Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer

Abstract

To grow and metastasize, solid tumours must develop their own blood supply by neo-angiogenesis. Thalidomide inhibits the processing of mRNA encoding peptide molecules including tumour necrosis factor-alpha (TNF-α) and the angiogenic factor vascular endothelial growth factor (VEGF). This study investigated the use of continuous low dose Thalidomide in patients with a variety of advanced malignancies. Sixty-six patients (37 women and 29 men; median age, 48 years; range 33–62 years) with advanced measurable cancer (19 ovarian, 18 renal, 17 melanoma, 12 breast cancer) received Thalidomide 100 mg orally every night until disease progression or unacceptable toxicity was encountered. Three of 18 patients with renal cancer showed partial responses and a further three patients experienced stabilization of their disease for up to 6 months. Although no objective responses were seen in the other tumour types, there were significant improvements in patients' sleeping ( P < 0.05) and maintained appetite ( P < 0.05). Serum and urine concentrations of basic fibroblast growth factor (bFGF), TNF-α and VEGF were measured during treatment and higher levels were associated with progressive disease. Thalidomide was well tolerated: Two patients developed WHO Grade 2 peripheral neuropathy and eight patients developed WHO grade 2 lethargy. No patients developed WHO grade 3 or 4 toxicity. Further studies evaluating the use of Thalidomide at higher doses as a single agent for advanced renal cancer and in combination with biochemotherapy regimens are warranted. © 2000 Cancer Research Campaign

A phase II trial of thalidomide in patients with refractory endometrial cancer and correlation with angiogenesis biomarkers: A Gynecologic Oncology Group study

“…Bertolini showed reductions in VEGF and bFGF levels which corresponded to clinical response in patients with multiple myeloma treated with thalidomide [13]. However, in a phase II study of low dose thalidomide (100 mg/day) to treat 66 patients with advanced renal cell carcinoma, melanoma, ovarian cancer, or breast cancer, no relationship was seen between serum VEGF or bFGF levels and treatment or response [36]. In an effort to better understand the role of angiogenesis in endometrial cancer, serum and plasma levels of VEGF and bFGF were measured prior to and after 4-6 weeks of thalidomide.…”

Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU‐68)

“…13 At the clinical level, a Phase I study of the natural sterol squalamine, 32 and Phase II studies of the T cell-and NK cell-regulating factor IL-12, 33 carboxyamidotriazole (a factor inhibiting transmembrane calcium influx in vascular endothelial cells) 34 and thalidomide (known as a phocomeliacausing drug and having powerful antiangiogenic activity) 35 have been reported. It has been confirmed that these molecular-targeting agents have tumor growth-suppressive activity and antiangiogenic activity in subcutaneous tumor models.…”

“…13 Tolerability to the 4 drugs at the Phase I and II clinical trial stages has been confirmed. [32][33][34][35] Single-agent IL-12 has a low response rate in recurrent ovarian cancer patients, 33 however, and single-agent carboxyamidotriazole has no tumor-regression activity, only suppressing tumor progression. 34 Because moleculartargeting therapy alone is limited to the tumor-regression effect, it is clinically used in combination with conventional anticancer drugs.…”

“…There have been few reports on severe side effects of angiogenesis inhibitors, unlike conventional anticancer drugs, because of their functional specificity. 19,[33][34][35]41,42 It is speculated that because angiogenesis inhibitors target normal cells such as vascular endothelial cells, but not cancer cells themselves, induction of resistance to them does not develop easily. 43 Therefore, as a therapeutic strategy using angiogenesis inhibitors such as SU6668 for ovarian cancer, long-term administration aimed at the prevention of recurrence after remission induction therapy may be useful.…”

Oesophageal cancer and cachexia: the effect of short‐term treatment with thalidomide on weight loss and lean body mass

“…26 Eisen et al used low-dose thalidomide as an anti-angiogenic agent in patients with advanced melanoma, ovarian and breast cancer. 27 Thalidomide has a direct effect on the cancer tissue itself through its anti-angiogenic properties. Tumour size reduction in implanted human oesophageal cancer in an animal model has been shown.…”