Research ArticleClinical Investigation

Efficacy and Toxicity Related to Treatment of Hepatocellular Carcinoma with 90Y-SIR Spheres: Radiobiologic Considerations

Lidia Strigari, Rosa Sciuto, Sandra Rea, Livio Carpanese, Giuseppe Pizzi, Antonella Soriani, Giuseppe Iaccarino, Marcello Benassi, Giuseppe Maria Ettorre and Carlo Ludovico Maini
Journal of Nuclear Medicine September 2010, 51 (9) 1377-1385; DOI: https://doi.org/10.2967/jnumed.110.075861

Abstract

Radioactive 90Y-selective internal radiation (SIR) sphere therapy is increasingly used for the treatment of nonresectable hepatocellular carcinoma (HCC). However, the maximum delivered dose is limited by severe injury to the nontarget tissue, including liver parenchyma. Our study aimed to implement radiobiologic models for both tumor control probability (TCP) and normal-tissue complication probability (NTCP) to describe more effectively local response and the liver toxicity rate, respectively. Methods: Patients with documented HCC, adequate bone marrow parameters, and regular hepatic and pulmonary function were eligible for the study. Patients who had pulmonary shunt greater than 20% of 99mTc-labeled macroaggregated albumin or any uncorrectable delivery to the gastrointestinal tract, reverse blood flow out of the liver, or complete portal vein thrombosis were excluded. Patients received a planned activity of the 90Y-SIR spheres, determined using the empiric body surface area method. The dose distribution was determined using posttreatment (3-dimensional) activity distribution and Monte Carlo dose voxel kernel calculations, and the mean doses to healthy liver and tumor were calculated for each patient. Response was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) and recommendations of the European Association for the Study of the Liver (EASL). Criteria were used to assess possible liver toxicities. The parameters of TCP and NTCP models were established by direct maximization of the likelihood. Results: Seventy-three patients were treated. With an average dose of 110 Gy to the tumor, complete or partial response was observed in 74% and 55% of patients according to the EASL guideline and RECIST, respectively, and the predicted TCPs were 73% and 55%, respectively. With a median liver dose of 36 Gy (range, 6–78 Gy), the ≥grade 2 (G2), ≥grade 3 (G3), and ≥grade 4 (G4) liver toxicities were observed in 32% (23/73), 21% (15/73), and 11% (8/73) of patients, respectively. The parameters describing the ≥G2 liver toxicity data using the NTCP model were a tolerance dose of the whole organ leading to a 50% complication probability of 52 Gy (95% confidence interval, 44–61 Gy) and a slope of NTCP versus dose of 0.28 (95% confidence interval, 0.18–0.60), assuming n = 1. Conclusion: The radiobiologic approach, based on patient-specific dosimetry, could improve the 90Y-microsphere therapeutic approach of HCC, maintaining an acceptable liver toxicity.

Hepatocellular carcinoma (HCC) is a malignant epithelial tumor arising from parenchymatous liver cells (1). Patients with localized HCC (involvement of a single lobe and absence of vascular invasion or extrahepatic disease) are generally evaluated for the potentially curative therapeutic options of either partial hepatectomy or orthotopic liver transplantation. In contrast, more than 50% of patients underwent palliation of symptoms with external-beam radiotherapy (EBRT), and only 20% experienced significant tumor shrinkage (2).

These data suggest that HCC is radioresistant. However, the delivered dose is limited by severe injury to the surrounding tissue, including the liver parenchyma and duodenum (3–5). Given the limited efficacy of nonsurgical treatment, several techniques have been proposed to deliver targeted tumor radiation by means of radiopharmaceuticals for HCC treatment. In particular, radioactive 90Y-microsphere therapy is increasingly used, and specific recommendations have been published (6).

