Treatment Of Anaplastic Astrocytoma Research Articles

Functionalized carbon nanostructures as temozolomide carriers; physicochemical and biopharmaceutical characterization

In this study, Temozolomide (TMZ), a drug used in the treatment of anaplastic astrocytoma and glioblastoma multiforme, was incorporated in multiwalled carbon nanotubes (MWCNTs) and hybrid carbon nanotubes with graphene (MWCNTs-G) functionalized by polyethylene glycol (PEG). The aim was to evaluate the potential of these nanocarriers for targeted delivery and sustained release of TMZ in brain tumor cells. Oxidized MWCNTs and MWCNTs-G were noncovalently functionalized with PEGs of different molecular weights and subsequently loaded with TMZ following standard procedures. Thorough physicochemical and biopharmaceutical characterization of the TMZ loaded carbon nanocarriers pointed to high encapsulation efficacy (up to 67%) and drug loading (up to 18% out of 25% theoretical value) and homogeneous particle size distribution, with z-average (160 to 300 nm) and zeta potential (-31 to -21 mV) of the particles adequate for crossing the blood-brain-tumor-barrier (BBTB) and entering into the tumor cells. Successful functionalization and TMZ loading were confirmed by SEM and TEM images, UV-Vis absorption, infrared and Raman spectroscopy and TGA analyses. Sustained release of TMZ from the carbon nanocarriers was observed in vitro. The presented findings form a fundamental platform for further investigation of these formulations against different types of glioma cells and in adequate animal models.

Predicting survival in anaplastic astrocytoma patients in a single-center cohort of 108 patients

BackgroundCurrent guidelines for the treatment of anaplastic astrocytoma (AA) recommend maximal safe resection followed by radiotherapy and chemotherapy. Despite this multimodal treatment approach, patients have a limited life expectancy. In the present study, we identified variables associated with overall survival (OS) and constructed a model score to predict the OS of patients with AA at the time of their primary diagnosis.MethodsWe retrospectively evaluated 108 patients with newly diagnosed AA. The patient and tumor characteristics were analyzed for their impact on OS. Variables significantly associated with OS on multivariable analysis were included in our score. The final algorithm was based on the 36-month survival rates corresponding to each characteristic.ResultsOn univariate analysis, age, Karnofsky performance status, isocitrate dehydrogenase status, and extent of resection were significantly associated with OS. On multivariable analysis all four variables remained significant and were consequently incorporated in the score. The total score ranges from 20 to 33 points. We designated three prognostic groups: A (20–25), B (26–29), and C (30–33 points) with 36-month OS rates of 23%, 71%, and 100%, respectively. The OS rate at 5 years was 8% in group A, 61% in group B and 88% in group C.ConclusionsOur model score predicts the OS of patients newly diagnosed with AA and distinguishes patients with a poor survival prognosis from those with a greater life expectancy. Independent and prospective validation is needed. The upcoming changes of the WHO classification of brain tumors as well as the practice changing results from the CATNON trial will most likely require adaption of the score.

Anaplastic Astrocytoma: State of the art and future directions.

Anaplastic Astrocytoma(AA) is a malignant, diffusely infiltrating, primary brain tumor. According to the WHO 2016 classification of central-nervous-system tumors, AA has been described as a glial tumor with no co-deletion of 1p/19q, and is divided into IDH mutated tumor, characterized by better prognosis, and IDH wild-type form, with worse prognosis. The standard of care is maximal safe resection followed by radiotherapy and chemotherapy with temozolomide. Several efforts have been made to evaluate, according to molecular selection, which is the best post-surgical treatment. At recurrence, the treatment remains challenging and some trials are ongoing to evaluate new potential drugs, alone or in combination with chemotherapy. We performed a description of the status of the art on diagnosis, molecular characteristics and treatment of AA. In particular, we focused our details on new drugs; indeed, a deeper knowledge of the molecular characteristics of gliomas could lead to to development of active personalized treatments according with precision medicine.

Anaplastic astrocytoma.

