Randomized Phase II Study Comparing Thalidomide With Medroxyprogesterone Acetate in Patients With Metastatic Renal Cell Carcinoma
the Department of Medicine, Royal Marsden Hospital, and Department of Clinical Neurophysiology, Chelsea and Westminster Hospital, London
St James's University Hospital, Leeds
Yorkshire Cancer Research Academic Unit of Oncology, Weston Park Hospital, Sheffield, United Kingdom
ABSTRACT
PURPOSE: To investigate escalating doses of thalidomide compared with medroxyprogesterone in patients with metastatic renal cell carcinoma (RCC), who had either progressed after first-line immunotherapy or who were not suitable for immunotherapy.
PATIENTS AND METHODS: Thalidomide was started at 100 mg/d orally (PO) and escalated by 100 mg/d every 2 weeks to the maximum dose of 400 mg/d. Medroxyprogesterone was given at a fixed dose of 300 mg PO daily.
RESULTS: Sixty patients were entered (thalidomide:medroxyprogesterone = 29:31; median age, 59 [thalidomide], 60 [medroxyprogesterone]; No. of patients assessable for response, 22 [thalidomide], 26 [medroxyprogesterone]). In the thalidomide arm, there was no objective response seen. The best response was SD in three patients lasting 5+, 6+, and 12 months, respectively. All patients in the medroxyprogesterone arm progressed. There was no difference in overall survival between the two arms; median survival in the thalidomide arm was 8.2 months compared with 4.8 months in the medroxyprogesterone arm (P = .62). Hazard ratio was 0.88 (95% CI, 0.67 to 1.94). Median duration of treatment was 73 days (range, 14 to 364 days) in the thalidomide arm, and 84 days (range, 7 to 175 days) in the medroxyprogesterone arm. The high incidence of toxicity in the thalidomide arm, mainly somnolence, constipation, fatigue and paraesthesia, meant that only 30.8% of patients were able to tolerate the maximum dose of 400 mg/d of treatment.
CONCLUSION: Thalidomide is not superior to medroxyprogesterone acetate in patients with metastatic RCC. Its risk/benefit ratio does not favor its use in this patient population.
INTRODUCTION
Patients with metastatic renal cell carcinoma (RCC) generally have a poor prognosis, with 5-year survival of less than 10% for patients with stage IV disease.1 Treatment options for metastatic disease are limited as RCC is largely resistant to chemotherapy.2 The standard first-line treatment is immunotherapy with interferon- or interleukin-2 as monotherapy or combination treatment, with an overall response rate of 10% to 20%.2,3 However, immunotherapy is associated with significant toxicity particularly at high-doses.
Thalidomide is a drug with immunomodulatory as well as antiangiogenic properties. It reduces the expression of potent angiogenic factors such as basic fibroblast growth factor, vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF).4,5 It suppresses TNF production by enhancing the degradation of TNF mRNA in monocytes.6,7 This mechanism of action probably explains its therapeutic effect in non-neoplastic conditions such as oral aphthous ulcers in patients with HIV,8 graft-versus-host disease,9 and erythema nodosum leprosum, which was associated with a decrease in TNF levels following treatment.10 In patients with pulmonary tuberculosis, treatment with thalidomide was shown to lead to significant weight gain, with an associated reduction in TNF level.11
Thalidomide has been shown to be active in some malignant conditions, including Kaposi's sarcoma,12,13 multiple myeloma,14 and hormone-refractory metastatic prostate cancer.15,16 We initially investigated low-dose thalidomide (100 mg/d) in patients with a variety of solid malignancy, including melanoma, breast, renal cell, and ovarian cancer.17 In this study, three of 18 patients with metastatic RCC showed partial responses (PRs), while a further three patients experienced stable disease (SD) for up to 6 months. No objective responses were seen in patients with the other tumor types. In a subsequent study, we investigated high-dose thalidomide (600 mg/d) in patients with metastatic RCC.18 Two of 22 patients experienced PR and a further seven patients experienced SD for more than 6 months.18 Furthermore, analysis of angiogenic markers showed a statistically significant decrease in levels of TNF during treatment in patients who experienced PR or SD (P = .05). The mean pretreatment level of TNF was also found to be higher in patients who derived clinical benefit from the treatment, compared with patients who did not, supporting the antiangiogenic effect of thalidomide. However, there was a high incidence of significant toxicities seen at 600 mg/d, and 400 mg/d was, therefore, proposed as the target dose in this study.
Hormonal agents, such as medroxyprogesterone, were initially shown to be active in metastatic RCC in the 1960s, although the response rates reported in various studies were modest, ranging between 7% and 25%.19-21 Despite this, it is currently being used in some countries in patients who have failed first-line treatment with immunotherapy, given it is generally well tolerated.21
In view of the promising results seen with thalidomide in previous studies above, we planned a randomized phase II/III study to investigate the activity of thalidomide at a dose of 400 mg/d, compared with medroxyprogesterone, as a standard treatment in patients with metastatic RCC, who had progressed on first-line immunotherapy or who were not suitable for immunotherapy.
PATIENTS AND METHODS
Study Design
This was a multicenter, randomized phase II/III study with the primary end point of response rate and the secondary end point of toxicity of thalidomide treatment in patients with metastatic RCC.
