of successful EP is an instant plasma membrane permeabilization in the treated tissue. A noninvasive means of monitoring such a tissue reaction represents a great clinical benefit since, in case of target miss, retreatment can be performed immediately. We propose diffusion-weighted magnetic resonance imaging (DW-MRI) as a method to monitor EP tissue, using the concept of the apparent diffusion coefficient (ADC). We hypothesize that the plasma membrane permeabilization induced by EP changes the ADC, suggesting that DW-MRI constitutes a noninvasive and quick means of EP verification. In this study we performed in vivo EP in rat brains, followed by DW-MRI using a clinical MRI scanner. We found a pulse amplitude–dependent increase in the ADC following EP, indicating that (1) DW-MRI is sensitive to the EP-induced changes and (2) the observed changes in ADC are indeed due to the applied electric field

The effect of electroporation pulses on functioning of the heart

Electrochemotherapy is an effective antitumor treatment currently applied to cutaneous and subcutaneous tumors. Electrochemotherapy of tumors located close to the heart could lead to adverse effects, especially if electroporation pulses were delivered within the vulnerable period of the heart or if they coincided with arrhythmias of some types. We examined the influence of electroporation pulses on functioning of the heart of human patients by analyzing the electrocardiogram. We found no pathological morphological changes in the electrocardiogram; however, we demonstrated a transient RR interval decrease after application of electroporation pulses. Although no adverse effects due to electroporation have been reported so far, the probability for complications could increase in treatment of internal tumors, in tumor ablation by irreversible electroporation, and when using pulses of longer durations. We evaluated the performance of our algorithm for synchronization of electroporation pulse delivery with electrocardiogram. The application of this algorithm in clinical electroporation would increase the level of safety for the patient and suitability of electroporation for use in anatomical locations presently not accessible to existing electroporation devices and electrodes

Electropermeabilization of endocytotic vesicles in B16 F1 mouse melanoma cells

It has been reported previously that electric pulses of sufficiently high voltage and short duration can permeabilize the membranes of various organelles inside living cells. In this article, we describe electropermeabilization of endocytotic vesicles in B16 F1 mouse melanoma cells. The cells were exposed to short, high-voltage electric pulses (from 1 to 20 pulses, 60 ns, 50 kV/cm, repetition frequency 1 kHz). We observed that 10 and 20 such pulses induced permeabilization of membranes of endocytotic vesicles, detected by release of lucifer yellow from the vesicles into the cytosol. Simultaneously, we detected uptake of propidium iodide through plasma membrane in the same cells. With higher number of pulses permeabilization of the membranes of endocytotic vesicles by pulses of given parameters is accompanied by permeabilization of plasma membrane. However, with lower number of pulses only permeabilization of the plasma membrane was detected

Consensus molecular subtypes (CMS) in metastatic colorectal cancer - personalized medicine decision

Colorectal cancer (CRC) is one of the most common types of cancer in the world. Metastatic disease is still incurable in most of these patients, but the survival rate has improved by treatment with novel systemic chemotherapy and targeted therapy in combination with surgery. New knowledge of its complex heterogeneity in terms of genetics, epigenetics, transcriptomics and microenvironment, including prognostic and clinical characteristics, led to its classification into various molecular subtypes of metastatic CRC, called consensus molecular subtypes (CMS). The CMS classification thus enables the medical oncologists to adjust the treatment from case to case. They can determine which type of systemic chemotherapy or targeted therapy is best suited to a specific patient, what dosages are needed and in what order

Consensus molecular subtypes (CMS) in metastatic colorectal cancer - personalized medicine decision

Colorectal cancer (CRC) is one of the most common types of cancer in the world. Metastatic disease is still incurable in most of these patients, but the survival rate has improved by treatment with novel systemic chemotherapy and targeted therapy in combination with surgery. New knowledge of its complex heterogeneity in terms of genetics, epigenetics, transcriptomics and microenvironment, including prognostic and clinical characteristics, led to its classification into various molecular subtypes of metastatic CRC, called consensus molecular subtypes (CMS). The CMS classification thus enables the medical oncologists to adjust the treatment from case to case. They can determine which type of systemic chemotherapy or targeted therapy is best suited to a specific patient, what dosages are needed and in what order

Molecular biomarkers and histological parameters impact on survival and response to first- line systemic therapy of metastatic colorectal cancer patients

Histological parameters of primary tumour and nodal metastases are prognostic factors for survival of operable colorectal (CRC) patients, but not predictive for response rate of systemic therapy. KRAS mutations in codons 12 and 13 were first recognized as a predictive factor for resistance to anti-EGFR monoclonal antibodies. Not all patients with wild-type KRAS (wtKRAS) respond to anti-EGFR antibody treatment. Additional mechanisms of resistance may activate mutations of the other main EGFR effectors pathway, such as other mutations in RAS gene, mutations in P13K and PTEN expression