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Keywords:

  • angiogenesis inhibitor;
  • phase 2 trial;
  • platinum sensitivity;
  • recurrent ovarian cancer;
  • System for Thalidomide Education and Prescribing Safety

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Thalidomide is an antiangiogenic agent with immune modulating potential. The objective of this study was to determine response rates among women who were treated for recurrent ovarian cancer using topotecan with or without thalidomide.

METHODS.

Women were enrolled in this multicenter, prospective, randomized phase 2 trial between April 2001 and July 2005. Eligible patients had recurrent epithelial ovarian carcinoma with measurable disease or elevated CA 125 values. Patients had received prior platinum-based chemotherapy. Treatment arms received topotecan at a dose of 1.25 mg/m2 on Days 1 through 5 of a 21-day cycle with or without thalidomide starting at a dose of 200 mg per day and then increasing the dose as tolerated. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria. The chi-square test was used to assess differences in response and toxicity, and the log-rank test was used to compare Kaplan-Meier survival curves.

RESULTS.

The analysis included 69 women (39 women in the control arm and 30 women in the thalidomide arm). Known prognostic factors, including platinum sensitivity, were represented equally in each arm. The median thalidomide dose was 200 mg per day. The overall response rate in the control arm was 21% (complete response [CR] rate, 18%; partial response [PR] rate, 3%) compared with 47% in the thalidomide arm (CR rate, 30%; PR rate, 17%) (P = .03). The median progression-free survival for the control arm was 4 months compared with 6 months in the thalidomide arm (P = .02). The median overall survival was 15 months in the control arm and 19 months in the thalidomide arm (P = .67). Toxicities were similar between groups.

CONCLUSIONS.

The addition of thalidomide to topotecan for the treatment of recurrent ovarian cancer appears to improve response rates, and the authors believe that it warrants study through larger phase 3 trials. Cancer 2008. © 2007 American Cancer Society.

Ovarian cancer is the leading cause of death from gynecologic malignancies and the fifth most common cause of cancer death among women in the U.S.1 The development of new chemotherapy options has improved the 5-year and 10-year survival for women who are diagnosed with this disease; however, because an estimated 15,000 women die from ovarian cancer annually, there is a need for new, more effective treatment options.

Thalidomide (Celgene Corporation, Summit NJ) is an immune-modulating drug with sedative and antiemetic properties. It was used widely in Europe until its teratogenic effects led to its withdrawal from the market in 1961. Further research has suggested that the teratogenicity of thalidomide results from its ability to inhibit angiogenesis and neovascularization.2 It has been demonstrated that thalidomide inhibits basic fibroblast growth factor-induced and vascular endothelial growth factor (VEGF)-induced angiogenesis, stimulates the degradation of tumor necrosis factor α, and reduces cellular values of interleukin 6 (IL-6) and IL-12.3, 4. The immune-modulating effects of thalidomide include inducing the production of interferon γ, IL-2 and IL-105 and enhancing cell-mediated immunity through costimulation of T cells.6 Thalidomide alters adhesion molecule expression7 and suppresses urokinase receptor expression.8 All of these mechanisms have the potential to inhibit tumor growth, making thalidomide an attractive agent for the treatment of cancer.

The cytotoxicity of topotecan (GlaxoSmithKline, London, U.K.) results from its binding to topoisomerase-1. By binding to and stabilizing topoisomerase-DNA complexes, topotecan induces double-strand DNA breakage. Topotecan has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of recurrent ovarian cancer. There is some evidence that topotecan has an inhibitory effect on endothelial cells, inhibiting angiogenesis in vivo at rates similar to TNP-470, another potent angiogenesis inhibitor.9

Based on the array of mechanisms of action offered by thalidomide and topotecan and their antiangiogenic properties, we hypothesized that the combination of these 2 drugs would be more effective in the treatment of recurrent or persistent epithelial ovarian cancer than topotecan alone. To test this hypothesis, we designed a prospective randomized trial to compare the response rates after treatment with thalidomide and topotecan with the response rates after treatment with topotecan alone in women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Population