Patients
Inclusion criteria were histologically-proven metastatic RCC of any histologic subtype, patient should not be suitable for immunotherapy, measurable disease (at least one lesion 1 cm in diameter) where the only assessable disease is bone metastasis and the lesions must be visible on plain x-ray or computed tomography scan, three sites of metastatic disease, any marker lesion used to assess response must not have been irradiated, life expectancy 12 weeks, Eastern Clinical Oncology Group performance status 2, white cell count > 3.4 x 109/L, platelets > 99 x 109/L, serum creatinine less than 2.5x upper limit of the normal range or 51Cr-EDTA > 59 mL/min, and liver function less than 1.5x upper limit of the normal range unless patient had liver metastasis.
Exclusion criteria were prior treatment with thalidomide or medroxyprogesterone (prior treatment with interferon-, interleukin-2, or combined biochemotherapy was allowed), anticancer treatment in the previous 4 weeks, previous history of a second malignancy other than nonmelanoma skin cancer or cervical carcinoma-in-situ, major surgery in the past 3 weeks, pre-existing peripheral neuropathy grade 2, or pregnant or breast-feeding patients.
The study protocol was approved by the ethics committee of all participating centers. All patients gave written informed consent.
Treatment
Following pretreatment assessment, patients were randomly assigned to receive either thalidomide or medroxyprogesterone. Patients randomly assigned to receive thalidomide followed this dose escalation scheme provided it was well tolerated: 100 mg orally nightly for the first 2 weeks, 200 mg nightly for the second 2 weeks, 300 mg nightly for the third 2 weeks, and 400 mg nightly, thereafter. Patients who tolerated treatment poorly would have their dose interrupted or reduced to the previous dose level on resolution or improvement of toxicity. Patients were advised to take thalidomide at least 2 hours following their evening meal as this appeared to reduce treatment-related fatigue.
Patients randomly assigned to receive medroxyprogesterone were treated at a fixed dose of 300 mg orally daily.
In both arms, treatment was continued until the occurrence of progressive disease or unacceptable toxicity. However, patients were allowed to continue treatment for palliative benefit despite objective evidence of disease progression at the investigator's discretion.
Thalidomide was provided by Penn Pharmaceuticals, Gwent, Wales, UK, in 100 mg capsules.
Assessment of response and toxicity. The following baseline clinical assessment and investigations were performed within 4 weeks of starting treatment: full blood count, serum biochemistry, liver function tests, erythrocyte sedimentation rate and lactate dehydrogenase, sensory nerve action potential (SNAP) test, tumor assessment with x-rays, computed tomography or magnetic resonance imaging scan.
Toxicities were assessed using National Cancer Institute Common Toxicity Criteria (Version 2). Following commencement of treatment, toxicity assessment was performed at 1, 3, and 6 months and then 3-monthly, thereafter. Laboratory investigations, as above, were performed every 3 months.
Imaging of tumor for response was performed at 3 and 6 months after commencement of treatment then 6-monthly, thereafter. Response was assessed according to the WHO criteria. A SNAP test was performed on the observation of thalidomide-related neurologic toxicity of any grade, and repeated 4 to 6 weeks, following thalidomide dose modification, and every 2 months until the SNAP test result stabilized or improved to baseline.
Patients who received treatment for 4 weeks were assessable for response to treatment.
Thalidomide dose modification. In patients who experienced treatment-related neurologic toxicity requiring a SNAP test, a deterioration of 40% compared with the baseline value required a 50% dose reduction. The SNAP test was then repeated in 4 to 6 weeks. If this was stable or had improved, the patient was allowed to continue on the reduced dose. If there had been a further 10% deterioration in the SNAP test result compared with the baseline value, then thalidomide was discontinued and the patient was taken off study. The patient was then followed up every 2 months until the SNAP test result stabilized.
Patients who experienced unacceptable side effects had their thalidomide dose reduced by 100 mg/d each time.
Statistical considerations. This trial was designed as a randomized phase II/III study. The phase II study would be assessed primarily on the response rates after the admission of the first 60 patients. From a previous Medical Research Council study,22 the response rate to medroxyprogesterone in metastatic RCC was found to be approximately 2%. One hundred seventy-six patients were treated with medroxyprogesterone in that study, giving an upper 95% CI for response rate of 5.3%. Assuming a response rate of 15% to thalidomide from a previous phase II study, with the entry of 30 patients there would be 67% power to demonstrate that the response rate had a lower 95% CI, which was higher than 5.3%. The 30 patients treated with medroxyprogesterone would be used to confirm that the response rate was of the order of 2% in this arm. If, after the admission of 30 patients, the response rate to thalidomide had a lower 95% CI of less than 5.3%, then the decision as to whether to proceed with the phase III study would be made depending on the response rates and survival in both arms.
The phase III study would be assessed primarily on survival at 1 year in the two arms. It was expected that approximately 30% of patients receiving medroxyprogesterone would survive a year. Assuming a two-sided significance level of 5% (5% type I error) and 90% power (10% type II error), then to detect an increase in 1-year survival rate to 45% it would be necessary to randomly assign 205 patients in each arm. It was expected that 3 years of accrual time and an additional 3 years of follow-up time would be required to complete the study.
