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UNIVERSITA’ DEGLI STUDI DI MESSINA:

UNIVERSITA’ DEGLI STUDI DI MESSINA SCUOLA DI SPECIALIZZAZIONE IN CHIRURGIA GENERALE 2^ SCUOLA DI SPECIALIZZAZIONE IN CHIRURGIA GENERALE DIRETTORE PROF. FRANCESCO LEMMA VILLACH 20-22 MAGGIO 2010 BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES DOTT.SSA CECILIA MUSCARA ’ TUTOR PROF. A.G. RIZZO

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES At this time, colorectal cancer is the cause of death in 52,000 patients annually. In most of these patients, metastatic disease is confined to the liver even at the time of death. Therefore, localized therapies are an attractive option and surgery to remove hepatic metastases due to colorectal cancer can result in long-term survival.

Slide 3:

Surgery is the only therapy that offers the possibility of cure for patients with hepatic metastatic diseases. Unfortunately, only 25 % of patients with colorectal liver metastases are candidates for liver resection. The large majority of patients are not candidates for surgery, most commonly because of multiple metastases. BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES radiofrequency ablation, which is suitable if there are 3 or fewer tumors that are smaller than 3 cm each systemic and hepatic artery chemotherapy (hepatic artery infusion, HAC, HAI), cryotherapy, radio frequency ablation (RFA), Hepatic artery chemoembolization, portal vein embolization, immunotherapy laser hyperthermia UNRESECTABLE METASTASES TREATMENT

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES Selective Internal Radiation Therapy (SIRT) is a relatively new commercially available microbrachytherapy technique for treatment of unresectable colorectal liver metastases, that utilizes new technologies to deliver radiation directly to the site of tumors. The treatment combines arterial micro-embolization with high-dose interstitial radiotherapy.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES In the U.S., the Food and Drug Administration granted pre-market approval (PMA) to SIR-Spheres in March 2002 for the treatment of unresectable colorectal hepatic metastases.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES Malignant lesions in the liver primarily receive their blood supply through arterial perfusion, whereas normal liver parenchyma is mostly fed through the portal vein. In addition, the micro-vascular density of liver tumors is 3-200 times greater than the surrounding liver parenchyma. These differences provide an opportunity to selectively deliver therapeutic agents to liver tumors, while sparing the rest of the organ.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES The microspheres themselves are made of glass or resin. The resin material tends to embolize more easily and thus can be used to stop blood supply to the tumors. The microscopic spheres, each approximately 35 microns, are bonded to yttrium-90 (Y-90). There are 2 types of microspheres: Therasphere and SIR-Spheres which differ in their radioactivity and their embolic effect.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES 90-Yttrium is a pure beta emitter with a half-life of 64.1 hours with an average energy of 0.94 MeV. This corresponds to a maximum range of 1.1 cm within tissue with a mean path of 2.5 mm.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES 90-Yttrium labeled resin microspheres (SIR-Spheres) are infused into the hepatic artery and they lodge primarily in the tumor microvasculature.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES The microspheres are trapped in the tumor's vascular bed, where they destroy the tumor by reducing its bloodsupply (embolic effect) and through local radiation damage to the cancer cells' DNA.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES The procedure is performed under conscious sedation and local anesthesia at the catheter insertion site. Under image guidance, an angiographic catheter is inserted and placed into the proper hepatic artery. Spheres are infused from a micro-catheter within the angiographic catheter to treat the entire liver. SIRT is administered to the patient in two separate treatments. One treatment is given to the right lobe and one to the left lobe. With the treatments occurring at least one month apart.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES A well-integrated team involving interventional radiology, nuclear medicine, medical oncology, surgical oncology, medical physics, and radiation oncology is essential for a successful program . Careful selection of patients through the combined expertise of the team can maximize therapeutic efficacy and reduce the potential for adverse effects.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES Patient Selection patients with colorectal metastatic disease that is confined to the liver or with minimal extra-hepatic involvement no longer respond to chemotherapy, cannot tolerate or refuse chemotherapy, or choose to receive both SIRT and chemotherapy adequate liver functions (bilirubin <2 mg/dl) portal vein patency adequate renal function (eGFR >30 ml/min/m2)

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES SIRT is contraindicated in patients who have: Had previous external beam radiation therapy to the liver Greater than 20 percent lung shunting (determined by the nuclear medicine breakthrough scan) Pre-assessment angiograms and MAA nuclear scans that demonstrate significant reflux of hepatic arterial blood to the stomach, pancreas or bowel Widely disseminated or extra-hepatic disease Been treated with capecitabine within the previous two months, or who will be treated with capecitabine at any time following treatment with SIR-Spheres

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES RADIOLOGICAL EVALUATION PET/CT : is performed to evaluate the extent of metastasis as well as to provide a baseline measure of metabolic activity of the tumors for the correct dosage of microspheres.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES FDG-PET : the treatment response after SIRT seems to be better assessed using metabolic response assessments with serial fluorodeoxyglucose positron emission tomography (FDG-PET) in cases of FDG-avid tumours than with morphological criteria measured on CT or MRI (RECIST or WHO trials).

