20 Yttrium-90 Radioembolotherapy for Hepatocellular Cancer 325 the tumor without impeding their egress into the hepatic vein. Once in the hepatic venous side, these particles then travel via the venous circulation of the heart into the pulmonary artery and subsequently embolize in t he arteriolar bed. 90 Y microspheres are considerably smaller, with a median diameter of 25μ. When these particles embed in the pulmonary interstitium, they irradiated in addition to causing vascular blockade. Therefore, inherent to the therapy is some element of pulmonary irradi- ation that is clinically silent until a threshold of 30 Gy is reached from a single or 50 Gy from cumulative exposure, but modern imaging techniques have called this threshold into question [29, 30]. Clinically apparent radiation pneumonitis is often fatal despite aggressive treatment with steroids. The magnitude of hepatopulmonary shunting is estimated via the hepatic arte- rial injection of 99m Tc MAA, acting as a microsphere surrogate in terms of both size and distribution. It is important that liver injection of MAA is delivered with flow rates and catheter position that mimic the anticipated 90 Y infusion rate and catheter position. The ratio of the lung to liver deposition corrected for background is expressed as a percentage of the injected activity. The factors that increase the likelihood of lung shunting are the histology of the primary tumor (HCC> neuroen- docrine>colorectal), tumor burden, and prior 90 Y radioembolotherapy [31]. Hepatic venous occlusion has been observed to decrease the shunt fraction to allow for safe radioembolotherapy. Dosimetry Users are directed to the product insert provided for each device. Dosimetry improvements represent a current area of intense research for many groups. The dose calculation methodologies currently available assume uniform distri- bution of the 90 Y microspheres in the end organ, although with the resin 90 Y microsphere equations that integrate relative tumor burden and lung shunting allows for refinement in dosimetry. Although these assumptions of uniformity are intrinsically erroneous, in clinical practice objective benefits observed thus far with mild to minimal toxicity have created an atmosphere of optimism for the therapy. The cumulative lung dose calculation is identical regardless of which device is utilized and is given by the following equation: Cumulative absorbed lung radiation dose = 50 × lung mass n i=1 A i × LSF i where A i = activity infused, LSF i = lung shunt fraction, n = number of infusions with the assumption of approximately lung blood volume mass = 1 kg. Activity reduction is allowed for resin microsphere using the following table. 326 R. Murthy et al. Hepatopulmonary shunting % Recommended dose reduction % <10 0 10–15 20 15–20 40 >20 100 Therasphere activity can be calculated using the following equation: A (Gbq) glass = D(Gy) × M (kg) 50 When the hepatopulmonary shunting is taken into account, the dose is then calculated as D(Gy) = [A(GBq) × 50 × (1 − LSF)]/M (kg) where A = Activity delivered to the liver, D = Absorbed dose to the target liver tumor, and M = Target liver mass. The mass is extrapolated from CT by using a conversion factor of 1.03 g/ml. SIR-spheres R can be calculated as per the package insert by two methodologies. The “Empiric method” is a simplified method in which tumor burden is used. Liver involvement by tumor % Recommended activity (GBq) <25 2.0 25–50 2.5 >50 3.0 Alternatively the activity can be calculated with the body surface area that factors the tumor burden in the liver A = (BSA − 0.2) (Tumor Volume)/(Tumor Volume + Liver) A resin is the activity of the 90 Y content of the resin microspheres (gigabec- querels). Post-procedure Evaluation Overall the treatment is associated with a favorable sub-acute and acute toxicity pro- file probably r elated to the low-level arterial occlusion following implantation. This allows for outpatient treatment. Empiric treatment with gastric mucosal-protectant agents is prescribed since small unmanned arteries that are undetectable with arteriography (resolution or reversal of flow) may supply extrahepatic structures. 