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DEBIRI* for Metastatic Colorectal Cancer * Drug-Eluting Bead Irinotecan DC Bead® with irinotecan Offering the benefits of DC Bead to more patients DC Bead® with irinotecan Offering the benefits of DC Bead to more patients DC Bead is a Drug Delivery Embolisation System capable of loading and releasing in a controlled manner high doses of chemotherapeutic agents. † DC Bead Presentation • Novel N-fil technology sulphonate modified hydrogel polymer • Blue tinted to aid visualisation • Delivered as vials containing 2ml Beads in 6ml saline • Precise calibration to achieve an accurate level of embolisation “My experience in using DEBIRI to treat more than 80 patients, with in excess of 180 procedures, shows that DEBIRI is an effective treatment option for patients with refractory metastatic colorectal disease. The lack of major complications with good control of post-embolisation syndrome gives DEBIRI a favourable safety profile” Camillo Aliberti, Professor of Interventional Radiology Delta Hospital Lagosanto, Ferrara, Italy DC Bead Irinotecan Mode of Loading Irinotecan Mode of Action Hydrated Beads Irinotecan is enzymatically cleaved in the body to the active metabolite SN-38 Grafting point PVA macromer backbone - SO3 3 SO Sulphonated polymer chain backbone - SO3 Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-strand breaks - SO3 3 SO SO - SO3 3 - SO3 - SO3 Hydration shell associated with PVA and ionic groups This inhibits Topoisomerase I which relieves torsional strain in DNA by inducing reversible single-strand breaks. - SO3 - SO3 O - SO3 N Bulk (non-bound) water 3 SO N C O O N Irinotecan Solution N Drug-loaded Beads O Irinotecan H2O Irt O OH SO3 Irt Interaction of irinotecan (Irt) with SO3- groups by an ion-exchange process displaces water from the hydration shells Irt SO3 SO3 Irt SO3 Irt SO3 Irt Irt Instructions For Use. SO3 SO3 Irt SO3 SO3 † Biocompatibles SO3 O Irt Irt Irt SO3 Irt SO3 Irt SO3 N N C OH HO O N N O SN-38 O OH “After more than 3 years experience with DC Bead, we are now giving 200mg of irinotecan and a solution of 2-4ml of 100-300µm and/or 300-500µm microspheres mixed with non-ionic contrast medium. This solution is injected into the artery. Our results show that DEBIRI is effective in the control of colorectal liver metastases recalcitrant to first and second-line chemotherapy” Giammaria Fiorentini, Professor of Medical Oncology General Hospital Nuovo San Giuseppe, Empoli (Florence), Italy DEBIRI ALGORITHM – Colorectal Metastases Note: These notes are for guidance only and should not be seen as a recommendation or used in isolation to make clinical decisions that relate to patient care or medication 1. Initial scanning assessment: Use 3 Phase CT +/- PET scan (if available) to confirm the extent of the disease and whether the disease is liver dominant – defined as the extent of liver involvement being greater than 80% of the overall tumour burden. If <80%, then the large amount of extrahepatic disease may pose a greater risk of mortality than that contained within the liver, and the benefits of liver-directed therapy must be carefully reconsidered. • Position the catheter in the right or left hepatic artery depending on the lobe to be treated. 2. Define amount of liver replacement: Unilobar or Bilobar and up to 60% of the liver replaced by tumour or greater than 60% liver replacement.* • Give a slow injection of loaded DC Bead in 1ml aliquots followed by saline over an approx 3-5 minute period. a. Unilobar disease and up to 60% liver replacement: Plan two treatments, each of them with a maximum of 100mg irinotecan loaded in one 100-300µm DC Bead vial, separated by four weeks. b. Bilobar disease and up to 60% liver replacement: Plan four lobar treatments each of them with one vial of 100-300µm DC Bead loaded with 100mg irinotecan every two weeks (treat alternate lobes – first treatment right lobe, wait two weeks and then treat the left lobe. Two weeks later, perform a second treatment of the right lobe, wait two weeks and then a second treatment of the left lobe. Repeat scan three months from FIRST dose. Patients should be closely monitored for signs and symptoms of hepatic and systemic toxicity, and consideration given to extending the intervals between treatments as necessary. * In case of greater than 60% liver replaced by tumour, chemoembolisation treatment is not recommended • Identify the cystic artery and that the catheter tip is placed past the cystic artery prior to injecting DC Bead. • Remove excess irinotecan solution from the vial of irinotecanloaded DC Bead. Mix the loaded DC Bead with non-ionic contrast media as per the instructions for use. • Inject sufficient loaded DC Bead to the point where either the desired dose is injected or near stasis is achieved. The injection of additional embolic is not required. 