Recently, some authors have applied radiobiologic principles to evaluate the biologic effect induced by therapies, with different time distributions of radiation. In particular, the linear-quadratic model has been extended to radionuclide therapy, including the biologic effective dose (BED) concept, which represents the dose producing the same biologic effect obtained under different irradiation conditions (7–9). The aim of this study was to apply 2 radiobiologic models, based on dosimetric and clinical data from a retrospective study, to adequately predict the clinical results on efficacy and toxicity of 90Y-selective internal radiation (SIR) sphere (SIRT Medical Limited; www.sirtex.com) treatment in HCC.

On the basis of posttreatment 3-dimensional activity distribution and Monte Carlo dose voxel kernel calculations, the dose distribution was used to calculate the mean dose to healthy liver and tumor in each patient.

Moreover, radiobiologic models for both tumor control probability (TCP) and normal-tissue complication probability (NTCP) were implemented to interpret the local response and liver toxicity rate in our cohort.

MATERIALS AND METHODS

Inclusion Criteria

All patients were selected according to strict inclusion and exclusion criteria and were asked to give informed consent. Eligible patients were older than 18 y, with measurable unresectable disease predominately involving the liver, adequate bone marrow (granulocytes > 1,500/mL; platelets > 60,000/mL), hepatic (total bilirubin ≤ 2.0 mg/dL) serum glutamic oxaloacetic transaminase or serum glutamic pyruvic transaminase or alkaline phosphatase less than 5 times the upper limit of normal, pulmonary function (forced expiratory volume in 1 s > 1 L), and no contraindications to angiography and selective visceral catheterization.

Absolute contraindications included pulmonary shunt greater than 20% of 99mTc-labeled macroaggregated albumin (99mTc-MAA) or any uncorrectable delivery to the gastrointestinal tract, reverse blood flow out of the liver, or complete portal vein thrombosis.

Radioactive Material

90Y is a pure β-emitter, which decays to stable 90Zr, with an average energy of 0.94 MeV and a half-life of 2.67 d (64.2 h). It is produced by neutron bombardment of 89Y in a commercial reactor, yielding 90Y β-radiation, with a mean tissue penetration of 2.5 mm and a maximum range of 1.1 cm. 90Y that had been permanently embedded within resin structures (SIR spheres) was used for patients with the approval of the Food and Drug Administration. Each resin sphere has a diameter of 32 ± 10 μm, causing terminal arterioles within the tumor to be permanently embolized. A standard dose of 90Y resin microspheres is 2 GBq, containing approximately 50 million microspheres (range, 40–80 million), with an activity per microsphere estimated to be 50 Bq. A maximum of 0.4% of administered 90Y activity is free from the resin spheres according to the SIR spheres manual (10).

Administered Activity and Dosimetry

The administered activity of the 90Y-SIR spheres was determined using the body surface area (BSA) empiric method given in the user's manual (10):A(GBq) = (BSA − 0.2) + Vtumor/Vliver,Eq. 1where Vtumor and Vliver are the volume of tumor and total liver, respectively, and BSA (m2) is calculated as 0.20247 × height (m)0.725 × weight (kg)0.425.

This activity was used to treat the entire liver in 35 patients. A lobar approach was used in 38 of 73 patients. The right lobe was treated in 35 patients and the left in 3 patients. The activity was calculated considering the lobe volume in Eq. 1. The total delivered activity was reduced by 20% and 40% in patients with lung shunt between 10% and 15% or 15% and 20%, respectively. Accordingly, the dose was applied intraarterially on the treatment date, usually 10–14 d after obtaining the screening arteriography, either to the entire liver or to a single lobe.

Hepatic Angiography

An angiogram was obtained to assess hepatic vasculature, determine the appropriate catheter position for treatment, and identify any collateral vessels that would result in inadvertent microsphere deposition to the gastrointestinal tract. To prevent nontarget embolization, the gastroduodenal and right gastric arteries were prophylactically embolized in all patients. Embolization of vessels to create flow redistribution was not performed in any patient (i.e., embolization of accessory right or accessory left hepatic arteries to redistribute flow).

