Jean Francois H Geschwind

New Intra-arterial Drug Delivery System for the Treatment of Liver Cancer: Preclinical Assessment in a Rabbit Model of Liver Cancer

Background: In the fight against cancer, new drug delivery systems are attractive to improve drug targeting of tumors, maximize drug potency, and minimize systemic toxicity. We studied a new drug delivery system comprising microspheres, with unique properties allowing delivery of large amounts of drugs to tumors for a prolonged time, thereby decreasing plasma levels. Liver tumors, unlike nontumorous liver, draw most of their blood supply from the hepatic artery. Exploiting this property, we delivered drug-eluting microspheres/beads (DEB) loaded with doxorubicin, intra-arterially, in an animal model of liver cancer (Vx-2). Purpose: The purpose of our study was to determine the pharmacokinetics and tumor-killing efficacy of DEB. Results: Our results show that plasma concentration of doxorubicin was minimal in the animals treated with DEB at all time points (0.009-0.05 μmol/L), suggesting high tumor retention of doxorubicin. This was significantly lower (70-85% decrease in plasma concentration) than control animals treated with doxorubicin intra-arterially. Within the tumor, doxorubicin concentration peaked at 3 days (413.5 nmol/g), remaining high to 7 days (116.7 nmol/g) before declining at 14 days (41.76 nmol/g), indicating continuous doxorubicin elution from beads. In control animals, peak tumor concentration of doxorubicin was 0.09 nmol/g. Tumor necrosis (approaching 100%) was greatest at 7 days, with minimal adverse local side effects reflected in liver function tests results. The plasma concentration of doxorubicinol (doxorubicin main metabolite) was minimal. Conclusions: Our results support the concept of DEBs as an effective way to deliver drugs to tumor. This new technology may prove to be a useful weapon against liver cancer.

Chemoembolization of hepatocellular carcinoma

Transcatheter arterial chemoembolization (TACE) is the mainstay of treatment for patients with unresectable hepatocellular carcinoma (HCC). Chemoembolization involves delivery of some type of chemotherapy combined with some type of arterial embolization to destroy tumor cells. Whereas diffuse tumors may require lobar embolization, smaller tumors may be treated selectively. The goal of TACE is to cause tumor necrosis and control tumor growth while preserving as much functional liver tissue as possible. The ultimate purpose, however, is to prolong life. Several different TACE protocols have been developed, with no consensus as to the most effective techniques. The effect of TACE on patient survival remains unclear. Several nonrandomized studies have demonstrated a beneficial effect of TACE on survival. This result has not been confirmed with randomized trials. It is clear, however, that TACE is a palliative procedure that has been unable to provide a cure for HCC. When combined with other procedures such as percutaneous ethanol injection, TACE has been more successful at achieving survival rates matching those obtained after surgical resection in similar patient populations. Finally, TACE may also be useful as a neoadjuvant therapy by improving the outcomes of potentially curative therapies and as a bridge to liver transplantation.

Phase II Trial of Sorafenib Combined With Concurrent Transarterial Chemoembolization With Drug-Eluting Beads for Hepatocellular Carcinoma

PURPOSE To evaluate safety and efficacy of combined transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEB) and sorafenib in patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS A prospective single-center phase II study was undertaken involving patients with unresectable HCC. The protocol involved sorafenib 400 mg twice per day combined with DEB-TACE. Safety and response were assessed. Results DEB-TACE in combination with sorafenib was successfully administered in 35 patients: mean age, 63 years; Childs A, 89%; Barcelona Clinic Liver Cancer stage C, 64%; Eastern Cooperative Oncology Group performance status of 0 and 1, 46% and 54%, respectively; and mean index tumor size, 7.7 cm (standard deviation, ± 4.2 cm). Patients underwent 128 cycles of therapy (sorafenib plus DEB-TACE, 60 cycles; sorafenib alone, 68 cycles). Median number of cycles per patient was two (range, one to five cycles); median number of days treated with sorafenib was 71 (range, 4 to 620 days). The most common toxicities during cycle one were fatigue (94%), anorexia (67%), alterations in liver enzymes (64%), and dermatologic adverse effects (48%). Although most patients experienced at least one grade 3 to 4 toxicity, most toxicities were minor (grade 1 to 2, 83% v grade 3 to 4, 17%). Toxicity during cycle two was decreased. Over the course of the study, there were 40 sorafenib dose interruptions and 25 sorafenib dose reductions. Sorafenib plus DEB-TACE was associated with a disease control rate of 95% (Response Evaluation Criteria in Solid Tumors Group)/100% (European Association for the Study of the Liver [EASL]), with an objective response of 58% (EASL). CONCLUSION The combination of sorafenib and DEB-TACE in patients with unresectable HCC is well tolerated and safe, with most toxicities related to sorafenib. Toxicity is manageable with dose adjustment of sorafenib. Preliminary efficacy data are promising.