20 Yttrium-90 Radioembolotherapy for Hepatocellular Cancer 327 Some clinicians prescribe a short, tapering course of methylprednisolone to mini- mize the edema and pain associated with capsular stretch due to the radiation. It is advisable to give patients a detailed sheet that identifies them as having received the implantation and it is unnecessary to shield patients from bystanders due to the low level of radiation at skin surface (<1 mrem per hour); however, standard radiation safety precautions are advisable. Unlike the glass microspheres, due to the ionic dissociation of 90 Y from the resin microsphere the urine will be marginally radioactive for the first day after delivery [24]. The optimal interval for imaging after treatment is not defined; however, most clinicians agree that an interval between 60 and 90 days is optimal to allow for resolution of treatment-related edema. Both MRI and CT have been utilized as surrogates for response. Kamel et al. reported on patients who prospectively underwent MR imaging pre- and post-therapy. Targeted tumors demonstrated a decrease in arterial enhancement, a decrease in venous enhancement of 25%, and unchanged tumor size in both targeted and non-targeted tumors [32]. Keppke et al reported on the imaging findings of 42 patients using 90 Y glass microspheres [33]. The response rates according to WHO, RECIST, necrosis, and combined criteria (RECIST & necrosis) were 26, 23, 57, and 59%, respectively. Tumor response was also reported by Salem et al. for 43 consecutive patients with HCC treated with glass 90 Y microspheres. Based on percent reduction in tumor size, 47% had an objective tumor response. When necrosis was used as a composite measure of response, 34 patients (79%) had an objective tumor response [34]. The most accurate assessment of tumor response after 90 Y radiotherapy appears to be volumetric with necrosis. Kennedy et al. analyzed four explanted livers previously treated with yttrium- 90 microspheres. Two patients underwent orthotopic liver transplantation, and two patients had advanced metastatic colon cancer. A complete histopathologi- cal analysis was performed including an assessment of microsphere distribution. Histopathology from the tumor liver parenchyma interface was sectioned for three- dimensional radiation dosimetry analyses. Heterogeneous deposition of micro- spheres at the interface with non-tumorous liver compared with the central zones without evidence of RILD in the surrounding parenchyma was noted [35]. This appeared to correlate with a zone of rim enhancement that can be appreciated on MRI. Riaz et al. reported their results of radiological–pathological correlation after liver explantation in 35 patients who harbored 38 lesions. CT or MRI was used for imaging and the explants were examined for assessment of necrosis and the corre- lation of radiological and histological findings was analyzed. All lesions harbored some degree of necrosis. Twenty three (61%) of target lesions showed complete pathologic necrosis, the vast majority of which were <3 cm. Imaging findings of response by EASL and WHO criteria were predictive of the degree of pathologic necrosis. Complete necrosis was s een in 100, 78, and 93% of the lesions that were shown to have complete response by EASL necrosis criteria, partial response by WHO criteria, or thin rim enhancement on post-treatment imaging, respectively. In contrast, complete necrosis was seen in only 52 and 38% of the lesions that showed partial response by EASL criteria and peripheral nodular enhancement, respectively. Rim enhancement was a characteristic that correlated well with necrosis [36]. 328 R. Murthy et al. Toxicity Fatigue is the most common toxicity occurring in the vast majority of patients and lasting for up to 2 weeks. Post-embolization syndrome (low-grade fever, abdom- inal pain) occurs in a minority of patients and is of significantly lower incidence than following chemoembolization. Goin et al. performed a historical compari- son of chemoembolization to radioembolotherapy utilizing glass 90 Y microspheres for incidence of post-embolization syndrome (PES). While the median survival was similar for each group the incidence of PES was nearly four times higher in the TACE group (p = 0.003; 95% CI, 1.6–16.3), demonstrating a toxicity profile strongly favoring radioembolization [37]. It is often self-limiting and treated with narcotic analgesics. Radiation-induced gastrointestinal injury can be occult, present with abdominal pain, hematemesis, or melena. Pancreatitis has also been described. Radiation pneumonitis has not been reported in the USA following use of either product. Radiation-induced liver disease (RILD) is related to excessive radiation exposure of normal liver tissue to radiation. This is manifested as a clinical syn- drome of anicteric hepatomegaly, ascites, and increased liver enzymes