Cancer Treatment

Radiofrequency ablation for the liver

Radiofrequency ablation (RFA) is a thermoablative technique which destroys tissue by heating cancer cells to temperatures exceeding 60°C. In RFA, temperature changes are induced using high-frequency alternating current applied via an electrode or electrodes placed within the tissue to generate ionic agitation. RFA can be applied percutaneously, laparoscopically or intraoperatively.

Percutaneous ablation is a commonly used modality of tratment when resection is not possible for HCC. Other local modalities are radiofrequency ablation or chemo embolization. Microwave coagulation therapy, one of the thermal ablation therapies now available, has been used in the treatment of liver metastases. To date, at least seven series have been published in the English-language literature  in which the results of microwave coagulation therapy of hepatic metastases have been described. However, these results were narrowly focused preliminary studies: a few clinical patient trials, principally as assessments of feasibility, safety, and short-term efficacy. Although the preliminary results are promising, few articles concerning the effect of microwave ablation on survival have been published. This is even more true in the setting of metastatic cancer.

A R Gillams
Liver ablation therapy
Br. J. Radiol., September 1, 2004; 77(921): 713 - 723.

P. Liang, B. Dong, X. Yu, Y. Yang, D. Yu, L. Su, Q. Xiao, and L. Sheng
Prognostic Factors for Percutaneous Microwave Coagulation Therapy of Hepatic Metastases
Am. J. Roentgenol., November 1, 2003; 181(5): 1319 - 1325.

http://www.nice.org.uk/nicemedia/pdf/ip/IPG092guidance.pdf

PTK787 for pancreat cancer

PTK 787 is a selective inhibitor of all three types of the VEGF receptors. It has been shown to reduce the number of tumor microvessels with resultant dilation of the remaining vessels. It has also been shown to inhibit VEGF receptors and has been effective in animal tumor models. In addition, dynamic contrast-enhanced MRI (DCE-MRI) and PET imaging have shown a reduction in blood flow to tumors after the administration of PTK 787.

A phase 1 study of the VEGF-receptor tyrosine kinase inhibitor vatalanib (PTK787/Z 222584) and gemcitabine in patients with advanced pancreatic cancer was conducted at Stanford University. All patients received vatalanib 1250 mg daily; gemcitabine was escalated from 700 mg/m2 to 850 mg/m2 to a maximum of 1000 mg/m2. To date, 32 cycles have been given to 8 patients with pancreatic cancer, with a median of 4 cycles per patient. Only 1 patient, in the first cohort, experienced dose-limiting toxicity (DLT), with grade 3 diarrhea and hypokalemia and grade 4 neutropenia occurring simultaneously and treated without sequelae. The remaining patients in this and the next cohort (850 mg/m2) have not experienced DLT. Beyond the first cycle, grade 3 toxicities included neutropenia (1), anemia (2), thromobocytopenia (1), hypertension (2), diarrhea (1), hypokalemia (1), thrombosis (1), and proteinuria (1). Two of 8 patients had stable disease as the best response by RECIST. The remaining patients had stable disease as the best response from 2 to 6 months. No disease progression was seen at or before the first evaluation with computed tomography. No unexpected toxicities have been observed. Accrual to higher-dose gemcitabine cohorts continues. A phse II study of PTJ787alone is also ongoing.

http://clinicaltrials.gov/ct/show/NCT00226005?order=1

Kuo T, Fitzgerald A, Kaiser H, Sikic BI, Fisher GA. A phase I study of the VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK 222584) and gemcitabine in patients with advanced pancreatic cancer. Program and abstracts of the 2006 Gastrointestinal Cancers Symposium; January 26-28, 2006; San Francisco, California. Abstract 127.

NCCN.ORG, Pancreatic

Intrahepatic therapies ablative therapies

Percutaneous ablation is a commonly used modality of treatment when resection is not possible for HCC. Other local modalities are radiofrequency ablation or chemo embolization. When direst intratumor injection is used, alcohol is most commonly used and it is FDA approved for this purpose. However, acetic acid is more potent in animal models. Only a few studies tested the various modlaities against one another.

