Cyclophosphamide versus ifosfamide for paediatric and young adult bone and soft tissue sarcoma patients
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Primary objective: To compare the possible effectiveness of cyclophosphamide with that of ifosfamide for paediatric and young adult patients with sarcoma.
Secondary objectives: To determine possible effects of these agents on toxicities (including late effects) and quality of life.
Background
Sarcomas are mesenchymal tumours that arise from bone and soft tissues. They can occur in all ages (Kasper 2005). The German Childhood Cancer Registry (GCCR 2004; GCCR 2004 appendix) describes incidence rates of 3.7% for rhabdomyosarcoma, which is the most common form of soft tissue sarcoma in childhood and adolescence (Stevens 2005), 2.3% for osteosarcoma and 2.1% for Ewing's sarcoma.
Although the prognosis of the different types of sarcomas in children still depends on several prognostic factors such as the presence of metastases, tumour volume and primary tumour site, it has been improving since the introduction of polychemotherapy, for example from a 25% cure rate for rhabdomyosarcoma in 1970 to 70% in 1991 (Crist 2001), in which alkylating agents, such as the oxazaphosphorines ifosfamide and cyclophosphamide, play a major role.
Cyclophosphamide is a widely employed cytotoxic agent, and also in use against childhood sarcomas, as it has shown good anti‐tumour efficacy in these malignancies (Spunt 2004; Lai 2005; Weller 2005; Umapathi 2005; Durkan 2005). Its anti‐tumour efficacy unfolds after metabolic activation and is the result of direct alkylation of target cell DNA leading to inter‐ and intra‐strand crosslinking, which ultimately induces apoptosis in non‐resistant cells; it also augments the efficacy of antitumour immune response and acts in an antiangiogenic capacity by destroying circulating endothelial progenitor cells (Zhang 2005).
However, since the early 1980s, its structural analogue ifosfamide has been increasingly substituted in its place for the treatment of childhood sarcomas (Paulussen 2001). This was initially done, because early data suggested a higher anti‐tumour efficacy compared to cyclophosphamide (Koscielniak 1999; Crist 2001). The equimyelotoxic dose of ifosfamide and cyclophosphamide was established in investigations of the Intergroup Rhabdomyosarcoma Study and has been calculated at 9.0 g/m² ifosfamide equivalent to 2.1 g/m² cyclophosphamide, resulting in an equivalency ratio regarding myelotoxicity of ifosfamide/cyclophosphamide of 4.3 (Ruymann 1995). However, there is still controversy as to their comparative anti‐tumour efficacy (Stevens 2005; Shaw 1990; Ashraf 1994; Carli 2003). There are studies that have shown that ifosfamide is superior to cyclophosphamide, such as early studies of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group in adults (Verweij 1995), and there are also studies that show no difference, such as the randomised‐controlled trial Intergroup Rhabdomyosarcoma Study IV, which showed that cyclophosphamide, ifosfamide or etoposide are equal when added to vincristine, dactinomycin and surgery with or without radiotherapy for local or regional rhabdomyosarcoma in paediatric patients (Crist 2001).
Differences in toxicity profile (like neurotoxicity, nephrotoxicity, myelotoxicity) are also important (Carli 2003; Nicolao 2003). Especially relevant in paediatric oncology are the different late effects of these agents, with ifosfamide inducing, for example, severe tubulopathies up to the full Fanconi syndrome (Skinner 2003), which has the potential to induce growth impairments in the children affected by it after cancer treatment (Stöhr 2006). This is not observed with cyclophosphamide (Rossi 1999). Also important is the gonadotoxic potential of cyclophosphamide and ifosfamide (Howell 2001; Fawaz 2005), as are the possible cardiotoxic effects (Simbre 2005).
Therefore, we elected to conduct a systematic review and compare the efficacy and possible adverse effects of these two alkylating agents in paediatric patients with a bone or soft tissue sarcoma.
Objectives
Primary objective: To compare the possible effectiveness of cyclophosphamide with that of ifosfamide for paediatric and young adult patients with sarcoma.
Secondary objectives: To determine possible effects of these agents on toxicities (including late effects) and quality of life.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) comparing the effectiveness of cyclophosphamide and ifosfamide in the treatment of paediatric and young adult sarcomas.
