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Medicas UIS

Print version ISSN 0121-0319

Medicas UIS vol.25 no.3 Bicaramanga Sept./Dec. 2012

 

How surgery, radiotherapy and chemotherapy
each contribute to the outcome of treatment
for adult patients with Glioblastoma?

Álvaro Rojas Villabona*

*MD. MSc Clinical Neuroscience. Institute of Neurology. University College London. London. United Kingdom.
Correspondence: Dr. Álvaro Rojas V. Calle 44 # 3-73 Lagos II. Bucaramanga. Colombia. e-mail: a.villabona.11@ucl.ac.uk.
Article received the 16th of September of 2012 and accepted for publication the 17th of November of 2012.


ABSTRACT

Introduction: glioblastoma is a common condition associated with high morbidity and mortality; most of newly diagnosed patients will die within two years. The current standard therapy is maximal surgical resection followed by radiotherapy plus concomitant and adjuvant temozolamide. Objective: it is the aim of this review to evaluate how determinant surgical resection, radiotherapy and chemotherapy are to the outcome of patients with glioblastoma. Methods: a literature search is done to identify trials evaluating the outcome of adults with glioblastoma after being treated with surgery, radiotherapy or chemotherapy. The Oxford Centre for Evidence-based Medicine Levels of Evidence model is used to grade the quality of the available evidence. Results: 18 articles, reporting results of 15 studies were included. Five trials evaluated the effect of surgery in survival. Surgical provides as much as 4.9 months benefit in overall survival in cases in which complete resection is possible. A systematic review and four clinical trials reported that radiotherapy increases the mean overall survival in a range from three to five months. The European organization for research and treatment of Cancer and The National Cancer Institute of Canada Clinical Trials Group (EORT-NCIC) described in 2005 an increase of the survival by two - three months on patients receiving concomitant and adjuvant TMZ compared to patients receiving radiotherapy alone. Addittion of a novel chemotherapeutic agent seems to improve the outcome of patients compared to the current standard of care. Conclusion: surgery, radiotherapy and chemotherapy, each have a modest effect in the outcome of adults with glioblastoma. (MÉD.UIS. 2012;25(3):209-19).

Keywords: Glioblastoma. General Surgery. Radiotherapy. Chemotherapy. Treatment Outcome.

Cirugía, radioterapia y quimioterapia, ¿cómo cada uno contribuye al resultado
del tratamiento en adultos con glioblastoma?

RESUMEN

Introducción: el glioblastoma es un tumor frecuente asociado a alta morbilidad y mortalidad, la mayoría de pacientes mueren antes de 2 años desde el diagnostico. La terapia estándar actual es resección quirúrgica máxima asociada a radioterapia mas temozolomida concomitante y coadyuvante. Objetivo: evaluar que tan determinantes son la resección quirúrgica, radioterapia y quimioterapia para el resultado del tratamiento en pacientes con glioblastoma. Métodología de búsqueda: una revisión de la literatura es hecha para identificar estudios que evalúen el resultado del tratamiento de adultos con glioblastoma tras ser tratados con cirugía, radioterapia o quimioterapia. El modelo de niveles de evidencia del Centro de Medicina basada en la evidencia de Oxford es usado para calificar la calidad de la evidencia encontrada. Resultados: 18 artículos, reportando resultados de 15 estudios son incluidos. Cinco estudios evalúan el efecto de cirugía en la sobrevida. La resección quirúrgica provee un beneficio tan alto como 4,9 meses en la sobrevida global en los casos en que la resección máxima es posible. Una revisión sistemática y cuatro ensayos clínicos han reportado que la radioterapia incrementa el promedio de sobrevida global en un rango de tres a cinco meses. La organización Europea para la investigación y manejo del Cáncer y el grupo de ensayos clínicos del instituto Nacional de Cáncer de Canadá (EORT-NCIC) describió en el 2005 un incremento en la sobrevida global en dos a tres meses en pacientes que reciben tratamiento concomitante y coadyuvante con temozolomida en comparación con pacientes que solo reciben radioterapia. La adición de uno de los nuevos agentes quimioterapéuticos parece mejorar el resultado del manejo comparado con el actual tratamiento estándar. Conclusión: el tratamiento quirúrgico, la radioterapia y la quimioterapia; cada uno tiene un efecto modesto en el resultado del tratamiento de pacientes con glioblastoma. (MÉD.UIS. 2012;25(3):209-19).

Palabras Clave: Glioblastoma. Cirugía General. Radioterapia. Quimioterapia. Resultado del Tratamiento.


INTRODUCTION

Glioblastoma (GB) is a diffusely growing malignant brain neoplasm classified by the World Health Organization (WHO) as a Grade IV astrocytoma. It has a yearly incidence of 3 to 5 newly diagnosed cases per 100.000 population and distinctive histological and clinical features that make it a particularly aggressive and devastating tumour1,2. The mean progression-free and overall survival (OS) times for patients treated with the current standard-of-care therapy (debulking surgery plus radiation plus concomitant and adjuvant temozolamide) within clinical trials are around 7 and 15 months, respectively3. Selected patient populations with favourable prognostic factors have been reported to have a mean OS of 19 to 22 months38. However, to date, not an effective curable treatment is available and more than 70% of patients will die in two years following diagnosis5. It is the aim of this review to evaluate how determinant surgical resection, Radiotherapy (RT) and Chemotherapy (CT) are in the outcome of patients with GB and how much each of those treatment modalities can add to the survival/outcome of the patients.

Histopathologically, GB is a hyper cellular diffusely infiltrating tumor with nuclear atypia and mitotic activity; which is also associated with necrosis and/ or micro vascular proliferation. The majority of GB raises de novo as primary GB; however, anaplastic gliomas can evolve to secondary GB and represent 10% of them. GB is the most aggressive and most studied tumor in the brain1 and most of the current knowledge comes from studies carried out in patients younger than 65 years.

Current standard treatment for patients younger than 65 years newly diagnosed with GB is maximal surgical resection when feasible, plus 60 Gy of focal fractioned irradiation on daily fractions of 2 Gy for six weeks. This associated to concomitant CT with Temozolamide (TMZ), seven days per week from the first to the last day of CT (six weeks) followed by six cycles of five days of adjuvant TMZ every 28 days. Biodegradable polymers, put into the tumour bed at surgery, can target residual tumour cells by gradually releasing carmustine over several weeks (gliadel) and is a therapeutic option approved for newly diagnosed High Grade Gliomas (HGG)8.

Almost a half of the patients with GB are older than 65 years, they are less responsive to treatment and have worst prognosis; the most common treatment for this group of age is hypo fractionated RT (40 Gy in 15 fractions). Depending on age and Karnofsky Performance Status (KPS), Debulking Surgery (DS) or concomitant and adjuvant CT can be considered10,11.

Despite optimal treatment, all malignant gliomas eventually recur; in those cases reoperation may be considered, and RT or CT have a modest controversial value12-4. Bevacizumab, an anti- Vascular Endothelial Growth Factor (VEGF) was approved in 2009 as a single agent for recurrent GB in the US15,16. Different antiangiogenic and inmunomodulator drugs, inhibitors of integrin receptors and glutamate receptor blockers are being studied; they target specific pathways on tumoral pathogenesis and appear to be promising17-9.

METHODS

A general search was performed in PubMed (United States National Library of Medicine) to find the most recent trials evaluating the outcomes of adults with GB after being treated with surgery, RT or CT. The following combination of words was used: "glioblastoma" or "grade iv gliomas" or "glioblastoma multiforme" or "high grade gliomas" and "surgery" or "resection" or "radiotherapy" or "chemotherapy" or "antineoplastic agents" and "outcome" or "treatment outcome". The search was then limited to adults (19 + years) and published since January 2010.

The search retrieved 243 papers, their titles and abstracts were reviewed and 31 papers considered relevant were selected. Their full texts were reviewed and their references used to identify key past trials that support the current treatment and outcome of GB. Studies that included patients with low grade and/or grade III gliomas were excluded as well as studies that did not evaluate the effect of the treatments separately. The Oxford Centre for Evidence-based Medicine Levels of Evidence model, updated in 2009 (see Table 1) is used to grade the quality of the available evidence.

