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Thalidomide for advanced hepatocellular carcinoma†
Is this a real alternative?
Article first published online: 24 NOV 2004
Copyright © 2004 American Cancer Society
Volume 103, Issue 1, pages 1–4, 1 January 2005
How to Cite
Wadler, S. (2005), Thalidomide for advanced hepatocellular carcinoma. Cancer, 103: 1–4. doi: 10.1002/cncr.20731
See referenced original article on pages 85–91, this issue.
- Issue published online: 17 DEC 2004
- Article first published online: 24 NOV 2004
- Manuscript Accepted: 31 AUG 2004
- Manuscript Revised: 26 AUG 2004
- Manuscript Received: 12 AUG 2004
Cancer of the liver, or hepatocellular carcinoma (HCC), is one of the most common malignancies worldwide; however, in the United States in 2004, it is an uncommon and poorly understood disease.1 Several factors account for this lack of understanding. First, HCC is a heterogeneous disease: for example, patients with alcoholic cirrhosis differ demographically from those who have hepatitis C or hepatitis B; in addition, some affected patients are drug abusers, whereas others find out on routine screening that they have abnormal liver functioning despite the fact that they have never used drugs. Second, HCC affects an economically diverse population, and thus, only a subset of patients with this disease have excellent insurance and social support. Third, HCC encompasses a wide range of natural histories, with some patients living many years despite a short overall median survival. (Along the same lines is the example of patients with carcinoma of the pancreas and patients with carcinoma of the biliary ducts; both of these sets of patients have short median survival durations, but there are more long-term survivors in the latter group.) Fourth, the etiology of HCC is complex. Some patients present with cryptogenic cirrhosis, some present with chronic active hepatitis, and some present with no underlying liver disease. Finally, patients who present with HCC in Asia, Europe, or South America tend to have very different presentations and natural histories compared with patients in the United States. Thus, it is difficult to define a typical population of patients with HCC. Consequently, the results of clinical trials are often, but not always, unreproducible, and there is much controversy regarding the optimal management of patients with hepatic carcinoma.
Liver transplantation should be included in the initial management of patients with small tumors who are candidates for this procedure. In a trial conducted by the National Cancer Institute of Italy in 1996.2 the role of orthotopic liver transplantation was studied in 48 patients with cirrhosis and small, unresectable HCC. After 4 years, the actuarial survival rate was 85%, and the recurrence-free survival rate was 92%. Those authors concluded that liver transplantation was an effective treatment for small, unresectable HCC in patients with cirrhosis. Two additional reviews have confirmed these original findings in larger subsets of patients.3, 4
In a survey of randomized, controlled clinical trials, among patients who were not immediate candidates for liver transplantation, arterial embolization improved 2-year survival compared with a control group (P = 0.017). Those authors concluded that chemoembolization improved survival and could become a standard treatment option.5–7
There may be survival benefits associated with other locoregional therapeutic options, such as wedge resection, radiofrequency ablation, and cryoablation, although if such benefits are present, they are very small.7 Ablative therapies, however, are effective temporizing measures while patients await liver transplantation.
Systemic therapy is the treatment of last resort for patients with metastatic HCC. A recent review of multiple Phase II and III trials detected no reproducible benefit associated with systemic therapy in patients with metastatic hepatic carcinoma.8 In that review, the authors recommended a no-treatment control group for Phase III trials. This recommendation may not be readily enforceable, however, because patients, at least in the United States, tend to be offered a choice of therapeutic options, even if one option offers questionable benefits and the other is experimental. A current review of agents in Phase II–III testing is shown in Table 1 and indicates the diversity of experimental and targeted agents that are available for patients with HCC.
|Epirubicin and celecoxib||COX-2 inhibitors|
|TAC 101||Retinoid, antiangiogenetic agent|
|PHY906 and capecitabine||Herb, antimetabolite|
|Flavopiridol and CPT-11||Antimitotic agent, topoisomerase I|
|Thalidomide and epirubicin||Antiangiogenesis, antimetabolite|
|Oblimerson and doxorubicin||Anti-Bcl-2 and antimetabolite|
Thalidomide, which is not on the list, was formerly used as a soporific agent for pregnant women in the 1960s, until it was found to be associated with profound perinatal defects, including limbless births. Thalidomide is known best as a major teratogen that caused birth defects in up to 12,000 children in the 1960s.9 It was shown that thalidomide inhibited growth factor–induced neovessel formation, a process that can explain its earlier devastating clinical toxicity. It is administered orally and is currently in multiple Phase II clinical trials.10
Thalidomide has unpredictable toxicities. It is a racemic glutamic acid analogue consisting of S(−) and R(+) enantiomers that interconvert under physiologic conditions.11 Whereas S(−) inhibits the release of tumor necrosis factor-α, the R(+) form acts as a sedative. At pH 7.0, thalidomide is degraded to 20 different products, all acting with different mechanisms; unfortunately, this characteristic cannot be invoked to explain the multiplicity of toxicities and anticancer effects associated with the drug.
It is believed that thalidomide exerts its therapeutic properties through the modulation of cytokines, particularly tumor necrosis factor-α, interferon, interleukins 10 and 12, cyclooxygenase 2, and nuclear factor κB. (For a more complete discussion, see Franks et al.11) In addition, thalidomide may have potent antiangiogenic activity.
Thalidomide has exhibited clinical activity against multiple myeloma, and it has been approved by the U.S. Food and Drug Administration for this indication. Recent evidence suggests that angiogenesis is increased in multiple myeloma and that the extent of angiogenesis has prognostic value for patients with this disease.12 Angiogenic cytokines, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, are expressed by myeloma cells and appear to play a role in the increased angiogenesis seen in myeloma. In addition, VEGF may serve as a paracrine growth factor for myeloma cells. Although its mechanism of action remains unclear, thalidomide appears to be active in 25–30% of patients with refractory myeloma. Major toxicities include constipation, sedation, rash, fatigue, and peripheral neuropathy. Studies are ongoing to determine the role of thalidomide as initial treatment and in combination regimens for the treatment of myeloma.
With regard to other malignancies, thalidomide has been studied in Waldenstrom macroglobulinemia, myelodysplastic syndromes, acute myeloid leukemia, myelofibrosis with myeloid metaplasia, renal cell carcinoma, malignant glioma, prostate carcinoma, Kaposi sarcoma, colorectal carcinoma, and HCC, among others. Although thalidomide has had reproducible, if modest, activity against a variety of plasma cell dyscrasias and low-grade lymphomas, this activity has not been reproducible in refractory solid tumors.
In this issue of Cancer, Lin et al.13 report the results of a Phase II trial of thalidomide in patients with refractory HCC. The trial was a joint project of the Santa Clara Valley Medical Center (San Jose, CA) and the Stanford University School of Medicine (Stanford, CA). Twenty-six patients with HCC were studied. Toxicities included Grade 3–4 somnolence (26%) and Grade 3–4 liver function abnormalities (> 40%). There was only 1 responder among 26 patients in the study cohort. Thus, the study confirms the original findings of Patt et al.,14 Kong et al.,15 Feun et al.,16 and Schwartz et al.,17 who showed that thalidomide lacks clinical activity in HCC and has relatively increased toxic effects. One caveat to this statement is that several investigators, particularly in Asia, have noted prolonged stabilization of disease in response to thalidomide treatment, a finding that has increased the level of enthusiasm for the use of this agent.
What is the importance of the study conducted by Lin et al.? At many institutions, thalidomide is routinely offered to patients with HCC in lieu of enrollment into clinical trials. Perceived as an oral agent that is relatively nontoxic and possesses some clinical activity (enough for entry into a clinical trial), thalidomide is a convenient alternative to treatment with cytotoxic agents. The problems with these assumptions are numerous. First, the drug is only marginally active; thus, patients will receive weeks of treatment that is unlikely to induce a tumor response or prolong progression-free or overall survival. Second, the drug is toxic, in that it is highly soporific and constipation inducing; in fact, one trialist at the University of Arkansas18 used thalidomide in combination with irinotecan to prevent diarrhea and succeeded. Third, off study, the drug is paid for at least in part by the patient, and there is no reimbursement to the institution for data management; in contrast, in industry-sponsored or Cancer Therapy Evaluation Program–sponsored trials, participating institutions can receive > $4000 per patient enrolled. Therefore, a process of reeducation is in order.
The article by Lin and colleagues serves as an important course correction for the academic oncologist. Assuming that the investigator understands that the drug is inactive, what alternatives are there for treating the patient? Patients can always be enrolled in clinical trials if they are willing to travel or if they have access to a large, academic medical center. This does not apply to all patients, however. Patients who are too sick or too unmotivated to enroll in a clinical trial can be treated by their local oncologist, although certain considerations must be heeded. For example, not all patients require treatment with a cytotoxic agent. Doxorubicin and interferon α have definite clinical activity against HCC, but at the cost of substantial toxicity. Capecitabine may be a reasonable, less toxic alternative, but it does not have a well established track record. As was reported by Lin and colleagues, targeted therapy options, unfortunately, remain untested or inactive in the setting of HCC and probably should not be offered routinely until better data are available. Another point to be considered is that the treating physician can always offer palliative care, including either inpatient or outpatient hospice care, pain control, nutritional support, and psychosocial support, to patients who reject these options. As discussed above, Nowak et al.8 noted that no-treatment control arms represented a reasonable option in HCC studies, although most patients would not necessarily choose such an option.
Future options include additional clinical trials involving thalidomide in combination with other drugs. More potent thalidomide derivatives, called IMiDs, also are being made available for clinical trials by Celgene (Warren, NJ) and others.19, 20 Such compounds may be more active and less toxic than the parent compound and may offer additional benefits that are not available with thalidomide. More active antiangiogenesis agents, such as bevacizumab, are being evaluated as well, and some are currently being tested in clinical trials. Translational studies aimed at gaining a better understanding of the molecular biology of HCC also are warranted, as is the testing of other targeted agents with potential activity against this uncommon but deadly disease.
- 14Phase II trial of Thalomid (thalidomide) for treatment of non-resectable hepatocellular carcinoma (HCC) [abstract]. Proc Am Soc Clin Oncol. 2000; 19: 266a., , , et al.
- 15Thalidomide in hepatocellular cancer with optional interferon-α upon progression [abstract]. Proc Am Soc Clin Oncol. 2003; 22: 301., , , , , .
- 16Phase II trial of thalidomide in unresectable hepatocellular carcinoma (HCC): a cancer therapeutics research study. Proc Am Soc Clin Oncol. 2001; 20: Abstract 2282., , , et al.
- 17Thalidomide as palliative care for patients with unresectable hepatocellular carcinoma. Proc Am Soc Clin Oncol. 2003; 22: 216., , , et al.