Non Smoking Area

Read More...

Summary only...

Large Studies Needed To Further Confirm Prostate Cancer Drug Abiraterone

Larger trials are needed to further examine and confirm the early findings on the experimental drug abiraterone acetate (CB7630). Researcher Dr. Johann de Bono, from the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust in the UK, who led two ongoing clinical trials of CB7630, said larger studies are necessary to find out the efficacy of the drug. "We believe we have made a major step forward in the treatment of end-stage prostate cancer patients," De Bono told BBC News. He, however, added that the phase 1 and 2 findings needed to be confirmed in larger trials.

An oral and irreversible inhibitor of the enzyme CYP17 that decreases testosterone and DHT to undetectable levels, CB7630 works by blocking the production of the hormones throughout the body. The latest abiraterone study, published in the Journal of Clinical Oncology, is based on just 21 patients with advanced, aggressive prostate cancer treated with the drug although data has been collected on a total of 250 patients in the US and the UK. The studies found significant tumour shrinkage and a drop in PSA in the majority of patients.

In an interview with Urosource, Prof. Fritz Schröder of the Department of Urology, Erasmus MC, University Medical Centre Rotterdam, The Netherlands, called the latest CB7630 findings an "important and exciting development" in ongoing research concerning androgen-independent prostate cancer (AIPC), but reiterated the view that there are still some key questions that require further studies and which can only be answered in larger trials.

In a paper published in the latest issue of European Urology, Schröder said that based on recent findings it is "evident that enzymes related to androgen metabolism that are over-expressed in AIPC could be targets for endocrine treatment." He said CBT7630 is a recent example.

Per-Anders Abrahamsson, Secretary-General of the EAU, said arbiraterone acetate targets a group of patients that are notoriously hard to treat, adding that it would be a breakthrough if abiraterone can fulfil the promises of the initial data. "Caution is indeed in order and it is too early to warrant too much excitement and raise expectations amongst patients just yet," said Abrahamsson.

Professor David Webb, an expert in clinical pharmacology at the University of Edinburgh, also said in a BBC News interview that although abiraterone acetate "clearly looks promising…it is still at the early stages of clinical development." "It will be crucial to look carefully at the balance between its benefits and harms, before drawing firm conclusions about the usefulness of this new drug," said Webb. "Important side effects often only emerge with the larger clinical studies that now need to be done."

Abiraterone, developed by the US-based Cougar Biotechnology (Los Angeles, California), is now being readied for phase 3 trials worldwide.

European Association of Urology

Read More...

Summary only...

Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma

Non-Hodgkin's lymphoma is the most common hematologic cancer in adults, with more than 66,000 incident cases anticipated in the United States in 2008.1 Approximately 85% of non-Hodgkin's lymphomas in adults are of B cell origin.2 Some B-cell non-Hodgkin's lymphomas are indolent, or slow-growing, yet incurable. In contrast, others are aggressive or very aggressive, and may be rapidly fatal, yet are often curable.
There has been a revolution in the treatment of B-cell non-Hodgkin's lymphomas, owing largely to the availability of therapeutic monoclonal antibodies. The concept that antibodies might be effective for the treatment of cancers originated more than a century ago with Paul Ehrlich's hypothesis that it would someday be feasible to develop a "magic bullet" that has an affinity for "parasites" but that spares normal tissues3; 100 years elapsed, however, before antibodies were developed as effective agents for the treatment of cancer. The first step was the development of hybridoma technology capable of producing adequate quantities of monoclonal antibodies for clinical use.4 The next step was to identify tumor-specific cell antigens as targets.5 Finally, on November 26, 1997, rituximab became the first monoclonal antibody approved by the Food and Drug Administration (FDA) for the treatment of a human cancer — relapsed or refractory, low-grade (indolent) or follicular, CD20+ non-Hodgkin's lymphoma. In the ensuing decade, considerable effort has been focused on improving the effectiveness of this agent, identifying other therapeutic monoclonal antibodies (Table 1), and integrating antibodies into standard treatment regimens.

Rituximab for Follicular and Low-Grade Lymphoma

Rituximab is a chimeric monoclonal antibody composed of murine variable regions from the anti-CD20 antibody 2B8 that are linked to a human Fc component directed against CD20 on B cells. Unfortunately, the optimal dose of rituximab has never been defined. Phase 1 studies of doses ranging from 10 to 500 mg per square meter of body-surface area, administered once, and of doses ranging from 125 to 375 mg per square meter, administered weekly for 4 weeks, identified no dose-limiting toxic effects.21,22 Athough fever, chills, nausea, vomiting, urticaria, orthostatic hypotension, and bronchospasm occur in more than 80% of patients and are moderate to severe in about 15% of patients, these problems are generally limited to the infusion period. The regimen of 375 mg per square meter weekly for 4 weeks was selected for further testing on the basis of pharmacokinetic and pharmacodynamic data, the supply of the drug, and the feasibility of outpatient administration of the drug.23,24,25

Rituximab was initially approved by the FDA largely on the basis of a study involving 166 patients with relapsed or refractory, follicular or low-grade non-Hodgkin's lymphoma.24 The overall response rate was 48%, with 6% of the patients having complete remissions; better response rates correlated with fewer previous treatments. The median duration of the response was about a year. The response rate among patients with bulky disease (nodes larger than 10 cm in diameter) was 43%, with 4% having complete remissions that lasted for a median of 5.9 months; the median time to progression among patients with a response was 8.1 months.26 Responses lasting from 1 to 2.5 years have been reported in about 70% of patients with previously untreated, indolent non-Hodgkin's lymphoma and a low tumor burden.27,28,29

Until recently, no chemotherapeutic regimen provided a survival benefit superior to that of chlorambucil and prednisone in patients with indolent lymphomas.30 However, single-group trials have suggested that adding rituximab to chemotherapy improves the rate and the duration of the response.31,32 Several randomized studies in which rituximab was added to various chemotherapy regimens showed not only increased rates of complete response but also prolonged survival as compared with chemotherapy alone (Table 2).33,34,41 Such results supported broadening the indications for rituximab in combination with chemotherapy to include its use as an initial treatment.

Ongoing attempts to improve on the rituximab molecule include modifications that permit binding to a better epitope, binding more tightly to CD20, increasing activation of antibody-dependent cellular cytotoxicity, and facilitating apoptosis (Figure 2). The product furthest along in clinical development is ofatumumab (HuMax-CD20, Genmab), a fully human IgG1{kappa} monoclonal antibody that targets a novel epitope of CD20. Preclinical studies indicate that ofatumumab is associated with greater complement-dependent cytotoxicity than rituximab, presumably because of a slower rate of dissociation from its antigen ("off rate") and greater interaction with the complement component C1q. In clinical trials, patients with follicular lymphoma and chronic lymphocytic leukemia had responses to ofatumumab, which profoundly depleted CD19+CD5+ B cells and had a toxicity profile similar to that of rituximab.88,89,90

Another humanized antibody, hA20 (IMMU-106), induces apoptosis of B cells in vitro and mediates antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.91 Early clinical trials suggest that patients have objective responses to this antibody.91,92 PRO131921, a third-generation rituximab product, is also being investigated in early clinical trials. Additional anti-CD20 antibodies under development include some with enhanced binding to Fc receptors and augmented antibody-dependent cellular cytotoxicity. Given the substantial activity and relative safety of rituximab, it will be challenging to show whether other anti-CD20 antibodies have an advantage when they are compared with rituximab and whether they will be effective in patients whose lymphoma is resistant to rituximab.

