Randomized Phase II Evaluation of 6 g/m2 of Ifosfamide Plus Doxorubicin and Granulocyte Colony-Stimulating Factor (G-CSF) Compared With 12 g
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《临床肿瘤学》
the Departments of Internal Medicine, Biostatistics, Orthopedic Surgery, Surgery, and Radiation Oncology, Division of Hematology/Oncology, and Clinical Trials Office, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
ABSTRACT
PATIENTS AND METHODS: Chemotherapy-naive patients with STS were randomly assigned to receive doxorubicin 60 mg/m2 and either SD ifosfamide (1.5 g/m2/d, days 1 through 4) or HD ifosfamide (3.0 g/m2, days 1 through 4) every 21 days. Patients were stratified by the presence or absence of metastatic disease. End points were overall survival (OS), 1-year disease-free survival (DFS), and toxicity.
RESULTS: The study group consisted of 79 patients (52 patients with localized disease and 27 patients with metastases). Both groups were well-balanced with respect to known prognostic factors. There was no significant difference in 1-year DFS comparing SD ifosfamide with HD ifosfamide (55% v 52%; P = .81). For SD ifosfamide, 2- and 3-year OS were 73% and 52% versus 57% and 49% for HD ifosfamide (P = .34). The incidence of grade 3/4 neutropenia, anemia, and thrombocytopenia were 49%, 23%, and 10%, respectively, on the SD ifosfamide arm, compared with 88%, 58%, and 63%, respectively, on the HD ifosfamide arm. There were five early deaths, all on the HD ifosfamide arm.
CONCLUSION: When combined with doxorubicin, HD ifosfamide did not improve 1-year DFS and OS. Toxicity was clearly greater with the HD ifosfamide arm, and lack of outcome differences might be explained by toxicities with HD ifosfamide. These results suggest that HD ifosfamide combination regimens should not be used as first-line therapy for patients with STS.
INTRODUCTION
Ifosfamide therapy yields clinical benefit in patients who have previously experienced treatment failure with doxorubicin-based regimens.9 Evidence supporting a dose-response relationship with ifosfamide was shown in sequential studies. In these trials, sarcoma patients previously treated with doxorubicin received single-agent ifosfamide in escalating doses. The response rate at 6 g/m2 was 10%, at 8 g/m2 was 14%, and at 10 g/m2 was 21%.10 A follow-up phase II study at a higher dose (14 g/m2) confirmed this dose-response relationship.11
To date, there are no published, randomized trials comparing doxorubicin in combination with a standard-dose (SD) ifosfamide regimen with doxorubicin in combination with a high-dose (HD) ifosfamide regimen as first-line therapy for patients with STS. One published study12 compared single-agent ifosfamide at a higher dose (3 g/m2 over 3 days) to a more standard regimen (5 g/m2 over 24 hours) as first- and second-line chemotherapy. Survival did not differ and toxicity was greater with the higher-dose arm. We designed a randomized phase II study to compare 1-year disease-free survival (DFS), OS, and toxicities of two combination regimens using equivalent doses of doxorubicin with SD ifosfamide versus HD ifosfamide as first-line therapy.
PATIENTS AND METHODS
Treatment Plan
Patients were stratified for localized versus metastatic disease. Patients were randomly assigned to receive doxorubicin 60 mg/m2, ifosfamide 6 g/m2, mesna 900 mg/m2/d, and filgrastim (granulocyte colony-stimulating factor) 5 μg/kg/dose or doxorubicin 60 mg/m2, ifosfamide 12 g/m2, mesna 1,800 mg/m2/d, and filgrastim 5 μg/kg/dose. All patients received chemotherapy as outpatients. Hydration with 5% dextrose with 120 mEq/L of sodium acetate, 500 mg/L of magnesium sulfate, and 40 mEq/L of potassium acetate was initiated at 500 mL/h 1 hour before ifosfamide administration. Before ifosfamide administration, patients receiving 6 g/m2 were treated with mesna 225 mg/m2/dose administered intravenously over 1 hour, whereas patients in the 12 g/m2 arm were treated with mesna 450 mg/m2/dose. Ifosfamide (1.5 g/m2/dose or 3.0 g/m2/dose) was instilled in 500 mL of normal saline and infused over 2 hours each day, days 1 through 4. Mesna was repeated at 4 and 8 hours after ifosfamide. Maintenance hydration was increased to 500 mL/h at the completion of ifosfamide and was discontinued at the finish of the 8-hour mesna infusion. Doxorubicin was administered by 72-hour continuous infusion via a portable pump into a double lumen central venous access device at the start of hydration. Twenty-four hours after the last dose of mesna, filgrastim was given subcutaneously at 5 μg/kg daily for 10 days. Treatment cycles were repeated every 21 days if complete recovery from toxicity occurred. Patients received four cycles for localized disease or six cycles for metastatic disease, unless unacceptable toxicity or disease progression precluded further treatment.
