Lung Shunt Research Articles

The effects of inhaled anesthetics on lung

挥发性吸入麻醉药对肺的作用目前尚未有定论,其中有较多争议之处.不同种类、不同吸入浓度以及不同生理条件下的吸入麻醉药对肺的作用不同,可以引起肺的损伤作用、导致肺内分流增加,也可以产生肺的缺血/再灌注损伤的保护作用,其机制尚未完全清楚。

Safety and efficacy of Y-90 microsphere treatment in patients with primary and metastatic liver cancer: The tumor selectivity of the treatment as a function of tumor to liver flow ratio

BackgroundTreatment records and follow-up data on 40 patients with primary and metastatic liver malignancies who underwent a single whole-liver treatment with Y-90 resin microspheres (SIR-Spheres® Sirtex Medical, Lake Forest, IL) were retrospectively reviewed. The objective of the study was to evaluate the anatomic and physiologic determinants of radiation dose distribution, and the dose response of tumor and liver toxicity in patients with liver malignancies who underwent hepatic arterial Y-90 resin microsphere treatment.MethodsLiver and tumor volume calculations were performed on pre-treatment CT scans. Fractional tumor and liver flow characteristics and lung shunt fractions were determined using hepatic arterial Tc-99m MAA imaging. Absorbed dose calculations were performed using the MIRD equations. Liver toxicity was assessed clinically and by liver function tests. Tumor response to therapy was assessed by CT and/or tumor markers.ResultsOf the 40 patients, 5 had hepatocellular cancer (HCC), and 35 had metastatic liver tumors (15 colorectal cancer, 10 neuroendocrine tumors, 4 breast cancer, 2 lung cancer, 1 ovarian cancer, 1 endometrial cancer, and 2 unknown primary adenocarcinoma). All patients were treated in a salvage setting with a 3 to 80 week follow-up (mean: 19 weeks). Tumor volumes ranged from 15.0 to 984.2 cc (mean: 294.9 cc) and tumor to normal liver uptake ratios ranged from 2.8 to 15.4 (mean: 5.4). Average administered activity was 1.2 GBq (0.4 to 2.4 GBq). Liver absorbed doses ranged from 0.7 to 99.5 Gy (mean: 17.2 Gy). Tumor absorbed doses ranged from 40.1 to 494.8 Gy (mean: 121.5 Gy). None of the patients had clinical venoocclusive disease or therapy-induced liver failure. Seven patients (17.5 %) had transient and 7 patients (17.5 %) had persistent LFT abnormalities. There were 27 (67.5%) responders (complete response, partial response, and stable disease). Tumor response correlated with higher tumor flow ratio as measured by Tc-99m MAA imaging.ConclusionDoses up to 99.5 Gy to uninvolved liver are tolerated with no clinical venoocclusive disease or liver failure. The lowest tumor dose producing a detectable response is 40.1 Gy. The utilization of MAA-based imaging techniques to determine tumor and liver blood flow for clinical treatment planning and the calculation of administered activity may improve clinical outcomes.

Selective internal radiation therapy (SIRT) for liver metastases secondary to colorectal adenocarcinoma

Selective internal radiation therapy (SIRT) is a relatively new commercially available microbrachytherapy technique for treatment of malignant hepatic lesions using (90)Y embedded in resin microspheres, which are infused directly into the hepatic arterial circulation. It is FDA approved for liver metastases secondary to colorectal carcinoma and is under investigation for treatment of other liver malignancies, such as hepatocellular carcinoma and neuroendocrine malignancies. A modest number of clinical trials, preclinical animal studies, and dosimetric studies have been reported. Here we review several of the more important results. High doses of beta radiation can be selectively delivered to tumors, resulting in impressive local control and survival rates. Ex vivo analyses have shown that microspheres preferentially cluster around the periphery of tumor nodules with a high tumor:normal tissue ratio of up to 200:1. Toxicity is usually mild, featuring fatigue, anorexia, nausea, abdominal discomfort, and slight elevations of liver function tests. Selective internal radiation therapy represents an effective means of controlling liver metastases from colorectal adenocarcinoma. Clinical trials have demonstrated improved local control of disease and survival with relatively low toxicity. Investigations of SIRT for other hepatic malignancies and in combination with newer chemotherapy agents and targeted biologic therapies are under way or in planning. A well-integrated team involving interventional radiology, nuclear medicine, medical oncology, surgical oncology, medical physics, and radiation oncology is essential for a successful program. Careful selection of patients through the combined expertise of the team can maximize therapeutic efficacy and reduce the potential for adverse effects.