4. Response – use modified RECIST or PET response: • If less than 80% objective response is observed, estimate the location and amount of residual disease and repeat the treatment based on this observation. If extrahepatic progression is observed/detected, collaboration with medical oncologist is required to decide next treatment steps and whether continued DEBIRI treatment alone, DEBIRI in combination with systemic therapy or systemic therapy alone is required. • If greater than 80% objective response is observed, then repeat CT or CT-PET every 3-4 months for the first year and every six months in the second year. If progress occurs in the liver, evaluate location and extent of liver involved and re-treat as above. If extrahepatic progression is observed/detected, collaboration with medical oncologist is required to decide next treatment steps and whether continued DEBIRI treatment alone, DEBIRI in combination with systemic therapy or systemic therapy alone is required. 3. Chemoembolisation procedure: • Peri-procedural medication: - Pain management protocol should include a major opioid (eg morphine) plus intra-arterial lidocaine (1% without adrenaline) injection 2-4ml prior to DC Bead injection. 5. Additional medications: • Certain patients have demonstrated hypertension after DEBIRI. Some investigators have found enalapril (IV 1.25mg or 2.5mg) has been effective in its management. - Antibiotic prophylaxis and all other peri-procedural medication (including anti-emetics) will be according to standard practice for a liver metastases chemoembolisation procedure. • Repeat treatment with DC Bead may lead to more severe nausea and a more aggressive anti-emetic therapy is recommended. “Critically, metastatic patients need to be approached for hepatic arterial therapy differently from those with HCC. Specifically my experience with DEBIRI would indicate that to optimise the therapy and ensure best practice patient management: 1. Include the use of intra-arterial lidocaine 2-4ml 1% prior to bead delivery as part of the pain management protocol 2. Plan for at least 2 treatments to appropriately assess response 3. To evaluate clinically relevant response, response should be assessed at least one month after treatment 4. Dynamic response criteria - EASL or PET should be utilised to assess response to therapy” Robert Martin, Associate Professor of Surgery Division of Surgical Oncology University of Louisville. Kentucky, USA DEBIRI ALGORITHM – Colorectal Metastases Note: These notes are for guidance only and should not be seen as a recommendation or used in isolation to make clinical decisions that relate to patients care or medication. Patient with liver predominant metastases from colorectal cancer Yes Unilobar Disease Lobar DEBIRI 100mg irinotecan in one 100-300µm vial No Bilobar Disease Lobar DEBIRI in most affected lobe 100mg irinotecan in one 100-300µm vial 2 weeks Second lobe DEBIRI 100mg irinotecan in one 100-300µm vial 4 weeks 2 weeks DEBIRI first lobe 100mg irinotecan in one 100-300µm vial 2 weeks Lobar DEBIRI 100mg irinotecan in one 100-300µm vial DEBIRI second lobe 100mg irinotecan in one 100-300µm vial 3 months tumour response, then every 3-4 months for 1 year, then every 6 months for second year Tumour response <80% Extrahepatic progression? No Yes Repeat treatment whenever residual tumour is found Other treatment options Tumour response >80% Imaging follow up “Currently available data suggest that patients with metastatic colorectal cancer may benefit from the addition of Drug-Eluting Bead irinotecan (DEBIRI) to their standard systemic chemotherapy.” Robert Martin, Associate Professor of Surgery Division of Surgical Oncology, University of Louisville. Kentucky, USA “From a Medical Oncologist’s perspective, I consider DEBIRI to be a valid treatment option for my patients with metastatic colorectal disease who have failed first-line systemic chemotherapy. DEBIRI could bring some hope to these patients whose response to systemic chemotherapy is very low.” Giammaria Fiorentini, Professor of Medical Oncology General Hospital Nuovo San Giuseppe, Empoli (Florence), Italy Surgical downstaging and neoadjuvant therapy in metastatic colorectal carcinoma with Drug-Eluting Bead irinotecan (DEBIRI) • Disease control, defined as complete response (CR), partial response (PR) and stable disease (SD), was seen in 89% of patients at 3 months, 80% at 6 months, 88% at 12 months. • Eleven patients (20%) were downstaged to resection or ablation. • DEBIRI is safe and shows potential efficacy in