BASL Guideline says: “The usefulness of positron emission tomography (PET scan) is not established in HCC.”

Chi-Lai Ho, Simon C.H. Yu, and David W.C. Yeung11C-Acetate PET Imaging in Hepatocellular Carcinoma and Other Liver Masses J Nucl Med 44: 213-221.

J.-W. Park, J. H. Kim, S. K. Kim, K. W. Kang, K. W. Park, J.-I. Choi, W. J. Lee, C.-M. Kim, and B. H. Nam
A Prospective Evaluation of 18F-FDG and 11C-Acetate PET/CT for Detection of Primary and Metastatic Hepatocellular Carcinoma
J. Nucl. Med., December 1, 2008; 49(12): 1912 – 1921.

Y-x He and Q-y Guo
Clinical applications and advances of positron emission tomography with fluorine-18-fluorodeoxyglucose (18F-FDG) in the diagnosis of liver neoplasms
Postgrad. Med. J., May 1, 2008; 84(991): 246 – 251.

Jonathan D Schwartz et al, Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: Review of the randomised clinical trials
(2002) Lancet Oncology, 3 (10), pp. 593-603.

http://gut.bmj.com/cgi/reprint/52/suppl_3/iii1.pdf

The most active single agent drugs tested have been doxorubicin, cisplatin, and fluorouracil. More recently, gemcitabine and capecitabine have been evaluated in clinical trials; response rates have been low and less than satisfactory; cisplatin-based combination regimens, such as gemcitabine and cisplatin (or oxaliplatin), have shown improved response rates around 20%, but to date, no survival advantage as compared to supportive care alone has been shown. No difference seems to exist in response rates between 2- or 3-drug regimens. Moreover, some of these combination regimens cause considerable toxicity. The combination of bevacizumab with gemcitabine and oxaliplatin, produced a 20% response rate with an additional 27% of patients who had stable disease.

More recently Foflox was shown to be effective. Nexavar and Adriamycin were reported in 2010 to be better than Adriamycin. Mdian time to progression was 6.4 months in the sorafenib-doxorubicin group (95% confidence interval [CI], 4.8-9.2), and 2.8 months (95% CI, 1.6-5) in the doxorubicin-placebo monotherapy group (P = .02). Median overall survival was 13.7 months (95% CI, 8.9–not reached) and 6.5 months (95% CI, 4.5-9.9; P = .006), and progression-free survival was 6.0 months (95% CI, 4.6-8.6) and 2.7 months (95% CI, 1.4-2.8) in these groups, respectively (P = .006). Toxicity profiles were similar to those for the single agents.

Simonetti RG, Liberati A, Angiolini C. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials. Ann Oncol. 1997;8:117-36.

Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol. Apr 20 2006;24(12):1898-903.

Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib improves survival in advanced hepatocellular carcinoma (HCC): results of a phase III randomized placebo-controlled trial (SHARP trial). J Clin Oncol. 2007;25(suppl):962s(abstract LBA1).

Faivre S, Raymond E,Douillard J, et al. Assessment of safety and drug-induced tumor necrosis with sunitinib in patients (pts) with unresectable hepatocellular carcinoma. J Clin Oncol. 2007;25:149s Abstract 3546.

Rougier P, Mitry E, Barbare JC, et al. Hepatocellular carcinoma (HCC): an update. Semin Oncol. Apr 2007;34(2 Suppl 1):S12-20.

Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T, Gansukh B, Saltz LB. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010 Nov 17;304(19):2154-60.

Yeo W, Mok TS, Zee B, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 2005;97:1532–1538

According to available literature, chemoembolization (TACE) may be indicated for symptomatic treatment of functional neuroendocrine cancers (i.e., carcinoid tumors and pancreatic endocrine tumors) involving the liver, in persons with adequate hepatic function (bilirubin < 2 mg/dl, absence of ascites; no portal vein occlusion; and tumor involvement of < 65 % of liver). For carcinoid tumors, TACE is indicated only in persons who have failed systemic therapy with octreotide to control carcinoid syndrome (e.g., debilitating flushing, wheezing and diarrhea). The safety and effectiveness of chemoembolization for breast cancer metastases is unknown as only case reports and series have so far been reported. The largest series reported in a 2008 abstract was of 217 pateints but this as not a prospective study.

In a comparative study with the three drugs versus mitomycin and doxorubicin for HCC, no advantage was found for the three drugs. For neuroadnocrine carcnoma, a comparative study found that: “Chemoembolization was not associated with a higher degree of toxicity than bland embolization. Chemoembolization demonstrated trends toward improvement in TTP, symptom control, and survival. Based on these results, a multicenter prospective randomized trial is warranted.”