Alemtuzumab

Alemtuzumab (Campath, Bayer HealthCare Pharmaceuticals) is a humanized anti-CD52 monoclonal antibody that has been approved by the FDA for the treatment of chronic lymphocytic leukemia. The recommended schedule for the administration of alemtuzumab is a dose of 3 mg on day 1 and 10 mg on day 2, followed by 30 mg three times weekly, as tolerated, for up to 12 weeks. About 30% of patients with chronic lymphocytic leukemia whose disease progressed after they received alkylating agents and fludarabine have had a response to alemtuzumab.93,94,95 When alemtuzumab is used as the initial therapy, the response rate is about 80%.93,94,95 Infusion-related rigors occur in about 90% of patients (14% of whom have moderate-to-severe reactions), fever in 85% (moderate to severe in 20%), mild-to-moderate nausea in 53%, vomiting in 38%, and rash in approximately 33%. These adverse events generally decrease in frequency and severity over the course of treatments. Subcutaneous administration has fewer toxic effects than intravenous administration but has similar efficacy and is now more widely used.96

Infections develop in more than 50% of patients who receive alemtuzumab; these infections are severe to life-threatening in 25% of the patients. Alemtuzumab has been associated with an increased risk of Pneumocystis jiroveci and herpesvirus infections; thus, antimicrobial prophylaxis and close monitoring for infection are essential. A reactivation of cytomegalovirus occurs in approximately 25% of patients, necessitating weekly polymerase-chain-reaction monitoring.

Galiximab

CD80 is an immune costimulatory molecule that is present on B cells.97 Galiximab (Biogen Idec) is a macaque–human chimeric anti-CD80 antibody with antilymphoma properties in vivo. About 15% of patients with recurrent follicular non-Hodgkin's lymphoma appear to have positive responses with galiximab, some of which occur as late as a year after treatment. Galiximab is reported to cause minimal adverse events — primarily mild fatigue, nausea, and headaches.98 On the basis of preclinical data suggesting synergy, a phase 1–2 study of galiximab together with rituximab was performed, and the results suggested that the combination therapy was superior to therapy with the single agents99; a randomized trial of rituximab as compared with galiximab plus rituximab in patients who have had a relapse is under way. The Cancer and Leukemia Group B (CALGB) recently studied the combination of galiximab and rituximab as the initial therapy for follicular lymphoma and reported a response in 69% of the study participants, including 41% with complete remissions.100

Anti-CD40 Antibodies

CD40, a member of the tumor necrosis factor–receptor family, is expressed on the surface of B cells from the pro-B stage to plasma cells. Preclinical studies of two anti-CD40 antibodies (SGN-40 [Seattle Genetics] and CHIR-12.12 [Novartis]) showed apoptotic effects and antibody-dependent cellular cytotoxicity. Durable, complete responses in patients with diffuse large-B-cell lymphoma in a phase 1 trial with SGN-40 stimulated further study of SGN-40 as a single agent and in combination with chemotherapy.101

Epratuzumab

CD22 is widely expressed on B cells and may be important in B-cell activation, modulation of antigen-receptor signaling, and cell-surface–receptor circlulation. Epratuzumab (Immunomedics), a humanized IgG1 anti-CD22 monoclonal antibody, has induced responses in 24% of patients with follicular lymphoma and in 15% of patients with recurrent diffuse large-B-cell lymphoma, without dose-limiting toxic effects.102,103 Results of treatment with a combination of rituximab and epratuzumab suggested at least an additive benefit, a finding that requires confirmation in a randomized study.104 Epratuzumab is also being evaluated as a treatment in combination with rituximab plus CHOP and as a therapy in other B-cell cancers and autoimmune disease.105

Lumiliximab

Chronic lymphocytic leukemia cells express the CD23 antigen, a target for the anti-CD23 antibody, lumiliximab (Biogen Idec), a macaque–human chimeric monoclonal antibody that inhibits IgE secretion in vitro and induces apoptosis of lymphoma cell lines. Lumiliximab binds complement and mediates antibody-dependent cellular cytotoxicity by binding Fc{gamma}RI and RII receptors. It appears to have limited effectiveness as a single agent among patients with chronic lymphocytic leukemia.106 However, in vitro data suggest that it has synergy with fludarabine and rituximab.107 When lumiliximab is added to the combination therapy of fludarabine, cyclophosphamide, and rituximab, the rates of response appear to be similar to those seen with the combination therapy without lumiliximab, but the proportion of complete responses is higher when lumiliximab is added.108 An international randomized study comparing fludarabine, cyclophosphamide, and rituximab with and without lumiliximab is under way.

Hu1D10

HLA class II antigens are expressed on B cells throughout differentiation and play a key role in cell cycling and proliferation. Anti-class II antibodies inhibit B-cell proliferation and induce apoptosis, at least in part through induction of the Fas–Fas ligand pathway or activation of Akt. Apolizumab (Hu1D10), a humanized anti-HLA-DR antibody capable of inducing complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and programmed cell death, has limited activity.109 Nevertheless, other anti–HLA-DR antibodies, including the anti-CD74 antibody milatuzumab (Immunomedics), are currently being studied for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and multiple myeloma.110

Read More...

Summary only...

Malignant Gliomas in Adults

Image via WikipediaMalignant gliomas account for approximately 70% of the 22,500 new cases of malignant primary brain tumors that are diagnosed in adults in the United States each year.1,2,3 Although relatively uncommon, malignant gliomas are associated with disproportionately high morbidity and mortality. Despite optimal treatment, the median survival is only 12 to 15 months for patients with glioblastomas and 2 to 5 years for patients with anaplastic gliomas. Recently, there have been important advances in our understanding of the molecular pathogenesis of malignant gliomas and progress in treating them. This review summarizes the diagnosis and management of these tumors in adults and highlights some areas under investigation.

Epidemiologic Features

The annual incidence of malignant gliomas is approximately 5 cases per 100,000 people.1,2 Each year, more than 14,000 new cases are diagnosed in the United States.1,2 Glioblastomas account for approximately 60 to 70% of malignant gliomas, anaplastic astrocytomas for 10 to 15%, and anaplastic oligodendrogliomas and anaplastic oligoastrocytomas for 10%; less common tumors such as anaplastic ependymomas and anaplastic gangliogliomas account for the rest.1,2 The incidence of these tumors has increased slightly over the past two decades, especially in the elderly,4 primarily as a result of improved diagnostic imaging. Malignant gliomas are 40% more common in men than in women and twice as common in whites as in blacks.2 The median age of patients at the time of diagnosis is 64 years in the case of glioblastomas and 45 years in the case of anaplastic gliomas.2,4

No underlying cause has been identified for the majority of malignant gliomas. The only established risk factor is exposure to ionizing radiation.4 Evidence for an association with head injury, foods containing N-nitroso compounds, occupational risk factors, and exposure to electromagnetic fields is inconclusive.4 Although there has been some concern about an increased risk of gliomas in association with the use of cellular telephones,5 the largest studies have not demonstrated this.4,6,7 There is suggestive evidence of an association between immunologic factors and gliomas. Patients with atopy have a reduced risk of gliomas,8 and patients with glioblastoma who have elevated IgE levels appear to live longer than those with normal levels.9 The importance of these associations is unclear. Gene polymorphisms that affect detoxification, DNA repair, and cell-cycle regulation have also been implicated in the development of gliomas.4

