NUOVA CURA 'AFFAMA' CELLULE NEL CERVELLO E NE BLOCCA CRESCITA

18 March 2009

Parte da Bologna la sperimentazione clinica mondiale del cilengitide, una nuova terapia per combattere il glioblastoma, il più aggressivo dei tumori cerebrali.

L'unità operativa complessa di Oncologia Medica dell'ospedale Bellaria-Maggiore di Bologna, diretta dalla dott.ssa Alba Brandes, sarà il primo centro al mondo a testare su pazienti umani il farmaco cilengitide, studiato per affamare il tumore diminuendo l'afflusso di sangue alle cellule maligne. Nel trial clinico saranno coinvolti i principali ospedali specializzati nella cura delle neoplasie encefaliche.

Cilengitide agisce inibendo le integrine, proteine che favoriscono la vascolarizzazione tumorale, portando il nutrimento e l'ossigeno necessari al cancro per crescere: l'azione del nuovo farmaco contrasta la capacità espansiva e metastatica del glioblastoma, impedendogli di colonizzare altre zone del cervello.

Cilengitide sarà dunque usato per la prima volta in Italia nella sperimentazione clinica di fase III in svolgimento a Bologna e condotta sotto il coordinamento dell'Eortc (European Organisation for Research and Treatment of Cancer).

La dottoressa Brandes spiega che cilengitide sarà associato ai trattamenti chemio e radioterapici già in uso, come quelli con temozolomide e radioterapia, in maniera da rendere il tumore più debole e vulnerabile all'attacco delle cure classiche.

L'esperta spiega che lo studio, partito recentemente, prevede che il tumore cerebrale, dopo essere stato asportato chirurgicamente, sia valutato a livello centralizzato in Europa in termini di caratteristiche genetiche e in particolare per lo stato di metilazione di un gene chiamato MGMT.

Queste le modalità di svolgimento dell'indagine clinica. Si formeranno due gruppi di pazienti in modo casuale: al primo gruppo di controllo verrà somministrata la chemio-radioterapia standard per 8 mesi, mentre al secondo verrà aggiunto a queste cure tradizionali il cilengitide per un periodo di 18 mesi.

Per controllare l'efficacia delle diverse terapie, le persone verranno sottoposte ogni due o tre mesi a una risonanza magnetica cerebrale. In questo modo, afferma la dottoressa Brandes, il medico potrà valutare se continuare o meno con quello specifico trattamento sulla base della risposta ottenuta.

È importantissimo sapere per tempo quali persone siano o meno portatori di un gene metilato coinvolto nel glioblastoma: per questo motivo, ricorda la Brandes, si deve immediatamente poter analizzare le caratteristiche genetiche del tessuto tumorale ottenuto dall'intervento d'asportazione, prima di iniziare la terapia sperimentale.

L'oncologa italiana coordina per il nostro paese questo studio mondiale, che potrebbe segnare una svolta decisiva nella guerra al glioblastoma: la dottoressa Brandes è tra i massimi esperti mondiali di tumori al cervello, è membro dell'Eortc e presidente del Gicno (Gruppo Italiano Cooperativo di neuro-oncologia).

Commento Personale: Con tutto l’ottimismo che posso metterci dire che la Cilengitide è una “svolta” nella guerra al glioblastoma mi sembra, francamente, un pò esagerato alla luce dei risultati ottenuti sin’ora (specialmente nei recidivanti). Innanzitutto occorre ricordare che questa sperimentazione è riservata ai nuovi diagnosticati e, pertanto, saranno poche le persone che saranno così “fortunate” da sapere dell’esistenza di questa nuova sperimentazione una volta diagnosticati di GBM. La sperimentazione, inoltre, è riservata esclusivamente a coloro i quali hanno l’enzima MGMT metilato, che andrà controllato dall’anatomopatologo immediatamente dopo la resezione chirurgica. In realtà presto ne verrà aperta un’altra, di sperimentazione, riservata anche a chi ha il gene MGMT non metilato. Tuttavia, per questi ultimi, il vantaggio della Cilengitide non è stato dimostrato,quindi mi sento di escluderlo per questa categoria di pazienti.

Source ASCA, ITALIA SALUTE

Brain cancer linked to youngsters using cellphones

17 March 2009

An international group of scientists is calling on Canada and other countries to bring in tougher safety standards for cellphone use after a Swedish team found a fivefold elevated risk of malignant brain tumours in children who begin using mobile phones before the age of 20.

The plea — and the science underlying it — is published in the forthcoming edition of Pathophysiology, devoted to peer-reviewed research about the biological effects of the global explosion of wireless technologies and devices like cellphones, cordless phones, wireless Internet and cell towers.

The findings of 15 studies from health researchers in six different countries, looking at the effects of electromagnetic fields and radio frequency radiation on living cells and on the health of humans, should jolt government agencies into action as a precautionary measure, Dr. David Carpenter, director of the Institute for Health & the Environment at the University at Albany, and one of the co-authors, said in an interview.

"What stands out is the consistency of the association of exposure and disease. The evidence, as I see it, is sufficiently strong that there needs to be public warnings, there needs to be establishments of exposure guidelines and that the present guidelines — in Canada, the United States or anyone else — are not protective of human health.

"I see us facing a major problem in the future because of the fact that young children are on cellphones constantly, and we may be setting ourselves up for an epidemic of brain cancer, the same thing we did with cigarette smoking and lung cancer."

According to Columbia University physiology professor Martin Blank, who edited the special issue, the laboratory studies "point to significant interactions" of both power frequency and radio frequency with cellular components, especially DNA.

The epidemiological studies "point to increased risk" of developing certain cancers associated with long-term exposure to radio frequency, he said.

Dr. Lennart Hardell is among the scientists who contributed to the special edition of the journal. The oncologist from Sweden's University Hospital found that after one or more years of cellphone use, there is a 5.2-fold elevated risk of malignant brain tumour in children who begin using mobile phones before the age of 20 years; the odds for other ages was 1.4.

"There should be special precaution for children and young persons about the use of mobile phones," Hardell said in an interview.

In Canada, 71 per cent of youth between the ages of 12 and 19 have a cellphone, according to new data compiled by Toronto-based Solutions Research Group. The penetration nears 80 per cent for this age bracket in Toronto and Vancouver, where cells are seen as an essential social tool as well as a matter of safety for parents, according to the research firm specializing in the youth market.

Solutions Research Group estimates that among nine- to 12-year-olds, one in four own cellphones. Also, their research shows 70 per cent of mothers with tweens share the cellphone with their kids occasionally for calls, texts or games.

Overall, there are 21.5 million Canadian wireless phone subscribers, representing a national wireless penetration rate of 67 per cent. And half of all phone connections in Canada are now wireless, according to the Canadian Wireless Telecommunications Association.

A spokesman from that agency, Marc Choma, said these subscribers, including parents of younger users, need to look at all the evidence about the safety of cellphones rather than cherry-picking a few.

