Brain tumors are by and large divided into primary or secondary tumors and so may be farther classified into either being gliomas or non-gliomas. Primarily radiation therapy and chemotherapy are used in symptoms relief and protraction of endurance since these tumors are incurable. Treatments depend on many different variables such as type of tumor, size of tumor and location, tumor class, patient ‘s age, the public presentation position and eventually on tumor being primary or secondary tumor. The predictive factors ( PFs ) in malignant gliomas ( MGs ) are patient ‘s age, Karnofsky public presentation position ( KPS ) mark, tumor class, and intervention ( remotion of tumor by surgery and postoperative therapy ) ( Fischbach et al 1991, Salcman et al 1994 and Winger et al 1989 ) . Currently research focal point is besides into placing molecular and familial change PFs in the gliomas. However in aged, the public presentation position and neurological map have the paramount importance in finding best therapy ( Stupp et al 2007 ) . A recent survey into the function of HIF1a in Grade III and IV patients concluded that addition in degree of HIF1a has positive correlativity with increasing histological class so hence it has paramount importance in foretelling overall endurance. The farther research into biomarkers of gliomas may increase our understanding and may assist to place appropriate combination of therapies ( Bergsland 2006 and Compostella et al 2007 ) . ( See Fig: 1 )
Figure 1. Molecular predictive factors of gliomas ( Patrick et al 2008 ) .
Malignant primary encephalon tumors are classed into different classs. Grade is a marker of how differentiated a cell is which can assist to foretell its growing rate and inclination of distributing. The World Health Organization ( WHO ) classifies astrocytomas into four predictive classs: class I ( pilocytic astrocytoma ) , grade II ( spread astrocytoma ) , grade III ( anaplastic astrocytoma ( AA ) ) , and rate IV ( glioblastoma multiforme ( GBM ) ) . Oligodendrogliomas divided harmonizing to WHO into two classs: oligoastrocytoma ( grade II ) , and anaplastic oligodendroglioma ( AO ) and anaplastic oligoastrocytoma ( AOA ) ( grade III ) . Ependymomas are divided into three classs ; grade I ( myxo-papillary ependymoma and sub-ependymoma ) , grade II ( ependymoma ) and grade III ( anaplastic ependymoma ( AE ) ) . Grade III and IV tumors are considered MGs. The scaling is based on histological scrutiny of tumour cells. ( Patrick et al 2008 )
High class glioma patients are ab initio treated by surgical intercession and so referred to other therapies because the MGs can non be wholly removed surgically due to their infiltrative nature ( Patrick et al 2008 and Stupp et al 2007 ) . Mostly radiation therapy is the pillar postoperative intervention as research has shown the addition in overall endurance merely by the add-on of radiation therapy to surgery ( Engelhard et al 2002 ) . After the initial radiation therapy, about 90 % of reoccurrence of tumor takes topographic point at the original tumor location. Recent progresss into bettering the irradiation dosage to tumour location have introduced the usage of brachytherapy and stereotactic radiosurgery ( SRS ) ( Patrick et al 2008 ) . ( See Fig: 2 )
Figure 2: Diagnosis and Treatment program for glioma patients. LGG ( low class glioma ) , MG ( malignant glioma ) and RT ( radiation therapy ) ( Grant 2004 )
There are figure of different radiation therapies to handle primary encephalon tumors. External-beam radiation delivers radiation externally to organic structure. A local radiation therapy technique includes external focal, brachytherapy ( involves capsules nidation which contains radioactive substances into the glioma ) and SRS ( present a high dosage of radiation in a individual fraction to the mark ) . The chief benefit of utilizing localised radiation is that there is less opportunity of enlightening environing healthy tissues. ( Salvati et al 2009 ) .
Chemotherapy is used either as post-radiotherapy or used in combination with radiation therapy in most tumour instances. Overall, recent research surveies has clearly shown the benefits of utilizing radio-chemotherapy in bettering survival rates compared to patients who receives radiotherapy entirely. Chemotherapy agents that are normally good for top-quality gliomas patients include procarbazine, platinum parallels, the nitrosureas, and temozolomide. Chiefly chemotherapy is reserved for recurrent gliomas ( RGs ) , as surveies have shown higher response rates in these tumors ( Madajewicz et al 2000 ) . This essay aims to summarize the function of radiation therapy and chemotherapy in direction of patients with high class gliomas and RGs. ( See Table: 1 )
Grade III tumor
- Anaplastic astrocytoma
- Anaplastic oligodendroglioma
- Anaplastic oligoastrocytoma
- Anaplastic ependymoma
- Glioblastoma multiforme
AAs often progress from a less malignant signifier and farther develop into Grade IV glioma. Almost all MG patients will see tumour return and finally decease due to disease patterned advance. Despite efforts at extremist resection, tumour reoccurrences takes topographic point about at the part of the old resection pit because complete resection of the tumor is impossible due to its infiltrating nature ( Stupp et al 2007 ) . The average endurance is about thirty-six months for patients with AA ( Madajewicz et al 2000 ) .
The intervention government for freshly diagnosed AA is radiotherapy entirely in Europe but it ‘s given in combination with carmustine ( BCNU ) in USA ( Soffietti et al 2007 ) but there was merely one prospective test which suggested some extra benefit of its usage. In 1987, Lange et al studied the combination of wireless and chemotherapy utilizing BCNU + Ifosfamide in 105 patients, which of 25 AA patients acquired a average clip to patterned advance of 92 hebdomads, with 43 % holding average endurance rate at 24 months ( Brandes et al 1996 ) . Accessory chemotherapy with either a nitrosourea or procarbazine or Pediapred or BCNU and Pediapred was compared in a stage III test and consequences showed there was no important difference between the four intervention groups. Based on randomised informations available, chemotherapy failed to better the result of patients with AA, while a meta-analysis showed a little, but important betterment in endurance promoting the usage of chemotherapy ( Yung et al 1999 and Salvati et al 2009 ) .
Recent randomized test comparing two intervention governments ( accessory PCV ( procarbazine+lomustine+vincristine ) vs. accessory PCV and an oritine decarboxylase inhibitor ( DFMO ) conducted by Levin et Al reported that the average endurance and clip to progression to be significantly longer in the PCV +DFMO group than other group. Median endurance times were 76 months in PCV/DFMO and 61 in the PCV entirely group ( Levin et al 2003 ) . Another randomization survey of 291 patients ( either treated with post-radiotherapy PCV or radiotherapy entirely ) consequences showed that the chemotherapy was able to somewhat better the PFS of patients but had no consequence on the average overall endurance ( MOS ) ( Stupp et al 2007 and Madajewicz et al 2000 ) .
Chemotherapy is better reserved for tumor return, since a multicentre Phase II survey showed a response rate of 35 % and a PFS6 ( patterned advance loose endurance ( PFS ) at 6 months ) of 46 % ( Yung et al 1999 and Salvati et al 2009 ) . In 1997, Boiardi A et Al showed that protocol of pre-irradiation chemotherapy and so overlapping 2nd chemotherapy with irradiation can be of good and is besides good tolerated in anaplastic glioma patients. Recently, chemotherapy with TMZ has been proven to be active and well-tolerated in stage II tests ( Stupp et al 2007 ) .
The major trademarks of AO are high mitotic activity, microvascular proliferation, and mortification. Oligodendrogliomas are thought to arise from an unnatural growing of oligodendrocytes. Most arise in the supratentorial white affair and remainder in the spinal cord and posterior pit ( Engelhard et al 2002 ) .
Oligodendrogliomas by and large demonstrate some molecular PFs which are independent forecasters of chemosensitivity ( with/without radiation therapy ) and overall endurance. These molecular markers are familial changes and enzyme markers. These familial changes are the presence of chromosome 1p/19q codeletion ( Smith et al 2000, Bent et al 2000 ) . The enzyme topoisomerase II which has besides been shown to be associated with really hapless forecast and high proliferation rate of tumor exists as a marker for patients who might profit from earlier accessory therapy ( Engelhard et al 2002 ) . In 1994, Reifenberger et Al were the first to do observation of presence of chromosome 1p/19q codeletion in oligodendrogliomas, and so it was shown to be strongly related with response to chemotherapy in anaplastic oligodendrogliomas by Cairncross et Al in 1998. Recent stage III surveies of radiation therapy with PCV chemotherapy vs. radiation therapy entirely in freshly diagnosed AOs or AOA patients showed that the radiation therapy with chemotherapy significantly impact the clip to tumour patterned advance but showed no grounds of betterment in MOS. In these surveies, patients who had the presence of 1p/19q codeletion, the response rate to PCV chemotherapy ranged from 59 to 92 % and ranged from 0 to 46 % merely in its absence ( Brandes et al 2006, Ducray et al 2009, Salvati et al 2009 and Patrick et al 2008 ) .
In 2007, Synyach et al studied 59 patients ( 35 AO patients ) who received either radiotherapy merely, radio-chemotherapy or merely chemotherapy as first line intervention. The consequences showed no important difference between groups in respects to PFS ( 47 months ) and MOS ( 109 months ) . However the surveies so far have besides proven to demo that radiation therapy entirely is every bit efficient as radio-chemotherapy and besides excludes the toxicity associated with intervention combinations ( Veninga et al 2001 ) but writers of the survey concluded that chemotherapy as first line of intervention consequences in drawn-out MOS in patients with confirmed pure oligodendroglioma ( Athanassios et al 2008 and Sunyach et al 2007 ) .
The recurrent oligodendrogliomas frequently progresses to Rate III or IV gliomas. Therefore the treating options available for perennial oligodendroglioma patients are either radiation therapy in combination with PCV chemotherapy or PCV chemotherapy entirely depending on which interventions had been used before. Patients who had been treated with radiation therapy before reoccurrence are more likely to react to PCV chemotherapy than radiation therapy and frailty poetry ( Engelhard et al 2002 ) . Recently PCV chemotherapy has been replaced by temozolomide as criterion of attention for patients with perennial AOs but PCV option is available for non-responder patients ( Bent et al 2003, Soffietti 2004 and Salvati et al 2009 ) .
AOAs are comparatively uncommon and constitutes of mixture of both neoplastic astrocytes and neoplastic oligodendria ( Engelhard et al 2002 ) . The AO are thought to be associated with good forecast than AOA but AOA has better forecast than AA because of familial change AOA are suggested to be more closely related to AO than AA. AOA patients normally have different results because of grade class ( OA Grade III vs. OA Grade IV ) and besides depend on per centum of pure astrocytoma in tumor ( Buckner et al 2007 ) .
In 1997 survey conducted by Boiardi et Al group devised a intervention protocol dwelling of 1 ) chemotherapy anterior radiation therapy 2 ) chemotherapy for RG 3 ) surgery. The writer concluded that utilizing aggressive protocol intervention ( chemotherapy prior radiation therapy and so overlapping 2nd chemotherapy with radiation therapy and surgical intercession performed whenever possible and good to patient ) significantly improved the status of patients with AGs. The intervention protocol gave patients average time-to-progression of 24.5 months and MOS of 38.8 months in AA, 38.7 and 71.8 in AOA and 58.2 and 73 in AO patients. The consequences besides showed grounds of enhanced chemo-sensitivity of AOs and Mixed AOAs prior to radiotherapy giving favorable response to chemotherapy.
In 1992, Glass et al conducted a survey were they made an highly important observation that AOAs responded to PCV therapy even though the responses were taken prior to radiotherapy usage. The PCV is on a regular basis used for AO and AOA interventions either used alone or in combination with other therapies ( Boiardi et al 1997 ) .
Recent research has shown the benefits of utilizing SRS in patients with RGs, but this therapy has inauspicious side effects ( McDermott et al 2004 ) Unlike SRS, fractionated stereotactic radiation therapy allows high preciseness irradiation to slightly larger tumors and its good tolerated therapy ( Combs et al 2005 ) .
In a stage II clinical test, patients with freshly diagnosed AO or AOA recurred tumors were treated with TMZ ; had response rate of 53 % and average PFS clip of 10.4 months. However patients who were non chemotherapy-naive prior to TMZ or carboplatin intervention had response rates of 13 % -44 % and average endurance of 16-26 months ( See et al 2007 ) .
Ependymomas are uncommon tumors of ependymal cells of the cardinal nervous system and may either arise in the encephalon or the spinal cord. The spinal ependymomas are less common and besides have good forecast than intracranial ependymomas. Recent researches into molecular predictive markers of AGs have provided some penetration into developing new curative marks, chiefly concentrating on signal transduction mechanisms ( Ruda et al 2008 ) .
The standard intervention provided for AEs are surgery intercession to accomplish complete tumor resection whenever possible, followed by radiation therapy to protract the endurance and so sing chemotherapy in RGs. The chief purposes of surgery are to do a histological diagnosing to corroborate the tumor class and besides to take obstructions from cerebral-spinal fluid ( CSF ) flow ( Metellus et al 2007 and Ruda et al 2008 ) . In 2007, Metellus et al conducted a survey of 152 grownup ependymomas patients where they reported the survival rate of 84.4 % for 5 twelvemonth and 76.5 % for 10 twelvemonth. The survey multivariate analysis therefore concluded the association of histological class, extent of surgery, patient ‘s age and KPS with overall endurance rate.
Different types of radiation therapies have been used for recurrent ependymomas, including SRS, FSRT and CSI ( craniospinal irradiation ) . As described above, in all of the radiation therapy signifiers, the SRS is most efficient in supplying the highest dosage of radiation to the smallest possible tumor volume. Therefore, SRS succeeds in supplying the highest local control of tumour patterned advance and highest rate of local toxicity. ( Krienger et al 2009 ) There is besides general sentiment among research workers that ependymomas tumors are significantly radio-resistant.
In the history, ependyomas tumors were mostly managed by whole-brain radiation therapy or craniospinal irradiation ( CSI ) therapy. Current intervention for localised ependymomas is limited-field radiation therapy intervention with doses up to 60 Gy, whereas in instance of CSF airing the CSI therapy is established ( Ruda et al 2008 ) . Recently, Combs et al group conducted a survey of 57 localized ependymomas ( 30 AE patients ) patients handling with local radiation therapy or CSI and the consequences showed no important difference in MOS between CSI and local radiation therapy. Other surveies conducted by Merchant et Al, Garrett et Al and Goldwein et Al. reported that increasing the dosage to & gt ; 45 Gy in patients with AEs had more positive result ( 50 % ) comparison with merely 14 % endurance with doses of & lt ; 45 Gy ( 31 ) ( Combs et al 2008 ) . On the other manus, there is no such informations available on the effects of detaining radiation therapy for grownup ependymoma patients as postoperative intervention on the overall endurance rate. Therefore the option of radiation therapy as a best postoperative intervention option remains controversial ( Reni et al 2007 ) .
In the instance of recurrent AEs, intervention by chemotherapy is considered. A survey showed the platinum-based regimens with response rates of 31-67 % compared to nitrosourea-based regimens of merely 25 % , showed former to be the best available intervention option for recurrent AE patients ( Ruda et al 2008 and Green et al 2009 ) . The research sing function of chemotherapy in AE is still non clear ( Niazi et al 2009 and Green et al 2009 ) . As AE are uncommon in grownups so hence most research has been conducted in pediatric patients. This complicates the state of affairs in respects to measuring the result and taking the optimal therapy for the grownup patients. ( Reni et al 2007 )
Grade IV tumor
GBM consists of ill differentiated neoplastic astrocytes and shows important variableness of histological characteristics but vascular hyper-proliferation and mortification are critical diagnostic characteristics of GBM that differentiate it from other classs of gliomas ( Kanu et al 2009 ) . The biomarkers such as chromosome 1p/19q codeletion and O-6-methylguanine-DNA methyltransferase position are the most critical PFs of GBM ; these besides assist in foretelling the overall endurance ( Ducray et al 2009 ) .
The intervention government for freshly diagnosed GBM is surgery and attendant with radiation therapy and chemotherapy with TMZ. In most cases, the accessory intervention is TMZ due to being shown to be the most efficient intervention process for GBM patients. ( Salvati et al 2009 ) . TMZ is besides approved for usage in combination or post-radiotherapy for freshly diagnosed GBM patients. Even after the aggressive intervention protocol and medical promotions the MOS after diagnosing remains about a twelvemonth. ( Okezie et al 2009 )
In 2002, a stage II survey conducted by Stupp et al consisted of 64 primary GBM patients who were treated with TMZ given concomitantly and afterwards to radiotherapy ( Stupp et al 2002 ) . The survey was shown to be clear success that it leads into stage III multicentre randomised survey with “Stupp protocol” . The survey was conducted by the European OrganizaAtion for Research and Treatment of Cancer ( EORTC ) and the National Cancer Institute of Canada ( NCIC ) Trials Group affecting 573 patients to have either “Stupp protocol” or radiation therapy with TMZ as an accessory intervention ( Stupp et al 2005 ) . This survey confirmed the pilot survey consequences: 14.6 months average endurance was reported for the “Stupp protocol” compared to merely 12.1 months for the RT-alone group. The survey besides showed the 26.5 % of 2 twelvemonth endurance for the “Stupp protocol” vs. 10.4 % merely for the radiotherapy-alone group. It ‘s hard to generalize the consequence for AGs as the survey was strictly tested in patients with GBM. However a meta-analysis survey consequences showed no important difference between GBM and anaplastic class 3 gliomas in concern to adjuvant chemotherapy [ 6 ] and consequences of recurrent AGs treated with TMZ were slightly similar to Stupp et Al survey ( Yung et al 1999 and Salvati et al 2009 ) . ( See Fig 3 )
Fig 3. Standard therapy of spongioblastoma ( Stupp et al 2007 ) .
In 2002, Madajewicz et al conducted a survey where the MOS rates for GBM patients after having chemotherapy or radio-chemotherapy were investigated. The survey showed that the MOS for patients who received chemotherapy prior to radiotherapy was three times greater than patients who received radio-chemotherpy. In contrast, some surveies have demonstrated that radiation therapy besides adds several months to MOS in patients with GBM. Whole-brain radiation therapy is normally suggested for multifocal GBM ( Adamson et al 2009 ) .