RESULTS

Preliminary search identified 31 papers reporting the outcomes of adults with GB after being treated with surgery, RT or CT. After detailed review 13 of these studies were found ineligible since they did not reported the effect of the treatment modalities separately or included patients with Grade II or III gliomas. 18 articles, reporting results of 15 trials were therefore eligible for inclusion; three papers reported subsequent analyses of trials whose primary results had been already published30,42,56.

The Table 2 summarizes the characteristics and main findings of five trials (six publications) evaluating the effect of surgery in the outcome of adult patients with GB. Not any of these trials reached the level of evidence 1. A systematic review (level of evidence 1a) and four clinical trials were found describing the impact of RT in the outcome of GB patients (see Table 3). As shown in Table 4, a systematic review and meta-analysis (level of evidence 1a) failed to show any beneficial effect for the different CT regimens used before concomitant and adjuvant TMZ was described. The European organization for research and treatment of Cancer and The National Cancer Institute of Canada Clinical Trials Group (EORTNCIC) described in 2005 an increase in survival of patients receiving concomitant and adjuvant TMZ compared to patients receiving RT alone55. This findings have been reconfirmed with further analysis and follow up of the same cohorts30-56. Addition of a novel chemotherapeutic agent seems to improve the outcome of patients compared to the current standard of care3 (see Table 4).

OS and Progression Free Survival (PFS) were the most commonly used outcome measures. OS is considered the gold standard end point for patients with HGG; it is thought to prove an objective and unequivocal clinical benefit particularly useful in GB given its short life expectancy. However, OS can be affected by the treatment start time, factors unrelated to the studied therapy, and salvage therapies used at recurrence20,21. PFS is the time from treatment initiation to progression or death from any cause and reflects the treatment effect without influences from recurrence therapies22. Radiographic methods used to determine progression in the case of PFS and the assessment of overall radiographic response become problematic or even unreliable after the introduction of new therapies and the description of pseudo progression. The use of corticosteroids and radiation can modify the permeability of tumoral blood vessels and therefore the correlation between tumour enhancement and tumour evolution23,24. Particularly important is pseudo progression; an increase in contrast enhancement and peritumoral edema sometimes associated to neurologic worsening described after RT plus TMZ25,26; or pseudo response, an apparent improvement in contrast enhancement due to diminished vascular permeability described after treatment with bevacizumab. Even when those changes do not reflect the real effect of the treatment, they modify the radiographic features that could be used to evaluate response or progression27. Nowadays, not any imaging based method can reliably assess progression or response in HGG; the recently defined Revised Assessment in Neuro-Oncology (RANO) criteria are expected to resolve these issues20.

DISCUSSION

Much has been trialled to improve the outcome of patients with GB; however, no current therapy is capable of modifying the process of the disease. Prolongation in survival and improvement in quality of life can be reached using the best available treatment. The first papers published about GB reported a survival of seven weeks in patients without any treatment; similar to the recent findings of two months on elderly patients who did not receive any treatment28,29. In the last three decades, implementation of DS, RT and CT has prolonged the survival of patients with GB to 12-18 months3,30. The aforementioned benefit on survival is not seen in all patients receiving optimal treatment, but some patients have been clearly identified to be no responsive. Several factors have been associated to either poor response or good prognosis29-37. Those factors are currently thought to be more important to outcome that the treatment by itself. For instance, age and KPS are such strong outcome predictors that patients older than 70 years and low KPS are usually treated with supportive care or RT alone29. The appearance of the tumour in the scans, its enhancement, size and location are important for surgery planning and determine the possible extent of resection without new neurological deficit31. The histological analysis of the tumour and WHO classification, do not entirely correlate the outcome due to the heterogeneity of malignant gliomas. However, new molecular analyses of the tumour seem to provide powerful prognostic factors. For instance, the methylation of DNA repair enzyme O-6 Methyl Guanine-DNA Methyl Transferase (MGMT) in GB is predictive of improved prognosis and better response to TMZ32,33. Mutation in codon 132 of the isocitrate dehydrogenase 1 (IDH 1) gene can help to diagnose secondary GB and confer a prognostic advantage on patients with anaplastic astrocytoma34,35. Also, 1p/19q co-deletion is an indicator of anaplastic oligodendroglioma vulnerability to a wide range of therapies including PVC36,37. These molecular features allow a better classification of tumours and aid in the differentiate patients who should receive aggressive initial treatment from those who do well regardless of the given treatment, thus allowing decision making based on side effects38. Nonetheless, given the short list of effective therapies, there is a long way to get the entire utility of those markers; such as, that patients with non-methylated MGMT promoter tumours who are known to be poor responders to TMZ are still treated with it because there is no better option available39.