Approximately 5% of patients with malignant gliomas have a family history of gliomas. Some of these familial cases are associated with rare genetic syndromes, such as neurofibromatosis types 1 and 2, the Li–Fraumeni syndrome (germ-line p53 mutations associated with an increased risk of several cancers), and Turcot's syndrome (intestinal polyposis and brain tumors).10 However, most familial cases have no identified genetic cause. Recently, an international consortium, GLIOGENE, was established to study the genetic basis of familial gliomas.11

Pathological Features

Malignant gliomas are histologically heterogeneous and invasive tumors that are derived from glia. The World Health Organization (WHO) classifies astrocytomas on the basis of histologic features into four prognostic grades: grade I (pilocytic astrocytoma), grade II (diffuse astrocytoma), grade III (anaplastic astrocytoma), and grade IV (glioblastoma).1 Grade III and IV tumors are considered malignant gliomas. Anaplastic astrocytomas are characterized by increased cellularity, nuclear atypia, and mitotic activity. Glioblastomas also contain areas of microvascular proliferation, necrosis, or both (Figure 1 and Figure 2). Uncommon glioblastoma variants include gliosarcomas, which contain a prominent sarcomatous element; giant-cell glioblastomas, which have multinucleated giant cells; small-cell glioblastomas, which are associated with amplification of the epidermal growth factor receptor (EGFR); and glioblastomas with oligodendroglial features, which may be associated with a better prognosis than standard glioblastomas.1,12 Oligodendrogliomas are divided by the WHO into two grades: well-differentiated oligodendrogliomas and oligoastrocytomas (WHO grade II), and anaplastic oligodendrogliomas and anaplastic oligoastrocytomas (WHO grade III) (Figure 1). All of these tumors may contain perinuclear halos (Figure 2C) and a delicate network of branching blood vessels (chicken-wire pattern).

Diagnosis

Clinical Presentation

Patients with malignant gliomas may present with a variety of symptoms, including headaches, seizures, focal neurologic deficits, confusion, memory loss, and personality changes. Although the classic headaches that are suggestive of increased intracranial pressure are most severe in the morning and may wake the patient from sleep, many patients experience headaches that are indistinguishable from tension headaches. When severe, the headaches may be associated with nausea and vomiting.

Imaging

The diagnosis of malignant gliomas is usually suggested by magnetic resonance imaging (MRI) or computed tomography. These imaging studies typically show a heterogeneously enhancing mass with surrounding edema. Glioblastomas frequently have central areas of necrosis and more extensive peritumoral edema than that associated with anaplastic gliomas.45 Functional MRI may help define the relationship of speech and motor areas to the tumor and aid in the planning of surgery. Diffusion-weighted imaging, diffusion tensor imaging, dynamic contrast-enhanced MRI to measure vessel permeability, and perfusion imaging to measure relative cerebral blood volume are increasingly used as diagnostic aids and as a means of monitoring the response to therapy.46 Proton magnetic resonance spectroscopy detects the levels of metabolites and may help differentiate a tumor from necrosis or benign lesions. In patients with malignant gliomas, this imaging technique typically shows an increase in the choline peak (reflecting increased membrane turnover) and a decrease in the N-acetyl aspartate peak (reflecting decreased neuronal cellularity), as compared with the findings in unaffected areas of the brain.45,46 Positron-emission tomography that uses isotopes such as 18F-fluorodeoxyglucose, 18F-fluoro-L-thymidine, 11C-methionine, and 3,4-dihydroxy-6-18F-fluoro-L-phenylalanine is being evaluated for its usefulness in diagnosis and in mon-itoring the response to therapy.47

In up to 40% of cases, the MRI studies that are performed in the first month after radiotherapy show increased enhancement.48 In 50% of these cases, the increased enhancement reflects a transient increase in vessel permeability as a result of radiotherapy, a phenomenon termed "pseudoprogression," which improves with time.48 Differentiating this transient effect from true progression of the cancer can be challenging initially, even with advanced imaging techniques.

Treatment

General Medical Management

Much of the care of patients with malignant gliomas involves general medical management. The most common problems include seizures, peritumoral edema, venous thromboembolism, fatigue, and cognitive dysfunction.49 Patients who present with seizures should be treated with antiepileptic drugs. Since antiepileptic drugs that induce hepatic cytochrome P-450 enzymes, such as phenytoin and carbamazepine, increase the metabolism of many chemotherapeutic agents, antiepileptic drugs that do not induce these enzymes, such as levetiracetam, are generally preferred. The use of prophylactic antiepileptic drugs in patients with malignant gliomas who have never had a seizure is controversial. The American Academy of Neurology issued a practice guideline indicating that there is no evidence that prophylactic antiepileptic drugs are beneficial and advises against the routine use of antiepileptic drugs in patients with brain tumors who have not had seizures.50

Corticosteroids such as dexamethasone are frequently used to treat peritumoral edema. Cushing's syndrome and corticosteroid myopathy may develop in patients who require prolonged treatment with high doses of corticosteroids. Patients with brain tumors who receive corticosteroids are at increased risk for Pneumocystis jiroveci pneumonitis, and prophylactic antibiotic therapy should be considered,49 although a recent meta-analysis did not show a benefit from this approach.51 As the rate of survival among patients with malignant glioma improves, long-term complications from treatment with corticosteroids, including osteoporosis and compression fractures, are becoming increasingly evident, and preventive measures, such as treatment with vitamin D, calcium supplements, and bisphosphonates, should be considered. Novel therapies such as corticotropin-releasing factor, bevacizumab (a humanized VEGF monoclonal antibody), and VEGFR inhibitors decrease peritumoral edema and may reduce the need for corticosteroids.49,52

Patients with malignant gliomas are at increased risk for venous thromboembolism from leg and pelvic veins, with a cumulative incidence of 20 to 30%.49,53 The risk of intratumoral hemorrhage associated with anticoagulation therapy in patients with gliomas who have venous thromboembolism is low,49,54 whereas inferior vena cava filters are associated with high complication rates.55 Unless a patient with malignant glioma and venous thromboembolism has an intracerebral hemorrhage or other contraindications, it is generally safe to provide anticoagulation therapy for the venous thromboembolism. Low-molecular-weight heparin may be more effective and safer than warfarin.56

Patients with malignant gliomas frequently experience fatigue and may benefit from treatment with modafinil or methylphenidate.57 Methylphenidate may also help abulia, and donepezil58 and memantine may reduce memory loss, although evidence supporting these approaches remains limited. Depression is underdiagnosed in patients with malignant gliomas, and antidepressants and psychiatric support are often invaluable.59

Specific Therapy for Newly Diagnosed Malignant Gliomas

The standard therapy for newly diagnosed malignant gliomas involves surgical resection when feasible, radiotherapy, and chemotherapy (Table 1). Malignant gliomas cannot be completely eliminated surgically because of their infiltrative nature, but patients should undergo maximal surgical resection whenever possible. Surgical debulking reduces the symptoms from mass effect and provides tissue for histologic diagnosis and molecular studies. Advances such as MRI-guided neuronavigation, intraoperative MRI, functional MRI, intraoperative mapping,60 and fluorescence-guided surgery61 have improved the safety of surgery and increased the extent of resection that can be achieved. The value of surgery in prolonging survival is controversial, but patients who undergo extensive resection probably have a modest survival advantage.60,61,62 Stereotactic biopsies should be performed only in patients who have inoperable tumors that are located in critical areas.
Radiotherapy is the mainstay of treatment for malignant gliomas. The addition of radiotherapy to surgery increases survival among patients with glioblastomas from a range of 3 to 4 months to a range of 7 to 12 months.63,64 Conventional radiotherapy consists of 60 Gy of partial-field external-beam irradiation delivered 5 days per week in fractions of 1.8 to 2.0 Gy. After standard radiotherapy, 90% of the tumors recur at the original site.65 Strategies to increase the radiation dose to the tumor with the use of brachytherapy66 and stereotactic radiosurgery67,68 have failed to improve survival. Newer chemotherapeutic agents,69 targeted molecular agents,20 and antiangiogenic agents70 may enhance the effectiveness of radiotherapy.