The Outcome of Liver Transplantation in Patients With Hepatocellular Carcinoma in the United States Between 1988 and 2001: 5-Year Survival Has Improved Significantly With Time

PURPOSE We hypothesized that the outcome of liver transplantation in patients with hepatocellular carcinoma (HCC) has improved over the past decade because of the application of published criteria for patient selection. In this study, we compared the outcome of liver transplantation in patients with and without HCC at different time periods using the United Network for Organ Sharing data. PATIENTS AND METHODS We excluded children, patients with multiple organ transplantation or retransplantation, and those with incomplete survival data. The study period was arbitrarily divided into three time intervals: 1987 to 1991, 1992 to 1996, and 1997 to 2001. RESULTS During the study period, 985 patients with HCC (HCC group), and 33,339 without HCC underwent liver transplantation (control group). Kaplan-Meier patient and graft survivals were significantly lower for the HCC group compared with the control group. Cox regression analysis (after adjusting for other confounding variables) confirmed a lower patient survival in the HCC group (1-year survival, 77.0% v 86.7%; hazard ratio [HR], 1.7; 95% CI, 1.5 to 2.0; P <.0001) compared with the control group (5-year survival, 48.2% v 74.7%; HR, 2.2; 95% CI, 1.9 to 2.4; P <.0001); HCC was an independent predictor of survival. Kaplan-Meier analysis showed a significant improvement in 5-year patient survival with time in patients with HCC (1987 to 1991, 25.3%; 1992 to 1996, 46.6%; 1997 to 2001, 61.1%; P <.0001). During the same period, there was only minimal improvement in survival among the control group. CONCLUSION Five-year survival of patients transplanted for HCC is excellent, with a steady improvement in survival over the past decade. It is possible that the published criteria for patient selection may have contributed to the better outcome.

Radioembolization with 90Y Microspheres: Angiographic and Technical Considerations

The anatomy of the mesenteric system and the hepatic arterial bed has been demonstrated to have a high degree of variation. This is important when considering pre-surgical planning, catheterization, and trans-arterial hepatic therapies. Although anatomical variants have been well described, the characterization and understanding of regional hepatic perfusion in the context of radioembolization have not been studied with great depth. The purpose of this review is to provide a thorough discussion and detailed presentation of the angiographic and technical aspects of radioembolization. Normal vascular anatomy, commonly encountered variants, and factors involved in changes to regional perfusion in the presence of liver tumors are discussed. Furthermore, the principles described here apply to all liver-directed transarterial therapies.

Yttrium-90 Microspheres: Radiation Therapy for Unresectable Liver Cancer

Hepatocellular carcinoma (HCC) constitutes a difficult health challenge because of its poor prognosis and limited treatment options. Most available therapies are used only for palliation. The use of yttrium-90 microspheres is a new intraarterial therapy consisting of beta-irradiating microspheres measuring 20-30 micro m in diameter that can be delivered directly to the tumors. (90)Y microspheres, which carry the radiation, are selectively taken up by the tumors, thus preserving normal liver. In several studies to date, (90)Y microspheres have proved to have a low toxicity profile and have generally been well tolerated by patients. Other than transient elevation in liver enzyme levels and mild fatigue and fever, no substantial treatment-related toxicities have been observed. Gastrointestinal toxicities occur in a limited number of cases and are preventable with proper knowledge of visceral arterial anatomy. The effect on survival is also promising, with median survival rates of 23 months (95% confidence interval = 14, 44) and 11 months (95% confidence interval = 6, 26) for patients with Okuda stage I and stage II disease, respectively. On the basis of these data, intraarterial delivery of (90)Y microspheres offers a new alternative in the treatment of unresectable HCC.

Safety and efficacy of transarterial chemoembolization in patients with unresectable hepatocellular carcinoma and portal vein thrombosis.

PURPOSE Despite the absence of conclusive data, portal vein (PV) thrombosis is considered a contraindication to transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC). The purpose of our study was to establish the safety of TACE in such patients and identify key prognostic factors and survival. MATERIALS AND METHODS Data were prospectively collected from 32 consecutive patients with unresectable HCC and PV thrombosis who underwent treatment with TACE. History and physical examination, relevant laboratory values, and contrast material-enhanced magnetic resonance (MR) images were obtained before each TACE procedure. Repeated TACE was performed every 6 weeks unless patients developed a contraindication or MR imaging showed complete response. RESULTS Median overall survival was 9.5 months (range, 3-50 months). Child-Pugh numerical disease stage was the prognostic factor most strongly related to survival. The 30-day mortality rate was zero and there was no evidence of TACE-related hepatic infarction or acute liver failure. The 6-, 9-, 12-, and 18-month survival rates were 60%, 47%, 25%, and 12.5%, respectively. CONCLUSIONS PV thrombosis should not be considered a contraindication to TACE. Compared with historical control subjects who received traditional forms of treatment, the patients in the present study had extended survival. However, prospective randomized trials are necessary to show this conclusively and to show which subgroups benefit.

