Volume 20 Number 5 Siddiqi and Devlin 665 Figure 1. Axial CT image in portal venous phase before treatment with 90 Y spheres. Low-density areas, some

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1 Radiation Lobectomy A Minimally Invasive Treatment Model for Liver Cancer: Case Report Nasir H. Siddiqi, MD, Phillip M. Devlin, MD Chemotherapy-resistant colon carcinoma metastases to a patient s right hepatic lobe progressed after right lobar radioembolization with yttrium-90. The metastasis-free left lobe had adequate volume as a future liver remnant. Repeat right lobar radioembolization with supratherapeutic activity of 90 Y caused shrinking of the tumors and the right lobe with no adverse outcome. With an adequate tumor-free future liver remnant, one hepatic lobe bearing a large tumor burden may be administered supratherapeutic activity of 90 Y, risking lobar ablation for greater probability of tumor eradication. This is analogous to hepatic lobectomy. This case is presented as a proof of principle. J Vasc Interv Radiol 2009; 20: Abbreviations: CEA carcinoembryonic antigen, FDG [ 18 F]fluorodeoxyglucose, PET positron emission tomography SELECTIVE hepatic artery embolization with yttrium-90 carrying microspheres is one treatment option for unresectable liver cancers that are liver-dominant or only in the liver. The technique of radioembolization targets the whole liver at once or each lobe sequentially, several weeks apart. The desired dose of radioactivity is calculated according to standard formulas (1). Low radiation tolerance of the liver limits the therapeutic efficacy of radioembolization (1). For suitable tumors confined to isolated segments of liver, a supratherapeutic dose of radioactivity may be selectively administered to the target segment(s) in a procedure termed radiation segmentectomy (2). This may maximize local cancer eradication with an understanding From the Division of Vascular and Interventional Radiology (N.H.S.), Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St. Louis, MO 63110; and Division of Brachytherapy, Department of Radiation Oncology (P.M.D.), Dana-Farber/ Brigham and Women s Cancer Center, Harvard Medical School, Boston, Massachusetts. Received March 7, 2008; final revision received and accepted January 20, Address correspondence to N.H.S.; siddiqin@mir.wustl.edu Neither of the authors has identified a conflict of interest. SIR, 2009 DOI: /j.jvir that the treated segment may become completely nonfunctional. Given the physical properties of 90 Y, untreated segments should be spared direct radiation damage and, if they are sufficient in volume, this should result in minimal overall effect on liver function. Massive liver tumors can replace a majority of the parenchyma of the involved anatomic unit. They may violate segmental boundaries but still remain unilobar in distribution. As an extension of the rationale underlying radiation segmentectomy, in certain cases, transarterial embolization of the disease-bearing lobe with a supratherapeutic dose of radioactivity may be an option (ie, radiation lobectomy). This case report exemplifies this concept. CASE REPORT Institutional review board authorization is not required for case reports at our institution. Iron-deficiency anemia in an otherwise healthy 68-year-old female subject prompted the first-ever colonoscopy for the patient. A friable, 7-cm-diameter polyp was seen in the ascending colon, which histologic examination showed to be villoglandular. At laparoscopic colectomy, the mass was found to have invaded the pericolonic fat. Several liver nodules were noted. Lymph node sampling and liver biopsy were performed at the time of surgery. On pathologic examination, the primary tumor was described as a moderately differentiated adenocarcinoma. The surgical margins were free of cancer. Two of the 20 lymph nodes and the liver biopsy specimen were positive for metastases. A staging computed tomography (CT) scan of the chest, abdomen, and pelvis performed after the surgery showed multiple liver metastases in the right lobe of liver, the largest approximately 6 cm in diameter. There was no evidence of metastatic disease elsewhere. The cancer was staged as T3N1M1 stage IV disease per American Joint Committee on Cancer guidelines (3). The patient was enrolled in a phase II trial and received 5-fluorouracil, leucovorin (Bedford Laboratories, Bedford, Ohio), oxaliplatin (Eloxatin; Sanofi- Synthelabo, New York, New York), bevacizumab (Avastin; Genentech, South San Francisco, California), and erlotinib (Tarceva; Genentech). After receiving 17 cycles of chemotherapy, an allergic reaction to oxaliplatin necessitated the patient s removal from the study. At that time, a CT scan showed progression of disease in the liver. The chemotherapy regimen was switched to irinotecan (Camptosar; Pfizer, New York, New York) and cetuximab (Erbitux; ImClone, Branchburg, New Jersey). Another CT scan approximately 4 months later re- 664