Patients who are older than 70 years of age have a worse prognosis than younger patients and represent a particular challenge. Among these patients, radiotherapy produces a modest benefit in median survival (29.1 weeks) as compared with supportive care (16.9 weeks).71 Since older patients often tolerate radiotherapy less well than younger patients, an abbreviated course of radiotherapy (40 Gy in 15 fractions over a period of 3 weeks)72 or chemotherapy with temozolomide (an oral alkylating agent with good penetration of the blood–brain barrier) alone73 may be considered, since the outcomes with these approaches are similar to the outcomes with conventional radiotherapy regimens.

Chemotherapy is assuming an increasingly important role in the treatment of malignant gliomas. Although early studies of adjuvant chemotherapy for malignant gliomas with the use of nitrosoureas failed to show a benefit,63,74 two meta-analyses have suggested that adjuvant chemotherapy results in a modest increase in survival (a 6 to 10% increase in the 1-year survival rate).75,76

The European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) conducted a phase III trial comparing radiotherapy alone (60 Gy over a period of 6 weeks) with radiotherapy and concomitant treatment with temozolomide (75 mg per square meter of body-surface area per day for 6 weeks), followed by adjuvant temozolomide therapy (150 to 200 mg per square meter per day for 5 days every 28 days for 6 cycles), in patients with newly diagnosed glioblastomas.64 As reported by Stupp et al., the combination of radiotherapy and temozolomide had an acceptable side-effect profile and, as compared with radiotherapy alone, increased the median survival (14.6 months vs. 12.1 months, P<0.001).64 In addition, the survival rate at 2 years among the patients who received radiotherapy and temozolomide was significantly greater than the rate among the patients who received radiotherapy alone (26.5% vs. 10.4%),64 establishing radiotherapy with concomitant and adjuvant temozolomide as a useful combination for newly diagnosed glioblastomas.

MGMT is an important repair enzyme that contributes to resistance to temozolomide. In a companion study to the EORTC–NCIC study reported by Stupp et al., tumor specimens from the patients were examined for epigenetic silencing of the MGMT gene.15 MGMT promoter methylation silences the gene, thus decreasing DNA repair activity and increasing the susceptibility of the tumor cells to temozolomide. Patients with glioblastoma and MGMT promoter methylation (45% of the total) who were treated with temozolomide had a median survival of 21.7 months and a 2-year survival rate of 46%. In contrast, patients without MGMT promoter methylation who were treated with temozolomide had a significantly shorter median survival of only 12.7 months and a 2-year survival rate of 13.8%.15 Currently, temozolomide is used in the treatment of glioblastomas regardless of MGMT promoter methylation status. However, if the importance of MGMT promoter methylation is confirmed by the results of an ongoing study by the Radiation Therapy Oncology Group (RTOG 0525), patients with unfavorable MGMT methylation status may be selected for other treatments in future investigations. Studies of dose-intensive temozolomide regimens to deplete MGMT and of combinations of temozolomide with inhibitors of MGMT, such as O6-benzylguanine, and inhibitors of other repair enzymes, such as poly-(ADP-ribose)-polymerase, are in progress.

Another chemotherapeutic approach involves the implantation of biodegradable polymers containing carmustine (Gliadel Wafers, MGI Pharma) into the tumor bed after resection of the tumor. The aim of treatment with these polymers, which release carmustine gradually over the course of several weeks, is to kill residual tumor cells. In a randomized, placebo-controlled trial that investigated the use of these polymers in patients with newly diagnosed malignant gliomas, median survival increased from 11.6 months to 13.9 months (P=0.03).77 This survival advantage was maintained at 2 and 3 years.78

Therapy for Anaplastic Gliomas

Anaplastic astrocytomas are treated with radiotherapy and either concurrent and adjuvant temozolomide (as for glioblastomas) or adjuvant temozolomide alone. Currently, there are no findings from controlled trials that support the use of concurrent temozolomide in patients with anaplastic astrocytomas.

Anaplastic oligodendrogliomas and anaplastic oligoastrocytomas are an important subgroup of malignant gliomas that are generally more responsive to therapy than are pure astrocytic tumors.79 A codeletion of chromosomes 1p and 19q,79 mediated by an unbalanced translocation of 19p to 1q,80 occurs in 61 to 89% of patients with anaplastic oligodendrogliomas and 14 to 20% of patients with anaplastic oligoastrocytomas. Tumors in patients with the 1p and 19q codeletion are particularly sensitive to chemotherapy with PCV — procarbazine, lomustine (CCNU), and vincristine — with response rates of up to 100%, as compared with response rates of 23 to 31% among patients without the deletion of chromosomes 1p and 19q.81,82 The reason for the increased chemosensitivity of tumors in patients with the 1p and 19q codeletion is unclear. One study suggested that 1p loss is associated with decreased levels of stathmin and an increased sensitivity to nitrosoureas.83 The status of chromosomes 1p and 19q, rather than standard histologic assessment, is now used as an eligibility criterion in studies involving patients with anaplastic oligodendrogliomas and anaplastic oligoastrocytomas, reflecting a paradigm shift in the design of clinical trials for patients with these tumors.

Two large phase III studies of PCV chemotherapy with radiotherapy, as compared with radiotherapy alone, in patients with newly diagnosed anaplastic oligodendrogliomas or anaplastic oligoastrocytomas, have been reported.84,85 In both studies, the addition of chemotherapy to radiotherapy increased the time to tumor progression by 10 to 12 months but did not improve overall survival (median, 3.4 and 4.9 years).84,85 The failure of chemotherapy to increase survival may be partly explained by the fact that patients who initially received radiotherapy alone subsequently received chemotherapy when they had a relapse, so that most patients in both groups eventually received chemotherapy. In both studies, patients with the codeletion of 1p and 19q had improved survival as compared with those without the codeletion of 1p and 19q. Although most studies involving patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas were conducted with PCV chemotherapy, temozolomide is likely to have similar activity and less toxicity79; however, studies directly comparing the two regimens have not been performed.

Therapy for Recurrent Malignant Gliomas

Despite optimal treatment, nearly all malignant gliomas eventually recur. For glioblastomas, the median time to progression after treatment with radiotherapy and temozolomide is 6.9 months.64 If the tumor is symptomatic from mass effect, reoperation may be indicated (Table 1). However, surgery performed in selected patients results in only limited prolongation of survival.86

The usefulness of radiotherapy for recurrent malignant gliomas is controversial.87 Although some reports have suggested that fractionated stereotactic reirradiation88 and stereotactic radiosurgery68 may be beneficial, selection bias may have influenced these results.

