Articles
Uncontrolled liver malignancies are a major cause of death in patients with cancer due to destruction of the critical functions performed by this essential organ.1,2 Therefore, the choice and sequence of therapies for hepatic neoplasms is of great importance.
Malignant liver tumors are either primary or secondary, with the most common lesions being hepatocellular carcinoma (HCC) and metastatic colorectal cancer (MCRC), respectively.
For patients who are not operative candidates at time of diagnosis and staging, local or systemic therapy may be considered, with the goal of reducing or controlling tumor volume to preserve as much normal liver function as possible, for as long as possible, and to render the patient potentially eligible for surgery with intent to cure.
The currently available local and systemic therapies in liver cancer are surveyed. New approaches now in development are described, including the novel light-activated drug Aptocine (talaporfin sodium), which may combine the most beneficial aspects of local and systemic therapies.
Local Therapies
Until recently, first line therapies focused on the use of intratumoral local ablation using various devices or injection of therapeutic agents into tumor-feeding blood vessels. Table 1 summarizes modalities utilized in these two categories. All listed treatments result in cellular necrosis as the final common pathway of cell death.
| Table 1. Current Localized Therapies | ||
| Modality | Main Indication | Mode of Action |
| Radiofrequency Ablation (RFA) | HCC, MCRC | Thermal |
| Transcatheter Arterial Chemoembolization (TACE) | HCC | Infarction/Anti-mitotic |
| Percutaneous Ethanol Injection | HCC | Denaturation |
| Radioembolization | HCC | Infarction/Anti-mitotic |
| Laser Interstitial Thermotherapy (LITT) | HCC, MCRC | Thermal |
Over time, in some cases over many years, these modalities have been developed and used outside the context of formal randomized controlled Phase 3 trials comparing one modality to another. Therefore, choice of modalities is largely determined by the treating clinician’s training and preference, rather than by established guidelines based on randomized controlled Phase 3 comparative trials. Worldwide, the most commonly utilized modalities are radiofrequency ablation (RFA) and transcatheter arterial chemoembolization (TACE), with RFA used for lesions less than 3 to 4 cm due to technical and safety limitations, and TACE used for small or larger lesions.
All localized therapies listed in Table 1 share a major drawback in that they produce tumor death through tumor necrosis and inflammation. While potentially useful in the short term, necrosis and inflammation can lead to tumor promotion through upregulation of growth-promoting cytokines, including vascular endothelial growth factor (VEGF) and other consequences of wound healing (See Table 2). VEGF is one of the best known tumor enhancers and is correlated with poor outcomes. Increased increased levels of VEGF and other tumor-enhancing growth factors have been documented after TACE in multiple studies.3-7
| Table 2. Soluble Tumor-Promoting Factors Associated with Surgery and Ablation8-10 | ||
| PDGF | Platelet Derived Growth Factor (PDGF) enhances tumor growth and angiogenesis.11 | |
| EGF | Epidermal Growth Factor (EGF) binding to EGF receptors expressed in epithelial cancers is critical for tumor growth.12 Targeted agents blocking the action of EGF are important in current treatment regimens.13 | |
| TGF-A | Transforming Growth Factor – Alpha (TGF-A) promotes tumor growth via an autocrine loop.14,15 | |
| FGF | Fibroblast Growth Factor (FGF) is a tumor promoter16 and a vascular mitogen.17 | |
| TNF | Tumor Necrosis Factor (TNF) encompasses a family of proteins which induce immunosupression and tumor promotion.18 | |
| IL-1,6,8 | Interleukins involved in wound healing also promote tumor angiogenesis19, transformation, and tumor promotion.18,20 IL-6 is antiapoptotic and confers tumor cell protection.21 IL-1 also promotes metastases.22 | |
| TGF-ß | Transforming Growth Factor - Beta (TGF-ß) is associated with malignant progression and tumor promotion.23,24 | |
| VEGF | Vascular Endothelial Growth Factor (VEGF) induces tumor growth, survival, and angiogenesis. VEGF is also generally immunosuppressive and both promotes suppressive immune cell function and inhibition of effector cell action.25 | |
| PGe2 | Prostaglandin e2 (PDe2) promotes tumor progression by inducing myeloid suppressor cells.26 | |
Systemic Therapy
As mentioned earlier, no randomized controlled Phase 3 trials have been conducted to evaluate the best front-line therapy to recommend for patients with liver predominant disease—local or systemic.
In 2007, sorafenib became the first agent and only Phase 3-tested therapy approved by the FDA for HCC. The approval led to the publication of a number of papers recommending sorafenib as first line therapy for all inoperable patients with HCC. However, sorafenib was not compared to local therapy, but rather to a placebo, mostly in patients not eligible for local therapy. Therefore, there is uncertainty as to the role of sorafenib in patients who are eligible for either mode of treatment.27 Similarly, patients with MCRC involving the liver may be urged to undergo systemic chemotherapy combined with targeted agents even if they are eligible for local therapy or surgery (Table 3).