Anaplastic astrocytoma (AA) is a diffusely infiltrating, malignant, astrocytic, primary brain tumor. AA is currently defined by histology although future classification schemes will include molecular alterations. AA can be separated into subgroups, which share similar molecular profiles, age at diagnosis and median survival, based on 1p/19q co-deletion status and IDH mutation status. AA with co-deletion of chromosomes 1p and 19q and IDH mutation have the best prognosis. AA with IDH mutation and no 1p/19q co-deletion have intermediate prognosis and AA with wild-type IDH have the worst prognosis and share many molecular alterations with glioblastoma. Treatment of noncodeleted AA based on preliminary results from the CATNON clinical trial consists of maximal safe resection followed by radiotherapy with post-radiotherapy temozolomide (TMZ) chemotherapy. The role of concurrent TMZ and whether IDH1 subgroups benefit from TMZ is currently being evaluated in the recently completed randomized, prospective Phase III clinical trial, CATNON.

Network analysis of microRNAs, transcription factors, target genes and host genes in human anaplastic astrocytoma.

Numerous studies have investigated the roles played by various genes and microRNAs (miRNAs) in neoplasms, including anaplastic astrocytoma (AA). However, the specific regulatory mechanisms involving these genes and miRNAs remain unclear. In the present study, associated biological factors (miRNAs, transcription factors, target genes and host genes) from existing studies of human AA were combined methodically through the interactions between genes and miRNAs, as opposed to studying one or several. Three regulatory networks, including abnormally expressed, related and global networks were constructed with the aim of identifying significant gene and miRNA pathways. Each network is composed of three associations between miRNAs targeted at genes, transcription factors (TFs) regulating miRNAs and miRNAs located on their host genes. Among these, the abnormally expressed network, which involves the pathways of previously identified abnormally expressed genes and miRNAs, partially indicated the regulatory mechanism underlying AA. The network contains numerous abnormal regulation associations when AA emerges. By modifying the abnormally expressed network factors to a normal expression pattern, the faulty regulation may be corrected and tumorigenesis of AA may be prevented. Certain specific pathways are highlighted in AA, for example PTEN which is targeted by miR-21 and miR-106b, regulates miR-25 which in turn targets TP53. PTEN and miR-21 have been observed to form feedback loops. Furthermore, by comparing and analyzing the pathway predecessors and successors of abnormally expressed genes and miRNAs in three networks, similarities and differences of regulatory pathways may be identified and proposed. In summary, the present study aids in elucidating the occurrence, mechanism, prevention and treatment of AA. These results may aid further investigation into therapeutic approaches for this disease.

A Phase II Study of Antineoplastons A10 and AS2-1 in Adult Patients with Primary Brain Tumors—Final Report (Protocol BT-09)

Antineoplastons A10 and AS2-1 (ANP) are synthetic derivatives of glutamine, isoglutamine, and phenylacetic acid. In 1993, a phase II clinical trial program began according to protocols based on the initial protocol, BT-06, which was transferred from the National Institutes of Health (NIH). Protocol BT-09 was designed for different types of primary brain tumors in adults that were not curable by standard treatment. The study was designed as a single arm, two-stage, phase II trial of ANP as a monotherapy in a high-risk, poor-prognosis population. The total number of registered subjects was 40. The majority of patients were diagnosed with high-grade tumors (N = 33). In this group, 12 patients carried diagnosis of anaplastic astrocytoma (AA) and 11 patients of glioblastoma. In the group of low-grade tumors (N = 7), there were 6 cases of low-grade glioma, and 1 neurocytoma grade 2. A group of 12 patients did not receive any prior treatment, 12 patients had surgical resection only, 5 patients received radiation therapy (RT) only, and 11 patients received both RT and chemotherapy. The median duration of ANP was 16.6 weeks. The median dosage of A10 was 7.16 g/kg/d and AS2-1 was 0.27 g/kg/d. Responses were accessed by gadolinium-enhanced magnetic resonance imaging (MRI). Objective responses (OR) in all patients were 22.5% and in the AA group were 41.7% of patients. The median progression-free survival (PFS) in the AA group was 5.4 months. The median overall survival (OS) was 12.7 months and OS at 1 and 2 years was 54.5% and 45.5% correspondingly. The treatment was well-tolerated with reversible grade 3 and 4 toxicities in 35% of all patients (N = 40). In conclusion, the study reached efficacy endpoint and ANP was well-tolerated and compared favorably to the current treatment of AA.

Chemotherapeutic resistance in anaplastic astrocytoma cell lines treated with a temozolomide–lomeguatrib combination

The treatment of anaplastic astrocytoma (AA) is controversial. New chemotherapeutic approaches are needed for AA treatment. Temozolomide (TMZ) is one of the chemotherapeutic drugs for the treatment of AA. The cytotoxic effects of TMZ can be removed by the MGMT (O(6)-methylguanine-DNA methyltransferase) enzyme. Then, chemotherapeutic resistance to TMZ occurs. MGMT inhibition by MGMT inactivators (such as lomeguatrib) is an important anticancer therapeutic approach to circumvent TMZ resistance. We aim to investigate the effect of TMZ-lomeguatrib combination on MGMT expression and TMZ sensitivity of SW1783 and GOS-3 AA cell lines. The sensitivity of SW1783 and GOS-3 cell lines to TMZ and to the combination of TMZ and lomeguatrib was determined by a cytotoxicity assay. MGMT methylation was detected by MS-PCR. MGMT and p53 expression were investigated by real-time PCR after drug treatment, and the proportion of apoptotic cells was analyzed by flow cytometry. When the combination of TMZ-lomeguatrib (50μM) was used in AA cell lines, IC50 values were reduced compared to only using TMZ. MGMT expression was decreased, p53 expression was increased, and the proportion of apoptotic cells was induced in both cell lines. The lomeguatrib-TMZ combination did not have any effect on the cell cycle and caused apoptosis by increasing p53 expression and decreasing MGMT expression. Our study is a pilot study investigating a new therapeutic approach for AA treatment, but further research is needed.

Chemotherapy plus radiotherapy versus radiotherapy alone in patients with anaplastic glioma: a systematic review and meta-analysis

The aim of this study was to answer whether overall survival and progression-free survival are increased in patients with anaplastic glioma who are treated with radiotherapy plus chemotherapy as compared with those who treated with radiotherapy alone. Searches of the MEDLINE (PubMed), Embase and Cochrane Library from January 2001 to May 2012 for relevant trials were undertaken. Selected studies based on the following criteria: First, only randomized clinical trial of adjuvant radiotherapy plus chemotherapy versus radiotherapy alone was permitted. Second, overall survival and/or progression-free survival was compared with patients in the studies. Third, cases were medically confirmed of anaplastic glioma. 4 randomized clinical trials were found eligible for this article (involving a total of 963 patients). The meta-analysis showed a significant increase in overall survival in patients treated with radiotherapy plus chemotherapy (HR = 0.84, 95 % CI 0.72-0.98, P = 0.031). Results of our meta-analysis indicated that adjuvant chemotherapy played a beneficial role in the treatment for anaplastic gliomas. But the role of adjuvant chemotherapy in the treatment for anaplastic astrocytoma or anaplastic oligodendroglioma/anaplastic oligoastrocytoma still needs further large randomized trials to demonstrate.

Phase II trial of anti-epidermal growth factor receptor radioimmunotherapy in the treatment of anaplastic astrocytoma

The efficacy and safety of adjuvant radioimmunotherapy with 125I-labeled anti-epidermal growth factor receptor 425 murine antibody (125I-425 mAb) in patients with newly diagnosed anaplastic astrocytoma (AA) is evaluated in this single-institution phase II study. Patients with newly diagnosed and histologically proven AA were eligible. A total of 80 patients received three weekly intravenous injections of 1.8 GBq of 125I-425 mAb following surgery and radiation therapy to a median dose of 60 Gy. Median overall survival was the primary endpoint and the secondary endpoint was toxicity. The median age was 43 years (range 22–75 years), and the median Karnofsky Performance Status was 80 (range 50–100). The percentage of patients who underwent surgical debulking, radiation therapy, temozolomide, and nitrosourea-based chemotherapy are 57.5, 99, 25, and 25 % respectively. The overall median survival was 55.6 months (95 % CI 42.7–68.5 months). The 2- and 5-year survivals were 74 and 47 %, respectively. There was no grade 3 or higher toxicity with the administration of 125I-425 mAb. Treatment with 125I-425 mAb in newly diagnosed AA patients was safe and well tolerated. Survival benefits are encouraging and warrant further study.

