- © 2005 by American Society of Clinical Oncology
Phase II Study of Doxorubicin and Bevacizumab for Patients With Metastatic Soft-Tissue Sarcomas
- David R. D'Adamo,
- Sibyl E. Anderson,
- Karen Albritton,
- Jennifer Yamada,
- Elyn Riedel,
- Kelly Scheu,
- Gary K. Schwartz,
- Helen Chen and
- Robert G. Maki
- From the Gastrointestinal Oncology Service and Developmental Chemotherapy Service, Department of Medicine and Department of Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, NY; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT; and Investigational Drug Branch, Clinical Trials Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD
- Address reprint requests to David D'Adamo, MD, PhD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: dadamod{at}mskcc.org
Abstract
Purpose To evaluate the antitumor activity and tolerability of bevacizumab and doxorubicin in patients with metastatic soft-tissue sarcoma (STS).
Patients and Methods Patients may have had up to one nonanthracycline line of therapy. Seventeen patients with metastatic STS were treated with doxorubicin at 75 mg/m2 intravenous (IV) push followed by bevacizumab 15 mg/kg IV every 3 weeks. Dexrazoxane was started for total doxorubicin dose exceeding 300 mg/m2.
Results A total of 85 cycles of doxorubicin/bevacizumab were administered, median four cycles (range, one to 11), with three patients receiving one to four cycles of bevacizumab maintenance after reaching 600 mg/m2 doxorubicin. All 17 patients were assessable for response. Two partial responses (12%, 95% CI = 1% to 36%) were observed, lasting seven and 12 cycles of therapy. Eleven patients (65%) had stable disease for four cycles or more. Six patients developed cardiac toxicity grade 2 or greater, with four patients grade 2 (cumulative doxorubicin 75, 150, 300, 300 mg/m2, respectively), one grade 3 (total doxorubicin 591 mg/m2), and one grade 4 (total doxorubicin 420 mg/m2). One patient with extensive lung disease died of recurrent bilateral pneumothoraces, possibly treatment-related.
Conclusion The 12% response rate for these patients was no greater than that observed for single-agent doxorubicin. However, the 65% of patients with stable disease lasting four cycles or longer suggests further study is warranted in STSs. The observed cardiac toxicity, despite close monitoring and standard use of dexrazoxane, obliges a change in the dose and/or schedule in future studies of this combination.
INTRODUCTION
Soft-tissue sarcomas (STSs) are malignant tumors of mesenchymal origin. Approximately 9,400 cases are diagnosed annually in the United States, accounting for fewer than 1% of all malignancies.1 Surgery, with or without adjuvant radiation therapy, is the mainstay of treatment for patients with early-stage disease. Despite surgical excision, between 40% and 60% of patients develop locally recurrent or metastatic disease. Although pulmonary metastasectomy can be curative for 15% to 30% for selected patients with lung-only disease,2 the majority of patients with metastatic sarcomas succumb in this setting, with a median survival time of 12 to 18 months.
Complete responses to chemotherapy for recurrent or metastatic STSs are rare. Most tumors rapidly develop drug resistance and patients develop progressive disease within months. For most patients, palliation is the main objective of treatment. Doxorubicin is the mainstay of treatment for metastatic sarcomas, with response rates of between 10% and 30%.3-5 The addition of ifosfamide and/or dacarbazine increases response rate without prolonging survival, at the cost of increased toxicity.6 Accordingly, patients with advanced and metastatic disease are appropriate candidates for investigational therapies.
The recombinant human monoclonal antibody bevacizumab is a novel antineoplastic agent that binds human vascular endothelial growth factor (VEGF). Bevacizumab has demonstrated safety in phase I studies administered as a single agent.7 As a single agent it is most promising in renal cell carcinoma, with a response rate of 10%, but with significant benefit in time to progression versus placebo in a randomized trial.8 In other diseases, bevacizumab shows activity in combination with standard chemotherapy. In advanced non–small-cell lung cancer, a randomized phase II trial showed a trend towards increased response rate and time to progression when bevacizumab was combined with paclitaxel and carboplatin.9 A large randomized trial was conducted in patients with metastatic breast cancer, who had received prior therapy both with an anthracycline and a taxane.10 Patients were treated with capecitabine and either bevacizumab or placebo. Although no survival benefit was demonstrated, the combination did have a significantly higher response rate.
