OR WAIT null SECS
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. A case report describing one of the patients involved in the pilot trial is included. [ONCOLOGY 14(Suppl 13):33-36, 2000]
ABSTRACT: 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. A case report describing one of the patients involved in the pilot trial is included. [ONCOLOGY 14(Suppl 13):33-36, 2000]
Currently available treatment of metastatic renal-cell carcinomais inadequate. Approximately 12,000 individuals died of this disease in 1999.Immune therapy with interleukin-2, interferon alfa, or both is consideredstandard. However, only approximately 15% of individuals experience an objectiveresponse and approximately 5% experience a complete response.[2-5] Traditionalchemotherapy tends to have little utility, in part due to the overexpression ofvarious proteins that render cells resistant to multiple drugs.[6,7] Thus, novelapproaches for treatment of metastatic renal-cell carcinoma are greatly needed.Because of the vascular nature of renal tumors, an antiangiogenesis approach isattractive. In addition, there is a suggestion that antiangiogenic agents maycircumvent the development of drug resistance.
Angiogenesis is important in embryogenesis, wound healing,diabetic retinopathy, and tumor progression.[8,9] The immunomodulary drugthalidomide (Thalomid) can inhibit angiogenesis and induce apoptosis ofestablished neovasculature in experimental models.[10,11] For these reasons,angiogenesis-inhibiting drugs such as thalidomide may be useful for treatingcancers that depend on neovascularization. Angiogenesis inhibitors are now underextensive clinical investigation. Antiangiogenic therapy appears to have optimumefficacy 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 apopulation of renal-cell carcinoma patients who had progressive disease despitechemotherapy and immunotherapy. Metastatic renal-cell carcinoma patients withadequate oral function were entered onto a study after signing an internalreview board-approved informed consent. There were no exclusion criteria forprior therapy. Nineteen previously treated patients and one untreated patientwith progressive renal-cell carcinoma received oral thalidomide as a singleagent. The starting dose was 200 mg and the dose was increased by 100 to 200 mgevery week until it reached 1,200 mg/d. Response was assessed on the basis of aradiographic reduction of the metastatic sites involved.
The following case report describes one of the patients involvedin 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 regardingrecurrent renal-cell cancer. At the time, he was a 40-year-old man who hadpresented to his physicians in January 1994 with an approximately 2-monthhistory of left-sided flank pain and intermittent hematuria. An intravenouspyelogram indicated a left renal pole mass, and a subsequent computed tomography(CT) scan confirmed a mass lesion in the left kidney suggestive of renal-cellcancer. No distant metastases were identified on subsequent CT scans of theabdomen, pelvis, and chest. Also, an initial bone scan revealed no metastaticdisease.
The patient subsequently underwent a left nephrectomy onFebruary 7, 1994. A 9-cm clear-cell renal-cell carcinoma was contained withinGerota’s fascia without extension into the vena cava, diagnosedpathologically. Unfortunately, the specimen did not include lymph nodes, andtherefore, lymph node status could not be evaluated.
The patient was treated tentatively as a stage II with surgeryonly and lost to follow-up until 1996. In September 1996, approximately 4 monthsbefore coming to M. D. Anderson, the patient developed polyuria and increasingfatigue, and was reevaluated by his primary physician. At that time, he wasdiagnosed with diabetes mellitus type II, with a very high blood sugar. A chestx-ray obtained at that time revealed multiple pulmonary nodules. This wasfollowed up with a CT scan of the abdomen and chest; the CT scan of the abdomenrevealed multiple nodule lesions in the liver suggestive of liver metastasis,and the CT scan of the chest confirmed multiple metastatic lesions. A bone scanwas repeated in October 1996 and a brain CT scan was ordered. Both were negativefor metastatic disease.
On evaluation at M. D. Anderson Cancer Center, the patientdenied any fatigue, fever or chills, shortness of breath, or abdominaldiscomfort. His left flank pain and intermittent hematuria had completelyresolved after surgery. He felt well overall and his performance status was 0 onthe Zubrod scale. He had experienced no weight loss.
The patient’s family and social history were unremarkableexcept for a 40 pack-year history of cigarette smoking. Physical examinationrevealed no adenopathy, and no significant cardiopulmonary or abdominal findingswere noted. The patient’s skin was significant for facial erythema that hadbeen chronic in the past several months, but no other rash or skin abnormalitywas noted. His extremities were without edema. The patient’s neurologic statuswas essentially normal without any focal abnormalities.
At the time of evaluation of this 40-year-old man with aclear-cell renal cancer recurrence, he had obvious metastatic disease in thelung and liver. His significant comorbid condition was newly diagnosed diabetesmellitus, yet his blood sugar had been reasonably well controlled in thepreceding 3 months to an extent that he had not been taking any medication for 3weeks and continued to be asymptomatic with normal blood sugar.
