Adjuvant chemotherapy for clinically localized tumors

A quantitative meta-analysis of updated data from 1,568 individual patients in 14 trials of doxorubicin-based adjuvant chemotherapy was reported. Only a small proportion of patients in this meta-analysis were treated with ifosfamide, an agent with demonstrated activity against soft tissue sarcoma.[40,41][Level of evidence B1] The following results were reported:

A quantitative meta-analysis of updated data from 1,568 individual patients in 14 trials of doxorubicin-based adjuvant chemotherapy was reported. Only a small proportion of patients in this meta-analysis were treated with ifosfamide, an agent with demonstrated activity against soft tissue sarcoma.[40,41][Level of evidence B1] The following results were reported:

An absolute benefit from adjuvant chemotherapy of 6% for local relapse-free interval (95% CI, 1%–10%), 10% for distant relapse-free interval (95% CI, 5%–15%), and 10% for RFS (95% CI, 5%–15%).

A quantitative meta-analysis of updated data from 1,568 individual patients in 14 trials of doxorubicin-based adjuvant chemotherapy was reported. Only a small proportion of patients in this meta-analysis were treated with ifosfamide, an agent with demonstrated activity against soft tissue sarcoma.[40,41][Level of evidence B1] The following results were reported:

No statistically significant OS benefit at 10 years was detected; the absolute difference was 4% (95% CI, -1% to +9%).

A quantitative meta-analysis of updated data from 1,568 individual patients in 14 trials of doxorubicin-based adjuvant chemotherapy was reported. Only a small proportion of patients in this meta-analysis were treated with ifosfamide, an agent with demonstrated activity against soft tissue sarcoma.[40,41][Level of evidence B1] The following results were reported:

A subset analysis suggested that patients with sarcomas of the extremities may have benefited from adjuvant chemotherapy, with a reported 7% absolute OS improvement at 10 years (hazard ratio [HR]death, 0.8; P = .029).[41]

In a small feasibility study, 59 patients with high-risk soft tissue sarcomas (58 of whom had an extremity or the trunk as the primary site) underwent primary resection plus PORT. They were then randomly assigned to observation versus a dose-dense regimen of six 14-day cycles of ifosfamide, dacarbazine (DTIC), and doxorubicin (IFADIC regimen) with granulocyte colony-stimulating factor (G-CSF) bone marrow support.[42]

In a small feasibility study, 59 patients with high-risk soft tissue sarcomas (58 of whom had an extremity or the trunk as the primary site) underwent primary resection plus PORT. They were then randomly assigned to observation versus a dose-dense regimen of six 14-day cycles of ifosfamide, dacarbazine (DTIC), and doxorubicin (IFADIC regimen) with granulocyte colony-stimulating factor (G-CSF) bone marrow support.[42]

There were no statistically significant differences in OS or RFS. However, the study was severely underpowered.

In a second trial performed by the Italian National Council for Research, high-risk patients were treated with local therapy (wide resection plus preRT or PORT, or amputation as clinically necessary) and were then randomly assigned to observation versus five 21-day cycles of 4-epidoxorubicin (epirubicin) plus ifosfamide (with mesna and G-CSF).[43,44]In summary, the trial was underpowered because it was stopped early, and the promising early results that led to stopping the trial diminished as the trial matured.

In a second trial performed by the Italian National Council for Research, high-risk patients were treated with local therapy (wide resection plus preRT or PORT, or amputation as clinically necessary) and were then randomly assigned to observation versus five 21-day cycles of 4-epidoxorubicin (epirubicin) plus ifosfamide (with mesna and G-CSF).[43,44]In summary, the trial was underpowered because it was stopped early, and the promising early results that led to stopping the trial diminished as the trial matured.

