Poor tolerability of thalidomide in end-stage oesophageal cancer. Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial. A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118). Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia. Controlled evaluation of three drug combination regimens versus fluorouracil alone for the therapy of advanced gastric cancer. North Central Cancer Treatment Group. Prospective randomised trial of two dose levels of megestrol acetate in the management of anorexia-cachexia syndrome in patients with metastatic cancer. A lower dose of thalidomide is better than a high dose in metastatic renal cell carcinoma. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Successful implementation of the randomized discontinuation trial design: an application to the study of the putative antiangiogenic agent carboxyaminoimidazole in renal cell carcinoma--CALGB 69901.
Oesophageal cancer cachexia is a significant clinical problem, resulting in excessive morbidity and mortality. In a pilot study, 10 patients with cachexia due to advanced cancer of the oesophagus gained weight, including lean tissue, after 14-day treatment with thalidomide. Here, we present randomised placebo controlled trial data over a 6-week period to test the hypothesis that thalidomide is superior to placebo in terms of weight gain in patients with cachexia caused by oesophageal cancer. Thalidomide, 200 mg daily, or an identical placebo was given to patients with advanced oesophageal cancer. Total body weight and lean body mass were assessed in addition to drug tolerability and performance indices. Thirty-four patients were recruited. Of these, six given thalidomide and 16 given placebo completed the protocol; all withdrawals were due to adverse drug reactions or complications of disease. Thalidomide showed no benefit over placebo in participants who completed the protocol. These data suggest that thalidomide is poorly tolerated in patients with advanced cancer of the oesophagus and may not ameliorate the progression of cachexia. In the absence of hard supportive evidence, off-licence treatment with thalidomide should be used with great caution as an adjunct to nutritional support in patients with advanced cancer.
                © 2011 Blackwell Publishing Ltd. Proinflammatory cytokines, especially tumour necrosis factor alpha (TNF-alpha), play a prominent role in the pathogenesis of cancer cachexia. Thalidomide, which is an inhibitor of TNF-alpha synthesis, may represent a novel and rational approach to the treatment of cancer cachexia.
                To assess the safety and efficacy of thalidomide in attenuating weight loss in patients with cachexia secondary to advanced pancreatic cancer.
                Fifty patients with advanced pancreatic cancer who had lost at least 10% of their body weight were randomised to receive thalidomide 200 mg daily or placebo for 24 weeks in a single centre, double blind, randomised controlled trial. The primary outcome was change in weight and nutritional status.
                Thirty three patients (16 control, 17 thalidomide) were evaluated at four weeks, and 20 patients (eight control, 12 thalidomide) at eight weeks. At four weeks, patients who received thalidomide had gained on average 0.37 kg in weight and 1.0 cm(3) in arm muscle mass (AMA) compared with a loss of 2.21 kg (absolute difference -2.59 kg (95% confidence interval (CI) -4.3 to -0.8); p = 0.005) and 4.46 cm(3) (absolute difference -5.6 cm(3) (95% CI -8.9 to -2.2); p = 0.002) in the placebo group. At eight weeks, patients in the thalidomide group had lost 0.06 kg in weight and 0.5 cm(3) in AMA compared with a loss of 3.62 kg (absolute difference -3.57 kg (95% CI -6.8 to -0.3); p = 0.034) and 8.4 cm(3) (absolute difference -7.9 cm(3) (95% CI -14.0 to -1.8); p = 0.014) in the placebo group. Improvement in physical functioning correlated positively with weight gain (r = 0.56, p = 0.001).
                Thalidomide was well tolerated and effective at attenuating loss of weight and lean body mass in patients with cachexia due to advanced pancreatic cancer. To compare whole-brain radiation therapy (WBRT) with WBRT combined with thalidomide for patients with brain metastases not amenable to resection or radiosurgery.
                Patients with Zubrod performance status 0-1, MRI-documented multiple (>3), large (>4 cm), or midbrain brain metastases arising from a histopathologically confirmed extracranial primary tumor, and an anticipated survival of >8 weeks were randomized to receive WBRT to a dose of 37.5 Gy in 15 fractions with or without thalidomide during and after WBRT. Prerandomization stratification used Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) Class and whether post-WBRT chemotherapy was planned. Endpoints included overall survival, progression-free survival, time to neurocognitive progression, the cause of death, toxicities, and quality of life. A protocol-planned interim analysis documented that the trial had an extremely low probability of ever showing a significant difference favoring the thalidomide arm given the results at the time of the analysis, and it was therefore closed on the basis of predefined statistical guidelines.
                Enrolled in the study were 332 patients. Of 183 accrued patients, 93 were randomized to receive WBRT alone and 90 to WBRT and thalidomide. Median survival was 3.9 months for both arms. No novel toxicities were seen, but thalidomide was not well tolerated in this population. Forty-eight percent of patients discontinued thalidomide because of side effects.
                Thalidomide provided no survival benefit for patients with multiple, large, or midbrain metastases when combined with WBRT; nearly half the patients discontinued thalidomide due to side effects. A phase III, randomized study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia-lean body mass (LBM), resting energy expenditure (REE), and fatigue-and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines.
                Three hundred thirty-two assessable patients with cancer-related anorexia/cachexia syndrome were randomly assigned to one of five treatment arms: arm 1, medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day); arm 2, oral supplementation with eicosapentaenoic acid; arm 3, L-carnitine (4 g/day); arm 4, thalidomide (200 mg/day); and arm 5, a combination of the above. Treatment duration was 4 months.
                Analysis of variance showed a significant difference between treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5; interleukin (IL)-6 decreased significantly in arm 5 and arm 4; GPS and Eastern Cooperative Oncology Group performance status (ECOG PS) score decreased significantly in arm 5, arm 4, and arm 3. Toxicity was quite negligible, and was comparable between arms.
                The most effective treatment in terms of all three primary efficacy endpoints and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents. The purpose of this study was to evaluate the therapeutic effectiveness of fluorouracil (5-FU), doxorubicin, and methyl lomustine (CCNU) (FAMe), 5-FU, doxorubicin, and cisplatin (FAP), and FAMe alternating with triazinate (TZT) when compared with a standard therapy of 5-FU alone in patients with advanced gastric cancer.
                Two hundred fifty-two eligible patients selected for study had proven locally unresectable and/or metastatic gastric adenocarcinoma. The majority had nonmeasureable disease. They were randomly assigned to receive one of the three drug combination regimens or to 5-FU alone administered by rapid injection in 5-day course. Survival was the primary study end point.
                None of the three drug combinations showed a significant advantage over 5-FU alone in improved performance score, weight gain, or patient survival. Each of the three combinations was more toxic than 5-FU alone.
                FAMe, FAP, or FAMe alternating with TZT cannot be recommended for the therapy of advanced gastric carcinoma. Therapy of this disease should remain an experimental endeavor. It would seem reasonable to prove the value of any new treatment approach by a randomized comparison to simple therapy with 5-FU alone. Two doses of megestrol acetate (MA) have been prospectively compared in a random fashion as treatment for cancer-related anorexia-cachexia syndrome (ACS) in 122 patients with progressive soft tissue sarcoma, colorectal, lung, head and neck and renal cancer resistant to systemic chemotherapy. After 30 days of MA, 55% of patients receiving MA at 160 mg day-1 reported an increase in appetite, 27% of patients no variation and 18% complained of a decrease in appetite. Patients treated with MA at 320 mg day-1 reported an increase in appetite in 68% of cases, a stabilisation in 20% of cases and a decrease in 12%. Although an increase in appetite was more frequently observed in patients receiving MA at 320 mg day-1, however this difference was not statistically significant (P = 0.305). After 30 days of MA, 31% of patients treated with MA at 160 mg day-1 showed an increase in body weight, 25% a stabilisation and 44% a decrease. In the group of patients treated with MA at 320 mg day-1, 45% reported an increase in body weight, 16% no change and 23% weight loss. Although there was a trend favouring the higher dose of MA, overall analysis however failed to detect any statistically significant difference between the two treatment arms (P = 0.242). Twenty-seven patients pretreated with 160 mg day-1 and 23 patients treated with 320 mg day-1 received further therapy with MA at the dose of 320 and 480 mg day-1 respectively. In the group of 22 patients treated with 320 mg day-1 four (18%) reported an increase in body weight, eight (36%) an improvement in appetite, but none had an increase in performance status. Among the 20 evaluable patients treated with 480 mg day-1, two (10%) had an increase in body weight, four (20%) an improvement in appetite, but none reported an increase in performance status. No difference in median survival was detected between the two arms. Toxicity was mild and predictable. In conclusion, the data achieved in the present study confirm the clinical safety and effectiveness of oral MA in the management of ACS in patients with advanced cancer resistant to systemic chemotherapy. Moreover, data concerning the dose escalation of MA dosage in unresponsive patients suggest that a step by step increase in MA dosage could be the best way of administering MA for the management of ACS and that the increase of MA dosage over 480 mg day-1 will probably be useless in the vast majority of cases. Data on body weight suggest that after 2 weeks' therapy MA could be stopped or its dosage tailored to patients' needs since the majority of patients respond after only 15 days of MA. To conduct a dose-finding trial using a single low dose and dose escalation of a higher dose of thalidomide in patients with metastatic renal cell carcinoma (RCC), and to evaluate the antineoplastic effectiveness of thalidomide as an anti-angiogenic agent on RCC.