Treatment Evaluations and Dose Modifications
Before enrollment, patients underwent history and physical examination. Pretherapy laboratory studies included a CBC with differential and platelet counts and serum chemistries. A chest x-ray and a computed tomography scan or magnetic resonance imaging were obtained to establish baseline disease measurements. Chemistries were monitored weekly and before each cycle. On days 1, 8, 10, 12, 15, 17, and 19 of each cycle, a CBC with differential and platelet counts was obtained.
National Cancer Institute Common Toxicity Criteria (version 1.0) were used to classify adverse events. Filgrastim was continued until absolute neutrophil counts were ≥ 1,500 cells/μL. Chemotherapy was delayed for platelet counts of less than 100,000 cells/μL and or absolute neutrophil count less than 1,500 cells/μL. If re-treatment was postponed more than 2 weeks because of hematologic toxicity, patients were taken off study. Patients hospitalized with febrile neutropenia had ifosfamide and doxorubicin dosages reduced 10% for subsequent cycles. If serum creatinine increased to 1.5x the ULN, ifosfamide dosage was reduced by 50%. A serum creatinine greater than 1.5x the ULN led to study removal. Patients developing ≥ grade 3 neurotoxicity were taken off study.
Response Criteria
Response was evaluated according to Response Evaluation Criteria in Solid Tumors after every two cycles of chemotherapy for patients with metastatic disease.13 Patients receiving neoadjuvant therapy had imaging performed before chemotherapy and at the completion of the fourth cycle. Patients with metastatic disease were assessed for response if they had received at least two chemotherapy cycles. After the completion of treatment, patients had follow-up physical examinations with chest x-rays every 3 months for the first 2 years and every 6 months thereafter.
Statistical Design
This study consisted of two strata, patients with localized only and patients with metastatic disease. We anticipated approximately 70% of enrolled patients to have localized disease and 30% to have metastatic disease. Within each strata, patients were randomly assigned to receive SD ifosfamide or HD ifosfamide. The randomization was undertaken in blocks of six within each strata. We anticipated the overall 1-year DFS to be 40% in the SD ifosfamide group. An improvement in overall 1-year DFS to at least 70% in patients receiving HD ifosfamide was considered to be of clinical interest. This provided an {alpha} error of .05 and a error of .80. A one-sided 5% level test comparing proportions provided at least 80% power of detecting this difference or greater, with 40 patients per treatment arm.
Statistical Analysis
One-year DFS was measured from the date of randomization to the corresponding date of the following year. All patients were followed up until death, and survival was measured from the date of randomization to the date of death. One-year DFS and OS at 3 years were determined using Kaplan-Meier estimates. The relative hazard ratio comparing SD and HD ifosfamide was determined using a stratified Cox proportional hazards model. The pattern of changes in hematologic parameters (WBC count, platelets, and hemoglobin) over the first four cycles was analyzed using a random effects model that included fixed effects for dose, cycle, day within each cycle, and interactions. Measurements of serum creatinine were converted into creatinine clearance using the Cockcroft-Gault formula.
RESULTS
Patient characteristics are listed in Table 1. A total of 41 women and 38 men were enrolled. The median age was 53 years (range, 18 to 78 years); most had a Zubrod performance status of zero. None had received prior chemotherapy. Most patient characteristics were well-balanced between the treatment arms. However, because stratification for neoadjuvant or adjuvant therapy did not occur before randomization, more patients treated with adjuvant chemotherapy received SD ifosfamide, whereas more patients treated with neoadjuvant chemotherapy received HD ifosfamide. Histologic tumor types and disease sites are listed in Table 2.
Treatment and Tolerance
Forty-four of 52 patients with localized disease completed four cycles of therapy (Table 3). In those with metastatic disease, however, only seven of 13 patients who received SD ifosfamide and four of 14 patients who received HD ifosfamide completed all six cycles. Eight patients (10%) failed to complete chemotherapy because of disease progression on chemotherapy (six patients assigned to SD ifosfamide and two patients assigned to HD ifosfamide). Fifteen patients (19%) discontinued therapy because of toxicity (three patients assigned to SD ifosfamide and 12 patients assigned to HD ifosfamide). Of those receiving HD ifosfamide, there were five early deaths, each within 120 days from randomization (two deaths from neutropenic sepsis and three deaths from tumor progression). Each of these five patients was older than 65 years of age.
Hematologic toxicities are listed in Table 4. This table reflects the nadir hematologic values and most severe toxicity observed during the entire course of treatment. Grade 3/4 neutropenia was documented in 49% and 87% of patients on the SD ifosfamide and HD ifosfamide arms, respectively. Similarly, anemia and thrombocytopenia were also more pronounced on the HD ifosfamide arm. Grade 3/4 anemia occurred in 23% of patients who received SD ifosfamide and 57% of patients who received HD ifosfamide. Overall, seven patients on the SD ifosfamide arm required blood transfusions versus 30 patients on the HD ifosfamide arm. Ten percent of patients developed grade 3/4 thrombocytopenia while receiving SD ifosfamide versus 62% of patients receiving HD ifosfamide.