This study was coordinated by the University of Minnesota Women's Cancer Center, and patients were recruited from this and 6 additional sites. The institutional review boards at each site approved the protocol. Participants had histologically diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer and, although primary pathology reports were reviewed, we did not perform a central pathology review of specimens from the initial diagnosis. Eligible participants had 1 of the following diagnoses: 1) persistent cancer after primary chemotherapy with a platinum- and taxane-based regimen or 2) their first or second recurrence. To be enrolled at the time of the second recurrence, patients had to have platinum-sensitive disease (disease recurrence occurring >6 months after the completion of their initial treatment with a platinum- and taxane-based regimen) and either must have developed disease progression during treatment of this recurrence or had to be within 6 months of completing their second course of platinum-based chemotherapy. Recurrent or persistent disease was diagnosed by physical examination or an imaging study that identified disease measuring ≥2 cm or by a rising CA 125 value that was above normal. Patients had to have adequate hematologic counts (hemoglobin ≥10 g/dL, white blood cell count ≥3,000/mm3, platelets ≥100,000/mm3), normal renal function (creatinine ≤1.5 mg/dL) and liver function (serum bilirubin ≤2 mg/dL; aspartate and alanine aminotransferase values and alkaline phosphatase value ≤2 times the upper limit of normal), and a Gynecologic Oncology Group performance status ≤2. Patients were ineligible if they had previously received topotecan or thalidomide, had a history of other malignancies (except nonmelanoma skin cancer), were receiving immunotherapy or radiation therapy, or were of child-bearing potential. Patients had to be willing and able to comply with the FDA-mandated System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) program. Patients agreed to abide by the birth-control and pregnancy testing requirements of the S.T.E.P.S. program.

Although the use of anticoagulants was not dictated by the protocol, the majority of patients (all those who were treated at the University of Minnesota) received warfarin at a dose of 1 mg per day while they were on the protocol. When this trial was initiated, anticoagulation was the standard of care at our institution for women with subcutaneous intravenous ports. During the course of the study, this policy changed; however, patients in this study were continued on warfarin because of the reported risk of thrombosis in cancer patients receiving thalidomide.

Treatment Plan

Women in the control arm received topotecan at a dose of 1.25 mg/m2 intravenously as a 30-minute infusion for 5 consecutive days every 21 days. Although this is not the FDA-approved dose of topotecan, in the setting of recurrent ovarian cancer, this reduced dose has been recommended for heavily pretreated patients to decrease hematologic toxicity.10 In addition to topotecan at the dose described above, patients in the experimental arm received oral thalidomide starting at 200 mg per day. The thalidomide dose was increased by 100 mg per day every 14 days until patients experienced symptoms that we believed were associated with thalidomide, including severe constipation, somnolence, peripheral neuropathy, dizziness, rash, or nausea. In these situations, the thalidomide dose was reduced by 100 mg per day every 7 days until the side effect resolved. The dose at which the patient no longer experienced side effects was considered the maximum tolerated dose. The maximum (not target) dose allowed was 800 mg per day. All patients were given a bowel regimen consisting of dietary fiber, fluid intake, and laxatives to avoid constipation.

Assessment

At each visit, patients had a physical examination, a complete blood count with differential, platelet counts, serum chemistries, and CA 125. Thalidomide compliance was monitored by reviewing a patient diary at each visit. Patients were monitored for toxicity before each cycle by completing a toxicity profile and by physician/nurse assessment. In accordance with the standard practice at the University of Minnesota, tumor status was assessed after the third cycle of topotecan. In the patients who had measurable disease, assessment was made by using the same modality that was used at the time of their enrollment. Patients who were enrolled based on CA 125 were assessed by computed tomography scan as well as CA 125. Patients who had progressive disease after 3 cycles were removed from the protocol. Patients who were removed from the trial continued to be followed for toxicity and survival data. Adverse events were monitored by the principal investigator and the Data Safety Monitoring Committee of the University of Minnesota Cancer Center.

Endpoints

Our primary outcome was response, as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, in the patients who were enrolled based on measurable disease.11 The use of CA 125 as a measure of response in phase 2 trials was reviewed by Guppy and Rustin.12 We used their criteria in the current trial. For the patients who were enrolled based on an elevated CA 125 value, a partial response (PR) was defined as a 50% reduction in CA 125 when the value remained >30 U/mL if no new disease was observed on imaging studies. A complete response (CR) was defined as normalization of an elevated CA 125 value with a reduction ≥50% from the enrollment value, again, if there was no evidence of new disease on imaging studies. Progressive disease was defined as an elevation of 25% in the CA 125 value. A CA 125 response was confirmed by obtaining a repeat value within 60 days. Response was assessed after the third and sixth courses of topotecan or more frequently if warranted by symptoms or findings on physical examination. Secondary outcomes included progression-free survival (PFS), which was defined as the time from enrollment to the diagnosis of progression of cancer, and overall survival (OS), which was defined as the time from enrollment to death. Toxicity was graded according to version 2 of the National Cancer Institute Common Toxicity Criteria.

Statistical Analysis

Patients were assigned randomly to 1 of the 2 treatment arms at the time of enrollment. Prior to initiation of the trial, a computer-generated randomization schedule was determined. Numbered cards designating the treatment arm were ordered according to the list, and the cards were kept in opaque envelopes and were not opened until the patient was registered with the University of Minnesota clinical research coordinator. Randomization sequence was concealed from investigators and staff. Neither the patients nor the investigators were blinded to treatment arm. Responses were assessed by radiologists who were not a part of the trial and were blinded to treatment arm.

Our trial included a heterogeneous population of women with measurable disease or elevated CA 125 and with platinum-sensitive or platinum-resistant disease. Therefore, we designed a randomized trial that would allow us to assess better any relative difference in response rates. Then, these preliminary data would be used as the basis for a larger phase 3 trial, perhaps in a more homogenous patient population, with traditional endpoints of OS or PFS. Our a priori statistical analysis included a plan to compare the 2 arms of this randomized phase 2 trial.

A preliminary report of single-agent thalidomide for the treatment of recurrent ovarian cancer described a response rate of 45%.13 That response rate was based on changes in tumor size and CA 125. In our sample size calculation, we used this response rate as the expected response in our experimental group. A large European study of women with recurrent ovarian cancer who received topotecan described an overall response rate of 17%,14 and we used that rate as the estimated response in our control group. Thus, accepting a type-1 error of 5% with 80% power, we would require 43 patients in each treatment arm to detect the difference between an overall response of 17% in the topotecan arm and 45% in the thalidomide/topotecan arm.

After a total of 50 patients were enrolled on the protocol, an interim analysis was conducted on response rate and toxicity of thalidomide. Using the multiple testing procedure described by O'Brien and Fleming,15 the level of significance for this interim analysis was set at .005.

Toxicity was monitored on an ongoing basis. The development of any grade 3 or 4 toxicity was considered an adverse experience. Stopping rules for toxicity were developed by using the FORTRAN program BEST.16

All randomized patients who received at least 1 dose of topotecan or thalidomide were included in the current analysis. The chi-square test was used to determine whether the response proportions or toxicity differed between treatment arms. Log-linear models were used to determine whether any of the following factors were associated with response: treatment arm, platinum sensitivity status, and criteria for enrollment (measurable tumor or elevated CA 125). Survival curves for PFS and OS were estimated by using the Kaplan-Meier method and were compared between treatment groups by using the log-rank test.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Between April 2001 and July 2005, 75 women, from 7 different research sites consented to participate in this trial (accrual was terminated prematurely because of financial restraints; after the 75th woman was consented, no additional patients were enrolled into this trial). Patients were followed for at least 6 months from the time of enrollment. Forty-one women were randomized to receive topotecan alone; of these, 2 women decided not to participate in the trial before they received any medication, and they were not treated by investigators associated with this study. Thirty-four women were randomized to receive thalidomide and topotecan; of these, 2 women worsened clinically before the initiation of therapy and declined any further treatment, and 2 others withdrew before treatment. The final analysis for response, survival, and toxicity included 39 women in the topotecan arm and 30 women in the thalidomide/topotecan arm. The analysis included 4 women (2 in each arm) who either had protocol violations or did not receive full treatment according to the protocol (Fig. 1).

thumbnail image

Figure 1. This diagram shows the flow of patients through the study. The analysis includes patients who were randomized to received at least 1 dose of study medication.

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The median number of completed cycles in both treatment arms was 6. For patients in the experimental arm, the median thalidomide dose was 200 mg per day (range, 100–600 mg per day). Dose escalation was attempted in all patients. Seventy percent of the patients received 200 mg or 300 mg per day for the majority of their cycles. Two patients received 100 mg per day for the majority of their cycles; in both patients, the dose reduction was caused by symptoms of fatigue and dizziness. The baseline demographics for the study participants are shown in Table 1.

Table 1. Patient Demographics
VariableNo. of patients (%) in treatment arm
TopotecanThalidomide/Topotecan
Total no. of patients included in the analysis3930
Cancer origin
 Ovary3629
 Fallopian tube20
 Primary peritoneal11
Criteria for recurrence
 CA 12523 (59)16 (53)
 Median CA 125 in patients enrolled based on CA 125 elevation, U/mL333513
 Measurable disease16 (41)14 (47)
Median age [range], y63 [44–86]58 [48–76]
Initial response to platinum-based chemotherapy
 Platinum resistant11 (28)9 (30)
 Platinum sensitive28 (72)21 (70)
Median time since last platinum therapy [range], mo7 [0–32]7 [0–34]

The overall response rate (CR + PR) for the topotecan arm was 21% (8 of 39 patients) compared with 47% (14 of 30 patients) for the topotecan/thalidomide arm (P = .036) (Table 2). Treatment arm, platinum sensitivity status, and criteria for enrollment (measurable disease or elevated CA 125) were each independent predictors of response. We used the log-linear method to determine the odds of response based on each predictor while controlling for the other independent predictors. When controlling for other predictors of response, the patients who were receiving topotecan and thalidomide were 10.4 times as likely to achieve a CR or PR (95% confidence interval [95% CI], 2.1–51.7; P = .004) as the patients who were receiving topotecan alone. The remaining predicting variables did not differ by study arm. Those variables were platinum sensitivity (odds ratio [OR], 36.4; 95% CI, 3.8–345.6 [P = .002]), platinum-free months (OR, 1.2 for each additional month; 95% CI, 1.04, 1.44 [P = .015]), and recurrence diagnosed by CA 125 elevation (compared with measurable disease: OR, 15.2; 95% CI, 2.7–83.8 [P = .002]).

Table 2. Response to Treatment
ResponseNo. of patients (%)
Topotecan, n = 39Topotecan/Thalidomide, n = 30
  • *

    P = .036.

Complete response7 (18)9 (30)
Partial response1 (3)5 (17)
Overall response*8 (21)14 (47)
Stable disease5 (13)5 (17)
Progressive disease24 (62)9 (30)
Not evaluated2 (5)2 (7)

Kaplan-Meier estimates of the median PFS for women who were receiving topotecan was 4 months (95% CI, 2.9–5.1 months) compared with 6 months (95% CI, 4.2–7.7 months) for women who were receiving topotecan with thalidomide (P = .02) (Fig. 2). The median OS was 14.8 months (95% CI, 13.2–28 months) for women who were receiving topotecan and 18.8 months (95% CI, 13.9–33.1 months) for women who were receiving topotecan and thalidomide (P = .67) (Fig. 3).

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Figure 2. Kaplan-Meier estimate of progression-free survival. Arm 1 is the control arm (topotecan alone), and Arm 2 is the experimental arm (topotecan with thalidomide). All patients were followed to disease progression, and there were no censored events. 95% CI indicates 95% confidence interval.

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thumbnail image

Figure 3. Kaplan-Meier estimate of overall survival. Arm 1 is the control arm (topotecan alone), and Arm 2 is the experimental arm (topotecan with thalidomide). Square markers represent censored events; 95% CI, 95% confidence interval.

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In the small subgroup of patients with platinum-resistant disease, 1 of 11 women (9%) who were receiving topotecan responded (CR + PR), and 3 of 9 women (33%) who were receiving topotecan and thalidomide responded. This subanalysis was performed for the purpose of hypothesis generation and to aid in the design of future clinical trials; the importance of confirming this finding in larger clinical trials cannot be understated.

The only grade 3 or 4 toxicities experienced by >20% of patients in either arm were considered hematologic toxicities (Table 3). The rates of hematologic toxicities were similar except for grade 3 or 4 thrombocytopenia; which was observed with greater frequency in women who were receiving thalidomide. None of the episodes of thrombocytopenia resulted in dose reductions or dose delays. Hematopoietic growth factors were used in 24% of patients in the control arm and in 31% of patients in the experimental arm. There also was similar use of granulocyte colony-stimulating factors (35% and 41% in the control and experimental arms, respectively). Fatigue and somnolence were experienced at similar rates in the control and experimental arms, although somnolence was the primary symptom that lead to dose reductions or prevented escalation of the thalidomide dose. The next most frequent toxicities that lead to thalidomide dose reduction or preventing escalation were lightheadedness or dizzy feelings, neurotoxicity, and syncope. These were experienced in 10% of women in the control arm and 33% of women in the thalidomide arm, and the most frequent was grade 1 or 2 lightheadedness. Grade 1 or 2 constitutional toxicity was observed in 20 of 39 women (51%) who were receiving topotecan and in 18 of 30 women (60%) who were receiving topotecan and thalidomide. Grade 3 or 4 constitutional toxicity was observed in 2 women on each arm. The incidence of constipation and gastrointestinal toxicity was similar between the arms. There was a trend toward increased incidence of peripheral neuropathy and rash in women who were receiving thalidomide. One patient was diagnosed with deep venous thrombosis (DVT); she was on the thalidomide arm at a dose of 300 mg per day. The DVT was diagnosed in her third cycle of chemotherapy and, during evaluation of the DVT, it was observed that she had disease progression, and she was removed from the protocol.

Table 3. Hematologic and Nonhematologic Toxicities
ToxicityNo. of patients (%)
Topotecan, n = 39Topotecan/Thalidomide, n = 30
Grade 1, 2Grade 3, 4Grade 1, 2Grade 3, 4
Neutropenia3 (8)28 (72)1 (3)26 (87)
Thrombocytopenia14 (36)14 (36)19 (63)6 (20)
Anemia20 (51)9 (23)21 (70)4 (13)
Auditory/hearing003 (10)0
Cardiovascular002 (7)0
Constitutional20 (51)2 (5)18 (60)2 (7)
Dermatology6 (15)05 (17)1 (3)
Endocrine2 (5)01 (3)0
Gastrointestinal15 (38)4 (10)12 (40)1 (3)
Genitourinary2 (5)1 (3)00
Hemorrhage1 (3)000
Infection03 (8)2 (7)2 (7)
Febrile neutropenia04 (10)02 (7)
Lymphatics1 (3)01 (3)0
Metabolic1 (3)1 (3)1 (3)0
Musculoskeletal3 (8)03 (10)0
Neurologic4 (10)07 (23)4 (13)
Peripheral neuropathy2 (5)04 (13)0
Ocular/visual2 (5)02 (7)1 (3)
Pain8 (21)2 (5)8 (27)0
Pulmonary4 (10)2 (5)4 (13)3 (10)
Thrombosis0001 (3)

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The current findings support our hypothesis that the response rate achieved with combination therapy with thalidomide and topotecan is greater than the response rate achieved with topotecan alone in women with recurrent ovarian and primary peritoneal cancer. We observed an overall response of 47% in the women who received topotecan and thalidomide. This compares with a response of 17% to single-agent topotecan, a rate similar to that reported in previous publications. In addition to improved response, we observed a 2-month improvement in disease-free survival. The observed 4-month improvement in OS was not statistically significant.

Patients who were receiving thalidomide were at an increased risk for thrombocytopenia. There has been a recent case report of isolated thrombocytopenia in a patient who was receiving maintenance thalidomide (200 mg per day) for multiple myeloma: Within weeks of starting the maintenance dose, he experienced grade 4 thrombocytopenia. The authors of that case report suspect that peripheral platelet destruction was the etiology of the thrombocytopenia.17 In our review, we did not identify other reports of isolated thrombocytopenia in patients who were receiving thalidomide.

Thalidomide is associated with an increased risk of thromboembolic events, particularly when it is used to treat hematologic malignancies and when it is combined with dexamethasone. This risk does not appear to be as great in patients with solid tumors, and we did not observe an obvious increase in thromboembolic events in our patients who received thalidomide. Current guidelines do not recommend the use of therapeutic or prophylactic anticoagulants in patients with solid tumors.18 This may be particularly important considering the increased risk of thrombocytopenia observed among the women in our cohort who received thalidomide.

Early closure is a limitation of this study. Early closure lead to an imbalance in the number of patients in the treatment arms, and this imbalance may have biased our analysis of PFS. Not meeting our original accrual goal also may have limited the precision of our estimates of overall response. Despite the smaller than planned accrual, we still observed a significant difference in response between treatment arms. We believe that this provides sufficient evidence that this regimen warrants further study through larger phase 3 randomized trials in women with recurrent ovarian cancer.

A second limitation is that there were no preclinical data to direct us in determining the optimal thalidomide dose. Without this information, we may have underestimated the potential impact of this combination if higher doses of thalidomide would have produced greater response rates.

Our patient population included women who were diagnosed with recurrent disease by elevated CA 125 levels without evidence of measurable disease. We believe that our randomized comparison was adjusted for the finding that CA 125 response occurs more frequently than measurable response. The treatment arms contained similar proportions of patients enrolled based on elevated CA 125 alone. Although the numbers were small, the response rates for the subgroups of patients enrolled based on measurable disease and CA 125 alone mirrored the overall response rates for each treatment arm (data not shown).

To our knowledge, this is the first report in which thalidomide has been combined with a cytotoxic chemotherapy to treat ovarian cancer. Chan et al. used single-agent thalidomide in a similar population and reported response rates of 18% based on changes in the size of measurable disease and 47% based on decreased serum CA 125 values.19 Eisen et al. reported on a trial of low-dose thalidomide (100 mg per day) in patients with advanced melanoma, renal cell carcinoma, breast cancer, and ovarian cancer. The highest response rate in their trial was observed in patients with renal cell carcinoma (17%), but no responses were observed in patients with melanoma, breast cancer, or ovarian cancer. In that trial, 1 of 19 women with ovarian cancer experienced stable disease for >3 months.20

Although to our knowledge there are few reports of thalidomide use for ovarian cancer, it has been studied in the phase 2 or 3 settings as a single agent or in combination for the treatment of central nervous system tumors, renal cell carcinoma, prostate cancer, and melanoma. Thalidomide has limited activity in these cancers as a single agent; however, its activity appears to be enhanced when thalidomide is combined with certain cytotoxic agents. Three reports described response rates from 5% to 12% when single-agent thalidomide was used for the treatment of glioblastoma or gliomas.21, 22 However, when thalidomide was combined with cytotoxic carmustine to treat gliomas, Fine et al. reported a response rate of 24%.23 Single-agent thalidomide trials in patients with prostate cancer have produced response rates from 15% to 27%.24, 25 In a randomized trial of patients with recurrent prostate cancer, investigators described a 50% reduction in the prostate-specific antigen level in 6 of 17 patients (35%) who received docetaxel alone compared with 19 of 36 patients (53%) who received with docetaxel and thalidomide.26

In a randomized trial of patients with metastatic melanoma, investigators reported a response or disease stabilization in 20% of patients (95% CI, 10–33%) who received temozolomide and in 25% of patients (95% CI, 15–38%) who received temozolomide combined with thalidomide.25 Similar to our results, those data suggest that combination therapy with cytotoxic agents may be more effective than the use of thalidomide as a single agent in the treatment of solid tumors.

These clinical observations are supported by preclinical models demonstrating both the efficacy of thalidomide and its synergy with cytotoxic agents. In a xenograft model of melanoma, thalidomide resulted in a 46% reduction in tumor growth compared with saline-treated animals. Furthermore, the combination of thalidomide and darcarbazine resulted in a 61% reduction in tumor size compared with darcarbazine alone and in an additional 32% reduction of tumor compared with thalidomide alone.26

Kobayashi et al. described a murine model in which thalidomide was combined with paclitaxel for the treatment of ovarian cancer. Athymic nude mice were injected with human ovarian cancer HRA cells to create a model of intraperitoneal metastatic ovarian cancer. Compared with saline-treated animals, there was a 25% reduction in tumor weight in animals that received thalidomide, and a 30% reduction was observed in animals that received paclitaxel. Although the combination of thalidomide and paclitaxel resulted in a 93% reduction in tumor weight, the authors suggested that the broad mechanisms of action attributable to the 2 agents, along with the findings that both agents inhibited VEGF and impaired angiogenesis, are the likely reasons for the synergistic inhibition of ovarian cancer growth.27

To summarize, the results of the current study have demonstrated that the administration of thalidomide and topotecan increases the response to treatment in women with recurrent ovarian cancer. Our preliminary data suggest that the thalidomide/topotecan combination warrants evaluation through a phase 3 trial that is powered to measure potential differences in survival to assess the full potential of this regimen. Our results also suggest that immune modulators and antiangiogenic agents may be useful therapeutically and should be studied in women with recurrent ovarian cancer in combination with traditional cytotoxic chemotherapy.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES