Ciclofosfamida versus ifosfamida para niños y adultos jóvenes con sarcoma de tejidos blandos y óseo
Resumen
Antecedentes
Los agentes alquilantes, como la ciclofosfamida y la ifosfamida, desempeñan una función principal en la mejoría de la supervivencia de niños y adultos jóvenes con sarcoma de tejidos blandos y óseo. Sin embargo, todavía existe controversia en cuanto la eficacia antitumoral comparativa y los posibles efectos adversos. Ésta es la segunda actualización de la primera revisión sistemática que evalúa el estado de la evidencia sobre la efectividad de la ciclofosfamida en comparación con la ifosfamida en el tratamiento de los niños y adultos jóvenes con sarcoma de tejidos blandos y óseo.
Objetivos
El objetivo principal fue comparar la eficacia, es decir, la tasa de respuesta, la supervivencia libre de eventos y la supervivencia general, de la ciclofosfamida con la de la ifosfamida en niños y adultos jóvenes con sarcoma. Los objetivos secundarios fueron determinar los efectos de esos agentes sobre los efectos tóxicos (incluidos los efectos tardíos) y la calidad de vida.
Métodos de búsqueda
Se hicieron búsquedas en CENTRAL (The Cochrane Library 2015, número 2), MEDLINE/PubMed (desde 1966 hasta marzo 2015) y en EMBASE/Ovid (desde 1980 hasta marzo 2015) con términos preespecificados. Además, se realizaron búsquedas en las listas de referencias de los artículos pertinentes, las actas de congresos y las bases de datos de ensayos en curso (www.controlled‐trials.com; búsqueda en junio de 2015).
Criterios de selección
Ensayos controlados aleatorizados (ECA) o ensayos clínicos controlados (ECC) que compararan la ciclofosfamida y la ifosfamida para el tratamiento de diferentes tipos de sarcoma en niños y adultos jóvenes (de menos de 30 años de edad al momento del diagnóstico). La quimioterapia diferente a la ciclofosfamida o la ifosfamida debía ser igual en ambos grupos de tratamiento.
Obtención y análisis de los datos
Dos autores realizaron la selección de los estudios de forma independiente.
Resultados principales
No se identificaron estudios que cumplieran los criterios de inclusión.
Conclusiones de los autores
No se identificaron ECA ni ECC que compararan la efectividad de la ciclofosfamida y la ifosfamida en el tratamiento del sarcoma de tejidos blandos y óseo en niños y adultos jóvenes. Por consiguiente, no se pueden establecer conclusiones definitivas acerca de los efectos de la ciclofosfamida y la ifosfamida en estos pacientes. Según la evidencia disponible en la actualidad, no se pueden hacer recomendaciones para la práctica clínica. Se necesitan más estudios de investigación de calidad alta.
PICO
Resumen en términos sencillos
Ciclofosfamida comparada con ifosfamida para el tratamiento del sarcoma en niños y adultos jóvenes
Los sarcomas son los tumores que surgen del hueso y los tejidos blandos. Pueden aparecer en todas las edades. Como resultado de la introducción de la poliquimioterapia, la supervivencia de los niños y adultos jóvenes con diferentes tipos de sarcoma ha mejorado drásticamente. Los agentes alquilantes, como la ciclofosfamida y la ifosfamida, han desempeñado una función principal en esta mejoría. Sin embargo, en la bibliografía todavía no existe consenso en cuanto a qué agente quimioterapéutico es más efectivo. Una decisión muy informada sobre el uso de la ciclofosfamida y la ifosfamida en el tratamiento de los niños y adultos jóvenes diagnosticados con sarcoma se debe basar en evidencia de calidad alta tanto sobre los efectos antitumorales como sobre los efectos adversos.
Esta revisión sistemática se centró en los estudios controlados (aleatorizados en el mejor de los casos). Los autores encontraron que no existían estudios de este tipo que compararan la ciclofosfamida y la ifosfamida en niños y adultos jóvenes con sarcoma. Se necesitan más estudios de investigación de calidad alta.
Authors' conclusions
Background
Sarcomas are mesenchymal tumours that arise from bone and soft tissues. They can occur in people of 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 the cure rate for rhabdomyosarcoma has changed from 25% in 1970 to 70% in 1991 (Crist 2001). Alkylating agents, such as the oxazaphosphorines ifosfamide and cyclophosphamide, have played a major role in this improvement.
Cyclophosphamide is a widely employed cytotoxic agent and is also used against childhood sarcomas as it has shown good anti‐tumour efficacy in these malignancies (Spunt 2004; Lai 2005; Weller 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 cross‐linking, which ultimately induces apoptosis in non‐resistant cells. It also augments the efficacy of anti‐tumour immune response and acts in an anti‐angiogenic capacity by destroying circulating endothelial progenitor cells (Zhang 2005). Since the early 1980s, its structural analogue ifosfamide has been increasingly substituted in its place for the treatment of childhood sarcomas (Paulussen 2001).
