IR Therapies for the Treatment of Colorectal Liver Metastases

Laurie M. Vance, MD Vascular and Interventional Radiologist Department of Diagnostic Radiology Providence Hospital Southfield, MI

Financial Disclosures

• I have nothing to disclose.

-Colorectal cancer is the second most common cause of cancer death in the Western World.

-Colorectal liver metastases (CLM) are detected at the time of diagnosis of the bowel primary in 20-25% of cases. A further 40-45% of patients will subsequently develop CLM [1].

-Without treatment, prognosis is poor, with median survival of 1 year, and few survivors beyond 3 years.

-Surgical resection is the gold standard, but majority are not eligible for this.

-60-70% of liver metastases are unresectable at diagnosis -Central location or bilobar disease -Major vascular/biliary involvement -Unresectable extrahepatic disease -Liver dysfunction/cirrhosis [2]

- Radiology plays an important role in the multidisciplinary care of patients with CLM.

- Imaging - Detection and characterization of liver metastases - Assists in surgical/locoregional treatment planning - Treatment - Portal Vein Embolization - Ablative therapies - Liver directed arterial therapies

- Understanding the timing and role of locoregional techniques is critical.

Imaging Recommendations for Colorectal Carcinoma

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Staging -

Contrast enhanced CT -Normal parenchyma enhances, mets are HYPOattenuating -Peripheral enhancement may be present -Questionable lesions

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MR or PET -

Surveillance

-PET/CT -Foci of increased radiotracer activity within the liver -False negative with highly mucinous mets

Liver Segmental Anatomy- Couinaud

CLM on CT

CLM on PET/CT

Ablation/TACE/RE Portal Vein Embolization

Portal Vein Embolization (PVE)

Embolization of the PV branches supplying the liver segments to be resected, redirects blood flow to the nondiseased liver.

-This redistribution induces hypertrophy of the future liver remnant (FLR), making it possible to safely undergo major hepatectomy.

-Indications

– Patients with primary/metastatic liver disease, who are otherwise hepatic resection candidates, except: • Cirrhosis/Advanced fibrosis and future liver remnant (FLR)/total liver volume (TLV) <40% • Extensive chemotherapy and and FLR/TLV <30% • Normal underlying liver and an FLR/TLV <20%

PVE

Contraindications

– Absolute • Overt clinical portal HTN • Extensive invasion of the portal vein precluding safe catheter manipulation • Complete lobar portal vein occlusion – Relative • Extrahepatic metastatic disease • Tumor extension to the FLR • Tumor precluding safe access into the portal venous system • Biliary dilatation of the FLR • Mild portal HTN • Uncorrectable coagulopathy • Renal insufficiency

PVE

Preprocedure preparation

– CT – – IV antibiotic prophylaxis • Ceftriaxone 1 gram IV Consider General Anesthesia

Procedure

– Ipsilateral approach • Puncture peripheral portal venous branch • Portography • If segment 4 embo required, ideally performed first • Microcatheter, embo with particles, small then large, then deposit coils in the more proximal segments • Final portography in main portal vein • Embolize tract with coils as exiting – Contralateral approach • Pros: Allows for antegrade catheterization without sharp angles • Cons: If any injury to left sided portal vein occurs, patient is no longer surgical candidate

PVE

Results

– Get CT 3-4 weeks post-embo to assess degree of FLR hypertrophy (DH) – Degree of hypertrophy is used as a predictor of postoperative course • DH <5%  Higher post-op complication rate – Recent study • 112 patients • Average increase in FLR volume ~9%

Complications

– Subcapsular hematoma, hemobilia, pneumothorax, AV fistula, arterioportal shunt, sepsis, nontarget embolization, portal HTN.