The Role of Functional MR Imaging in the Assessment of Tumor Response after Chemoembolization in Patients with Hepatocellular Carcinoma

PURPOSE To assess treatment response of hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) with use of diffusion and dynamic contrast medium-enhanced magnetic resonance (MR) imaging. MATERIALS AND METHODS MR imaging studies before and after TACE in 38 patients with HCC (33 male patients and five female patients) were evaluated. Diffusion and dynamic contrast medium-enhanced MR imaging was performed on a 1.5-T unit. The imaging protocol included T2-weighted fast spin-echo, breath-hold diffusion-weighted echoplanar, and breath-hold unenhanced and contrast medium-enhanced T1-weighted three-dimensional fat-saturation gradient-recalled echo imaging in the arterial and portal venous phases. Tumor size, percent enhancement, and apparent diffusion coefficient (ADC) values were recorded before and after treatment. Survival analysis was also performed. RESULTS The study included 38 lesions with a mean diameter of 8.0 cm. Mean reduction in tumor diameter was 8 mm after treatment (t test; P = .0005), which did not fulfill Response Evaluation Criteria in Solid Tumors for complete or partial response. Reduction in tumor enhancement in the arterial (30%) and venous (47%) phases was statistically significant (signed-rank test; P = .0003 and P < 0.00005, respectively). Tumor ADC value increased from 0.0015 mm(2)/sec to 0.0018 mm(2)/sec after treatment (t test; P = .026), whereas the ADC values for the liver, spleen, and muscle remained unchanged. Median patient survival was 19 months. CONCLUSIONS After TACE, tumors demonstrated decreased size and enhancement with increases in ADC values. In this cohort, diffusion and dynamic contrast medium-enhanced MR imaging parameters were significantly altered after TACE, and these could be useful tools in the assessment of tumor response.

Tumor glycolysis as a target for cancer therapy: progress and prospects.

Altered energy metabolism is a biochemical fingerprint of cancer cells that represents one of the “hallmarks of cancer”. This metabolic phenotype is characterized by preferential dependence on glycolysis (the process of conversion of glucose into pyruvate followed by lactate production) for energy production in an oxygen-independent manner. Although glycolysis is less efficient than oxidative phosphorylation in the net yield of adenosine triphosphate (ATP), cancer cells adapt to this mathematical disadvantage by increased glucose up-take, which in turn facilitates a higher rate of glycolysis. Apart from providing cellular energy, the metabolic intermediates of glycolysis also play a pivotal role in macromolecular biosynthesis, thus conferring selective advantage to cancer cells under diminished nutrient supply. Accumulating data also indicate that intracellular ATP is a critical determinant of chemoresistance. Under hypoxic conditions where glycolysis remains the predominant energy producing pathway sensitizing cancer cells would require intracellular depletion of ATP by inhibition of glycolysis. Together, the oncogenic regulation of glycolysis and multifaceted roles of glycolytic components underscore the biological significance of tumor glycolysis. Thus targeting glycolysis remains attractive for therapeutic intervention. Several preclinical investigations have indeed demonstrated the effectiveness of this therapeutic approach thereby supporting its scientific rationale. Recent reviews have provided a wealth of information on the biochemical targets of glycolysis and their inhibitors. The objective of this review is to present the most recent research on the cancer-specific role of glycolytic enzymes including their non-glycolytic functions in order to explore the potential for therapeutic opportunities. Further, we discuss the translational potential of emerging drug candidates in light of technical advances in treatment modalities such as image-guided targeted delivery of cancer therapeutics.

Unresectable Hepatocellular Carcinoma: Serial Early Vascular and Cellular Changes after Transarterial Chemoembolization as Detected with MR Imaging

PURPOSE To prospectively assess serial changes in contrast material-enhanced and diffusion-weighted (DW) magnetic resonance (MR) imaging values within 1 month after transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS Institutional review board approval was obtained for this prospective HIPAA-compliant study. MR imaging was performed before and within 24 hours after TACE in 24 patients with HCC (21 male, three female; mean age, 59 years and 62 years, respectively). Serial MR imaging was subsequently performed 1, 2, 3, and 4 weeks after therapy. The imaging protocol included fast spin-echo T2-weighted MR imaging, breath-hold DW echo-planar MR imaging, and breath-hold unenhanced and contrast-enhanced T1-weighted three-dimensional fat-suppressed gradient-recalled-echo MR imaging in the arterial and portal venous phases. Tumor size, enhancement, and apparent diffusion coefficient (ADC) values were recorded before and sequentially after treatment. Regression models for the correlated data were used to assess changes in these parameters over time after TACE. RESULTS Mean tumor size was 7.5 cm and was unchanged up to 4 weeks after therapy. Reduction in tumor enhancement in the arterial phase occurred immediately after TACE, with a consistent reduction occurring 1-3 weeks after therapy (P = .001). Reduction in tumor enhancement in the portal venous phase also occurred immediately after TACE, with a consistent reduction occurring 1-3 weeks after therapy (P = .0003). The increase in tumor ADC value was significant 1-2 weeks after therapy (P = .004), borderline significant 3 weeks after therapy, and insignificant 24 hours and 4 weeks after therapy. CONCLUSION Significant reduction in tumor enhancement occurred within 24 hours after TACE and persisted up to 4 weeks after TACE. Lesser changes in the ADC value appeared 1 week after TACE, persisted through 2 weeks after TACE, and became less apparent 3 and 4 weeks after TACE. No change in tumor size was recorded during the follow-up period.