When no RCTs are identified, we will include controlled clinical trials (CCTs). A CCT is a study that compares one or more intervention groups to one or more control groups (Cochrane Handbook).
Types of participants
Paediatric and young adult patients (<30 years of age at diagnosis) with soft tissue sarcoma, osteosarcoma or Ewing's sarcoma of all stages who received either ifosfamide or cyclophosphamide.
Types of interventions
Patients should receive either cyclophosphamide or ifosfamide as part of their treatment. However, the dosage and duration of administration of cyclophosphamide and ifosfamide may differ. Chemotherapy other than either cyclophosphamide or ifosfamide should be the same in both treatment groups.
Types of outcome measures
Primary outcomes:
(1)Response rate (defined as the number of patients with a complete or partial remission)
(2)Event‐free survival (defined as the time to recurrence or progression of disease)
(3)Overall patient survival (defined as the time to death from any cause)
Secondary outcomes:
(1) Toxicities including late effects of treatment, in particular gonadotoxicity, nephrotoxicity, urotoxicity, neurotoxicity and cardiotoxicity.
(2) Quality of life
Search methods for identification of studies
See: Childhood Cancer Review Group search strategy
See: Collaborative Review Group search strategy
The following electronic databases will be searched:
MEDLINE/PubMed (from 1966 to March 2006), EMBASE/Ovid (from 1980 to March 2006) and CENTRAL (Cochrane Library, issue 1, 2006).
(1) For ifosfamide the following subject headings and textwords will be used:
ifosfamide OR iphosphamide OR iso‐endoxan OR iso endoxan OR isophosphamide OR isofosfamide OR holoxan OR asta z 4942 OR NSC‐109,724 OR NSC 109,724 OR NSC109,724 OR NSC 109724 OR NSC‐109724 OR NSC109724 OR cyclic p‐oxides OR ethylamines OR oxazines OR ifosfa* OR iphospha* OR isofosfa* OR isophospha*
(2) For cyclophosphamide the following subject headings and textwords will be used:
cyclophosphamide OR cyclophosphane OR cytophosphan OR B‐518 OR cyclophosphamide monohydrate OR monohydrate, cyclophosphamide OR endoxan OR cytoxan OR neosar OR procytox OR sendoxan OR NSC‐26271 OR NSC 26271 OR NSC26271 OR cyclophosphamide, (R)‐isomer OR cyclophosphamide, (S)‐isomer OR cyclophosphamide, (+)‐isomer OR endox* OR cyclophospha*
(3) For sarcoma the following subject headings and textwords will be used:
sarcoma OR sarcomas OR sarcoma, soft tissue OR sarcomas, soft tissue OR soft tissue sarcoma OR soft tissue sarcomas OR sarcoma, epithelioid OR epithelioid sarcoma OR epithelioid sarcomas OR sarcomas, epithelioid OR sarcoma, spindle cell OR sarcomas, spindle cell OR spindle cell sarcoma OR spindle cell sarcomas OR sarcom* OR adenosarcoma OR adenosarcom* OR carcinosarcoma OR carcinosarcom* OR chondrosarcoma OR chondrosarcom* OR fibrosarcoma OR fibrosarcom* OR dermatofibrosarcoma OR dermatofibrosarcom* OR neurofibrosarcoma OR neurofibosarcom* OR neurogenic sarcoma OR hemangiosarcoma OR hemangiosarcom* OR haemangiosarcom* OR angiosarcoma OR angiosarcom* OR leiomyosarcoma OR leiomyosarcom* OR liposarcoma OR liposarcom* OR lymphangiosarcoma OR lymphangiosarcom* OR myxosarcoma OR myxosarcom* OR synovial sarcoma OR sarcoma synovial OR sarcoma, small cell OR small cell sarcoma OR sarcoma, granulocytic OR granulocytic sarcoma OR sarcoma, alveolar soft part OR alveolar soft part sarcoma OR sarcoma, clear cell OR clear cell sarcoma OR osteosarcoma OR osteosarcomas OR osteosarcom* OR osteogenic sarcoma OR osteogenic sarcomas OR sarcoma, osteogenic OR sarcomas, osteogenic OR osteosarcoma, juxtacortical OR osteosarcomas, juxtacortical OR juxtacortical osteosarcoma OR juxtacortical osteosarcomas OR rhabdomyosarcoma OR rhabdomyosarcomas OR rhabdomyosarcom* OR myosarcoma OR myosarcomas OR myosarcom* OR embryonal rhabdomyosarcoma OR embryonal rhabdomyosarcomas OR rhabdomyosarcomas, embryonal OR alveolar rhabdomyosarcoma OR alveolar rhabdomyosarcomas OR rhabdomyosarcomas, alveolar OR sarcoma, ewing's OR ewing's sarcoma OR sarcoma, ewing OR sarcoma, ewings OR ewing tumor OR ewing tumors OR ewing's tumor OR tumor ewing's OR ewing*
The different searches will be combined as (1) AND (2) AND (3).
