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Inoperable Hepatocellular Carcinoma: Transarterial ¹⁸⁸Re HDD–Labeled Iodized Oil for Treatment—Prospective Multicenter Clinical Trial¹

¹ From the Departments of Nuclear Medicine (A.K., C.B., G.S.P., G.P.B.), Radiology (D.N.S., S.T., S.S.), and Biostatistics (P.C.), All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India 110029; and Departments of Nuclear Medicine (T.T.M.C., N.V.H., L.H.T., T.Q.X., N.X.C.), Radiology (H.D.L.), and Surgery (L.T.C.), Cho Ray Hospital, Ho Chi Minh City, Vietnam. Received July 25, 2005; revision requested September 28; revision received December 20; accepted January 20, 2006; final version accepted, September 14. Supported in part by the International Atomic Energy Agency. Address correspondence to D.N.S. (e-mail: drdeepsrivastava{at}rediffmail.com).

	ABSTRACT

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Purpose: To prospectively evaluate, in a multicenter clinical trial, dosimetry-guided transarterial radionuclide therapy (TART) with rhenium 188 (¹⁸⁸Re) 4-hexadecyl 1,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol (HDD)–labeled iodized oil in inoperable hepatocellular carcinoma (HCC).

Materials and Methods: Ninety-three patients were recruited from 2000 to 2005 for this ethics committee–approved study. Informed written consent was obtained. After complete clinical evaluation (including assessment of liver status, serum -fetoprotein [AFP] level, tumor size, portal vein status, Child-Pugh classification, Okuda staging), radiation absorbed dose (RAD) to various organs, including tumor, was calculated after injecting 185 MBq of ¹⁸⁸Re HDD iodized oil via the hepatic artery. From this value, the maximum tolerable activity of ¹⁸⁸Re, defined as the amount of radioactivity delivering no more than 12 Gy of RAD to lungs, 30 Gy to normal liver, or 1.5 Gy to bone marrow, was calculated and injected.

Results: Mean patient age was 53 years (80 men and 13 women). Sixty-eight percent of patients had serologic evidence of hepatitis B and/or C; 40% had clinicoradiologic evidence of cirrhosis. Mean tumor diameter was 10.3 cm ± 4.4, with 40% of patients having more than three lesions; in 50% of patients, tumor was either unilateral, occupying 50% or more of the liver, or bilateral. AFP was elevated in 68% of patients and was elevated to more than 300 ng/mL in 44% of patients. There was portal vein thrombosis in 38% of patients, Child-Pugh status B disease in 37% of patients, and Okuda stage II or III disease in 50% of patients. Mean first administered activity was 5.3 GBq ± 1.6, which delivered 88 Gy of RAD to the tumor. Treatment was tolerated well. Of 66 patients in whom complete tumor response occurred, five (8%) had complete tumor mass ablation, 17 (26%) had a partial response (>50% tumor reduction), and 23 (35%) had stable disease. Only RAD to the tumors was found to be significantly (P = .001) associated with tumor and/or AFP response. Survival rates at 6, 9, 12, 24, and 36 months among patients with objective tumor response were 100%, 95%, 90%, 58%, and 30%, respectively, with a median survival of 980 days.

Conclusion: TART appears to be a safe, effective, and promising therapeutic option in patients with inoperable HCC.

© RSNA, 2007

	INTRODUCTION

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Patients with hepatocellular carcinoma (HCC) have a poor prognosis, with a 5-year survival rate of less than 5% and a median survival rate of less than 4 months if the disease is unresectable (1–3). Indeed, curative treatment (liver transplantation, surgical resection, percutaneous ablation) can only be performed in less than 25% of patients. This is either because of contraindications to surgery (advanced cirrhosis in particular), the presence of locally advanced disease (multifocal lesions, invasion of the portal vein), or, more rarely, technical reasons (lesion difficult to access, subcapsular or diaphragmatic location) (4). One of the various therapeutic options available for such patients is internal therapy in the form of transarterial radionuclide therapy (TART). Although a variety of radionuclides can be used for this purpose, rhenium 188 (¹⁸⁸Re) appears to be a promising radionuclide for this purpose because of its shorter half-life (16.9 hours), high-energy ß (ß_max, 2.1 MeV) but low-energy (155 keV) emissions, and availability through the tungsten 188 (¹⁸⁸W)-¹⁸⁸Re generator system.

Thus, the purpose of our study was to prospectively evaluate, in a multicenter clinical trial, dosimetry-guided TART performed by using ¹⁸⁸Re 4-hexadecyl 1,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol (HDD)–labeled iodized oil in the care of patients with inoperable HCC.