"You have to look at the overwhelming amount of research that is out there. It's been done for decades now, and you have vast amounts of scientists around the world that have been studying this issue, and you can't just look at one study or you can't just look at two studies. You have to look at in the totality of all the work that's out there."

Government agencies responsible for compiling and analyzing this body of work — including Health Canada and the World Health Organization — "continue to say that the evidence that is out there that has been reviewed for years and years and years, that there is no demonstrated risk for human health," said Choma.

But Toronto Public Health last year recommended parents take precautions to minimize any potential risks to their children from cellphone use, acknowledging the "uncertainty in the science on health risks from cellphone use, particularly where it concerns children."

After the agency released its position last July on cellphone use and kids, Health Canada issued a statement, reaffirming that the department "currently sees no scientific reason to consider the use of cellphones as unsafe. There is no convincing evidence of increased risk of disease from exposure to radio frequency electromagnetic fields from cellphones."

Health Canada was not available Monday to comment on the latest research.

In a statement Monday, Toronto Public Health said it's "important that the public is aware of the ongoing debate and research into this area, however inconclusive. Toronto Public Health will continue to monitor emerging research addressing health risks associated with cellphone use, and our position will be informed by any significant new information."

Source Calgary Herald

Antigenics’ Oncophage Cancer Vaccine Receives European Orphan Drug Designation for Brain Cancer

10 March 2009

Antigenics Inc. today announced that Oncophage® (vitespen) has been granted a positive recommendation for orphan drug designation for the treatment of glioma by the Committee for Orphan Medical Products (COMP) of the European Medicines Agency (EMEA). This designation provides Antigenics with, among other benefits, 10 years of potential market exclusivity if the product is approved for marketing in the European Union (EU).

This is the second indication for which the EMEA has granted orphan drug status to Oncophage. In April 2005, Oncophage received orphan drug designation in the European Union for the treatment of renal cell carcinoma (kidney cancer). Subsequently, Antigenics submitted a Marketing Authorization Application (MAA) to the EMEA in October 2008 requesting approval for Oncophage in earlier-stage, localized renal cell carcinoma.

“We are committed to supporting the evaluation of Oncophage in patients diagnosed with glioma, as this remains a life-threatening disease with limited treatment options,” stated Garo Armen, PhD, chairman and CEO of Antigenics. “Furthermore, orphan drug status has the potential to accelerate the development of Oncophage in this patient population, which is critical given the poor survival rates.”

The EMEA regulation on orphan medicinal products is designed to promote the development of drugs, which may provide significant benefit to patients suffering from rare diseases identified as “life-threatening or very serious.” In addition to potential 10-year EU market exclusivity following marketing approval, orphan drug status provides regulatory assistance, reduced regulatory fees associated with applying for marketing approval, and protocol assistance.

Source BusinessWire

MGMT methylation predicts glioblastoma response to temozolomide plus RT

9 March 2009

The benefits of adjuvant temozolomide with radiation therapy for glioblastoma persist through 5 years of follow-up, although long-term survival rates remain low. Methylation status of the methyl-guanine methyl transferase gene (MGMT) is an independent predictor of response to the combination treatment.

In The Lancet Oncology, published online on March 9, investigators report the final results of the European/Canadian EORTC-NCIC trial, which involved 573 patients ages 18 to 70 with newly diagnosed glioblastoma, WHO grade IV. Patients were randomized to radiation therapy (n = 286) or radiation plus temozolomide (n = 287). Radiotherapy comprised 60 Gy given in 30-day fractions of 2 Gy. Temozolomide was administered at 75 mg/m² daily for up to 49 days, followed by up to six cycles of temozolomide, 150-200 mg/m² for 5 days every 28 days.

The original 2-year analysis showed survival of 27.2% in the combined therapy group versus 10.9% in the radiation alone group. At 5 years, mortality was 89% with temozolomide and 97% with radiation alone. All prognostic subgroups benefited from combined therapy, but the largest gain occurred in those with the most favorable characteristics, whose survival at 5 years was 28%. The hazard ratio for death in the temozolomide group relative to the radiotherapy group was 0.63 (p < 0.001).

"Nevertheless," lead author Dr. Roger Stupp at the University of Lausanne, Switzerland, and fellow researchers report, "most patients successfully treated with combined therapy eventually had tumor recurrence and died."

Among 226 patients for whom the methylation status of the MGMT promoter was determined, this factor turned out to be the strongest predictor of survival (HR 0.49, p = 0.001). Median survival was nearly doubled in the combined therapy group among those with methylated MGMT (23.4 months vs 12.6 months).

At this point, cure of glioblastoma is still "not possible," the researchers state. "Rational choice of drugs, mechanism-based translational research, and systematic assessment of new targets and drugs are needed to improve outcome for patients with glioblastoma."

Source Lancet Oncology

Is my chemo working? Scans may give faster answer

4 March 2009

When Mike Stevens learned his lungs were riddled with cancer, it took only a week to start chemotherapy — but six weeks to find out if it was doing any good.

"You're going through all this suffering and stuff and you want to know, am I going to survive? Is this stuff working?" said Stevens, 48, of La Jolla, Calif. "Your whole life is in sort of a limbo."

Doctors typically must wait weeks or months to see if a treatment is shrinking tumors or at least halting their growth. But researchers are exploring a new use for medical imaging that could shorten the stay in purgatory, possibly revealing within a few days whether chemo is working.

That speed could save both lives and money. It would allow doctors to switch more quickly from an ineffective drug to a different one, and save health care dollars by waving doctors off expensive but futile treatments.

The same approach may also prove useful for monitoring radiation therapy.

This experimental imaging relies on a familiar hospital workhorse: PET scans, typically used for things like detecting cancer or revealing the effects of a heart attack. Unlike CT scans or MRIs, PET scans can show a tumor's internal activity, not just its size.

When used to assess the effects of cancer treatment, it can reveal inside information about what the therapy is doing to a tumor even when there's no outward sign.

To do a PET scan, doctors inject a patient with a radioactive substance that shows up on the scan in places where certain processes are happening — like hungry cancer cells gobbling up a lot of blood sugar. Think of it as looking around your neighborhood late at night for light in bedroom windows to see who is still awake.

Many cancer patients get PET scans now to assess their disease before treatment, or to spot recurrences later on. But except for lymphoma, PET scans aren't routinely used to get a quicker answer on how cancers are responding to therapy.

The new research tests both standard PET scans and a newer approach that involves injecting a different tracer substance.

The standard scan, which looks for blood sugar usage, has gotten good results in tests with a variety of tumors including breast, prostate, colorectal and esophageal cancers, said Dr. Steven Larson of the Memorial Sloan-Kettering Cancer Center in New York.

"I think it's going to be extremely valuable for most tumors where there are effective treatments," he said. Some experiments have revealed chemo's effects within 10 days to two weeks.

As a practical matter, the goal of researchers is to convince federal regulators to cover the procedure under Medicare and Medicaid, which would open the door to routine use. That might take two or three years, he said.

Farther out on the research horizon is a PET scan that uses injections of a different radioactive material and has revealed chemotherapy's impact even faster. Larson figures it will be especially useful for assessing newer drugs that aim to stop a patient's cancer from growing rather than killing the tumor.

