• Verma S, Younus J, Stys-Norman D, Haynes AE, Blackstein M, Sarcoma Disease Site Group. Ifosfamide-based combination chemotherapy in advanced soft tissue sarcoma: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Apr 11. 28 p. (Evidence-based series; no. 11-4). [40 references]

Inoperable locally advanced or metastatic soft tissue sarcoma

Assessment of Therapeutic Effectiveness
Treatment

Oncology

Physicians

• To evaluate whether combination chemotherapy regimens containing ifosfamide have an advantage in terms of response rate, time to progression, or survival, compared with similar regimens without ifosfamide, when used as first-line therapy in adult patients with inoperable locally advanced or metastatic soft tissue sarcoma
• To evaluate the adverse effects and effects on quality of life of ifosfamide-containing combination chemotherapy, compared with similar regimens without ifosfamide

Adult patients with inoperable locally advanced or metastatic soft tissue sarcoma

Combination chemotherapy regimens containing ifosfamide

• Response rate
• Time to progression
• Survival
• Adverse effects
• Quality of life

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

The literature search identified three randomized phase III trials and 23 single-arm phase II trials that met the inclusion criteria for this systematic review of the evidence.

Expert Consensus (Committee)

Not applicable

Meta-Analysis of Randomized Controlled Trials
Systematic Review with Evidence Tables

Synthesizing the Evidence

To estimate the effect of ifosfamide-containing combination chemotherapy on response rate and survival in patients with locally advanced or metastatic soft tissue sarcoma (STS), published data from randomized controlled trials (RCTs) were pooled in a meta-analysis by the guideline developers. Objective tumour response data (i.e., number of complete and partial responses) were obtained from the text of published trial reports, and one-year mortality data were extracted from published survival curves. The numbers of eligible patients were used as denominators for all pooled analyses. One year was selected as the time point at which to pool mortality data, because the expected median survival of patients with inoperable locally advanced or metastatic soft tissue sarcoma is nine to 12 months. Data were pooled and analyzed using the MetaView analysis component of the Cochrane Collaboration Review Manager 4.2 software. The results of the meta-analysis are expressed as a relative risk (RR) with a corresponding 95% confidence interval (CI). For tumour response, a relative risk <1.0 indicates that patients in the experimental treatment group (ifosfamide-based combination chemotherapy) had a higher probability of a complete or partial response compared with the control group (non-ifosfamide chemotherapy); conversely, a relative risk of response >1.0 favours the control group (non-ifosfamide chemotherapy).

For one-year mortality, a relative risk <1.0 indicates that the patients in the experimental treatment group (ifosfamide-based combination chemotherapy) experienced higher survival rates than the control group (non-ifosfamide chemotherapy). Data were analyzed using the random effects model (Mantel-Haenszel). Heterogeneity was considered to be significant when p was less than 0.1 on the chi-square test for statistical heterogeneity.

Expert Consensus

This evidence-based series was developed by the Sarcoma Disease Site Group (DSG) of Cancer Care Ontario's Program in Evidence-based Care (PEBC). Evidence was selected and reviewed by one member of the PEBC Sarcoma DSG and methodologists.

The series is a convenient and up-to-date source of the best available evidence on ifosfamide-based combination chemotherapy for patients with inoperable locally advanced or metastatic soft tissue sarcoma (STS), developed through systematic review, evidence synthesis, and input from practitioners in Ontario.

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

Report Approval Panel

Prior to submission of this evidence-based series report for external review, the report was reviewed and approved by the Program in Evidence-Based Care (PEBC) Report Approval Panel, which consists of two members, including an oncologist, with expertise in clinical and methodology issues. Key issues raised by the Panel were that the inclusion of the word "routine" in the recommendation created ambiguity in light of the compelling evidence demonstrating lack of benefit and that a rationale for using response as an important and policy-determining outcome was required, as was a rationale for including phase II studies, given the availability of three randomized controlled trials (RCTs). In response, the Disease Site Group (DSG) removed the word "routine", noted that response is an important outcome in this patient population given their limited treatment options, and noted that the inclusion of phase II studies reflected the previous approach, of including both randomized controlled trials and phase II studies, at the time the report was initially started.

External Review

Following the review and discussion of Sections 1 and 2 of this evidence-based series, the Sarcoma DSG circulated the clinical practice guideline and systematic review to clinicians in Ontario for review and feedback. Feedback was obtained through a mailed survey of 74 practitioners in Ontario that included medical oncologists, radiation oncologists, and surgeons. The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. The survey was mailed out on February 22, 2006. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Sarcoma DSG reviewed the results of the survey.

In patients with metastatic soft tissue sarcoma, the addition of ifosfamide to standard first-line doxorubicin containing regimens is not recommended over single-agent doxorubicin. However, in patients with symptomatic, locally-advanced, or inoperable soft tissue sarcoma, in whom tumour response might potentially result in reduced symptomatology or render a tumour resectable, it is reasonable to use ifosfamide in combination with doxorubicin.

None provided

The recommendations are supported by randomized phase III trials and single-arm phase II trials.

• A small, statistically significant improvement in tumour response rate was observed with ifosfamide-containing chemotherapy compared to non-ifosfamide-containing chemotherapy (relative risk, 1.52; 95% confidence interval, 1.11 to 2.08; p=0.009).
• Meta-analysis of published one-year mortality rates from three randomized trials did not detect a significant difference between ifosfamide and non-ifosfamide-containing chemotherapy (relative risk, 0.98; 95% confidence interval, 0.85 to 1.13; p = 0.28).

Higher rates of adverse events, particularly grade 3-4 myelosuppression were observed in patients who received regimens that contained ifosfamide. A higher rate of toxic deaths was reported in two of the three randomized trials reviewed, for the ifosfamide-containing regimen.

• In combination with doxorubicin-containing regimen, the dose of ifosfamide should not exceed 7.5 g/m² given as either a split bolus or continuous infusion.
• Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the practice guideline is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding their content or use or application and disclaims any for their application or use in any way.

An implementation strategy was not provided.

Living with Illness

Effectiveness

• Verma S, Younus J, Stys-Norman D, Haynes AE, Blackstein M, Sarcoma Disease Site Group. Ifosfamide-based combination chemotherapy in advanced soft tissue sarcoma: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Apr 11. 28 p. (Evidence-based series; no. 11-4). [40 references]

Not applicable: The guideline was not adapted from another source.

2006 Apr 11

Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]

The Program in Evidence-based Care (PEBC) is a Province of Ontario initiative sponsored by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Cancer Care Ontario
Ontario Ministry of Health and Long-Term Care

Provincial Sarcoma Disease Site Group

The members of the Sarcoma Disease Site Group disclosed potential conflicts of interest relating to the topic of this systematic review. No potential conflicts were declared.

None available

This NGC summary was completed by ECRI on June 22, 2006. The information was verified by the guideline developer on July 6, 2006.