2 Volume 20 Number 5 Siddiqi and Devlin 665 Figure 1. Axial CT image in portal venous phase before treatment with 90 Y spheres. Low-density areas, some with calcification, represent tumor. The tumor is confined to the right lobe of liver. There is a relatively large left lobe of liver. vealed further progression of disease in the liver. There was no extrahepatic metastatic disease. The serum carcinoembryonic antigen (CEA) level had increased to 69.8 ng/ml (normal, 2.5 ng/ml) from a value of 2.9 ng/ml approximately 5 months earlier. The patient was reevaluated but considered not suitable for liver surgery by a surgical oncologist experienced in hepatobiliary surgery as a result of poor prognostic factors at the time of initial presentation, such as synchronous, multiple liver metastases, with some larger than 5 cm; local lymph node involvement with the primary cancer; and, later in the course, increasing serum CEA level. Local ablative therapy was not a consideration as a result of the size and number of tumors. At the time of referral to the interventional radiology clinic 16 months after the initial diagnosis, the patient was asymptomatic, with an Eastern Cooperative Oncology Group (4) performance status of 0. The hematologic and chemical laboratory parameters were normal. Serum CEA level was 216 ng/ml. A positron emission tomography (PET)/CT scan showed large tumors involving only the right lobe of liver (Figs 1,2). The patient was offered radioembolization with resin 90 Y spheres (SIR Spheres; SIRTex, Wilmington, Massachusetts). After preparatory angiography and liver lung shunt study (5), the patient was found eligible for radioembolization with resin 90 Y spheres. Only the right lobe of liver was treated. The administered activity of resin 90 Y spheres (1.43 GBq) was calculated according to the manufacturer s recommended formula based on body surface area and ratio of tumor to liver volume, as described in detail elsewhere (5). A nuclear medicine Bremsstrahlung scan after radioembolization showed the expected radioactivity in the right lobe of the liver with no nontarget embolization. At clinic follow-up 2 weeks after radioembolization, the patient was well clinically, with normal blood counts and serum chemistry values. Serum CEA value was increased at ng/ml, which was attributed to tumor necrosis. At follow-up 6 weeks after treatment, the patient was doing well clinically and by laboratory parameters, but the CEA level had increased to 295 ng/ml. CT scan of abdomen and pelvis revealed an increase in size and number of multiple hepatic metastases in the right lobe. There was a new low-attenuation area in the left lobe of the liver suspicious for metastasis (Fig 3). An [ 18 F]fluorodeoxyglucose (FDG) PET/CT examination was performed, which confirmed progression of disease in the right lobe of liver. There was no FDG-avid disease elsewhere (Fig 4). In interdisciplinary deliberation, it was noted that, given multiple poor prognostic signs, surgery was not a feasible option. Treatment with all approved drugs for colorectal cancer had failed in this patient. One option was a Figure 2. Coronal FDG PET image before first treatment with 90 Y spheres. The tumor activity is limited to the right lobe of liver. combination of 5-FU, leucovorin, and irinotecan (ie, FOLFIRI) with bevacizumab, but these agents had failed in other combinations. It was suggested that, should the disease progress beyond the liver, regional liver therapy would no longer be an option. The patient was opposed to further chemotherapy. At that juncture, repeat treatment with a supratherapeutic dose of 90 Y spheres was proposed. The risk of radiation injury to liver parenchyma was estimated. The left lobe constituted 47.03% of the total liver volume (liver volume, 1, cm 3 ; left lobe volume, cm 3 ) based on three-dimensional volumetric analysis. The left lobe was judged to have adequate functional reserve in a noncirrhotic liver, in case the right lobe was to be ablated. The treatment plan would not preclude subsequent systemic chemotherapy. The patient was informed of the treatment plan and the risks, benefits, alternatives, and lack of direct data to support this approach. The patient requested that the treatment be performed and gave informed consent. After repeat preparatory angiography and study of liver lung shunting, a