M . Giroux , R . Baum , M . Soulen. Chemoembolization of Liver Metastasis from Breast Carcinoma .
Journal of Vascular and Interventional Radiology , Volume 15 , Issue 3 , Pages 289 – 291, 2004

Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: Meta-analysis of randomized controlled trials. Radiology. 2002;224(1):47-54.

T. J. Vogl, R. Bauer, K. Eichler, T. Gruber Repeated transarterial chemoembolization (TACE) in the treatment of patients with liver metastases of breast cancer: Local tumor control and survival.
J Clin Oncol 26: 2008 (May 20 suppl; abstr 549)

Alexander T. Ruutiainen et al, Chemoembolization and Bland Embolization of Neuroendocrine Tumor Metastases to the Liver Journal of Vascular and Interventional Radiology
Volume 18, Issue 7, July 2007, Pages 847-855

TheraSphere — a therapy that consists of millions of microscopic, radioactive glass microspheres (20-30 microns diameter) — is infused into the arteries that feed inoperable liver tumors, bathing the malignancy in high levels of extremely localized radiation. In some studies of highly selected pateints the response rates and stabilization rates ranged between 20-40 percent. No survival benefit has been demonstrated and the technique is still in phase II studies. This therapy is currently considered to be investigational. A recent guideline states: “radio-labeled Yttrium glass beads, radio-labeled lipiodol or immunotherapy cannot be recommended as standard therapy for advanced HCC outside clinical trials”.

A recent study(Salem 2010) may be changing the standard of care. It enrolled 291 patients (77% male, 25% were more than 75 years old, and 73% had multifocal disease). This is the largest series ever presented of the treatment of primary unresectable liver cancer using radiation microspheres. Results showed that overall time to progression was 7.9 months (95% confidence interval [CI], 6.0 – 10.3). Using World Health Organization guidelines, the overall response rate was 42%. Using the European Association for the Study of the Liver guidelines, the overall response rate was 57%. Survival times differed significantly by cancer staging system (26.9 months for BCLC A vs 17.2 months for BCLC B) and by liver function score (17.2 months for Child-Pugh A vs 7.7 months for Child-Pugh B). The promise here is that the disease can be converted to something that can become surgically resectable or that the patients may be able to be liver transplanted.

Although the phase III trials of radioembolization are ongoing as a first-line treatment of patients with metastatic colorectal cancer, there are sufficient phase II and retrospective clinical data supporting its use in salvage therapy for most patients. Patients with hepatocellular cancer, neuroendocrine tumors, and other primary sites, including breast and lung, although they also have also shown promising response and survival increases in multi-institutional experiences.

L. A. Dawson Hepatic Arterial Yttrium 90 Microspheres: Another Treatment Option for Hepatocellular Carcinoma J. Vasc. Interv. Radiol., February 1, 2005; 16(2): 161 – 164.

Andrew Kennedy, Subir Nag, Riad Salem, Ravi Murthy, Alexander J. McEwan, Charles Nutting, Al Benson, Joseph Espat, Jose Ignacio Bilbao, Ricky A. Sharma Recommendations for Radioembolization of Hepatic Malignancies Using Yttrium-90 Microsphere Brachytherapy: A Consensus Panel Report from the Radioembolization Brachytherapy Oncology Consortium International Journal of Radiation Oncology*Biology*Physics, Volume 68, Issue 1, Pages 13-23
R. Salem, R. J. Lewandowski, B. Atassi, S. C. Gordon, V. L. Gates, O. Barakat, Z. Sergie, C.-Y. O. Wong, and K. G. Thurston Treatment of Unresectable Hepatocellular Carcinoma with Use of 90Y Microspheres (TheraSphere): Safety, Tumor Response, and Survival J. Vasc. Interv. Radiol., December 1, 2005; 16(12): 1627 – 1639

Bruix J, Sherman M, Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005 Nov;42(5):1208-36. [322 references]

R. Salem, Society of Interventional Radiology (SIR) 35th Annual Scientific Meeting: Abstract 34. Presented March 14, 2010.

Chemoresistance assays are a modification that tests resistance to chemo rather than sensitivity. They work on the assumption that if celss show reesistance to very high concentrations of a drug in vitro, they will also be resistant in vivo to that drug.

Going back years, the article by Schrag et al criticized the field of chemosensitivity and chemo resistance(SRA), concluding that these types of in vitro assays are not yet ready for prime time. The panel of authors attempted to present evidence that in vitro drug response assays should not be used clinically. This issue was first addressed by an exhaustive Medicare Coverage Advisory Committee (MCAC) in 1999. A panel of physicians selected by the Department of Health and Human Services reviewed hundreds of articles from the literature and heard two days of testimony by experts in the field in an open hearing. The panel voted unanimously that although chemosensitivity assays should not be covered, drug resistance assays should be paid for. This became a cause celebre with a vigorous debate in the literature and variant opinions offered by professional bodies. The American Society of Clinical Oncology vigorously objected and recommended: ”
The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient’s health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.”  I believe that the So. California branch of ASCO dissented from this recommendation, see http://weisenthal.org/medicareletter.pdf.