Regional Yttrium-90 Microsphere Treatment of Surgically Unresectable and Chemotherapy-Refractory Metastatic Liver Carcinoma

The aim of this prospective study was to assess the safety and tumor response of intra-arterial Y-90 microspheres for the treatment of surgically unresectable and chemotherapy-refractory liver metastases. Forty-six (46) patients with metastatic cancer to the liver from various solid tumors, with tumor progression despite polychemotherapy, were included. All patients had baseline computed tomography (CT), 18-Fluoro-2-deoxy-D-glucose-positron emission tomography (F-18 FDG-PET), hepatic angiography, and intra-arterial Tc-99m macroaggregated albumin (MAA) scan for the assessment of extrahepatic aberrant perfusion and lung shunting fraction. Twenty-seven (27) and 19 patients were treated with Y-90 glass- or resin-based microspheres (but not both), respectively, on a lobar basis and were monitored over 3 months after last treatment using dedicated attenuation corrected PET. For each patient, regions of interest (ROIs) were drawn along the liver edge to measure total liver standard uptake value (SUV) on axial images covering the entire liver for comparing pre- and post-treatment total liver SUV change. There was a significant decrement in total liver SUV after treatment by either glass- or resin-based microspheres (p = 0.0013 and 0.028, respectively). There was no significant difference in the amplitudes of the mean percentage reduction of tumor metabolism between these two agents (20% +/- 25% vs. 10% +/- 30% for glass- vs. resin-based microspheres; p = 0.38). None of the patients in the glass-based group developed complications, whereas 3 patients had complications related to hyperbilirubinemia (1 transient and 2 permanent) in the resin-based group. Results suggest that there is significant mean reduction of hepatic metastatic tumor load (metabolism), as evaluated objectively by PET after Y-90 microsphere, for the treatment of unresectable metastatic disease to the liver. The Y-90 therapy provides encouraging and safe results by arresting the progression of metastatic cancer to the liver with decreasing tumor metabolism.

Reduction of Metastatic Load to Liver after Intraarterial Hepatic Yttrium-90 Radioembolization as Evaluated by [18F]Fluorodeoxyglucose Positron Emission Tomographic Imaging

To assess the response of hepatic metastases after treatment with intraarterial yttrium 90 radioembolization (ie, use of SIR-Spheres) with use of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Nineteen patients with metastatic cancer to the liver from various solid tumors with progression despite polychemotherapy were included. All patients underwent baseline computed tomography, FDG PET, hepatic angiography, and intraarterial technetium 99 m macroaggregated albumin scan for assessment of lung shunting fraction. Patients were treated with 90Y resin microspheres on a lobar basis and were monitored for 3 months with use of dedicated attenuation-corrected PET. For each patient, regions of interest were drawn along the liver edge to measure total liver standard uptake value (SUV) on axial images, covering the entire liver. Visual estimates were also performed and graded as +1, 0, -1, -2, or -3 for progression, no change, and mild, moderate, and dramatic improvement by posttreatment PET. The median absorbed dose for the tumor was 76 Gy. There was a significant overall decrease in total liver SUV after treatment (baseline, 71,134 +/- 38,055; after SIR-Sphere treatment, 59,941 +/- 26,509; P = .028) for the entire group. Visual estimates placed 15 patients (79%) in response categories (-3 to -1) and four patients (21%) in nonresponse categories (0 to +1) for the liver. The percentage change of total liver SUV after treatment in the response group (-19%) was significantly greater and different in direction than that in the nonresponse group (+27%; P = .03). This percentage change was also correlated significantly with the respective visual estimates (r = 0.72; P < .0005) for each individual patient. Three patients had major complications related to hyperbilirubinemia (transient, n = 1; permanent, n= 2). The results suggest that there is significant reduction of hepatic metastatic load as evaluated objectively by PET after 90Y radioembolization for the treatment of unresectable metastatic disease to the liver. 90Y radioembolization provides encouraging results by arresting progression of metastatic cancer to the liver.

