Procarbazina, lomustina y vincristina para el glioma de alto grado recidivante
Resumen
Antecedentes
El glioma de alto grado (GAG) recidivante tiene muy mal pronóstico. Actualmente no existe atención estándar ni recomendaciones basadas en guías. La quimioterapia con fármacos múltiples con nitrosourea o PCV (procarbazina, lomustina [CCNU] y vincristina) es una de las opciones de tratamiento para la recidiva. No se han realizado metanálisis que examinen los efectos beneficiosos y perjudiciales de la quimioterapia con PCV en pacientes adultos con GAG recidivante.
Objetivos
Evaluar la efectividad y la seguridad de la quimioterapia con procarbazina, lomustina y vincristina (PCV) versus otras intervenciones en pacientes adultos con glioma de alto grado recidivante. Investigar si subgrupos predefinidos de pacientes se benefician en mayor o menor grado con la quimioterapia.
Métodos de búsqueda
Se hicieron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL número 4, 2017), MEDLINE (1946 hasta el 22 mayo 2017), y en Embase (1980 hasta 22 mayo 2017). Se hicieron búsquedas en registros de ensayos incluyendo la World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch) y en los National Institutes of Health (NIH; ClinicalTrials.gov). Se hicieron búsquedas en las listas de referencias de todos los estudios identificados; la tabla electrónica de contenidos del Journal of Neuro‐Oncology (1983 a 2016) y en Neuro‐Oncology (1999 a 2016); y en los resúmenes de congresos de la Society for Neuro‐Oncology (SNO) y de la American Society of Clinical Oncology (ASCO 2004 a 2016). También se buscó bibliografía gris inédita y otras bases de datos regionales. No hubo restricciones de idioma.
Criterios de selección
Ensayos controlados aleatorios (ECA), ensayos cuasialeatorios o ensayos clínicos controlados (ECC) en los que se utilizó PCV para tratar a pacientes adultos con GAG recidivante. El brazo de comparación incluyó ninguna quimioterapia, otra quimioterapia de segunda línea o el mejor tratamiento médico de apoyo.
Obtención y análisis de los datos
Dos autores de la revisión extrajeron los datos y realizaron la evaluación del "Riesgo de sesgo" y la evaluación crítica de los estudios.
Resultados principales
Se identificaron dos ECA que cumplieron los criterios de inclusión. Los dos ensayos evaluaron diferentes comparaciones.
Un ECA incluyó a 35 participantes y comparó PCV con quimioterapia con fármacos múltiples que incluye "ocho fármacos en un día", que es una combinación de fármacos con diferentes mecanismos de acción. La mediana de supervivencia fue seis meses en el grupo de PCV y 6,5 meses en el grupo de "ocho fármacos en un día". Los resultados eventos adversos no se calificaron ni se cuantificaron. La supervivencia libre de progresión (SLP) y la calidad de vida (CdV) no se describieron en los métodos y no fueron resultados de interés. El tamaño de la muestra en este estudio fue pequeño, lo que dio lugar a un poder estadístico insuficiente para detectar diferencias clínicas. Según el enfoque GRADE se consideró que la calidad de la evidencia fue baja para el resultado de supervivencia y muy baja para la toxicidad de la quimioterapia
El segundo ECA multiinstitucional incluyó 447 participantes y comparó PCV con temozolomida (TMZ). Los participantes se asignaron al azar a tres brazos para recibir PCV y dos regímenes diferentes de TMZ en una proporción 2:1:1 en la primera recidiva. El ensayo informó una mediana de supervivencia general de 6,7 meses y 7,2 meses en el grupo de PCV y en el grupo de TMZ, respectivamente. Informó una SLP de 3,6 meses en el grupo de PCV y 4,7 meses en el grupo de TMZ. No se observaron diferencias en el efecto sobre la supervivencia general (cociente de riesgos instantáneos [CRI] 0,91; IC del 95%: 0,74 a 1,11; P = 0,35) ni en la SLP (CRI 0,89; IC del 95%: 0,73 a 1,08; P = 0,23) en los participantes que recibieron quimioterapia con PCV o TMZ. La proporción de pacientes con al menos un evento adverso grado 3 o 4 no fue clínicamente importante, con 9,2% versus 12,2% en los brazos de PCV y TMZ, respectivamente. Las puntuaciones medias de la CdV calculadas al inicio, a las 12 semanas y a las 24 semanas fueron 51,9 versus 59,8 a favor de la TMZ (p = 0,04), que son estadísticamente pero no clínicamente significativas y menores que los 10 puntos de cambio predeterminados para la mejoría moderada. Se consideró que la calidad GRADE de la evidencia fue moderada para la supervivencia general, la SLP y la toxicidad de la quimioterapia, y baja para la CdV.
Conclusiones de los autores
La evidencia se basa en el análisis de un ensayo grande único debido a que el otro ensayo fue pequeño, con un poder estadístico insuficiente para detectar diferencias en la supervivencia. En los pacientes con la primera recidiva del GAG y que nunca recibieron quimioterapia se obtienen resultados de supervivencia y tiempo hasta la progresión similares cuando reciben tratamiento con PCV o TMZ. Los eventos adversos fueron similares y las puntuaciones de la CdV fueron estadística pero no clínicamente significativas entre TMZ y PCV. Se deben realizar ECA adicionales con poder estadístico suficiente y que sigan las guías CONSORT, con hincapié en los resultados de la CdV.
PICO
Resumen en términos sencillos
Quimioterapia con PCV para el glioma de alto grado recidivante
El problema
Los gliomas son tumores cerebrales primarios que surgen de las células de sostén del cerebro o la médula espinal. La Organización Mundial de la Salud (OMS) clasifica la afección en glioma de bajo grado y glioma de alto grado (GAG) según su apariencia bajo el microscopio. Grados mayores se correlacionan con peores resultados. Uno de los resultados es la recidiva del glioma.
Objetivo de la revisión
El glioma de alto grado recidivante tiene muy mal pronóstico. Las opciones de tratamiento son limitadas cuando ocurre la recidiva. La PCV es una quimioterapia con fármacos múltiples con nitrosourea que se puede utilizar para la recidiva. Un régimen con fármacos múltiples elimina las células cancerosas de varias maneras, por lo que se supone que es más efectivo. Hay una falta de conocimientos acerca de la eficacia y los efectos adversos de la PCV cuando se utiliza para tratar el GAG recidivante.
