Commentary on Abstract #2396
Commentary on Abstract #2396
The authors of abstract #2396 conducted a 6-week trial of thalidomide (Thalomid), 100 and 200 mg at bedtime, in 15 cachectic patients. The main findings of this uncontrolled study were cessation of weight loss, increased body fat percentage, decreased nocturnal awakenings, and increased sleep time. Thalidomide was generally well tolerated at this dose level. This study focused on the clinical effects of thalidomide, cachexia, and symptoms such as insomnia and pain.
Thalidomide in Palliative Cancer Care
The results of this study should be interpreted cautiously because of the lack of a control group, the absence of blinding (making subjective variables such as sleep, pain, and quality of life unreliable), and the extremely small number of patients. However, this preliminary report suggests that randomized control trials on the nutritional and symptomatic effects of thalidomide are justified.
Cachexia and Chronic Nausea
These are some of the important novel uses for thalidomide in palliative cancer care (Drugs 60:1-20, 2000). Cachexia occurs in more than 80% of patients with advanced cancer. In recent years this complication has been understood to result from major metabolic abnormalities involving tumor by-products and host cytokine release, in particular tumor necrosis factor–alpha (TNF-alpha), rather than a simple increase in energy consumption by the tumor and starvation by the patient. Thalidomide is capable of significantly influencing cytokine levels and may play a pivotal role in the therapeutic immunomodulation of patients with advanced cancer. A preliminary report has shown that thalidomide at a dose of 100 mg at bedtime led to significant improvement in appetite, nausea, and sensation of well-being in 37 evaluable cachectic cancer patients (Ann Oncol 10:857-859, 1999). Thalidomide has also been successfully used in halting and reversing body weight loss in AIDS-associated cachexia, which is similar to cancer cachexia with high levels of TNF-alpha.
Chronic nausea is a distressing and frequent symptom in patients with advanced cancer. It is part of the cachexia syndrome, and it is also associated with opioid therapy, constipation, autonomic failure, and other metabolic abnormalities. In the early era of thalidomide the drug was frequently used as an antiemetic and was found to be effective in nausea associated with pregnancy and vomiting caused by drugs and malignancy (Drugs 60:1-20, 2000).
Some of the older literature as well as preliminary reports such as this abstract suggest that there is a potential role for thalidomide in cachexia and chronic nausea. This role should be studied in randomized controlled trials. There is already significant preliminary evidence to suggest that a dose of 100 to 200 mg/d given at nighttime is appropriate. With regard to the control group, the most useful studies will be those comparing thalidomide with established drugs for the treatment of cachexia, such as megestrol acetate. Outcomes of these studies should include symptomatic relief for anorexia, chronic nausea, and fatigue; functional status, body weight, and other nutritional variables such as caloric intake and body composition; and quality of life.
Insomnia is another frequent problem in patients with advanced cancer. Benzodiazapines are generally poorly tolerated in these patients due to their borderline cognitive function and their need for multiple medications such as opioids and other psychotropic drugs. Earlier studies recognized that thalidomide was effective as a mild hypnotic and anxiolytic in the elderly, and reported an absence of hangover that could be useful in this debilitated population. To maintain the highest possible quality of life, cognitive and psychomotor function should be maintained in patients requiring palliative care. The authors of abstract #2396 have attempted to measure cognition using the Mini Mental Status Examination. Future studies should complement this assessment with simple bedside psychomotor function tests. In the short-term management of insomnia, thalidomide should be compared with short- and medium-term–acting benzodiazepines and the newer nonbenzodiazepine hypnotics. Additionally, the interaction with opioid analgesics should be studied.
The abstract briefly makes reference to pain as an outcome of thalidomide administration. This is relevant because 60% to 90% of patients with advanced cancer experience substantial pain. Recent evidence suggests that cytokines such as TNF and interleukins can potentially modify nociception and synaptic transmission, and are thought to be involved in the cascade of transactions resulting in cancer pain (particularly neuropathic pain). Early studies suggested that thalidomide had adjuvant analgesic effects. When used in leprosy, thalidomide was discovered to rapidly relieve pain associated with subcutaneous nodules and peripheral neuropathy associated with erythema nodosum.
In rat models of neuropathic pain, preemptive treatment with thalidomide reduced mechanical allodynia and thermal hyperalgesia during the early stage of the pain syndrome.
In summary, thalidomide may have analgesic properties based on the selective suppression of the immune mediators, such as TNF-alpha and interleukin-6, as well as by direct brain effects. Clinical trials of thalidomide in cancer pain will test its role as an adjuvant, rather than as a primary analgesic drug, and should focus on neuropathic pain models such as peripheral neuropathy or plexopathy. One important consideration in patients will be the need to carefully monitor for the possibility of thalidomide-induced peripheral neuropathy that could further aggravate the tumor-induced nerve damage.
Thalidomide has a number of interesting and promising effects on multiple clinical syndromes in patients with advanced cancer. These potential effects should be investigated. Because of its potentially wide availability and low cost, thalidomide might be particularly beneficial in many developing countries. Appropriate measures need to be implemented in order to eliminate the risk of teratogenesis that might result from inappropriate use of this potentially valuable agent.