The value of conventional chemotherapy for recurrent malignant gliomas is modest. In general, chemotherapy is more effective for anaplastic gliomas than for glioblastomas.79,87 Temozolomide was evaluated in a phase II study involving patients with recurrent anaplastic gliomas who had previously been treated with nitrosoureas; the study showed a 35% response rate. The 6-month rate of progression-free survival was 46%,89 comparing favorably with the 31% rate of progression-free survival at 6 months for therapies that were reported to be ineffective.90 In contrast, temozolomide has only limited activity in patients with recurrent glioblastomas (response rate, 5.4%; 6-month rate of progression-free survival, 21%).91 Other chemotherapeutic agents that are used for recurrent gliomas include nitrosoureas, carboplatin, procarbazine, irinotecan, and etoposide. Carmustine wafers have modest activity, increasing the median survival by approximately 8 weeks in patients with recurrent glioblastomas.92

Investigational Therapies

Targeted Molecular Therapies

The improved understanding of the molecular pathogenesis of malignant gliomas has allowed a more rational use of targeted molecular therapies (Figure 3).18,20,21 Particular interest has focused on inhibitors that target receptor tyrosine kinases such as EGFR,93 PDGFR,94 and VEGFR,52 as well as on signal-transduction inhibitors targeting mTOR,95,96 farnesyltransferase,97 and PI3K (Table 2). Single agents have only modest activity, with response rates of 0 to 15% and no prolongation of 6-month progression-free survival.3,20,21 These disappointing results are due to several factors. Most malignant gliomas have coactivation of multiple tyrosine kinases,98 as well as redundant signaling pathways, thus limiting the activity of single agents. In addition, many of these agents have poor penetration across the blood–tumor barrier. There has been considerable interest in identifying molecular features of the tumor that predict a response, so that patients who are most likely to benefit can be selected for a particular treatment. EGFR inhibitors appear to be more effective in patients who have tumors with EGFRvIII mutations and intact PTEN than in patients who do not have these molecular changes99; patients who have tumors with increased activity of the PI3K–Akt pathway, as indicated by an increase in phosphorylated Akt, generally do not have a response.100 Current experimental strategies to increase the effectiveness of targeted molecular therapies include the use of a single agent targeted against several kinases, combinations of agents that inhibit complementary targets such as EGFR and mTOR (Table 2 and Figure 5A through 5D), and targeted agents combined with radiotherapy and chemotherapy.3,18,20,21
Antiangiogenic Agents

Malignant gliomas are among the most vascular of human tumors,18 making them especially attractive targets for angiogenesis inhibitors.29 Although older antiangiogenic agents such as thalidomide had only modest activity,101 newer and more potent angiogenesis inhibitors show promising activity. In preliminary studies, treatment with the combination of bevacizumab and irinotecan was associated with a low incidence of hemorrhage and response rates of 57 to 63% among patients with malignant gliomas (Figure 5E through 5H).102,103 Some of the improvement that is seen on radiographic images may be artifactual, caused by reduced vascular permeability and decreased contrast enhancement as a result of the inhibition of VEGF. However, this regimen also has antitumor activity, as evidenced by the fact that it increased the 6-month rate of progression-free survival to 46% among patients with recurrent glioblastomas,102,103 as compared with a 6-month rate of progression-free survival of 21% for patients who were receiving treatment with temozolomide.91 Recently, a large, randomized phase II trial of bevacizumab alone and bevacizumab with irinotecan was completed. Preliminary results confirmed the safety of bevacizumab and showed an increase in the 6-month rate of progression-free survival to 35.1% for patients receiving bevacizumab alone and 50.2% for patients receiving the combination of bevacizumab and irinotecan.104 A phase II trial of the pan-VEGFR inhibitor cediranib in patients with recurrent glioblastomas showed response rates in excess of 50% and prolongation of the 6-month rate of progression-free survival to approximately 26%.52 These agents also decrease peritumoral edema, potentially allowing for a reduction in corticosteroid requirements. Since antiangiogenic agents may have synergistic activity with radiotherapy, there is increasing interest in combining them with radiotherapy and temozolomide in patients with newly diagnosed glioblastomas.29,70 As noted previously, glioma stem cells produce VEGF39 and require a vascular niche for optimal function.40 Antiangiogenic agents may therefore also target glioma stem cells.

Other Therapies

Other investigational therapies for malignant gliomas include chemotherapeutic agents that cross the blood–tumor barrier more effectively, gene therapy,105 peptide and dendritic-cell vaccines,106 radiolabeled monoclonal antibodies against the extracellular matrix protein tenascin,107 synthetic chlorotoxins (131I-TM-601),108 and infusion of radiolabeled drugs and targeted toxins into the tumor and surrounding brain by means of convection-enhanced delivery (Table 2).109

Prognostic Factors

The most important adverse prognostic factors in patients with malignant gliomas are advanced age, histologic features of glioblastoma, poor Karnofsky performance status, and unresectable tumor.110 There are ongoing efforts to identify biologic and genetic alterations in the tumors that may provide additional prognostic information, as well as guidance in making decisions about optimal therapy.15,16,82

Summary

Recently, there has been important progress in the treatment of malignant gliomas111 and in our understanding of the molecular pathogenesis of these tumors and the critical role that stem cells play in their development and resistance to treatment. As our understanding of the molecular correlates of response improves, it may be possible to select the most appropriate therapies on the basis of the patient's tumor genotype. These advances provide real opportunities for the development of effective therapies for malignant gliomas.

Supported by grants from the National Institutes of Health (U01 CA062407, to Dr. Wen; and KO8 CA1240804, to Dr. Kesari), a Sontag Foundation Distinguished Scientist Grant (to Dr. Kesari), and research support from the Elizabeth Atkins and Will Kraft Brain Tumor Research Funds (to Dr. Wen) and the John Kenney Brain Tumor Research Fund (to Dr. Kesari).

Dr. Wen reports receiving speaking fees from Schering-Plough, serving as a consultant for AngioChem, and receiving research funding from Exelixis, Schering-Plough, Genentech, GlaxoSmithKline, Amgen, AstraZeneca, and Celgene. Dr. Kesari reports receiving consulting fees from Bristol–Myers Squibb, speaking fees from Enzon, and research funding from Adnexus. No other potential conflict of interest relevant to this article was reported.

We thank Drs. Andrew Norden and Elizabeth Claus for helpful comments.

This article is dedicated to the memories of Elizabeth Atkins, Will Kraft, and John Kenney.


Source Information

From the Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital; and the Center for Neuro-Oncology, Dana–Farber Cancer Institute — both in Boston.

Address reprint requests to Dr. Wen at the Center for Neuro-Oncology, Dana–Farber/Brigham and Women's Cancer Center, SW430D, 44 Binney St., Boston, MA 02115, or at pwen@partners.org.