CT Volumetric for PVE

Chemical/Thermal Ablation

Chemical Ablation Involves percutaneous direct infusion into the tumor of a denaturing materal (EtOH or Acetic acid), usually under CT guidance Limited success and not routinely used anymore Thermal Ablation - Involves killing of tissue by freezing it (cryoablation) or heating it (microwave, laser or radiofrequency) - Many institutions world wide have employed RF ablation, which has proven more effective at local control of tumor burden and fewer treatment sessions

Thermal Ablation

- Performed by directing an alternating current (460kHz) to create local agitation at the molecular level, heat and irreversible cellular damage - Procedure is done percutaneously under image guidance (CT or US) and involves insertion of a needle tip electrode with an insulated shaft and an active uninsulated tip into the tumor

May also be performed intraoperative

Thermal Ablation

-Can be used as stand-alone therapy or in conjunction with other treatments -Reserved for treatment of focal or multifocal lesions that are unresectable -Treatment success

Varies with the size of lesion and surrounding normal liver Studies have shown 80-90% complete tumor necrosis (while some patients required more than one session) With larger lesions, a study of 126 patients showed only 48% complete tumor necrosis (mean size = 5.4 cm)

-As with surgical resection, immediate complete tumor necrosis does not equate with long-term survival NO definite criteria for use of thermal ablation, but factors to consider:

Lesion size Individual lesions should be no larger than 5 cm Number of Lesions Fewer than 3 lesions Degree of underlying hepatic impairment Typically Child-Pugh class A or B

-Ideal objective is a 1cm margin of ablation around the mass, similar to surgical resection

Thermal Ablation

Advantages -Repeatability -High local efficacy -Sparing of normal liver -Low complication/cost Complications -Pain/Nausea -Hemorrhage

Coagulopathy and ascites increase the risk of uncontrolled bleeding and should be corrected prior to treatment

-Abscess

There should be no active infection Higher risk in patients with a choledochojejunal anastomosis

-Tumor seeding the tract -Thermal injury of adjacent organs

Usually a problem with peripheral tumors Especially Gallbladder and adjacent ribs

Transcathether Arterial Therapies

Therapeutic advantage due to the dual blood supply to the liver and the propensity for masses to derive their blood supply from arterial circulation Developed for patients who are ineligible for more definitive treatment of HCC

Problem is that most have such severe liver dysfunction that they are usually not candidates, as they cannot tolerate any additional stress on the surrounding liver Patients with Child-Pugh class C are ineligible and referred for systemic therapy

Comorbidities can add substantially to the risk

Severe thrombocytopenia or leukopenia Cardiac or renal insufficiency Uncorrectable coagulopathy Ascites Portal vein occlusion with hepatofugal flow Atypical or diseased arterial anatomy that increases the risk of injury to adjacent gastrointestinal organs from non-target embolization

Selective Chemoembolization (TACE)

- Catheter based treatment where the chemotherapeutic agent is injected into the vessels feeding the mass

Usually combined with an embolization or sclerotic agent (spheres or EtOH)

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Selective Chemoembolization (TACE)

- Tumors known to respond

HCC Mets from Colorectal Neuroendorcine Ocular melanoma Gastrointestinal sarcoma -

Exclusion criteria

Clinically apparent jaundice Hepatic encephalopathy Hepatofugal portal vein flow Liver rupture or tumor penetration of liver capsule Biliary obstruction WBC < 2.5 Platelet count < 60k Pregnancy

Clinical considerations -Portal vein patency

Can use low dose if partially occluded

-No extrahepatic tumors that will potentially kill the patient within 3 months -Adequate residual uninvolved liver and adequate function

No consensus on a number…studies vary from 50 – 75%

-Want serum bilirubin <3 mg/dL -Multiple treatments may be needed -F/U CT Scans in 1d, 1m, 3m, 6m and 1y -Tumor markers drawn before and after treatment

Selective Chemoembolization (TACE)

-Various chemo agent and embolization protocols have be used in TACE

Embospheres (typically 300-500um) Epirubicin (50mg), doxorubicin (50mg), cisplatin (100mg), mitomycin (10mg) Ethiodol – helps achieve concentration of the drugs in the tumor bed

-Technical Consideration artery?