occurring weeks to months after therapy. While it is known that RILD will develop when the whole liver is exposed to more than 40–45 Gy of external beam radiation, 90 Y microspheres are point sources of radioactivity and the tolerance is thought to be much higher approximating 70–80 Gy. More recently a study by Gulec et al. con- cluded that doses up to 100 Gy to the uninvolved liver were tolerated without the development of veno-occlusive disease or liver failure [38]. It also appears that there is a low occurrence of toxicity even with cumulative radiation doses of 390 Gy and 196 Gy, respectively [39]. An analysis of the biochemical liver toxicities was studied by Goin et al. in 88 patients who harbored [40] multifocal HCC (50%), >50% of liver replaced with tumor (16%), and portal vein thrombosis or portal vein compromise (17%). The most frequent liver abnormalities included ascites, elevated bilirubin, increased aminotransferase levels, and the majority (78%) of liver toxici- ties resolved. In this patient population, RILD was not seen and other forms of liver dysfunction were only transient. Lymphopenia without sequelae of clinical immuno- suppression has been described; the etiology remains unknown [41]. Bile ducts are exclusively supplied by the hepatic artery and ischemic injury can occur. These rare complications can manifest as biliary necrosis, biloma, abscess and cholecys- titis [42, 43]. While the exact incidence of radiation induced gall bladder injury requiring cholecystectomy is unknown, some investigators advocate routine empiric embolization of the cystic artery. Clinical Studies The first published manuscript of the modern experience of 90 Y radioembolother- apy appeared in a phase II study involving 22 patients by Dancey et al. [44] to determine the duration and frequency of response and to gain a renewed 20 Yttrium-90 Radioembolotherapy for Hepatocellular Cancer 329 understanding of the toxicities following treatment. Of the 20 evaluable patients, nine patients were Okuda Stage I/II. The median dose delivered was 104 Gy. Fourteen patients experienced serious adverse events; most of which were hepato- cellular dysfunction and gastrointestinal ulceration. A 20% response rate was noted with one complete response. Median time to progression and survival were 44 and 54 weeks, respectively. Multivariate analysis suggested that a total dose > 104 Gy, Okuda Stage I, and 99m Tc MAA tumor to liver uptake ratio ≥2 were associated with prolonged survival. In s eparate studies, Lau et al. was able to demonstrate a dose–response and dose–survival relationship in a phase I/II and II trial involving 18 and 73 patients, respectively. Tumor regression and survival improved in patients receiving > 120 Gy [45].The same group published a retrospective analysis of 82 patients treated over an 8-year period [24,46]. Patients were sub-classified as “short survivors” (mortality < 1 year; 62%) or “long survivors” (mortality > 1 year; 34%). Comparisons between groups suggested high 99m Tc MAA tumor to liver uptake ratios favored longer survival. Carr et al. [41] also reported the results of a single institutional study that sup- ported both the safety and the efficacy of glass 90 Y microspheres for inoperable HCC. Sixty-five patients with biopsy-proven HCC received a median radiation dose of 134 Gy. Major toxicities included two episodes of cholecystitis and transient hepatocellular transaminase elevations in 25 patients. Interestingly, the majority of patients developed lymphopenia, a previously unreported finding, not associated with adverse clinical events such as opportunistic infections. Median survival was more than double compared with historical controls of 649 and 302 days for Okuda I and II patients, respectively, a finding common to other studies. Geschwind et al. in 2004 reported on 80 patients from a multi-institutional database of 121 patients who were treated with glass 90 Y microspheres using varied approaches [47]. Patients were staged using the Child-Pugh, Okuda, or Cancer of the Liver Italian Program (CLIP) scoring systems. Among the three systems, the pretreatment CLIP scores were found to be the best means of stratifying risk. Survival was found to be 628 and 324 days for Okuda I (68%) and II (32%) patients, respectively. In 2004, Liu et al. presented a retrospective review of 14 patients treated for unresectable HCC [48]. The response rate was 65% (Table 20.2). Table 20.2 90 Y microspheres: recent published experience in HCC Investigator Device N