References

1. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumors of the central nervous system. Lyon, France: IARC Press, 2007.
2. CBTRUS 2008 statistical report: primary brain tumors in the United States, 1998-2002. Central Brain Tumor Registry of the United States, 2000-2004. (Accessed July 7, 2008, at http://www.cbtrus.org/reports/2007-2008/2007report.pdf.)
3. Sathornsumetee S, Rich JN, Reardon DA. Diagnosis and treatment of high-grade astrocytoma. Neurol Clin 2007;25:1111-1139. [CrossRef][ISI][Medline]
4. Fisher JL, Schwartzbaum JA, Wrensch M, Wiemels JL. Epidemiology of brain tumors. Neurol Clin 2007;25:867-890. [CrossRef][ISI][Medline]
5. Hardell L, Carlberg M, Soderqvist F, Mild KH, Morgan LL. Long-term use of cellular phones and brain tumours: increased risk associated with use for > or =10 years. Occup Environ Med 2007;64:626-632. [Free Full Text]
6. Lahkola A, Auvinen A, Raitanen J, et al. Mobile phone use and risk of glioma in 5 North European countries. Int J Cancer 2007;120:1769-1775. [CrossRef][ISI][Medline]
7. Inskip PD, Tarone RE, Hatch EE, et al. Cellular-telephone use and brain tumors. N Engl J Med 2001;344:79-86. [Free Full Text]
8. Linos E, Raine T, Alonso A, Michaud D. Atopy and risk of brain tumors: a meta-analysis. J Natl Cancer Inst 2007;99:1544-1550. [Free Full Text]
9. Wrensch M, Wiencke JK, Wiemels J, et al. Serum IgE, tumor epidermal growth factor receptor expression, and inherited polymorphisms associated with glioma survival. Cancer Res 2006;66:4531-4541. [Free Full Text]
10. Farrell CJ, Plotkin SR. Genetic causes of brain tumors: neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and other syndromes. Neurol Clin 2007;25:925-946. [CrossRef][ISI][Medline]
11. Malmer B, Adatto P, Armstrong G, et al. GLIOGENE, an international consortium to understand familial glioma. Cancer Epidemiol Biomarkers Prev 2007;16:1730-1734. [Free Full Text]
12. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol (Berl) 2007;114:97-109. [Erratum, Acta Neuropathol 2007;114:547.] [CrossRef][Medline]
13. Nutt CL, Mani DR, Betensky RA, et al. Gene expression-based classification of malignant gliomas correlates better with survival than histological classification. Cancer Res 2003;63:1602-1607. [Free Full Text]
14. Pelloski CE, Ballman KV, Furth AF, et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol 2007;25:2288-2294. [Free Full Text]
15. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997-1003. [Free Full Text]
16. Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 2006;9:157-173. [CrossRef][ISI][Medline]
17. Collins VP. Mechanisms of disease: genetic predictors of response to treatment in brain tumors. Nat Clin Pract Oncol 2007;4:362-374. [CrossRef][ISI][Medline]
18. Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 2007;21:2683-2710. [Free Full Text]
19. Lee da Y, Gutmann DH. Cancer stem cells and brain tumors: uprooting the bad seeds. Expert Rev Anticancer Ther 2007;7:1581-1590. [CrossRef][ISI][Medline]
20. Chi AS, Wen PY. Inhibiting kinases in malignant gliomas. Expert Opin Ther Targets 2007;11:473-496. [CrossRef][ISI][Medline]
21. Sathornsumetee S, Reardon DA, Desjardins A, Quinn JA, Vredenburgh JJ, Rich JN. Molecularly targeted therapy for malignant glioma. Cancer 2007;110:13-24. [CrossRef][ISI][Medline]
22. Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol 2007;170:1445-1453. [Free Full Text]
23. Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 1996;6:217-223. [ISI][Medline]
24. Ueki K, Ono Y, Henson JW, Efird JT, von Deimling A, Louis DN. CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res 1996;56:150-153. [Free Full Text]
25. Lee JC, Vivanco I, Beroukhim R, et al. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med 2006;3:e485-e485. [CrossRef][Medline]
26. Kesari S, Stiles CD. The bad seed: PDGF receptors link adult neural progenitors to glioma stem cells. Neuron 2006;51:151-153. [CrossRef][ISI][Medline]
27. Steck PA, Perhouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997;15:356-362. [CrossRef][ISI][Medline]
28. Guo P, Hu B, Gu W, et al. Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am J Pathol 2003;162:1083-1093. [Free Full Text]
29. Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev Neurosci 2007;8:610-622. [ISI][Medline]
30. Ligon KL, Huillard E, Mehta S, et al. Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron 2007;53:503-517. [CrossRef][ISI][Medline]
31. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992;255:1707-1710. [Free Full Text]
32. Assanah M, Lochhead R, Ogden A, Bruce J, Goldman J, Canoll P. Glial progenitors in adult white matter are driven to form malignant gliomas by platelet-derived growth factor-expressing retroviruses. J Neurosci 2006;26:6781-6790. [Free Full Text]
33. Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med 2005;353:811-822. [Free Full Text]
34. Stiles CD, Rowitch DH. Glioma stem cells: a midterm exam. Neuron 2008;58:832-846. [CrossRef][ISI][Medline]
35. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004;432:396-401. [CrossRef][ISI][Medline]
36. Dirks PB. Brain tumor stem cells: bringing order to the chaos of brain cancer. J Clin Oncol 2008;26:2916-2924. [Free Full Text]
37. Beier D, Hau P, Proescholdt M, et al. CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 2007;67:4010-4015. [Free Full Text]
38. Vescovi AL, Galli R, Reynolds BA. Brain tumour stem cells. Nat Rev Cancer 2006;6:425-436. [CrossRef][ISI][Medline]
39. Bao S, Wu Q, Sathornsumetee S, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 2006;66:7843-7848. [Free Full Text]
40. Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007;11:69-82. [CrossRef][ISI][Medline]
41. Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444:756-760. [CrossRef][ISI][Medline]
42. Liu G, Yuan X, Zeng Z, et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 2006;5:67-67. [CrossRef][Medline]
43. Salmaggi A, Boiardi A, Gelati M, et al. Glioblastoma-derived tumorospheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype. Glia 2006;54:850-860. [CrossRef][ISI][Medline]
44. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer 2005;5:275-284. [CrossRef][ISI][Medline]
45. Cha S. Update on brain tumor imaging: from anatomy to physiology. AJNR Am J Neuroradiol 2006;27:475-487. [Free Full Text]
46. Young GS. Advanced MRI of adult brain tumors. Neurol Clin 2007;25:947-973. [CrossRef][ISI][Medline]
47. Chen W. Clinical applications of PET in brain tumors. J Nucl Med 2007;48:1468-1481. [Free Full Text]
48. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 2008;9:453-461. [CrossRef][ISI][Medline]
49. Wen PY, Schiff D, Kesari S, Drappatz J, Gigas D, Doherty L. Medical management of patients with brain tumors. J Neurooncol 2006;80:313-332. [CrossRef][Medline]
50. Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54:1886-1893. [Free Full Text]
51. Green H, Paul M, Vidal L, Leibovici L. Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials. Mayo Clin Proc 2007;82:1052-1059. [ISI][Medline]
52. Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83-95. [CrossRef][ISI][Medline]
53. Gerber DE, Grossman SA, Streiff MB. Management of venous thromboembolism in patients with primary and metastatic brain tumors. J Clin Oncol 2006;24:1310-1318. [Free Full Text]
54. Ruff RL, Posner JB. Incidence and treatment of peripheral venous thrombosis in patients with glioma. Ann Neurol 1983;13:334-336. [CrossRef][ISI][Medline]
55. Levin JM, Schiff D, Loeffler JS, Fine HA, Black PM, Wen PY. Complications of therapy for venous thromboembolic disease in patients with brain tumors. Neurology 1993;43:1111-1114. [Free Full Text]
56. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-153. [Free Full Text]
57. Meyers CA, Weitzner MA, Valentine AD, Levin VA. Methylphenidate therapy improves cognition, mood, and function of brain tumor patients. J Clin Oncol 1998;16:2522-2527. [Abstract]