The disease in which bevacizumab has had the greatest impact is metastatic colorectal cancer. After a randomized phase II study showed encouraging results when low-dose bevacizumab was combined with fluorouracil and leucovorin,11 Hurvitz et al conducted a large randomized phase III trial of irinotecan, bolus fluorouracil, and leucovorin with bevacizumab or placebo.12 The addition of bevacizumab demonstrated increased response rate, time to progression, and a 4.7 month increase in overall survival, leading to its approval by the US Food and Drug Administration for the treatment of metastatic colon cancer.
The rationale for this trial was to improve the efficacy of single-agent doxorubicin when combined with bevacizumab. STSs are highly vascular tumors. Several studies have shown correlation between prognosis and surrogates for angiogenesis, including microvessel density and circulating VEGF and basic Fibroblast Growth Factor (bFGF).13,14 Neo-angiogenesis is also required for development of metastatic disease.15 The aim of this study was to test the safety and efficacy of bevacizumab in combination with doxorubicin for the treatment of metastatic STS.
PATIENTS AND METHODS
Patient Eligibility
Eligible patients had histologically confirmed metastatic STS, with measurable disease. Patients were anthracycline naive and had zero to one prior treatment regimens for metastatic disease. Other inclusion criteria included an age of at least 18 years, recovery from prior chemotherapy or radiation, Karnofsky performance status of at least 80%, and a cardiac ejection fraction (EF) of at least 50%. Adequate hematologic, hepatic, and renal function (including proteinuria of no more than 500 mg per day) were also required.
Patients with brain metastases, deep venous thrombosis, pulmonary embolism or other condition requiring anticoagulation, clinically significant cardiovascular disease, active infection or nonhealing wound, recent surgery within 21 days or needle biopsy within 7 days, another malignancy (except for basal cell carcinoma of the skin or cervical carcinoma-in-situ) diagnosed within 5 years, and pregnant women were all excluded.
Written informed consent was required. The study was approved by the Institutional Review Boards of all participating centers and conducted in accordance with the US Food and Drug Administration Good Clinical Practice requirements.
Therapy
After registration, patients were treated with doxorubicin at 75 mg/m2 as an IV push over 5 to 10 minutes. Bevacizumab was then administered at 15 mg/kg over 90 minutes (first dose), 60 minutes (second dose), or 30 minutes (third or later dose). Therapy was repeated every 3 weeks. After a cumulative dose of doxorubicin of 300 mg/m2, patients received dexrazoxane at 10 times the dose of doxorubicin within 30 minutes before administering doxorubicin.
Patients with National Cancer Institute Common Toxicity Criteria version 2.0 grade 4 toxicity for neutrophils or leukocytes lasting 7 days or longer, or who experienced a neutropenic fever, were re-treated after a dose reduction (60 mg/m2 level-1 dose, 50 mg/m2 level-2 dose) and resolution of toxicity to ≤ National Cancer Institute Common Toxicity Criteria version 2.0 grade 1. Patients whose doxorubicin was held because of doxorubicin-related toxicity received bevacizumab at 5 mg/kg/wk until re-treatment with both agents. The cumulative doxorubicin dose was capped at 600 mg/m2 (with dexrazoxane). Patients with continued clinical response or stable disease were eligible to receive single-agent bevacizumab until disease progression. All patients received standard supportive care including antiemetics, blood transfusions, erythropoietin, and antibiotics as medically indicated.
