The treatment of advanced renal cell cancer with high-dose oral thalidomide

Stebbing, Justin; Benson, Charlotte; Eisen, Tim; Pyle, L; Smalley, Keiran S.M.; Bridle, Helen; Mak, Ian; Sapunar, Francisco; A’Hern, Roger; Gore, Martin

doi:10.1054/bjoc.2001.2025

Cited by 93 publications

(23 citation statements)

References 34 publications

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“…48 The initial positive responses observed as well as the small patient number inherent in the Phase I trial prompted investigation of thalidomide/IL-2 combination therapy into a larger Phase II analysis. An additional 37 Phase II patients were treated with the determined MTD combination of thalidomide at 400 mg and low-dose IL-2 (7 mIU/m 2 ) to preserve activity, while limiting adverse (46) events typically associated with either agent. 49 Grade 3/4 flu-like symptoms, fluid retention, hypotension, nausea/emesis, and diarrhea have been reported previously with high-dose IL-2 therapy, 23,50 and somnolence, constipation, rash, and neuropathy are associated with thalidomide treatment.…”

Section: Discussionmentioning

confidence: 99%

Phase I/II study of thalidomide in combination with interleukin‐2 in patients with metastatic renal cell carcinoma

Amato

Morgan

Rawat

2006

Cancer

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BACKGROUNDThe purpose of the study was to determine, in a Phase I/II study, the efficacy and safety profile of thalidomide with interleukin‐2 (IL‐2) in patients with metastatic renal cell carcinoma (MRCC).METHODSFifteen patients (8 of whom were previously treated) enrolled in Phase I were treated with escalating doses of oral thalidomide (200–600 mg) and a fixed dose of IL‐2 (7 mIU/m2) by subcutaneous injection. A course was 6 weeks, with the exception of Course 1, which was 7 weeks. Thirty‐seven Phase II patients who had not received prior chemotherapy or immunotherapy for renal cell carcinoma (RCC) received an initial thalidomide dose of 200 mg at Week 0, which was escalated to 400 mg after 48 hours. Subcutaneous IL‐2 was administered at the same fixed daily dose used in Phase I.RESULTSFifty‐one of 52 Phase I/II patients were evaluable. Twenty‐seven patients (52%) experienced disease control, including 4 (8%) complete responses, 15 (29%) partial responses, and 8 (15%) cases of stable disease. Disease progression was observed in 24 patients (47%). Survival in the 2 phases ranged from 4 weeks to 45.2+ months. At the time of last follow‐up, 2 of 51 patients (4%) remained on maintenance thalidomide therapy and continue to be followed. Three of the 51 patients with CRs (6%) ceased thalidomide therapy at 23–25 months and have maintained their responses to date. One complete responder was lost to follow‐up. As of January 2005, 14 of 51 patients (27%) remained alive. Toxicities were mild to moderate, including Grade 1 to 2 somnolence, constipation, neuropathy, rash, flu‐like symptoms, fluid retention, hypotension, and hypothyroidism (according to version 2.0 of National Cancer Institute Common Toxicity Criteria). In addition, two patients experienced deep venous thrombosis.CONCLUSIONSThalidomide in combination with IL‐2 is tolerable and can produce durable, active responses in patients with MRCC. To evaluate the merits of thalidomide as a valuable agent against MRCC and to more fully determine the efficacy of thalidomide/IL‐2 combination therapy, the scrutiny of Phase III testing is required. Further development of thalidomide/IL‐2 combination therapy will be the focus of this group. Cancer 2006. © 2006 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Phase I/II study of thalidomide in combination with interleukin‐2 in patients with metastatic renal cell carcinoma

Amato

Morgan

Rawat

2006

Cancer

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“…Thalidomide [a(N-phthalimido)-glutarimide, a derivative of glutamic acid with two rings and two optically active forms] is an odorless, white crystalline compound with low solubility in water and has a cytotoxic effect on a number of cancer cell lines, including breast cancer (3,4).…”

Section: Introductionmentioning

confidence: 99%

DMSO exhibits similar cytotoxicity effects to thalidomide in mouse breast cancer cells