This scan is called FLT PET, after radioactive fluorothymidine. These scans show whether cancer cells are dividing. Uncontrolled division is a hallmark of active cancer, and stopping that division should be an early effect of successful chemotherapy.

"Our hope ... is you might be able to give a single dose of a chemotherapy agent and within a day or two figure out whether the tumor is going to respond," says Dr. Michael Graham of the University of Iowa.

If the tumor doesn't respond, doctors would "go on to Plan B," he said. "This is really ... giving us the ability to tailor the therapy to the disease."

Research into FLT PET is still in the early stages. Graham said there are maybe a dozen published human studies so far, most involving too few patients to draw a firm conclusion.

One report that impressed him involved 28 patients in Korea who were treated for advanced lung cancer — just like Stevens, who had to wait six weeks to learn whether it was working. The researchers reported that just one week after treatment began, they could tell with 93 percent certainty which patients would eventually respond to the drug and which would not.

In a much smaller study at the University of Wisconsin in Madison, seven patients with acute myeloid leukemia were scanned at various times during a week of aggressive chemotherapy. Normally, doctors wait a month after chemo is stopped to see if it worked. But the FLT PET scans offered an answer as soon as a day after treatment started.

"It's always hard to get too excited about a study that just involves seven people," said Dr. Mark Juckett, one of the authors. But "in these few patients, it looked like we could predict those who were going to respond well to chemotherapy and those who weren't."

Other preliminary studies suggest the new PET technology might be useful in gauging treatment for breast and brain cancers as well as lymphoma. Graham figures there's a good chance FLT PET scans will become routine for assessing therapy in the next 10 years. "It's a terrible waste of money to spend thousands and thousands of dollars on these patients when it doesn't do any good," he said.

Graham, president-elect of the Society of Nuclear Medicine, has been involved in discussions between the society and drug companies about incorporating FLT PET in their studies of experimental cancer drugs.

The hope is that, over time, FLT PET would prove reliable for giving a faster answer on whether an experimental treatment is working. That would save companies a lot of money, because they could spot ineffective drugs more quickly and not waste further research on them. And the drug company research would produce data to help persuade federal regulators to approve FLT PET for use in tracking therapy.

Dr. Samuel C. Blackman of pharmaceutical giant Merck & Co. said he couldn't comment on the specifics of talks with the nuclear medicine group, but he said, "We're definitely enthusiastic about FLT PET" for cancer drug research.

Mike Stevens, the lung cancer patient, has seen his disease held generally stable by continuing chemotherapy since 2005. And along with the scientists, he also likes the idea of an earlier end to the limbo of not knowing whether a new treatment is working.

"It's like having a rope tied around you and you're leaning over a canyon at about a 45-degree angle, and you don't know if someone is going to pull you back in, or let go of it," he said. "If you get that encouragement earlier on that you're doing well ... you've got something to fight for."

Source Clinical Trials

Independent association of extent of resection with survival in patients with malignant brain astrocytoma

2 January 2009

Independent association of extent of resection with survival in patients with malignant brain astrocytoma.

McGirt MJ, Chaichana KL, Gathinji M, Attenello FJ, Than K, Olivi A, Weingart JD, Brem H, Quiñones-Hinojosa AR.

Department of Neurosurgery and Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

OBJECT: With recent advances in the adjuvant treatment of malignant brain astrocytomas, it is increasingly debated whether extent of resection affects survival. In this study, the authors investigate this issue after primary and revision resection of these lesions. METHODS: The authors retrospectively reviewed the cases of 1215 patients who underwent surgery for malignant brain astrocytomas (World Health Organization [WHO] Grade III or IV) at a single institution from 1996 to 2006. Patients with deep-seated or unresectable lesions were excluded. Based on MR imaging results obtained < 48 hours after surgery, gross-total resection (GTR) was defined as no residual enhancement, near-total resection (NTR) as having thin rim enhancement of the resection cavity only, and subtotal resection (STR) as having residual nodular enhancement. The independent association of extent of resection and subsequent survival was assessed via a multivariate proportional hazards regression analysis. RESULTS: Magnetic resonance imaging studies were available for review in 949 cases. The mean age and mean Karnofsky Performance Scale (KPS) score at time of surgery were 51 +/- 16 years and 80 +/- 10, respectively. Surgery consisted of primary resection in 549 patients (58%) and revision resection for tumor recurrence in 400 patients (42%). The lesion was WHO Grade IV in 700 patients (74%) and Grade III in 249 (26%); there were 167 astrocytomas and 82 mixed oligoastrocytoma. Among patients who underwent resection, GTR, NTR, and STR were achieved in 330 (35%), 388 (41%), and 231 cases (24%), respectively. Adjusting for factors associated with survival (for example, age, KPS score, Gliadel and/or temozolomide use, and subsequent resection), GTR versus NTR (p < 0.05) and NTR versus STR (p < 0.05) were independently associated with improved survival after both primary and revision resection of glioblastoma multiforme (GBM). For primary GBM resection, the median survival after GTR, NTR, and STR was 13, 11, and 8 months, respectively. After revision resection, the median survival after GTR, NTR, and STR was 11, 9, and 5 months, respectively. Adjusting for factors associated with survival for WHO Grade III astrocytoma (age, KPS score, and revision resection), GTR versus STR (p < 0.05) was associated with improved survival. Gross-total resection versus NTR was not associated with an independent survival benefit in patients with WHO Grade III astrocytomas. The median survival after primary resection of WHO Grade III (mixed oligoastrocytomas excluded) for GTR, NTR, and STR was 58, 46, and 34 months, respectively. CONCLUSIONS: In the authors' experience with both primary and secondary resection of malignant brain astrocytomas, increasing extent of resection was associated with improved survival independent of age, degree of disability, WHO grade, or subsequent treatment modalities used. The maximum extent of resection should be safely attempted while minimizing the risk of surgically induced neurological injury.

Commento Personale: Uno studio interessante che dimostra come attraverso le nuove tecniche chirurgiche, a seconda del tipo di resezione ottenuta (totale, quasi totale o subtotale), si amplifica o diminuisce la sopravvivenza dei malati con GBM. In particolare una resezione totale ha garantito una mediana di sopravvivenza di 13 mesi rispetto agli 11 di chi ha avuto una resezione parziale e agli 8 mesi di coloro i quali hanno ricevuto una resezione subtotale. Lo stesso miglioramento della sopravvivenza lo si ottiene anche alla seconda resezione chiururgica e si evidenzia come, in quest’ultimo caso, la resezione sia da preferire solo se totale o pressochè quasi totale per garantire un aumento della sopravvivenza.