Grade 3/4 neurotoxicity, noted in four patients, was only observed on the HD ifosfamide arm. Renal toxicity, as described by a decline in creatinine clearance, is shown in Table 5. All patients had baseline creatinine clearances of ≥ 50 mL/min. After one or more courses of chemotherapy, only two patients (5%) who received SD ifosfamide had a decline in creatinine clearance, both of which were to less than 20 mL/min. Ten patients on the HD ifosfamide arm had reductions in creatinine clearance, nine patients to 20 to 50 mL/min and one patient to less than 20 mL/min.
Response to Treatment
Response to therapy is detailed in Table 6. Responses were characterized in a post hoc analysis because this was not an original objective of this proposal. Patients who received neoadjuvant or adjuvant chemotherapy were not stratified before randomization, thus the groups were imbalanced. All patients who received SD ifosfamide as neoadjuvant therapy had stable disease. In the HD ifosfamide arm, three (18%) of 17 patients achieved objective responses, whereas 11 patients had stable disease. There were no complete responses in either arm. In patients with metastatic disease treated with SD ifosfamide, three (23%) of 13 patients attained an objective response, including two complete responses. In the HD ifosfamide arm, three (25%) of 12 patients had an objective response, including one complete response.
Survival is tabulated in Table 7. No significant survival benefit was observed in either arm. In the SD ifosfamide arm, the 2- and 3-year survival rates were higher, 73% and 52%, respectively, as compared with 57% and 49% in the HD ifosfamide arm. The relative hazard ratio of death for the HD ifosfamide group compared with the SD ifosfamide group was 1.39 (95% CI, 0.70 to 2.77; P = .34; Fig 1). The 1-year DFS was 55% for all patients in the SD ifosfamide arm compared with 52% for all patients in the HD ifosfamide arm (Fig 2). The relative hazard ratio of disease recurrence after treatment with HD ifosfamide versus SD ifosfamide was 1.08 (95% CI, 0.56 to 2.09; P = .81).
Figure 1
Figure 2
Both treatment arms were analyzed according to the presence or absence of metastatic disease. Overall survival and DFS were higher in patients with localized disease, regardless of the treatment arm. The 3-year OS was 60% in the nonmetastatic group and 35% in the metastatic group. In the nonmetastatic patient population, 1-year DFS was 75% in the SD ifosfamide arm compared with 65% in the HD ifosfamide arm (Table 7). At 2 years, OS was 88% in the SD arm compared with 64% in the HD arm. The relative hazard ratio of death for the HD ifosfamide arm versus the SD ifosfamide arm was 1.64 (95% CI, 0.62 to 4.31). In patients with metastatic disease, 1-year DFS was slightly lower in the SD ifosfamide arm versus the HD ifosfamide arm (15% v 29%). However, the 2-year OS rate was 46% in both treatment arms. The relative hazard ratio of death for the HD ifosfamide arm versus the SD ifosfamide arm was 1.18 (95% CI, 0.44 to 3.14).
DISCUSSION
Despite improvements in response rates with combination chemotherapy, these multidrug regimens provide no OS benefit in comparison with single-agent doxorubicin.3,5 However, improved efficacy with combination regimens when used as neoadjuvant and adjuvant treatment may be expected. When administered as single agents, both doxorubicin and ifosfamide have response rates of approximately 25%, and response rates are generally improved when these agents are combined.3,6,11,24,25 The dosage of doxorubicin was limited in our study to 60 mg/m2, given the difficulty in administering 75 mg/m2 or greater with 12 g/m2 of ifosfamide. Published data fail to show a survival benefit from dose escalation of doxorubicin beyond 60 mg/m2 in the treatment of patients with STS.4,16 Similarly, new data from the breast cancer literature also report no improvement in OS with the administration of 75 mg/m2 of doxorubicin versus 60 mg/m2.26
This is the first randomized trial comparing an SD ifosfamide regimen with an HD ifosfamide regimen, with each arm receiving identical doses of doxorubicin. The results of this study show no improvement in 1-year DFS or OS in patients receiving HD ifosfamide and suggest a worse overall outcome with the higher dosage. Furthermore, when analyzed separately, neither patients with localized disease nor metastatic disease seem to have benefited from HD chemotherapy.
An argument can be made that this study was underpowered. We were looking for an improvement in 1-year DFS from 40% with SD ifosfamide/doxorubicin to 70% with the HD ifosfamide/doxorubicin having an 80% power, using a one-sided test to detect that difference with 80 patients. In our study design, we estimated that approximately 70% of the patients would have nonmetastatic disease and 30% would have metastatic disease. We accrued 79 assessable patients, 52 patients (65%) with localized, nonmetastatic disease and 27 patients (35%) with metastatic disease. To detect a smaller difference from 40% to 60%, 86 patients in each study arm would be required, and 325 patients would be needed to detect a difference from 40% to 50%. Initiatives to collaborate with other institutions were made in an attempt to accrue larger numbers of patients. However, strong prior opinions on whether HD or SD ifosfamide should be administered as first-line therapy for STS forced us to conduct this trial as a single-institution, phase II study. We chose to include patients with poor prognosis (high grade, > 5 cm) tumors with both localized and metastatic disease to have a large enough patient population to conduct a single-institution, randomized trial.