The Breslow-Day 2 and McNemar tests for trend would be used to assess differences in quality of life. Survival analysis would be generated using the Kaplan-Meier life-table method.
RESULTS
Demographics
Between July 2000 and December 2002, 60 patients were entered onto the study at the three participating centers in the United Kingdom: The Royal Marsden Hospital (London and Sutton sites), St James's University Hospital (Leeds), and Weston Park Hospital (Sheffield).
After randomization, 29 patients were treated with thalidomide and 31 patients received medroxyprogesterone (Table 1). Patients were stratified according to the treating center and their treatment status at study entry (whether they had progressed after standard first-line immunotherapy or they were not suitable for standard immunotherapy). Four of these patients were later declared ineligible (two patients in each arm did not have histologic diagnosis).
Response and Survival
In the thalidomide arm, 22 patients were assessable for response. Seven patients were not assessable because of treatment period less than 4 weeks (n = 4), lost to follow-up (n = 1), and patient ineligible (n = 2). There were no complete responses or PRs. Three patients (10.3%) experienced SD, which lasted 5+ (175 days), 6+ (182 days), and 12 months (364 days), respectively, before they eventually progressed; the maximum doses achieved were 200 mg/d, 300 mg/d, and 300 mg/d, respectively. All three patients had evidence of progressive disease on imaging before study entry. All the other patients progressed. On the basis of the intention-to-treat analysis (n = 28), median duration of treatment was 73 days (range, 14 to 364 days). The percentages of patients who received treatment for less than 8 weeks, 8 to 12 weeks, and > 12 weeks are 38.5%, 26.9%, and 34.6%, respectively.
In the medroxyprogesterone arm, 26 patients were assessable for response. Five patients were not assessable because of treatment period less than 4 weeks (n = 2), lost to follow-up (n = 1), and patient ineligible (n = 2). All assessable patients progressed on treatment. On the basis of the intention-to-treat analysis (n = 29), median duration of treatment was 84 days (range, 7 to 175 days).
Median survival of patients treated with thalidomide (n = 29) was 8.2 months (245 days) compared with 4.8 months (144 days) in the medroxyprogesterone arm (n = 31; P = .62; Fig 1). Hazard ratio was 0.88 (95% CI, 0.67 to 1.94). Five patients are still alive at last follow-up.
Time to treatment failure on the basis of the intention-to-treat analysis showed no difference between the two groups (Fig 2). Median time to treatment failure in the thalidomide arm was 74 days (range, 14 to 364 days) compared with 84 days (range, 7 to 175 days) in the medroxyprogesterone arm (P = .89), with a hazard ratio of 0.96 (95% CI, 0.58 to 1.61)
Toxicity
Twenty-six patients in the thalidomide arm were assessable for toxicity on the basis of the intention-to-treat analysis. Three patients, who were lost to follow-up, were not assessable.
The most common toxicities were somnolence, constipation, fatigue, and paraesthesia (Table 2). Less common toxicities included rash and nausea. Of the 26 assessable patients, three patients came off study after less than 3 weeks because of grade 2 somnolence and grade 3 fatigue at 200 mg/d (n = 1), grade 3 arrhythmia (supraventricular tachycardia) at 100 mg/d (n = 1), and pulmonary embolus at 200 mg/d (n = 1). The other 23 patients had at least 4 weeks' treatment. Constipation was generally manageable using standard supportive measures, while somnolence and fatigue mostly improved on dose interruption or cessation. Of the seven patients who developed paraesthesia, five patients reported improvement or resolution of their symptoms on dose interruption or reduction; this includes one patient who developed grade 3 paresthesia, whose SNAP tests subsequently improved back to baseline. The progress of two patients who developed grade 1 paraesthesia is unknown as they were lost to follow-up. Two patients in the thalidomide arm developed thromboembolic events. The only hematologic toxicity was grade 1 neutropenia (n = 4). None of these were of clinical consequence and all resolved completely either while still on treatment (n = 3) or on cessation of treatment (n = 1). There were no other hematologic or biochemical toxicities seen.
Of the 26 patients assessable for toxicity, thalidomide was discontinued because of disease progression (n = 16; 61.5%), development of disease-related complications (n = 4; 15.4%), drug-related toxicity (n = 5; 19.2%), which included fatigue (n = 2), somnolence (n = 1), dizziness (n = 1), and arrhythmia (n = 1), and thromboembolic event (n = 1; 3.8%).
Eight patients (30.8%) were able to tolerate the maximum dose of 400 mg/d of thalidomide with a median duration of treatment of 90 days (range, 79 to 120 days). The other patients received lower doses (100 to 300 mg/d) of thalidomide.
In the medroxyprogesterone arm, 28 patients were assessable for toxicity (Table 2). Three patients were not assessable because of being lost to follow-up (n = 2) and withdrawal from study (n = 1). Treatment was well tolerated with no grade 4 toxicities seen. Peripheral edema was the most common toxicity, which was generally mild and infrequent. One patient experienced grade 3 arrhythmia (supraventricular tachycardia). This patient died a month later from progressive disease.
DISCUSSION
Several phase II studies of single-agent thalidomide in metastatic RCC have been reported recently. Most of these studies showed an overall response rate varying between 0% and 17%, and a disease stabilization rate varying between 10% and 64% (Table 3). We report the first randomized phase II/III study of thalidomide compared with another treatment, which in this study is medroxyprogesterone acetate, in patients with metastatic RCC.