	MATERIALS AND METHODS

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Patient Selection
The ethics committees of the participating hospitals approved the use of ¹⁸⁸Re HDD iodized oil for the treatment of unresectable HCC on humanitarian grounds. Patients were informed of the potential risks and benefits of hepatic angiography and the proposed radioconjugate treatment, and written consent was obtained. HCC was diagnosed histopathologically or clinically in patients who had consistently (>15 days) elevated (>500 ng/mL) serum -fetoprotein (AFP) levels and space-occupying lesion(s) thought to be consistent with HCC at triple-phase computed tomography (CT).

Eligibility Criteria
Study eligibility criteria were as follows: (a) Patients had to have inoperable tumor and be willing to participate in the trial; (b) patients had to have been not undergoing chemotherapy or immunotherapy for at least 4 weeks and not receiving bronchodilators and/or steroids for at least 8 weeks before entry into the study; (c) female patients of childbearing age had to have a negative result on a pregnancy test performed 1 day before study entry and were asked to use effective contraception during the study; (d) patients had to be ambulatory, with a Karnofsky performance status score of 60 or greater; (e) patients had to have a serum creatinine level of 1.2 mg/dL (106 µmol/L) or lower, a leukocyte count of 1500/µL or greater, a platelet count of 100 000/µL or greater, and a prothrombin time of 1.3 times the control value or less or an international normalized ratio of 1.5 or less; and (f) patients had to sign an informed consent form for participation in this study.

Exclusion Criteria
Study exclusion criteria were as follows: (a) patients with Child-Pugh status C disease, (b) patients with advanced cardiac or pulmonary diseases, and (c) patients with evidence of extrahepatic spread of disease.

Radioconjugate
Rhenium 188 in the form of sodium perrhenate was obtained by elution and a ¹⁸⁸W-¹⁸⁸Re generator. The perrhenate solution was concentrated by passing through ion exchange columns as previously described (5). The concentrated eluate (3–6 mL) was mixed with HDD and 1 mL of phosphate buffer and heated in a water bath for 30–60 minutes to produce ¹⁸⁸Re-HDD complex, which was then physically mixed and extracted into 3–6 mL of iodized oil (Lipiodol; Andre Guerbet, Aulnay-sous-Bois, France) to be used for transarterial injection (6). Radiochemical purity of the final product was determined with thin-layer chromatography as previously described (6) and was persistently found to be more than 95%.

Administration of Radioconjugate
All patients were admitted for hepatic angiography and radioconjugate therapy. The amount of radioconjugate administered was based on radiation absorbed dose (RAD) to critical normal organs, calculated with individual dosimetry after transarterial administration of a small scout dose of radioconjugate. The organs at greatest risk for radiation toxicity are normal liver, lungs, and bone marrow. Dosimetry was used to determine maximum tolerated activity, defined as the amount of radioactivity calculated to deliver no more than 12 Gy to lungs, 30 Gy to normal liver, or 1.5 Gy to bone marrow, because these doses have been found to be safe in multiple trials of external beam therapy (7,8).

On the day before treatment, transmission scans with a ¹⁸⁸Re flood source were performed to determine attenuation correction factors for lung and liver to be used in the dosimetric calculations the following day. The transarterial infusion of radioconjugate was performed after placing a 5-F preshaped angiographic catheter in the hepatic artery branches supplying the tumor selectively after femoral puncture by one of four authors (D.N.S., H.D.L., S.T., and S.S., who had 14, 12, 8, and 7 years of experience, respectively, with such techniques). Initially, about 185 MBq (5 mCi) of ¹⁸⁸Re HDD iodized oil (scout dose) was injected through the catheter. With the catheter in place in the feeding artery and with asepsis maintained by using a taped sterile plastic cover at the femoral puncture site, patients were transported to the nuclear medicine department, and whole-body imaging was performed along with a standard source of 100 µCi (3.7 MBq) of ¹⁸⁸Re HDD iodized oil and a gamma camera (Orbitor/Millennium VG; Siemens, Erlangen, Germany) with a high or medium energy collimator (conjugate view imaging).

Both anterior and posterior images were obtained to enable the calculation of geometric mean counts. Corrections for scatter (by acquiring images in both photopeak and scatter windows) and attenuation were also performed. Regions of interest were placed over lungs, the whole liver including tumor, and tumor only by one of five authors (A.K., T.T.M.C., C.B., N.V.H., and G.S.P.). The mean size of the regions of interest over the lungs, liver, and tumor only was 4783 pixels ± 808 (standard deviation), 3382 pixels ± 1059, and 1713 pixels ± 947, respectively (1 pixel = 2.2 mm²). The counts per pixel were obtained (as geometric means) to enable the calculation of RAD (as centigrays per megabecquerel of injected activity) to normal liver parenchyma, lungs, and tumor by using a specially designed spreadsheet (Excel; Microsoft, Redmond, Wash) based on medical internal radiation dosimetry schema and by adjusting the pertinent S factors for the difference in total body and organ masses between the patient and the anthropomorphic model. On the basis of the above-mentioned maximum tolerated absorbed dose limit, the respective absorbed doses per unit of administered activity were used to calculate the maximum tolerated activity. In the first few patients, a 1-mL plasma sample was also obtained and counted for 5 minutes; the counts were then entered into the spreadsheet to enable the calculation of RAD to the bone marrow. But because this dose was found to be negligible, we stopped obtaining blood samples.