Study Parameters
Baseline evaluation included assessment of Karnofsky performance status, standard hematology, chemistry, liver function tests, lactate dehydrogenase, urinalysis, international normalized ratio (INR)/partial thromboplastin time, and physical examination. Complete blood counts were performed weekly while patients were on therapy. Baseline tumor assessments included a chest x-ray and computed tomography scans. ECG was performed before each treatment. Assessment of cardiac EF either by echocardiogram or multiple gated acquisition (MUGA) scan was performed every two cycles. Tumor status was assessed every two cycles for the first six cycles then every three cycles thereafter, using Response Evaluation Criteria in Solid Tumors (RECIST).16 Safety evaluations, including physical examination, laboratory tests, and vital sign monitoring were performed before, during, and after bevacizumab infusions. Patients were questioned regarding use of concomitant medications and adverse events at the start of each cycle of therapy.
Statistical Considerations
The primary efficacy end point was response rate. This phase II study had a Simon two-stage design,17 with a projected response rate of 20% for doxorubicin and an increase to 40% with the addition of bevacizumab. If three or fewer major responses (complete response and partial response [PR]) were observed among the first 17 patients treated, the study was to be closed. If four or more major responses were achieved, enrollment was to be extended to 37 patients. If 11 or more responses were observed among the 37 patients, the study was to be considered to have a positive result and this regimen would be considered worthy of further testing in this disease. This design yielded power of 0.90 to discriminate between true response rates of 20% and 40%.
Secondary objectives were to determine time to treatment failure, time to progression, overall survival, and to further characterize the toxicity profile of bevacizumab given with doxorubicin in this group of patients. Time to treatment failure was defined as time from treatment start date to off-study date; progression or death while on-study or a major toxic event were considered treatment failures. Time to progression was defined as time from treatment start date to date of progression or last follow-up. Overall survival was defined as time from treatment start date to death or last follow-up. Time to treatment failure, time to progression, and overall survival were determined using Kaplan-Meier estimators.18
RESULTS
Patient Characteristics and Disposition
The study was conducted in two centers in North America. Patient characteristics are presented in Table 1. Notably, 13 patients (76%) were female and 11 patients (65%) had leiomyosarcoma, seven of uterine origin; leiomyosarcoma typically constitute only 20% to 30% of all STSs. All patients enrolled received at least one course of combination therapy and were assessable for toxicity. One patient completed only one cycle of therapy before stopping for toxicity, but is included in an intention to treat analysis regarding response.
Patient Characteristics
Efficacy of Therapy
Two of 17 patients, both with uterine leiomyosarcoma, had PR as assessed by RECIST (31% decrease and 45% decrease in unidimensional disease for 12 cycles and 15 cycles, respectively). There were no complete responses. The overall response rate was 12% (95% CI, 1% to 36%). An additional 11 patients (65%) had stable disease for 12 weeks or greater. Median time to treatment failure (progression of disease or excess toxicity) was 4 months (Fig 1). Median time to progression was 8 months (Fig 1). Two patients have not progressed, both with 10 months of follow-up. Median overall survival is 16 months (Fig 1B) with 13 patients still alive as of September 2004, with follow-up ranging from 3 months to 21 months.
(A) Time to progression and time to treatment failure. (B) Overall survival.
Safety and Toxicity
The toxicity of bevacizumab and doxorubicin was similar to that reported for single-agent doxorubicin (Table 2). There was modest nausea and vomiting, well controlled with standard antiemetics. There were no cases of grade 3 to 4 nausea or vomiting. alopecia was universal. Hematologic toxicity was typical for this dose of doxorubicin. There were two cases of febrile neutropenia, and no septic deaths. No filgrastim or pegfilgrastim was used in the initial therapy of these patients, but was added routinely in subsequent cycles after episodes of febrile neutropenia. The toxicity of doxorubicin at 75 mg/m2 is significant and all eight patients staying on study more than four cycles required protocol-mandated doxorubicin dose reductions.
Treatment-Related Toxicity
Toxicities typically ascribed to bevacizumab were not frequently observed. There were no cases of proteinuria greater than grade 1. There was no hypertension greater than grade 1. bleeding was minor, with several patients reporting self-limited epistaxis. There was one case of grade 2 vaginal bleeding in a patient with uterine leiomyosarcoma that was attributed to progression of disease. No patients required transfusions. There were no bowel perforations. There were no arterial embolic complications such as cerebrovascular accident or myocardial infarction. There was one upper extremity deep venous thrombosis in a previously radiated field.