Treatment of hepatocellular carcinoma by means of radiopharmaceuticals

Several techniques have been developed for radionuclide therapy of hepatocellular carcinoma (HCC). Medical literature databases (Pubmed, Medline) were screened for available literature and articles were critically analysed as to their scientific relevance. In a palliative setting, intra-arterial administration of 131I-Lipiodol yields responses in 17-92% of patients. According to a randomised study, 131I-Lipiodol was far better tolerated than classic chemo-embolisation. The additive value of a single 131I-Lipiodol administration following partial liver resection for HCC was evaluated and evidence is available that adjuvant radionuclide treatment reduces the recurrence rate. Data concerning the role of 131I-Lipiodol in bridging patient to liver transplantation are scarce but suggest a potential benefit in terms of reducing the drop-out rate while patients are listed for transplantation. 188Re- and 90Y-labelled conjugates are emerging and initial clinical data are promising. Treatment of HCC with 90Y-labelled microspheres is likely as efficacious as treatment with radiolabelled Lipiodol but pretreatment 99mTc-MAA scintigraphy is required in order to exclude patients with significant lung shunting. Several antibodies targeting antigens expressed on HCC have been radiolabelled, almost exclusively with 131I, and evaluated in a preclinical or clinical setting. The use of radiolabelled Lipiodol and microspheres allows for selective targeting of HCC with limited toxicity. Prospective, randomised controlled trials demonstrating that both treatment modalities may provide a survival benefit in a palliative setting are mandatory. In addition, future research should focus on the complementary role of radionuclide treatment in patients at risk for recurrent disease following partial liver resection or while awaiting liver transplantation.

SU‐FF‐I‐42: Imaging Technique in Estimating Lung Shunting of Yttrium‐90 Microspheres

Purpose: This study was to evaluate lung shunting from Tc99m MAA and Y90 imaging, and its effect on treatment planning. Y90 Microspheres (Therasphere, MDS Nordion) have been used for the treatment of unresectable hepatocellular carcinoma (HCC). Tc99m MAA imaging is utilized to assess pulmonary shunting which will affect treatment dose. Standard shunting compares the ratios of activity in the liver and lungs. Method and Materials: Twenty five patients were randomly selected to examine shunting ratios. Eight studies required the redrawing of RoIs to correct the variance in geometric mean. Actual activity was determined following treatment planning guidelines based on standard and measured shunting. Y‐90 imaging of patients was also investigated for radionuclide distribution. Results: Inadequate RoIs were identified in 8 patients, which yielded up to 5% (mean 0.79%, STD 1.76%) difference (p=0.90) in lung shunting. The treatment dose showed 5.29% (mean 0.74%, STD 2.21%) deviation (p=0.91) caused by the ratios. It was further compared with standard ratios of 4% for none‐HCC and 7% for HCC. Difference in the treatment doses from corrected ratios and the standard was: mean 9.01%, STD 19.7%, p=0.19 for the 4% and mean 5.18%, STD 19.0%, p=0.55 for the 7%. Y‐90 patients images did not provide activity distribution in lungs when there was high shunting based on Tc99m MAA imaging, but demonstrated Y‐90 activity in liver. Conclusion: Tc99m MAA imaging is important in treatment planning to avoid error from lung shunting. RoIs should be accurate and consistent to reduce error in treatment dose. Y‐90 imaging depends on scatter characteristic of tissue and does not yield appropriate shunting images with Yttrium‐90.

Effects of sevoflurane and propofol on oxygenation and lung perfusion during one-lung ventilation in an animal model