Slide 18:

( A) Axial CT (pre-SIRT) of the liver in a patient with colon cancer shows metastasis (arrow) in segment 8 of the liver. (B) PET image of same patient showing high focal uptake (arrow) of 18F-FDG in the tumor. (C) CT image of same patient 6 weeks after treatment with SIRT showing complete necrosis of the tumor. (D) PET image of same patient, 6 weeks after treatment showing diminished uptake of FDG.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES Angiography: will be used to assess the patient ’ s hepatic artery and celiac axis. The gastroduodenal artery and right gastric arteries are generally coil-embolized at this time to prevent reflux of the resin microspheres

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES (A) Pre-treatment angiogram shows normal celiac artery. (B) Angiogram after coil embolization of the gastroduodenal artery (GDA) (single arrow) and right gastric artery (RGA) (two arrows) shows successful embolization with no flow in to these vessels. This is performed to prevent accidental reflux of SIR-Spheres from the hepatic artery to the gut vessels.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES Perfusion Scintigraphy : 99mTc-macro aggregated albumin (MAA) are infused into the proper hepatic artery for perfusion scintigraphy. MAA particles are similar in size to SIR-Spheres and provide information about blood flow from the hepatic artery, in particular to the lungs and abdominal organs. If more than 20% of the radioactivity reaches the lungs via hepato-pulmonary shunting, SIRT is contraindicated because of the risk of developing radiation pneumonitis. If 10-20% reaches the lungs, it is possible to perform SIRT with a reduced dose of 90Y. If <10% reaches the lungs, the procedure can be conducted using the standard protocol .

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES (A) In one patient the hepatopulmonary shunt is less than 5%. (B) In another patient the hepatopulmonary shunt is >20%, which makes the patient ineligible for SIRT.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES Complications Toxicity is usually mild, featuring fatigue, anorexia, nausea, abdominal discomfort, and slight elevations of liver function tests. Low-grade fever, loss of appetite, lethargy, and fatigue are common for up to 6 weeks after the procedure. Acute abdominal/epigastric pain and/or nausea has been reported to occur in 30%. In one study, gastric ulcers were reported in 5% of patients. Unfortunately, radiation-induced ulcers do not heal well. Radiation-induced liver disease or pancreatitis is very rare.

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES PET-CT imaging : PET is more sensitivce than CT for the assessment of early response. tumor markers : is used to assess response 6 weeks after initial treatment and at subsequent 3-month intervals for the first year and every 6 months thereafter to detect recurrence or spread of disease. FOLLOW-UP

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES Data on the outcome following SIRT are limited. In one study of 208 patients, 87% of whom had undergone first, second, and third line chemotherapy, the response rate was 85% as measured by FDG-PET scanning. The median survival for responders was 10.5 months, compared to 4.5 months for non-responding patients. Massachusetts General Hospital Department of Radiology

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES In one study 100 patients with extensive colorectal metastases not amenable to resection or ablation are treated in one institution. The estimated survival at 18 and 30 months was 32% ± 4.7 and 9% ± 2.9%. The majority of patients who died did so with progressive extra-hepatic disease. Stubbs, RS, O'Brien, I and Correia, MM. (2006) Selective internal radiation therapy with 90Y microspheres for colorectal liver metastases: single-centre experience with 100 patients . ANZ J Surg 76 : 696-703

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES:

BRACHYTHERAPY IN THE TREATMENT OF LIVER METASTASES CONCLUSIONS Treatment with SIR-Spheres is generally not regarded as a cure, but has been shown to shrink the cancer when combined with chemotherapy more than chemotherapy alone. This can increase life expectancy and improve quality of life. On occasion, patients treated with SIR-Spheres have had such marked shrinkage of the liver cancer that the cancer can be surgically removed at a later date. This has resulted in a long-term cure for some patients.

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