¿Cuáles son los principales hallazgos?
En esta revisión se encontraron dos ensayos controlados aleatorios que estudiaron la PCV en pacientes con GAG recidivante. El comparador fue temozolomida (TMZ) en uno y la quimioterapia con fármacos múltiples que incluye "ocho fármacos en un día" en otro. Los resultados de los dos ensayos no se combinaron porque compararon PCV con tratamientos diferentes.
¿Cuál es la calidad de la evidencia?
Las conclusiones se deben examinar con cuidado porque se basan en el análisis de un ensayo único debido a que el otro ensayo fue demasiado pequeño y tuvo poco poder estadístico para detectar diferencias significativas. Los efectos adversos y los resultados de la CdV se basan en el análisis de un ensayo único. La proporción de participantes que presentaron eventos adversos graves con la PCV fue similar a la TMZ. Las puntuaciones de la CdV fueron mayores con la TMZ, pero no fueron clínicamente significativas. Se le atribuyó una calidad de la evidencia de grado moderado a la supervivencia general, a la supervivencia libre de progresión y a la toxicidad de la quimioterapia, y la evidencia fue de grado bajo para la CdV.
¿Cuáles son las conclusiones?
En los pacientes con la primera recidiva del GAG y que nunca recibieron quimioterapia se obtienen resultados de supervivencia y tiempo hasta la progresión similares cuando reciben tratamiento con PCV o TMZ. Los eventos adversos fueron similares y las puntuaciones de la CdV fueron estadística pero no clínicamente importantes entre la TMZ y la PCV. Los resultados no se aplican a los pacientes actuales con GAG recidivante porque la mayoría de ellos recibiría quimioterapia como atención estándar después del diagnóstico original. Los participantes de este ensayo sólo recibieron radioterapia antes de la recidiva. No se utilizaron marcadores moleculares para la toma de decisiones, que en la actualidad es el estándar de atención.
Authors' conclusions
Summary of findings
| 'Eight drugs in one day' compared with PCV for recurrent GBM in adults | ||||||
| Patient or population: Adults with recurrent GBM Settings: Hospital setting in Milan, Italy Intervention: 'Eight drugs in one day' multi‐drug chemotherapy Comparison: PCV | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| PCV | "eight in one" | |||||
| Overall Survival | See comments | See comments | Not provided | 35 (1 study) | ⊕⊕⊝⊝ | Small sample size, exclusion criteria not explicit, baseline characteristic and statistical tests reporting inadequate. HR and survival data not provided |
| Chemotherapy toxicity | See comments | See comments | Not provided | 35 (1 study) | ⊕⊝⊝⊝ | Unblinded for detection and performance. Toxicity not graded. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 OS was downgraded from high to low because of limitation in design due to inadequate reporting of allocation concealment leading to selection bias. Even though CI was not calculated it was at high risk of imprecision because of small sample size. 2 Chemotherapy toxicity was downgraded from moderate to very low because of limitations in design leading to selection bias, due to lack of allocation concealment and imprecision because of small sample size. Toxicity was not measured on a graded scale. | ||||||
| PCV compared with TMZ for recurrent HGG in adults | ||||||
| Patient or population: Adults with recurrent HGG Settings: Mutiple hospitals and centres in United Kingdom Intervention: PCV Comparison: TMZ | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| TMZ | PCV | |||||
| Overall survival median follow‐up 12 months | See comments | See comments | HR 0.91 (0.74 to 1.11); P = 0.35 | 447 (1 study) | ⊕⊕⊕⊝ | Due to the way HR are estimated the assumed and corresponding risks would not take into account the outcome. |
| PFS Median follow‐up 12 months | See comments | See comments | HR 0.89 (0.73 to 1.08); P = 0.23 | 447 (1 study) | ⊕⊕⊕⊝ | Good concordance between independent and local assessor. Risk of inaccurate assessment because of limitation of diagnosis method. No assumed risk could be calculated |
| QoL EORTC QoL questionnaire C30; at baseline, 12 weeks and 24 weeks | See comments | See comments | 51.9 for PCV versus 59.8 for TMZ arm (P = 0.04) | 415 (1 study) | ⊕⊕⊝⊝ | Unblinded study at risk for performance and detection bias. Measured at fixed intervals and thus at risk of survival bias. No assumed risk could be calculated |
| Chemotherapy toxicity During 1st 12 weeks of treatment | See comments | See comments | Not estimable | 441 (1 study) | ⊕⊕⊕⊝ moderate4 | At risk of performance and detection bias because of unblinding. No assumed risk could be calculated |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 OS quality of evidence was downgraded from high to moderate because of indirectness of population, as the trial population had not received chemotherapy at original diagnosis which will be standard of care now. 3 QoL evidence was double downgraded from high to low because of the large effect of unblinding in a subjective outcome like this. 4 Chemotherapy toxicity evidence was downgraded from high to moderate because of bias introduced by unblinding. | ||||||
Background
Description of the condition
Gliomas are primary brain tumours arising from supporting cells of the brain or spinal cord. The World Health Organization (WHO) separates gliomas into low‐grade (I or II) and high‐grade gliomas (grade III or IV) based on features reflecting aggressiveness and infiltration. Higher grade correlates with poorer clinical outcome. Grade III gliomas include anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA or mixed glioma). Grade IV gliomas are glioblastomas (GBM) (Louis 2007). In a recent update of WHO classification of central nervous system (CNS) tumours there has been a major restructuring of diffuse gliomas, with incorporation of genetically defined entities (Louis 2016).
The overall incidence rate for primary malignant brain and CNS tumours is estimated to be 7.27/100,000 per year for all age groups with peak incidence in the fifth and sixth decades. Astrocytoma and GBM combined account for about three‐quarters of gliomas (Ostrom 2013). Data from the International Agency for Research on Cancer (IARC) estimates 256,213 worldwide cases of brain and CNS tumour, which is 1.8% of all estimated cancers, and 189,394 deaths, which is 2.3% of all cancer‐related deaths (Ferlay 2015). An estimated 13,700 deaths were attributed to HGG in the brain and CNS in the USA in 2012 (Siegel 2012).