We recognize that histologic subtypes may have different responses to various systemic therapies. For example, gastrointestinal stomal tumors (GIST), formally thought of as epithelioid leiomyosarcomas of the gastrointestinal tract, were quite refractory to cytotoxic regimens, with response rates of less than 5%. The tyrosine kinase inhibitor, imatinib, has now revolutionized the treatment of GIST, with nearly 80% of patients with metastatic GIST having clinical benefit.27,28 In our study, we excluded the known histologic subtypes that had better response rates to specific cytotoxic regimens (ie, childhood rhabdomyosarcoma) or subtypes with known records of failure to doxorubicin and/or ifosfamide (ie, alveolar soft part sarcoma). The problem with clinical trials in STS without attention to the importance of histologic subtypes remains chronic and recurrent. It is possible that we may have missed the impact of ifosfamide dose-intensity in one or more of the subtypes. However, from studies in metastatic patients, there is no evidence of such an impact. Clearly, new methodologies in clinical trial design are warranted. Equally as clear is the need for new methods of collaboration among institutions with relatively large populations of these patients so that these important clinical questions can be addressed.
The role of adjuvant chemotherapy in the treatment of STS for localized disease remains controversial. However, data from a meta-analysis from 14 trials comparing surgery alone to surgery followed by adjuvant chemotherapy demonstrated a 7% improvement in OS at 10 years (P = .029).29 More recent data from Italy also indicate a benefit to adjuvant chemotherapy with regard to improvement in both DFS and OS in patients with high-grade sarcomas of the extremities.30 The role of neoadjuvant chemotherapy in the treatment of STS is not yet well documented.31
The overall response rate in patients treated with the HD regimen was 21% versus 15% in the SD regimen (Table 6). Although our findings are consistent with the response rates of HD and SD ifosfamide currently reported in the literature, it must be noted that the arms were not equally balanced in the subgroup analysis. Nineteen of the 27 patients treated neoadjuvantly were randomly assigned to the HD arm, and the majority of patients treated adjuvantly were randomly assigned to the SD arm. This was a chance occurrence, as patients were not stratified by neoadjuvant versus adjuvant status. We do not believe that this imbalance had any impact on the overall outcomes of our study in terms of DFS and OS.
The lack of difference in OS and 1-year DFS may be explained in part by a decline in renal function and increased toxicities, which prevented patients from completing planned courses of treatment or which led to early deaths. Before treatment, the patient population was considered fit, with only one patient having a Zubrod performance status of 2. Additionally, all registered patients had two functioning kidneys with adequate renal function. Of those patients with metastatic disease, fewer than one half who were randomly assigned to receive HD ifosfamide completed treatment. Toxicity and early death were the two contributing factors. All five patients with early death were ≥ 65 years of age. For reasons that are not entirely clear, our findings suggest that older age may contribute to lack of treatment response and an increase in toxicity, despite these patients having an adequate performance status. Thus if we were more selective, particularly in limiting enrollment by age, we might have improved the outcome in those treated with the HD ifosfamide regimen.
It is well known that HD ifosfamide regimens are more toxic than lower-dose regimens.11,24,32 The results of our study are no exception. Although granulocyte colony-stimulating factor was required in both arms, grade 3/4 myelosuppression were greater with the HD group (Table 4). The toxic effects of ifosfamide were cumulative with subsequent chemotherapy cycles. Anemia was common in both arms but was worse in the HD ifosfamide arm. The HD ifosfamide treatment group also experienced more thrombosuppressive toxicity. Renal toxicity with HD ifosfamide was similar in our study as in other reports.11 Ten patients on the HD arm developed worsening of their renal function. All but one recovered full function, and no patients required dialysis. Neurotoxicity was noted in four patients treated with 12 g/m2 of ifosfamide. No toxic deaths were attributed to CNS events. Findings from this study confirm that HD ifosfamide is more toxic. Clearly, patients must be counseled about the potential severity of this approach, even if they are in excellent general health and have a good performance status.
In conclusion, we attempted to explore the relative value of incorporating HD ifosfamide in combination with doxorubicin as first-line therapy for STS. Our findings, based on a combination of increased toxicity and lack of apparent benefit, do not support its routine use. Rather, standard doses of ifosfamide in combination with doxorubicin should be considered.
Authors’ Disclosures of Potential Conflicts of Interest
ACKNOWLEDGMENTS
We thank Yolanda Tra, PhD, of the Department of Biostatistics, for her support with biostastical analysis, and Monica Orians, of the Clinical Trials Office, for her support with data management.