Laboratory studies disclosed the following values: baselinecreatinine 1.0 mg%; blood urea nitrogen (BUN) 14 mg/dL; sodium 137 mmol/L;potassium 4.4 mmol/L; chloride 106 mmol/L; CO2content 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; meancorpuscular volume 88 mm3; mean corpuscularhemoglobin 25 pg/cell; MCAC 32.4; differential blood count: neutrophils 78%,bands 6%, lymphocytes 9%, monocytes 7%; absolute neutrophil count 7.3; bands8.6; lymphocytes 0.8; monocytes 0.7; platelet count 155,000/mL; urinalysisnegative; lactate dehydrogenase (LDH) 507 U/L; serum glutamic-oxaloacetictransaminase (SGOT) 20 U/L.
Both the patient’s brain MRI and bone scan were negative. Hischest CT showed bilateral pulmonary nodules, and his abdomen/pelvis CT indicatedhepatic metastasis.
The patient’s pathology report revealed clear-cell carcinoma(Furman’s nuclear grade III), with vascular and urothelial margins free oftumor. Tumor was focally present in adipose tissue at the renal hilum. There wasno tumor present in the adrenal gland. Fibrous adipose tissue showed no lymphnodes or tumor present, at designated hilar nodes. The outside pathology reportstates that the tumor measures 8.7 cm in diameter.
In January 1997 the patient began interferon with fluorouraciland interleukin-2. An evaluation was performed every 12 weeks, showing no newdisease, with no progression or regression. Upon reevaluation in February 1998,the patient had progressive bilateral pulmonary nodules and progressive hepaticmetastasis. At this time, the patient was started on interferon,fluorodeoxyuridine, and 13 cis-retinoic acid. By July 1998 he haddeveloped progressive bilateral pulmonary nodules and hepatic metastasis. He wastaken off therapy and offered thalidomide, which he accepted. He returned inSeptember 1998 to begin week 1 of thalidomide.
Our overall impression was that the patient should enroll in thethalidomide study. He was informed about the various side effects, the dosingregimen, and the need to practice safe sex. He was initiated on 200 mg ofthalidomide per day, to return weekly for a dose escalation of 200 mg/wk. Thiswas achieved in a 6-week period of time, and the patient began to receive 1,200mg 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 48U/L; bilirubin 0.7, creatinine 1.2 mg/dL; BUN 17 mg/dL; blood sugar 214; calcium9.6 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 1998indicated further progression of bilateral pulmonary nodules and hepaticmetastatic disease.
The patient tolerated the increased escalation of thalidomidewell. He was taking Senokot-S for constipation and lactulose as needed, and madedietary adjustments that included increased fiber as well as increased fluids.The medication was taken in the evening. Although he maintained his performancestatus and continued working, the patient did have complaints of some fatigueand sedation. The April 27, 1999, chest CT stated that the right upper lobe masshad slightly increased, and that the liver was unchanged or slightly increased.
The patient remained on thalidomide at full dose, and at theJune 1999 evaluation began showing improvements in the lung and liver, achievingpartial response (defined as greater than 50% reduction in size of metastasis).He continued on thalidomide. However, in May 2000 he developed a single focus ofbrain metastasis. He was started on anticonvulsants and dexamethasone, and histhalidomide was put on hold. He underwent neurosurgery for removal of themetastatic deposit, and following recovery reinstituted thalidomide whiletapering off of dexamethasone and continuing phenytoin.
At the time of his initial improvement, which was demonstratedin 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 at200. In August 1999 his hemoglobin was 16.8, and his hematocrit was 49.8. Thisdecreasing trend continued. In October 1999 his hemoglobin was 15.8 and hishematocrit was 47.0, with other laboratory values remaining normal.
When administered to this pretreated patient with metastaticrenal-cell carcinoma, thalidomide exhibited antitumor activity. The objectiveresponse started 10 months into thalidomide therapy. Thalidomide has a number ofproperties that could explain this activity in renal-cell carcinoma. The drugcan suppress the production of tumor necrosis factor-alpha, increase theproduction of interleukin-10, and enhance cell-mediated immunity by directlystimulating cytotoxic T cells.[12-14] Thalidomide inhibits angiogenesis inducedby fibroblast growth factor and vascular endothelial growth factor in a rabbitcornea micropocket assay and murine model corneal vascularization.[10,11] Italso causes apoptosis of established tumor-associated angiogenesis.Renal-cell carcinoma is highly vascular and quite immunogenic. These propertiesmay make it particularly sensitive to thalidomide’s effects.
The antitumor properties of thalidomide are being evaluatedextensively in various malignant diseases. Presently, only limited data of theefficacy, toxicity, and dose range are available. The prolonged responses tothalidomide in some patients with advanced, previously treated renal-cellcarcinoma suggest that the mechanism of action of thalidomide is distinctlydifferent from that of other agents.[15,16] Thalidomide increases the totalnumber of lymphocytes as well as CD8+ and CD4+T-cell counts, along with substantially increasing mean plasma levels of solubleinterleukin-2 receptor.
Thalidomide in Combination
The above-mentioned properties and the absence of severe adverseeffects suggest that thalidomide could be an ideal agent for use in combinationwith interleukin-2 or other adaptive immunotherapeutic strategies. With theabsence of myelosuppression, thalidomide is being evaluated in combination withchemotherapy. This approach has merit, as it has been shown to have greaterantitumor activity than chemotherapy alone in a murine model of breastcancer. This may be a rationale for combining thalidomide withbiochemotherapy as a possible way of reducing side effects and increasingefficacy of treatment for renal-cell carcinoma.