Based on power calculations, the planned study size was 190 patients, but the trial was stopped after 104 patients had been entered because an interim analysis revealed a statistically significant (P = .001) difference in DFS favoring the chemotherapy arm. By the time of the initial peer-reviewed report of the study, the DFS still favored the chemotherapy arm (median DFS of 48 months vs. 16 months), but the P value had risen to .04.[43]

In a second trial performed by the Italian National Council for Research, high-risk patients were treated with local therapy (wide resection plus preRT or PORT, or amputation as clinically necessary) and were then randomly assigned to observation versus five 21-day cycles of 4-epidoxorubicin (epirubicin) plus ifosfamide (with mesna and G-CSF).[43,44]In summary, the trial was underpowered because it was stopped early, and the promising early results that led to stopping the trial diminished as the trial matured.

Although there was no difference in metastasis-free survival at the time of the report, there was an improvement in median OS (75 months for the chemotherapy arm vs. 46 months for the observation arm; P = .03).

In a second trial performed by the Italian National Council for Research, high-risk patients were treated with local therapy (wide resection plus preRT or PORT, or amputation as clinically necessary) and were then randomly assigned to observation versus five 21-day cycles of 4-epidoxorubicin (epirubicin) plus ifosfamide (with mesna and G-CSF).[43,44]In summary, the trial was underpowered because it was stopped early, and the promising early results that led to stopping the trial diminished as the trial matured.

At the follow-up report (median follow-up of 89.6 months in a range of 56–119 months), OS differences were no longer statistically significant (58.5% in the chemotherapy arm vs. 43.1% in the observation arm; P = .07).[44]

In a second trial performed by the Italian National Council for Research, high-risk patients were treated with local therapy (wide resection plus preRT or PORT, or amputation as clinically necessary) and were then randomly assigned to observation versus five 21-day cycles of 4-epidoxorubicin (epirubicin) plus ifosfamide (with mesna and G-CSF).[43,44]In summary, the trial was underpowered because it was stopped early, and the promising early results that led to stopping the trial diminished as the trial matured.

The DFS difference had also lost statistical significance (47.2% in the chemotherapy arm vs. 16.0% in the observation arm; P = .09).[44]

In a third, underpowered, single-center trial, 88 patients with high-risk soft tissue sarcomas (64 with extremity or trunk primary tumors) underwent surgery (with or without radiation) and were then randomly assigned to receive four 21-day cycles of chemotherapy, epirubicin (n = 26) or epirubicin plus ifosfamide (n = 19), versus no adjuvant chemotherapy (n = 43).[45] The trial was closed prematurely because of a slow accrual rate.

In a third, underpowered, single-center trial, 88 patients with high-risk soft tissue sarcomas (64 with extremity or trunk primary tumors) underwent surgery (with or without radiation) and were then randomly assigned to receive four 21-day cycles of chemotherapy, epirubicin (n = 26) or epirubicin plus ifosfamide (n = 19), versus no adjuvant chemotherapy (n = 43).[45] The trial was closed prematurely because of a slow accrual rate.

After a median follow-up of 94 months, the 5-year DFS rates were 69% in the chemotherapy arm and 44% in the control arm (P = .01).

In a third, underpowered, single-center trial, 88 patients with high-risk soft tissue sarcomas (64 with extremity or trunk primary tumors) underwent surgery (with or without radiation) and were then randomly assigned to receive four 21-day cycles of chemotherapy, epirubicin (n = 26) or epirubicin plus ifosfamide (n = 19), versus no adjuvant chemotherapy (n = 43).[45] The trial was closed prematurely because of a slow accrual rate.

The 5-year OS rates were 72% in the chemotherapy arm and 47% in the control arm (P = .06).

In a third, underpowered, single-center trial, 88 patients with high-risk soft tissue sarcomas (64 with extremity or trunk primary tumors) underwent surgery (with or without radiation) and were then randomly assigned to receive four 21-day cycles of chemotherapy, epirubicin (n = 26) or epirubicin plus ifosfamide (n = 19), versus no adjuvant chemotherapy (n = 43).[45] The trial was closed prematurely because of a slow accrual rate.