Aydemir

Fışkın

2012

Oncol Lett

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Abstract. The purpose of this study was to evaluate the cytotoxic effect of thalidomide on 4T1 and 4THMpc mouse breast cancer cell lines. Mouse breast cancer cells (4T1) and cells derived from metastatic lesions (4THMpc) were treated with various doses of thalidomide [10 -2 -100 µM dissolved in dimethyl sulfoxide (DMSO) as recommended] and 1.4 µM DMSO (maximum DMSO concentration in the highest thalidomide dose) as a DMSO control against the untreated control groups. MTT was used to evaluate the cytotoxic effects of the treatments. Therefore, we investigated the role of thalidomide on apoptosis. A fluorometric EnzChek caspase-3 enzyme activity assay kit was used to evaluate the apoptotic effects of thalidomide. Thalidomide dissolved in DMSO exhibited cytotoxic effects on 4T1 and 4THMpc cells compared to the control groups incubated without any supplement. Treatment with thalidomide resulted in apoptosis of mouse breast cancer cells in a time-and dose-dependent manner as demonstrated by caspase-3 enzyme activity. However, DMSO alone suppressed cell proliferation more effectively than thalidomide. In cultured mouse breast cancer cells the inhibitory effect of thalidomide may be partially attributed to the solvent DMSO alone. IntroductionBreast cancer, which is the second leading cause of cancer mortality in women, occurs at a high frequency (1). Although there have been significant advances in diagnosing and treating breast cancer, a number of major unresolved clinical and scientific problems remain and investigations are ongoing (2).Thalidomide [a(N-phthalimido)-glutarimide, a derivative of glutamic acid with two rings and two optically active forms] is an odorless, white crystalline compound with low solubility in water and has a cytotoxic effect on a number of cancer cell lines, including breast cancer (3,4).Thalidomide has been shown to be clinically useful in a number of situations due to its ability to inhibit TNF-α synthesis. However, its use is restricted by potentially serious side effects, including teratogenicity (5). Furthermore, insolubility may cause serious problems in terms of systemic bioavailability. The major solvent of thalidomide is dimethyl sulfoxide (DMSO) and it has been shown to mimic the cytotoxic effects of thalidomide (6).The aim of this study was to evaluate the effect of thalidomide and DMSO on the viability of cultured 4T1 and 4THMpc mouse breast cancer cell lines. Materials and methodsThalidomide. Thalidomide was purchased from SigmaAldrich (Cat. No. T 144; St. Louis, MO, USA). A 100 µM stock solution dissolved in DMSO (14.08 mM) was prepared and then the solution was aliquoted into standard Eppendorf tubes in quantities of 500 µl for daily assays. These aliquots were stored at -70˚C until required.Cell lines and in vitro cell culture conditions. 4T1 breast cancer cells and 4T1 heart metastases post capsaicin (4THM), a cell line obtained from orthotopically transplanted 4T1 breast cancer cells, were used in this study. The cell lines were a kind gift from Dr Nuray Erin (Akdeniz Unive...

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“…Alternative approaches have included the use of thalidomide; although its effect on this disease remains unclear, occasional dramatic responses have been seen (Stebbing et al, 2001). It has been suggested that this works as an antiangiogenic agent, although direct proof of this is lacking.…”

Section: Discussionmentioning

confidence: 99%

IPM chemotherapy in cytokine refractory renal cell cancer

et al. 2003

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Renal cell carcinoma (RCC) is notoriously chemoresistant. Current management of metastatic disease usually includes immunological agents of which the most clearly evaluated is alpha interferon. Following the failure of such agents no clear second-line therapy exists. The use of a novel combination of cisplatin, irinotecan and mitomycin may offer some palliative benefit in this situation. Thirty-three patients with cytokine refractory RCC and documented progression and documented active progressive disease with performance status 0 -3 were enrolled. Therapy consisted of cisplatin 40 mg m À2 on day 1 and day 15, irinotecan 100 mg m À2 on day 1 and day 15, and mitomycin 6 mg m À2 on day 1 of a 28-day cycle. The results showed that one patient (3%) had a partial response, eight (24%) had minor responses and nine (27%) had stable disease, overall 61% had symptomatic responses. Quality-of-life (QOL) assessment did not change significantly during therapy. Seventy-one percent of those who had primary refractory disease to cytokine therapy subsequently responded to IPM. The median progression-free interval was 4.8 months in this cohort on chemotherapy, compared to 3.9 months with their previous cytokine treatment. In conclusion, IPM produced symptomatic relief for a majority of patients with cytokine refractory RCC without any deterioration in QOL. Disease stabilisation on radiological assessment and symptomatic improvement were associated with prolonged survival. A degree of non-crossresistance to cytokine therapy was seen. IPM may be considered in patients with renal cancer following failure of cytokines. British Journal of Cancer (2003) Renal cell carcinoma (RCC) is a relatively common condition and when localised it is best treated by nephrectomy. Once the disease becomes metastatic, treatment options are limited. Current management has concentrated on the use of immunological agents, most commonly interferon alpha, which has shown a survival advantage when compared to medroxyprogesterone acetate in metastatic disease (Anonymous, 1999). The addition of interleukin-2 appears to improve the response rate but not the overall survival (Negrier et al, 1998). Nephrectomy in patients with metastatic disease appears to have an advantage over the use of interferon alone (Mickisch et al, 2001). To date, the most impressive results have been obtained with the combination of interferon alpha, interleukin-2 and fluorouracil, with response rate of 30 -40% being reported (Allen et al, 2000;Atzpodien et al, 2001). Whether this treatment is a genuine advance over interferon alone in patients who are relatively fit is currently being examined by an MRC trial. The use of chemotherapy in RCC has been disappointing. It has been suggested that this may be because of the fact that renal cells produce large amounts of multidrugresistance protein leading to the efflux of cytotoxics (Tobe et al, 1995;Reese et al, 2000). Chemotherapy in RCC has generally been based on either fluorouracil or its activated metabolite floxuridine (Reese et al, 2...

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The treatment of advanced renal cell cancer with high-dose oral thalidomide

Cited by 93 publications

References 34 publications

Phase I/II study of thalidomide in combination with interleukin‐2 in patients with metastatic renal cell carcinoma

Phase I/II study of thalidomide in combination with interleukin‐2 in patients with metastatic renal cell carcinoma

DMSO exhibits similar cytotoxicity effects to thalidomide in mouse breast cancer cells

IPM chemotherapy in cytokine refractory renal cell cancer

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