Currently available treatment of metastatic renal-cell carcinoma is inadequate. Approximately 12,000 individuals died of this disease in 1999. Immune therapy with interleukin-2, interferon alfa, or both is considered standard. However, only approximately 15% of individuals experience an objective response and approximately 5% experience a complete response.[2-5] Traditional chemotherapy tends to have little utility, in part due to the overexpression of various proteins that render cells resistant to multiple drugs.[6,7] Thus, novel approaches for treatment of metastatic renal-cell carcinoma are greatly needed. Because of the vascular nature of renal tumors, an antiangiogenesis approach is attractive. In addition, there is a suggestion that antiangiogenic agents may circumvent the development of drug resistance.
Angiogenesis is important in embryogenesis, wound healing, diabetic retinopathy, and tumor progression.[8,9] The immunomodulary drug thalidomide(Drug information on thalidomide) (Thalomid) can inhibit angiogenesis and induce apoptosis of established neovasculature in experimental models.[10,11] For these reasons, angiogenesis-inhibiting drugs such as thalidomide may be useful for treating cancers that depend on neovascularization. Angiogenesis inhibitors are now under extensive clinical investigation. Antiangiogenic therapy appears to have optimum efficacy if administered over a long time period.
A pilot study was performed at The University of Texas M. D. Anderson Cancer Center to determine the feasibility of using thalidomide in a population of renal-cell carcinoma patients who had progressive disease despite chemotherapy and immunotherapy. Metastatic renal-cell carcinoma patients with adequate oral function were entered onto a study after signing an internal review board-approved informed consent. There were no exclusion criteria for prior therapy. Nineteen previously treated patients and one untreated patient with progressive renal-cell carcinoma received oral thalidomide as a single agent. The starting dose was 200 mg and the dose was increased by 100 to 200 mg every week until it reached 1,200 mg/d. Response was assessed on the basis of a radiographic reduction of the metastatic sites involved.
The following case report describes one of the patients involved in the pilot trial./
J.R. is a patient who was referred to The University of Texas M. D. Anderson Cancer Center on January 8, 1997, for a second opinion regarding recurrent renal-cell cancer. At the time, he was a 40-year-old man who had presented to his physicians in January 1994 with an approximately 2-month history of left-sided flank pain and intermittent hematuria. An intravenous pyelogram indicated a left renal pole mass, and a subsequent computed tomography (CT) scan confirmed a mass lesion in the left kidney suggestive of renal-cell cancer. No distant metastases were identified on subsequent CT scans of the abdomen, pelvis, and chest. Also, an initial bone scan revealed no metastatic disease.
The patient subsequently underwent a left nephrectomy on February 7, 1994. A 9-cm clear-cell renal-cell carcinoma was contained within Gerota’s fascia without extension into the vena cava, diagnosed pathologically. Unfortunately, the specimen did not include lymph nodes, and therefore, lymph node status could not be evaluated.
The patient was treated tentatively as a stage II with surgery only and lost to follow-up until 1996. In September 1996, approximately 4 months before coming to M. D. Anderson, the patient developed polyuria and increasing fatigue, and was reevaluated by his primary physician. At that time, he was diagnosed with diabetes mellitus type II, with a very high blood sugar. A chest x-ray obtained at that time revealed multiple pulmonary nodules. This was followed up with a CT scan of the abdomen and chest; the CT scan of the abdomen revealed multiple nodule lesions in the liver suggestive of liver metastasis, and the CT scan of the chest confirmed multiple metastatic lesions. A bone scan was repeated in October 1996 and a brain CT scan was ordered. Both were negative for metastatic disease.
On evaluation at M. D. Anderson Cancer Center, the patient denied any fatigue, fever or chills, shortness of breath, or abdominal discomfort. His left flank pain and intermittent hematuria had completely resolved after surgery. He felt well overall and his performance status was 0 on the Zubrod scale. He had experienced no weight loss.
The patient’s family and social history were unremarkable except for a 40 pack-year history of cigarette smoking. Physical examination revealed no adenopathy, and no significant cardiopulmonary or abdominal findings were noted. The patient’s skin was significant for facial erythema that had been chronic in the past several months, but no other rash or skin abnormality was noted. His extremities were without edema. The patient’s neurologic status was essentially normal without any focal abnormalities.