Given the absence of comparative trials, the conundrum of first line local versus systemic/combination therapy should be carefully evaluated in the context of what is known about liver function in patients with liver tumors. First, preservation of liver function is essential to patient well-being and quality of life. If liver replacement and destruction by tumor progresses unchecked, organ dysfunction leading to failure causes a distressing cascade of increasing symptoms, eventually resulting in death (See Table 4).
| Table 3. A Summary of the Major Systemic Agents Used against HCC and MCRC | ||
| Drug | Drug Action | |
| Sorafenib (Nevaxar, Bayer Healthcare) | Tyrosine kinase inhibitor | |
| 5-Fluorouracil/leucovorin | Thymidylate synthase inhibitor | |
| Oxaliplatin | Platinum alkylating agent | |
| Irinotecan | Topoisomerase inhibitor | |
| Bevacizumab (Avastin, Genentech/Roche) | VEGF binding antibody | |
| Cetuximab | Epidermal Growth Factor Receptor blocker | |
Against the backdrop of the need to preserve normal liver structure and cell function, existing local and systemic therapy is acknowledged to have the potential to worsen and in some cases precipitate liver failure. Sorafenib does not reduce the size of HCC and may worsen liver function, especially in Child-Pugh B class patients.28-30 Similarly, it is widely known that chemotherapy used in patients with MCRC causes different forms of hepatoxicity—in some cases increasing the risk of postoperative complications and liver failure.31-33 In the movement to expose patients to lines of chemotherapy with many toxic side effects immediately upon diagnosis, it is not clear what percentage of patients are made worse in an effort to downstage tumors for surgery.
The possible outcome of good quality of life combined with long-term survival is available only for R0 resective surgery, which may include liver transplant in the case of HCC patients. Unfortunately, only a small minority of patients are candidates for surgery, and of those, some may suffer complications and death as a direct result of surgery, with morbidity rates of up to 45% in MCRC patients.2 Even in the case of a successful operation, one of the largest contemporary surgical MCRC studies reported a 4% mortality rate at 30 days, an 8.2% mortality at 90 days, and a 5-year survival rate of only 25.5% in patients resected with intent to cure.34
| Table 4. Some Consequences of Progressive Liver Failure | ||
| • Cachexia (anorexia, weight loss) • Jaundice • Fatigue • Nausea/Vomiting • Ascites • Bleeding • Hepatic Encephalopathy • Coma • Death |
||
In the case of HCC, liver surgery, including partial and total hepatectomy (transplant) and local therapy is associated with a five-year survival as low as 40% for patients with early, limited disease.35 Patients with more advanced disease fare far worse, with much faster recurrence which cannot be prevented by adjuvant therapies.36
Emerging Role of Aptocine in Liver Cancer
Given the view that preservation of liver parenchyma is the primary therapeutic outcome that will lead to prolonged survival, Aptocine is being developed as a first-in-class directed therapy, which is currently undergoing two Phase 3 studies in patients with HCC and MCRC to liver. Both trials have active therapy comparator arms rather than a difficult-to-justify placebo arm in patients with advanced cancer and limited life expectancy. In addition to other current therapies, Aptocine potentially represents an option in treatment of liver cancer:
• Multiple synergistic mechanisms of action based on apoptosis (rather than necrosis)
• Direct cytoreduction which favorably affects the tumor microenvironment, followed by potential vaccine-like action
• Potential for a neoadjuvant role in resectable patients
• Lack of downstream or delayed tumor promotion effects
• Possible combination role with systemic therapy
• Lack of debilitating side effects even in seriously ill patients
Aptocine is a water-soluble drug targeted inside a tumor by a small, single-use, disposable drug activator included with the drug. The drug activator contains light-emitting diodes (LEDs). An energized Aptocine molecule results in the production of singlet oxygen, which can kill target tissues with minimal side effects through vascular closure and apoptosis. Illumination with low-intensity light can continuously energize each molecule of Aptocine, resulting in a constant supply of singlet oxygen molecules during the illumination period.
Importantly, Aptocine has been demonstrated in animals to stimulate the immune system to attack untreated tumors. Data from preclinical (Aptocine) and human studies have demonstrated that apoptosis occurring in tumors after light-activated drug therapies, yields tumor-specific clones of CD8+ T-cells that infiltrate distant, untreated tumors and destroy them. Human trials of Aptocine have produced images that demonstrate reduction or destruction of untreated tumors, consistent with a systemic immune effect. In contradistinction to chemotherapy, Aptocine has not been shown to be hepatotoxic.37,38 A favorable direct cytotoxic and delayed vaccine-like effect on tumor has been demonstrated in tumor models, which further supports an early role for Aptocine.39
Recent human studies have demonstrated tumor-antigen-specific immune response following light-activated drug therapy, and have additionally shown that the response is much stronger with low fluence rates, a unique feature of Aptocine.40
Conclusion
There are many distinct differences from the mechanisms of cell death, to toxicity profile, to delayed effects of Aptocine compared with standard ablative and systemic therapies used in liver cancers. The potential immune-modulating effects and lack of delayed tumor-promoting properties may justify positioning Aptocine as a potential primary intervention in a regimen including systemic therapy. Reduction of tumor mass which preserves functional liver, lack of evolving resistance, potential to prevent local and distant tumor recurrence through immunomodulation, and favorable safety constitute important features of Aptocine and its potential wide role for cancer of the liver.
About the Authors
Dr. Keltner leads LSO as it develops Aptocine, a first-in-class light-activated drug product for patients with solid tumor cancers. He is known for his expertise on the approval of new pharmacologic entities. Dr. Chen co-founded LSO and is focused on advancing the development of Aptocine for easy use by physicians to provide tolerable, effective and repeatable treatments to patients.
References
1. Bartlett DL, Di Bisceglie AM, Dawson LA. Cancer of the liver. In: DeVita VTJ, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology, ed. 8, vol. 1 Philadelphia: Lippincott Williams & Wilkins, 2008:1129-56.
2. Ribero D, Chun YS, Vauthey J-N. Surgery for colorectal metastases. In: Vauthey J-N, Hoff PMG, Audisio RA, Poston GJ, eds. Liver Metastases London: Springer-Verlag, 2009:25-38.
3. Li X, Feng GS, Zheng CS, Zhuo CK, Liu X. Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 2004;10(19):2878-82.
4. Momiyama K, Nagai H, Sumino Y. Changes of host immunity in relation to efficacy in liver cirrhosis patients with advanced hepatocellular carcinoma treated by intra-arterial chemotherapy. Cancer Chemother Pharmacol 2008.
5. Schwartz JD, Zuo Q, Lehrer D, Marcotrigiano MC, Gabrilove JL: Serum vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are increased following transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC) ASCO 2006 Gastrointestinal Symposium 2006:Abstract 218.
6. Sergio A, Cristofori C, Cardin R, Pivetta G, Ragazzi R, Baldan A, et al. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol 2008;103(4):914-21.
7. Shim JH, Park JW, Kim JH, An M, Kong SY, Nam BH, et al. Association between increment of serum VEGF level and prognosis after transcatheter arterial chemoembolization in hepatocellular carcinoma patients. Cancer Sci 2008;99(10):2037-44.
8. Branski RC, Sandulache VC, Dohar JE, Hebda PA. Mucosal wound healing in a rabbit model of subglottic stenosis: biochemical analysis of secretions. Arch Otolaryngol Head Neck Surg 2005;131(2):153-7.
9. De la Torre J, Sholar A, Stadelmann W, Wound healing, chronic wounds, Available at http://www.emedicine.com/plastic/TOPIC477.HTM, (2006).
10. Rosenberg LZ, de la Torre J, Wound healing, growth factors, Available at http://www.emedicine.com/plastic/TOPIC457.HTM, (2006).
11. Ng SS, MacPherson GR, Gutschow M, Eger K, Figg WD. Antitumor effects of thalidomide analogs in human prostate cancer xenografts implanted in immunodeficient mice. Clin Cancer Res 2004;10(12 Pt 1):4192-7.
12. Mendelsohn J. The epidermal growth factor receptor as a target for cancer therapy. Endocr Relat Cancer 2001;8(1):3-9.
13. Weekes CD, Hidalgo M. Targeted therapeutics in cancer treatment. In: Prendergast GC, Jaffe EM, eds. Cancer Immunotherapy: Immune Suppression and Tumor Growth Amsterdam: Elsevier, 2007:117-48.
14. El-Obeid A, Hesselager G, Westermark B, Nister M. TGF-alpha-driven tumor growth is inhibited by an EGF receptor tyrosine kinase inhibitor. Biochem Biophys Res Commun 2002;290(1):349-58.
15. Tang P, Steck PA, Yung WK. The autocrine loop of TGF-alpha/EGFR and brain tumors. J Neurooncol 1997;35(3):303-14.
16. Baird A, Mormede P, Bohlen P. Immunoreactive fibroblast growth factor (FGF) in a transplantable chondrosarcoma: inhibition of tumor growth by antibodies to FGF. J Cell Biochem 1986;30(1):79-85.
17. Seghezzi G, Patel S, Ren CJ, Gualandris A, Pintucci G, Robbins ES, et al. Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol 1998;141(7):1659-73.
18. Suganuma M, Okabe S, Marino MW, Sakai A, Sueoka E, Fujiki H. Essential role of tumor necrosis factor alpha (TNF-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice. Cancer Res 1999;59(18):4516-8.
19. Chen JJ, Yao PL, Yuan A, Hong TM, Shun CT, Kuo ML, et al. Up-regulation
of tumor interleukin-8 expression by infiltrating macrophages: its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer. Clin Cancer Res 2003;9(2):729-37.
20. Michiel DF, Oppenheim JJ. Cytokines as positive and negative regulators of tumor promotion and progression. Semin Cancer Biol 1992;3(1):3-15.
21. Lin MT, Juan CY, Chang KJ, Chen WJ, Kuo ML. IL-6 inhibits apoptosis and retains oxidative DNA lesions in human gastric cancer AGS cells through up-regulation of anti-apoptotic gene mcl-1. Carcinogenesis 2001;22(12):1947-53.
22. Apte RN, Dotan S, Elkabets M, White MR, Reich E, Carmi Y, et al. The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions. Cancer Metastasis Rev 2006;25(3):387-408.
23. Elliott RL, Blobe GC. Role of transforming growth factor Beta in human cancer. J Clin Oncol 2005;23(9):2078-93.
24. Jakowlew SB. Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev 2006;25(3):435-57.
25. Kim R. Cancer immunoediting: from immune surveillance to immune escape. In: Prendergast GC, Jaffe EM, eds. Cancer Immunotherapy : Immune Suppression and Tumor Growth Amsterdam: Elsevier, 2007:9-27.
26. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 2007;67(9):4507-13.
27. Abou-Alfa GK. Selection of patients with hepatocellular carcinoma for sorafenib. J Natl Compr Canc Netw 2009;7(4):397-403.
28. Abou-Alfa G, Llovet JM, Schwartz LH, Hepatocellular carcinoma: an in-depth look at local and systemic therapies, Available at http://www.medscape.com/viewprogram/9020_pnt, (2008).
29. Kane RC, Farrell AT, Madabushi R, Booth B, Chattopadhyay S, Sridhara R, et al. Sorafenib for the treatment of unresectable hepatocellular carcinoma. Oncologist 2009;14(1):95-100.
30. Witjes CD, Verhoef C, Verheul HM, Eskens FA. Systemic treatment in hepatocellular carcinoma; 'A small step for man...' Neth J Med 2009;67(3):86-90.
31. Alberts SR, Wagman LD. Chemotherapy for colorectal cancer liver metastases. Oncologist 2008;13(10):1063-73.
32. Chun YS, Laurent A, Maru D, Vauthey JN. Management of chemotherapy-associated hepatotoxicity in colorectal liver metastases. Lancet Oncol 2009;10(3):278-86.
33. Nordlinger B, Van Cutsem E, Gruenberger T, Glimelius B, Poston G, Rougier P, et al. Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel. Ann Oncol 2009.
34. Robertson DJ, Stukel TA, Gottlieb DJ, Sutherland JM, Fisher ES. Survival after hepatic resection of colorectal cancer metastases: a national experience. Cancer 2009;115(4):752-9.
35. Pleguezuelo M, Germani G, Marelli L, Xiruochakis E, Misseri M, Pinelopi M, et al. Evidence-based diagnosis and locoregional therapy for hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2008;2(6):761-84.
36. Bruix J, Llovet JM. Major achievements in hepatocellular carcinoma. Lancet 2009;373(9664):614-6.
37. Kujundzic M, Vogl TJ, Stimac D, Rustemovic N, Hsi RA, Roh M, et al. A Phase II safety and effect on time to tumor progression study of intratumoral light infusion technology using talaporfin sodium in patients with metastatic colorectal cancer. J Surg Oncol 2007;96(6):518-24.
38. Lustig RA, Vogl TJ, Fromm D, Cuenca R, Hsi AR, D'Cruz AK, et al. A multicenter Phase I safety study of intratumoral photoactivation of talaporfin sodium in patients with refractory solid tumors. Cancer 2003;98(8):1767-71.
39. Bromley E, Owczarczak B, Keltner L, Wang S, O. GS. Characterization of an Anti-Tumor Immune Response after Light-Activated Drug Therapy Using Talaporfin Sodium in a Spontaneously Metastasizing Mammary Tumor Model. Proceedings of ASCO Annual Meeting 2009:Abstract 3052.
40. Kabingu E, Oseroff AR, Wilding GE, Gollnick SO. Enhanced systemic immune reactivity to a Basal cell carcinoma associated antigen following photodynamic therapy. Clin Cancer Res 2009;15(13):4460-6.