In the present study, there was no objective response seen in the thalidomide arm. The best response was disease stabilization in three (10.3%) of 29 patients lasting 5 to 12 months. Two of these patients had not had resection of their primary tumor. None of them were able to tolerate 400 mg/d of thalidomide, and, therefore, were treated with lower doses of 200 mg/d (n = 1) and 300 mg/d (n = 2) until disease progression. This SD rate is not statistically significant (P = .11) when compared with the medroxyprogesterone group. Furthermore, there was no statistically significant difference in median overall survival. Nevertheless, useful information regarding tolerability of thalidomide was obtained from this study.
The overall response rate observed in this study is significantly lower than that seen in other studies (Table 3). In all of these, except the study by Eisen et al,17 the dose of thalidomide used was significantly higher (target dose, 600 to 1,200 mg/d), which could explain the lower rate of overall response seen in our study. Furthermore, a large percentage of patients (38.5%) in the thalidomide arm in this study received less than 8 weeks’ treatment, which may not be adequate to produce an effect significant enough to be considered a radiologic response, given the cytostatic rather than cytotoxic mechanism of action of thalidomide,23 which also had to be interrupted in a significant number of patients in this study because of toxicity. There are intrinsic difficulties in assessing the efficacy of cytostatic drugs such as thalidomide using conventional response criteria that define response to treatment as objective tumor shrinkage, which may not be the appropriate end point for antiangiogenic agents.24-26 It has been suggested that surrogate end points for efficacy such as progression-free survival or time to progression, should be used instead of response rate in studies of cytostatic agents.24-26 In this study, we were not able to measure time to progression given that the majority of assessable patients (86.4%) in the thalidomide arm progressed in the first 3 months of study. Analysis of time to treatment failure as a surrogate end point for response did not show a statistically significant difference between the two groups.
Thalidomide was not as well tolerated as medroxyprogesterone, with 18 patients (69.2%) failing to achieve the target dose of 400 mg/d because of toxicity or disease-related complications. Only 30.8% patients were able to tolerate the planned maximum dose of 400 mg/d. The most common side effects observed were constipation, fatigue, somnolence, and neurologic toxicity consistent with previous data. The incidence of grade 3 or 4 toxicities was low compared with other studies using doses of thalidomide higher than 400 mg daily, up to 1,200 mg daily.27-33 Peripheral neuropathy was relatively common (26.9%), although this was mild and reversible in all cases where there was follow-up.
The findings of this study support the results of a recent randomized phase III study comparing the combination of interferon- and thalidomide with interferon- alone in previously untreated patients.34 In the combination arm, the target dose of thalidomide was 1,000 mg/d, which is higher than that in our study, although a majority of patients were not able to tolerate doses greater than 600 mg/d. There was no statistically significant difference in overall response rate, progression-free, or overall survival between the two groups. Toxicity was higher in the combination arm, as expected.
The present study has shown that single-agent thalidomide is inactive, and that the risk/benefit ratio clearly does not favor the use of thalidomide in this patient population. This study confirms data from the randomized phase III study by Gordon et al,34 showing the lack of activity of thalidomide, and was, therefore, not taken to phase III stage. We believe thalidomide should not be used in patients with advanced or metastatic RCC outside the setting of a clinical trial. Furthermore, several new antiangiogenic agents have recently been developed, which may have more promising activity in metastatic RCC, a tumor often driven by mutation or hypermethylation of Von Hippel-Lindau and consequent overexpression of VEGF and platelet-derived growth factor. For example, bevacizumab, a neutralizing antibody against VEGF, has been shown to prolong time to disease progression in patients with metastatic RCC.35 Other relevant new agents include the kinase inhibitor BAY 43-9006 (sorafenib)36,37 and SU11248 (sunitinib),38 both of which have shown promising results in clinical trials to date.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Author Contributions
Conception and design: Poulam M. Patel, Peter J. Selby, Ian Mak, Roger A'Hern, Martin E. Gore, Tim Eisen
Financial support: Tim Eisen
Administrative support: Lynda Pyle, Maggie G. James, Debbie A. Beirne, Sarah Steeds, Tim Eisen
Provision of study materials or patients: Poulam M. Patel, Peter J. Selby, Barry W. Hancock, Ian Mak, Martin E. Gore, Tim Eisen
Collection and assembly of data: Chooi P. Lee, Lynda Pyle, Maggie G. James, Debbie A. Beirne, Sarah Steeds, Martin E. Gore, Tim Eisen
Data analysis and interpretation: Chooi P. Lee, Poulam M. Patel, Peter J. Selby, Ian Mak, Roger A'Hern, Martin E. Gore, Tim Eisen
Manuscript writing: Chooi P. Lee, Poulam M. Patel, Peter J. Selby, Ian Mak, Lynda Pyle, Maggie G. James, Debbie A. Beirne, Sarah Steeds, Roger A'Hern, Martin E. Gore, Tim Eisen
Final approval of manuscript: Chooi P. Lee, Poulam M. Patel, Peter J. Selby, Barry W. Hancock, Ian Mak, Lynda Pyle, Maggie G. James, Debbie A. Beirne, Sarah Steeds, Roger A'Hern, Martin E. Gore, Tim Eisen
Acknowledgment
We thank David Chao, PhD, MRCP, for useful discussions.