Initial presentation for people with glioma reflects the fast‐growing nature of HGG and includes intractable headaches, cognitive changes such as generalised slowing or personality changes, memory and language difficulty, neurologic deficits such as weakness or numbness of extremity, and seizures (Hildebrand 2005). People suspected to have a CNS tumour are evaluated preferably by magnetic resonance imaging (MRI) of the brain or spinal cord, or both. HGG commonly demonstrates enhancement of margins with contrast. Surgery to remove as much tumour as possible safely and obtain a histologic diagnosis is optimal, as this can influence management and prognosis.
For GBM (grade IV), one RCT reported a survival benefit of 2.5 months in the group receiving concomitant chemo‐radiation therapy followed by adjuvant chemotherapy with oral Temozolomide (TMZ) compared with the group treated only with radiation therapy (Stupp 2005). Anaplastic gliomas (grade III) are a heterogeneous group of tumours resulting in varied clinical course and survival influenced by type. AA fares worse than AO. These tumours tend to occur in a younger age group than GBM and response to chemotherapy is more likely. In one RCT on AA, there was delay in progression in people receiving chemotherapy compared to radiation therapy alone (Wick 2009). A Cochrane Review of trials comparing treatment interventions in AO or AOA demonstrated people receiving procarbazine, lomustine plus vincristine chemotherapy (PCV) and radiation therapy living longer (Abdulkarim 2014).
These trials discovered certain molecular bio‐markers and genetic mutations with predictive and prognostic value. AO and AOA tumours with chromosomal abnormality 1p/19q co‐deletions had superior survival. Isocitrate dehydrogenase (IDH‐1 and 2) gene mutations are important markers for glial tumours. The O⁶ methylguanine DNA‐methyltransferase (MGMT) gene encodes for a protein responsible for deoxyribonucleic acid (DNA) repair and MGMT promoter methylation disables it from making that protein. It has prognostic value in HGG and is a predictor of response to treatment in GBM.
Description of the intervention
Although adjuvant radiation therapy plus chemotherapy improves survival, death is inevitable from recurrence (Eisele 2013). The management of recurrent disease is challenging as there is no widely agreed standard of care. The current treatment options include re‐irradiation or surgery or both for localised recurrence with or without placing carmustine (bis‐chloroethylnitrosourea (BCNU)) chemotherapy‐containing wafers within the tumour cavity; or second‐line chemotherapy, i.e. TMZ or nitrosourea as a single agent or in a combination PCV regimen; or anti‐angiogenics (medicines that inhibit formation of new blood vessels within tumours); or both BCNU and second‐line chemotherapy (Wang 2013).
At first recurrence, some benefit of chemotherapy has been shown for people with a good performance status (a measure of a person's functional capacity) who have not received prior adjuvant chemotherapy. There is evidence of activity of nitrosourea as a single agent or in a combination PCV regimen in recurrent disease. There are subtle differences in the doses of these chemotherapy agents used in different countries. In practice, single‐agent TMZ is widely used at recurrence of HGG as it delays progression and has better QoL (Hart 2013). In a Cochrane Review on anti‐angiogenic therapy, it appeared to delay progression without prolonging life and with unclear QoL benefit (Khasraw 2014).
A PCV regimen is associated with systemic toxicities. The main concern regards the haematological adverse effects. One study had a 64% frequency of serious (grade III to IV) haematological toxicities (Cairncross 2012); and 46% in another with no treatment‐associated deaths (Van den Bent 2012). Alternative single‐agent chemotherapy using TMZ would also have significant haematological adverse effects in recurrent HGG (Villano 2012).
How the intervention might work
For recurrent HGG, systemic therapy with PCV has been used in people who have not previously received chemotherapy or following failure of radiation therapy and concomitant and adjuvant chemotherapy such as TMZ. Single‐agent nitrosourea therapy, such as lomustine, achieves tumour control in some people with recurrent glioma (Buckner 1995; Rajan 1994).
Two separate studies evaluating response to PCV in people with recurrent GBM demonstrated a similar trend and improvement in PFS and overall survival (Kappelle 2001; Schmidt 2006).
Procarbazine and nitrosoureas (BCNU, lomustine, and semustine) achieve good concentrations in the brain and cerebrospinal fluid (CSF; fluid around the brain and spinal cord). They mainly work by altering the structure and function of DNA, ribonucleic acid (RNA), and certain proteins. Vincristine is a vesicant (can cause tissue injury) and needs to be administered in large veins close to the heart (central vein). It works by inhibiting cell division. It has been argued that it does not cross the blood‐brain barrier (BBB) (Boyle 2004); however, the BBB is not intact in people with AO and hence there is delivery of medicine across the BBB (Arismendi‐Morillo 2005; Brooks 1984).
The combination of PCV may provide the most potent activity for people who have not responded to traditional therapy with radiation or TMZ chemotherapy, where treatment options are limited. Its use in recurrent disease may also be affected by prior usage.
Why it is important to do this review
We found no systematic reviews on the value of PCV chemotherapy in recurrent HGG. Trials are usually performed with a small subset of participants and only a meta‐analysis might demonstrate significant activity associated with PCV use in recurrent HGG. The adverse effect profile of PCV is not well established in the treatment of recurrent disease and may vary based on the prior dosage and regimen of chemotherapy received. Our analysis will guide clinicians on the benefit or not of prescribing this combination chemotherapy.
Administering and monitoring PCV is cumbersome, which is one of the reasons physicians have historically been hesitant in prescribing it. However modern high‐quality evidence that chemotherapy is advantageous as part of first‐line therapy has encouraged re‐appraisal of therapy at recurrence.
Objectives
To assess the effectiveness and safety of procarbazine, lomustine, and vincristine (PCV) chemotherapy with other interventions in adults with recurrent high‐grade glioma. To investigate whether predefined subgroups of people benefit more or less from chemotherapy.
Methods
Criteria for considering studies for this review
Types of studies
RCTs meeting the inclusion criteria were evaluated.
Types of participants
We included adults (aged 18 years or older) with previously treated and histologically confirmed grade III or IV glioma based on WHO criteria at the time of original diagnosis.
Types of interventions
Studies where all variations of PCV chemotherapy in either arm have been evaluated with respect to dosage, intensity, median number of cycles received, and duration of treatment, were eligible. Other salvage therapy could have included corticosteroids, re‐irradiations with different dosages, and re‐surgeries with or without BCNU chemotherapy‐containing wafers within the tumour cavity (as long as it is similar in both arms).