A systematic review of RCTs published from 1978 to 2002 identified seven RCTs including a total of 516 patients comparing embolization vs. conservative management, five of which assessing chemoembolization with doxorubicin or cisplatin. Survival benefits were obtained in two studies, one of which identifies treatment response as an independent predictor of survival. Meta-analysis showed a beneficial survival effect of embolization/chemoembolization in comparison with the control group. Overall, this effect may be considered modest, as is expected to occur in advanced neoplasms. Survival benefits were not identified with embolization alone, but the number of individuals analyzed is still low. There is no good evidence for the best chemotherapeutical agent and the optimal re-treatment strategy.

Three small RCT assessing either chemoembolization in combination with percutaneous ablation or lipiodolization have been published in this period A German study reported no survival differences between a combination of chemoembolization and PEI vs. chemoembolization alone in 58 patients. Therapy using reservoir intra-arterial infusion has been employed in patients with advanced HCC with disappointing results. A low-quality study assessing lipiodolization with carboplatin (150 mg/m2) compared with doxorubicin (20 mg/m2) in 65 Chinese patients, showed significant survival benefits favoring the carboplatin arm (16.9 vs. 12.1 months, P = 0.0257). Further studies are required to confirm these data.

In summary, there is no conclusive evidence to consider intrahepatic injection to be better or even equivalent to emblolization; however, alcohol ablation is widely used in the USA. Acetic acid is less frequently used and there are no comparative studies of it versus alcohol. NCCN speaks of "ablation" and thus avoids the issue of the agent (alcohol versus acetic acid);however, it considers "ablation" standard of care.

Brunken C, Topp S, Tesch C, et.al. System Effects and Side Effects of Interstitial Techniques Used in Liver Tissue.  American College of Surgeons 1999; 188, No.6: 636-642.

Usha Dutta (2000) Treatment of hepatocellular carcinoma Journal of Gastroenterology and Hepatology 15 (8), 822–824.

Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37: 429–42.

Akamatsu M, Yoshida H, Obi S, et al. Evaluation of transcatheter arterial embolization prior to percutaneous tumor ablation in patients with hepatocellular carcinoma: a randomized controlled trial. Liver Int 2004; 24: 625–9.

Becker G, Soezgen T, Olschewski M, et al. Combined TACE and PEI for palliative treatment of unresectable hepatocellular carcinoma. World J Gastroenterol 2005; 11: 6104–9.

http://nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf

Gemcitabine Taxotere and Xeloda (GTX) for pancreatic cancer

Although both Xeloda and Gemcitabine/Taxotere have phase II (and for the latter phase III) trial support, putting all three together is investigational. Preliminary work is ongoing at Coulumbia University. Combining Gemzar with Taxotere® (docetaxel) and Xeloda® (capecitabine, the oral drug that metabolizes into 5-FU within tumor cells) shows intriguing signs of efficacy, according to Robert L. Fine, MD, director of the experimental therapeutics program, Columbia College of Physicians and Surgeons, New York. Xeloda sabotages the DNA replication needed for tumor growth in a different way than Gemzar, and Taxotere gums up one of the cancer cell’s structural proteins. Together, the “GTX” drugs, as they are known, may be synergistic in their antitumor effects.
In a recent pilot study, Dr. Fine and his colleagues administered the GTX combination to 44 patients with advanced pancreatic cancer. A “partial response”—which, he explains, is more than 50% shrinkage at tumor sites—was observed in the liver metastases of 15 of 32 patients. Liver metastases completely disappeared on CT and MRI scans in three of the original 15 patients when the GTX regimen was continued for a total of eight to nine cycles. Another 28% of patients had minor response to GTX or stable disease in their liver tumors. Tumors in 12 other subjects were initially inoperable but hadn’t spread to the liver. After drug treatment and radiation, eight of these patients had successful Whipple surgery with negative margins and showed no signs of disease. For patients who failed GTX and received alternating GX-T chemotherapy, a 30% response rate and 40% stable disease rate was seen. Thus, a triple drug regimen of Xeloda, Gemzar, and Taxotere® (docetaxel) produced a 47% response rate (9% complete response rate) in 32 patients with liver metastases, which may represent an improvement over monotherapy.