3 666 Hepatic Radiation Lobectomy May 2009 JVIR Figure 3. Portal venous-phase axial CT image 6 weeks after first treatment with 90 Y spheres. Low-attenuation areas representing tumor have increased in size and appear more confluent. In the setting of an increase in serum CEA level and FDG uptake on PET/CT, this most likely represents disease progression and not tumor necrosis. Figure 4. Coronal FDG PET image 6 weeks after first treatment with 90 Y spheres. There is increased activity, still limited to the right lobe of liver. This, together with clinical and laboratory data, represents a lack of response to conventional radioembolization. Figure 5. Anterior and posterior views of Bremsstrahlung scan after repeat radioembolization of the right lobe of liver show activity confined to the target volume. second round of right hepatic artery radioembolization was accomplished with 2.0 GBq of resin 90 Y spheres, 9 weeks after the first radioembolization treatment. Activity was again calculated according to the manufacturer s formula, with an estimated dose to the right lobe of the liver of 100 Gy. A Bremsstrahlung scan after treatment showed successful administration with activity limited to the target volume (Fig 5). The patient was discharged the same day, after 4 hours of observation. Two weeks later, the patient was in stable condition by clinical and laboratory parameters. The patient started a chemotherapy regimen with 5-FU/ leucovorin/irinotecan plus bevacizumab a few weeks later. The patient developed diarrhea, necessitating hospitalization and reduction of irinotecan to half the original dose. A follow-up abdominal CT examination 6 weeks after repeat radioembolization showed shrinkage of tumors in the right lobe (Fig 6). Laboratory markers of liver function were normal, and the serum CEA level had decreased to 92.7 ng/ml. At 3-month follow-up, the patient was doing well clinically. There was no laboratory evidence of hepatic dysfunction (Table 1), and the serum CEA level had further decreased to 35.4 ng/ml (Table 2). A repeat PET/CT study revealed interval decrease in disease activity in the right lobe of liver. Previously FDG-avid large hepatic metastases had been replaced by photopenic voids, consistent with successful ablation of the target tumors (Figs 7,8). There was new focal FDG avidity in segment IVA and in a left retrocrural lymph node (Fig 8). The right hepatic lobe had shrunken to a

4 Volume 20 Number 5 Siddiqi and Devlin 667 Figure 6. Portal venous-phase axial CT image approximately 6 weeks after second treatment with 90 Y spheres. The low-density areas in the right lobe have become more confluent and decreased in attenuation, suggestive of tumor necrosis. Figure 7. Portal venous-phase axial CT image 12 weeks after the second treatment with 90 Y spheres. The tumor and the entire right lobe have shrunken in volume. The left lobe has increased in size. Table 1 Liver Function Markers and Platelet Counts before and after 90 Y Treatment Laboratory Value Normal Range First Visit After Treatment 1 After Treatment 2 2 Weeks 6 Weeks 2 Weeks 6 Weeks 12 Weeks ALT (U/L) AST (U/L) ALP (U/L) Total bilirubin (mg/dl) Albumin (g/dl) Platelets ( 1,000/mm 3 ) Note. ALP alkaline phosphatase; ALT alanine aminotransferase; AST aspartate aminotransferase. Table 2 Serum CEA Levels during Treatment Time Point CEA Level (ng/ml) First visit After 90 Y treatment 1 2 weeks weeks After 90 Y treatment 2 2 weeks weeks weeks 35.4 fraction of its original size based on visual estimate on CT; volumetric calculations were not performed, and irreversible radiation injury was presumed to be the diagnosis. By consensus, the patient continued to receive 5-FU/leucovorin/irinotecan plus bevacizumab, with irinotecan at half the original dose. During subsequent follow-up, there was progression of extrahepatic disease, and systemic