Imaging

All 73 patients were evaluated via chest, abdomen, and pelvic CT scans to detect extrahepatic metastases and to determine liver tumor location, size, and number. All scans were obtained with 3-mm slices.

After embolization of collateral vessels, 99mTc-MAA scans (anterior or posterior planar scans of lungs and abdomen and SPECT acquisition of abdomen) were obtained (within 30 min after embolization) to detect any unobserved gastrointestinal flow and estimate the percentage of injected activity that may shunt to the lungs. Therefore, pretherapy imaging was used to determine the liver–lung shunt.

Posttherapy (bremsstrahlung 90Y-microspheres) planar and tomographic images were obtained to study the radioactivity distribution within 6 h after 90Y injection. The SPECT scan was acquired using a triple-head γ-camera (Irix; Philips) equipped with a standard medium-energy general-purpose collimator. A wide window (from 55 to 245 keV) was used; 120 frames of 25 s were acquired using an elliptic orbit in a 128 × 128 image matrix with a magnification of 1.42.

Image Fusion, Image Quantification, and Dosimetry

Transaxial, coronal, and sagittal slices were reoriented with respect to the canthomeatal plane and reconstructed by an iterative method.

CT and SPECT images were registered and fused using a dedicated software program (Syntegra; Philips). A typical activity distribution using 99mTc-MAA and posttherapy bremsstrahlung microsphere images after hepatic embolization are shown in Figures 1A and 1C, respectively. Typical target regions of interest (ROIs) (tumor and liver) delineated on an axial CT slice are shown in Figure 1B.

FIGURE 1.
FIGURE 1.

Typical activity distribution after hepatic embolization using 99mTc-MAA (A) and posttherapy bremsstrahlung 90Y-microsphere images (C) fused with CT images (B). Typical target ROIs (tumor and liver) are delineated on axial CT slice (B).

Attenuation correction was performed using an ellipse determination (based on an automated threshold of about 10% maximum count), with a constant linear attenuation coefficient of 0.11 cm−1 using the Chang method. No scatter correction was performed.

The patient–lesion calibration factor was obtained by determining the ratio between the net administered activity (i.e., the difference between the activity—transferred in the V vial—to be delivered and the residual activity after the angiographic procedure, taking into account the physical decay) and total counts of all voxels included in the total liver ROI after background subtraction. The absorbed dose was obtained using in-house software by the convolution of the activity matrix from SPECT bremsstrahlung images and the dose voxel kernel value precalculated in water by Monte Carlo simulation, as described elsewhere (11). We observed 1, 2, 3, and more lesions in patients 21, 8, 6, and 38, respectively, and in each patient the tumor was identified by the largest lesion. Tumor and normal-liver ROIs were manually delineated by a radiologist or nuclear medicine physician (Fig. 1). The in-house software, developed using assembler language and installed on a high-performance personal computer, allowed us to calculate the dose volume histograms (DVHs), from which the mean dose to lesion and normal liver was obtained for each patient.

The time–activity curves for the source organs (liver and, in the case of a shunt, lungs, gastroduodenal tract, etc.) were supposed to decrease because of the physical decay only. The mean dose to lungs was calculated assuming a uniform microsphere distribution.

The tumor–to–normal-liver activity ratio (TNR) was calculated as:TNR=total tumor countstotal hepatic counts−total tumor counts.Eq. 2

Tumor Response

Response was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) (12) and recommendations of the European Association for the Study of the Liver (EASL) (13), using World Health Organization criteria and taking into account tumor necrosis recognized by nonenhanced areas (Table 1).

View this table:
TABLE 1.

Criteria for Assessment of Response to 90Y-Microsphere Treatment

Generally, CT may require 4–8 mo to reveal full response after 90Y-SIR therapy (14); thus, only patients with an adequate minimum follow-up were included in this analysis.

Toxicity

Patients were followed closely until all acute toxicities were resolved, or at least every 2 wk for 6 wk, then monthly for 3 mo to observe the possible radiation hepatitis or other toxicities. The Common Terminology Criteria for Adverse Events (version 4; National Cancer Institute, Cancer Therapy Evaluation Program) were used as appropriate, according to the severity of the liver toxicity (Table 2).

View this table:
TABLE 2.

Criteria for Assessment of Liver Toxicity after 90Y-SIR Treatment

Radiobiologic Models

The radiobiologic models, based on the linear-quadratic model, have been largely used to describe the surviving fraction (sf) of cells in the tissue exposed to a total radiation dose D. Recently, these models have been applied to systemic therapy (9).

The BED delivered to target and liver was calculated as follows:BED=D+D2λ(μ+λ)1α/β,Eq. 3where D is expressed in Gy, α and β are tissue-specific parameters related to cell radiosensitivity (expressed in Gy−1 and Gy−2, respectively), μ is a parameter incorporating the repair of sublethal radiation damage and μ = ln(2)/T1/2,rep (expressed as h−1) is the repair half-time of sublethal damage, and λ is the biologically effective decay constant λ = ln(2)/T1/2,phys (expressed as h−1). The α-to-β ratio was equal to 10 and 2.5 Gy for tumor and normal liver, respectively (15).The T1/2,rep was 1.5 and 2.5 h for tumor and normal liver, respectively (16).

The sf can be written as follows:sf=×exp{−[α×BED]}.Eq. 4

The TCP, using the linear-quadratic model incorporating Poisson's law, can be written as:TCP(D)=exp[−N0×sf(BED)],Eq. 5where N0 is the initial number of clonogenic cells.

To take into account the inhomogeneity in the population sensitivity and density of clonogenic cells, the TCP can be written as follows:TCP(D)=exp(−∑iηi × N0 × sf(BED)),Eq. 6whereηi=12π1σln(N)exp{−12(ln(Ni)−ln(N0)σln(N))2}Eq. 7is the fraction of cells obtained from gaussian distributions of ln(Ni) values, with a mean value of ln(N0) and an SD of σln(N) (17).

A modified formalism of the NTCP model for the treatment of HCC, based on the Lyman–Burman Kutcher model, was used to evaluate specific radiobiologic parameters.

To compare the doses delivered during SIR procedures and EBRT, the adsorbed dose may be converted to an equivalent dose (EQ2) delivered at 2 Gy/fraction (the typical dose per fraction used in conventional EBRT), using the following equation (18):EQ2=BED1+d/(α/β)=[D +D2λ(μ + λ)1(α/β)]11+ d/(α/β),Eq. 8where α/β = 2.5 and 10 Gy for liver and tumor, respectively.

The NTCP was expressed as:NTCP(t)=12π∫−∞texp(−s22)ds,Eq. 9where s is a parameter defined as:s=1m × TD50(EQ2−TD50),Eq. 10where m is the slope of NTCP versus dose and TD50 is the tolerance dose of the whole organ leading to a 50% complication probability.

The full formulation of the Lyman–Burman Kutcher model includes another parameter, n, to convert an inhomogeneous into a homogeneous equivalent dose distribution. The values of this parameter range from zero (for a serial organ) to unity (for a parallel organ, such as the liver). In this article, we assumed n = 1 for liver (19).

Maximum-Likelihood Estimation

The standard BSA method used to determine the administered activity produced a wide-range dose to both lesions and liver.

The model parameters were established by direct likelihood maximization of the following equation:L(m,TD50(1))=∑i=1N[ln(pi)Ri+ln(1−pi)1 − Ri].Eq. 11

A probit model was assumed for the probability (pi) of ≥grade 2 (G2) liver toxicity in the i-th patient:pi=p(m,TD50(1);ti)=NTCP(ti),Eq. 12and all model parameters were adjusted to maximize the probability of predicting complications for those patients who did or did not experience liver toxicity (Ri = 1 or 0, respectively). In particular, the NTCP curve was calculated considering all ≥G2 liver toxicity as a complication.

A probit model was also assumed for π = TCP(ti), and model parameters were adjusted to maximize the probability of predicting the tumor control using both RECIST and EASL criteria.

For binomially distributed data, the log likelihood for the entire data was maximized by means of a in-house optimization package written in Visual Basic (Microsoft), already used by our group (20).

The observed endpoint (toxicity or tumor control) was used as truth—that is, the gold standard for nonparametric clustered receiver-operating-characteristic (ROC) analysis—to evaluate the predictive utility of a modified NTCP–TCP model (21). By comparing observed and calculated data, the true-positive and false-positive ratios were plotted in the form of an ROC curve. When a perfect correlation of the predicted versus observed control or ≥G2 liver toxicity was found, the area under curve (AUC) was 1. Random assignment of outcome led to a ROC AUC of 0.5. The goodness of fit was assessed using ROC AUC and its 95% confidence interval (CI).

RESULTS

Patients and Tumors

From January 2007 to July 2009, 73 patients (58 men, 15 women) with HCC lesions were treated with 90Y-microspheres and retrospectively analyzed to assess tumor and normal-liver tissue dose. Median age was 66 y (range, 41–84 y).

On the basis of the Child–Pugh classification (22), 58 patients were Child–Pugh A, 13 Child–Pugh B, and 2 Child–Pugh C.

Tumor volumes (indicating the single or largest lesion for each patient) ranged from 2 to 1,932 cm3 (median, 100 cm3), whereas the liver volumes ranged from 360 to 3,816 cm3 (median, 1,783 cm3).

Administered activities calculated using the standard BSA method ranged from 1.00 to 2.26 GBq, with a median of 1.73 GBq (Table 3).

View this table:
TABLE 3.

0th (Minimum), 25th, 50th (Median), 75th, and 100th (Maximum) Percentiles of Dosimetric Data

Image Analysis

99mTc-MAA SPECT images of the abdomen after pretherapeutic embolization were sufficiently predictive of the 90Y-SIR sphere distribution in more than 80% of patients. Moreover, before SIR treatment a further embolization was performed to avoid any flow redistribution during the time between the 2 embolization procedures. However, this topic deserves a separate paper.

Tumor Control and Toxicity

Complete response (CR), partial response (PR), stable disease, and progressive disease (PD) were seen in 1% (1/73), 53% (39/73), 43% (31/73), and 3% (2/73), respectively, using RECIST. According to the EASL guidelines, CR, PR, stable disease, and PD were seen in 26% (19/73), 51% (37/73), 20% (15/73), and 3% (2/73), respectively.

With a median liver dose of 36 Gy (range, 6–78 Gy) and an EQ2 of 33 Gy (3–90 Gy), ≥G2 liver toxicity was observed in 31% (23/73), ≥grade 3 (G3) liver toxicity in 21% (15/73), and ≥grade 4 (G4) liver toxicity in 11% (8/73) of the patients. With a median lung dose of 5 Gy (range, 1–15 Gy), no lung toxicity was observed. Gastroduodenal ulcers developed in 1 patient. No hematologic toxicity was observed in our cohort of patients.

Dosimetry and Radiobiologic Model

Analysis of the bremsstrahlung images of the 73 patients provided a median TNR of 2.7 (1.7–6.0). Median absorbed doses per unit activity were 18 (3–50) Gy/GBq to the nontumor liver and 60 (13–251) Gy/GBq to the tumor.

CR, PR, stable disease, and PD were observed in 19, 37, 15, and 2 patients, respectively, using the EASL guidelines, and according to RECIST, CR, PR, stable disease, and PD were found in 1, 39, 31, and 2 patients, respectively (Fig. 2).

FIGURE 2.
FIGURE 2.

Tumor response observed in our patients according to EASL guideline and RECIST.

CT scans of a patient before therapy and 5 mo after therapy are shown in Figure 3, together with the dose distribution and the DVH of total liver and target. In this patient, a PR (according to RECIST) and CR (according to the EASL guidelines) were registered, whereas no ≥G2 liver toxicity was observed.

FIGURE 3.
FIGURE 3.

Pretherapy (A) and 5-mo posttherapy (B) CT scan of patient PR according to RECIST and CR according to EASL. (B) Evident necrosis with reduced peripheral enhancement is observed in place of HCC lesion (between V and VIII segments). Dose distribution (C) is shown over pretherapy CT scan. DVH of total liver and target is reported in D. Grade 1 (G1) liver toxicity was observed.

The mean and median doses necessary to obtain CR using the EASL guidelines were 150 and 111 Gy, respectively, and the mean and median doses needed to obtain CR or PR were 110 and 97 Gy, respectively. For CR and PR using RECIST, the mean and median doses were 122 and 99 Gy, respectively.

The dose versus response type for the EASL guideline or RECIST is reported in Figure 4, and the calculated TCPs in terms of CR or PR are reported in Figure 5.

FIGURE 4.
FIGURE 4.

Lesion mean dose vs. tumor response type according to EASL guideline and RECIST. In box-and-whisker plot, central box represents values from lower to upper quartile (25th to 75th percentile). Middle line represents median. Vertical line extends from minimum to maximum value, excluding outside (circle) values, which are displayed as separate points. Outside values are values larger than upper quartile plus 1.5 times interquartile range.

FIGURE 5.
FIGURE 5.

Tumor control probability vs. tumor mean dose according to EASL criteria and RECIST. Solid and dotted curves represent TCP for more (TCPh) or less (TCPl) radioresistant tumors, respectively, in our study. Upper (TCPtot,EASL) and lower (TCPtot,RECIST) dashed curves represent weighted sum of above population to describe tumor response according to EASL and RECIST, respectively. ◆ and ○ represent experimental data. Gray area indicate no lesions received dose lower than about 20 Gy. DT = tumor dose.

TCP curves were obtained from gaussian distributions of ln(N) values—the first (more radioresistant) with an α-value of 0.001/Gy, a mean value of ln(N0) equal to 23, and an SD (σln(N)) of 18, and the second (less radioresistant) with an α-value of 0.005/Gy, an ln(N0) of 6.9, and an σln(N) of 6.2. The fit of the tumor control, based on RECIST and EASL criteria, indicates that 2 populations having 60% and 40% more radioresistant cells, respectively, were observed in our cohort.

Assuming all ≥G2 liver toxicity as a complication after 90Y sphere treatment of HCC, the observed and predicted liver toxicity rate versus the mean BED to the liver was calculated and plotted in Figure 6, with a 95% CI. The parameters resulting from fittings to clinical toxicity data were a TD50 of 52 Gy (95% CI, 44–61 Gy) and an m of 0.28 (95% CI, 0.18–0.60), assuming n = 1. In Equation 3, the tolerance BED of the whole organ leading to a 50% complication probability (BED50) was 93 Gy (95% CI, 79–110 Gy).

FIGURE 6.
FIGURE 6.

Normal-tissue complication probability of liver toxicity (solid line) vs. liver BED. Dashed line represents 95% CI. Vertical bars represent SD (caused by number of data in each group that created each point). Exp = experimental data.

The predicted and observed toxicity in our group was 34%, and the AUC of the NTCP model was 0.612 (95% CI, 0.466–0.759). The predicted TCPs were 73% and 55%, and the AUCs of TCP models were 0.513 (95% CI, 0.340–0.685) and 0.594 (95% CI, 0.437–0.711) for RECIST and EASL criteria, respectively.

DISCUSSION

Selecting an appropriate treatment strategy for patients with HCC depends on careful tumor staging and assessment of the underlying liver disease.

Moreover, bremsstrahlung image quantification is still under evaluation. Recent publications have shown the possibility of using these images for dosimetry but after nontrivial important or significant calibration procedures and image corrections (23).