Source J Neurosurg. 2009 Jan;110(1):156-62

European Commission and United States Food and Drug Administration (FDA) Both Approve New Options for Patients With Certain Primary Brain Tumors

3 March 2009

Schering-Plough Corporation today announced that the European Commission and the US FDA both approved the intravenous (IV) formulation of temozolomide as an alternative to the already approved oral form of the drug. Temozolomide is marketed as TEMODAL(R) in the EU and as TEMODAR(R) in the US. The EU Commission Decision was based on the positive opinion from the European Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) in November 2008. On January 22, 2009, the Commission approved a sachet packaging presentation for TEMODAL Capsules. This new presentation provides greater patient convenience and flexibility. On February 17, 2009, the Commission approved an IV formulation of TEMODAL. On February 27, 2009, Schering-Plough received approval from the US FDA for the TEMODAR IV formulation.

TEMODAL is a chemotherapy agent approved in the EU for treatment of patients with newly diagnosed glioblastoma multiforme (GBM) concomitantly with radiotherapy and subsequently as monotherapy, and for patients with malignant gliomas, such as GBM or anaplastic astrocytoma (AA), showing recurrence or progression after standard therapy. In the US, TEMODAR is approved for the treatment of adult patients with newly diagnosed GBM concomitantly with radiotherapy and then as maintenance treatment, as well as for refractory AA, i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

"TEMODAR is a well recognized, effective treatment for patients with newly diagnosed GBM. The newly approved IV formulation of TEMODAR provides patients with an important alternative method of administration, and the European TEMODAL sachet presentation offers flexibility and a convenient alternative form of packaging," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "These two new options recognize Schering-Plough's commitment to providing effective treatments in a variety of presentations for specific patient needs and patient convenience."

Commento Personale: E’ stato approvato l’utilizzo del Temodal anche per via endovenosa aggiungendo ulteriore flessibilità per tutti i pazienti affetti da glioblastoma multiforme. Ora non sò con che tempi, francamente, gli ospedali italiani si possano adeguare a questa novità. Sappiate, tuttavia, che i malati ora hanno il diritto di valutare anche l’utilizzo del Temodal, oltre che per via orale, per via endovenosa.

Source PrNewswire

Surveyed Oncologists Indicate that Avastin has Advantages over Temodar/Temodal in Increasing Overall Survival of High-Grade Glioma

9 March 2009

Drug That Improves Survival, When Added to Temodar/Temodal, Would Earn a 65 Percent Patient Share in the U.S. and a 30 Percent Patient Share in Europe in Newly Diagnosed Glioblastoma Multiforme, According to a New Report from Decision Resources.

Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that surveyed oncologists identify a therapy's effect on overall survival as the attribute that most influences their prescribing decisions in high-grade glioma. Clinical data and the opinions of interviewed thought leaders indicate that Roche/Genentech/Chugai's Avastin has advantages in this attribute over Schering-Plough's Temodar/Temodal (temozolomide), the sales-leading agent in the market.

The new report entitled High-Grade Glioma: Prolonged Survival over Temozolomide Will Be Integral to Market Success finds that a therapy, when added to temozolomide, that increases median overall survival compared with temozolomide alone would earn a 65 percent patient share in the United States and a 30 percent share in Europe in newly diagnosed glioblastoma multiforme, according to surveyed U.S. and European oncologists.

In 2008, Decision Resources' proprietary clinical gold standard for high-grade glioma was Avastin. Although Avastin is not formally approved for the treatment of high-grade glioma, the drug is widely prescribed off-label as a result of promising Phase II clinical trial data. Based on expert opinion, Avastin will retain clinical gold standard status through 2017, owing to its high efficacy.

"Avastin emerges as our gold standard because of its efficacy, the attribute surveyed oncologists rated as the most important in treating high-grade glioma," said Decision Resources Analyst Ramya Kollipara, Ph.D. "Because the prognosis for high-grade glioma patients is so poor, interviewed thought leaders welcome Avastin's entry into this market because of its high efficacy, despite its associated side effects and less convenient delivery."

About the Report

High-Grade Glioma: Prolonged Survival over Temozolomide Will Be Integral to Market Success is a DecisionBase 2009 report. DecisionBase 2009 is a decision-support tool that provides in-depth analysis of unmet need, physician expectations of new therapies and commercial dynamics to help pharmaceutical companies optimize their investments in drug development.

The report can be purchased by contacting Decision Resources. Members of the media may request an interview with an analyst.

About Decision Resources

Decision Resources (www.decisionresources.com) is a world leader in market research publications, advisory services and consulting designed to help clients shape strategy, allocate resources and master their chosen markets. Decision Resources is a Decision Resources, Inc. company.

Commento Personale: Questo dimostra come l’Avastin sia già il “gold standard” nei pazienti nuovi diagnosticati affiancato, magari, al Temodal negli Stati Uniti. E’ quindi necessario richiedere ed ottenere questo farmaco già in Italia per tutti i pazienti. Considerati i tempi di adeguamento lentissimi del nostro Paese (ci vorranno ancora molti anni perchè venga utilizzato in modo standard) solo dietro esplicita richiesta agli oncologi più importanti (Riccardo Soffietti a Torino, Gaetano Finocchiaro a Milano per citarne alcuni) oggi si riuscirà ad ottenere questo farmaco anche nel nostro Paese. E’ di ieri la notizia che l’FDA americana, l’agenzia del farmaco locale, discuterà della approvazione dell’Avastin in USA come terapia ufficiale per il glioblastoma il prossimo 31 Marzo.

Source The Earth Times

Mobile phone base stations-Effects on wellbeing and health

2 March 2009

Kundi M, Hutter HP.

Institute of Environmental Health, Center for Public Health, Medical University of Vienna, Kinderspitalgasse 15, A-1095 Vienna, Austria.

Studying effects of mobile phone base station signals on health have been discouraged by authoritative bodies like WHO International EMF Project and COST 281. WHO recommended studies around base stations in 2003 but again stated in 2006 that studies on cancer in relation to base station exposure are of low priority. As a result only few investigations of effects of base station exposure on health and wellbeing exist. Cross-sectional investigations of subjective health as a function of distance or measured field strength, despite differences in methods and robustness of study design, found indications for an effect of exposure that is likely independent of concerns and attributions. Experimental studies applying short-term exposure to base station signals gave various results, but there is weak evidence that UMTS and to a lesser degree GSM signals reduce wellbeing in persons that report to be sensitive to such exposures. Two ecological studies of cancer in the vicinity of base stations report both a strong increase of incidence within a radius of 350 and 400m respectively. Due to the limitations inherent in this design no firm conclusions can be drawn, but the results underline the urgent need for a comprehensive investigation of this issue. Animal and in vitro studies are inconclusive to date. An increased incidence of DMBA induced mammary tumors in rats at a SAR of 1.4W/kg in one experiment could not be replicated in a second trial. Indications of oxidative stress after low-level in vivo exposure of rats could not be supported by in vitro studies of human fibroblasts and glioblastoma cells. From available evidence it is impossible to delineate a threshold below which no effect occurs, however, given the fact that studies reporting low exposure were invariably negative it is suggested that power densities around 0.5-1mW/m(2) must be exceeded in order to observe an effect. The meager data base must be extended in the coming years. The difficulties of investigating long-term effects of base station exposure have been exaggerated, considering that base station and handset exposure have almost nothing in common both needs to be studied independently. It cannot be accepted that studying base stations is postponed until there is firm evidence for mobile phones.