After scout dose imaging and dosimetry studies, the patients were sent back to the radiology department (angiography room) to ensure that there had been no change in catheter position and for injection of the calculated treatment dose by one of three authors (A.K., C.B., and T.T.M.C., with 7, 17, and 25 years of experience in nuclear medicine, respectively), usually within 1 hour of injection of the scout dose. Patients were monitored for adverse events and biochemical alterations and were discharged on the 2nd or 3rd day. Posttherapy scanning was also performed immediately after treatment and/or at the time of discharge. In a few patients, serial whole-body scanning was performed at 1–3, 24, 48, 72, and 96 hours after injection of the treatment dose to enable us to evaluate the biodistribution of ¹⁸⁸Re HDD iodized oil and estimate the effective half-life of ¹⁸⁸Re.

Posttreatment Evaluation
Complete hemography (hemoglobin, red blood cell, platelet, and total and differential leukocyte counts) and liver and renal function testing was performed 24 and 48 hours; 2, 4, 8, and 12 weeks; and then every 2 months after treatment. Extent of disease was measured with AFP levels and volumetric analysis of lesions at triple-phase CT (by consensus of D.N.S., H.D.L., and S.T. at one institution and by S.S. at another institution; these investigators had 17, 15, 12, and 11 years of experience, respectively, in liver CT) within 2 weeks after the start of treatment, between 8 and 12 weeks after therapy, and then at 2- or 3-month intervals.

Response parameters.—Tumor response was categorized as one of the following: (a) complete response (disappearance of all measurable disease), (b) partial response (50% or greater reduction in the product of two perpendicular diameters of any measurable lesion and the appearance of no new lesion), (c) stable disease (no change or decrease in the size of lesions but less than a partial response with no new lesions), or (d) progression (appearance of new lesions or increase by 25% or more in the size of any measurable lesion). AFP response was categorized as one of the following: (a) complete biologic response (normalization), (b) partial response (decrease by > 50% from the baseline value), (c) stable (between –50% and +50% of the baseline value), or (d) progression (more than +50% of the baseline value). Complete and partial response taken together was objective response.

Toxicity.—Toxicity was graded in accordance with the Common Toxicity Scale developed by the U.S. National Cancer Institute.

Adverse events.—An adverse event was any new undesirable medical experience or change in an existing condition that occurred during or after administration of the radiopharmaceutical, whether or not it was considered agent related. Abnormal laboratory findings considered to be clinically important were also considered adverse events.

Statistical Analysis
Quantitative (continuous) variables have been expressed as means ± standard deviations, and frequencies (percentages) have been used to summarize qualitative (categoric) data. Medians and ranges have been reported for skewed (nonnormal) data. One-way analysis of variance with post hoc analysis and ² testing was used to compare the various quantitative and qualitative parameters, respectively, in various groups of tumor and AFP response. Nonparametric one-way analysis of variance—that is, the Kruskal-Wallis test—was applied for skewed (nonnormal) data.

Receiver operating characteristic analysis was performed to determine the suitable cutoff value of RAD to the tumor for tumor response. Bivariate (Pearson) correlation was used to assess the linear relationship between RAD and survival time. Repeated-measures analysis of variance with post hoc analysis was used to assess treatment-related toxicity at various time points. Univariate Kaplan-Meier survival analysis was performed to determine overall and groupwise survival. Furthermore, the log-rank test was applied to determine any statistical difference in survival among various subgroups. In addition, the multivariate Cox regression method was used to assess the significant effect of various prognostic factors on survival time. P < .05 was considered to indicate a significant difference. Statistical software packages (SAS, version 8.2, SAS Institute, Cary, NC; SPSS, version 11.5, SPSS, Chicago, Ill) were used for the statistical analyses.

	RESULTS

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Patients
From March 2000 to March 2005, a total of 93 patients (80 men and 13 women) with a mean age of 53 years (range, 31–76 years) were recruited in this trial. Most of the patients had a large tumor burden and mildly deranged liver function at presentation. Tumor diameter varied from 1.0 to 20 cm (mean, 10.3 cm ± 4.4), with almost 40% of patients having more than three lesions. In almost 50% of patients, the tumor was either unilateral, occupying 50% or more of the liver, or bilateral. There was extension of tumor mass in the portal vein (portal vein thrombosis) in 38% of patients. Sixty-eight percent of patients had serologic evidence of hepatitis B or C infection. Forty percent of patients had clinicoradiologic evidence of cirrhosis, which was confirmed at histopathologic examination in most of these patients. Serum AFP level was elevated in 68% of patients, with 44% of patients having a serum AFP value of more than 300 ng/mL. Thirty-seven percent of patients had Child-Pugh status B disease, and almost 50% of patients were classified as having Okuda stage II or III disease. Demographic, clinical, and biochemical data for all patients are given in Table 1.

View larger version (168K): [in this window] [in a new window] [Download PPT slide]   Figure 1a: Images in 69-year-old man with two HCC lesions involving both lobes of the liver. Both lesions were completely ablated after two doses of 188Re HDD iodized oil at three monthly intervals. At the time of this writing, the patient was alive and ambulatory with normal serum AFP levels and no evidence of a mass at 3-year follow-up CT. (a) Pretherapy transverse CT scan shows two lesions (arrows): One each in segments IV (subdiaphragmatic) and VIII. (b) Angiogram shows increased vascularity in both lesions (arrows). (c) Posttreatment 188Re whole-body scan shows radiotracer accumulation in the tumors (arrows), with faint visualization of lungs and no radiotracer uptake in the thyroid, gastrointestinal tract, or anywhere else. (d) Repeat transverse CT scan obtained 3 months after the second dose shows complete disappearance of both lesions (arrows). Small radioopaque area in segment IV lesion (appearing to be enhancing HCC mass in larger arterial phase image) is actually a small amount of iodized oil, which was seen in all CT scanning phases (noncontrast, arterial, portal venous, and delayed). (e) Positron emission tomography/CT scan obtained 2 years after treatment also shows no evidence of residual or recurrent disease (arrows). Inset images show segment IV lesion.

View larger version (123K): [in this window] [in a new window] [Download PPT slide]   Figure 1b: Images in 69-year-old man with two HCC lesions involving both lobes of the liver. Both lesions were completely ablated after two doses of 188Re HDD iodized oil at three monthly intervals. At the time of this writing, the patient was alive and ambulatory with normal serum AFP levels and no evidence of a mass at 3-year follow-up CT. (a) Pretherapy transverse CT scan shows two lesions (arrows): One each in segments IV (subdiaphragmatic) and VIII. (b) Angiogram shows increased vascularity in both lesions (arrows). (c) Posttreatment 188Re whole-body scan shows radiotracer accumulation in the tumors (arrows), with faint visualization of lungs and no radiotracer uptake in the thyroid, gastrointestinal tract, or anywhere else. (d) Repeat transverse CT scan obtained 3 months after the second dose shows complete disappearance of both lesions (arrows). Small radioopaque area in segment IV lesion (appearing to be enhancing HCC mass in larger arterial phase image) is actually a small amount of iodized oil, which was seen in all CT scanning phases (noncontrast, arterial, portal venous, and delayed). (e) Positron emission tomography/CT scan obtained 2 years after treatment also shows no evidence of residual or recurrent disease (arrows). Inset images show segment IV lesion.

View larger version (183K): [in this window] [in a new window] [Download PPT slide]   Figure 1c: Images in 69-year-old man with two HCC lesions involving both lobes of the liver. Both lesions were completely ablated after two doses of 188Re HDD iodized oil at three monthly intervals. At the time of this writing, the patient was alive and ambulatory with normal serum AFP levels and no evidence of a mass at 3-year follow-up CT. (a) Pretherapy transverse CT scan shows two lesions (arrows): One each in segments IV (subdiaphragmatic) and VIII. (b) Angiogram shows increased vascularity in both lesions (arrows). (c) Posttreatment 188Re whole-body scan shows radiotracer accumulation in the tumors (arrows), with faint visualization of lungs and no radiotracer uptake in the thyroid, gastrointestinal tract, or anywhere else. (d) Repeat transverse CT scan obtained 3 months after the second dose shows complete disappearance of both lesions (arrows). Small radioopaque area in segment IV lesion (appearing to be enhancing HCC mass in larger arterial phase image) is actually a small amount of iodized oil, which was seen in all CT scanning phases (noncontrast, arterial, portal venous, and delayed). (e) Positron emission tomography/CT scan obtained 2 years after treatment also shows no evidence of residual or recurrent disease (arrows). Inset images show segment IV lesion.