All the benefit associated with chemotherapy appeared restricted to the 19 patients who received epirubicin plus ifosfamide.

In another underpowered trial, 134 patients with high-risk soft tissue sarcomas (93% with extremity or trunk primary tumors) were randomly assigned to undergo surgical resection (with or without radiation) or to receive three preoperative 21-day cycles of doxorubicin plus ifosfamide.[46] This multicenter trial from the European Organisation for Research and Treatment of Cancer (EORTC) (EORTC-62874) was closed because of slow accrual and results that were not promising enough to warrant continuation of the trial.

In another underpowered trial, 134 patients with high-risk soft tissue sarcomas (93% with extremity or trunk primary tumors) were randomly assigned to undergo surgical resection (with or without radiation) or to receive three preoperative 21-day cycles of doxorubicin plus ifosfamide.[46] This multicenter trial from the European Organisation for Research and Treatment of Cancer (EORTC) (EORTC-62874) was closed because of slow accrual and results that were not promising enough to warrant continuation of the trial.

With a median follow-up of 7.3 years, the 5-year DFS rates were 52% in the surgery-alone arm and 56% in the chemotherapy-plus-surgery arm (P = .35).

In another underpowered trial, 134 patients with high-risk soft tissue sarcomas (93% with extremity or trunk primary tumors) were randomly assigned to undergo surgical resection (with or without radiation) or to receive three preoperative 21-day cycles of doxorubicin plus ifosfamide.[46] This multicenter trial from the European Organisation for Research and Treatment of Cancer (EORTC) (EORTC-62874) was closed because of slow accrual and results that were not promising enough to warrant continuation of the trial.

The 5-year OS rates were 64% in the surgery-alone arm and 65% in the chemotherapy-plus-surgery arm (P = .22).

The previous four trials have been combined with the 14 first-generation trials in a trial-level meta-analysis.[47] Of the 18 randomized trials of patients with resectable soft tissue sarcomas, 5 trials used a combination of doxorubicin (50–90 mg/m2 per cycle) plus ifosfamide (1,500–5,000 mg/m2 per cycle). The remaining 13 trials used doxorubicin (50–70 mg/m2 per cycle) alone or with other drugs.[47][Level of evidence A1]

The previous four trials have been combined with the 14 first-generation trials in a trial-level meta-analysis.[47] Of the 18 randomized trials of patients with resectable soft tissue sarcomas, 5 trials used a combination of doxorubicin (50–90 mg/m2 per cycle) plus ifosfamide (1,500–5,000 mg/m2 per cycle). The remaining 13 trials used doxorubicin (50–70 mg/m2 per cycle) alone or with other drugs.[47][Level of evidence A1]

The absolute risk reduction in local recurrence rates associated with any chemotherapy added to local therapy was 4% (95% CI, 0%–7%), and it was 5% (95% CI, 1%–12%) when ifosfamide was combined with doxorubicin.

The previous four trials have been combined with the 14 first-generation trials in a trial-level meta-analysis.[47] Of the 18 randomized trials of patients with resectable soft tissue sarcomas, 5 trials used a combination of doxorubicin (50–90 mg/m2 per cycle) plus ifosfamide (1,500–5,000 mg/m2 per cycle). The remaining 13 trials used doxorubicin (50–70 mg/m2 per cycle) alone or with other drugs.[47][Level of evidence A1]

The absolute reduction in overall mortality was 6% with any chemotherapy (95% CI, 2%–11%; this was a reduction from 46% to 40%), 11% for doxorubicin plus ifosfamide (95% CI, 3%–19%; this was a reduction from 41% to 30%), and 5% for doxorubicin without ifosfamide.