Because of the administration of 90Y-SIR treatment, specific calibrator factors have been carried out for each patient to calculate the activity in each voxel of attenuation-corrected SPECT images, based on the net administered activity. The absorbed dose was obtained using in-house software through the convolution of the activity matrix from SPECT bremsstrahlung images and the dose voxel kernel estimation (11). DVHs were calculated from the liver and lesion ROIs delineated on CT images to obtain the mean dose. Dosimetric and clinical data were interpolated by TCP–NTCP models. In patients with HCC, the goal of all locoregional therapies (ablation or chemoembolization) is to obtain necrosis of the tumor, regardless of the shrinkage of the lesion. Even if an extensive tumor necrosis is achieved, this may not accompany a reduction in the dimension.

Regarding toxicity, substantial data are available on the acute and late side effects of 90Y-SIR spheres in HCC patients. Symptoms including fatigue, nausea, and abdominal pain are quite common for patients undergoing 90Y-SIR sphere therapy, who experience mild postembolization syndrome on the day of treatment and for up to 3 d thereafter.

Radioembolization to nontarget organs can also cause other acute damage, resulting in gastrointestinal ulceration, pancreatitis, and radiation pneumonitis. The incidence of radiation effects could be minimized if meticulous angiographic techniques and dosimetry are used (24). Strict adherence to accepted limits on radiation dose (<30 Gy) to the lung prevents this complication (25). No lung toxicity was observed in our patients. Despite careful evaluation before treatment and attempts to reduce SIR sphere exposure, gastroduodenal ulcers did develop in 1 patient.

A long-term sequela of 90Y treatment may be radiation-induced liver disease (26–29). When the whole liver is exposed to external-beam radiation at a mean radiation dose of more than 40 Gy, more than 50% of patients develop liver dysfunction (30). Many other researchers have also reported tolerance doses for individual organs and 90Y-SIR sphere therapy, but data concerning late liver toxicity are scarce. In particular, dose escalation in 10 patients showed that up to 138 Gy to the nontumorous liver by SIR treatment did not cause clinical radiation hepatitis (31). Moreover, 70 Gy by SIR treatment to the nontumorous part of the liver is tolerable in cirrhosis (32). Biopsies in 4 patients receiving up to 75 Gy by SIR treatment showed a minimal histologic effect in the healthy liver (31). When the normal-liver dose was estimated separately, the maximum average dose was 75 Gy, with up to 147 Gy delivered to the tumor (33). From their study of a dog model, Wollner et al. (34) estimated that the human liver can easily tolerate 100 Gy. Assuming all ≥G2 liver toxicity as a complication after 90Y-SIR spheres treatment of HCC, and n = 1, the estimated parameters of the NTCP curve were a BED50 of 93 Gy and an m of 0.28. The value of the estimated BED50 is higher than the 72 Gy reported for late effect—that is, liver failure—by Emami et al. (30). Although factors other than dose distribution may be significant, this apparent discrepancy could be reconciled if the distribution of microspheres was more macroscopically nonuniform (33) because of the vasculature of the major vessels. Moreover, the fact that toxicity occurred within 4–6 mo after treatment in our series might be due to the high–dose-rate effect generated by SIR treatment, probably because the dose to liver is delivered in a shorter time (about 10 d) than in EBRT, producing early or premature vascular damage.

Moreover, our results are higher than those of Dawson et al. (19), who found a TD50 of 39.8 Gy (BED50 = 64 Gy), an m of 0.12, and an n of 0.97 for primary liver tumors treated at a dose fraction of 1.5 Gy. Furthermore, our parameters are lower in terms of BED50 but similar in terms of m and n to those obtained by Xu et al. (35) for primary liver patients with Child–Pugh A cirrhosis treated at a dose fraction of 4.6 Gy (TD50 = 40.5 Gy, BED50 = 115 Gy, m = 0.28, and n = 1.1). This difference might be because 21% (15/73) of our patients had pretreatment Child–Pugh B or C cirrhosis. From a radiobiologic point of view, these differences could be further explained by the fact that in the typical dose distribution delivered using 90Y-SIR spheres the higher doses were received in smaller volumes, increasing the probability of cross-firing with a possible loss of biologic effect.