                The 14 patients enrolled in the study had progressive measurable metastatic RCC and consented to participate. Patients were randomized to either a fixed low dose of 200 mg of thalidomide or to a high dose of 800 mg that was increased to a maximum dose of 1200 mg daily. Patients were evaluated for response after 8 weeks of therapy.
                Stable disease was achieved in six patients and was seen in both the low-dose and high-dose thalidomide groups. The median overall survival was 9 months. The low-dose thalidomide regimen was better tolerated and patients survived longer than those on the high-dose regimen (16 vs 6 months, P = 0.04)
                The use of low-dose thalidomide in patients with metastatic RCC was well tolerated and they survived for longer than those on the high-dose regimen. Newer chemotherapeutic protocols as well as high-dose chemotherapy have increased the response rate in myeloma. However, these treatments are not curative. Effective maintenance strategies are now required to prolong the duration of response. We conducted a randomized trial of maintenance treatment with thalidomide and pamidronate. Two months after high-dose therapy, 597 patients younger than age 65 years were randomly assigned to receive no maintenance (arm A), pamidronate (arm B), or pamidronate plus thalidomide (arm C). A complete or very good partial response was achieved by 55% of patients in arm A, 57% in arm B, and 67% in arm C (P = .03). The 3-year postrandomization probability of event-free survival was 36% in arm A, 37% in arm B, and 52% in arm C (P < .009). The 4-year postdiagnosis probability of survival was 77% in arm A, 74% in arm B, and 87% in arm C (P < .04). The proportion of patients who had skeletal events was 24% in arm A, 21% in arm B, and 18% in arm C (P = .4). Thalidomide is an effective maintenance therapy in patients with multiple myeloma. Maintenance treatment with pamidronate does not decrease the incidence of bone events. To assess the disease-stabilizing activity of carboxyaminoimidazole (CAI) in patients with metastatic renal cell cancer (RCC) using a randomized discontinuation trial (RDT) design.
                Recruited patients had a performance status of 0 to 2, minimal neuropathy or cerebellar dysfunction, measurable disease, and normal organ function. Treatment with 250 mg/d CAI was initiated in all patients and continued until disease progression in those with an objective response. Protocol treatment was discontinued for unacceptable toxicity or progressive disease; patients with stable disease at the 16-week evaluation point were randomly assigned in a double-blind manner to continued CAI or placebo. The primary end point was the stable disease rate in the randomized groups.
                A total of 368 patients were accrued and received therapy. Ninety percent had a performance status of 0 or 1, 80% underwent a prior nephrectomy, and 41% had received no prior systemic therapy. Serious or life-threatening toxicity was experienced by 34%, with asthenia (15%) and neuropsychiatric difficulties (7%) being most common. At the randomization point, 51% of patients had progressed, 30% withdrew, 1% experienced a partial response, and 17% had stable disease and were randomly assigned. A Bayesian futility analysis utilizing the first 49 randomly assigned patients suggested that the probability of demonstrating a higher stable disease rate in the experimental group was less than 9% even under the most optimistic a priori assumptions, and further trial accrual was halted.
                CAI is inactive in RCC. The RDT design should be further explored for evaluating activity of putative disease stabilizing agents.
The review authors cannot confirm or refute previous literature on the use of thalidomide for patients with advanced cancer who have cachexia and there is inadequate evidence to recommend it for clinical practice. Additional, well conducted, large RCTs are needed to test thalidomide both singularly and in combination with other treatment modalities to ascertain its true benefit, if any, for this population. Furthermore, one study (out of the three reviewed) highlighted that thalidomide was poorly tolerated and its use needs to be explored further in light of the frailty of this population.