An additional multicenter randomized trial (EORTC-62931 [NCT00002641]) that used adjuvant doxorubicin (75 mg/m2) plus ifosfamide (5,000 mg/m2) was not included in the previous meta-analysis.[48] After local therapy, 351 patients were randomly assigned to five 21-day cycles of adjuvant therapy versus observation. The results of EORTC-62931 differed from those reported in the previous meta-analysis.[47]

An additional multicenter randomized trial (EORTC-62931 [NCT00002641]) that used adjuvant doxorubicin (75 mg/m2) plus ifosfamide (5,000 mg/m2) was not included in the previous meta-analysis.[48] After local therapy, 351 patients were randomly assigned to five 21-day cycles of adjuvant therapy versus observation. The results of EORTC-62931 differed from those reported in the previous meta-analysis.[47]

The OS rate did not differ significantly between groups (HR, 0.94; 95% CI, 0.68–1.31; P = .72); neither did the RFS rate (HR, 0.91, 0.67–1.22; P = .51).

An additional multicenter randomized trial (EORTC-62931 [NCT00002641]) that used adjuvant doxorubicin (75 mg/m2) plus ifosfamide (5,000 mg/m2) was not included in the previous meta-analysis.[48] After local therapy, 351 patients were randomly assigned to five 21-day cycles of adjuvant therapy versus observation. The results of EORTC-62931 differed from those reported in the previous meta-analysis.[47]

The 5-year OS rates were 66.5% (95% CI, 58.8%–73%) in the chemotherapy group and 67.8% (95% CI, 60.3%–74.2%) in the control group.

In a subsequent analysis of pooled individual patient data, the EORTC investigators combined data from this trial (EORTC-62931) with data from their previous trial (EORTC-62771) [49] of adjuvant cyclophosphamide plus doxorubicin plus dacarbazine (CYVADIC), representing the two largest trials of adjuvant therapy for adults with soft tissue sarcoma in the literature (N = 819 patients).[50] [Level of evidence A1];[51]

In a subsequent analysis of pooled individual patient data, the EORTC investigators combined data from this trial (EORTC-62931) with data from their previous trial (EORTC-62771) [49] of adjuvant cyclophosphamide plus doxorubicin plus dacarbazine (CYVADIC), representing the two largest trials of adjuvant therapy for adults with soft tissue sarcoma in the literature (N = 819 patients).[50] [Level of evidence A1];[51]

Large tumor size, high histological grade, and R1 resection emerged as independent adverse prognostic factors for RFS and OS.

In a subsequent analysis of pooled individual patient data, the EORTC investigators combined data from this trial (EORTC-62931) with data from their previous trial (EORTC-62771) [49] of adjuvant cyclophosphamide plus doxorubicin plus dacarbazine (CYVADIC), representing the two largest trials of adjuvant therapy for adults with soft tissue sarcoma in the literature (N = 819 patients).[50] [Level of evidence A1];[51]

Adjuvant chemotherapy was an independent favorable prognostic factor for RFS but not for OS.

In a subsequent analysis of pooled individual patient data, the EORTC investigators combined data from this trial (EORTC-62931) with data from their previous trial (EORTC-62771) [49] of adjuvant cyclophosphamide plus doxorubicin plus dacarbazine (CYVADIC), representing the two largest trials of adjuvant therapy for adults with soft tissue sarcoma in the literature (N = 819 patients).[50] [Level of evidence A1];[51]

Males and patients older than 40 years had a significantly better RFS in the treatment arms, while adjuvant chemotherapy was associated with a marginally worse OS in females and patients younger than 40 years.

In a subsequent analysis of pooled individual patient data, the EORTC investigators combined data from this trial (EORTC-62931) with data from their previous trial (EORTC-62771) [49] of adjuvant cyclophosphamide plus doxorubicin plus dacarbazine (CYVADIC), representing the two largest trials of adjuvant therapy for adults with soft tissue sarcoma in the literature (N = 819 patients).[50] [Level of evidence A1];[51]

The combined analysis showed no improvement in either RFS or OS associated with adjuvant chemotherapy.