PR Okuda Survival Okuda I Survival Okuda II Carr [41] TS 65 25 I – 65% II – 35% 649 d 302 d Liu et al. [48] TS 14 8 I – 64% II – 36% 11 m 7 m Geschwind et al. [47] TS 80 nr I – 68% II – 32% 628 d 324 d Salem et al. [34] TS 43 51% I – 49% II – 51% 24 m 13 m 330 R. Murthy et al. Survival results were also reported by Salem et al. in 43 patients treated with glass 90 Y microspheres [36]. The median survival reported in this study was 20.8 months for a low-risk group, whereas high-risk patients with diffuse disease faired worse with a median survival from the first treatment of 11.1 months. There were no life-threatening adverse events related to the treatment [34]. Gulec et al. ret- rospectively analyzed the data from a heterogeneous cohort of 40 patients with liver malignancies who underwent single whole liver treatments using 90 Y resin micro- spheres. Tumor absorbed doses ranged from 40.1 to 494.8 Gy. Sixty-seven percent of the treated cohort responded to therapy again with responses favoring patients with higher 99m Tc MAA tumor ratio [38]. Portal venous thrombosis is a uniformly poor prognostic variable and concerns over excessive toxicity following traditional embolotherapies exist. In 2004 a report on a series of 15 patients with unresectable HCC and portal vein thrombosis of at least the first order and related segmental portal venous branches received glass 90 Y microspheres. Two patients developed bilirubin toxicity and had evidence of disease progression. Eight patients continued to demonstrate stable or improved liver function after a second treatment cycle with no procedure-related complica- tions. This clinical experience showed that in a select group of patients with compro- mised portal venous flow, glass 90 Y microspheres treatment is technically feasible and relatively safe [49]. Subsequently, Kulik et al. reported on the results of glass 90 Y microspheres in a 118 patient cohort, with a 37 patient subset analysis compar- ing patients with and without portal vein thrombosis [50]. Patients were stratified by Okuda, Child-Pugh, baseline bilirubin, ECOG, presence of cirrhosis, and location of portal vein thrombosis (none, branch, and main). The cumulative dose adminis- tered to those with and without portal vein thrombosis were 139.7 Gy and 131.9 Gy, respectively. Liver-related adverse events (bilirubin, ascites, and encephalopathy) were more in patients with cirrhosis versus no cirrhosis and the minimal embolic effect of 90 Y glass microspheres was not felt to have increased the risk of liver decompensation. Median survival from the date of first treatment for patients with- out portal vein thrombosis and cirrhosis was 27 months versus patients with branch portal vein thrombosis, survival was 10 months. Sangro et al. reported on 24 HCC patients with Child-Pugh A disease who underwent 90 Y radioembolization with resin microspheres. The overall response rate was 88% with a volume reduction noted in 19 patients. Two patients became jaundiced and two treatment-related deaths were noted. At median follow-up of 12.5 months none of the treated patients progressed [51]. Results of a recent pilot phase II study were presented by Ertle et al. A total of 60 patients predominantly with cirrhosis and preserved liver func- tion (87% Childs A, 93% cirrhosis, 50% PVT) were treated with glass microspheres [52]. The volumetric response rate was 52% and this increased to 80% with the addition of necrosis. Median survival was 12.1 months. Preliminary results have been reported recently by many authors. Romito et al. presented the results of glass microsphere therapy in 23 HCC patients, most with either main or branch portal vein thrombosis were treated with the glass micro- sphere. The response rate was 25 and 74% were alive at 9 months (57% with PVT, 100% no PVT) [53]. Iñarrairaegui et al. recently presented data with resin 20 Yttrium-90 Radioembolotherapy for Hepatocellular Cancer 331 microsphere use in 62 patients (77% cirrhosis, 20% PVT). The median survival was 10 months favoring those patients with higher dose delivered (>3 GBq 15m ver- sus <3 GBq 6 m and paucinodular disease; ≤5 nodules 23 m, >5 nodules 7 m) [54]. Additional results supporting the efficacy of resin microspheres for HCC was presented by D’Avola et al. The survival of 23 patients (72% cirrhosis, 32% PVT) was superior compared with a match-controlled cohort of 14 versus 8 months (p = <0.05) [55]. Similar survival benefit was noted by Carpenese et al. who treated 22 predominantly Childs A cirrhotics