PMID: 19261451 [PubMed - as supplied by publisher]

Source Pathophysiology. 2009 Mar 2

Toxin-nanoparticle combo inhibits brain cancer invasion while imaging tumors

18 January 2009

Working with a nanoparticle designed to target and image glioblastoma, a form of brain cancer, investigators at the University of Washington in Seattle have found that these same nanoparticles inhibit tumor cell invasion, one of the key events that leads to the metastatic spread of cancer. The investigators have also determined how the nanoparticles exert this potentially beneficial effect.

Miqin Zhang, Ph.D., principal investigator of the Nanotechnology Platform for Pediatric Brain Cancer Imaging and Therapy project, and her colleagues had shown previously (click here and here to see earlier stories) that chlorotoxin, a small peptide toxin produced by the death stalker scorpion, is highly effective as a tumor-targeting agent when chemically linked to a variety of nanoparticles. In this work, whose results appear in the journal Small, Dr. Zhang's team linked chlorotoxin to magnetic iron oxide nanoparticles, which can act as tumor imaging agents in conjunction with magnetic resonance imaging (MRI).

When added to glioblastoma cells growing in culture, the chlorotoxin-targeted nanoparticles were rapidly taken up by the tumor cells. This internalization occurs when chlorotoxin binds to a surface protein known as MMP-2 that is overexpressed by many highly invasive tumors, including glioblastoma. As a consequence of nanoparticle binding and internalization, the amount of MMP-2 remaining on the surface of the tumor cells drops significantly, which greatly reduces the invasive properties of the treated cells.

Quantifying this effect, the investigators showed that the nanoparticle produced a 98% inhibition of cell invasiveness. By way of comparison, invasiveness fell by less than 50% when cells were treated with chlorotoxin alone.

This work, which was detailed in the paper "Inhibition of tumor-cell invasion with chlorotoxin-bound superparamagnetic nanoparticles," was supported in part by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer. Investigators from the National Cancer Institute and Johns Hopkins University also participated in this study. An abstract of this paper is available at the journal's Web site. View abstract

Source NewsMedical.net

Gene May Lead To Early Onset Of Brain Tumor

27 January 2009

People with a particular gene variant may be more likely to develop brain tumors, and at an earlier age, than people without the gene, according to a study published in the January 27, 2009, print issue of Neurology®, the medical journal of the American Academy of Neurology.

The study involved 254 people with brain tumors and 238 people with no cancers. All those with tumors had glioblastoma multiforme, the most common type of brain cancer. People with this type of tumor survive an average of 12 to 15 months.

Through blood samples, researchers looked at the tumor suppressor TP53 gene. This gene acts as a tumor suppressor and is involved in preventing cancer.

People younger than 45 with brain tumors were more likely to have the Pro/Pro variant of the gene than older people with brain tumors or the healthy participants. A total of 20.6 percent of the young people with brain tumors had the gene variant, compared to 6.4 percent of the older people with brain tumors and 5.9 percent of the healthy participants.

"Eventually we may be able to use this knowledge to help identify people who have a higher risk of developing brain tumors at an early age. However the risk of this population remains low, even multiplied by three or four as shown here, because these brain tumors (glioblastomas) are infrequent in young people," said study author Marc Sanson, MD, PhD, of the French National Institute of Health and Medical Research (INSERM) in Paris, France.

The study was supported by the Public Assistance Hospitals of Paris.

Source Science Daily

Preservation of quality of life by preradiotherapy stereotactic radiosurgery for unresectable glioblastoma multiforme.

21 December 2006

Kong DS, Nam DH, Lee JI, Park K, Kim JH.

Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea.

OBJECT: The authors conducted a retrospective study to evaluate the efficacy of Gamma Knife surgery (GKS) followed by radiotherapy for the treatment of unresectable glioblastomas multiforme (GBMs) on patient survival and quality of life. METHODS: A total of 19 patients with unresectable GBMs located in eloquent areas of the brain were eligible for this study. Beginning in January 2002, 10 patients underwent GKS followed by fractionated radiotherapy. Nine patients who had undergone radiotherapy alone after biopsy-proven diagnosis served as the control group. The mean patient ages were 53 years and 56 years, respectively. Preoperative Karnofsky Performance Scale (KPS) scores were 80 (range 60-100) and 90 (range 50-100), respectively. The median margin dose for GKS was 12 Gy (9-16 Gy), and the total dose for radiotherapy was 60 Gy in 30 fractions. The mean follow-up duration was 7.2 months, the median patient survival time was 52 weeks (95% confidence interval [CI] 22-110.6 weeks) in the GKS group, and the median overall survival time was 28 weeks (95% CI 22.5-33.5 weeks) in the control group. The difference was not statistically significant (p = 0.0758). The estimated progression-free survival rate at 3 months was 75% in the GKS group and 45% in the control group (p = 0.082). The posttreatment KPS scores were either unchanged or improved in the GKS group, whereas it deteriorated by 20 or more points in six of nine patients of the control group (p = 0.004). CONCLUSIONS: Gamma Knife surgery prior to radiotherapy may be helpful in preserving patients' daily activities in the adjuvant management of unresectable GBM.

PMID: 18503347 [PubMed - in process]

Commento Personale: L’utilizzo di radiochirurgia stereotassica con Gamma Knife in pazienti non operabili seguita da radioterapia esterna tradizionale aiuta ad aumentare la sopravvivenza. Il gruppo di pazienti infatti trattati con entrambe le tecniche ha mantenuto una sopravvivenza mediana di 52 settimane contro 28 settimane nei pazienti trattati con sola radioterapia. Sebbene la sopravvivenza venga aumentata nei pazienti non operabili attraverso questa combinazione di radioterapie, essa rimane sempre decisamente bassa.

Source J Neurosurg. 2006 Dec

Cilengitide: Does It Really Represent a New Targeted Therapy for Recurrent Glioblastoma?