Anaplastic Glioma

The treatment of anaplastic glioma (AG) varies depending on histopathology of the tumor, molecular markers, and individual patient characteristics. Maximal surgical resection is desirable for all types of AG if technically feasible, with an acceptable level of risk, and with the goal of preserving neurologic function. As opposed to the standard treatment of glioblastoma, based on a large, randomized, phase 3 trial, there is no accepted standard treatment for AG. Anaplastic astrocytoma (AA) is most often treated with radiotherapy (RT), with or without concomitant temozolomide (TMZ) and with or without adjuvant temozolomide. Rarely is AA treated with chemotherapy alone, although different treatment modalities are being evaluated in ongoing trials. The treatment of anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) is influenced by the 1p/19q status, as allelic co-deletion of chromosomes 1p and 19q predicts increased sensitivity to chemotherapy and prolonged survival. In contrast to the treatment of AA, carefully selected patients with AO and AOA may be treated with chemotherapy alone. Temozolomide has largely replaced PCV (procarbazine, CCNU, vincristine) as the chemotherapeutic agent for AO and AOA, largely due to greater tolerability and less potential for toxicity. However, whether temozolomide has similar efficacy to PCV has not been fully evaluated. Patients with AO and AOA with significant residual tumor after surgery, intractable seizures, and/or non co-deleted 1p/19q status are often treated with RT with or without concomitant chemotherapy and with or without adjuvant chemotherapy. There is no standard postoperative care for anaplastic ependymoma (AE). The efficacy of upfront versus delayed RT has not been evaluated. Surgery may be indicated for patients with recurrent AG. There may be benefit on overall survival, although this has not been clearly proven. Reoperation may also provide symptomatic relief and confirm the pathology, including differentiation of radiation necrosis from recurrent tumor. Confirmation of tumor grade is often important for enrollment in clinical trials, a reasonable treatment choice for patients with recurrent tumor. Treatment of recurrent AG often depends on prior treatments. Patients who have progressed after RT alone may be treated with temozolomide or PCV. Patients treated previously with chemotherapy alone may be treated with RT at time of progression. Dose-intense temozolomide, bevacizumab alone, or bevacizumab in combination with a cytotoxic agent are other treatment options. Focused radiation such as stereotactic radiosurgery has no proven role in treating recurrent AG. A number of other treatment modalities are currently under active investigation, including targeted molecular inhibitors, immunotherapies, convection enhanced delivery, and viral gene therapies. There is no standard treatment for recurrent AE. Most patients undergo re-resection followed by RT if RT was not previously given. Chemotherapy may be given, but there is no standard chemotherapeutic regimen. Ongoing trials are evaluating the role of bevicizumab and targeted molecular agents in the treatment of AE.

Convection-enhanced delivery of a transforming growth factor- 2 inhibitor trabedersen for recurrent high-grade gliomas: efficacy real or imagined?, in reference to Bogdahn et al. (Neuro-Oncology 2011;13:132-142)

Dr Bogdahn et al. reported on the convection-enhanced delivery (CED) of the transforming growth factor-β2 (TGF-β2) inhibitor trabedersen for recurrent high-grade glioma.1 The trial was designed as a randomized phase 2b study comparing two doses of trabedersen to chemotherapy, either temozolomide (TMZ) or procabazine-lomustine-vincristine (PCV). Several comments regarding the study I believe are warranted. Firstly, the trial was never properly powered to detect a difference in trabedersen dose vs. best standard chemotherapy. Notwithstanding this serious limitation, the trial was clearly negative with respect to recurrent glioblastoma. Much more problematic are the conclusions with respect to recurrent anaplastic astrocytoma (AA) in which the authors assert there is compelling evidence of trabedersen effectiveness to proceed to a randomized phase 3 trial (SAPPHIRE). Concerning in particular is the remarkably small numbers of recurrent AAs studied (39 randomized to 1 of 3 treatment arms) from which these conclusions are based. Furthermore, efficacy of trabedersen is based upon a secondary endpoint (progression-free survival at 14 months: PFS-14) not the prespecified primary endpoint (progression-free survival at 6 months: PFS-6). To my knowledge, PFS-14 has never been validated as a glioma trial endpoint and, consequently, it is uncertain what this construct represents.2,3 Remarkably, from 1/3 to 2/3 of all patients with recurrent AA had not been treated with chemotherapy before study entry, creating differences in the treatment groups and in effect subdividing an already small group of patients into 2 separable populations (chemotherapy-experienced or -naive). At least in the United States, it would be highly unlikely to find such a chemotherapy-naive population, as TMZ is widely used in the upfront treatment of such tumors. How to assess a study performed in non-traditional neuro-oncology centers where standards of care likely differ from European and U.S. centers are challenging, though admittedly is becoming more common as financial and regulatory considerations shift new drug studies offshore. What was not a study inclusion criteria, prespecifying that all recurrent AA patients had been treated with either PCV or TMZ would have resulted in more comparable subgroups, a design utilized in the German NOA-04 recurrent anaplastic glioma trial.4 Additionally and not stated was the salvage therapy employed after study treatment failure, a highly relevant issue with respect to recurrent AA, as salvage therapy has a significant impact in overall survival. Confusingly, the recurrent AA treatment groups had no significant difference in tumor control at 6 months (presumably though not explicitly stated PFS-6) but did differ with respect to median duration of response favoring trabedersen. There also was an improvement favoring low-dose trabedersen in median time to progression. Notwithstanding the considerable investment in the trial, no central radiology review was performed, a process that is blinded to treatment allocation and without bias (unlike investigator-assessed response determinations). Without specifying endpoint definitions these descriptions appear confusing and contradictory. Not mentioned lastly is the prior lack of success utilizing CED as a means of drug delivery exemplified by the PRECISE and TransMID trials for recurrent glioblastoma. The failure of these trials begs the question of whether CED is a practical or feasible drug delivery system. What appears needed based upon this study is a properly designed and statistically powered phase 2 study of trabedersen in the treatment of recurrent AA that utilizes acceptable endpoints and a similarly pretreated cohort of patients. This critique is not intended to diminish the considerable effort by the study investigators but rather draw attention to prematurely moving investigational agents into randomized phase 3 trials without first establishing robust phase 2 trial results.

Temozolomide (Temodar)

Temozolomide, an oral alkylating agent, is a commonly used medicine in the treatment of anaplastic astrocytoma and glioblastoma multiforme. This paper will present the mechanism of action as well as the clinical role for this chemotherapeutic drug.

Prognostic significance of surgery and radiation therapy in cases of anaplastic astrocytoma: retrospective analysis of 170 cases

The purpose of this retrospective study was to estimate the prognostic impact of treatment parameters for 170 patients with anaplastic astrocytoma (AA). Survival outcome and prognostic factors were analyzed for 170 patients with AA. In the multivariate analysis, site of lesion (frontal or parietal lobe, p = 0.002), extent of surgery (total or subtotal resection, p = 0.001), Karnofsky Performance Scale status (0-2, p = 0.021), age (< or = 50 years, p = 0.024), and total dose of radiation therapy (> 60 Gy, p = 0.029) were significant favorable prognostic factors. In the analysis of groups according to extent of surgery, patients who underwent total or subtotal resection had a significantly more favorable prognosis than did patients who underwent partial resection or biopsy (5-year survival rate 54.0% for total or subtotal resection compared with 17.5% for partial resection or biopsy; median survival time [MST] 62.6 months compared with 22.9 months [p < 0.0001, log-rank test]; hazard ratio [HR] 0.67; and 95% confidence interval [CI] 0.52-0.85 [p = 0.001]). In the analysis of groups according to total radiation dose, the group of patients who received doses greater than 60 Gy had a significantly more favorable prognosis than did the group who received 60 Gy or less (5-year survival rate 45.0% for patients who received doses greater than 60 Gy compared with 21.1% for those receiving 60 Gy or less; MST 48.9 months compared with 21.6 months [p = 0.0006, log-rank test]; HR 0.96; 95% CI 0.93-0.99 [p = 0.029]). The most important parameter in the treatment of AA was extent of surgery, and total radiation dose was the second most important factor. Resection of as much of the tumor as possible and delivery of a total radiation dose of greater than 60 Gy seem to be required for local control of AA.

Anaplastic astrocytoma: Diagnosis, prognosis, and management

The designation of a tumor as anaplastic astrocytoma (AA) reflects a distinct histologic classification of malignant glioma characterized by an abundance of pleomorphic astrocytes with evidence of mitosis. Although these tumors are malignant, they have a better prognosis and a higher likelihood of response to treatment than glioblastoma. Despite advances in brain tumor imaging, making an accurate diagnosis requires the evaluation of tumor tissue and is essential for treatment planning. Currently, most patients undergo maximal surgical debulking of tumor followed by external beam radiation, often with subsequent adjuvant chemotherapy. However, despite the use of these treatment modalities, most tumors recur within a few years and these recurrent tumors are more refractory to subsequent therapies. This review examines the diagnosis, prognosis, and treatment of AAs. Ongoing clinical research investigations are also summarized, reflecting advances in our knowledge of the molecular pathogenesis of these tumors and providing hope for significant improvements in patient outcomes.

Management of Anaplastic Astrocytoma

Learning Objectives: After reading this article, the participant should be able to: 1. Provide an update on the incidence and clinical presentation and diagnosis of anaplastic astrocytoma. 2. Recall the genetics of anaplastic astrocytoma. 3. Describe the current treatment of newly diagnosed and recurrent anaplastic astrocytoma. 4. Describe the new approaches and future trends in the treatment of anaplastic astrocytoma.

RTOG 99-04: a phase-3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BudR for the treatment of anaplastic astrocytoma

RTOG 99-04: a phase-3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BudR for the treatment of anaplastic astrocytoma

Health-related quality of life in patients with anaplastic astrocytoma during treatment with temozolomide

One of the objectives of this phase II study was to determine whether temozolomide (TMZ) improved the health-related quality of life (HRQL) of patients with recurrent anaplastic astrocytoma (AA). HRQL was assessed at baseline (pretreatment) and every 4 weeks at each treatment cycle using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) (version 2.0) and the Brain Cancer Module (BCM20). Changes from baseline in the scores of seven preselected HRQL domains (role and social functioning, global QL, visual disorder, motor dysfunction, communication deficit and drowsiness) were determined at 6 months as well as prior to, and at the time of, disease progression. The significance of the changes was assessed by calculating statistical significance, effect sizes and the proportions of patients with improvement in their HRQL scores (changes of ⩾10 points). After 6 months of treatment, patients who were free of progression of disease reported either an improvement or maintenance of all the preselected HRQL domains scores. Patients with disease progression by 6 months usually experienced improvement in HRQL before progression, but there was a sharp decline in most of the preselected domains at progression. We conclude that treatment of recurrent AA with temozolomide is associated with significant HRQL benefits.

8 Phase III randomized study of radiotherapy plus PCV with or without BUdR for the treatment of anaplastic astrocytoma: RTOG 9404 interim report

8 Phase III randomized study of radiotherapy plus PCV with or without BUdR for the treatment of anaplastic astrocytoma: RTOG 9404 interim report

Radical Proposal for the Treatment of Malignant Astrocytoma

The traditional treatment for anaplastic astrocytoma (AAF) and glioblastoma multiforme (GBM) leads to local relapse. The recurring element is assumed to be previously radioresistant, reorganizing hypoxic cells that require up to three times the traditional photon irradiation dose for inactivation. We are proposing to coagulate the original lesion with high-dose precision brachytherapy, immediately followed by resection to save the patient from secondary effects of the necrotic region. The treatment then continues with adjuvant external beam radiation therapy to the local surrounding brain and concomitant chemotherapy. The approach inverts the traditional regimen. It has the virtue of being precise, avoiding secondary effects of the necrotic tumor, and satisfying accepted radiobiological principles.

Combined treatment of anaplastic astrocytoma (grade 3?4) with diacetyl-dianhydro-galactitol (DADAG)

Autoradiographic studies of labeled diacetyldianhydro-galactitol (DADAG) with tumor bearing animals revealed that the CNS accumulates high amounts of DADAG-derived radioactivity and the elimination from the brain seems to be relatively slow. This observation and the activity of DADAG against murine ependymoblastoma classified the drug as a promising agent for the treatment of malignant brain tumors. In a series of 30 evaluable consecutive patients who were operated on for anaplastic astrocytomas, DADAG has been applied during and subsequent to postoperative radiotherapy. No severe toxicity occurred. Survivals were compared with a group of patients who got irradiation alone. Statistical analysis did not show significantly better survivals in the DADAG treated group: median value was 46.5 weeks, p = 0.232.