However, there is still controversy as to the comparative anti‐tumour efficacy of these agents (Shaw 1990; Carli 2003). Differences in toxicity profile (such as neurotoxicity, nephrotoxicity, myelotoxicity) are also important (Knijnenburg 2013). 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 2007). 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).
This is the second update of the first systematic review evaluating the state of evidence on the anti‐tumour efficacy and possible adverse effects of cyclophosphamide as compared to ifosfamide for paediatric and young adult patients with a bone or soft tissue sarcoma (Mulder 2010; Mulder 2012).
Objectives
Primary objective
To compare the effectiveness of cyclophosphamide with that of ifosfamide for paediatric and young adult patients with sarcoma.
Secondary objectives
To determine 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). If no RCTs were identified we planned to include controlled clinical trials (CCTs). A CCT is a study that compares one or more intervention groups to one or more control groups (Higgins 2005).
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.
Types of interventions
Patients should have received either cyclophosphamide or ifosfamide as part of their treatment. However, differences in the dosage and duration of administration of cyclophosphamide and ifosfamide were allowed. Chemotherapy, other than either cyclophosphamide or ifosfamide, should have been the same in both treatment groups.
Types of outcome measures
Primary outcomes
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Response rate (defined as the number of patients with a complete or partial remission).
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Event‐free survival (defined as the time to recurrence or progression of disease).
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Overall patient survival (defined as the time to death from any cause).
Secondary outcomes
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Toxicities including late effects of treatment, in particular gonadotoxicity, nephrotoxicity, urotoxicity, neurotoxicity and cardiotoxicity.
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Quality of life.
Search methods for identification of studies
We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2015, issue 2), MEDLINE/PubMed (from 1966 to March 2015) and EMBASE/Ovid (from 1980 to March 2015).
The search strategies for the different electronic databases are shown in Appendix 1, Appendix 2 and Appendix 3.
We located information about trials not registered in CENTRAL, MEDLINE or EMBASE, either published or unpublished, by searching the reference lists of relevant articles and review articles. We also scanned the conference proceedings of the Sarcoma Meeting Stuttgart (SMS) (2005) and the Société Internationale d' Oncologie Pédiatrique (SIOP) (2003 to 2014), if available electronically and otherwise by handsearching. We searched for ongoing trials by scanning the ISRCTN register and the National Institute of Health register (www.controlled‐trials.com; June 2015). We imposed no language restriction.
Data collection and analysis
Selection of studies
After employing the search strategy described previously, two authors independently undertook identification of studies meeting the inclusion criteria. Discrepancies between authors were resolved by consensus. No third party arbitration was needed. We obtained any study seemingly meeting the inclusion criteria on the grounds of the title, abstract, or both in full for closer inspection. We clearly stated details of reasons for exclusion of any study considered for review.
Data extraction and management
Since no eligible studies were identified, data extraction by two independent authors using a standardised form could not be performed.
Assessment of risk of bias in included studies
If eligible studies had been identified, two independent authors would have assessed the risk of bias in these studies according to the criteria of the Cochrane Childhood Cancer Group (http://ccg.cochrane.org/). However, since no eligible studies were identified the assessment of risk of bias was not applicable.
Data synthesis
No eligible studies were identified. As a result, data analyses could not be performed.
Results
Description of studies
After performing the searches of the electronic databases of CENTRAL, MEDLINE/PubMed and EMBASE/Ovid (in November 2008) we identified 724 references. Following initial screening of the titles, abstracts, or both we excluded 714 references which clearly did not meet all criteria for considering studies for this review. We obtained 10 articles in full. However, these studies were not eligible for inclusion in this review (see the 'Characteristics of excluded studies' table for the exact reasons).
Running the searches for the update in CENTRAL, MEDLINE/PubMed and EMBASE/Ovid (in March 2012) yielded a total of 161 new references. Following screening of the titles, abstracts, or both we excluded 160 references which clearly did not meet all inclusion criteria for this review. We obtained 1 article in full. However, this study was not eligible for inclusion in this review (Paulussen 2008; see the 'Characteristics of excluded studies' table for the exact reason).
Running the searches for the second update in CENTRAL, MEDLINE/PubMed and EMBASE/Ovid (in March 2015) yielded a total of 107 new references. Following screening of the titles, abstracts, or both we excluded 104 references which clearly did not meet all inclusion criteria for this review. We obtained 3 articles in full. However, these studies were not eligible for inclusion in this review (Gaspar 2012; Gupta 2012; Le Deley 2014; see the 'Characteristics of excluded studies' table for the exact reason).