Current treatment options for pancreatic cancer include surgery, radiation, and chemotherapy. Although single-agent chemotherapy with gemcitabine has been a standard treatment for pancreatic cancer, research has increasingly focused on the development of combination regimens. Recently, the U.S. Food and Drug Administration approved the combination of the targeted therapy Tarceva ® (erlotinib) and gemcitabine for the treatment of locally advanced, inoperable, or metastatic pancreatic cancer.

Xeloda is an oral chemotherapy drug that belongs to a class of drugs called antimetabolites. According to researchers from Europe, the addition of the drug Xeloda (capecitabine) to Gemzar (gemcitabine) improves the duration of survival in patients with advanced stage pancreatic cancer. These results were recently presented at the 2005 annual meeting of the American Society of Clinical Oncology. Researchers from Austria evaluated the effects of Gemzar® with or without Xeloda® in 83 patients with metastatic pancreatic cancer. 3 Forty-two patients received bi-weekly Gemzar® (2200 mg per square meter as a 30 min. infusion) and 41 patients received the same GemzarÒ dose and schedule plus oral Xeloda® at a dose of 2500 mg per square meter from days 1 to 7. The PR rate was 14 % for the Gemzar® alone group and 17% for the Gemzar® plus Xeloda® group. Stable disease was observed in 43% of Gemzar® alone patients and 56% of the combined group. Median survival was 4 months for the Gemzar® group and 5.1 months for the Xeloda® group, with overall survivals of 8.2 and 9.5 months, respectively. Using a clinical benefit scale, there was clinical benefit for 33% of patients receiving Gemzar® alone and 48.3% for those receiving Gemzar® and Xeloda®. The toxicities of the two regimens appeared to be equivalent and these investigators were enthusiastic about this drug combination. However, there was no improvement in objective or subjective response. It was speculated that the number of patients studied was too small, possibly the dosage was suboptimal and possibly these agents are not really additive or synergistic.

The Hoosier Oncology Group evaluated a regimen of Gemzar® and Taxotere®. The response rate was 24%, with a median duration of response of 16 weeks. Thirty-five percent of patients had stable disease. The one-year survival was 27.3% and toxicity appeared to be acceptable. German researchers also evaluated the combination of Gemzar® and Taxotere® for the treatment of patients with advanced pancreatic cancer. 6 They observed a 24% response rate, with 3% (one patient) achieving a CR. The median survival was 9 months and toxicity was mild to moderate. The EORTC-GI Group compared a regimen of Taxotere® and Gemzar® to a regimen of Taxetore® and Platinol® for the treatment of advanced or metastatic (80%) pancreatic cancer. 2 This was a randomized trial, with 49 patients receiving Taxotere® and Gemzar® and 47 receiving Taxotere® and Platinol®. Six cycles of treatment were administered to 44% of patients, with 29% receiving more than 6 cycles. The Gemzar®/Taxotere® arm was associated with low platelets and edema, while the Taxotere®/Platinol® arm had more neutropenia. The response rate was 15.8% for the Gemzar®/Taxotere® arm and 16.1% for the Taxotere®/Platinol® arm. The median survival was 7.4 months for Gemzar®/Taxotere® and 6.3 months for the Taxotere®/Platinol®. There were 11 patients alive in the Gemzar®/Taxotere® arm and 9 in the Taxotere®/Platinol® arm. They concluded that the Gemzar®/Taxotere® arm had more manageable toxicity and possibly better activity. They will be performing a randomized phase III trial to confirm these results.