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Should you completely embolize the feeding

Pros You obtain tissue ischemia, leading to cell death Anoxia causes an increase in tissue permeability and local concentration of the chemo Blocking inflow delays washout of the chemo agent Cons Evidence of hypoxia causing angiogenesis Permanent occlusion preclude subsequent treatments

Selective Chemoembolization (TACE)

Inadvertant Uptake - Lung – not uncommon

Usually of no clinical consequence Lobar collapse is usually a result of pain and resultant hypoventilation

- Celiac Artery Branches

Pancreas – Uncommon and can cause pancreatitis GDA – Can coil prior to embolization

- Gastric Uptake

- Uncommon and patients usually asymptomatic

- Gallbladder

- Uncommon - Usually asymptomatic, but can cause emphysematous cholecystitis or infarction

- Spleen

- Very uncommon, but can cause infarction

Selective Internal Radiation Therapy

- External beam radiation if delivered in sufficient doses is lethal to neoplastic tissue, with normal hepatocytes having an even lower tolerance

- However, when the whole liver is exposed to EBRT at a mean radiation dose of 43 Gy, more than 50% of patient develop liver dysfunction

- Stereotactic radiation can be used to deliver much higher doses to more focal areas, however this is difficult in CLM where many patients have multifocal masses that are irregular in size/margins - Isotope bearing microspheres, unlike EBRT, are point sources of radiation that preferentially localize in the peritumoral and intratumoral arterial vasculature

- Thus you can deliver very high doses of radiation to tumors, while radiation exposure to the normal hepatic parenchyma remains within tolerable limits

Selective Internal Radiation Therapy

-Delivery of radioactive material into the arterial blood supply -Much more involved and patients must undergo preprocedure angiography/mapping -Various isotopes have been used, with yttrium 90 (y-90) most commonly used in the United States

B-emitting isotope 64.2 hour half-life (94% in 11 days) Decays to stable Zirconium 90 Tissue penetration of 0.25 cm – 1.1 cm

Selective Internal Radiation Therapy

-Delivery is via nonbiodegradable glass or resin microspheres that have embedded radioisotope, which like TACE the microspheres are injected into the arterial blood supply

Contraindications

Absolute 1.Exaggerated hepatopulmonary shunting 2.Reflux into arteries that supply the gastroduodenal region -Two Commercially available microspehere devices

Glass beads  Thera-Sphere Resin  SIR-Spheres

-The spheres are neither metabolized nor excreted but remain in the liver as a permanent implant Relative 1.Subsequent to EBRT, as the effects of internal radiation after EBRT has not been studied 2.Treatment with capecitabine can increase toxicity 3.Ascites – indication of decreased hepatocellular reserve 4.Increased Bilirubin (>2) 5.Portal venous thrombosis (package insert warning, but studies show it can be done)

Selective Internal Radiation Therapy

Therapy Planning -Initial workup should include

CT or MRI of the liver for assessment of tumor, normal liver volume and patency of portal vein Check of presence of extrahepatic disease -

-Labs

Serum bilirubin level should be less than 2mg/dL Check for renal insufficiency to limit amount of contrast used

-Arteriography for Hepatopulmonary Shunt Calculation

May need to coil accessory arteries to prevent GI deposition of the spheres MAA is injected during this arteriogram, used as a sphere surrogate HP shunt fraction greater than 20% of injected dose or when shunt fraction indicates potential exposure of the lung to an absorbed dose of more than 30 Gy should preclude the patient

-SPECT done 30 hrs after treatment

Selective Internal Radiation Therapy

Results: (Therasphere) Complications: -Initial studies largely took place in Canada -100Gy well tolerated by patients -Increased survival

635 days vs 323 days 20% response rate

-Studies in the US have shown similar favorable results

US studies also demonstrated safety for patients with portal vein thrombosis

-Ongoing studies showing similar favorable results in metastatic colorectal cancer, even in those that showed no response to chemo -Low incidence -GI complications less than 5% -Pancytopenia, as a result of bone marrow suppression from leaching of the isotope -Life-threatening complication of progressive pulmonary insufficiency…never reported in the US -Cholecystitis, inject distal to cystic artery

Conclusion

- Presenting newly diagnosed patients at multidisciplinary tumor board is the key to providing optimum treatment.

- Locoregional therapies may limit unnecessary resections, contributing to the preservation of patient quality of life.

- Interventional Radiologic therapies allow the physician to manage the unresectable patient, to extend disease-free periods and overall survival, as well as convert some patients to resection for possible cure.

THANK YOU

References

Radio-frequency Ablation of Liver Tumors: Assessment of Therapeutic Response and Complications. October 2001 RadioGraphics, 21, S41-S54. Yttrium-90 Microsphere Therapy for Hepatic Malignancy: Devices, Indications, Technical Considerations, and Potential ComplicationsOctober 2005 RadioGraphics, 25, S41-S55.