At the time of evaluation of this 40-year-old man with a clear-cell renal cancer recurrence, he had obvious metastatic disease in the lung and liver. His significant comorbid condition was newly diagnosed diabetes mellitus, yet his blood sugar had been reasonably well controlled in the preceding 3 months to an extent that he had not been taking any medication for 3 weeks and continued to be asymptomatic with normal blood sugar.
Laboratory studies disclosed the following values: baseline creatinine 1.0 mg%; blood urea(Drug information on urea) nitrogen (BUN) 14 mg/dL; sodium 137 mmol/L; potassium 4.4 mmol/L; chloride 106 mmol/L; CO2 content 24 mmol/L; white blood cell count (WBC) 9.3 ´ 109/L; red blood cell count 7.3 ´ 1012/L; hemoglobin 10.2; hematocrit 59.2; mean corpuscular volume 88 mm3; mean corpuscular hemoglobin 25 pg/cell; MCAC 32.4; differential blood count: neutrophils 78%, bands 6%, lymphocytes 9%, monocytes 7%; absolute neutrophil count 7.3; bands 8.6; lymphocytes 0.8; monocytes 0.7; platelet count 155,000/mL; urinalysis negative; lactate dehydrogenase (LDH) 507 U/L; serum glutamic-oxaloacetic transaminase (SGOT) 20 U/L.
Both the patient’s brain MRI and bone scan were negative. His chest CT showed bilateral pulmonary nodules, and his abdomen/pelvis CT indicated hepatic metastasis.
The patient’s pathology report revealed clear-cell carcinoma (Furman’s nuclear grade III), with vascular and urothelial margins free of tumor. Tumor was focally present in adipose tissue at the renal hilum. There was no tumor present in the adrenal gland. Fibrous adipose tissue showed no lymph nodes or tumor present, at designated hilar nodes. The outside pathology report states that the tumor measures 8.7 cm in diameter.
In January 1997 the patient began interferon with fluorouracil(Drug information on fluorouracil) and interleukin-2. An evaluation was performed every 12 weeks, showing no new disease, with no progression or regression. Upon reevaluation in February 1998, the patient had progressive bilateral pulmonary nodules and progressive hepatic metastasis. At this time, the patient was started on interferon, fluorodeoxyuridine, and 13 cis-retinoic acid. By July 1998 he had developed progressive bilateral pulmonary nodules and hepatic metastasis. He was taken off therapy and offered thalidomide, which he accepted. He returned in September 1998 to begin week 1 of thalidomide.
Our overall impression was that the patient should enroll in the thalidomide study. He was informed about the various side effects, the dosing regimen, and the need to practice safe sex. He was initiated on 200 mg of thalidomide per day, to return weekly for a dose escalation of 200 mg/wk. This was achieved in a 6-week period of time, and the patient began to receive 1,200 mg daily.
Baseline laboratory values as of September 1998 were as follows: magnesium 1.9 mEq/L; carbon dioxide content 28 mmol/L; chloride 101 mmol/L; potassium 4.3 mmol/L, sodium 139 mmol/L, alkaline phosphatase 158 U/L; LDH 48 U/L; bilirubin 0.7, creatinine 1.2 mg/dL; BUN 17 mg/dL; blood sugar 214; calcium 9.6 mg/dL; albumin 4.0 g/dL, hemoglobin 18.4; WBC 10.4 ´ 109/L; platelet count 180 ´ 109/L.
The patient’s radiographic analysis for September 1998 indicated further progression of bilateral pulmonary nodules and hepatic metastatic disease.
The patient tolerated the increased escalation of thalidomide well. He was taking Senokot-S for constipation and lactulose(Drug information on lactulose) as needed, and made dietary adjustments that included increased fiber as well as increased fluids. The medication was taken in the evening. Although he maintained his performance status and continued working, the patient did have complaints of some fatigue and sedation. The April 27, 1999, chest CT stated that the right upper lobe mass had slightly increased, and that the liver was unchanged or slightly increased.