Three patients received eight cycles of bevacizumab maintenance therapy after a cumulative dose of doxorubicin of 600 mg/m2. Two patients received one cycle each of bevacizumab only during combination therapy, while doxorubicin was held for anthracycline-related toxicity. The toxicity of these 10 cycles of bevacizumab monotherapy (Table 3) was quite modest. One patient experienced transient elevation of liver enzymes on therapy, in the setting of stable liver metastases.
Treatment-Related Toxicity of Bevacizumab-Only Maintenance Therapy
One patient died of recurrent bilateral pneumothoraces, possibly treatment related. She had innumerable pulmonary nodules, many of which were pleural based. After two cycles of bevacizumab and doxorubicin she developed bilateral pneumothoraces that required chest tube placement. CT scan showed stable disease in the chest. After this first episode resolved, she was re-treated with bevacizumab and doxorubicin, complicated again by lung collapse. She was admitted to an outside facility, where she declined chest tube placement and subsequently expired.
Cardiac Toxicity
Greater than expected cardiac toxicity was observed in this study. Patients had evaluation of left ventricular ejection fraction (LVEF) with either echocardiogram or with MUGA scan before treatment and every two cycles while on trial. LVEF declined significantly (grade 2 or worse) in more than one third of patients (six of 17), all of whom were removed from study. Four patients had grade 2 declines in EF after one, two, four, and four cycles of combination therapy with bevacizumab and doxorubicin. Grade 3 and Grade 4 cardiac toxicity was experienced by one patient each after 11 cycles and eight cycles of combination therapy, respectively. LVEF over time for all patients is illustrated in Figure 2. Cardiac toxicity was often reversible, however. Among those six patients with decreased EF, follow-up demonstrated improvement in the LVEF in five.
Left ventricular ejection fraction (LVEF) by treatment cycle. Patients represented by black lines experienced no significant decline in LVEF. Colored lines represent each patient who experienced grade 2 or greater cardiac toxicity. Arrows designate time point at which the patient was removed from study. Follow-up evaluations after removal from trial when available are shown. One patient (blue line) had documentation of recovery of EF to 55%, 1 year after last treatment on trial (not depicted above).
DISCUSSION
The mainstay of treatment for metastatic STS is the anthracycline doxorubicin. The addition of other agents such as ifosfamide, dacarbazine or cyclophosphamide, vincristine, and dactinomycin has shown an increase in response rate, without an advantage in overall survival.5,6,19 There have been no new agents approved for the treatment of metastatic nongastrointestinal stromal tumor sarcomas since the use of ifosfamide became widely accepted in the late 1980s. Because the growth of sarcomas is in part dependent on neoangiogenesis, sarcomas provide an attractive model for testing combination cytotoxic and antiangiogenic therapy. Preclinical models of sarcomas have shown little activity for antiangiogenic therapy per se but at least additive if not synergistic effects when combined with conventional chemotherapy. This study was designed to test if the addition of the anti-VEGF antibody bevacizumab could increase the response rate of STS to doxorubicin and to define the toxicities of this combination regimen.
The combination of bevacizumab and doxorubicin failed to increase the response rate of STS from 20% to 40%. That our trial design was overly optimistic is underscored by randomized studies in colon cancer and breast cancer showing only a 10% increase in response rate when bevacizumab was added to either capecitabine or an irinotecan, fluorouracil, and folinic acid combination. The observed response rate, 12%, was relatively low for single-agent doxorubicin. However, other studies, using outside review of radiographs, show that the response rate to doxorubicin may be as low as 10%.20 Additional studies have identified a dose response to doxorubicin, but it cannot be claimed that the doxorubicin dose in this study, 75 mg/m2 every 3 weeks, was inadequate. The variability of patient histology is a well recognized factor that can affect the response rate to any given chemotherapy agent for STSs,19 emphasizing the need for subtype-specific studies of chemotherapy agents in this heterogeneous group of diseases.