View larger version (168K): [in this window] [in a new window] [Download PPT slide]   Figure 1d: Images in 69-year-old man with two HCC lesions involving both lobes of the liver. Both lesions were completely ablated after two doses of 188Re HDD iodized oil at three monthly intervals. At the time of this writing, the patient was alive and ambulatory with normal serum AFP levels and no evidence of a mass at 3-year follow-up CT. (a) Pretherapy transverse CT scan shows two lesions (arrows): One each in segments IV (subdiaphragmatic) and VIII. (b) Angiogram shows increased vascularity in both lesions (arrows). (c) Posttreatment 188Re whole-body scan shows radiotracer accumulation in the tumors (arrows), with faint visualization of lungs and no radiotracer uptake in the thyroid, gastrointestinal tract, or anywhere else. (d) Repeat transverse CT scan obtained 3 months after the second dose shows complete disappearance of both lesions (arrows). Small radioopaque area in segment IV lesion (appearing to be enhancing HCC mass in larger arterial phase image) is actually a small amount of iodized oil, which was seen in all CT scanning phases (noncontrast, arterial, portal venous, and delayed). (e) Positron emission tomography/CT scan obtained 2 years after treatment also shows no evidence of residual or recurrent disease (arrows). Inset images show segment IV lesion.

View larger version (124K): [in this window] [in a new window] [Download PPT slide]   Figure 1e: Images in 69-year-old man with two HCC lesions involving both lobes of the liver. Both lesions were completely ablated after two doses of 188Re HDD iodized oil at three monthly intervals. At the time of this writing, the patient was alive and ambulatory with normal serum AFP levels and no evidence of a mass at 3-year follow-up CT. (a) Pretherapy transverse CT scan shows two lesions (arrows): One each in segments IV (subdiaphragmatic) and VIII. (b) Angiogram shows increased vascularity in both lesions (arrows). (c) Posttreatment 188Re whole-body scan shows radiotracer accumulation in the tumors (arrows), with faint visualization of lungs and no radiotracer uptake in the thyroid, gastrointestinal tract, or anywhere else. (d) Repeat transverse CT scan obtained 3 months after the second dose shows complete disappearance of both lesions (arrows). Small radioopaque area in segment IV lesion (appearing to be enhancing HCC mass in larger arterial phase image) is actually a small amount of iodized oil, which was seen in all CT scanning phases (noncontrast, arterial, portal venous, and delayed). (e) Positron emission tomography/CT scan obtained 2 years after treatment also shows no evidence of residual or recurrent disease (arrows). Inset images show segment IV lesion.

View larger version (117K): [in this window] [in a new window] [Download PPT slide]   Figure 2a: Images in 55-year-old man with large biopsy-proved inoperable HCC in right lobe of liver. There was an approximately 85% reduction in tumor size with necrosis and fibrosis after one dose of 188Re HDD iodized oil. The serum AFP level also decreased to 249 from 55 582 ng/mL. At the time of this writing, the patient was alive and fully ambulatory. (a) Transverse CT scan shows large mass in right lobe of liver. (b) Angiogram in same patient. (c) Posttreatment 188Re whole-body scan shows good radiotracer accumulation in tumor, with faint visualization of lungs and liver. (d) Transverse CT scan obtained 6 months after treatment shows approximately 85% reduction in tumor size with necrosis and fibrosis. Also seen is iodized oil in the shrunken lesion.

View larger version (169K): [in this window] [in a new window] [Download PPT slide]   Figure 2b: Images in 55-year-old man with large biopsy-proved inoperable HCC in right lobe of liver. There was an approximately 85% reduction in tumor size with necrosis and fibrosis after one dose of 188Re HDD iodized oil. The serum AFP level also decreased to 249 from 55 582 ng/mL. At the time of this writing, the patient was alive and fully ambulatory. (a) Transverse CT scan shows large mass in right lobe of liver. (b) Angiogram in same patient. (c) Posttreatment 188Re whole-body scan shows good radiotracer accumulation in tumor, with faint visualization of lungs and liver. (d) Transverse CT scan obtained 6 months after treatment shows approximately 85% reduction in tumor size with necrosis and fibrosis. Also seen is iodized oil in the shrunken lesion.

View larger version (148K): [in this window] [in a new window] [Download PPT slide]   Figure 2c: Images in 55-year-old man with large biopsy-proved inoperable HCC in right lobe of liver. There was an approximately 85% reduction in tumor size with necrosis and fibrosis after one dose of 188Re HDD iodized oil. The serum AFP level also decreased to 249 from 55 582 ng/mL. At the time of this writing, the patient was alive and fully ambulatory. (a) Transverse CT scan shows large mass in right lobe of liver. (b) Angiogram in same patient. (c) Posttreatment 188Re whole-body scan shows good radiotracer accumulation in tumor, with faint visualization of lungs and liver. (d) Transverse CT scan obtained 6 months after treatment shows approximately 85% reduction in tumor size with necrosis and fibrosis. Also seen is iodized oil in the shrunken lesion.