NOTES
Supported by Amgen Inc, Thousand Oaks, CA.
Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002, and the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
PATIENTS AND METHODS: Chemotherapy-naive patients with STS were randomly assigned to receive doxorubicin 60 mg/m2 and either SD ifosfamide (1.5 g/m2/d, days 1 through 4) or HD ifosfamide (3.0 g/m2, days 1 through 4) every 21 days. Patients were stratified by the presence or absence of metastatic disease. End points were overall survival (OS), 1-year disease-free survival (DFS), and toxicity.
RESULTS: The study group consisted of 79 patients (52 patients with localized disease and 27 patients with metastases). Both groups were well-balanced with respect to known prognostic factors. There was no significant difference in 1-year DFS comparing SD ifosfamide with HD ifosfamide (55% v 52%; P = .81). For SD ifosfamide, 2- and 3-year OS were 73% and 52% versus 57% and 49% for HD ifosfamide (P = .34). The incidence of grade 3/4 neutropenia, anemia, and thrombocytopenia were 49%, 23%, and 10%, respectively, on the SD ifosfamide arm, compared with 88%, 58%, and 63%, respectively, on the HD ifosfamide arm. There were five early deaths, all on the HD ifosfamide arm.
CONCLUSION: When combined with doxorubicin, HD ifosfamide did not improve 1-year DFS and OS. Toxicity was clearly greater with the HD ifosfamide arm, and lack of outcome differences might be explained by toxicities with HD ifosfamide. These results suggest that HD ifosfamide combination regimens should not be used as first-line therapy for patients with STS.
INTRODUCTION
Ifosfamide therapy yields clinical benefit in patients who have previously experienced treatment failure with doxorubicin-based regimens.9 Evidence supporting a dose-response relationship with ifosfamide was shown in sequential studies. In these trials, sarcoma patients previously treated with doxorubicin received single-agent ifosfamide in escalating doses. The response rate at 6 g/m2 was 10%, at 8 g/m2 was 14%, and at 10 g/m2 was 21%.10 A follow-up phase II study at a higher dose (14 g/m2) confirmed this dose-response relationship.11
To date, there are no published, randomized trials comparing doxorubicin in combination with a standard-dose (SD) ifosfamide regimen with doxorubicin in combination with a high-dose (HD) ifosfamide regimen as first-line therapy for patients with STS. One published study12 compared single-agent ifosfamide at a higher dose (3 g/m2 over 3 days) to a more standard regimen (5 g/m2 over 24 hours) as first- and second-line chemotherapy. Survival did not differ and toxicity was greater with the higher-dose arm. We designed a randomized phase II study to compare 1-year disease-free survival (DFS), OS, and toxicities of two combination regimens using equivalent doses of doxorubicin with SD ifosfamide versus HD ifosfamide as first-line therapy.
PATIENTS AND METHODS
Treatment Plan
Patients were stratified for localized versus metastatic disease. Patients were randomly assigned to receive doxorubicin 60 mg/m2, ifosfamide 6 g/m2, mesna 900 mg/m2/d, and filgrastim (granulocyte colony-stimulating factor) 5 μg/kg/dose or doxorubicin 60 mg/m2, ifosfamide 12 g/m2, mesna 1,800 mg/m2/d, and filgrastim 5 μg/kg/dose. All patients received chemotherapy as outpatients. Hydration with 5% dextrose with 120 mEq/L of sodium acetate, 500 mg/L of magnesium sulfate, and 40 mEq/L of potassium acetate was initiated at 500 mL/h 1 hour before ifosfamide administration. Before ifosfamide administration, patients receiving 6 g/m2 were treated with mesna 225 mg/m2/dose administered intravenously over 1 hour, whereas patients in the 12 g/m2 arm were treated with mesna 450 mg/m2/dose. Ifosfamide (1.5 g/m2/dose or 3.0 g/m2/dose) was instilled in 500 mL of normal saline and infused over 2 hours each day, days 1 through 4. Mesna was repeated at 4 and 8 hours after ifosfamide. Maintenance hydration was increased to 500 mL/h at the completion of ifosfamide and was discontinued at the finish of the 8-hour mesna infusion. Doxorubicin was administered by 72-hour continuous infusion via a portable pump into a double lumen central venous access device at the start of hydration. Twenty-four hours after the last dose of mesna, filgrastim was given subcutaneously at 5 μg/kg daily for 10 days. Treatment cycles were repeated every 21 days if complete recovery from toxicity occurred. Patients received four cycles for localized disease or six cycles for metastatic disease, unless unacceptable toxicity or disease progression precluded further treatment.