downstaging patients with unresectable colorectal metastases of the liver. Tumour Response (RECIST) 3 Months 6 Months 12 Months 18 Months Complete Response 6% 7% 6% 8% Partial Response 33% 35% 50% 83% Stable Disease 52% 54% 32% 0% Progressive Disease 9% 4% 12% 8% Source: Dr Matthew Bower, University of Louisville, USA. Oral Presentation American Hepato-Pancreato-Biliary Association Annual Meeting, Miami, Florida, USA. March 14th 2009 Hepatic intra-arterial injection of irinotecan Drug-Eluting Beads in unresectable colorectal liver metastases refractory to standard systemic chemotherapy • Systemic chemotherapy for unresectable metastatic colorectal cancer (MCC) is the optimal initial management of these patients. However, after a patient has failed first-line and in some case second-line chemotherapy, the response rates fall to as low as 12%. The aim of this study was to evaluate the efficacy of precision hepatic arterial irinotecan therapy in MCC patients who have failed first-line and/or second-line chemotherapy. • Hepatic arterial infusion with irinotecan was safe and effective in the treatment of MCC refractory to multiple lines of systemic chemotherapy. Total N = 55 Prior Therapy # Patients Median # DEBIRI Treatments (Range) Median Total Dose Irinotecan (Range) SAE Tumour Response (EASL) FOLFOX + Avastin 17 2 (1-3) 200 (50-600) 1 (6%) Grade 3 75% 3 Months 55% 6 Months 60% 12 Months FOLFOX + Avastin & FOLFIRI + Eribitux 14 2 (1-4) 200 (50-450) 1 (7%) Grade 3 1 (7%) Grade 5 80% 3 Months 70% 6 Months 75% 12 Months FOLFOX + Avastin & FOLFIRI + Eribitux & Xelox + Vectibex Other 24 2 (1-5) 200 (50-600) 2 (8%) Grade 3 1 (4%) Grade 5 50% 3 Months 60% 6 Months 75% 12 Months Source: Dr Robert Martin, University of Louisville, USA. Abstract, ASCO Gastrointestinal Cancers Symposium, San Francisco, California, USA. January 15-17th 2009 Loading of DC Bead® Using Irinotecan DC Bead should be prepared under aseptic conditions 1ml of DC Bead absorbs up to 50mg of irinotecan Step 1 Step 3 Remove as much saline as possible from DC Bead vial(s). using a syringe with a small gauge needle. Pierce bung with a second needle to eliminate vacuum. During the 2-hour loading period, agitate the beads occasionally. This will help ensure effective loading. A change in the bead colour from blue to turquoise will be observed. If a filter needle is not available, place flattened tip of needle against side of vial to prevent beads being drawn up the needle. Step 4 At the end of the loading time, remove excess solution from the vial and discard. Label Colour Nominal Bead Size Loading Time Product Code Yellow 100-300µm 2 hours DC2V103 Step 2 Using a syringe and needle add the appropriate volume of irinotecan solution to the DC Bead vial(s) to give the desired dose and total DC Bead volume. Step 5 Prior to use, add 5ml of water for injection and 5ml of non-ionic contrast medium to the vial. Transfer the contents of the vial to a syringe. Invert the syringe gently to obtain an even suspension of beads. DC Bead Bibliography Intraarterial Hepatic Chemoembolization of Liver Metastases from colorectal cancer Adopting Irinotecan-eluting Beads: Results of a Phase II Clinical Study. Preservation of the active lactone form of irinotecan using drug eluting beads for the treatment of colorectal cancer metastases. Fiorentini, G., Aliberti, C., Turrisi, G. et al In vivo 21: 1085-1092 (2007) Tang, Y., Czuczman, P.R., Chung, S.T. et al Journal of Controlled Release 127 (2008) 70-78 Trans-arterial Chemoembolization (TACE) of Liver Metastases from colorectal cancer Using Irinotecan-Eluting Beads: Preliminary Results. Irinotecan drug eluting beads for use in chemo-embolization: In vitro and in vivo evaluation of drug release properties. Aliberti C., Tilli M., Benea G., Fiorentini G. Anticancer Research 26:3779-3782 (2006). Reprinted from Anticancer Research 26, with permission from the Anticancer Research Institute. DC Bead is a registered trademark of Biocompatibles UK Ltd. DC Bead® is not currently available for sale or distribution in the USA. EC09-033(T) © 2009 Biocompatibles UK Ltd. Chemoembolisation of rat colorectal liver metastases with drug eluting beads loaded with irinotecan or doxorubicin. Eyol, E., Boleij, A., Taylor, R. et al Clinical and Experimental Metastasis (2008) 25: 273-282 Taylor, R.R., Tanga, Y., Gonzalez, M.V. et al. European Journal of Pharmaceutical Sciences 30 (2007) 7-14. Reprinted from European Journal of Pharmaceutical Sciences 30, with permission from Elsevier. Biocompatibles UK Limited, Chapman House, Farnham Business Park, Weydon Lane, Farnham, Surrey, GU9 8QL, UK. Tel: +44 (0)1252 732 710 Fax: +44 (0)1252 732 703 email: [email protected] www.biocompatibles.com