View larger version (111K): [in this window] [in a new window] [Download PPT slide]   Figure 2d: Images in 55-year-old man with large biopsy-proved inoperable HCC in right lobe of liver. There was an approximately 85% reduction in tumor size with necrosis and fibrosis after one dose of 188Re HDD iodized oil. The serum AFP level also decreased to 249 from 55 582 ng/mL. At the time of this writing, the patient was alive and fully ambulatory. (a) Transverse CT scan shows large mass in right lobe of liver. (b) Angiogram in same patient. (c) Posttreatment 188Re whole-body scan shows good radiotracer accumulation in tumor, with faint visualization of lungs and liver. (d) Transverse CT scan obtained 6 months after treatment shows approximately 85% reduction in tumor size with necrosis and fibrosis. Also seen is iodized oil in the shrunken lesion.

Tumor and AFP responses were significantly associated with survival time: Patients with better responses had increased survival time (Figs 3, 4). Whereas overall survival rates at 3, 6, 9, 12, 24, and 36 months were 90%, 75%, 65%, 50%, 30%, and 20%, respectively, with a median survival of 356 days (Fig 5), corresponding survival rates among patients with objective tumor response were 100%, 100%, 95%, 90%, 58%, and 30%, with a median survival of 980 days. Univariate Kaplan-Meier survival analysis and comparison of survival curves with the log-rank test showed that patients with serum bilirubin level of 2.0 mg/dL (34.2 µmol/L) or greater, albumin level of less than 3.0 mg/dL, tumor burden more than 50% of liver mass, thrombosed portal vein, cirrhosis, ascites, Child-Pugh score of B, Okuda stage of II or III, AFP level of 300 ng/mL or greater, and Karnofsky performance status score of 70% or less had significantly decreased survival (Table 4). However, there was a strong positive correlation between RAD and survival time (Fig 6). Multivariate Cox regression analysis revealed that portal vein thrombosis (hazard ratio: 1.9; 95% confidence interval: 1.05, 3.5; P = .033), presence of ascites (hazard ratio: 12.9; 95% confidence interval: 5.04, 33.1; P < .001), and a Child-Pugh score of B (hazard ratio: 2.8; 95% confidence interval: 1.5, 5.3; P = .001) were significantly associated with decreased survival time.

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Figure 3: Kaplan-Meier survival curve (with log-rank test) shows significant difference in survival among different categories of tumor response (median survival for patients with objective response, stable disease, and progression, respectively, was 980 days [solid line], 356 days [dotted line], and 116 days [dashed line]).

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Figure 4: Kaplan-Meier survival curve (with log-rank test) shows significant difference in survival among different categories of AFP response (median survival for patients with objective response, stable disease, and progression, respectively, was 980 days [solid line], 336 days [dotted line], and 118 days [dashed line]).

View larger version (9K): [in this window] [in a new window] [Download PPT slide]   Figure 5: Kaplan-Meier survival curve shows overall survival in all patients (median survival, 356 days).

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 6: Graph shows relationship between RAD to tumor and survival time.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE References

 
Radionuclide therapy provides an option for the treatment of unresectable HCC, as shown by results of studies involving radionuclides such as iodine 131 (¹³¹I), yttrium 90 (⁹⁰Y) microspheres, holmium 166, phosphorus 32, and ¹⁸⁶Re conjugated to monoclonal antibodies, iodized oil, or chemical compounds and injected systemically or transarterially (9–14). The aim of internal radionuclide therapy (in TART) is to deliver the maximum amount of radionuclide to the hepatic or portal vein tumor, where it must reside for a period sufficient to deliver the scheduled dose of radiation, while the amount delivered to the nontumorous liver parenchyma and other organs is as low as possible. This is achieved by making use of the dual blood supply of the liver. Unlike transcatheter arterial chemoembolization, which is relatively contraindicated in patients with portal vein thrombosis, particularly when such thrombosis is extensive, TART can be used safely in such patients, because the hepatic artery is not embolized. In addition, transarterially injected radionuclide may accumulate and act on such thrombi, as these tumor thrombi have been found to be arterially vascularized (15). Furthermore, in TART, the tumoricidal effect of the radionuclide does not depend on the cellular characteristics (eg, MDR/MRP gene expression) of tumor cells, because it is not necessary or required for the radionuclides to be taken up by the cells for their effect to occur. It is sufficient to put the radionuclide in the vicinity of the tumor cells, because cell destruction is mediated through ß and radiation.