NOTES
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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St James's University Hospital, Leeds
Yorkshire Cancer Research Academic Unit of Oncology, Weston Park Hospital, Sheffield, United Kingdom
ABSTRACT
PURPOSE: To investigate escalating doses of thalidomide compared with medroxyprogesterone in patients with metastatic renal cell carcinoma (RCC), who had either progressed after first-line immunotherapy or who were not suitable for immunotherapy.
PATIENTS AND METHODS: Thalidomide was started at 100 mg/d orally (PO) and escalated by 100 mg/d every 2 weeks to the maximum dose of 400 mg/d. Medroxyprogesterone was given at a fixed dose of 300 mg PO daily.
RESULTS: Sixty patients were entered (thalidomide:medroxyprogesterone = 29:31; median age, 59 [thalidomide], 60 [medroxyprogesterone]; No. of patients assessable for response, 22 [thalidomide], 26 [medroxyprogesterone]). In the thalidomide arm, there was no objective response seen. The best response was SD in three patients lasting 5+, 6+, and 12 months, respectively. All patients in the medroxyprogesterone arm progressed. There was no difference in overall survival between the two arms; median survival in the thalidomide arm was 8.2 months compared with 4.8 months in the medroxyprogesterone arm (P = .62). Hazard ratio was 0.88 (95% CI, 0.67 to 1.94). Median duration of treatment was 73 days (range, 14 to 364 days) in the thalidomide arm, and 84 days (range, 7 to 175 days) in the medroxyprogesterone arm. The high incidence of toxicity in the thalidomide arm, mainly somnolence, constipation, fatigue and paraesthesia, meant that only 30.8% of patients were able to tolerate the maximum dose of 400 mg/d of treatment.
CONCLUSION: Thalidomide is not superior to medroxyprogesterone acetate in patients with metastatic RCC. Its risk/benefit ratio does not favor its use in this patient population.
INTRODUCTION
Patients with metastatic renal cell carcinoma (RCC) generally have a poor prognosis, with 5-year survival of less than 10% for patients with stage IV disease.1 Treatment options for metastatic disease are limited as RCC is largely resistant to chemotherapy.2 The standard first-line treatment is immunotherapy with interferon- or interleukin-2 as monotherapy or combination treatment, with an overall response rate of 10% to 20%.2,3 However, immunotherapy is associated with significant toxicity particularly at high-doses.
Thalidomide is a drug with immunomodulatory as well as antiangiogenic properties. It reduces the expression of potent angiogenic factors such as basic fibroblast growth factor, vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF).4,5 It suppresses TNF production by enhancing the degradation of TNF mRNA in monocytes.6,7 This mechanism of action probably explains its therapeutic effect in non-neoplastic conditions such as oral aphthous ulcers in patients with HIV,8 graft-versus-host disease,9 and erythema nodosum leprosum, which was associated with a decrease in TNF levels following treatment.10 In patients with pulmonary tuberculosis, treatment with thalidomide was shown to lead to significant weight gain, with an associated reduction in TNF level.11
Thalidomide has been shown to be active in some malignant conditions, including Kaposi's sarcoma,12,13 multiple myeloma,14 and hormone-refractory metastatic prostate cancer.15,16 We initially investigated low-dose thalidomide (100 mg/d) in patients with a variety of solid malignancy, including melanoma, breast, renal cell, and ovarian cancer.17 In this study, three of 18 patients with metastatic RCC showed partial responses (PRs), while a further three patients experienced stable disease (SD) for up to 6 months. No objective responses were seen in patients with the other tumor types. In a subsequent study, we investigated high-dose thalidomide (600 mg/d) in patients with metastatic RCC.18 Two of 22 patients experienced PR and a further seven patients experienced SD for more than 6 months.18 Furthermore, analysis of angiogenic markers showed a statistically significant decrease in levels of TNF during treatment in patients who experienced PR or SD (P = .05). The mean pretreatment level of TNF was also found to be higher in patients who derived clinical benefit from the treatment, compared with patients who did not, supporting the antiangiogenic effect of thalidomide. However, there was a high incidence of significant toxicities seen at 600 mg/d, and 400 mg/d was, therefore, proposed as the target dose in this study.
Hormonal agents, such as medroxyprogesterone, were initially shown to be active in metastatic RCC in the 1960s, although the response rates reported in various studies were modest, ranging between 7% and 25%.19-21 Despite this, it is currently being used in some countries in patients who have failed first-line treatment with immunotherapy, given it is generally well tolerated.21
In view of the promising results seen with thalidomide in previous studies above, we planned a randomized phase II/III study to investigate the activity of thalidomide at a dose of 400 mg/d, compared with medroxyprogesterone, as a standard treatment in patients with metastatic RCC, who had progressed on first-line immunotherapy or who were not suitable for immunotherapy.
PATIENTS AND METHODS
Study Design
This was a multicenter, randomized phase II/III study with the primary end point of response rate and the secondary end point of toxicity of thalidomide treatment in patients with metastatic RCC.
Patients
Inclusion criteria were histologically-proven metastatic RCC of any histologic subtype, patient should not be suitable for immunotherapy, measurable disease (at least one lesion 1 cm in diameter) where the only assessable disease is bone metastasis and the lesions must be visible on plain x-ray or computed tomography scan, three sites of metastatic disease, any marker lesion used to assess response must not have been irradiated, life expectancy 12 weeks, Eastern Clinical Oncology Group performance status 2, white cell count > 3.4 x 109/L, platelets > 99 x 109/L, serum creatinine less than 2.5x upper limit of the normal range or 51Cr-EDTA > 59 mL/min, and liver function less than 1.5x upper limit of the normal range unless patient had liver metastasis.
Exclusion criteria were prior treatment with thalidomide or medroxyprogesterone (prior treatment with interferon-, interleukin-2, or combined biochemotherapy was allowed), anticancer treatment in the previous 4 weeks, previous history of a second malignancy other than nonmelanoma skin cancer or cervical carcinoma-in-situ, major surgery in the past 3 weeks, pre-existing peripheral neuropathy grade 2, or pregnant or breast-feeding patients.
The study protocol was approved by the ethics committee of all participating centers. All patients gave written informed consent.
Treatment
Following pretreatment assessment, patients were randomly assigned to receive either thalidomide or medroxyprogesterone. Patients randomly assigned to receive thalidomide followed this dose escalation scheme provided it was well tolerated: 100 mg orally nightly for the first 2 weeks, 200 mg nightly for the second 2 weeks, 300 mg nightly for the third 2 weeks, and 400 mg nightly, thereafter. Patients who tolerated treatment poorly would have their dose interrupted or reduced to the previous dose level on resolution or improvement of toxicity. Patients were advised to take thalidomide at least 2 hours following their evening meal as this appeared to reduce treatment-related fatigue.
Patients randomly assigned to receive medroxyprogesterone were treated at a fixed dose of 300 mg orally daily.
In both arms, treatment was continued until the occurrence of progressive disease or unacceptable toxicity. However, patients were allowed to continue treatment for palliative benefit despite objective evidence of disease progression at the investigator's discretion.
Thalidomide was provided by Penn Pharmaceuticals, Gwent, Wales, UK, in 100 mg capsules.
Assessment of response and toxicity. The following baseline clinical assessment and investigations were performed within 4 weeks of starting treatment: full blood count, serum biochemistry, liver function tests, erythrocyte sedimentation rate and lactate dehydrogenase, sensory nerve action potential (SNAP) test, tumor assessment with x-rays, computed tomography or magnetic resonance imaging scan.
Toxicities were assessed using National Cancer Institute Common Toxicity Criteria (Version 2). Following commencement of treatment, toxicity assessment was performed at 1, 3, and 6 months and then 3-monthly, thereafter. Laboratory investigations, as above, were performed every 3 months.
Imaging of tumor for response was performed at 3 and 6 months after commencement of treatment then 6-monthly, thereafter. Response was assessed according to the WHO criteria. A SNAP test was performed on the observation of thalidomide-related neurologic toxicity of any grade, and repeated 4 to 6 weeks, following thalidomide dose modification, and every 2 months until the SNAP test result stabilized or improved to baseline.
Patients who received treatment for 4 weeks were assessable for response to treatment.
Thalidomide dose modification. In patients who experienced treatment-related neurologic toxicity requiring a SNAP test, a deterioration of 40% compared with the baseline value required a 50% dose reduction. The SNAP test was then repeated in 4 to 6 weeks. If this was stable or had improved, the patient was allowed to continue on the reduced dose. If there had been a further 10% deterioration in the SNAP test result compared with the baseline value, then thalidomide was discontinued and the patient was taken off study. The patient was then followed up every 2 months until the SNAP test result stabilized.
Patients who experienced unacceptable side effects had their thalidomide dose reduced by 100 mg/d each time.
Statistical considerations. This trial was designed as a randomized phase II/III study. The phase II study would be assessed primarily on the response rates after the admission of the first 60 patients. From a previous Medical Research Council study,22 the response rate to medroxyprogesterone in metastatic RCC was found to be approximately 2%. One hundred seventy-six patients were treated with medroxyprogesterone in that study, giving an upper 95% CI for response rate of 5.3%. Assuming a response rate of 15% to thalidomide from a previous phase II study, with the entry of 30 patients there would be 67% power to demonstrate that the response rate had a lower 95% CI, which was higher than 5.3%. The 30 patients treated with medroxyprogesterone would be used to confirm that the response rate was of the order of 2% in this arm. If, after the admission of 30 patients, the response rate to thalidomide had a lower 95% CI of less than 5.3%, then the decision as to whether to proceed with the phase III study would be made depending on the response rates and survival in both arms.
The phase III study would be assessed primarily on survival at 1 year in the two arms. It was expected that approximately 30% of patients receiving medroxyprogesterone would survive a year. Assuming a two-sided significance level of 5% (5% type I error) and 90% power (10% type II error), then to detect an increase in 1-year survival rate to 45% it would be necessary to randomly assign 205 patients in each arm. It was expected that 3 years of accrual time and an additional 3 years of follow-up time would be required to complete the study.
The Breslow-Day 2 and McNemar tests for trend would be used to assess differences in quality of life. Survival analysis would be generated using the Kaplan-Meier life-table method.