SURGERY

Surgical approach to patients with GB is critical since it reduces the symptoms of increased intracranial pressure and mass effect, and provides tissue for histologic classification and molecular evaluation, which allows classification, prognosis and therapeutic approach. Further than allowing histological diagnosis and reducing mass effect, surgical resection effect on survival is minimal and difficult to evaluate due to ethical issues on randomization of non-surgical management or subtotal resection. One prospective study randomized biopsy or DS on 30 patients older than 65 years with radiologic evidence of malignant gliomas and found a modest survival benefit (2.9 months) on patients with tumour resection; however, this was a small and unblinded trial on patients with poor prognosis40. Stummer et al described that GB patients who underwent complete resection of contrast enhancing tumour under fluoroscopic guide with 5-aminolevulinic acid had a significantly higher PFS at six months (41%) than patients with less extensive resection done under conventional white light microsurgery (21.1%)41. A follow up of the same study controlled different bias and variables and concluded a 4.9 months benefit of complete resection42. Several trials have reached the same conclusion and there is an established consensus that total resection improves OS43,44. As total resection is not always possible, it has been evaluated what is the minimal resection needed to have a benefit. Lacroix and colleagues studied the effect of Extent Of Resection (EOR) in patients with GB and concluded a longer survival in patients who had a resection of more than 98% of the tumour especially if age, KPS score and primary imaging features were favourable45; it became a paradigm in neurosurgery and clinical decisions were for long time based in that retrospective, non-randomized trial. Recently, 500 adults consecutively diagnosed with GB were evaluated to see the role of EOR on survival; a significant benefit was seen with as low as 78% and the benefit increased proportionally with the EOR31. This has been also proven in the elderly population with GB46,47.

The benefit of surgery is related to better response to adjuvant therapies and does not come solely from the surgery; patients with complete resection and TMZ have significantly higher OS than incomplete resection plus TMZ42. Surgery is of paramount importance for treatment of GB since it allows histological diagnosis and decompression, has a modest benefit in OS that increases proportionally with the EOR and seems to improve the response to CT. New surgical technologies such as neuronavigation, intraoperative MRI, functional MRI, intra operative mapping, and fluorescence guided surgery are being used to improve safety and EOR43,48.

RADIOTHERAPY

RT was firstly described as increasing the mean OS in a range from three to five months49-51. Laperriere et al conducted a systematic review and found a significant survival benefit favouring post-operative RT with a risk ratio of 0.81 (CI 95 % 0.74-0.88). No significant difference between whole brain and local radiation was found, and a modest benefit on survival on 60 Gy divided in 30 fractions over 45 Gy in 20 fractions was described52. No benefit from RT in patients older than 70 was found. Not much research has been done on the evaluation of RT in GB over the last ten years, and the evidence found comes from some works in elderly patients who are still thought no to benefit from RT or CT. A multi-institutional trial randomized 85 subjects with GB from 10 institutions to RT plus supportive care or supportive care alone and found that patients in the RT group lived three months longer10. Those results were recently reconfirmed by a large population based study which proved that an abbreviated course of RT with a total dose of 40 Gy in 15 fractions is as effective as the standard scheme29. It is now widely accepted that RT prolongs the survival of young patients with GB in three to five months and around two months in patients older than 70 years10,53.