Background. Thoracic surgery often requires one-lung ventilation. During one-lung ventilation, arterial oxygenation depends on the distribution of lung perfusion between the ventilated and the non-ventilated lung. Objectives. This study investigates the effects of sevoflurane and propofol on pulmonary perfusion and arterial oxygenation during one-lung ventilation in living animals at comparable mean arterial pressures. Material and Methods. A prospective study with a crossover design involving 12 pigs was carried out at the Institute for Experimental Animals, University of Jena, Germany. After the induction of anesthesia, a left-sided double-lumen tube was inserted via tracheotomy. One-lung ventilation was started with 1.0 FiO2, and anesthesia was continued with either propofol or sevoflurane (2.6% end-tidal concentration). After stabilization, the hemodynamic parameters and oxygenation were recorded, and differential lung perfusion was measured with colored microspheres. Then the anesthetic was changed and, after another stabilization period, the measurements were repeated. Results. The arterial oxygenation, mixed venous pO2, non-ventilated lung perfusion and shunt fraction were comparable during one-lung ventilation with both agents, whereas cardiac output was reduced during sevoflurane anesthesia (p < 0.05). Conclusions. In a clinically relevant animal model of one-lung ventilation, sevoflurane, as compared with propofol, did not increase the non-ventilated lung perfusion and shunt fraction and did not worsen arterial oxygenation (Adv Clin Exp Med 2011, 20, 3, 249–253).

Use of Yttrium-90 Glass Microspheres (TheraSphere) for the Treatment of Unresectable Hepatocellular Carcinoma in Patients with Portal Vein Thrombosis

Intra-arterial injection of Yttrium-90 glass microspheres ((90)Y- microS; TheraSphere, MDS Nordion, Ottawa, Canada) is indicated for treatment of unresectable hepatocellular carcinoma (HCC) in the presence of acceptable liver function. This study presents hepatic toxicity results after unilobar and bilobar intra-arterial administration of (90)Y- microS in patients with unresectable HCC who had known portal vein thrombosis (PVT) without evidence of cavernous transformation. Fifteen patients with unresectable HCC and PVT of one or both first order and related segmental portal venous branches received a total of 29 infusions of (90)Y- microS for treatment of HCC. All patients had pretreatment evaluation including: computed tomography (CT) imaging, alpha-fetoprotein (AFP) levels, liver function tests, technetium-99m macroaggregated albumin ((99)Tc-MAA) scan for evaluation of lung and visceral shunting, and angiography with visualization into the portal venous phase. (90)Y- micro S dose was based on lobar hepatic volume with adjustment for lung shunt activity. Liver toxicity was assessed by serum total bilirubin graded for severity according to the NIH NCI Clinical Toxicity Criteria (CTC version 2.0). Other adverse events were reported according to the standards established by the Society of Interventional Radiology. There were no procedural complications with delivery of (90)Y- microS, and treatment was well tolerated by all patients. Increased post-treatment bilirubin levels were observed across all treatments in five patients, four of whom had CT or AFP evidence of intrahepatic disease progression. After initial treatment, two patients developed bilirubin toxicity (grades 1 and 2); one patient demonstrated an increment in bilirubin toxicity grade (grade 1 to grade 3) and one patient had an improvement in grade after initial treatment. There were no new treatment-related toxicities in nine patients after a second treatment. (90)Y- microS treatment was well tolerated and appears to be safe to use in patients with compromised portal venous flow in one or both first order and related segmental portal venous branches and no evidence of cavernous transformation. In patients who did not exhibit disease progression, there appeared to be no clinically significant change in bilirubin.

Liver tumors: MR imaging of radioactive holmium microspheres--phantom and rabbit study.

To investigate the use of magnetic resonance (MR) imaging in the administration and biodistribution of holmium-loaded poly(L-lactic acid) microspheres (Ho-PLLA-MS) in liver tumors. MR imaging measurements were obtained in phantoms, three ex vivo rabbit livers, and four livers in living rabbits. When applicable, measurements were compared with those on scintigraphic images. The transverse relaxivity R2* of the Ho-PLLA-MS was determined in a phantom study. The in vivo animal experiments were performed by using rabbits with an implanted VX2 tumor. Detection of passing Ho-PLLA-MS to estimate lung shunting was performed in a scaled model of the vena cava. In the ex vivo liver experiments, the feasibility of real-time MR imaging during administration of microspheres was demonstrated. The in vivo rabbit experiments demonstrated that MR imaging can depict radioactive, nonradioactive, and decayed Ho-PLLA-MS after treatment for as long as they remain in the body. Furthermore, this study showed the ability of dynamic MR imaging to detect single doses of passing Ho-PLLA-MS. Ho-PLLA-MS used for internal radionuclide therapy can be imaged clearly in vivo with MR imaging.