chemotherapy was continued. The patient was alive at the time of manuscript submission, 20 months after being referred to the interventional radiology service for the lack of another viable treatment option. DISCUSSION Liver cancers are prevalent, with few curative options (6). No more than 15% 20% of patients are candidates for surgery (7,8), and chemotherapy is only palliative in this disease (9,10). There are limitations for image-guided tumor ablation (11). The external radiation dose required to destroy solid tumors, approximately 70 Gy, is greater than the liver tolerance limit of 35 Gy (1). Recent external radiation techniques, such as conformal and intensity-modulated therapy and proton beam therapy, appear promising, but with limitations (12). Minimally invasive locoregional transhepatic arterial treatments are gaining broader acceptance. Hepatic neoplastic blood vessels are plentiful and structurally abnormal and form plexuses at the tumor periphery (13). Particles m in size, administered to the hepatic arteries, mostly lodge in the peritumoral arterioles (14). Loaded with pure -emitting (99.99%), nonleaching 90 Y, such particles become a source of intense focal radiation with a 300-Gy local dose cloud that reduces to 100 Gy within 4 mm (14). There is no absolute cellular resistance to radiation. Collateral radiation injury to the normal cells is the key concern limiting radiation dose to tumors. Radiation segmentectomy concentrates

5 668 Hepatic Radiation Lobectomy May 2009 JVIR Figure 8. Coronal FDG PET image 12 weeks after the second treatment with 90 Y spheres. Decreased FDG uptake in the right lobe of liver and photopenic voids instead of previously FDG-avid metastases suggest successful ablation of the target tumors. radiation in the target area (2). In the United States, a minority of patients with primary liver cancer would have a favorable disease distribution for radiation segmentectomy due to an advanced stage at presentation; such a favorable disease distribution would be much less common in patients with cancer metastases of the liver. Additionally, in cases with massive tumor burden, there is violation of segmental boundaries, eg, by direct invasion or through recruitment of extrasegmental blood vessels. Still, the disease may asymmetrically involve one lobe of liver with limited or no tumor burden in the other lobe. Hepatic lobectomy or trisegmentectomy with or without previous portal vein embolization is one treatment option for these patients (15). However, many patients have inoperable disease at this stage. Other patients with unilobar disease would not be surgical candidates because of factors such as comorbidity, operative risk, and bulky tumors. In these cases, radiation lobectomy may be considered: a supratherapeutic dose of transarterial radiation may be administered, targeting the entire disease-bearing lobe with the primary intent to expose the cancer cells to a supralethal radiation dose while accepting the risk of radiation ablation of the parenchyma of the treated lobe. This concept is analogous to surgical hepatic lobectomy, albeit in a minimally invasive fashion. The ideal radiation dose for solid tumor ablation in the liver is not known. However, it is assumed that doses of Gy provide a balance between tumor response and hepatic fibrosis risk with glass 90 Y spheres (1). For resin 90 Y spheres, 1 GBq is supposed to deliver a cumulative dose of 50 Gy per kilogram of tissue (1). The minimum radiation dose required to ablate the whole target lobe is not known, but logically it would be much higher than the therapeutic dose. The patient presented here was suitable for this treatment model. Hepatic surgery and image-guided ablation were not among viable options for the reasons mentioned earlier. Multiple lines of systemic chemotherapy had failed. Aside from the pelvic lymph nodes, the metastases were confined to the right lobe of liver. There was no evidence of hepatic dysfunction or portal vein compromise. There was a sizeable, relatively disease-free left lobe of the liver. The patient had an excellent performance status, and the hepatic arterial anatomy was favorable. Assuming that 1 GBq of resin 90 Y spheres delivers 50 Gy to 1 kg of tissue (1), the first treatment with 1.43 GBq delivered approximately 71.5 Gy to the right lobe. The disease progressed, and a second 2.0-GBq treatment was performed