CHEMOTHERAPY

In 2002 the Glioma Meta-analysis Trialist (GMT) group published the results of a meta-analysis of 12 randomized trials that failed to prove CT useful in patients with GB54. However, the history of CT for GB hanged in 2005 when the European Organization for Research and Treatment of Cancer (EORTC) and the National Canada Institute of Cancer (NCIC) published a trial on 573 patients from 85 centres randomized to RT alone or RT plus concomitant and adjuvant TMZ for newly diagnosed GB. The median OS was 2.5 months longer in the group with RT plus TMZ, and the two-years survival of 26.5% on subjects with RT plus TMZ was significantly higher than 10.4% in the group with RT alone55. Those findings were complemented with the five year follow up of the same patients showing a sustained benefit of RT plus TMZ over time in all of the prognostic groups30. Furthermore, as pretreatment prognostic factors can be more relevant to the outcome than the therapy, the EORTC study was recently tested with a recursive partitioning analysis; the overall prognostic significance was retained between the different recursive groups; and as expected, particularly strong in patients with favourable prognostic factors56. Nowadays, new treatments for GB are compared with postsurgical RT plus TMZ and new chemotherapeutic agents are evaluated in addition to that gold standard. Anaplastic oligodendroglioma was the first described malignant brain tumor to be uniquely chemo sensitive as PCV was demonstrated to be effective in those patients57. Later, CT with PCV and TMZ were shown to be equally valuable to improve the outcome, although TMZ showed a better safety profile6,44,58.

Recently, the New Approaches to Brain Tumors Therapy (NABTT) consortium evaluated the addition of new chemotherapeutic agents to RT plus TMZ in patients with GB. The addition of talampanel, poly-ICLC or cilengetide to the standard treatment increased the OS from 14.6 months as described in the EORTC study in 2006 to 19.6 months in the new agent added group3. The trial was designed as a four single-cohorts study with historical controls accrued internationally from 2000 to 2002 and not strong enough to support the addition of a novel agent to the standard treatment. However, it is significant that it shows how CT has contributed to improve the outcome of these patients. For instance patients treated with postsurgical RT in 2000 had a mean OS of 12 months and only 8% of them survived for more than two years40; while the mean OS of patients treated in 2010 with postsurgical RT plus TMZ plus a new chemotherapeutic agent was 19.6 months and 37% of them lived for more than two years3. Although part of that benefit must be due to improvement in general care of oncologic conditions; most of it can be reliably attributed to CT.

Research on surgery, RT and CT for GB in the elderly and in patients with low KPS is rapidly evolving. However, some patients are still found to have only biopsy and support care or RT alone. This allows an individual evaluation of each treatment modality. Patients with different kinds of treatments can be conveniently stratified and the predictive factors can be controlled to evaluate the independent effect of an intervention. As can be seen in Table 5, two retrospective trials on contemporary patients assessed the individual value of surgery, RT and CT and confirmed that all of them actively contributed to an improved outcome in patients with GB (Level of evidence 3b)59,60. It is evident that the population in the study by Marina et al had a worse prognosis, but the proportion of improvement was similar in both studies, showing again that surgery, RT and CT, each have a modest but significant effect in the outcome of adults with GB.

CONCLUSION

In the last three decades, the implementation of DS, RT and CT has prolonged the survival of patients with GB to 12-18 months. Although the outcome seems to be more related to predictive factors such as age, KPS and molecular profile of the tumor, each modality of treatment has shown to improve the outcome by itself. Surgery is determinant since it reduces the symptoms of increased intracranial pressure and mass effect and provides tissue for histologic and molecular analysis. Surgery provides a modest benefit of three months OS in the case of GB and as much as 4.9 months when complete resection is possible. RT has been found to increase the mean OS in a range from three to five months and has shown itself useful in the elderly population. Concomitant and adjuvant TMZ increases the OS by two-three months and some studies suggest a further two month increase in OS when a new chemotherapeutic agent is added to postsurgical radio-chemotherapy. Surgery, RT and CT, each have a modest effect in the outcome of adults with GB; nonetheless, when used together as the best available treatment, they considerably improve the outcome. Future research must focus on evaluation of molecular outcome predictors and development of targeted agents that can impact the natural history of the disease.

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