Another question for future studies is the observation of prolongation of response and prolonged stable disease in patients enrolled in this study. In the pivotal trial in metastatic colon cancer, the increase in time to progression with bevacizumab was 4 months, more than that observed in any other phase III trial in colon cancer; whereas, the increase in response rate was modest, from 35% to 45%.12 The time to progression and overall survival in this study of patients with metastatic STS were encouraging, but the number of patients on trial was too small to draw any firm conclusions.
Patient responses in this trial were evaluated using RECIST. RECIST works well with spherical tumors. However, STSs are often irregular, with variable areas of necrosis, and can be larger cranio-caudally than they are transversely or in an anterior-posterior axis. Sarcomas could progress or respond more in the short axis rather than in the long axis. Furthermore, for large tumors such as sarcomas, growth is potentially limited anatomically by the body cavity or muscle group in which it resides. These are all factors that make difficult the accurate measurement of sarcomas using standard axial CT imaging for at least some patients, exemplified in this study by one patient with stable disease by RECIST but a confirmed PR by WHO criteria. In a study of gastrointestinal stromal tumor, Choi et al21 found response by fluorodeoxyglucose-positron emission tomography and decrease in tumor vascularity provided valuable additional information for determining overall tumor response, in conjunction with RECIST.
Another patient with a large synovial sarcoma of the leg with lung and abdominal metastases received 5 cycles of combination therapy and had stable disease by RECIST. Like the patient with bilateral pneumothoraces and tumor cavitation, there was almost complete central necrosis of the tumor mass, with only a small rim of viable tumor on the outside of the mass, recapitulating animal models of antiangiogenic therapy22 (Fig 3). The patient was taken off study for toxicity and 2 months later, after treatment with gemcitabine, the tumor had collapsed in on itself and met criteria for PR. This observation raises the issue of the sequence and dose of chemotherapy and antiangiogenic therapy. As pointed out by Jain, perhaps the goal of antiangiogenic therapy should be normalization of vasculature (“euangiogenesis”) as opposed to overtly inhibiting23 all new blood vessel formation.
(A) Antiangiogenic therapy may have effects that are underappreciated by Response Evaluation Criteria in Solid Tumors (RECIST). (Left panel) Synovial sarcoma, pre-treatment 3/4/2003; (middle panel) after 4 cycles bevacizumab and doxorubicin, central necrosis but stable, by RECIST 5/22/2003; (right panel) after six doses of gemcitabine 10/2/03. (B) Tumor-prone mice with angiogenesis defects reproduce the effect of central necrosis seen in patients treated with chemotherapy and antiangiogenic agents. MMTV/Her2/Neu mammary carcinomas in wild type (left) and angiogenesis defective [Id1(−/−)/Id3(+/−)] (right) mice. In Id knockout mice, lesions are cystic and necrotic with a rim of viable tumor. Reprinted with permission from de Candia et al, Proc Natl Acad Sci USA 21:12337-12342, 2003.
Regarding toxicity and adverse events unique to this study, although pneumothorax resulting from treatment is an exceedingly rare phenomenon, there is at lease one case report of a patient with leiomyosarcoma with lung metastases who developed recurrent pneumothoraces while receiving CyVADIC chemotherapy, a doxorubicin-based combination regimen.24 Of greater importance is the observation that the combination of doxorubicin and bevacizumab resulted in an unacceptably high exacerbation of the cardiomyopathy associated with the anthracycline doxorubicin. The reported rates of cardiomyopathy from doxorubicin are 1% to 2% for a cumulative doxorubicin dose below 300 mg/m2, rising to 7% at a doxorubicin dose of 575 mg/m2, and 21% at a cumulative dose greater than 700 mg/m2. The observed 35% rate of grade 2 or greater cardiotoxicity with the combination of bevacizumab and doxorubicin is greater than would have been expected in this patient population. Of the patients who experienced this adverse event, none had received prior chest radiotherapy or high-doses of alkylating agents (two risk factors for increasing the risk of anthracycline associated cardiomyopathy).