The control arm could receive any of the following: placebo; best supportive care; an active intervention with second‐line chemotherapy or re‐challenge with TMZ; anti‐angiogenics (medicines that inhibit formation of new blood vessels within tumours); novel therapy such as electrical stimulation; or combination drug regimens that may include one or two of procarbazine, lomustine, or vincristine.
Types of outcome measures
Primary outcomes
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Overall survival defined as time from randomisation to death from any cause.
Secondary outcomes
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Progression‐free survival (PFS), defined as time from randomisation to progression of disease. Criteria for recurrence was based on McDonald criteria extrapolated to MRI (Macdonald 1990) (Table 1); or Response Assessment in Neuro‐Oncology (RANO) criteria (Wen 2010) (Table 2).
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Quality of life (QoL), measured using the European Organisation for Research and Treatment of Cancer (EORTC) Core QoL Questionnaire (QLQ‐C30) or Brain Cancer Module (BCM) scale, or both; Functional Assessment of Cancer Therapy ‒ General (FACT‐G) or Functional Assessment of Cancer Therapy ‒ Brain (FACT‐Br) scale (Mauer 2008).
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The proportion of participants experiencing chemotherapy toxicity. Grades of toxicity were grouped according to Common Terminology Criteria for Adverse Events (CTCAE 2010).
| Response | Criteria |
| Complete response | Requires all of the following: complete disappearance of all enhancing measurable and non‐measurable disease sustained for at least 4 weeks; no new lesions; no corticosteroids; and stable or improved clinically. |
| Partial response | Requires all of the following: ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no new lesions; stable or reduced corticosteroid dose; and stable or improved clinically. |
| Stable disease | Requires all of the following: does not qualify for complete response, partial response, or progression; and stable clinically. |
| Progression | Defined by any of the following: ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration. |
| Response | Criteria |
| Complete response | Requires all of the following: complete disappearance of all enhancing measurable and non‐measurable disease sustained for at least 4 weeks; no new lesions; stable or improved non‐enhancing (T2/FLAIR) lesions; and participant must be off corticosteroids or on physiological replacement doses only, and stable or improved clinically. In the absence of a confirming scan 4 weeks later, this response will be considered only stable disease. |
| Partial response | Requires all of the following: ≥ 50% decrease, compared with baseline, in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no progression of non‐measurable disease; no new lesions; stable or improved non‐enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and participant must be taking a corticosteroid dose not greater than the dose at the time of baseline scan and is stable or improved clinically. In the absence of a confirming scan 4 weeks later, this response will be considered only stable disease. |
| Stable disease | Stable disease occurs if participant does not qualify for complete response, partial response, or progression (see next section) and requires the following: stable non‐enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan and clinically stable status. In the event that corticosteroid dose was increased for new symptoms and signs without confirmation of disease progression on neuroimaging, subsequent follow‐up imaging shows that this increase in corticosteroids was required because of disease progression; the last scan considered to show stable disease will be the scan obtained when the corticosteroid dose was equivalent to the baseline dose. |
| Progression | Progression is defined by any of the following: ≥ 25% increase in sum of products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; significant increase in T2/FLAIR non‐enhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; appearance of any new lesions; clear progression of non‐measurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumour, or to decrease in corticosteroid dose. Failure to return for evaluation as a result of death or deteriorating condition should also be considered as progression. |
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Haematologic (leukopenia, anaemia, thrombocytopenia, neutropenia, haemorrhage).
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Gastrointestinal (nausea, vomiting, anorexia, diarrhoea, hepatobiliary, proctitis).
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Genitourinary.
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Skin (stomatitis, mucositis, alopecia, allergy).
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Neurologic (peripheral and central).
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Pulmonary.
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Search methods for identification of studies
Electronic searches
The following large databases were searched. Foreign language journals were eligible for inclusion.
Appendix 1 lists the CENTRAL search strategy; Appendix 2 lists the MEDLINE search strategy; and Appendix 3 lists the Embase search strategy.
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Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 4).
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MEDLINE (1946 to 22 May 2017 May).
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Embase (1980 to 22 May 2017).
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International Clinical Trials Register (ICTRP) Search Portal (apps.who.int/trialsearch/AdvSearch.aspx).
Searching other resources
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We searched the reference lists of all identified studies.
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We handsearched and also searched the electronic table of contents of the Journal of Neuro‐Oncology and Neuro‐Oncology to identify trials. We searched the conference reports of the Society for Neuro‐Oncology (SNO) and the American Society of Clinical Oncology (ASCO 2004 to 2015).
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We searched the reference lists of neuro‐oncology textbooks, review articles, and relevant studies.
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We contacted investigators known to be involved in previous studies to seek information about unpublished data.
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We searched for unpublished grey literature on www.OpenGrey.eu.
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We searched other regional databases as given in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions.
Data collection and analysis
Selection of studies
We used EndNote to download all studies identified by search methods and removed duplicates. Two review authors (SP and GT) independently screened all titles and abstracts of remaining references. We discarded records that were not applicable and retrieved the full‐text reports of potentially relevant studies and reviews. Two review authors (SP and GT) independently assessed the reports to identify studies satisfying the inclusion criteria (Figure 1).
Study flow diagram.
We resolved disagreements at all stages by discussion. When disagreement was due to a difference in interpretation, a third review author (JV) resolved the deadlock by arbitration.
Data extraction and management
For included studies, two review authors (SP and GT) extracted data on characteristics of participants and interventions, outcomes, study quality and deviation from protocol. Studies with intention‐to‐treat analyses were used. A prespecified form in an Excel spreadsheet was used to collect data and complete the Characteristics of included studies (Appendix 4).
We extracted outcome data as follows.
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For time‐to‐event data (overall survival and PFS), we extracted the log of the hazard ratio (log (HR)) and its standard error from trial reports. If studies did not report these, we attempted to estimate the log (HR) and its standard error using the methods of Parmar 1998. If these variables could not be estimated, we reported available proportions with corresponding P values.
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For dichotomous outcomes (adverse events or deaths), if it was not possible to use HRs we extracted the number of participants in each treatment arm who experienced the outcome of interest and the number of participants assessed at endpoint, in order to estimate a risk ratio (RR).
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For continuous outcomes, we extracted the final value and standard deviation (SD) of the outcome of interest and the number of participants assessed at endpoint in each treatment arm at the end of follow‐up, in order to estimate the mean difference (MD) (if trials measured outcomes on the same scale), or standardised MDs (if trials measured outcomes on different scales) between treatment arms and its standard error.
Where possible, we extracted all data relevant to an intention‐to‐treat analysis, analysing participants in the groups to which they were assigned. We noted the time points at which trials collected and reported outcomes.
Differences were reconciled by discussion or by consultation with third review author (JV). Data integration into Review Manager 5 (RevMan 5) was performed by single author (SP) (Review Manager 2014).
Assessment of risk of bias in included studies
Two review authors (SP and JG) assessed the risk of bias and critically appraised the included studies as described in the Cochrane 'Risk of bias' assessment tool (Higgins 2011). Risk of bias was classified as high, low, or unclear as per the Cochrane H andbook for Systematic Reviews of Interventions. We resolved any disputes through discussion. Results are presented as a 'Risk of bias' graph (Figure 2); and a 'Risk of bias' summary (Figure 3). The seven domains assessed were:
Risk of bias graph: review authors' judgements about each risk of bias item for each included study.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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sequence generation (selection bias);
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allocation concealment (selection bias);
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masking of participants and personnel (performance bias);
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masking of outcome assessors (detection bias);
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selective outcome reporting (reporting bias);
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incomplete outcome data (attrition bias);
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other sources of bias (e.g. funding source).
Measures of treatment effect
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For time‐to‐event data (overall survival and PFS), we used hazard ratio (HR) with 95% confidence intervals (CIs) where possible.
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For dichotomous outcomes (adverse events), we presented results as RR with 95% CIs.
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For continuous outcomes (QoL), we used MD or standardised mean difference (SMD) where possible.
Dealing with missing data
We did not impute missing data for any of the outcomes (Higgins 2011).
Data synthesis
We carried out data synthesis and analyses using RevMan 5 (Review Manager 2014).
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For time to event data we planned to pool the HR and its variance using the generic inverse variance facility of RevMan 5 (Review Manager 2014).
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For continuous outcomes, we planned to pool the MDs between the treatment arms at the end of follow‐up using the MD method if all trials had measured the outcome on the same scale, or the SMD method if different scales had been used.
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For dichotomous outcomes, we planned to calculate the RR for each study and then pool all studies.
Summary of findings
For each comparison, we prepared summary of findings Table for the main comparison and summary of findings Table 2. Two review authors (SP and GT) independently assessed the quality of the evidence using the five GRADE considerations: study limitations; inconsistency; indirectness; imprecision; and publication bias.
Assessment of heterogeneity and reporting biases was planned but not carried out because the two studies tested different comparisons. Results are based on single trial analysis.
Results
Description of studies
See Characteristics of included studies , Characteristics of excluded studies , Characteristics of ongoing studies
Results of the search
A directed search on large databases yielded 1336 results with 279 references from the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 4) in the Cochrane Library (searched 22 May 2017); 296 from MEDLINE (1946 to 22 May 2017); and 761 references from Embase (1980 to 22 May 2017). Other regional databases, as per Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions, did not yield any results. A very broad search of the National Institutes of Health, ClinicalTrials.gov, yielded 6902 studies. The search on ICTRP, apps.who.int/trialsearch/AdvSearch.aspx, yielded 877 results. A total of 9115 references were identified. We download all studies into EndNote and deleted 5068 duplicates. We screened all titles and abstracts of remaining references, discarding 4034 records that were not applicable and retaining records of 13 references as being potentially relevant. We retrieved the full‐text reports of records classified as being potentially relevant and identified two studies meeting the inclusion criteria for the review (Boiardi 1992; Brada 2010).
Please refer to Figure 1 for the PRISMA flow diagram process.
Included studies
See Characteristics of included studies table.
Two trials were eligible for inclusion and analysis (Boiardi 1992; Brada 2010).
Brada 2010
This was a multi‐centred randomised controlled trial (RCT) conducted in the United Kingdom and enrolling 447 adult participants between 2003 and 2007 at first recurrence of HGG. All had histologically verified WHO grade 3 or 4 at original diagnosis and underwent primary treatment including radiotherapy. Diagnosis of recurrence was based on contrast‐enhanced imaging. Participants with life expectancy of more than a month, World Health Organization (WHO) performance status (PS) of 0,1, 2 or 3, and adequate renal, hepatic and haematologic reserve were randomised to three arms to receive PCV and two different regimens of TMZ, in a ratio of 2:1:1. Primary analysis and outcomes of interest were overall survival, PFS, quality of life and adverse events. Would‐be participants were excluded if they were pregnant, had oligodendroglial pathology, had WHO PS of 4 or had received chemotherapy, radiosurgery or brachytherapy for HGG.
PCV was administered in the control arm every six weeks for up to six cycles or until progression, and it comprised of procarbazine (100 mg/m²) on days 1 through 10, lomustine (100 mg/m²) and intravenous vincristine (1.5 mg/m² capped at 2 mg) on day 1. TMZ was administered orally. The TMZ‐5 group received 200 mg/m² for 5 days repeated every 28 days for up to nine cycles or until progression. The TMZ‐21 (dose dense) group received 100 mg/m² for 21 days repeated every 28 days for up to nine cycles or until progression.
PFS was measured both on a clinical and radiological basis and formal assessment was performed every 12 weeks. For QoL, mean score was measured using the European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire C30 with brain tumour module at baseline and at 12 and 24 week, along with the proportion of patients reporting a moderate improvement (defined as a 10‐point change) from baseline to 12 weeks and baseline to 24 weeks. All patients were included in the analysis.
Boiardi 1992
This was a RCT conducted in hospitals in Milan, Italy enrolling 35 adult participants with recurrent GBM between 1988 and 1990. All participants had prior treatment with surgery and radiotherapy; and about 60% with chemotherapy. Diagnosis of recurrence was based on computed tomography (CT) imaging. Participants with Karnofsky performance scale (KPS) greater than 60%, life expectancy more than two months, no significant toxicity after prior chemotherapy, with normal renal, hepatic and haematological functions were randomised to two arms to receive 'eight drugs in one day' multidrug chemotherapy (n = 19, mean age = 56) and PCV (n = 16, mean age = 61). Primary outcomes of interest were adjunctive disease‐free survival time (ADFS) in patients with objective response, median adjunctive survival time of the whole group, 18‐month survival time, and adverse events.
The 'eight drugs in one day' multidrug chemotherapy protocol was given every 4 to 5 weeks and included drugs with different actions: vincristine 2 mg; lomustine (CCNU) 75 mg/m²; procarbazine 75 mg/m²; hydroxyurea 1500 mg/m²; cisplatin 90 mg/m²; cytosine arabinoside 300 mg/m²; Dacarbazine (DTIC) 150 mg/m²; and methylprednisolone 300 mg/m². This cocktail was administered three times each day at 6‐hourly intervals. PCV was given in standard dose: CCNU 110 mg/m² on day 1, procarbazine 60 mg/m² daily for 14 days from day 8, and vincristine 1.4 mg/m² on day 8 and 29 of each 6‐week treatment period. Response to therapy was evaluated by monthly neurological examination and every other month by contrast‐enhanced CT scan. The response definition used were similar to McDonald’s criteria (Table 1). Toxicity was monitored after each successive cycle.
Excluded studies
We excluded 11 studies after full‐text review. Please refer to the Characteristics of excluded studies for reasons for exclusions.
Risk of bias in included studies
Risk of bias was assessed as per the Cochrane tool for assessing risk of bias (Higgins 2011). It is summarised in Figure 2 and Figure 3.
Allocation
In Boiardi 1992 random number generation was performed by drawing lots. Brada 2010 used minimisation with stratification factors of centre, tumour grade (3 or 4 or high grade unspecified), and PS (0 or 1 vs 2 or 3) across all three groups for randomizations and was performed by telephone call to the trials unit. Both studies were at low risk. There was no statement of an effort to conceal allocation in Boiardi 1992, giving high risk of selection bias.
Blinding
Both studies were unblinded. It was not possible to blind the participants or providers to the treatment, given the nature of interventions. Both studies were at high risk of performance bias.
For detection bias we assessed the effect of blinding on each outcome. For overall survival and median survival time, both the studies were at low risk. Boiardi 1992 was at high risk of detection bias for adverse event outcomes. Brada 2010 was at high risk of bias for QoL and adverse event outcomes. Radiological assessment of PFS was verified by an independent central review with high degree of concordance thus reducing detection bias between independent and local assessors.
Incomplete outcome data
There was no missing data in either of the studies. Brada 2010 had complete data for overall survival and PFS. For toxicity outcomes a total of six patients were not included in analysis as they died or did not receive the intended treatment prior to initiation of the study. There was overall low risk of bias on this account.
There are no missing data for survival outcomes in Boiardi 1992, giving low risk of bias. For toxicity outcomes there is unknown risk of bias as there is no reported loss to follow‐up.
Selective reporting
Boiardi 1992 did not have a pre‐published protocol hence is at high risk of selective reporting bias. Brada 2010 had a registered protocol and reported all pre‐planned outcomes and has low risk of bias.
Other potential sources of bias
Boiardi 1992 had small sample size, introducing high likelihood of baseline imbalance. It was likely inadequately powered to detect differences in the stated outcomes.
In Brada 2010 radiological measurement of PFS was done at fixed time points of 12 and 24 weeks and may have missed interim changes. In patients without symptoms, radiological changes could also represent treatment effect rather than true progression. This may lead to inaccurate assessment of PFS.
There was survivor bias introduced in the measurement of QoL outcomes as it was done at fixed time points and excluded participants who died. Even though studies were not combined there was high likelihood of unequal treatment effect as these studies were done more than a decade apart.
Some authors had a financial relationship with pharmaceutical companies. The relationships were clearly disclosed and pharmaceutical companies had no role in the design and analysis of the study.
Effects of interventions
See: Summary of findings for the main comparison ; Summary of findings 2
See summary of findings Table for the main comparison and summary of findings Table 2 of the two studies. We did not combine the data of these two RCTs as they tested different comparisons.
Overall survival
Boiardi 1992 included 35 patients with recurrent GBM in the analysis of median survival time. Hazard ratio (HR) was not performed and it was not possible to report risk ratio (RR). Median survival time for the PCV group and the 'eight drugs in one day" chemotherapy group was 6 months and 6.5 months respectively (low‐quality evidence).
Brada 2010 included 447 patients in the analysis, 223 in the TMZ arm and 224 in the PCV arm. There was no significant difference between the groups (HR 0.91, 95% CI 0.74 to 1.11; P = 0.35). Overall survival was 6.7 months and 7.2 months for the PCV and TMZ arms respectively (moderate‐quality evidence).
Progression‐free survival
It is not possible to comment on this as it was not an outcome of interest in Boiardi 1992.
Brada 2010 analysed 447 patients in the PCV and TMZ arms. There was no significant difference between the groups (HR 0.89, 95% CI 0.73 to 1.08; P = 0.23). PFS was 3.6 months and 4.7 months for the PCV and TMZ arms respectively (moderate‐quality evidence).
Quality of life
It is not possible to comment on this as it was not an outcome of interest in Boiardi 1992.
Brada 2010 reported QoL data using the EORTC QOL‐30 questionnaire. Increase in 10 points on the scale defined moderate improvement. Scores were calculated at baseline, 12 weeks and 24 weeks. At 24 weeks the mean score for the PCV group was 51.9 versus 59.8 for the TMZ arm (P = 0.04) favouring TMZ. Results were statistically but not clinically significant (low‐quality evidence).
Chemotherapy toxicity
The adverse event reporting does not appear to be of the required quality in Boiardi 1992. In general, adverse events were more common in patients pre‐treated with chemotherapy. Five patients experienced haematological toxicity in the 'eight drugs in one day' arm and none were recorded in the PCV arm. Nausea and vomiting were not evaluated quantitatively, but generally were moderate and less than expected: one patient had seizure and four patients had polyneuropathy in each arm (very low quality evidence).
Brada 2010 reported grade 3 and 4 toxicities only. For the purpose of evaluation, adverse events were combined according to system organ class as per CTCAE 2010. The total proportion of patients with at least one grade 3 or 4 adverse event was not statistically significant at 9.2% versus 12.2% in the PCV and TMZ arms respectively. The total number of adverse events was less in the PCV arm, mainly driven by fewer neurological adverse events. Other organ system adverse events involving the haematological, gastrointestinal, and integumentary systems were similar in both arms. Genitourinary and pulmonary adverse events were not reported (moderate‐quality evidence).
Subgroup analysis
Subgroups were analysed in Brada 2010. Amongst various pre‐specified subgroups there was improved survival seen in patients within age group 51 to 60 (HR 0.67, 95% CI 0.47 to 0.95) and in patients with PS‐3 (HR 0.37, 95% CI 0.18 to 0.79) in favour of TMZ. Between‐study subgroup analyses was not performed as data were not pooled.
Discussion
Summary of main results
This systematic review identified two studies that investigated the benefits and harms of PCV with two different chemotherapy regimens in adults with recurrent HGG. Conclusions are derived from a single trial analysis as the other trial was small and therefore underpowered.
Brada 2010 included 447 participants and compared PCV to Temozolomide (TMZ). We found no difference in overall survival or progression‐free survival (PFS) between PCV and TMZ. The proportion of participants experiencing grade 3 or 4 adverse events was similar in both groups. When combined into organ classes, there were fewer neurological events in the PCV arm compared to TMZ. In other organ classes, i.e. haematological, gastrointestinal and integumentary, there were similar numbers of events. Quality of life (QoL) scores were statistically but not clinically significant in the TMZ group. There was statistically significant overall survival in favour of TMZ on subgroup analyses in the 51 to 60 age group and in participants with WHO PS 3 (summary of findings Table 2).
The second trial, Boiardi 1992, enrolled 35 patients and compared 'eight drugs in one day' chemotherapy to PCV. It reported median survival time which was similar in both groups. Hazard ratio was not reported. PFS and QoL were not outcomes of interest. Adverse events were not graded according to CTCAE and occurred in more than half the patients in both arms. They were more common in patients pre‐treated with chemotherapy (summary of findings Table for the main comparison).
Overall completeness and applicability of evidence
We analysed two studies that evaluated PCV with different regimens of chemotherapy. These studies were done in different time periods when the use of chemotherapy for HGG in an adjuvant setting was not the standard of care.
Boiardi 1992 was a small study and was underpowered to detect clinical difference. Exclusion criteria were not explicit, with inadequate reporting of baseline characteristics and statistical methods. Hazard ratio and survival curve were not calculated. Adverse event outcomes were not graded. It was at high risk of selection bias and selective reporting bias. A typical contemporary patient with recurrent GBM would be treated differently at initial diagnosis than in the study. Due to lack of internal validity and other insufficiencies its results are not applicable to our current patient population.
The second study, Brada 2010, was a large and well‐designed study. Participants with recurrence of HGG were treated only with radiotherapy at initial diagnosis. Baseline characteristics were similar in all the groups after randomization. Radiological assessment of PFS was based on increased enhancement on CT or MRI and was done at fixed intervals which may have led to inaccurate assessment. The study was unblinded and at risk of performance and detection bias for subjective outcomes such as QoL. There was risk of bias because of the industry association of the authors. On subgroup analysis there was a survival advantage favouring TMZ for patients aged between 51 and 60, and WHO PS of 0,1, 2, or 3.
This study grouped together grade 3 and 4 gliomas, which we know have different natural histories. Molecular markers were not used in decision making. These results are not applicable to our current patients as chemotherapy in adjuvant setting has become the standard of care at original diagnosis. Incidence of adverse effects and QoL scores were similar in both studies; however these could be more pronounced because of cumulative toxicity in contemporary patients already treated with chemotherapy at initial diagnosis. The evidence on QoL can be cautiously and very selectively applied in patients while formulating a treatment plan. Dose and timing of the multidrug PCV chemotherapy regimen was different compared to the standard recommended protocol today.
Quality of the evidence
There were two studies identified for the systematic review, one with 35 and the other with 447 participants. Boiardi 1992 was done in a earlier time period with different standards of care. It was inadequately powered to detect differences in survival outcomes. It was an unblinded study at risk of selection bias and selective reporting bias. There was sub‐optimal reporting of methodology, exclusion criteria, baseline characteristics and outcomes. The study was unblinded and at high risk of bias for assessment of adverse effects. Boiardi 1992 had low GRADE quality of evidence for median survival and very low certainty for chemotherapy toxicity (summary of findings Table for the main comparison).
Brada 2010 was a large well‐designed RCT study. It included patients with recurrent HGG treated with prior radiation therapy only. Patients were randomised with explicit methods. A power calculation to reject the null hypothesis was done. Baseline characteristics were similar. It was at low risk of selection bias with complete reporting, as per protocol. It was an unblinded study with risk of performance and detection bias for QoL data. QoL data were also at risk of survival bias because they were measured at fixed intervals. PFS outcome was at risk of inaccurate assessment because of a potential false reading of treatment‐related changes at progression. Another risk of bias was because of an industry association of authors to manufacturers of one of the study drugs (summary of findings Table 2).
We rated Brada 2010 as moderate GRADE certainty of evidence for overall survival because it was adequately powered to detect survival difference, had robust methodology with a published protocol and explicit criteria for randomisation. Unblinding of participants does not have impact on mortality outcomes. Additional trials may produce different results and would increase the power of meta‐analysis.
Quality of evidence for PFS was moderate as it was adequately powered with robust methodology. There was very good concordance between the local and the independent radiological assessor thus removing inter‐observer variability. Radiological assessment at fixed intervals may have missed interim changes and inaccurately assessed pseudo progression as true progression; however it accounted only for a total of 10% of participants. The questionnaire used to determine clinical progression in Brada 2010 was not available. There was risk of bias on account of unblinding, which was minimised by having objective criteria for assessing progression. Overall we feel with reasonable certainty that the evidence presented is of moderate quality.
Chemotherapy toxicity was assessed as moderate certainty of evidence because of methodological robustness: objective CTCAE criteria were used to measure the outcome. Risk of performance bias and detection bias was introduced because of unblinding but we thought the effect to be small.
Evidence for QoL outcome was low mainly because it introduced survival bias, as it was done at fixed intervals and excluded deceased patients from analysis.
Potential biases in the review process
We performed a thorough and comprehensive search, including grey literature. We screened all identified studies and two review authors independently extracted data. We restricted the included studies to RCTs as these provide the strongest level of evidence available. There were only two studies with one being very small and imprecise hence this is essentially a single‐trial analysis.
Agreements and disagreements with other studies or reviews
Currently we are not aware of any other systematic review of RCTs studying efficacy of PCV in recurrent HGG. Nitrosourea‐ and/or Procarbazine‐based single and/or multidrug chemotherapy has been studied in retrospective or prospective non‐randomised settings. Buckner 1995 and Rajan 1994 showed efficacy of a nitrosourea‐based regimen in recurrent HGG patients in a prospective single arm study. Brandes 2002 studied PCV in recurrent GBM patients in a prospective setting, and reported benefit. Triebels 2004 studied PCV in patients with recurrent AOD. Yung 2000's RCT studied TMZ against Procarbazine in participants with recurrent GBM and reported 6‐month improvement in PFS and QoL with TMZ. Wick 2009 studied sequential radiochemotherapy in primary anaplastic glioma. Participants in the radiation therapy arm were randomised to PCV or TMZ at recurrence. Results of the subset randomised to chemotherapy PCV and TMZ after recurrence are not available.
These studies demonstrated benefit with PCV or TMZ independently in recurrent HGG patients.
Study flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item for each included study.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
| 'Eight drugs in one day' compared with PCV for recurrent GBM in adults | ||||||
| Patient or population: Adults with recurrent GBM Settings: Hospital setting in Milan, Italy Intervention: 'Eight drugs in one day' multi‐drug chemotherapy Comparison: PCV | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| PCV | "eight in one" | |||||
| Overall Survival | See comments | See comments | Not provided | 35 (1 study) | ⊕⊕⊝⊝ | Small sample size, exclusion criteria not explicit, baseline characteristic and statistical tests reporting inadequate. HR and survival data not provided |
| Chemotherapy toxicity | See comments | See comments | Not provided | 35 (1 study) | ⊕⊝⊝⊝ | Unblinded for detection and performance. Toxicity not graded. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 OS was downgraded from high to low because of limitation in design due to inadequate reporting of allocation concealment leading to selection bias. Even though CI was not calculated it was at high risk of imprecision because of small sample size. 2 Chemotherapy toxicity was downgraded from moderate to very low because of limitations in design leading to selection bias, due to lack of allocation concealment and imprecision because of small sample size. Toxicity was not measured on a graded scale. | ||||||
| PCV compared with TMZ for recurrent HGG in adults | ||||||
| Patient or population: Adults with recurrent HGG Settings: Mutiple hospitals and centres in United Kingdom Intervention: PCV Comparison: TMZ | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| TMZ | PCV | |||||
| Overall survival median follow‐up 12 months | See comments | See comments | HR 0.91 (0.74 to 1.11); P = 0.35 | 447 (1 study) | ⊕⊕⊕⊝ | Due to the way HR are estimated the assumed and corresponding risks would not take into account the outcome. |
| PFS Median follow‐up 12 months | See comments | See comments | HR 0.89 (0.73 to 1.08); P = 0.23 | 447 (1 study) | ⊕⊕⊕⊝ | Good concordance between independent and local assessor. Risk of inaccurate assessment because of limitation of diagnosis method. No assumed risk could be calculated |
| QoL EORTC QoL questionnaire C30; at baseline, 12 weeks and 24 weeks | See comments | See comments | 51.9 for PCV versus 59.8 for TMZ arm (P = 0.04) | 415 (1 study) | ⊕⊕⊝⊝ | Unblinded study at risk for performance and detection bias. Measured at fixed intervals and thus at risk of survival bias. No assumed risk could be calculated |
| Chemotherapy toxicity During 1st 12 weeks of treatment | See comments | See comments | Not estimable | 441 (1 study) | ⊕⊕⊕⊝ moderate4 | At risk of performance and detection bias because of unblinding. No assumed risk could be calculated |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 OS quality of evidence was downgraded from high to moderate because of indirectness of population, as the trial population had not received chemotherapy at original diagnosis which will be standard of care now. 3 QoL evidence was double downgraded from high to low because of the large effect of unblinding in a subjective outcome like this. 4 Chemotherapy toxicity evidence was downgraded from high to moderate because of bias introduced by unblinding. | ||||||
| Response | Criteria |
| Complete response | Requires all of the following: complete disappearance of all enhancing measurable and non‐measurable disease sustained for at least 4 weeks; no new lesions; no corticosteroids; and stable or improved clinically. |
| Partial response | Requires all of the following: ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no new lesions; stable or reduced corticosteroid dose; and stable or improved clinically. |
| Stable disease | Requires all of the following: does not qualify for complete response, partial response, or progression; and stable clinically. |
| Progression | Defined by any of the following: ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration. |
| Response | Criteria |
| Complete response | Requires all of the following: complete disappearance of all enhancing measurable and non‐measurable disease sustained for at least 4 weeks; no new lesions; stable or improved non‐enhancing (T2/FLAIR) lesions; and participant must be off corticosteroids or on physiological replacement doses only, and stable or improved clinically. In the absence of a confirming scan 4 weeks later, this response will be considered only stable disease. |
| Partial response | Requires all of the following: ≥ 50% decrease, compared with baseline, in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no progression of non‐measurable disease; no new lesions; stable or improved non‐enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and participant must be taking a corticosteroid dose not greater than the dose at the time of baseline scan and is stable or improved clinically. In the absence of a confirming scan 4 weeks later, this response will be considered only stable disease. |
| Stable disease | Stable disease occurs if participant does not qualify for complete response, partial response, or progression (see next section) and requires the following: stable non‐enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan and clinically stable status. In the event that corticosteroid dose was increased for new symptoms and signs without confirmation of disease progression on neuroimaging, subsequent follow‐up imaging shows that this increase in corticosteroids was required because of disease progression; the last scan considered to show stable disease will be the scan obtained when the corticosteroid dose was equivalent to the baseline dose. |
| Progression | Progression is defined by any of the following: ≥ 25% increase in sum of products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; significant increase in T2/FLAIR non‐enhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; appearance of any new lesions; clear progression of non‐measurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumour, or to decrease in corticosteroid dose. Failure to return for evaluation as a result of death or deteriorating condition should also be considered as progression. |