Lutz MP, Ducreux M, Wagener T, et al, Docetaxel/gemcitabine or docetaxel/cisplatin in advanced pancreatic carcinoma: a randomized phase II study of the EORTC-GI group. Proceedings of the American Society of Clinical Oncology 2002;21:125a, abstract 498

Scheithauer W, Schüll B, Ulrich-Pur H, et al, Gemcitabine alone or in combination with capecitabine in patients with advanced pancreatic adenocarcinoma. Proceedings of the American Society of Clinical Oncology;21:126a, abstract number 500

Schneider BP, Ganjoo KN, Seitz DE, et al, Phase II study of gemcitabine and docetaxel in combination for advanced pancreatic cancer - a Hoosier Oncology Group study. Proceedings of the American Society of Clinical Oncology 2002; 21:137a, abstract number 546

Schmidt C, Fahlke J, Kettner E, et al, Phase II multicenter study of gemcitabine and docetaxel in patients with inoperable or metastatic pancreatic cancer. Proceedings of the American Society of Clinical Oncology 2002;21:145a, abstract number 5779.

Fine RL, Fogelman DR, Sherman W, et al. The GTX regimen: A biochemically synergistic combination for advanced pancreatic cancer (PC). Proceedings from the 39th Annual Meeting of the American Society of Clinical Oncology. Chicago IL. 2003; Abstract #112 Moore M, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a Phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology [early online publication]. April 23, 2007.

Revised 3/5/2008

Chemoembolization

Lay Summary: TACE is often used for hepatocellular carcinoma and neuroendocrine cancers of the liver.

This technique takes advantage of the fact that HCC is a very vascular (contains many blood vessels) tumor and gets its blood supply exclusively from the branches of the hepatic artery. This procedure is similar to intra-arterial infusion of chemotherapy. But in TACE, there is the additional step of blocking (embolizing) the small blood vessels with different types of compounds, such as gelfoam or even small metal coils. Thus, TACE has the advantages of exposing the tumor to high concentrations of chemotherapy and confining the agents locally since they are not carried away by the blood stream. At the same time, this technique deprives the tumor of its needed blood supply, which can result in the damage or death of the tumor cells.There is no established standard protocol for TACE.If the procedure is successful (>50% lipiodol uptake in necrotic tumor demonstrated on the postprocedural CT scan), the embolization is repeated in 6-8 weeks. If the lipiodol uptake is less than 50%, the authors repeat the CT scan in 6-8 weeks. If the size of the tumor is reduced, repeat TACE may be considered.The second TACE treatment should first be performed in previously untreated tumors.The third treatment completes a normal course, but further treatments are performed in patients with residual disease.


The type and frequency of complications of TACE and intra-arterial chemotherapy are similar. The potential disadvantage of TACE is that blocking the feeding vessels to the tumor(s) may make future attempts at intra-arterial infusions impossible. Moreover, so far, there are no head-to-head studies directly comparing the effectiveness of intra-arterial infusion versus chemoembolization. Studies in Japan have shown that TACE can downstage HCC. In other words, the tumors shrank enough to lower (improve) the stage of the cancer. From the practical point of view, shrinking the tumor creates the option for surgery in some of these patients. Otherwise, these patients had tumors that were not operable (eligible for operation) because of the initial large size of their tumors. More importantly, these same studies showed an improvement in survival in patients whose tumors became considerably smaller. In the U.S., trials are underway to see whether doing TACE before liver transplantation increases patient survival as compared to liver transplantation without TACE.

It is safe to say that TACE or intra-arterial chemoinfusion are palliative treatment options for HCC. However, they are not curative (Fewer than 50% of patients will have some shrinkage in tumor size. Further, they can be used only in patients with relatively preserved liver function. Several randomized trials have established this procedure as standard of care for hepatocellular cacrinoma and neuroendocrine carcinoma. 

Livraghi T .Guidelines for treatment of liver cancer. Eur J Ultrasound. 2001 Jun;13(2):167-76.

Blue Cross Blue Shield Association, Transcatheter Arterial Chemoembolization of Hepatic Tumors. TEC Assessment, March 2001; (15): 22.

 

EVIDENCE-BASED PRACTICE:
Calogero Cammà, Filippo Schepis, Ambrogio Orlando, Maddalena Albanese, Lillian Shahied, Franco Trevisani, Pietro Andreone, Antonio Craxì, and Mario Cottone
Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma: Meta-Analysis of Randomized Controlled Trials
Radiology, Jul 2002; 224: 47 - 54.

NCCN Drugs and Biologicals Compendium VI 2006