Current Status of Thalidomide in the Treatment of Cancer

Introduction

Thalidomide (Thalomid) has made a big comeback into clinical practice. It is actively being investigated for the treatment of a wide variety of malignant and nonmalignant conditions in the United States and around the world. Although the US Food and Drug Administration (FDA) has licensed thalidomide(Drug information on thalidomide) only for use in erythema nodosum leprosum (a type of immune reaction seen in leprosy), most prescriptions written today are for the treatment of various cancers, particularly multiple myeloma. Over the last 2 to 3 years, there has been a substantial increase in the number of studies of this agent for the treatment of cancer, and the results are being reported ongoingly. This article reviews the history, pharmacology, and current status of thalidomide in the treatment of cancer. Other related uses, including its role in the treatment of cancer cachexia, insomnia, and graft-vs-host disease, are beyond the scope of this review and are not discussed.

Brief Historical Background

Thalidomide was first introduced into clinical practice as a sedative. Beginning in the late 1950s, it was marketed in more than 40 countries. In the United States, the FDA was concerned about nerve damage and did not approve thalidomide for clinical use. In countries in which it was available, thalidomide became popular because of its association with good sleep quality and an unusually low risk of fatal overdose (unlike other sedatives marketed at the time).

Subsequently, thalidomide was found to be effective in the treatment of pregnancy-related morning sickness. Unfortunately, many women took thalidomide before its severe teratogenic potential was realized in 1961. As a result, almost 10,000 children worldwide were born with birth defects. The fetal malformations associated with thalidomide involved the extremities (phocomelia), ears, eyes, and the gastrointestinal tract.[1,2] Thalidomide was withdrawn from the market in 1962.

Pregnant women are vulnerable to its teratogenic effects between days 27 and 40 of gestation. The mechanism of its teratogenicity is unclear, but may be related to its antiangiogenic properties or inhibition of tumor necrosis factor-alpha (TNF-alpha) production.[3] Free-radical-mediated oxidative damage to DNA has also been postulated as a mechanism of its teratogenic effects.[4] A single pill (50 mg) may be sufficient to cause the teratogenic effects.

Despite its tragic past, thalidomide has reentered clinical practice due to its immunomodulatory and antiangiogenic properties. It was reported to be effective in the treatment of erythema nodosum leprosum in the mid-1960s.[5] Over the past 10 years, studies of thalidomide have confirmed its efficacy in the treatment of AIDS-related cachexia and aphthous ulcers. It has also been effective in the treatment of aphthous ulcers in patients with Behçet’s disease and in the treatment of chronic graft-vs-host disease. In 1998, the FDA approved thalidomide for use in erythema nosodum leprosum, with substantial precautions.

Early Clinical Trials of Thalidomide in Cancer

Thalidomide began to be studied as an anticancer agent within months of the discovery that it caused teratogenicity. In 1962, only 4 months after the initial reports of its severe teratogenicity, Rogerson questioned whether a drug with such remarkable inhibitory powers on growing tissues can be used as an anticancer agent.[6] Within a week, Woodyatt responded that he had used thalidomide to treat a woman with a malignant mixed mesodermal tumor of the uterus, and was waiting to see if it demonstrated any activity.[7]

Over the next few years, interest in studying the drug as an anticancer agent persisted, and led to the initiation of at least two trials in the early 1960s. The Eastern Cooperative Oncology Group (ECOG) administered thalidomide to 21 patients with 14 types of advanced cancer, at doses ranging from 600 to 2,000 mg/d.[8] Included in the ECOG study were two patients with multiple myeloma. Although no tumor responses were noted, significant subjective palliation of symptoms was seen in seven patients (33%). The researchers also noted that there probably was a slowing of tumor growth in two patients with rapidly progressive disease. They concluded that further study was warranted.

Grabstad and Golbey reported on 71 patients who received treatment with thalidomide for a variety of cancers.[9] Doses ranged from 300 to 2,000 mg/d. One patient with renal cell carcinoma achieved resolution of pulmonary metastases. No other responses were seen. In addition to these two published studies, there was at least one other investigation conducted in more than 100 patients with advanced cancer, which failed to show any response to thalidomide therapy.[8]

It is not clear whether the lack of response seen in these trials was due to the advanced stage of the disease in the patients receiving treatment or whether it was just a reflection of the inadequate imaging methods used to measure response. In any case, following the completion of these initial trials, interest in thalidomide as an anticancer agent diminished greatly.

Tumor Angiogenesis

Angiogenesis—the formation of new blood vessels—occurs physiologically during embryonal growth, wound healing, and in the female genital system during the menstrual cycle. Angiogenesis is critical for the proliferation and metastases of most malignant neoplasms.[10] In the absence of angiogenesis, tumors cannot grow beyond 1 to 2 mm in size.[10] Increased angiogenesis is an adverse prognostic factor in several tumors, including hematologic malignancies such as myeloma.[11-15]

Over the past few years, there has been a marked interest in tumor angiogenesis, especially after the discovery of angiostatin and endostatin, two potent antiangiogenic compounds.[16,17] Enthusiasm for studying thalidomide as an anticancer agent has paralleled the increased interest in tumor angiogenesis due to reports suggesting that the drug possessed potent antiangiogenic properties.[18]

Thalidomide Therapy in Multiple Myeloma

Single-Agent Therapy in Relapsed Myeloma

Singhal and colleagues at the University of Arkansas conducted the first trial investigating the activity of thalidomide in relapsed myeloma.[19] Most patients in this study had failed stem cell transplantation. Treatment consisted of oral doses of thalidomide at 200 mg/d initially for 2 weeks, then increased by 200 mg/d every 2 weeks, up to a maximum daily dose of 800 mg/d, depending on toxicity. The overall response rate was 32%. Median time to response was 1 month. Approximately 10% of patients achieved ³ 90% reduction in paraprotein levels. Paraprotein responses were accompanied by improvements in anemia and other symptoms.