In last 23 old ages, BCNU-impregnated biodegradable polymer therapy is the first therapy to obtain FDA blessing for patients with GBM ( Adamson et al 2009 and Niedery et al 2009 ) . This was due to randomise, multi-institutional, double-blinded, placebo-controlled surveies demoing addition MOS in freshly diagnosed and RG patients ( Niedery et al 2009 ) .
In period of last 10 old ages, TMZ has been peculiarly developed for RG patients ( Stupp et al 2007 ) . In perennial AG patients, TMZ demonstrated a response rate of 35 % in a stage II clinical test. In contrast, patients with perennial GBMs had no important response with TMZ intervention. However other chemotherapeutic interventions ( For illustration: carmustine wafers ) have demonstrated to increase the MOS by approximately 8 hebdomads in perennial GBM patients ( Patrick et al 2008 ) .
Appraisal for Treatment
Patients may show with different symptoms depending on tumor location, size and associated encephalon hydrops. Normally these symptoms are ictuss, distorted vision, focal shortages, concerns and confusion, memory loss, and personality alterations. Image diagnosings are normally carried out by CT with contrast or MRI scan which are utile in finding the presence of lesion, location and size of tumor. Differential diagnosing includes abscess or metastatic encephalon tumor. To find the nature of the tumor ( Primary or malignant ) , different scrutinies are carried out of different parts of the organic structure. As CT or MRI scan are non wholly accurate in finding the tumor class or type ; histological scrutiny verification is obtained by stereotactic biopsy or sample obtained after tumour resection eventually confirms the diagnosings. Frequently, diffusion-weighted imagination, diffusion tensor imagination, dynamic contrast-enhanced MRI are besides used to mensurate vessel permeableness and comparative intellectual blood volume by perfusion imagination, as they are obtained to help in diagnosings. After diagnosings, common predictive factor and other information are taken into history when make up one’s minding the best possible intervention regimen ( Patrick et al 2008, Stupp et al 2007 and Grant 2004 ) ( See Table 2 )
Immediate Side Effectss
Radiation therapy is classified as outpatient intervention. ISE of radiation therapy include sickness, purging, weariness, loss of appetency, concern, skin annoyance and hair loss. Most of radiation therapy associated ISE are manageable with supportive attention and medicines ( Merchant et al 2005 ) . Cranial radiation ISE can be divided into local effects and CNS effects. The terrible side effects of CNS are: acute brain disorder, subacute demyelination, delayed radiation mortification and chronic leucoencephalopathy ( Grant 2004 ) .
BCNU cause sickness, giddiness, bone marrow suppression, hazards of infection, hemorrhage, fatigue and lung toxicity. Procarbazine causes haematological and GI symptoms, but besides causes roseola, and neurological symptoms ( concerns, paresthesia and giddiness ) . Vincristine causes neurotoxicity ( neuropathy, myopathy, and autonomic perturbation ) and GI symptoms. Platinum-Based drugs cause neurotoxicity ( peripheral neuropathy and hearing loss ) , nephritic toxicity, and bone marrow suppression. Temozolomide cause bone marrow suppression, irregularity, sickness, weariness, and concern. ( Grant 2004 ) ( See Table 3 )
A survey reported by Werner-Wasik et Al in 1999 about immediate side effects ( ISE ) associated with FSRT and SRS from series of 78 patients. The survey consequences showed that overall 35 % of patients experienced at least one ISE. The writers grouped the ISE in two classs of mild ISE and moderate ISE. 87 % ISE were mild effects, dwelling of ictuss, giddiness, sickness and new continual concerns. Moderate effects include 2 episodes of deteriorating neurological shortages, 2 of orbital hurting and in 3 instances computing machine imaging of encephalon revealed increased perilesional hydrops. ( Werner-Wasik et al 1999 )
Recent medical progresss have yet non discovered the remedy for extremely MGs and new optimum therapies give the MOS of merely 12-15 months for GBM patients and 2-5 old ages for AG patients. ( Patrick et al 2008 ) . However postoperative radiation therapy or radio-chemotherapy significantly improves overall endurance of patients from several hebdomads to several months with good quality of life. The surveies cited in this essay clearly demonstrated the function of radiation therapy to be overall survival protraction therapy with some inauspicious side effects ( Berg et al 2003 ) . The absence of widely approved and known PFs has leaded us to the absence of standardised curative guidelines. ( Metellus et al 2007 ) . In most instances, chemotherapy is non used as accessory intervention but instead reserved for patients with RGs. However, new chemotherapy agents are emerging as promising therapies for figure of gliomas ( Ruda et al 2008 ) .
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