The patient remained on thalidomide at full dose, and at the June 1999 evaluation began showing improvements in the lung and liver, achieving partial response (defined as greater than 50% reduction in size of metastasis). He continued on thalidomide. However, in May 2000 he developed a single focus of brain metastasis. He was started on anticonvulsants and dexamethasone(Drug information on dexamethasone), and his thalidomide was put on hold. He underwent neurosurgery for removal of the metastatic deposit, and following recovery reinstituted thalidomide while tapering off of dexamethasone and continuing phenytoin(Drug information on phenytoin).
At the time of his initial improvement, which was demonstrated in June 1999, the patient’s hemoglobin was 17.3 and his hematocrit was 52.5. All other laboratory parameters were unremarkable. His blood sugar remained at 200. In August 1999 his hemoglobin was 16.8, and his hematocrit was 49.8. This decreasing trend continued. In October 1999 his hemoglobin was 15.8 and his hematocrit was 47.0, with other laboratory values remaining normal.
When administered to this pretreated patient with metastatic renal-cell carcinoma, thalidomide exhibited antitumor activity. The objective response started 10 months into thalidomide therapy. Thalidomide has a number of properties that could explain this activity in renal-cell carcinoma. The drug can suppress the production of tumor necrosis factor-alpha, increase the production of interleukin-10, and enhance cell-mediated immunity by directly stimulating cytotoxic T cells.[12-14] Thalidomide inhibits angiogenesis induced by fibroblast growth factor and vascular endothelial growth factor in a rabbit cornea micropocket assay and murine model corneal vascularization.[10,11] It also causes apoptosis of established tumor-associated angiogenesis. Renal-cell carcinoma is highly vascular and quite immunogenic. These properties may make it particularly sensitive to thalidomide’s effects.
The antitumor properties of thalidomide are being evaluated extensively in various malignant diseases. Presently, only limited data of the efficacy, toxicity, and dose range are available. The prolonged responses to thalidomide in some patients with advanced, previously treated renal-cell carcinoma suggest that the mechanism of action of thalidomide is distinctly different from that of other agents.[15,16] Thalidomide increases the total number of lymphocytes as well as CD8+ and CD4+ T-cell counts, along with substantially increasing mean plasma levels of soluble interleukin-2 receptor.
Thalidomide in Combination
The above-mentioned properties and the absence of severe adverse effects suggest that thalidomide could be an ideal agent for use in combination with interleukin-2 or other adaptive immunotherapeutic strategies. With the absence of myelosuppression, thalidomide is being evaluated in combination with chemotherapy. This approach has merit, as it has been shown to have greater antitumor activity than chemotherapy alone in a murine model of breast cancer. This may be a rationale for combining thalidomide with biochemotherapy as a possible way of reducing side effects and increasing efficacy of treatment for renal-cell carcinoma.
The toxicity profile of antiangiogenic agents is varied and is quite different from cytotoxic agents. The grading of some toxicities is difficult with the use of present grading systems. Although many drugs have only grade 1 and 2 side effects, the need for long-term use makes even moderate side effects significant for patients’ quality of life. This will need to be addressed in further studies with thalidomide and other antiangiogenic agents. The most common adverse events observed with thalidomide are somnolence/drowsiness, dizziness/orthostatic hypertension, constipation, and rash. Peripheral neuropathy, neutropenia, and bradycardia may also occur. The most serious toxicity associated with thalidomide is its documented human teratogenicity.
Although only a small number of studies of previously treated progressive patients with renal-cell carcinoma have been performed, thalidomide is thought to have activity in this disease. It can induce marked and durable responses in some patients with renal-cell carcinoma, as demonstrated in this case report. Further studies of thalidomide are therefore warranted in patients with renal-cell carcinoma. Issues that would need to be addressed are as follows:
Whether a dose response relationship exists, thus permitting titration on an individual patient basis
Whether a chronic schedule is necessary, or can one safely administer thalidomide on an intermittent schedule with a rest period
Whether this is an agent strictly for minimal tumor burden or intermediate and/or advanced tumor burden patients
How one defines protocol response criteriawhether to use the conventional response rate or time to progression and survival
How to develop thalidomide in combination with cytokines, other angiogenic inhibitors, and chemotherapy
For those developing clinical trials of thalidomide, collecting data on quality of life, evaluating the changes in tumor perfusion, evaluating changes in tumor tissue, and developing laboratory correlative studies are essential.