2 March 2009

TO THE EDITOR: Reardon et al1 are to be congratulated for their recently reported phase II trial of cilengitide for recurrent glioblastoma (GBM). I would like to make several comments regarding the report and the use of cilengitide to treat recurrent GBM. It is curious that Reardon et al compared their study results to those of the prior temozolomide (TMZ) trial2 for recurrent GBM, when it has become usual and customary in neuro-oncology trials involving the treatment of recurrent GBM to evaluate results on the basis of the aggregate phase II studies by Wong et al3 (pre-TMZ era) and Lambert et al4 (post-TMZ era). In both these studies, 15% progression-free survival at 6 months was demonstrated, providing a validated end point in trials of recurrent GBM, as opposed to response rates or overall survival. In addition, agents considered of interest for additional study in treating recurrent GBM require a 10% improvement in progression-free survival at 6 months (progression-free survival of at least 25%), a standard clearly not achieved in the cilengitide trial by Reardon et al. By this benchmark, the trial results are no more compelling than those of the recently reported trial of metronomic TMZas treatment for recurrent GBM.5 Viewed in this context, it is far from clear what advantage cilengitide offers over other agents previously studied for the treatment of recurrent GBM. The remarkable response and survival benefit seen with the administration of bevacizumab, with or without a cytotoxic,6,7 is a new complexity that has arisen in reporting results of phase II trials in recurrent GBM. Not reported in the cilengitide trial by Reardon et al was the number of patients treated with bevacizumab after treatment with cilengitide failed, a factor that likely affects overall survival by prolonging it. Early reports on the use of cilengitide in the adjuvant treatment of GBM suggest stratification by tumor methylguanine methyltransferase (MGMT) expression best defines a patient subpopulation likely to benefit from adjuvant cilengitide treatment.8 Patients with MGMT promoter methylation derive significant benefit from adjuvant cilengitide treatment. Reardon et al did not report response to salvage cilengitide as a function of MGMT expression, a probable biomarker predicting for response; this determination could permit selection of patients responsive to cilengitide. Lastly, the use of an intravenous agent like cilengitide— administered twice per week without interruption except in the case of disease progression or treatment-related toxicity—likely negatively impacts quality-of-life and medical economic issues not addressed by Reardon et al. These comments are not meant to diminish the significant efforts of Reardon et al in exploring a novel targeted agent in the treatment of recurrent GBM. Rather, they are intended to ask how new agents like cilengitide should be integrated, if at all, into the care and management of patients with GBM.

Marc C. Chamberlain

Department of Neurology and Neurological Surgery, University of Washington;

Fred Hutchinson Research Cancer Center; and Seattle Cancer Care Alliance, Seattle, WA

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Reardon DA, Fink KL, Mikkelsen T, et al: Randomized phase II study of cilengitide, an integrin-targeting argine-glycine-aspartic acid peptide, in recurrent glioblastoma. J Clin Oncol 26:5610-5617, 2008

2. Yung WK, Albright RE, Olson J, et al: A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83:588-593, 2000

3. Wong ET, Hess KR, Gleason MJ, et al: Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572-2578, 1999

4. Lamborn KR, Yung WK, Chang SM, et al: Progression-free survival: An important end point in evaluating therapy for recurrent high-grade gliomas. NeuroOncol 10:162-170, 2008

5. Perry JR, Rizek P, Cashman R, et al: Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: The “rescue” approach. Cancer 113:2152-2157, 2008

6. Vredenburgh JJ, Desjardins A, Herndon JE, et al: Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722-4729, 2007

7. Cloughesy TF, Prados MD, Mikkelsen T, et al: A phase II, randomized, non-comparative trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM). J Clin Oncol 26:91s, 2008 (suppl; abstr 2010b)

8. Stupp R, Goldbrunner R, Neyns B, et al: Phase I/IIa trial of cilengitide (EMD121974) and temozolomide with concomitant radiotherapy, followed by temozolomide and cilengitide maintenance therapy in patients (pts) with newly diagnosed glioblastoma (GBM). J Clin Oncol 25:75s, 2007 (suppl; abstr 2000) 

Source March 2, 2009 as 10.1200/JCO.2008.21.5871

Occupational exposure to magnetic fields and the risk of brain tumors

20 February 2009

Coble JB, Dosemeci M, Stewart PA, Blair A, Bowman J, Fine HA, Shapiro WR, Selker RG, Loeffler JS, Black PM, Linet MS, Inskip PD.

Division of Cancer Epidemiology and Genetics, Occupational and Environmental Epidemiology Branch, National Cancer Institute, Bethesda, MD; USA.

The authors investigated the association between occupational exposure to extremely low frequency magnetic fields (MF) and the risk of glioma and meningioma. Occupational exposure to MF was assessed for 489 glioma cases, 197 meningioma cases, and 799 controls enrolled in a hospital-based case-control study. Lifetime occupational history questionnaires were administered to all subjects and supplemented for 24% of jobs with job-specific questionnaires, or job modules, to obtain information on the use of electrically powered tools or equipment at work. Job-specific quantitative estimates for exposure to MF in milligauss (mG) were assigned using a previously published job exposure matrix (JEM) with modification based on the job modules. Jobs were categorized as <1.5 mG, 1.5 to <3.0 mG, and greater than or equal to 3.0 mG. Four exposure metrics were evaluated: 1) maximum exposed job; 2) total years of exposure above 1.5 mG; 3) cumulative lifetime exposure; and 4) average lifetime exposure. Odds ratios were calculated using unconditional logistic regression with adjustment for the age, gender and hospital site. The job modules increased the number of jobs with exposure equal to or greater than 3.0 mG from 4% to 7% relative to the JEM. No statistically significant elevation in odds ratios or trends in odds ratios across exposure categories was observed using four different exposure metrics for the three tumor types analyzed. Occupational exposure to magnetic fields assessed using job modules was not associated with an increase in the risk for glioma, glioblastoma or meningioma among the subjects evaluated in this study.

PMID: 19234232 [PubMed - as supplied by publisher]

Commento Personale: Similarmente a quanto appena pubblicato non esistono rischi statistici elevati di glioblastoma negli adulti che sono a contatto, per lavoro, con diversi range di campi magnetici a bassa frequenza.

Source Neuro Oncol. 2009 Feb 20

Cisplatinum and BCNU chemotherapy in primary glioblastoma patients

11 February 2009

Silvani A, Gaviani P, Lamperti EA, Eoli M, Falcone C, Dimeco F, Milanesi IM, Erbetta A, Boiardi A, Fariselli L, Salmaggi A.

Istituto Nazionale Neurologico Carlo Besta, Milan, Italy, silvani@....

Background The prognosis of patients with glioblastoma is very poor with a mean survival of 10-12 months. Currently available treatment options are multimodal, which include surgery, radiotherapy, and chemotherapy. However, these have been shown to improve survival only marginally in glioblastoma multiforme (GBM) patients. Methylated methylguanine methyltransferase (MGMT) promoter is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. Methods A retrospective analysis on 160 adult patients (>/=16 years) treated for histologically confirmed GBM between 2003 and 2005 at our Institution was performed. All patients were treated with conventional fractionated radiotherapy and a combined chemotherapy treatment with Cisplatin (CDDP) (100 mg/sqm on day 1) and carmustine (BCNU) (160 mg/sqm on day 2); the treatment was repeated every 6 weeks for five cycles. Toxicity, progression free survival and overall survival were assessed. Results The median number of chemotherapy cycles delivered to each patient was 5 (range 3-6), with no patients discontinuing treatment because of refusal or toxicity. Dose reduction was required in 16 patients (10%), and all patients completed radiotherapy, whereas 5 patients discontinued chemotherapy before completing all planned cycles for disease progression. The primary toxicities were: neutropenia (grade 3-4: 23%), thrombocytopenia (grade 3-4: 18.5%), and nausea and vomiting (13%). Median progression-free survival times and 1-year progression free survival were 7.6 months (95% CI 6.6-8.5) and 17.3%, respectively. OS was 15.6 months (95% CI 14.1-17.1). Conclusions Our results for PFS and overall survival are comparable with those obtained with temozolomide, but the toxicity occurring in our series was more frequent and persistent. The toxicity, and mainly the modalities of administration associated with cisplatin and BCNU combination, argues against future use in the treatment of patients with GBM.