Lung perfusion, shunt fraction, and oxygenation during one-lung ventilation in pigs: The effects of desflurane, isoflurane, and propofol

Objective: To study how desflurane, isoflurane, and propofol affect pulmonary perfusion, shunt fraction, and systemic oxygenation during one-lung ventilation (OLV) in vivo. Design: Prospective animal study with a crossover design. Setting: Animal laboratory of a university hospital. Participants: Twelve female pigs. Interventions: The pigs were anesthetized, tracheally intubated, and mechanically ventilated. After placement of femoral arterial and thermodilution pulmonary artery catheters, a left-sided, double-lumen tube (DLT) was placed via tracheotomy. After DLT placement, FIO2 was adjusted at 0.8, and anesthesia was continued in random order with 1 minimal alveolar concentration of desflurane, 1 minimal alveolar concentration of isoflurane, or propofol. Measurements and Main Results: Measurements of respiratory and hemodynamic parameters were made after stabilization at each anesthetic. During OLV, perfusion of the nonventilated lung and shunt fraction were comparable during all 3 anesthetics. PaO2 was lower during desflurane and isoflurane anesthesia as compared with propofol anesthesia. Mixed venous PO2 and cardiac output were lower with desflurane and isoflurane as compared with propofol. Conclusions: In a clinically relevant model of OLV cardiac output, PaO2 and mixed venous PO2 decreased during desflurane and isoflurane as compared with propofol, whereas perfusion of the nonventilated lung and shunt fraction remained comparable. Copyright 2003, Elsevier Science (USA). All rights reserved.

Methylprednisolone and the Systemic Inflammatory Response Syndrome

We appreciate Dr. Chaney's interest in our article (1) and the opportunity to provide more details about our article. We reported that methylprednisolone (MPS) prevented lung injury in patients with systemic inflammatory response syndrome (SIRS) induced by intraperitoneal hyperthermic perfusion (IPHP). In contrast, Chaney et al. (2) reported that MPS worsened pulmonary function in patients undergoing coronary artery bypass grafting (CABG) in the immediate postoperative period. Although it is important to measure alveolar-arterial oxygen gradient, dynamic pulmonary compliance, static lung compliance, shunt, and dead space, these variables were not measured in our study. Instead, we determined the lung injury score postoperatively, including the chest radiograph score, hypoxemia score (PaO2/PAO2), and positive end-expiratory pressure score, as recommended by Marks et al. (3). Using this score, our results confirmed that pretreatment with MPS prevented lung injury. The discrepancy between the two studies might be caused by the following reasons. Serum levels of tumor necrosis factor-α were increased in patients with gastric cancer undergoing IPHP without pretreatment of MPS in our study. Denizot et al. (4) reported that no variation of tumor necrosis factor-α levels were found in patients undergoing CABG in pre- and postoperative periods. These findings strongly suggest that differences in the severity of SIRS might contribute to the difference in MPS response between IPHP and CABG. In fact, all our patients with gastrointestinal cancer, in whom IPHP was performed, showed severe lung injury caused by SIRS compared with those undergoing CABG studied by Chaney et al. (2). In their study, 58 of 60 (97%) patients were tracheally extubated within 24 h of arrival in the intensive care unit, compared with only 2 of 17 (12%) patients in our study within the same period. Gott et al. (5) indicated that “ventilatory support for more than 48 h” is associated with high pulmonary morbidity after cardiopulmonary bypass. The time of extubation is determined clinically, based on several factors, such as lung function, level of consciousness, and cardiac function. In our study, intubation was prolonged in our MPS-treated and untreated patients compared with the other study (2). Measurements of lung function were performed at different times in the two studies. We examined lung injury scores between 1 and 6 postoperative days, whereas Chaney et al. (2) measured alveolar-arterial gradient, dynamic pulmonary compliance, static lung compliance, shunt, and dead space at 10 min after intubation to 60 min after arrival in the intensive care unit. We did not analyze the lung injury score during operation or at the early postoperative period. The dose of MPS used in the two studies was somewhat different. We used a dose of 50 mg/kg MPS compared with 60 mg/kg in the other study (2). This difference, though small, might produce a different response. The correct dose of MPS to prevent lung injury could not be determined at the present stage. Further evidence for lung injury in our patients is demonstrated in preliminary studies showing recruitment of leukocytes into the lung. However, the discrepancy in the response to MPS between patients undergoing CABG (3) and those with IPHP (1) must not be ignored, and further work is needed. Megumi Sumida MD Miwako Kawamata MD

Beneficial Effect of Atrial Natriuretic Peptide on Pulmonary Gas Exchange in Patients With Acute Lung Injury

The purpose of this study was to investigate the effect of i.v. infusion of atrial natriuretic peptide (ANP) on hemodynamics, pulmonary gas exchange, and urine volume during mechanical ventilation with positive end-expiratory pressure (PEEP) in patients with acute lung injury. Prospective, randomized, comparable study. ICU of a university hospital. Forty patients with moderate acute lung injury (lung injury score > or = 2.0) who required mechanical ventilation with PEEP were studied. The patients were randomly divided into two groups: ANP group (n=20) and control group (n=20). The ANP group received genetic recombination alpha-human ANP (carperitide) at the rate of 0.1 microg/kg/min for 24 h. The control group did not receive ANP. Hemodynamic and blood gas parameters, and urine volume were measured at baseline, 3 h, and 24 h after initiating the ANP infusion. Plasma ANP concentrations markedly (p<0.01) increased from 112.0+/-27.0 to 1,868.3+/-385.3 pg/mL after 24 h in the ANP group, whereas they remained unchanged in the control group. In the ANP group, hemodynamic parameters did not change, but PaO2/FIO2 (fraction of inspired oxygen) and thoracic compliance significantly (p<0.01) increased at 24 h after initiating the ANP infusion, associated with significant (p<0.01) decreases in lung injury score and shunt. Urine volume significantly (p<0.01) increased during 0 to 3 h after initiating the ANP infusion. In the control group, hemodynamics, pulmonary gas exchange, and urine volume did not significantly change during the study period. There were significant differences in PaO2/FIO2 (24 h), thoracic compliance (24 h), lung injury score (24 h), and urine volume (3 h) between the two groups. The results suggest that ANP infusion induces diuresis and improves pulmonary gas exchange in patients with acute lung injury during mechanical ventilation with PEEP.

Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres

Purpose : To evaluate the efficacy of intraarterial 90yttrium ( 90Y) microspheres in nonresectable hepatocellular carcinoma (HCC). Methods and Materials : Patients with nonresectable HCC, but without extrahepatic disease, who also had lung shunting < 15% and tumor-to-normal ratio ≥2, as determined by simulation using 99mtechnetium macroaggregated albumin, were entered into the study. The radiation dose delivered to the lungs, tumor, and normal liver was estimated by a partition model. 90Y microspheres were infused into the hepatic artery at the time of hepatic angiography or through an implanted arterial portacatheter under fluoroscopy. Repeated treatments were given for residual or recurrent tumor. Response to treatment was monitored by serum alpha-fetoprotein or ferritin levels together with serial computed tomography. Results : Seventy-one patients, including 20 patients with postoperative recurrence, were initially treated with an activity of 0.8 to 5.0 Giga-Becquerel (GBq) (21.6–135.1 mCi) (median 3.0 GBq or 81.1 mCi) of 90Y microspheres. There was a 50% reduction in tumor volume in 19 (26.7%) patients after the first treatment. However, the overall objective response in terms of changes in alpha-fetoprotein levels was 89% [partial response (PR) 67%, complete response (CR) 22%] among the 46 patients with raised pretreatment levels. The serum ferritin level in the other 25 patients dropped by 34 to 99% after treatment. Treatment was repeated in 15 patients. The maximum number of treatments was 5 and the maximum total activity was 13.0 GBq (351.4 mCi), given in 3 treatments. The estimated radiation doses to the nontumorous liver ranged from 25 to 136 Gy (median 52 Gy) in the first treatment and the highest total radiation dose was estimated to be 324 Gy. For the tumors, the estimated radiation doses ranged from 83 to 748 Gy (median 225 Gy) in the initial treatment and the highest cumulative dose reached was 1580 Gy. The residual tumors were resected in 4 patients. Two of these had complete histological remission, but only occasional viable tumor cells were found in the necrotic centers of the tumors resected from the other 2 patients. The median survival of the 71 patients was 9.4 months (range 1.8 to 46.4 months). Treatment was well tolerated and there was no bone-marrow toxicity, or clinical evidence of radiation hepatitis or pneumonitis. Conclusions : Selective internal radiation therapy using 90Y microspheres is effective for selected cases of nonresectable HCC and is well tolerated. The objective response rate in terms of drop in tumor marker levels is higher than that based on reduction in tumor volume shown by computed tomography. The nontumorous liver appears more tolerant to internal radiation than external beam radiation. Selective internal radiation treatment may convert nonresectable tumors to resectable ones.