Among the 48 patients who underwent repeat bone marrow analysis after thalidomide therapy, 81% had confirmation of paraprotein responses. The best predictor of response was a plasma cell labeling index < 0.2. Median duration of response had not been reached after 14.5 months of follow-up. Considering that 90% of patients in this study had failed transplantation, these results are impressive. An update to this study confirmed the activity of thalidomide in 169 patients with relapsed myeloma.[20,21] Overall survival at 18 months was 55%, and event-free survival was 30%.

We reported on 16 patients with relapsed myeloma treated at the Mayo Clinic on a similar schedule of thalidomide.[22,23] Of these patients, 25% had failed prior stem cell transplantation; 88% had received two or more chemotherapy regimens prior to beginning thalidomide therapy, including 25% who had failed four or more regimens. Four patients (25%) achieved a partial response to therapy, thus confirming the initial results obtained at the University of Arkansas. A larger Mayo Clinic phase II study of thalidomide in relapsed myeloma reconfirmed these findings.[24]

Several other groups have also demonstrated the single-agent activity of thalidomide in relapsed and refractory myeloma.[21, 23-34] Table 1 summarizes the results of the major trials of single-agent thalidomide in relapsed myeloma.[21,23-34] Response rates ranged from 25% to 75%. Based on the evidence thus far, thalidomide can clearly be recommended for the treatment of relapsed myeloma, although the FDA has not yet approved it for this indication.

Combination Therapy in Relapsed Myeloma

Ongoing studies are assessing the efficacy of thalidomide in combination with other effective agents for myeloma (Table 2).[33,35,36] In one investigation conducted by Weber and colleagues, 24 of 47 patients (52%) with resistant myeloma responded to the combination of thalidomide and dexamethasone(Drug information on dexamethasone).[35] Single-agent therapy with dexamethasone and thalidomide had previously failed in many (46%) of these patients, suggesting a synergistic effect with this combination.

Barlogie and colleagues have used thalidomide in a combination chemotherapy regimen known as DT-PACE (dexamethasone, thalidomide, cisplatin(Drug information on cisplatin) [Platinol], doxorubicin [Adriamycin], cyclophosphamide(Drug information on cyclophosphamide) [Cytoxan, Neosar], etoposide) for patients with aggressive myeloma and plasma cell leukemia.[37] Responses were observed in four of five patients, including three who achieved a complete response. Updated results reported for 43 patients indicate a 40% response rate after two cycles of therapy, and no unfavorable effects on subsequent stem cell harvest.[38]

Coleman and colleagues are studying the combination of thalidomide, low-dose dexamethasone, and clarithromycin(Drug information on clarithromycin) (Biaxin). Preliminary results show significant activity.[36] More data are needed, however, and the role of clarithromycin in the combination needs to be clarified. Kropff and colleagues are evaluating a combination of hyperfractionated cyclophosphamide, pulsed dexamethasone, and thalidomide.[39]

Previously Untreated Myeloma

Given the activity of thalidomide in relapsed myeloma, studies are now evaluating the effect of this agent as first-line therapy in previously untreated patients with myeloma (Table 1). Preliminary results from an ongoing Mayo Clinic study showed that the combination of thalidomide and dexamethasone is very active in this setting, with a response rate of 77%.[33] The initial protocol called for escalation of the dose of thalidomide up to 800 mg/d. However, among the first seven patients treated, two developed grade 3/4 skin toxicity including one patient with toxic epidermal necrolysis.[40] The protocol was then amended to stop dose escalation of thalidomide, and keep the dose constant at 200 mg for the subsequent 19 patients studied.

Major grade 3/4 toxicities included the development of a rash in three patients, and syncope, sedation, constipation, arrhythmia, and myalgia in one patient each. This regimen may be an appropriate oral alternative to infusional chemotherapy with VAD (vincristine, doxorubicin(Drug information on doxorubicin) [Adriamycin], dexamethasone) as initial treatment of myeloma in preparation for stem cell transplantation. However, these results are preliminary and require further confirmation.

ECOG is developing a randomized trial of thalidomide plus dexamethasone vs dexamethasone alone in newly diagnosed symptomatic myeloma. This study will help confirm the activity of combination therapy with thalidomide plus dexamethasone in previously untreated myeloma and determine if there is any significant excess toxicity associated with this regimen. An ongoing randomized study at the University of Arkansas is investigating whether the addition of thalidomide to a chemotherapy regimen has a role in the management of newly diagnosed myeloma, and whether thalidomide has a role in posttransplant maintenance.

Thalidomide is also being studied as a single agent in patients with previously untreated asymptomatic myeloma. Initial reports show a response rate of approximately 35%.[33,34] However, because the main goal of therapy in patients with smoldering and indolent myeloma is to delay the need for chemotherapy, more data on the durability of response are needed before this strategy can be recommended for standard clinical practice. Moreover, the effect of prolonged thalidomide therapy on stem cell harvest is unknown.

Summary of Thalidomide Therapy in Myeloma

It is clear from the data discussed above that thalidomide is effective in the treatment of relapsed and refractory myeloma. In patients who are refractory to thalidomide, the addition of dexamethasone may induce a response, even if patients have previously failed steroid therapy. Studies are ongoing to define the role of thalidomide alone or in combination with other chemotherapeutic agents or dexamethasone in previously untreated myeloma. In light of toxicity concerns, previously untreated patients should receive thalidomide therapy primarily in the context of carefully conducted clinical trials. Further studies are needed to determine whether thalidomide has a role in maintenance therapy following transplantation.