Scanning the reference lists of relevant studies and reviews and scanning the conference proceedings of the Sarcoma Meeting Stuttgart (SMS) and Société Internationale d' Oncologie Pédiatrique (SIOP) did identify six possibly eligible studies, which we obtained in full. Three of these studies were identified during the original review (2008) and the other three during the second update (2015); no studies were identified during the first (2012) update. None of the six studies were eligible for inclusion in this review and they were added to the 'Characteristics of excluded studies' table. Scanning the ongoing trials databases did not identify any eligible ongoing studies.
In summary, our search did not identify any eligible RCTs or CCTs evaluating cyclophosphamide versus ifosfamide in paediatric and young adult sarcoma patients, in which chemotherapy other than either cyclophosphamide or ifosfamide was the same in both treatment groups.
Risk of bias in included studies
Since no eligible studies were identified, the assessment of the risk of bias in included studies is not applicable.
Effects of interventions
Anti‐tumour efficacy
Since no eligible studies were identified, the comparative anti‐tumour efficacy of cyclophosphamide versus ifosfamide for the treatment of sarcoma in children and young adults remains unclear.
Toxicities and quality of life
Since no eligible studies were identified, toxicities and quality of life associated with cyclophosphamide versus ifosfamide for the treatment of sarcoma in children and young adults remain unclear.
Discussion
As a result of the introduction of polychemotherapy, the survival of children with different types of sarcoma has greatly improved. Alkylating agents, such as cyclophosphamide and ifosfamide, have played a major role in this improvement. However, there is still controversy as to their comparative anti‐tumour efficacy and possible adverse effects. This is the second update of the first systematic review evaluating the current state of evidence on the effectiveness of cyclophosphamide versus ifosfamide in the treatment of paediatric and young adult patients with bone or soft tissue sarcoma (Mulder 2010; Mulder 2012).
To evaluate the effectiveness of cyclophosphamide versus ifosfamide in the treatment of sarcoma adequately the best study design is a randomised controlled trial (RCT) in which the only difference between the intervention and control group is the use of cyclophosphamide and ifosfamide. Unfortunately, we could not identify any such study. We were also unable to identify any eligible controlled clinical trials (CCTs). We did identify a RCT in which patients with non‐metastatic rhabdomyosarcoma, aged less than 21 years, were randomised to either cyclophosphamide (2.2 g/m2 for one day per cycle) or ifosfamide (1.8 g/m2/d for five days) (Crist 2001; Gupta 2012). However, during continuation therapy all patients received cyclophosphamide. This was done to limit the cumulative ifosfamide dose and its potential nephrotoxic effects (Raney 1994). As a result, only data obtained prior to the time point where all patients received cyclophosphamide are eligible to answer the question of this review, but unfortunately these data are not available. Also, even if these data had been available, the eligible follow‐up period was short (28 weeks), so only results for short‐term outcomes would have been available.
It should be noted that in this systematic review RCTs and CCTs including both children and adults were only eligible for inclusion if the maximal age of the participants did not exceed 30 years or if data were presented separately for patients aged less than 30 years. There is some evidence on anti‐tumour efficacy and adverse effects of treatment with cyclophosphamide as compared to treatment with ifosfamide from studies including both children and adults. In an RCT by Bramwell et al (Bramwell 1993), patients (eligible for inclusion if, among other things, aged 15 to 75 years) with advanced soft tissue sarcomas received either cyclophosphamide 1.5 g/m2 (n = 68) or ifosfamide 5 g/m2 (n = 67). Overall response rate (defined as complete or partial remission), although not significantly different between both treatment groups, was higher in patients treated with ifosfamide (i.e. 18% in patients treated with ifosfamide versus 7.5% in patients treated with cyclophosphamide; P = 0.13). Responses were mainly observed in synovial sarcomas, mixed mesodermal sarcomas and fibrosarcomas. The reason that no significant difference in overall response rate between the treatment groups was identified could be the fact that the number of patients in this study was too small (i.e. low power). Leukopenia was significantly greater in patients treated with cyclophosphamide, whereas nausea/vomiting was significantly worse in patients treated with ifosfamide. Other adverse effects did not differ significantly between both treatment groups.
However, extrapolation of these data to children is risky. The aetiology of malignancies in children and adults seems to be different (Burke 1999; Van den Berg 2002). Also, pharmacokinetics and pharmacodynamics of many drugs vary with age, and their beneficial and adverse effects may be different in adults and children (Burke 1999; Groninger 2004). High‐quality RCTs in children with different types of sarcoma are therefore needed.