58. Shaw EG, Rosdhal R, D'Agostino RB Jr, et al. Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. J Clin Oncol 2006;24:1415-1420. [Free Full Text]
59. Litofsky NS, Farace E, Anderson F Jr, Meyers CA, Huang W, Laws ER Jr. Depression in patients with high-grade glioma: results of the Glioma Outcomes Project. Neurosurgery 2004;54:358-366. [ISI][Medline]
60. Asthagiri AR, Pouratian N, Sherman J, Ahmed G, Shaffrey ME. Advances in brain tumor surgery. Neurol Clin 2007;25:975-1003. [CrossRef][ISI][Medline]
61. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 2006;7:392-401. [CrossRef][ISI][Medline]
62. Lacroix M, Abi-Said D, Fourney D, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 2001;95:190-198. [ISI][Medline]
63. Walker MD, Alexander E Jr, Hunt WE, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial. J Neurosurg 1978;49:333-343. [ISI][Medline]
64. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-996. [Free Full Text]
65. Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology 1980;30:907-911. [Free Full Text]
66. Selker RG, Shapiro WR, Burger P, et al. The Brain Tumor Cooperative Group NIH Trial 87-01: a randomized comparison of surgery, external radiotherapy, and carmustine versus surgery, interstitial radiotherapy boost, external radiation therapy, and carmustine. Neurosurgery 2002;51:343-355. [ISI][Medline]
67. Souhami L, Seiferheld W, Brachman D, et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 2004;60:853-860. [CrossRef][ISI][Medline]
68. Tsao MN, Mehta MP, Whelan TJ, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys 2005;63:47-55. [ISI][Medline]
69. Stupp R, Hegi ME, Gilbert MR, Chakravarti A. Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol 2007;25:4127-4136. [Free Full Text]
70. Duda DG, Jain RK, Willett CG. Antiangiogenics: the potential role of integrating this novel treatment modality with chemoradiation for solid cancers. J Clin Oncol 2007;25:4033-4042. [Free Full Text]
71. Keime-Guibert F, Chinot O, Taillandier L, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med 2007;356:1527-1535. [Free Full Text]
72. Roa W, Brasher PM, Bauman G, et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 2004;22:1583-1588. [Free Full Text]
73. Glantz M, Chamberlain M, Liu Q, Litofsky NS, Recht LD. Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas. Cancer 2003;97:2262-2266. [CrossRef][ISI][Medline]
74. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol 2001;19:509-518. [Free Full Text]
75. Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 1993;71:2585-2597. [CrossRef][ISI][Medline]
76. Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 2002;359:1011-1018. [CrossRef][ISI][Medline]
77. Westphal M, Hilt D, Bortey E, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 2003;5:79-88. [Abstract]
78. Westphal M, Ram Z, Riddle V, Hilt D, Bortey E. Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien) 2006;148:269-275. [CrossRef][Medline]
79. van den Bent MJ. Anaplastic oligodendroglioma and oligoastrocytoma. Neurol Clin 2007;25:1089-1109. [CrossRef][ISI][Medline]
80. Jenkins RB, Blair H, Ballman KV, et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res 2006;66:9852-9861. [Free Full Text]
81. Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998;90:1473-1479. [Free Full Text]
82. Ino Y, Betensky RA, Zlatescu MC, et al. Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis. Clin Cancer Res 2001;7:839-845. [Free Full Text]
83. Ngo TT, Peng T, Liang XJ, et al. The 1p-encoded protein stathmin and resistance of malignant gliomas to nitrosoureas. J Natl Cancer Inst 2007;99:639-652. [Free Full Text]
84. Cairncross G, Berkey B, Shaw E, et al. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol 2006;24:2707-2714. [Free Full Text]
85. van den Bent MJ, Carpentier AF, Brandes AA, et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol 2006;24:2715-2722. [Free Full Text]
86. Keles GE, Lamborn KR, Chang SM, Prados MD, Berger MS. Volume of residual disease as a predictor of outcome in adult patients with recurrent supratentorial glioblastomas multiforme who are undergoing chemotherapy. J Neurosurg 2004;100:41-46. [ISI][Medline]
87. Butowski NA, Sneed PK, Chang SM. Diagnosis and treatment of recurrent high-grade astrocytoma. J Clin Oncol 2006;24:1273-1280. [Free Full Text]
88. Combs SE, Thilmann C, Edler L, Debus J, Schulz-Ertner D. Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients treated in a single institution. J Clin Oncol 2005;23:8863-8869. [Free Full Text]
89. Yung WK, Prados MD, Yaya-Tur R, et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse: Temodal Brain Tumor Group. J Clin Oncol 1999;17:2762-2771. [Erratum, J Clin Oncol 1999;17:3693.] [Free Full Text]
90. 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 1999;17:2572-2578. [Free Full Text]
91. 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 2000;83:588-593. [CrossRef][ISI][Medline]
92. Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent malignant gliomas: the Polymer-brain Tumor Treatment Group. Lancet 1999;345:1008-1012.
93. Rich JN, Reardon DA, Peery T, et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 2004;22:133-142. [Free Full Text]
94. Wen PY, Yung WK, Lamborn KR, et al. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res 2006;12:4899-4907. [Free Full Text]
95. Galanis E, Buckner JC, Maurer MJ, et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 2005;23:5294-5304. [Free Full Text]
96. Chang SM, Wen P, Cloughesy T, et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 2005;23:357-361. [CrossRef][ISI][Medline]
97. Cloughesy TF, Wen PY, Robins HI, et al. Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol 2006;24:3651-3656. [Free Full Text]
98. Stommel JM, Kimmelman AC, Ying H, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 2007;318:287-290. [Free Full Text]
99. Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005;353:2012-2024. [Erratum, N Engl J Med 2006;354:884.] [Free Full Text]
100. Haas-Kogan DA, Prados MD, Lamborn KR, Tihan T, Berger MS, Stokoe D. Biomarkers to predict response to epidermal growth factor receptor inhibitors. Cell Cycle 2005;4:1369-1372. [ISI][Medline]
101. Fine HA, Wen PY, Maher EA, et al. Phase II trial of thalidomide and carmustine for patients with recurrent high-grade gliomas. J Clin Oncol 2003;21:2299-2304. [Free Full Text]
102. Vredenburgh JJ, Desjardins A, Herndon JE II, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 2007;13:1253-1259. [Free Full Text]
103. Vredenburgh JJ, Desjardins A, Herndon JE II, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007;25:4722-4729. [Free Full Text]
104. Cloughesy TF, Prados MD, Wen PY, et al. A phase II, randomized, non-comparative clinical 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 2008;26:Suppl:91s-91s.
105. Fulci G, Chiocca EA. The status of gene therapy for brain tumors. Expert Opin Biol Ther 2007;7:197-208. [CrossRef][ISI][Medline]
106. Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Bigner DD. Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol (in press).
107. Reardon DA, Akabani G, Coleman RE, et al. Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results. J Clin Oncol 2006;24:115-122. [Free Full Text]
108. Mamelak AN, Rosenfeld S, Bucholz R, et al. Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma. J Clin Oncol 2006;24:3644-3650. [Free Full Text]
109. Ferguson S, Lesniak MS. Convection enhanced drug delivery of novel therapeutic agents to malignant brain tumors. Curr Drug Deliv 2007;4:169-180. [CrossRef][Medline]
110. Curran WJ Jr, Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 1993;85:704-710. [Free Full Text]
111. Brem SS, Bierman PJ, Black PH, et al. Central nervous system cancers. J Natl Compr Canc Netw 2008;6:456-504. [Medline]