PMID: 19212704 [PubMed - as supplied by publisher]

Source J Neurooncol. 2009 Feb 11

Birth month and risk of glioma in adults: a registry-based study in Bavaria

26 February 2009

Staykov D, Radespiel-Tröger M, Meyer M, Petsch S, Schwab S, Handschu R.

Neurology Department, University Erlangen-Nuremberg, Erlangen, Germany. dimitre.staykov@...

The aim of the present study was to evaluate the possible seasonality of birth in adult patients suffering from glioma. For this purpose, data from the database of the population-based cancer registry of Bavaria (Germany) were retrieved. For the period 2002-2005, we identified a total of 2174 patients born between 1931 and 1986 diagnosed with malignant glioma. Statistical analyses failed to document a significant annual periodicity of glioma risk in either men or women with respect to birth month in the observed cohort. Thus, we found no association between month of birth and the risk of glioma. In contrast, an analysis of the official birth rate data of Bavaria revealed marked annual variation in birth rates up until 1965, which decreased markedly in prominence in the years thereafter. Our findings confirm the results of a recent similar study conducted in The Netherlands. Therefore, we support the hypothesis of possible etiological factors of glioma acting in adulthood rather than in the perinatal period.

PMID: 19212841 [PubMed - in process]

Commento Personale: Studio curioso ma che dimostra che non vi è legame fra mese di nascita (o stagione) e gliomi. In passato si era osservata una maggiore diagnosi di tumori cerebrali nei bambini nei mesi invernali. In un altro studio negli adulti era stata individuata, al contrario, una relazione fra il mese di nascita e il rischio di gliomi e meningiomi per coloro i quali sono nati (come me) nei mesi di Febbraio/Gennaio.

Source Chronobiol Int. 2009 Feb;26(2):282-92

Maternal occupational exposure to extremely low frequency magnetic fields and the risk of brain cancer in the offspring

19 February 2009

Li P, McLaughlin J, Infante-Rivard C.

Department of Epidemiology, Biostatistics and Occupational Health, Faculty of Medicine, McGill University, 1110 Pine Avenue West, Montreal, QC, H3A 1A3, Canada.

OBJECTIVES: To examine the contribution of maternal occupational exposure to extremely low frequency magnetic fields (ELF-MF) shortly before and during pregnancy on the incidence of childhood brain tumors. METHODS: A total of 548 incident cases and 760 healthy controls recruited between 1980 and 2002 from two Canadian provinces (Québec and Ontario) were included in this study, and their mothers were interviewed. Quantitative occupational ELF-MF exposure in microTesla units was estimated using individual exposure estimations or a job exposure matrix. We used three metrics to analyze exposure: cumulative, average, and maximum level attained. RESULTS: Using the average exposure metric measured before conception, an increased risk was observed for astroglial tumors (OR = 1.5, 95% CI = 1.0-2.4). During the entire pregnancy period, a significantly increased risk was observed for astroglial tumors as well as for all childhood brain tumors with the average metric (OR = 1.6, 95% CI = 1.1-2.5 and OR = 1.5, 95% CI = 1.1-2.2, respectively). Based on job titles, a twofold risk increase was observed for astroglial tumors (OR = 2.3, 95% CI = 0.8-6.3) and for all childhood brain tumors (OR = 2.3, 95% CI = 1.0-5.4) among sewing machine operators. CONCLUSIONS: Results are suggestive of a possible association between maternal occupational ELF-MF exposure and certain brain tumors in their offspring.

PMID: 19224378 [PubMed - as supplied by publisher]

Commento Personale: Questo studio ha rivelato delle correlazioni fra occupazione di lavoro di una madre in contesti nei quali sono presenti campi magnetici a bassa frequenza e tumori cerebrali (in particolari astrocitomi) nei rispettivi figli. In particolare questo rischio è addirittura raddoppiato nelle madri che lavorano con macchine da cucire. Cercherò di reperire lo studio per saperne di più.

Source Cancer Causes Control. 2009 Feb 18

Evaluation of radiotherapy effect in resveratrol-treated medulloblastoma cancer stem-like cells

19 February 2009

Lu KH, Chen YW, Tsai PH, Tsai ML, Lee YY, Chiang CY, Kao CL, Chiou SH, Ku HH, Lin CH, Chen YJ.

Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.

OBJECTIVES: Resveratrol (RV), a natural polyphenol derived from red wine, recently showed the potential of anticancer and radiosensitizing effects. A recent study has suggested that the cancer stem cells (CSCs) may reflect the clinical refractory malignancy of brain tumors, including medulloblastoma (MB). The aim of the present study is to investigate the possible role of RV in radiosensitivity of MB cells and MB-associated CSCs. MATERIALS AND METHODS: MB-associated CSCs were isolated and cultured by serum-free medium with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). The parental MB cells and MB-CSCs were treated with RV in different concentrations and assessed for cell viability. The treatment includes RV alone, radiation alone, or radiation combined with RV. RESULTS: MB-CSCs selected by serum-free medium with bFGF and EGF can form 3D spheroid formation and display enhanced self-renewal and highly co-expressed "stem cell" genes (Oct-4, Nanog, Nestin, and Musashi-1) as well as antiapoptotic genes (Bcl-2 and Bcl-xL). These MB-CSCs showed significant resistance to radiotherapy as compared to the parental MB cells. Importantly, 100 muM RV could effectively inhibit the proliferation of MB-CSCs and significantly enhance the radiosensitivity in RV-treated MB-CSCs. CONCLUSIONS: Our data suggest that RV can effectively inhibit the proliferation and tumorigenicity of MB-CSCs and significantly synergistically enhance radiosensitivity in RV-treated MB-CSCs.

PMID: 19225784 [PubMed - as supplied by publisher]

Source Childs Nerv Syst. 2009 Feb 19

Effect of adding temozolomide to radiation therapy on the incidence of pseudo-progression

17 February 2009

Gerstner ER, McNamara MB, Norden AD, Lafrankie D, Wen PY.

Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital, 55 Fruit Street, Yawkey 9E, Boston, 02114, MA, USA, egerstner@....

Recently, there has been greater awareness that combination radiation and temozolomide used to treat glioblastomas may cause increased contrast enhancement on the first post radiation MRI scan. However, this increased enhancement may stabilize or decrease over time and represent pseudo-progression (psPD) rather than true progressive disease. It has never been shown that this phenomenon is greater with combination therapy than radiation alone. To address this question, we reviewed MRI scans in glioblastoma patients treated with radiation alone versus patients treated with radiation and concomitant temozolomide and compared the frequency of psPD in the two groups. Eighteen of 47 patients (38%) treated with radiation alone demonstrated enlargement on their first post-radiation MRI scan and 11 of these 18 (61%) proved to have psPD as defined by no further enlargement on stable therapy for 3 months following radiation. Twenty-four of 45 patients (53%) treated with radiation and temozolomide had enlargement on their first post-radiation MRI scan and 13 of these 24 (54%) had psPD. Median overall survival (OS) in patients with psPD treated with radiation alone was 15.6 versus 12.8 months in those without psPD. Median OS in patients treated with radiation and concomitant temozolomide who had psPD was 24.4 versus 15.9 months in those who did not have psPD. We were unable to detect a difference in OS between the four groups. Presence of psPD, independent of treatment, was associated with prolonged progression-free survival (P = 0.05) but not OS. psPD may be more common in combination therapy but most likely by a small margin.

PMID: 19221865 [PubMed - as supplied by publisher]

Commento Personale: Le pseudoprogressioni simulano la ripresa della malattia ma, in realtà, si tratterebbe di falsi segnali. In questo studio con il termine pseudoprogressione si intende una stabilità dell’enanchement per tre mesi successivi (a terapie stabili) all’aumento dello stesso registrato nella prima risonanza post-radioterapia. In altre parole, in questi casi, si suole credere che l’aumento di area considerata tumore subito dopo aver effettuato la radioterapia possa essere, in realtà, un falso segnale (più probabilmente radionecrosi). Se questo “aumento di area” resta fermo per altri tre mesi allora viene, appunto, confermata dai medici come una pseudoprogressione. Questo studio è stato diviso in due braccia: il primo che monitorava solo pazienti trattati con radioterapia; l’altro braccio con radioterapia + Temodal. Mentre nel primo gruppo le pseudoprogressioni non hanno avuto impatto sulla sopravvivenza globale (15.6 mesi chi aveva avuto PsPD vs. 12.8 chi no), con l’utilizzo congiunto del Temodal si sono ottenuti aumenti della sopravvivenza significativa fra coloro che registravano pseudoprogressioni (24.4 mesi) e coloro i quali, al contrario, si confermavano nuove recidive (15.9 mesi). E’ altresì probabile che vi sia una forte relazione fra pseudoprogressioni e stato dell’enzima MGMT, non valutato in questo studio retrospettico.

Source J Neurooncol. 2009 Feb 17

Randomized Phase II Trial of Erlotinib Versus Temozolomide or Carmustine in Recurrent Glioblastoma

27 October 2008

van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, Clement PM, Frenay M, Campone M, Baurain JF, Armand JP, Taphoorn MJ, Tosoni A, Kletzl H, Klughammer B, Lacombe D, Gorlia T.

Daniel den Hoed Cancer Center, Rotterdam; and Medisch Centrum Haaglanden, the Hague, the Netherlands; Medical Oncology Department, Bellaria-Maggiore Hospital, Bologna, Italy; Beatson Oncology Centre, Glasgow, United Kingdom; Hopital de la Salpêtrière, Paris; Centre Antoine Lacassagne, Nice; Centre Rene Gauducheau, Nantes, St. Herblain; and Institute Gustave Roussy, Villejuif Cedex, France; Medical Oncology, University Hospital Gasthuisberg, Leuven; Cliniques Universitaires St. Luc, Brussels; and European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium; and F. Hoffmann-La Roche Ltd, Basel, Switzerland.

PURPOSE: Approximately 50% of glioblastomas (GBMs) are characterized by overexpression of the epidermal growth factor receptor (EGFR) and EGFR gene amplification. In approximately 25% of instances, constitutively activated EGFR mutants are present. These observations make EGFR-inhibiting drugs a logical approach for trials in recurrent GBM. PATIENTS AND METHODS: In a randomized, controlled, phase II trial, 110 patients with progressive GBM after prior radiotherapy were randomly assigned to either erlotinib or a control arm that received treatment with either temozolomide or carmustine (BCNU). The primary end point was 6-month progression-free survival (PFS). Tumor specimens obtained at first surgery were investigated for EGFR expression; EGFRvIII mutants; EGFR amplification; EGFR mutations in exons 18, 19, and 21; and pAkt. These results were correlated with outcome. Pharmacokinetic analysis was part of the study. RESULTS: Treatment was well tolerated in general; skin toxicity was the most frequent adverse effect of erlotinib. The 6-month PFS rate in the erlotinib arm was 11.4% (95% CI, 4.6% to 21.5%), and it was 24% in the control arm. Of all explored biomarkers, only low pAkt expression appeared to be of borderline significance to an improved outcome. None of the eight patients who had tumors with EGFRvIII mutant presence and PTEN expression had 6-month PFS. The use of enzyme-inducing anticonvulsants significantly increased erlotinib clearance, but pharmacokinetic findings were not related to outcome. CONCLUSION: Erlotinib has insufficient single-agent activity in unselected GBM. No clear biomarker associated with improved outcome to erlotinib was identified.

PMID: 19204207 [PubMed - as supplied by publisher]

Commento Personale: Un altro studio che dimostra la totale inefficiacia per ora dei farmaci anti-EGFR come, appunto, l’Erlotinib.

Source J Clin Oncol. 2009 Feb 9

Phase II Trial of Temozolomide Plus O6-Benzylguanine in Adults With Recurrent, Temozolomide-Resistant Malignant Glioma

9 February 2009

Quinn JA, Jiang SX, Reardon DA, Desjardins A, Vredenburgh JJ, Rich JN, Gururangan S, Friedman AH, Bigner DD, Sampson JH, McLendon RE, Herndon JE 2nd, Walker A, Friedman HS.

Departments of Surgery, Pathology, Biostatistics, and Bioinformatics, Duke University Medical Center, Durham, NC.

PURPOSE: This phase II trial was designed to define the role of O(6)-benzylguanine (O(6)-BG) in restoring temozolomide sensitivity in patients with recurrent or progressive, temozolomide-resistant malignant glioma and to evaluate the safety of administering O(6)-BG in combination with temozolomide. PATIENTS AND METHODS: Patients were accrued into two independent strata on the basis of histology: glioblastoma multiforme (GBM) and anaplastic glioma. Both temozolomide and O(6)-BG were administered on day 1 of a 28-day treatment cycle. Patients were administered a 1-hour O(6)-BG infusion at a dose of 120 mg/m(2) followed immediately by a 48-hour infusion at a dose of 30 mg/m(2)/d. Temozolomide was administered orally within 60 minutes of the end of the 1-hour O(6)-BG infusion at a dose of 472 mg/m(2). The primary end point was objective response rate. Secondary end points included progression-free survival, overall survival, and safety. RESULTS: Sixty-six of 67 patients who enrolled were treated with temozolomide and O(6)-BG. One of 34 patients (3%) with GBM (95% CI, 0.1% to 15%) and five of 32 assessable patients (16%) with anaplastic glioma (95% CI, 5% to 33%) were responders. The most commonly reported adverse events were grade 4 hematologic events experienced in 48% of the patients. CONCLUSION: O(6)-BG when added to a 1-day dosing regimen of temozolomide was able to restore temozolomide sensitivity in patients with temozolomide-resistant anaplastic glioma, but there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant GBM.

PMID: 19204199 [PubMed - as supplied by publisher]

Source J Clin Oncol. 2009 Feb 9