Rhenium 188 has recently been introduced to treat HCCs and appears to be a promising radionuclide and superior to most of the radionuclides used currently because of the following reasons: The maximum energy of its ß emission (responsible for the destruction of tumor tissue) is 2.1 MeV. Thus, its maximum range in tumor tissue is up to 10.1 mm, which is larger than that of ¹³¹I (2.4 mm) and comparable with that of ⁹⁰Y (10.8 mm), making it very effective in tumor destruction—even larger tumors. Unlike ⁹⁰Y, it has 155-keV emissions, which makes imaging for biodistribution studies and external dosimetry possible, as is possible with ¹³¹I. Its short physical half-life and the fact that most emissions are at 155 keV only (unlike ¹³¹I) result in very low radiation exposure to relatives and hospital staff. According to the U.S. Nuclear Regulatory Commission regulatory guide 8.39, patients treated with ¹⁸⁸Re HDD iodized oil may be discharged if the radiation level within the body is less than 790 mCi (29 230 MBq). Therefore, no hospitalization is required from the radiation-protection point of view at the level of activity usually administered for TART. It can be easily and stably labeled with iodized oil, thus enhancing its tumoral retention. Unlike ¹³¹I, which has to be incorporated into the iodized oil molecule, thus making radiolabeling cumbersome, complex, and less yielding, ¹⁸⁸Re is mixed physically with iodized oil after making it lipophilic with any suitable pharmaceutical such as HDD, thus increasing the radiolabeling yield in a way that is technically much simpler and more straightforward. It is available in a generator form, which makes its storage, transportation, elution, and usage convenient and cost-effective, particularly at remote places and in developing countries. The ¹⁸⁸W-¹⁸⁸Re generator has a long and useful shelf life of several months, thus providing a constant yield of carrier-free ¹⁸⁸Re on a routine basis. This is not possible with ¹³¹I/⁹⁰Y, which is produced with a reactor/cyclotron and hence is rather expensive and has to be supplied weekly from various countries. Therefore, ¹⁸⁸Re appears to be the most suitable radionuclide available for TART. In the initial experiences of Sundram et al (16,17), results of phase I and preliminary results of phase II trials sponsored by the International Atomic Energy Agency have shown TART with ¹⁸⁸Re HDD iodized oil to be safe and effective in patients with HCC.

Preparation of the ¹⁸⁸Re HDD iodized oil was simple, and its labeling and stability was good in that the radionuclide remained localized in the tumor only and there was no radiotracer uptake in the thyroid, gastrointestinal tract, or elsewhere, except in the bladder and sometimes faintly in the lungs, as was evidenced on posttherapy ¹⁸⁸Re whole-body scans. The lung uptake was due to the nature of ¹⁸⁸Re HDD iodized oil and/or to the various levels of arteriovenous shunting usually encountered in these patients. Dosimetry was simple and helped in deciding the maximum possible activity of ¹⁸⁸Re that could be safely administered to the patient.

The majority of patients in this series remained asymptomatic until the tumors were discovered late or during other examinations, and the tumors were frequently inoperable owing to large size, multicentricity, cirrhosis, and/or portal vein thrombosis. Therefore, these patients posed a therapeutic challenge, and, because they were not suitable for treatment with most of the available therapeutic modalities, they were offered TART. However, ¹⁸⁸Re appeared to have good tumoricidal effect, as evidenced by the complete or partial disappearance of tumor or stable disease in 68% of patients, despite the mean tumor size being more than 10 cm. Also, tumor and/or AFP response was associated with increased survival.

Although it is difficult to directly compare our results with those obtained by using other therapeutic modalities, they appear to be impressive when compared with the lack of effectiveness in terms of the antitumoral effect and survival for various hormonal agents and immunotherapy, the 5%–15% partial response rate and no survival benefits for systemic chemotherapy, the 20%–30% partial response rate with no definite evidence of survival advantage for intraarterial chemotherapy, the 20%–50% partial response rate and increased survival in a stringently selected group of patients with small (<5 cm) tumors only with chemoembolization (18–21), and partial response rates of 20%–40% and survival rates of 33%–60%, 6%–50%, and 0%–23% at 6 months and 1 and 2 years, respectively, for ¹³¹I-Lipiodol or ⁹⁰Y microspheres (9,10) and considering the fact that reported median survival in such untreated patients is less than 4 months (3). Furthermore, in our study, patients with Okuda stage I disease had 59% survival at 1 year, which is comparable with the 1-year survival rates of 62%, 56%, and 63% in patients with Okuda stage I disease after transcatheter arterial chemoembolization (in a large multicenter French trial, with 90% of patients being classified as having Okuda stage I disease), ¹³¹I-Lipiodol, and ⁹⁰Y microspheres, respectively (11,12,22).