Read More...

Summary only...

Sorafenib in Liver Cancer — Just the Beginning

Image via Wikipedia

Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of death from cancer, resulting in more than 600,000 deaths per year. The major risk factors for hepatocellular carcinoma are chronic hepatitis B or hepatitis C virus infection, alcoholic cirrhosis, and nonalcoholic steatohepatitis.1 Cancer probably develops in the cirrhotic liver through the induction of accelerated cycles of cell injury, death, and regeneration in an altered fibrotic and inflammatory microenvironment. Abnormal immortalized cell clones arise, and these cells develop genetic and epigenetic alterations that provide a survival and proliferative advantage, resulting in unconstrained proliferation, a key hallmark of cancer. Early-stage hepatocellular carcinoma is amenable to potentially curative therapies; however, only about 30% of patients who present at most centers have early-stage disease. Liver cancer in an intermediate or advanced stage is particularly difficult to treat, for several reasons. Liver cancers typically retain active drug-metabolizing systems that contribute to an intrinsic resistance to chemotherapy drugs. Liver cancers also have enhanced expression of transporters of the multidrug resistance protein family, which mediate the export of chemotherapeutic drugs across the plasma membrane. Other factors also militate against response to therapy. Many drugs have intrinsic hepatotoxicity that may exacerbate the underlying liver disease. Leukopenia and thrombocytopenia that are caused by splenic sequestration from portal hypertension compromise therapy with agents that induce bone marrow suppression.
Until now there has been no proven medical therapy for advanced hepatocellular carcinoma. Therefore, randomized, placebo-controlled trials involving patients with advanced hepatocellular carcinoma are ethical and scientifically desirable.2 We have entered an era of targeted therapies for human cancers that may be beneficial for both early-stage and advanced-stage tumors. Targeted therapies attack pathways that are critical for cancer survival and progression and minimize off-target toxicity. Active and sustained efforts to elucidate the molecular pathogenesis of hepatocellular carcinomas have demonstrated the critical importance of activation of growth signaling pathways, including multiple receptor tyrosine kinase pathways, and inactivation of key tumor-suppressor genes.3,4 The highly vascular nature of hepatocellular carcinoma reflects profound activation of angiogenic signaling pathways, many of which are activated through receptor tyrosine kinases, resulting in stimulation of the Ras GTPase and Raf and mitogen-activated protein kinase molecules and their downstream targets, including the c-jun and c-fos transcriptional activators.

With the recently acquired elucidation of critical pathways for cancer survival and progression and the advent of new small-molecule and antibody-based therapies against cellular growth signaling and angiogenic pathways, investigators have looked with hope to the potential use of such targeted agents against this intractable cancer. A number of phase 1 and 2 studies have suggested that targeted agents that are administered singly or in combination may provide meaningful improvements in survival for patients with hepatocellular carcinoma. Notably, these targeted agents do not induce the tumor involution and radiologic remission typical of the cytotoxic chemotherapies but rather result in disease stabilization and prolongation of survival, a new paradigm in cancer therapeutics.

In this issue of the Journal, Llovet et al. describe the positive results of a phase 3 study called the Sorafenib Hepatocarcinoma Assessment Randomized Protocol (SHARP; ClinicalTrials.gov number, NCT00105443 [ClinicalTrials.gov] ), which assessed the use of sorafenib in patients with unresectable hepatocellular carcinoma.5 Sorafenib, a bisaryl urea, potently inhibits the serine–threonine kinase Raf-1 and both wild-type and V600E mutant variants of the Raf homologue B-Raf.6,7 In addition, sorafenib has substantial activity against multiple-receptor tyrosine kinases involved in tumor growth and angiogenesis, including vascular endothelial growth factor receptor (VEGFR) 1, VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor β. In preclinical studies, sorafenib showed broad antitumor activity against colon, breast, and non–small-cell lung cancers and in liver xenograft models. The drug was approved for the treatment of advanced renal-cell carcinoma in 2005 and showed promising results in both phase 1 and 2 studies involving patients with hepatocellular carcinoma.

The investigators in the SHARP trial observed that in a population of patients with relatively preserved liver function (Child–Pugh class A cirrhosis), the use of sorafenib resulted in a modest but significant 3-month gain in survival over placebo. This improvement in survival occurred despite a surprisingly limited partial response rate of 2%. Survival was extended because the drug was able to retard tumor progression. This represents an important first step in the application of targeted therapies for hepatocellular carcinoma. On the basis of these results, sorafenib was approved for the treatment of advanced hepatocellular carcinoma by the European Agency for the Evaluation of Medicinal Products in October 2007 and by the Food and Drug Administration in November 2007.

We now look forward to combination trials of sorafenib and similar agents with other treatment approaches and classes of agents to determine whether progressive improvement in survival can be achieved, as has occurred in the treatment of other solid tumors. For example, during the past 10 years, chemotherapy for colorectal cancer has advanced from single-agent therapy with fluorouracil to combination therapy with oxaliplatin, irinotecan, bevacizumab, cetuximab, or panitumumab. These advances have resulted in an increase in the overall survival of patients with advanced colorectal cancer from 6 months with best supportive care to more than 2 years with the use of various combinations of active agents.8

The advent of sorafenib now provides a benchmark against which other agents and combinations can be tested. In particular, given that the SHARP study almost exclusively involved patients with Child–Pugh class A cirrhosis and relatively compensated liver disease, it will be important to determine the efficacy and side-effect profile of sorafenib in patients with Child–Pugh class B cirrhosis. Other important questions are whether the drug prevents disease recurrence after surgery or ablative therapies or extends survival in patients undergoing chemoembolization.

It will be important to carefully monitor adverse events associated with sorafenib in postmarketing surveillance to ensure that no additional risks are identified in patients with liver cancer. Key side effects in patients with renal-cell carcinoma include a significant risk of hypertension and other cardiovascular complications.9 Sorafenib has also been implicated in the development of the reversible posterior leukoencephalopathy syndrome. Other important adverse effects include diarrhea, weight loss, rash, fatigue, and hand–foot skin reactions.

In summary, the SHARP trial sets a benchmark for a new era of targeted therapies in hepatocellular carcinoma. These results give hope for further advances in therapy during the exploration of the potential efficacy of sorafenib and other agents in combination with local or locoregional therapies.

A final, necessary concern that applies particularly to the era of targeted therapies for cancer is the issue of cost. The pharmacy price of sorafenib is approximately $5,400 per month in the United States, {euro}3,562 per month in France, $1,400 per month in Korea, and $7,300 per month in China. Even in industrial nations, the high cost of new drugs produces significant stresses on health-system budgets. As we have learned in recent years from the worldwide epidemic of the acquired immunodeficiency syndrome, there are substantial ethical implications in having effective therapies available for life-threatening diseases that are priced beyond the reach of the populations most in need of therapy. This is particularly applicable for liver cancer. Although the disease is the third most common cause of death from cancer worldwide, over half of the more than 600,000 deaths per year occur in China alone, and most of the remaining deaths occur in poor countries of sub-Saharan Africa. We therefore have another dilemma on hand — that of having coals in Newcastle without the ability to distribute them through the countryside. This situation stresses the importance of worldwide public–private partnerships to enhance the research enterprise, bring new agents to market in a more cost-effective fashion, and provide effective therapies to suffering patients at costs that are within their reach.

Dr. Roberts reports receiving consulting fees from Isis Pharmaceuticals and Rosetta Genomics and grant support from Wako Diagnostics. No other potential conflict of interest relevant to this article was reported.


Source Information

From the Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, MN.
NEJM

Read More...

Summary only...