Tumour-to-normal uptake ratio of 90Y microspheres in hepatic cancer assessed with 99Tcm macroaggregated albumin.

The selective delivery of a high dose of radiation to malignant hepatic tumours by infusion of non-biodegradable yttrium-90 (90Y) microspheres via the hepatic artery while sparing the non-tumorous liver parenchyma depends on the tumour-to-normal uptake ratio (T/N) of the therapeutic radiopharmaceutical. Using intrahepatic arterial technetium-99m macroaggregated albumin (99Tcm-MAA), the effect of tumour type, tumour vascularity assessed by hepatic angiography (HAG), tumour size and the degree of extrahepatic shunting on the T/N was investigated in 377 patients with hepatocellular carcinoma (HCC) and 25 patients with colorectal liver metastases. HCC was shown to have a wider range of T/N (0.2-26.5) compared with liver metastases (2.3-7.2). HCC with vascularity grade 1 on HAG had significantly lower T/N but there was no significant difference in HCC with higher vascularity grades. This confirmed that vascularity on HAG does not predict T/N. Overall there was no correlation between T/N and tumour size. Large tumours (> 20 cm) had a significantly lower T/N, probably due to necrosis in the tumour centres. A decrease in mean T/N with increasing percentages of lung shunting was observed in HCC. Determination of T/N by simulation with 99Tcm-MAA is recommended before internal radiation therapy with 90Y microspheres.

Clinical evaluation of the partition model for estimating radiation doses from yttrium-90 microspheres in the treatment of hepatic cancer.

Radiation doses to the tumour and non-tumorous liver compartments from yttrium-90 microspheres in the treatment of hepatic cancer, as estimated by a partition model, have been verified by correlation with the actual doses measured with a beta probe at open surgery. The validity of the doses to the lungs, the tumour and non-tumorous liver compartment as estimated by the partition model was further evaluated in clinical settings. On the basis of the observation that one of three patients who received more than 30 Gy from a single treatment and one of two patients who received more than 50 Gy from multiple treatments developed radiation pneumonitis, it was deduced that an estimated lung dose < 30 Gy from a single treatment and a cumulative lung dose < 50 Gy from multiple treatments were probably the tolerance limits of the lungs. Three of five patients who received lung doses > 30 Gy as estimated by the partition model and were predicted to develop radiation pneumonitis, did so despite the use of partial hepatic embolization to reduce the degree of lung shunting. Furthermore, a higher radiological response rate and prolonged survival were found in the group of patients who received higher tumour doses, as estimated by the partition model, than in the group with lower estimated tumour doses. Thus the radiation doses estimated by the partition model can be used to predict (a) complication rate, (b) response rate and (c) duration of survival in the same manner as the actual radiation doses measured with a beta probe at open surgery. The partition model has made selective internal radiation therapy using 90Y microspheres safe and repeatable without laparotomy.

Radioembolisation of hepatocellular carcinoma with 90-yttrium resin particles

In 19 patients (34 applications) radioembolisation with Y-90 resin particles applied superselectively with microcatheters was carried out as a palliative treatment of liver cell carcinoma. The calculations of tumour dose and of exposure to the liver parenchyma and lung were made following angioscintigraphy with 99mTc-MAP. In 27 patients the tumour dose was between 50 and 470 Gy, in 5 patients 800 Gy. The adjacent liver parenchyma was exposed to 13% of the targeted tumour dose (mean 34 Gy). The lung shunt in 31 applications was between 0 and 8%, in three instances between 12 and 14%. Complications due to shunt or reflux were observed in 2 patients. Small solitary hypervascularised tumours showed the most improvement (high dose/low-volume embolisation). In multisegmental/lobar tumours, radioembolisation with smaller doses ( < 100 Gy) showed good palliative effects (medium dose/limited-volume embolisation).