The toxicity profile of antiangiogenic agents is varied and isquite different from cytotoxic agents. The grading of some toxicities isdifficult with the use of present grading systems. Although many drugs have onlygrade 1 and 2 side effects, the need for long-term use makes even moderate sideeffects significant for patients’ quality of life. This will need to beaddressed in further studies with thalidomide and other antiangiogenic agents.The most common adverse events observed with thalidomide aresomnolence/drowsiness, dizziness/orthostatic hypertension, constipation, andrash. Peripheral neuropathy, neutropenia, and bradycardia may also occur. Themost serious toxicity associated with thalidomide is its documented humanteratogenicity.
Although only a small number of studies of previously treatedprogressive patients with renal-cell carcinoma have been performed, thalidomideis thought to have activity in this disease. It can induce marked and durableresponses in some patients with renal-cell carcinoma, as demonstrated in thiscase report. Further studies of thalidomide are therefore warranted in patientswith renal-cell carcinoma. Issues that would need to be addressed are asfollows:
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, collectingdata on quality of life, evaluating the changes in tumor perfusion, evaluatingchanges in tumor tissue, and developing laboratory correlative studies areessential.
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics,1999. CA Cancer J Clin 49:8-31, 1999.
2. Stadler WM, Vogelzang NJ: Low-dose interleukin-2 in thetreatment of metastatic renal cell carcinoma. Semin Oncol 22:67-73, 1995.
3. Hawkins MJ: Immunotherapy with high-dose interleukin-2, inVogelzang NJ, Scardino PT, Shipley WU, et al (eds): Comprehensive Textbook ofGenital Urinary Oncology, pp 242-247. Baltimore, Williams & Wilkins, 1996.
4. Minasian LM, Motzer RJ, Cluck L, et al: Interferon alpha 2Ain advanced renal cell carcinoma: Treatment results and survival in 159 patientswith long-term follow-up. J Clin Oncol 11:1368-1375, 1993.
5. Negrier S, Escudier D, Lasset C, et al: Recombinant humaninterleukin-2, recombinant human interferon alpha 2A or both in metastatic renalcell carcinoma. N Engl J Med 338:1272-1278, 1998.
6. Chapman AE, Goldstein LJ: Multiple drug resistance: Biologicbasis and clinical significance in renal cell carcinoma. Semin Oncol 22:17-28,1995.
7. Kim WJ, Kakehi Y, Kinoshita H, et al: Expression patterns ofmultidrug-resistance (MDRI), multidrug resistance-associated protein (MRP),glutathione-S-transferase-pi (GST-pi) and DNA topoisomerase II (Topo II) genesin renal cell carcinomas in normal kidney. J Urol 156:506-511, 1996.
8. Battekay EJ: Angiogenesis: Mechanistic insights, neovasculardisease, and therapeutic prospects. J Mol Med 73:333-346, 1995.
9. Folkman J: Angiogenesis in cancer, vascular, rheumatoid andother disease. Natl Med 1:27-31, 1995.
10. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is aninhibitor of angiogenesis. Pro Natl Acad Sci USA 91:4082-4085, 1994.
11. Kenyon BM, Browne F, D’Amato RJ: Affects of thalidomideand related metabolists in a mouse corneal model of neovascularization. Exp Eye64:971-978, 1997.
12. Sampaio EP, Sarno EN, Galill YR, et al: Thalidomideselectively inhibits tumor necrosis factor alpha production by stimulated humanmonocytes. J Exp Med 173:669-703, 1991.
13. Corral LJ, Mueller GW, Moreira AL, et al: Selection of novelanalogs of thalidomide with enhanced tumor necrosis factor alpha inhibitoryactivity. Mol Med 2:506-515, 1996.
14. Haslett PAJ, Corral LJ, Albert M, et al: Thalidomideco-stimulates primary human T lymphocytes, preferentially inducingproliferation, cytokine production, and cytotoxic responses in the CDA positivesubset. J Exp Med 187:1885-1892, 1998.
15. Minor D, Elias L: Thalidomide treatment of metastatic renalcell carcinoma (abstract 1384). Proc Am Soc Clin Oncol 19:352a, 2000.
16. Eisen T, Boshoff C, Mak I, et al: Continuous low-dosethalidomide: A phase 2 study on advanced melanoma, renal cell, ovarian andbreast cancer. Br J Cancer 82(4):812-817, 2000.
17. McHugh SM, Rifkin IR, Deighton J, et al: Theimmunosuppressive drug thalidomide induces T helper cells type 2 (Th2) andconcomitantly inhibits Th1 cytokine production in myogen and antigen stimulatedhuman blood peripheral blood mononuclear cell cultures. Clin Exp Immun99:160-167, 1995.
18. Nguyen M, Tran C, Barsky JR, et al: Thalidomide andchemotherapy combination: Preliminary results of pre-clinical and clinicalstudies. Int J Oncol 10:965-969, 1997.