Finally, the results of this search will be combined with the highly sensitive search strategy for RCTs and CCTs as described in the Cochrane Handbook (Cochrane Handbook).
For EMBASE and the Cochrane Library we will use adaptations of the same search strategy. Any new terms found in the results of our search will be added to the search strategy. Information about trials not registered in MEDLINE, EMBASE or the Cochrane Library, either published or unpublished, will be located by searching the reference lists of relevant articles and review articles. We also plan to scan the conference proceedings of the Sarcoma Meeting Stuttgart (SMS) and the Société Internationale d' Oncologie Pédiatrique (SIOP) from 2001 to 2005, if available electronically and otherwise by hand searching. We will search for ongoing trials by contacting researchers involved in this area and also by scanning the ISRCTN register and the National Institute of Health register. Language restriction will not be imposed. We will update our review every two years.
Data collection and analysis
STUDY IDENTIFICATION
After employing the search strategy described previously, identification of studies meeting the inclusion criteria will be undertaken by two reviewers independently. Discrepancies between reviewers will be resolved by consensus. If consensus cannot be reached final resolution will be made using a third party arbitrator. Any study seemingly meeting the inclusion criteria on grounds of the title, or abstract, or both, will be obtained in full for closer inspection. Details of reasons for exclusion of any study considered for review will be clearly stated.
QUALITY ASSESSMENT OF INCLUDED STUDIES
Assessment of quality for RCTs will be made by two reviewers independently according to the following criteria: concealment of treatment allocation, blinding of the care provider, blinding of the patients, blinding of the outcome assessor, and completeness of follow‐up. Allocation concealment will be described as adequate, inadequate, or unclear (Schulz 1995). In case CCTs are included in this review, the guidelines of the Childhood Cancer Review Group for the assessment of non‐RCTs will be followed. Discrepancies between reviewers will be resolved by consensus. If consensus cannot be reached final resolution will be made using a third party arbitrator.
DATA EXTRACTION
Data extraction will be performed independently by two reviewers using standardised forms. Data of the characteristics of participants (age, sex, type of tumour, stage of disease, previous antineoplastic therapy), of interventions (route of delivery, dose, timing and treatment length), of outcome measures and of length of follow‐up will be extracted. In cases of disagreement, the abstracts and articles will be re‐examined and discussed until consensus is achieved. If this is impossible, final resolution will be made using a third party arbitrator.
DATA ANALYSIS
The data will be entered into RevMan and analysed according to the guidelines of the Cochrane Handbook. Dichotomous outcomes will be related to risk using the relative risk (RR); continuous outcomes will be related to risk using the weighted mean difference (WMD). The data will be extracted by allocation intervention, irrespective of compliance with the allocated intervention, in order to allow an 'intention‐to‐treat' analysis. If this is not possible this will be stated. Heterogeneity will be assessed both by visual inspection of forest plots and by a formal statistical test for heterogeneity. If there is evidence of significant heterogeneity, the possible reasons for this will be investigated and reported. We will use a random effects model throughout the review. Pooling will only be performed for studies using the same treatment schedule in both treatment groups. For the assessment of survival, we will use Parmar's method (Parmar 1998) if hazard ratios have not been explicitly presented in the study. Studies for which pooling is not possible will be summarised qualitatively. Where possible, data will be separated for different types of sarcoma. These groups will be treated as subgroups if there are a sufficient number of trials of an adequate size. The quality of studies included in the analyses will be taken into account in the interpretation of the review's results. We will perform a sensitivity analysis for the used quality criteria.