It is interesting to speculate on the mechanism of this toxicity. It is known that VEGF is crucial for angiogenesis and revascularization of cardiac tissue following myocardial infarction.25,26 Some of the earliest gene therapy trials involved delivery of VEGF to damaged myocardium to relieve angina.27 VEGF is essential to embryonic development, because VEGF is one of the only genes that is embryonic lethal even with only one copy deleted.28 Cardiac malformations are prominent in the developmental abnormalities of VEGF knockout mice. What is unusual about the cardiac toxicity observed in our study is that it was seen at low cumulative doses as well as at higher doses. This suggests that doxorubicin can cause cardiac toxicity even at low doses, but that this damage can be repaired in a VEGF-dependent fashion, not becoming clinically apparent until later. The fact that the cardiomyopathies observed here were largely reversible is consistent with this model. Presumably, after discontinuation of bevacizumab, VEGF levels would return to normal allowing repair of damaged myocardium. An alternative explanation is that the cardiac assessment was done too close to the time of chemotherapy, which resulted in stunned myocardium without overt permanent damage to the myocardium.
This is not the first report of cardiomyopathy associated with antiangiogenic therapy. Sunitinib (SU1248), a vascular endothelial growth factor receptor inhibitor, is reported to have a low incidence (< 10%) of cardiomyopathy with extended use, which was also largely reversible.29 There were no reports of grade 3 or grade 4 cardiotoxicity associated with its use. Karp et al investigated the use of bevacizumab with mitoxantrone and cytarabine in patients with relapsed or poor risk leukemia.30 There were two cases of fatal cardiomyopathy in their study. In patients who received two cycles of therapy, the incidence of significant decline in EF was 7%. Interestingly, this toxicity was most frequently observed in patients with secondary myelodysplastic syndrome, who had previously received substantial cumulative dose of anthracyclines. The recently reported trial of Miller et al of capecitabine with or without bevacizumab did note an increase in grade 3 and grade 4 cardiac toxicity on the bevacizumab-containing arm (7 v 2 patients).10 All patients on that trial had received prior anthracycline treatment. Because routine evaluation of LVEF was not required by that trial, it cannot be determined whether there was also an increase in grade 2 toxicity, which we are reporting in this study. Ongoing studies of bevacizumab and doxorubicin in locally advanced breast cancer have not noted substantial decline in EF. This trial achieved high peak concentrations of both doxorubicin (75 mg/m2 q 3 weeks) and bevacizumab (15 mg/kg every 3 weeks), so there may be a dose-response associated with this toxicity.
The combination of doxorubicin and bevacizumab is toxic at this dose and schedule, and a worrisome combination to consider without modification of the treatment scheme. Although the response rate is not higher than that expected for single-agent doxorubicin, time to progression and overall survival data are encouraging and suggest further investigation of alternative antiangiogenic strategies for the treatment of STSs. Preclinical and animal studies have suggested that antiangiogenic therapy should not have the typical acute toxicities of cytotoxic chemotherapy. Nonetheless, as these agents enter clinical practice we are now observing new toxicities, specifically hypertension, deep venous thrombosis, pulmonary embolism, cerebrovascular accidents, myocardial infarction, hemorrhage, bowel perforation, and now, apparent acceleration of cardiomyopathy. Although the clinical use of antiangiogenic agents is promising, as observed with the results of bevacizumab in colon cancer, it cannot be recommended that they should be incorporated routinely into other regimens without appropriate safety and efficacy studies.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgments
We thank Judith Karp, MD, for useful discussions. We are grateful to patients and their families for their participation in this trial.
Footnotes
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Supported in part by Grants No. PPG P01 CA47179 and N01-CM17105, as well as the Dibner Fund for Sarcoma Research and Abolish Cancer Today.
D.R.D. and S.E.A. contributed equally to this study.
This study was presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
- Received February 17, 2005.
- Accepted June 14, 2005.