Radiation pneumonitis after selective internal radiation treatment with intraarterial 90Yttrium-microspheres for inoperable hepatic tumors

To investigate the clinical, histopathological, and radiological features of radiation pneumonitis arising as a complication of selective internal radiation treatment for liver tumors. To correlate the development of radiation pneumonitis with the degree of lung shunting as assessed by 99mTechnetium-labeled macroaggregated albumin (Tc-MAA) scan. Five out of 80 patients who had inoperable hepatic tumors and underwent treatment with intraarterial 90Yttrium- (90Y)-microspheres, developed progressive restrictive ventilatory dysfunction without an infective or cardiovascular cause. Histopathological evidence of a pneumonitis and the presence of microspheres in the lung tissue suggested a diagnosis of radiation pneumonitis. The clinical course, radiological and histopathological findings, percentage tumor shunting to the lungs (lung shunting, as predicted by gamma camera scanning after intraarterial Tc-MAA), and the estimated radiation dose to the lungs were analyzed. In an attempt to reduce pulmonary shunting of the microspheres, three patients received partial hepatic embolization with inert particles before selective internal radiation therapy. In the five patients who developed radiation pneumonitis, lung shunting percentages (as predicted by Tc-MAA scan) ranged from 13.1 to 45.6% (median 23.7%). The estimated whole lung radiation dose ranged from 10.43 Gy to 36.44 Gy (median 25.04 Gy). Among 75 patients who did not develop radiation pneumonitis, the percentage lung shunting ranged from less than 1% to 15% (median 6%). Nine patients had lung shunting greater than 13% and five of them developed radiation pneumonitis, whereas this developed in none of those in whom shunting was below 13%. The onset of radiation pneumonitis ranged from 1 to 6 months after internal radiation treatment. All five patients exhibited characteristic plain radiographic and computerized tomographic changes comprising extensive consolidation with well-defined lateral margins. Clinical improvement after corticosteroid treatment was seen in two patients. Three patients died from respiratory failure and two from other causes. Partial hepatic arterial embolization reduced the degree of lung shunting to less than 13%, but did not prevent the development of radiation pneumonitis. Radiation pneumonitis may become a complication after intraarterial 90Y-microspheres treatment when lung shunting, as assessed by Tc-MAA scan, is high (above 13%). Prescribed activity of 90Y and lung shunting of Tc-MAA should be considered together before giving selective internal radiation (SIR) therapy for hepatic tumors, and preferably avoided if the lung shunting is above 13%.

Is liver to lung shunting in colorectal liver metastasis the cause of toxicity following treatment with cytotoxic microsphere aggregates?

Incorporation of cytotoxic drugs into microspheres reduces but does not eliminate systemic toxicity. The extent of liver to lung shunt was measured in 26 patients with colorectal liver metastasis. Liver to lung shunting correlated with proportion of liver replacement but did not exceed 4.4% and therefore is unlikely to cause systemic toxicity.

Modulation of liver tumor blood flow with hepatic arterial epinephrine: a SPECT study.

Changes in the relative arterial flow to hepatic tumors and adjacent normal liver, in response to varied doses of hepatic arterial epinephrine, were studied with single photon emission computed tomography. In 18 patients with known hepatic tumors, hepatic artery perfusion scans were obtained with the concurrent infusion of technetium-99m-labeled macroaggregated albumin and escalating doses of epinephrine (0-10 micrograms/min). Regions of interest were drawn around tumor and adjacent normal liver in three planes, and the average tumor-to-liver ratio (T:L) was calculated. In all 18 patients, there was a measurable baseline T:L perfusion advantage (range, 1.7-18.7; mean, 4.8). In 12 of 18 patients, this ratio increased with epinephrine (range, 1.1-53.6 times the baseline value; mean, 7.1). In six patients, no improvement in T:L could be demonstrated. In 14 patients the lung shunt index, a measurement of arteriovenous shunting, increased with escalating doses of epinephrine. This pilot study suggests that the infusion of epinephrine may improve the therapeutic index of certain regional therapies such as bolus drug infusions, hepatic arterial embolization, and radioactive microsphere therapy.