that delivered approximately an additional 100 Gy to the right lobe. The follow-up PET/CT examination showed an impressive response in the treated lobe. The large FDG activity voids had replaced previously FDG-avid metastases, even 3 months after treatment (Figs 2,4,8). This is unlikely to have been caused by subsequent systemic chemotherapy. The individual drugs being used had failed in other combinations, and irinotecan was being used at half the originally prescribed dose as a result of gastrointestinal toxicity. The radiation lobectomy procedure met the goals to ablate the metastases in the right hepatic lobe without adverse effects on the patient s health and quality of life. Given the high specific activity (2,500 Bq per sphere) and smaller size (25 m 10) of glass 90 Y spheres, they may be better suited for this treatment model than resin 90 Y spheres. However, resin 90 Y spheres are the only option at our institution. This treatment model requires meticulous attention to detail. Careful preparation angiography is required to eliminate the possibility of embolization of the nontarget hepatic lobe, gastrointestinal tract, and lungs. Three-dimensional volumetric studies of the lobes of the liver must be carefully evaluated to ascertain that there is sufficient functional reserve in the future liver remnant. Baseline liver dysfunction, such as in patients with hepatic cirrhosis and diabetes, would change the criteria for a sufficient remnant. We consider this treatment model only for patients with approximately 50% 70% replacement of a hepatic lobe by cancer. For most other cases, repeat treatment with a therapeutic dose of radiation is a safer option. This is a case report. The results cannot be generalized or overly emphasized, and more data are needed. This treatment model might have the potential to accomplish, in carefully selected patients, an equivalent outcome to surgical hepatic lobectomy. It has the advantages of a minimally invasive, outpatient interventional radiology procedure performed under moderate sedation with same-day discharge and minimal recovery time. It avoids the risks and expense of general anesthesia, hepatic surgery, and postsurgical recovery. Further study is warranted. References 1. Kennedy A, Nag S, Salem R, et al. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys 2007; 68: Lewandowski R, Salem R, Thurston K, et al. Radiation segmentectomy of unresectable of liver carcinoma using selective infusion of intraarterial yttrium-90 TheraSphere. Presented at the Radiological Society of North America; November 28 to December 3, 2004; Chicago, IL. 3. Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual. New York: Springer, Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5:

6 Volume 20 Number 5 Siddiqi and Devlin Murthy R, Nunez R, Szklaruk J, et al. Yttrium-90 microsphere therapy for hepatic malignancy: devices, indications, technical considerations, and potential complications. Radiographics 2005; 25(suppl 1):S41 S Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, CA Cancer J Clin 2007; 57: Bentrem DJ, Dematteo RP, Blumgart LH. Surgical therapy for metastatic disease to the liver. Annu Rev Med 2005; 56: Liu JH, Chen PW, Asch SM, Busuttil RW, Ko CY. Surgery for hepatocellular carcinoma: does it improve survival? Ann Surg Oncol 2004; 11: Wolpin BM, Meyerhardt JA, Mamon HJ, Mayer RJ. Adjuvant treatment of colorectal cancer. CA Cancer J Clin 2007; 57: Taieb J, Barbare JC, Rougier P. Medical treatments for hepatocellular carcinoma (HCC): what s next? Ann Oncol 2006; 17(suppl 10): Garrean S, Hering J, Helton WS, Espat NJ. A primer on transarterial, chemical, and thermal ablative therapies for hepatic tumors. Am J Surg 2007; 194: Dawson LA. Hepatic arterial yttrium 90 microspheres: another treatment option for hepatocellular carcinoma. J Vasc Interv Radiol 2005; 16: Lien WM, Ackerman NB. The blood supply of experimental liver metastases. II: a microcirculatory study of the normal and tumor vessels of the liver with the use of perfused silicone rubber. Surgery 1970; 68: Kennedy AS, Nutting C, Coldwell D, Gaiser J, Drachenberg C. Pathologic response and microdosimetry of (90)Y microspheres in man: review of four explanted whole livers. Int J Radiat Oncol Biol Phys 2004; 60: Hemming AW, Reed AI, Howard RJ, et al. Preoperative portal vein embolization for extended hepatectomy. Ann Surg 2003; 237: