Response to “Acute Tumor Lysis Syndrome After Thalidomide Therapy in Advanced Hepatocellular Carcinoma”
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《肿瘤学家》
I read with great interest the report by Lee and colleagues, illustrating the development of tumor lysis syndrome (TLS) following thalidomide (Thalomid®; Celgene Corporation, Warren, NJ) treatment in a patient with advanced hepatocellular carcinoma (HCC). To my knowledge, this is the first reported case of TLS with thalidomide in any solid tumors.
Thalidomide has an unpredictable toxicity profile and poorly understood mechanisms of action. Under physiologic conditions, it is a racemic glutamic acid analogue consisting of S(–) and R(+) enantiomers that interconvert. In addition, it can be degraded into 20 different products, all with different mechanisms of action. Unfortunately, this characteristic cannot be invoked to explain the multiplicity of toxicities and anticancer effects associated with the drug. Thalidomide might exert its therapeutic properties through its antiangiogenic activity and modulation of cytokines, including tumor necrosis factor- interferon, interleukins 10 and 12, cyclooxygenase-2, and nuclear factor B.
Because of the concern for unpredictable toxicity in individual patients, we elected to use a lower starting daily dose of thalidomide, at 200 mg, in our study, allowing intra-patient dose escalation if tolerated. This may explain, at least in part, the generally good tolerability to thalidomide in our study patients.
HCC is a very heterogeneous disease in terms of etiology and underlying liver disease as well as biological and clinical behavior. Patients with HCC in Asia and other parts of the world may have different clinical presentations and natural histories than patients in the U.S. Although systemic chemotherapy for HCC has a poor track record, with a low response rate and no improvement in overall survival, TLS has been reported previously following chemoembolization and experimental therapy [1, 2]. For patients with large HCCs, no significant underlying cirrhosis, and new onset of presentation, the concern for TLS should be raised, and patients should be monitored vigilantly while undergoing treatment either on or off clinical studies.
The limited activity of thalidomide coupled with its unpredictable and potentially life-threatening toxicity, as shown in this case, strongly argue against the routine use of thalidomide in HCC off clinical study. As has been commented previously [3], oncologists should resist the temptation to use thalidomide as a routine alternative in HCC. It is imperative to identify more active and tolerable systemic agents and regimens for this deadly disease through vigorous clinical research.
REFERENCES
Burney IA. Acute tumor lysis syndrome after transcatheter chemoembolization of hepatocellular carcinoma. South Med J 1998;91:467–470.
van der Graaf WT, Zijlstra JG, de Vries EG et al. In vitro and in vivo studies on the action of BW502U83, an arylmethylaminopropanediol. Anti-cancer Drugs 1995;6:34–39.
Wadler S. Thalidomide for advanced hepatocellular carcinoma: is this a real alternative? Cancer 2005;103:1–4.(Andrew X. Zhu)
Thalidomide has an unpredictable toxicity profile and poorly understood mechanisms of action. Under physiologic conditions, it is a racemic glutamic acid analogue consisting of S(–) and R(+) enantiomers that interconvert. In addition, it can be degraded into 20 different products, all with different mechanisms of action. Unfortunately, this characteristic cannot be invoked to explain the multiplicity of toxicities and anticancer effects associated with the drug. Thalidomide might exert its therapeutic properties through its antiangiogenic activity and modulation of cytokines, including tumor necrosis factor- interferon, interleukins 10 and 12, cyclooxygenase-2, and nuclear factor B.
Because of the concern for unpredictable toxicity in individual patients, we elected to use a lower starting daily dose of thalidomide, at 200 mg, in our study, allowing intra-patient dose escalation if tolerated. This may explain, at least in part, the generally good tolerability to thalidomide in our study patients.
HCC is a very heterogeneous disease in terms of etiology and underlying liver disease as well as biological and clinical behavior. Patients with HCC in Asia and other parts of the world may have different clinical presentations and natural histories than patients in the U.S. Although systemic chemotherapy for HCC has a poor track record, with a low response rate and no improvement in overall survival, TLS has been reported previously following chemoembolization and experimental therapy [1, 2]. For patients with large HCCs, no significant underlying cirrhosis, and new onset of presentation, the concern for TLS should be raised, and patients should be monitored vigilantly while undergoing treatment either on or off clinical studies.
The limited activity of thalidomide coupled with its unpredictable and potentially life-threatening toxicity, as shown in this case, strongly argue against the routine use of thalidomide in HCC off clinical study. As has been commented previously [3], oncologists should resist the temptation to use thalidomide as a routine alternative in HCC. It is imperative to identify more active and tolerable systemic agents and regimens for this deadly disease through vigorous clinical research.
REFERENCES
Burney IA. Acute tumor lysis syndrome after transcatheter chemoembolization of hepatocellular carcinoma. South Med J 1998;91:467–470.
van der Graaf WT, Zijlstra JG, de Vries EG et al. In vitro and in vivo studies on the action of BW502U83, an arylmethylaminopropanediol. Anti-cancer Drugs 1995;6:34–39.
Wadler S. Thalidomide for advanced hepatocellular carcinoma: is this a real alternative? Cancer 2005;103:1–4.(Andrew X. Zhu)