RESULTS
Demographics
Between July 2000 and December 2002, 60 patients were entered onto the study at the three participating centers in the United Kingdom: The Royal Marsden Hospital (London and Sutton sites), St James's University Hospital (Leeds), and Weston Park Hospital (Sheffield).
After randomization, 29 patients were treated with thalidomide and 31 patients received medroxyprogesterone (Table 1). Patients were stratified according to the treating center and their treatment status at study entry (whether they had progressed after standard first-line immunotherapy or they were not suitable for standard immunotherapy). Four of these patients were later declared ineligible (two patients in each arm did not have histologic diagnosis).
Response and Survival
In the thalidomide arm, 22 patients were assessable for response. Seven patients were not assessable because of treatment period less than 4 weeks (n = 4), lost to follow-up (n = 1), and patient ineligible (n = 2). There were no complete responses or PRs. Three patients (10.3%) experienced SD, which lasted 5+ (175 days), 6+ (182 days), and 12 months (364 days), respectively, before they eventually progressed; the maximum doses achieved were 200 mg/d, 300 mg/d, and 300 mg/d, respectively. All three patients had evidence of progressive disease on imaging before study entry. All the other patients progressed. On the basis of the intention-to-treat analysis (n = 28), median duration of treatment was 73 days (range, 14 to 364 days). The percentages of patients who received treatment for less than 8 weeks, 8 to 12 weeks, and > 12 weeks are 38.5%, 26.9%, and 34.6%, respectively.
In the medroxyprogesterone arm, 26 patients were assessable for response. Five patients were not assessable because of treatment period less than 4 weeks (n = 2), lost to follow-up (n = 1), and patient ineligible (n = 2). All assessable patients progressed on treatment. On the basis of the intention-to-treat analysis (n = 29), median duration of treatment was 84 days (range, 7 to 175 days).
Median survival of patients treated with thalidomide (n = 29) was 8.2 months (245 days) compared with 4.8 months (144 days) in the medroxyprogesterone arm (n = 31; P = .62; Fig 1). Hazard ratio was 0.88 (95% CI, 0.67 to 1.94). Five patients are still alive at last follow-up.
Time to treatment failure on the basis of the intention-to-treat analysis showed no difference between the two groups (Fig 2). Median time to treatment failure in the thalidomide arm was 74 days (range, 14 to 364 days) compared with 84 days (range, 7 to 175 days) in the medroxyprogesterone arm (P = .89), with a hazard ratio of 0.96 (95% CI, 0.58 to 1.61)
Toxicity
Twenty-six patients in the thalidomide arm were assessable for toxicity on the basis of the intention-to-treat analysis. Three patients, who were lost to follow-up, were not assessable.
The most common toxicities were somnolence, constipation, fatigue, and paraesthesia (Table 2). Less common toxicities included rash and nausea. Of the 26 assessable patients, three patients came off study after less than 3 weeks because of grade 2 somnolence and grade 3 fatigue at 200 mg/d (n = 1), grade 3 arrhythmia (supraventricular tachycardia) at 100 mg/d (n = 1), and pulmonary embolus at 200 mg/d (n = 1). The other 23 patients had at least 4 weeks' treatment. Constipation was generally manageable using standard supportive measures, while somnolence and fatigue mostly improved on dose interruption or cessation. Of the seven patients who developed paraesthesia, five patients reported improvement or resolution of their symptoms on dose interruption or reduction; this includes one patient who developed grade 3 paresthesia, whose SNAP tests subsequently improved back to baseline. The progress of two patients who developed grade 1 paraesthesia is unknown as they were lost to follow-up. Two patients in the thalidomide arm developed thromboembolic events. The only hematologic toxicity was grade 1 neutropenia (n = 4). None of these were of clinical consequence and all resolved completely either while still on treatment (n = 3) or on cessation of treatment (n = 1). There were no other hematologic or biochemical toxicities seen.
Of the 26 patients assessable for toxicity, thalidomide was discontinued because of disease progression (n = 16; 61.5%), development of disease-related complications (n = 4; 15.4%), drug-related toxicity (n = 5; 19.2%), which included fatigue (n = 2), somnolence (n = 1), dizziness (n = 1), and arrhythmia (n = 1), and thromboembolic event (n = 1; 3.8%).
Eight patients (30.8%) were able to tolerate the maximum dose of 400 mg/d of thalidomide with a median duration of treatment of 90 days (range, 79 to 120 days). The other patients received lower doses (100 to 300 mg/d) of thalidomide.
In the medroxyprogesterone arm, 28 patients were assessable for toxicity (Table 2). Three patients were not assessable because of being lost to follow-up (n = 2) and withdrawal from study (n = 1). Treatment was well tolerated with no grade 4 toxicities seen. Peripheral edema was the most common toxicity, which was generally mild and infrequent. One patient experienced grade 3 arrhythmia (supraventricular tachycardia). This patient died a month later from progressive disease.
DISCUSSION
Several phase II studies of single-agent thalidomide in metastatic RCC have been reported recently. Most of these studies showed an overall response rate varying between 0% and 17%, and a disease stabilization rate varying between 10% and 64% (Table 3). We report the first randomized phase II/III study of thalidomide compared with another treatment, which in this study is medroxyprogesterone acetate, in patients with metastatic RCC.
In the present study, there was no objective response seen in the thalidomide arm. The best response was disease stabilization in three (10.3%) of 29 patients lasting 5 to 12 months. Two of these patients had not had resection of their primary tumor. None of them were able to tolerate 400 mg/d of thalidomide, and, therefore, were treated with lower doses of 200 mg/d (n = 1) and 300 mg/d (n = 2) until disease progression. This SD rate is not statistically significant (P = .11) when compared with the medroxyprogesterone group. Furthermore, there was no statistically significant difference in median overall survival. Nevertheless, useful information regarding tolerability of thalidomide was obtained from this study.
The overall response rate observed in this study is significantly lower than that seen in other studies (Table 3). In all of these, except the study by Eisen et al,17 the dose of thalidomide used was significantly higher (target dose, 600 to 1,200 mg/d), which could explain the lower rate of overall response seen in our study. Furthermore, a large percentage of patients (38.5%) in the thalidomide arm in this study received less than 8 weeks’ treatment, which may not be adequate to produce an effect significant enough to be considered a radiologic response, given the cytostatic rather than cytotoxic mechanism of action of thalidomide,23 which also had to be interrupted in a significant number of patients in this study because of toxicity. There are intrinsic difficulties in assessing the efficacy of cytostatic drugs such as thalidomide using conventional response criteria that define response to treatment as objective tumor shrinkage, which may not be the appropriate end point for antiangiogenic agents.24-26 It has been suggested that surrogate end points for efficacy such as progression-free survival or time to progression, should be used instead of response rate in studies of cytostatic agents.24-26 In this study, we were not able to measure time to progression given that the majority of assessable patients (86.4%) in the thalidomide arm progressed in the first 3 months of study. Analysis of time to treatment failure as a surrogate end point for response did not show a statistically significant difference between the two groups.
Thalidomide was not as well tolerated as medroxyprogesterone, with 18 patients (69.2%) failing to achieve the target dose of 400 mg/d because of toxicity or disease-related complications. Only 30.8% patients were able to tolerate the planned maximum dose of 400 mg/d. The most common side effects observed were constipation, fatigue, somnolence, and neurologic toxicity consistent with previous data. The incidence of grade 3 or 4 toxicities was low compared with other studies using doses of thalidomide higher than 400 mg daily, up to 1,200 mg daily.27-33 Peripheral neuropathy was relatively common (26.9%), although this was mild and reversible in all cases where there was follow-up.
The findings of this study support the results of a recent randomized phase III study comparing the combination of interferon- and thalidomide with interferon- alone in previously untreated patients.34 In the combination arm, the target dose of thalidomide was 1,000 mg/d, which is higher than that in our study, although a majority of patients were not able to tolerate doses greater than 600 mg/d. There was no statistically significant difference in overall response rate, progression-free, or overall survival between the two groups. Toxicity was higher in the combination arm, as expected.
The present study has shown that single-agent thalidomide is inactive, and that the risk/benefit ratio clearly does not favor the use of thalidomide in this patient population. This study confirms data from the randomized phase III study by Gordon et al,34 showing the lack of activity of thalidomide, and was, therefore, not taken to phase III stage. We believe thalidomide should not be used in patients with advanced or metastatic RCC outside the setting of a clinical trial. Furthermore, several new antiangiogenic agents have recently been developed, which may have more promising activity in metastatic RCC, a tumor often driven by mutation or hypermethylation of Von Hippel-Lindau and consequent overexpression of VEGF and platelet-derived growth factor. For example, bevacizumab, a neutralizing antibody against VEGF, has been shown to prolong time to disease progression in patients with metastatic RCC.35 Other relevant new agents include the kinase inhibitor BAY 43-9006 (sorafenib)36,37 and SU11248 (sunitinib),38 both of which have shown promising results in clinical trials to date.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Author Contributions
Conception and design: Poulam M. Patel, Peter J. Selby, Ian Mak, Roger A'Hern, Martin E. Gore, Tim Eisen
Financial support: Tim Eisen
Administrative support: Lynda Pyle, Maggie G. James, Debbie A. Beirne, Sarah Steeds, Tim Eisen
Provision of study materials or patients: Poulam M. Patel, Peter J. Selby, Barry W. Hancock, Ian Mak, Martin E. Gore, Tim Eisen
Collection and assembly of data: Chooi P. Lee, Lynda Pyle, Maggie G. James, Debbie A. Beirne, Sarah Steeds, Martin E. Gore, Tim Eisen
Data analysis and interpretation: Chooi P. Lee, Poulam M. Patel, Peter J. Selby, Ian Mak, Roger A'Hern, Martin E. Gore, Tim Eisen
Manuscript writing: Chooi P. Lee, Poulam M. Patel, Peter J. Selby, Ian Mak, Lynda Pyle, Maggie G. James, Debbie A. Beirne, Sarah Steeds, Roger A'Hern, Martin E. Gore, Tim Eisen
Final approval of manuscript: Chooi P. Lee, Poulam M. Patel, Peter J. Selby, Barry W. Hancock, Ian Mak, Lynda Pyle, Maggie G. James, Debbie A. Beirne, Sarah Steeds, Roger A'Hern, Martin E. Gore, Tim Eisen
Acknowledgment
We thank David Chao, PhD, MRCP, for useful discussions.
NOTES
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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