In our study, RAD was related to tumor and/or AFP response and survival time not only in patients with good prognostic factors but even in patients with poor clinical characteristics and bad prognostic indexes, such as cirrhosis, Child-Pugh B status, portal vein thrombosis, or Okuda stage II disease. Among 20 patients with portal vein thrombosis in whom tumor response data were available, four had objective response and nine had stable disease, with a median survival of 7 months; these results are meaningful, considering the fact that such patients have virtually no treatment options left and are comparable with the reported median survival with ¹³¹I-Lipiodol or ⁹⁰Y (13,14). Furthermore, there is a theoretical possibility that ¹⁸⁸Re HDD iodized oil might ablate microscopic metastatic foci, thus decreasing the possibility of future recurrences; this has indeed been found to be the case in adjuvant therapy (with radionuclides) before/after curative resection of HCC (23,24).

The treatment was found to be safe. A large amount of ¹⁸⁸Re (up to 25.6 GBq) was administered to the patients without any clinically important side effects or bone marrow, renal, or hepatic toxicity. It is important to note that the patients had a large tumor burden, with portal vein invasion in many patients, and a substantial number of patients had deranged hepatic function with underlying cirrhosis. This is important in view of the several and sometimes severe side effects associated with transcatheter arterial chemoembolization (22,25). Another important feature of the therapy was that the majority of patients who underwent this treatment had only a short stay in hospital and were able to resume their normal work in a week (indicating good performance status).

A limitation of this study was that the final yield of ¹⁸⁸Re HDD iodized oil was only 50%–60% with the proposed labeling method, and this problem was further accentuated when the ¹⁸⁸W-¹⁸⁸Re generator got older and produced a lower yield of ¹⁸⁸Re. Therefore, it was not always possible to deliver treatment activity at near-maximum permissible maximum tolerated activity levels—hence, the need to repeat the treatments. Another limitation was that gamma-camera dosimetry tends to result in underestimation of the percentage of injected dose in the liver and tumor, despite good biolocalization of treatment activity in the liver. This underestimation may be inherent in using gamma-camera dosimetry for mixed high-energy - and ß-ray emitters, despite attenuation correction. Scatter corrections were not required (26). Finally, the effectiveness of this new radioconjugate for the treatment of HCC needs to be confirmed in a randomized study that includes comparison with transcatheter arterial chemoembolization.

Thus, the results of our clinical trial are encouraging and promising, and it appears that, in addition to having better and more favorable physical characteristics, ¹⁸⁸Re has a good tumoricidal effect that is associated with increased survival. With individual dosimetry, one can safely administer the maximum possible amount of ¹⁸⁸Re HDD iodized oil to the tumor without jeopardizing other organs, and, in patients in whom dosimetry is not possible, empirically about 5.5 GBq (150 mCi) of activity can be safely administered and will deliver adequate radiation dose to the tumor in most patients. Besides using TART for palliative treatment of large tumors, it may be used to manage portal vein thrombosis and sometimes may be used with curative intent for multiple but small and inoperable tumors. Therefore, TART with ¹⁸⁸Re HDD iodized oil appears to be a safe, effective, and promising therapeutic option in patients with inoperable large and/or multifocal HCCs and has opened a new vista and given some hope to these patients.

	ADVANCES IN KNOWLEDGE

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE References

 

• With individual dosimetry, one can safely administer the maximum possible amount of rhenium 188 4-hexadecyl 1,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol (HDD) iodized oil to the tumor without jeopardizing other organs.
  
• Rhenium 188 HDD iodized oil appears to have good tumoricidal effect and is associated with increased survival.
  

	ACKNOWLEDGMENTS

 
The authors are grateful to the International Atomic Energy Agency for initiating, coordinating and providing partial financial assistance through Co-ordinated Research Project E1.30.19.

	FOOTNOTES

 

Abbreviations: AFP = -fetoprotein • HCC = hepatocellular carcinoma • HDD = 4-hexadecyl 1,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol • RAD = radiation absorbed dose • TART = transarterial radionuclide therapy

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, D.N.S., T.T.M.C., H.D.L., L.T.C., N.V.H., L.H.T., T.Q.X., N.X.C.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, A.K., D.N.S., P.C., S.S., G.S.P.; clinical studies, A.K., D.N.S., T.T.M.C., H.D.L., C.B., L.T.C., N.V.H., S.T., S.S., L.H.T., T.Q.X., N.X.C., G.P.B.; experimental studies, A.K., D.N.S., S.T., S.S., G.S.P.; statistical analysis, A.K., D.N.S., P.C.; and manuscript editing, A.K., D.N.S., C.B., P.C., S.T., S.S., G.S.P., G.P.B.

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TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE References

 

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