The Extreme Drug Resistance Assay (EDR) Assay is a laboratory test performed on a patient’s tumor cells. This lab test is claimed to determine the probability of a tumor’s resistance to a specific chemotherapy drug. If the tumor cells grow in the presence of very high concentrations of chemotherapy drug, then the cancer cells are considered resistant to that drug.

Drug sensitivity and resistance assays have been examined for their potential utility in ovarian cancer by a number of clinical investigators. Unfortunately, analysis of these studies has suffered greatly from the absence of an appropriate control population. The majority of these trials have compared the survival of individuals whose treatment was selected by a particular assay with a historical/retrospective patient group treated at the same institution. A report in the Gynecologic Cancer session described an important attempt by investigators in Europe to directly address the value of the adenosine triphosphate (ATP)-based tumor chemosensitivity assay, by randomizing patients with platinum-resistant ovarian cancer (n = 180) to either “assay-directed therapy” or the treatment of the “physician’s choice”. The objective response rate was 40.5% for the assay-directed group vs 31.5% for the physician’s choice of treatment. Progression-free survival (intention-to-treat analysis) was 104 days in the assay-directed vs 93 days in the physician’s choice groups. In addition, there was no difference in overall survival between the strategies. This study provides support for the conclusion that the ATP-based tumor chemosensitivity assay is not superior to physician’s choice in the selection of chemotherapy in women with platinum-resistant ovarian cancer.Some experts claim that resistance assays are different from chemosensitivity assays and Medicare does cover them. However, this distinction has not been sufficiently demonstrated and most experts vigorously dispute this.

In conclusion, the technologies and the questions that they raise are quite different. It Oncotech Sensitivy testing not yet been  recommended by professional societies and gudielines pending completion of a phase III trial. With Oncotech ER the situation is more uncertain, NCCN says that “current evidence is not sufficient to supplant standard of care chemotherapy”.

More recently in ASCO 2008, researchers affiliated with Precision Therapeutics and Columbia University reported that a test of chemoresponsiveness (ChemoFX®) can predict survival of patients with advanced ovarian cancer. This remains something that must be confirmed by future studies. NCCN says that “chemosensitivity.resistance assays are being used in some NCCN centers”, which I consider something less than an endorsement. This is a level 3 recommendations, which is defined as: “The recommendation is based on any level of evidence but reflects major disagreement.”

Burstein et al (2011) updated the ASCO Technology Assessment guidelines on CSRAs published in 2004.  An Update Working Group reviewed data published between December 1, 2003, and May 31, 2010.  Medline and the Cochrane Library were searched yielding 11,313 new articles.  The limits for “human and English” were used, and then standard ASCO search strings for randomized controlled trials (RCTs), meta-analyses, guidelines, and reviews were added, yielding 1,298 articles for abstract review.  Of these, only 21 articles met pre-defined inclusion criteria and underwent full text review, and 5 reports of RCTs were included for data extraction.  Review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice.  The authors concluded that the use of CSRAs to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting.  They noted that oncologists should make chemotherapy treatment recommendations based on published reports of clinical trials and a patient’s health status and treatment preferences.  Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.

Schrag D, Garewal HS, Burstein HJ, et al: American Society of Clinical Oncology technology assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22 : 3631 -3638, 2004

John P. Fruehauf In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins Journal of Clinical Oncology, Vol 23, No 15 (May 20), 2005: pp. 3641-3643

P. Hwu, A. Y. Bedikian, and E. A. Grimm
Challenges of chemosensitivity testing.
Clin. Cancer Res., September 15, 2006; 12(18): 5258 – 5259.

Cree IA. Chemosensitivity and chemoresistance testing in ovarian cancer. Curr Opin Obstet Gynecol. 2009;21(1):39-43.

C.Rass K, Hassel JC. Chemotherapeutics, chemoresistance and the management of melanoma. G Ital Dermatol Venereol. 2009;144(1):61-78.

Lyons JM 3rd, Abergel J, Thomson JL, et al. In vitro chemoresistance testing in well-differentiated carcinoid tumors. Ann Surg Oncol. 2009;16(3):649-655.

National Comprehensive Cancer Network (NCCN). Ovarian cancer including fallopian tube cancer and primary peritoneal cancer. NCCN Clinical Practice Guidelines in Oncology v.2.2011. Fort Washington, PA: NCCN; 2011.

Burstein HJ, Mangu PB, Somerfield MR, et al. American society of clinical oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol. 2011;29(24):3328-3330.