Regarding tumor control, the mean dose to the tumor may be predictive of final therapy outcome (i.e., cure) but may not be the best predictor of tumor response. Likewise, the average dose seems to be more adequate for parallel organs, such as the liver, capable of maintaining function when a limited part of an organ receives a higher dose. Doses to the tumor higher than 110–120 Gy are able to obtain PR or CR (according to both criteria) in at least 50% of patients. All the values discussed above were higher than 100 Gy, which is the recommended target-absorbed dose for nonresectable HCC (36).

However, tumor response varies according to the criteria applied. In fact, according to the EASL guidelines or RECIST, a significant difference in the CR or PR was registered (i.e., in 74% or 55% of patients, respectively, using an average dose of 110 Gy). This difference could be because RECIST evaluates only 1-dimensional tumor measurements and disregards the extent of the necrosis, which is the objective of all locoregional therapy used for HCC, including ablation and intraarterial procedures such as chemoembolization. Considering that a multivariate analysis of survival clearly demonstrated that the complete tumor necrosis was associated with significantly better survival (odds ratio, 1.83; 95% CI, 1.1–3.1; P = 0.020) (37), the use of combined (size and necrosis) criteria might lead to a more accurate assessment of response to 90Y radioembolization than criteria based on size alone (38).

Recently, Coldwell et al. (39) introduced the response based on 18F-FDG PET—which demonstrated a high degree of response, compared with RECIST (CR or PR 91% vs. 47%), and appears to be well demonstrated by the survival of the patients in their series.

In our series, the CR or PR based on RECIST was similar to that reported by Coldwell et al. (39), whereas that based on the EASL guidelines was 77% for intermediate values with respect to the RECIST and 18F-FDG PET criteria. Consequently, 18F-FDG PET is expected to improve the assessment of tumor response. However, our study was based on CT/MR images and RECIST and EASL criteria, before the installation of 2 PET/CT devices at our institute.

Moreover, the behavior of the TCP curves suggests that the role of the inhomogeneity should be investigated, and DVH might be a valid method to assess the inhomogeneity of dose distribution; however, more advanced mathematic models still need to be applied (40,41). In addition, although the availability of a map of dose distribution allows correlations at the voxel level to be performed, the shrinkage of the tumor and the healthy remodeling of the liver could make a conclusive correlation more difficult.

The use of a more simplified model based on mean dose could provide robust results when the target dose distribution is sufficiently homogeneous and the liver can be considered a parallel organ (i.e., the liver failure probability increases with the liver mean dose). Assuming the same dosage to both tumor and liver, the BED for liver is higher than that for tumor. However, the angiographic approach, limiting liver involvement, decreases the mean dose to the healthy liver. Moreover, on the basis of these preliminary findings the TCP and NTCP models permit the outcome to be predicted and the activity giving the highest therapeutic gain to be calculated. When the expected NTCP of the liver is higher than the acceptable cutoff (generally 20%–30%), the use of a superselective approach or the possibility of multicycle treatments (15) should be carefully evaluated.

CONCLUSION

90Y-SIR sphere therapy is a complex procedure that requires multidisciplinary management for safety and success. Our results support that a radiobiologic approach, based on patient-specific dosimetry, is a feasible and effective method to increase treatment efficacy sparing normal-tissue 90Y therapy.

According to the NTCP–TCP model, new clinical protocols should be designed to improve the risk–benefit balance. Additional data on a larger cohort are required to improve the outcome prediction.

Acknowledgments

We thank Paula Franke for the English revision of the manuscript.

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  • Received for publication February 8, 2010.
  • Accepted for publication June 10, 2010.
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