with resin microspheres. The response rate was 81% and the median survival for Childs A patients was 12 months [56]. Given the survival benefits, tumor response, and minimal toxicity profile, radioem- bolization should be considered as a viable therapy for patients with portal vein thrombosis and preserved liver function. It is a reasonable treatment option for disease stabilization in patients who were awaiting transplant. In order to improve outcomes in patients with limited volume disease, Rhee et al. tested a procedure employing catheter-directed CT angiography. This technique delineates the arterial supply to HCC, which in turn allows for s elective adminis- tration of supra-therapeutic radioactivity to segments/lobes of liver. This concept is referred to as radiation “segmentectomy” [57]. This allows for significantly greater radiation doses (range, 105–857 Gy) to small portions of liver parenchyma treating all viable neoplastic and non-neoplastic tissue without increased toxicity. Kulik et al. reported on 21 patients from a large database of 251 patients who had undergone glass 90 Y microsphere therapy and subsequently bridged to transplan- tation [58]. Target tumor dose administered was 120 Gy with toxicities including fatigue in the majority of patients (42%). The authors reported a mean reduction in alpha fetoprotein (AFP) of 33% from pretreatment levels. The investigators noted complete necrosis by pathologic exam in 14 patients (66%). Four of 21 patients had disease recurrence, a finding not uncommon following transplantation. Summary 90 Y radioembolotherapy is a promising outpatient transarterial therapy for unre- sectable hepatocellular cancer. It is a unique form of brachytherapy that shares characteristics of radiopharmaceuticals and a radiation therapy source, requiring multidisciplinary involvement. Knowledge of technical aspects of embolization, hepatic artery anatomy, and flow characteristics are essential for safe and effec- tive delivery of this new therapy. Published data from multiple independent sources support enhancement of survival in a distinct subset of patients with hypervas- cular tumors and intact liver function. Unlike other embolotherapies, portal vein thrombosis is not considered to be a major contraindication. 90 Y radioembolother- apy has served as an effective instrument to downstage to resection or as a bridge to transplantation. Compared to historical controls, the post-embolization syn- drome following 90 Y radioembolotherapy is milder than chemoembolization while conferring a similar survival advantage. 332 R. Murthy et al. Future Directions Historically transarterial therapies have been utilized for unresectable lesions not amendable to thermal ablation. The advent of molecular targeted agents has brought new perspectives to cancer therapy especially HCC. The recent FDA approval of sorafenib for the treatment of unresectable HCC has created a regulatory benchmark and renewed interest for HCC therapies. Until such treatments become standard of clinical care, integration of these agents with local-regional therapies may maximize benefits to the patients and should be the focus of future endeavors with therapies such as 90 Y radioembolotherapy. References 1. Jemal A, Siegel R, Ward E et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96 2. El-Serag HB (2007) Epidemiology of hepatocellular carcinoma in USA. Hepatol Res 37(Suppl 2):S88–S94 3. Mazzaferro V, Regalia E, Doci R et al (1996) Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693–699 4. Dawson LA (2005) Hepatic arterial yttrium 90 microspheres: another treatment option for hepatocellular carcinoma. 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Carpanese LPG, Vallati G et al (2008) Selective internal radiation therapy 90Y (SIRT) in multifocal HCC: clinical preliminary results in one year follow-up. World Conference on Interventional Oncology 2008, Poster P69 . imaging pre- and post -therapy. Targeted tumors demonstrated a decrease in arterial enhancement, a decrease in venous enhancement of 25%, and unchanged tumor size in both targeted and non -targeted. et al. [44] to determine the duration and frequency of response and to gain a renewed 20 Yttrium-90 Radioembolotherapy for Hepatocellular Cancer 329 understanding of the toxicities following treatment radioembolotherapy is a promising outpatient transarterial therapy for unre- sectable hepatocellular cancer. It is a unique form of brachytherapy that shares characteristics of radiopharmaceuticals and