Tumors secrete growth factors that help them to grow and metastasize. Some of these factors are angiogenic, some immunomodulatory, and several fall into both categories. Angiogenesis is an important new target for anticancer drugs. As shown in Figure 1, thalidomide(Drug information on thalidomide) (Thalomid) may interfere with the expression or release of several angiogenic factors,[3-6] including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), from renal carcinoma cells, and may interfere indirectly with vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).[7,8]
These factors may stimulate cell growth in a paracrine or autocrine manner. For example, the combined activity of TNF-alpha and IL-6 is quite potent as an autocrine and paracrine growth factor, at least in vitro. A number of patients with renal cell carcinoma appear to have metastatic bone disease and little or no disease in other soft tissue. It is interesting to speculate that IL-6 may be an important factor in this pattern of disease, since it is often expressed at high levels in bone.
Data are also accumulating for thalidomide’s effects on growth factor suppression and immunomodulation.
Earlier this year, we published data in the British Journal of Cancer, reporting on work done primarily at the Royal Marsden Hospital. The study investigated the use of low-dose thalidomide (100 mg orally, every night) in patients with a variety of advanced malignancies, including melanoma, renal-cell carcinoma, ovarian, and breast cancers. The aims of the study were to assess the toxicity and gain an early indication of the efficacy of continuous low-dose thalidomide. We also attempted to assess biological responses by serial measurements of TNF-alpha, VEGF, and bFGF concentrations in stored serum samples.
Thalidomide was administered on a continuous schedule rather than a shorter, higher-dose regimen because data suggest that an antiangiogenic agent may have optimum effect if given over a long period. Using thalidomide over a long period, however, increases the risk of peripheral neuropathy. We therefore started our study at an extremely cautious dose of 100 mg every night.
Patients and Methods
All patients in the study had histologically confirmed, measurable, progressive disease. None of them had had any anticancer therapy, including surgery, in the previous 4 weeks because of our concern that patients receiving thalidomide might have some interference with their ability to heal after surgery. Using our standard criterion, women of childbearing age agreed to use adequate contraception for the duration of the study and for 6 months afterwards. Patients showing any signs of peripheral neuropathy were excluded to avoid exacerbation.
Patients were assessed initially and at 1 month, then at 3, 6, 9, and 12 months, until they showed evidence of disease progression or they experienced unacceptable toxicity. Assessments included full blood count, serum biochemistry, and the sensory nerve action potential (SNAP) test for peripheral neuropathy. We also froze serum and urine for later enzyme-linked immunosorbent assay (ELISA) of biomarkers (bFGF, VEGF, and TNF-alpha). We also asked patients to complete symptom distress scales (Hospital Anxiety and Depression [HAD] and Rotterdam scores).
A total of 66 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) were enrolled in the study (Table 1). Several patients had poor performance status and most had received cancer treatment prior to enrollment.
Complete response was defined as the disappearance of all known disease determined by two observations not less than 4 weeks apart. Partial response was defined as a decrease by at least 50% of the sum of the products of the largest perpendicular diameters of all measurable lesions as determined by two observations not less than 4 weeks apart.
Progressive disease was defined as a more than 25% increase in the size of the lesion or the appearance of a new lesion. Stable disease was defined as where there had been a less than 50% decrease and a less than 25% increase in the sum of products of the largest perpendicular diameters of all measurable lesions for two observations not less than 4 weeks apart.
Three partial responses were seen in the 18 patients with renal-cell carcinoma. Two of these patients had had extensive pretreatment. One response lasted 5 months, and the other two partial responses continued after 5 and 11 months of follow-up. Thirteen patients with renal-cell carcinoma experienced stabilization of their previously progressive disease. Three had stable disease for 3 months or longer; 10 had stable disease for only 1 to 3 months.
Objective results (partial response or stable disease) in the remaining 48 patients were disappointing. However, three patients had a differential response; one patient with rapidly progressive skin deposits of melanoma on his leg experienced symptomatic improvement and was able to walk more than 100 yards, having been previously confined to a chair. Thalidomide may be of more interest as part of a multiple modality regimen in melanoma.
Of 15 patients who completed serial HAD and Rotterdam scores, 11 experienced improvements in sleeping and 14 experienced a maintained or enhanced appetite. Both findings were statistically significant (P < .05), although based on a small number of patients.
One patient’s case serves to illustrate the results of our low-dose study. This man had progressed on treatment for renal-cell carcinoma, with deteriorating performance status 2 months after receiving a combination of interleukin-2 (IL-2), interferon alfa, and fluorouracil(Drug information on fluorouracil). He had several large pulmonary and lymph node mestastases and had developed increasingly severe night sweats and weight loss.
The patient was started on 100 mg of thalidomide at night. At his first assessment at 1 month, he denied feeling any different. However, his wife said that he was, in fact, a changed man. The patient’s appetite had returned, his sweats had stopped, and he was more active. Over the next 4 months of treatment with thalidomide he had a gradual disease response, which resolved to a single residual lung mass in the right lung showing only necrotic tissue on bronchoscopy.
It is well recognized that rarely, spontaneous or late responses to immunotherapy may be seen in patients with renal-cell carcinoma. This is unlikely to be the explanation for this man’s response for two reasons: first, the patient had rapidly progressive disease following biochemotherapy, and second, he obtained significant palliative benefit within a short time of starting thalidomide.
After 9 months in the study, a SNAP test detected peripheral neuropathy and the thalidomide was stopped, according to the study protocol. The patient did not want to stop treatment then because he was feeling much better and had not noticed the peripheral neuropathy. After 1 month without thalidomide, his SNAP improved and he was restarted at a lower dose (50 mg). He developed peripheral neuropathy again after a month, at which time treatment was stopped. Eleven months later progressive disease was noted in the right lung. Restaging showed no evidence of relapsed disease at other sites and a pneumonectomy was performed. The patient remains well now, 3 years after starting thalidomide.
This case illustrates several points. First, responses to thalidomide may be slow. Second, the palliative response is separate from the objective tumor response, and is much faster and not consistent with an antiangiogenic action. Third, although peripheral neuropathy is a problem, it can be managed safely by appropriate dose reduction and where necessary, cessation of treatment. Fourth, responses and palliative benefit may be obtained in patients with metastatic renal-cell carcinoma who have progressed on immunotherapy.