Treatment Evaluations and Dose Modifications
Before enrollment, patients underwent history and physical examination. Pretherapy laboratory studies included a CBC with differential and platelet counts and serum chemistries. A chest x-ray and a computed tomography scan or magnetic resonance imaging were obtained to establish baseline disease measurements. Chemistries were monitored weekly and before each cycle. On days 1, 8, 10, 12, 15, 17, and 19 of each cycle, a CBC with differential and platelet counts was obtained.
National Cancer Institute Common Toxicity Criteria (version 1.0) were used to classify adverse events. Filgrastim was continued until absolute neutrophil counts were ≥ 1,500 cells/μL. Chemotherapy was delayed for platelet counts of less than 100,000 cells/μL and or absolute neutrophil count less than 1,500 cells/μL. If re-treatment was postponed more than 2 weeks because of hematologic toxicity, patients were taken off study. Patients hospitalized with febrile neutropenia had ifosfamide and doxorubicin dosages reduced 10% for subsequent cycles. If serum creatinine increased to 1.5x the ULN, ifosfamide dosage was reduced by 50%. A serum creatinine greater than 1.5x the ULN led to study removal. Patients developing ≥ grade 3 neurotoxicity were taken off study.
Response Criteria
Response was evaluated according to Response Evaluation Criteria in Solid Tumors after every two cycles of chemotherapy for patients with metastatic disease.13 Patients receiving neoadjuvant therapy had imaging performed before chemotherapy and at the completion of the fourth cycle. Patients with metastatic disease were assessed for response if they had received at least two chemotherapy cycles. After the completion of treatment, patients had follow-up physical examinations with chest x-rays every 3 months for the first 2 years and every 6 months thereafter.
Statistical Design
This study consisted of two strata, patients with localized only and patients with metastatic disease. We anticipated approximately 70% of enrolled patients to have localized disease and 30% to have metastatic disease. Within each strata, patients were randomly assigned to receive SD ifosfamide or HD ifosfamide. The randomization was undertaken in blocks of six within each strata. We anticipated the overall 1-year DFS to be 40% in the SD ifosfamide group. An improvement in overall 1-year DFS to at least 70% in patients receiving HD ifosfamide was considered to be of clinical interest. This provided an {alpha} error of .05 and a error of .80. A one-sided 5% level test comparing proportions provided at least 80% power of detecting this difference or greater, with 40 patients per treatment arm.
Statistical Analysis
One-year DFS was measured from the date of randomization to the corresponding date of the following year. All patients were followed up until death, and survival was measured from the date of randomization to the date of death. One-year DFS and OS at 3 years were determined using Kaplan-Meier estimates. The relative hazard ratio comparing SD and HD ifosfamide was determined using a stratified Cox proportional hazards model. The pattern of changes in hematologic parameters (WBC count, platelets, and hemoglobin) over the first four cycles was analyzed using a random effects model that included fixed effects for dose, cycle, day within each cycle, and interactions. Measurements of serum creatinine were converted into creatinine clearance using the Cockcroft-Gault formula.
RESULTS
Patient characteristics are listed in Table 1. A total of 41 women and 38 men were enrolled. The median age was 53 years (range, 18 to 78 years); most had a Zubrod performance status of zero. None had received prior chemotherapy. Most patient characteristics were well-balanced between the treatment arms. However, because stratification for neoadjuvant or adjuvant therapy did not occur before randomization, more patients treated with adjuvant chemotherapy received SD ifosfamide, whereas more patients treated with neoadjuvant chemotherapy received HD ifosfamide. Histologic tumor types and disease sites are listed in Table 2.
Treatment and Tolerance
Forty-four of 52 patients with localized disease completed four cycles of therapy (Table 3). In those with metastatic disease, however, only seven of 13 patients who received SD ifosfamide and four of 14 patients who received HD ifosfamide completed all six cycles. Eight patients (10%) failed to complete chemotherapy because of disease progression on chemotherapy (six patients assigned to SD ifosfamide and two patients assigned to HD ifosfamide). Fifteen patients (19%) discontinued therapy because of toxicity (three patients assigned to SD ifosfamide and 12 patients assigned to HD ifosfamide). Of those receiving HD ifosfamide, there were five early deaths, each within 120 days from randomization (two deaths from neutropenic sepsis and three deaths from tumor progression). Each of these five patients was older than 65 years of age.
Hematologic toxicities are listed in Table 4. This table reflects the nadir hematologic values and most severe toxicity observed during the entire course of treatment. Grade 3/4 neutropenia was documented in 49% and 87% of patients on the SD ifosfamide and HD ifosfamide arms, respectively. Similarly, anemia and thrombocytopenia were also more pronounced on the HD ifosfamide arm. Grade 3/4 anemia occurred in 23% of patients who received SD ifosfamide and 57% of patients who received HD ifosfamide. Overall, seven patients on the SD ifosfamide arm required blood transfusions versus 30 patients on the HD ifosfamide arm. Ten percent of patients developed grade 3/4 thrombocytopenia while receiving SD ifosfamide versus 62% of patients receiving HD ifosfamide.
Grade 3/4 neurotoxicity, noted in four patients, was only observed on the HD ifosfamide arm. Renal toxicity, as described by a decline in creatinine clearance, is shown in Table 5. All patients had baseline creatinine clearances of ≥ 50 mL/min. After one or more courses of chemotherapy, only two patients (5%) who received SD ifosfamide had a decline in creatinine clearance, both of which were to less than 20 mL/min. Ten patients on the HD ifosfamide arm had reductions in creatinine clearance, nine patients to 20 to 50 mL/min and one patient to less than 20 mL/min.
Response to Treatment
Response to therapy is detailed in Table 6. Responses were characterized in a post hoc analysis because this was not an original objective of this proposal. Patients who received neoadjuvant or adjuvant chemotherapy were not stratified before randomization, thus the groups were imbalanced. All patients who received SD ifosfamide as neoadjuvant therapy had stable disease. In the HD ifosfamide arm, three (18%) of 17 patients achieved objective responses, whereas 11 patients had stable disease. There were no complete responses in either arm. In patients with metastatic disease treated with SD ifosfamide, three (23%) of 13 patients attained an objective response, including two complete responses. In the HD ifosfamide arm, three (25%) of 12 patients had an objective response, including one complete response.
Survival is tabulated in Table 7. No significant survival benefit was observed in either arm. In the SD ifosfamide arm, the 2- and 3-year survival rates were higher, 73% and 52%, respectively, as compared with 57% and 49% in the HD ifosfamide arm. The relative hazard ratio of death for the HD ifosfamide group compared with the SD ifosfamide group was 1.39 (95% CI, 0.70 to 2.77; P = .34; Fig 1). The 1-year DFS was 55% for all patients in the SD ifosfamide arm compared with 52% for all patients in the HD ifosfamide arm (Fig 2). The relative hazard ratio of disease recurrence after treatment with HD ifosfamide versus SD ifosfamide was 1.08 (95% CI, 0.56 to 2.09; P = .81).
Figure 1
Figure 2
Both treatment arms were analyzed according to the presence or absence of metastatic disease. Overall survival and DFS were higher in patients with localized disease, regardless of the treatment arm. The 3-year OS was 60% in the nonmetastatic group and 35% in the metastatic group. In the nonmetastatic patient population, 1-year DFS was 75% in the SD ifosfamide arm compared with 65% in the HD ifosfamide arm (Table 7). At 2 years, OS was 88% in the SD arm compared with 64% in the HD arm. The relative hazard ratio of death for the HD ifosfamide arm versus the SD ifosfamide arm was 1.64 (95% CI, 0.62 to 4.31). In patients with metastatic disease, 1-year DFS was slightly lower in the SD ifosfamide arm versus the HD ifosfamide arm (15% v 29%). However, the 2-year OS rate was 46% in both treatment arms. The relative hazard ratio of death for the HD ifosfamide arm versus the SD ifosfamide arm was 1.18 (95% CI, 0.44 to 3.14).
DISCUSSION
Despite improvements in response rates with combination chemotherapy, these multidrug regimens provide no OS benefit in comparison with single-agent doxorubicin.3,5 However, improved efficacy with combination regimens when used as neoadjuvant and adjuvant treatment may be expected. When administered as single agents, both doxorubicin and ifosfamide have response rates of approximately 25%, and response rates are generally improved when these agents are combined.3,6,11,24,25 The dosage of doxorubicin was limited in our study to 60 mg/m2, given the difficulty in administering 75 mg/m2 or greater with 12 g/m2 of ifosfamide. Published data fail to show a survival benefit from dose escalation of doxorubicin beyond 60 mg/m2 in the treatment of patients with STS.4,16 Similarly, new data from the breast cancer literature also report no improvement in OS with the administration of 75 mg/m2 of doxorubicin versus 60 mg/m2.26
This is the first randomized trial comparing an SD ifosfamide regimen with an HD ifosfamide regimen, with each arm receiving identical doses of doxorubicin. The results of this study show no improvement in 1-year DFS or OS in patients receiving HD ifosfamide and suggest a worse overall outcome with the higher dosage. Furthermore, when analyzed separately, neither patients with localized disease nor metastatic disease seem to have benefited from HD chemotherapy.
An argument can be made that this study was underpowered. We were looking for an improvement in 1-year DFS from 40% with SD ifosfamide/doxorubicin to 70% with the HD ifosfamide/doxorubicin having an 80% power, using a one-sided test to detect that difference with 80 patients. In our study design, we estimated that approximately 70% of the patients would have nonmetastatic disease and 30% would have metastatic disease. We accrued 79 assessable patients, 52 patients (65%) with localized, nonmetastatic disease and 27 patients (35%) with metastatic disease. To detect a smaller difference from 40% to 60%, 86 patients in each study arm would be required, and 325 patients would be needed to detect a difference from 40% to 50%. Initiatives to collaborate with other institutions were made in an attempt to accrue larger numbers of patients. However, strong prior opinions on whether HD or SD ifosfamide should be administered as first-line therapy for STS forced us to conduct this trial as a single-institution, phase II study. We chose to include patients with poor prognosis (high grade, > 5 cm) tumors with both localized and metastatic disease to have a large enough patient population to conduct a single-institution, randomized trial.
We recognize that histologic subtypes may have different responses to various systemic therapies. For example, gastrointestinal stomal tumors (GIST), formally thought of as epithelioid leiomyosarcomas of the gastrointestinal tract, were quite refractory to cytotoxic regimens, with response rates of less than 5%. The tyrosine kinase inhibitor, imatinib, has now revolutionized the treatment of GIST, with nearly 80% of patients with metastatic GIST having clinical benefit.27,28 In our study, we excluded the known histologic subtypes that had better response rates to specific cytotoxic regimens (ie, childhood rhabdomyosarcoma) or subtypes with known records of failure to doxorubicin and/or ifosfamide (ie, alveolar soft part sarcoma). The problem with clinical trials in STS without attention to the importance of histologic subtypes remains chronic and recurrent. It is possible that we may have missed the impact of ifosfamide dose-intensity in one or more of the subtypes. However, from studies in metastatic patients, there is no evidence of such an impact. Clearly, new methodologies in clinical trial design are warranted. Equally as clear is the need for new methods of collaboration among institutions with relatively large populations of these patients so that these important clinical questions can be addressed.
The role of adjuvant chemotherapy in the treatment of STS for localized disease remains controversial. However, data from a meta-analysis from 14 trials comparing surgery alone to surgery followed by adjuvant chemotherapy demonstrated a 7% improvement in OS at 10 years (P = .029).29 More recent data from Italy also indicate a benefit to adjuvant chemotherapy with regard to improvement in both DFS and OS in patients with high-grade sarcomas of the extremities.30 The role of neoadjuvant chemotherapy in the treatment of STS is not yet well documented.31
The overall response rate in patients treated with the HD regimen was 21% versus 15% in the SD regimen (Table 6). Although our findings are consistent with the response rates of HD and SD ifosfamide currently reported in the literature, it must be noted that the arms were not equally balanced in the subgroup analysis. Nineteen of the 27 patients treated neoadjuvantly were randomly assigned to the HD arm, and the majority of patients treated adjuvantly were randomly assigned to the SD arm. This was a chance occurrence, as patients were not stratified by neoadjuvant versus adjuvant status. We do not believe that this imbalance had any impact on the overall outcomes of our study in terms of DFS and OS.
The lack of difference in OS and 1-year DFS may be explained in part by a decline in renal function and increased toxicities, which prevented patients from completing planned courses of treatment or which led to early deaths. Before treatment, the patient population was considered fit, with only one patient having a Zubrod performance status of 2. Additionally, all registered patients had two functioning kidneys with adequate renal function. Of those patients with metastatic disease, fewer than one half who were randomly assigned to receive HD ifosfamide completed treatment. Toxicity and early death were the two contributing factors. All five patients with early death were ≥ 65 years of age. For reasons that are not entirely clear, our findings suggest that older age may contribute to lack of treatment response and an increase in toxicity, despite these patients having an adequate performance status. Thus if we were more selective, particularly in limiting enrollment by age, we might have improved the outcome in those treated with the HD ifosfamide regimen.
It is well known that HD ifosfamide regimens are more toxic than lower-dose regimens.11,24,32 The results of our study are no exception. Although granulocyte colony-stimulating factor was required in both arms, grade 3/4 myelosuppression were greater with the HD group (Table 4). The toxic effects of ifosfamide were cumulative with subsequent chemotherapy cycles. Anemia was common in both arms but was worse in the HD ifosfamide arm. The HD ifosfamide treatment group also experienced more thrombosuppressive toxicity. Renal toxicity with HD ifosfamide was similar in our study as in other reports.11 Ten patients on the HD arm developed worsening of their renal function. All but one recovered full function, and no patients required dialysis. Neurotoxicity was noted in four patients treated with 12 g/m2 of ifosfamide. No toxic deaths were attributed to CNS events. Findings from this study confirm that HD ifosfamide is more toxic. Clearly, patients must be counseled about the potential severity of this approach, even if they are in excellent general health and have a good performance status.
In conclusion, we attempted to explore the relative value of incorporating HD ifosfamide in combination with doxorubicin as first-line therapy for STS. Our findings, based on a combination of increased toxicity and lack of apparent benefit, do not support its routine use. Rather, standard doses of ifosfamide in combination with doxorubicin should be considered.
Authors’ Disclosures of Potential Conflicts of Interest
ACKNOWLEDGMENTS
We thank Yolanda Tra, PhD, of the Department of Biostatistics, for her support with biostastical analysis, and Monica Orians, of the Clinical Trials Office, for her support with data management.
NOTES
Supported by Amgen Inc, Thousand Oaks, CA.
Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002, and the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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