Management of central nervous system tumours in the elderly.

Brain tumours in the elderly show differences from the general population in their spectrum of incidence, their molecular profile and their response to treatment. Furthermore, this population also finds it more difficult to tolerate the treatments applied to younger patients. For these reasons it is justified to investigate older patients separately and to devise treatments applicable specifically to this population. In recent years important information has come from the research literature that allows us to make specific recommendations for the management of elderly patients with brain tumours. Here we review the important publications and document these recommendations.

Chk1 is essential for chemical carcinogen-induced mouse skin tumorigenesis.

Chk1 is a key regulator of DNA damage checkpoint responses and genome stability in eukaryotes. To better understand how checkpoint proficiency relates to cancer development, we investigated the effects of genetic ablation of Chk1 in the mouse skin on tumors induced by chemical carcinogens. We found that homozygous deletion of Chk1 immediately before carcinogen exposure strongly suppressed benign tumor (papilloma) formation, and that the few, small lesions that formed in the ablated skin always retained Chk1 expression. Remarkably, Chk1 deletion rapidly triggered spontaneous cell proliferation, γ-H2AX staining and apoptosis within the hair follicle, a principal site of origin for carcinogen-induced tumors. At later times, the ablated skin was progressively repopulated by non-recombined Chk1-expressing cells and ultimately normal sensitivity to tumor induction was restored when carcinogen treatment was delayed. In marked contrast, papillomas formed normally in Chk1 hemizygous skin but showed an increased propensity to progress to carcinoma. Thus, complete loss of Chk1 is incompatible with epithelial tumorigenesis, whereas partial loss of function (haploinsufficiency) fosters benign malignant tumor progression.

The concepts, diagnosis and management of early imaging changes after therapy for glioblastomas.

Since postoperative radiotherapy plus concomitant temozolomide followed by adjuvant temozolomide has become standard treatment for glioblastoma, the phenomenon of early post-treatment enlargement of the imaged tumour volume, usually without clinical deterioration, has become widely recognised. The term pseudoprogression has been used to describe a poorly understood pathophysiological process. In this review, the pathophysiological concepts, relevance, diagnosis and management of patients with 'pseudoprogression' and 'pseudoresponse' are discussed. Guidelines are given with respect to radiological imaging modality, mode and frequency. Further biological and clinical insights into these phenomena require carefully designed prospective studies.

Assessment in vitro of a novel therapeutic strategy for glioma, combining herpes simplex virus HSV1716-mediated oncolysis with gene transfer and targeted radiotherapy.

Genetically engineered herpes simplex virus ICP34.5 null mutants replicate only in dividing cells and have shown potential for the treatment of malignant disease, including glioma. Phase I trials have demonstrated the safety of these viruses in various clinical settings but it is envisaged that for full efficacy they will be used in combination with other therapeutic modalities. To enhance virus-induced tumour cytotoxicity, we have engineered an ICP34.5 null mutant (HSV1716) of HSV1 which expresses the noradrenaline transporter gene (NAT). This virus is designated HSV1716/NAT. We have shown previously that introduction of the NAT gene into a range of tumour cells, via plasmid-mediated transfection, conferred the capacity for active uptake of the radiopharmaceutical [131I]MIBG and resulted in dose-dependent toxicity. In this study, combination therapy utilising HSV1716/NAT and [131I]MIBG was assessed in vitro by the MTT assay. We demonstrate that the NAT gene, introduced by HSV1716/NAT into cultured glioma cells, was expressed 1 h after viral infection, enabling active uptake of [131I]MIBG. The combination of viral oncolysis and induced radiopharmaceutical uptake resulted in significantly enhanced cytotoxicity compared to either agent alone and the response was dose- and time-dependent. These studies show that the combination of oncolytic HSV therapy with targeted radiotherapy has the potential for effective tumour cell kill and warrants further investigation as a treatment for malignant glioma.

HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: safety data and long-term survival.

Following standard treatment, the prognosis remains poor in patients with high-grade glioma and new therapies are urgently required. Herpes simplex virus 1716 (HSV1716) is an ICP34.5 null mutant that is selectively replication competent and shown to be safe and to replicate following injection into high-grade glioma. We demonstrate that following surgical resection, HSV1716 is safe when injected into the brain adjacent to excised tumour. In all, 12 patients with recurrent or newly diagnosed high-grade glioma underwent maximal resection of the tumour. HSV1716 was injected into eight to 10 sites around the resulting tumour cavity with the intent of infecting residual tumour cells. As clinically indicated, patients proceeded to further radiotherapy or chemotherapy. There has been no clinical evidence of toxicity associated with the administration of HSV1716. Longitudinal follow-up has allowed the assessment of overall survival compared to that of similar patients not treated with HSV1716. Three patients remain alive and clinically stable at 15, 18 and 22 months postsurgery and HSV1716 injection. Remarkably, the first patient in the trial, who had extensive recurrent disease preprocedure, is alive at 22 months since injection of HSV1716 and 29 months since first diagnosis. Imaging has demonstrated a reduction of residual tumour over the 22-month period despite no further medical intervention since the surgery and HSV1716 injection. In this study, we demonstrate that on the basis of clinical observations, there has been no toxicity following the administration of HSV1716 into the resection cavity rim in patients with high-grade glioma. The survival and imaging data, in addition to the lack of toxicity, give us confidence to proceed to a clinical trial to demonstrate efficacy of HSV1716 in glioma patients.

Updated European core curriculum for radiotherapists (radiation oncologists). Recommended curriculum for the specialist training of medical practitioners in radiotherapy (radiation oncology) within Europe.

AIM: To produce updated state-of-the-art recommendations for harmonised medical specialist training in radiotherapy within Europe. MATERIAL AND METHODS: The Minimum Curriculum for the Theoretical Education in Radiation Oncology in Europe from 1991 was updated under consideration of new developments in medicine in general, and in radiotherapy and its basic sciences in particular. Recent medical developments, national guidelines and training programmes from European countries, as well as equivalent documents from the USA and Australia were reviewed by an expert panel jointly appointed by the European Society of Therapeutic Radiology and Oncology and the European Board of Radiotherapy. A draft document prepared by this group was circulated among the national and professional societies for radiotherapy in Europe for review before a European consensus conference took place in Brussels in December 2002. RESULTS: The updated European Core Curriculum for Radiotherapists (Radiation Oncologists) was endorsed by representatives of 35 European nations during the Brussels consensus conference on December 14, 2002. Compared to the earlier version the updated document contains specific recommendations not only for the 5 year training curriculum but also for organisatoric and infrastructural aspects of teaching departments, and for supplementation of the training by formal teaching courses. CONCLUSION: The updated European core curriculum is an important step on the way to fully harmonise medical specialist training in Europe and to guarantee equal access for all European citizens to highest quality medical care. The responsibility for the implementation of the standards and guidelines set in the updated Core Curriculum for radiotherapy (radiation oncology) will lie with the local and/or national training bodies and authorities.

Phase II study of XR5000 (DACA) administered as a 120-h infusion in patients with recurrent glioblastoma multiforme.

BACKGROUND: XR5000 is a tricyclic carboxamide that intercalates DNA and inhibits both topoisomerase I and II. The aim of this study was to evaluate the efficacy and tolerability of XR5000 in patients with recurrent glioblastoma multiforme previously untreated with chemotherapy at relapse. PATIENTS AND METHODS: Patients received XR5000 at a dose of 3010 mg/m2 as a 120-h central venous infusion every 3 weeks. An independent panel assessed response every two cycles using McDonald's criteria (tumour size, steroid intake and neurological status); toxicity was graded according to the National Cancer Institute-Common Toxicity Criteria, version 2.0. RESULTS: Sixteen patients were enrolled (one ineligible patient was excluded from efficacy evaluation). Performance status was zero (five patients), one (nine patients) or two (one patient). They received 30 cycles of XR5000 (median 2, range 1-5). Haematological toxicity was mild, with only one patient experiencing grade 3 neutropenia. Other related grade 3/4 adverse events included chest pain (one patient), axillary vein thrombosis (one patient) and rigors/fever in the absence of neutropenia (one patient). There were no objective responses, 14 patients progressing on XR5000 and one having stable disease. CONCLUSIONS: Although XR5000 was generally well tolerated, these results do not support further evaluation in patients with glioblastoma multiforme using this dose and schedule.

The potential for efficacy of the modified (ICP 34.5(-)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study.

We have previously demonstrated the safety of intratumoural administration of the selectively replication-competent herpes simplex virus mutant HSV1716 in patients with high-grade glioma (HGG). Here we show its potential for efficacy by demonstrating that the virus survives and replicates when injected into the tumours of patients. Since HSV replication is a cytolytic process it must result in tumour cell killing. Twelve patients with biopsy-verified HGG received an intratumoural injection of 10(5) plaque-forming units (p.f.u.) of HSV1716. Four to 9 days after inoculation, tumours were removed and assayed for evidence of viral replication. In two patients, HSV1716, in excess of the input dose was recovered from the injection site. HSV DNA was detected by PCR at the sites of inoculation in 10 patients and at distal tumour sites in four. HSV-specific antigen was detected in tumour tissue from two patients. In five patients an immunological response to HSV1716, as detected by changes in levels of IgG and IgM, was demonstrated. This study demonstrates that HSV1716 replicates in HGG without causing toxicity in both HSV-seropositive and -seronegative patients.

Don't wait for a sensory level--listen to the symptoms: a prospective audit of the delays in diagnosis of malignant cord compression.

AIM: To report details concerning symptoms (especially pain) preceding the development of malignant cord compression (MCC); delays between onset/reporting of symptoms and confirmed diagnosis of MCC; accuracy of investigations carried out. METHODS: A prospective observational study examined the diagnosis, management and outcome of 319 patients diagnosed with MCC at three Scottish cancer centres between January 1998-April 1999. The process was considered from the perspectives of the patient, the GP and the hospital doctor. RESULTS: At diagnosis, most patients (82%) were either unable to walk or only able to do so with help. Pain was reported by nearly all patients interviewed (94%) and had been present for approximately 3 months (median=90 days). It was severe in 84% of cases, with the distribution and characteristics of nerve root pain in 79%. The site of pain did not correspond to the site of compression. Where reported, weakness and/or sensory problems had been noticed by the patient for some time before diagnosis (median intervals 20 and 12 days, respectively). Most patients reported early symptoms to their General Practitioner (GP) and diagnosis was established, following referral and investigation, approximately 2 months (median=66 days) later. CONCLUSION: Patients who develop spinal metastases are at risk of irreversible spinal cord damage. Weakness and sensory abnormalities are reported late and identified even later, despite patients having reported pain for a considerable time. Patients with cancer who describe severe back or spinal nerve root pain need urgent assessment on the basis of their symptoms, as signs may occur too late. Plain films and bone scans requested for patients in this audit predicted accurately the level of compression in only 21% and 19% of cases, respectively. The only accurate investigation to establish the presence and site of a compressive lesion is magnetic resonance imaging (MRI). A referral guideline based on suspicious symptoms in addition to suspicious signs is suggested.

Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse.

BACKGROUND: Recurrent glioblastoma multiforme (GBM) is resistant to most therapeutic endeavors, with low response rates and survival rarely exceeding six months. There are no clearly established chemotherapeutic regimens and the aim of treatment is palliation with improvement in the quality of life. PATIENTS AND METHODS: We report an open-label, uncontrolled, multicenter phase II trial of temozolomide in 138 patients (intent-to-treat [ITT] population) with glioblastoma multiforme at first relapse and a Karnofsky performance status (KPS) > or = 70. One hundred twenty-eight patients were histologically confirmed with GBM or gliosarcoma (GS) by independent central review. Chemotherapy-naïve patients were treated with temozolomide 200 mg/m2/day orally for the first five days of a 28-day cycle. Patients previously treated with nitrosourea-containing adjuvant chemotherapy received 150 mg/m2/day for the first five days of a 28-day cycle. In the absence of grade 3 or 4 toxicity, patients on the 150 mg/m2 dose schedule were eligible for a 200 mg/m2 dose on the next cycle. RESULTS: The primary endpoint was six-month progression-free survival assessed with strict radiological and clinical criteria. Secondary endpoints included radiological response and Health-related Quality of Life (HQL). Progression-free survival at six months was 18% (95% confidence interval (CI): 11%-26%) for the eligible-histology population. Median progression-free survival and median overall survival were 2.1 months and 5.4 months, respectively. The six-month survival rate was 46%. The objective response rate (complete response and partial response) determined by independent central review of gadolinium-enhanced magnetic resonance imaging (MRI) scans was 8% for both the ITT and eligible-histology populations, with an additional 43% and 45% of patients, respectively, having stable disease (SD). Objectively assessed response and maintenance of a progression-free status were both associated with HQL benefits (characterized by improvements over baseline in HQL domains). Temozolomide had an acceptable safety profile, with only 9% of therapy cycles requiring a dose reduction due to thrombocytopenia. There was no evidence of cumulative hematologic toxicity. CONCLUSIONS: Temozolomide demonstrated modest clinical efficacy, with an acceptable safety profile and measurable improvement in quality of life in patients with recurrent GBM. The use of this drug should be explored further in an adjuvant setting and in combination with other agents.

Long-term survival following extra-neural metastasis from a pineoblastoma.

A young woman presented with a pineoblastoma treated initially with whole neuraxis radiotherapy. She had biopsy confirmed metastatic disease to the left lateral pelvis which was treated on 2 separate occasions, and biopsy confirmed metastatic disease to the subcutaneous tissues of the left thigh. She currently remains well 8 years after the primary diagnosis and 6 years after the first systemic relapse.

A medical research council randomized trial in patients with primary cerebral non-Hodgkin lymphoma: cerebral radiotherapy with and without cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy.

BACKGROUND: The role of chemotherapy in the treatment of patients with primary central nervous system lymphoma (PCL) remains unclear, with no randomized trials available to aid in the interpretation of the current data. The Medical Research Council therefore conducted the current randomized trial to assess the impact on survival of postradiotherapy chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in nonimmunocompromised adult patients with pathologically proven PCL. METHODS: After surgery, patients were randomized at a ratio of 1:2 to radiotherapy alone (RT: 40 grays [Gy] in 20 fractions to the whole brain followed by a 14-Gy boost to the tumor plus a 2-cm tumor margin) or to the same radiotherapy followed by six cycles of CHOP chemotherapy given at 3-week intervals (RT-CHOP). The target sample size was 90 patients, which allowed 90% power to detect a doubling of the median survival time. RESULTS: Between 1988 and 1995, 53 patients were randomized: Fifteen patients were randomized to RT, and 38 patients were randomized to RT-CHOP. The trial closed earlier than planned through poor accrual. The median patient age was 57 years, 57% of the patients were male, and 75% of the patients had unifocal disease. The median number of chemotherapy cycles received was 6 (mean, 4 cycles). Forty-three patients have died, and the median follow-up of survivors is 5 years (range, 1-9 years). There was no evidence of a benefit from RT-CHOP with respect to overall survival (hazard ratio [HR], 1.19; 95% confidence interval, 0.51-2.76) after adjustment for prognostic factors (patient age and neurologic performance status) in an analysis in which HR > 1 favored the control (RT) group. CONCLUSIONS: CHOP has no clear role in the postradiotherapy treatment of patients with PCL. Chemotherapy is poorly tolerated and largely palliative in older, less fit patients. In younger patients, initial chemotherapy designed to penetrate the blood-brain barrier warrants further investigation.

A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.

A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.

Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma.

The herpes simplex virus (HSV) ICP34.5 null mutant 1716 replicates selectively in actively dividing cells and has been proposed as a potential treatment for cancer, particularly brain tumours. We present a clinical study to evaluate the safety of 1716 in patients with relapsed malignant glioma. Following intratumoural inoculation of doses up to 10(5) p.f.u., there was no induction of encephalitis, no adverse clinical symptoms, and no reactivation of latent HSV. Of nine patients treated, four are currently alive and well 14-24 months after 1716 administration. This study demonstrates the feasibility of using replication-competent HSV in human therapy.

Non-Hodgkin's lymphoma presenting with spinal cord compression; a clinicopathological review of 25 cases.

The aim of this study was to retrospectively examine 25 patients with newly diagnosed non-Hodgkin's lymphoma (NHL) presenting with spinal cord or cauda equina compression as the first symptom that were referred to our department between 1985 and 1996. At presentation 17 patients were non-ambulatory; dual sphincter impairment was found in 9 patients with a further 8 patients having bladder dysfunction only. All patients had a tissue diagnosis. Five low-grade and 20 intermediate or high-grade tumours were identified. In this latter group 4 patients were treated palliatively and the remaining 16 patients received combination chemotherapy and/or radical radiation therapy. The overall survival at 5 years is 59%. The majority of patients became ambulatory, even if paretic at presentation. This is in marked contrast to reports of patients presenting in this fashion due to metastatic carcinoma. We urge this diagnosis be considered in all patients presenting with spinal cord compression attributed to malignancy.

Comparison of different methods of intracerebral administration of radioiododeoxyuridine for glioma therapy using a rat model.

The Auger electron emitting agent 5-[125I]iodo-2'-deoxyuridine (i.e. [125I]IUdR) holds promise for the treatment of residual glioma after surgery because this thymidine analogue kills only proliferating cells. However, malignant cells which are not synthesizing DNA during exposure to the radiopharmaceutical will be spared. To determine whether tumour incorporation of [125I]IUdR could be enhanced by protracted administration, we used a C6 cell line, growing in the brains of Wistar rats, as a glioma model and compared three methods of intracerebral delivery of [125I]IUdR. Twenty-four hours after administration of drug, autoradiography of brain sections demonstrated nuclear uptake of the radiopharmaceutical in cells throughout tumour while normal brain cells remained free of radioactivity. The [125I]IUdR labelling indices (% +/- s.e.m.) achieved were 6.2 (0.4) by single injection, 22.5 (4.1) using a sustained release polymer implant (poly(lactide-co-glycolide)) and 34.3 (2.0) by mini-osmotic pump. These results emphasize the need for a sustained delivery system as a prerequisite for effective treatment. These findings are also encouraging for the development of a sustained release system for radiolabelled IUdR for use in the treatment of intracranial tumours, particularly in the immediate postoperative setting.

Radiation myelopathy.

Radiation myelitis has long been recognised as a sinister consequence of spinal irradiation and has limited the acceptable dose of therapeutic radiation to the cord. Over the past 10 years, the pathogenesis has been increasingly understood through the use of animal models. The importance of 'dose per fraction' and 'inter-fraction interval' have been incorporated into new mathematical models which suggest that, for small fractions, the cord may tolerate higher doses of radiation than was previously thought. Clinical recognition of the condition has improved through the description of characteristic magnetic resonance imaging changes. However little advance has been made in its treatment.

Modern aspects of radiation therapy for glial tumours of the brain.

Radiation was conclusively proved to be of value in the treatment of malignant gliomas in the late 1970's where it enabled an approximate doubling of the survival time. Further study defined a number of prognostic factors which provide a basis for selecting patients for treatment. The introduction of computer tomography (and later magnetic resonance) scanning allowed a more rational approach to target volume definition and a reduction in radiation-related morbidity. Dose-ranging studies defined a standard approach to treatment (60 Gray in 30 fractions). Since then numerous attempts have been made to improve on these results. Marginal benefits have been claimed for altered fractionation schemes, limited volume dose escalation (implants and stereotaxy), radiation sensitisers and particle therapies. However none has become routine in clinical practice. Advances in planning technology have allowed a further reduction in the volume of normal brain irradiated and the potential for dose escalation. Low grade astrocytoma has not been examined in the same way and great doubt exists with respect to optimal treatment. There is a great opportunity for research to realise the potential in the new techniques for improving the outlook for patients with malignant glioma and in clarifying the role of radiation in low grade tumours.

Modelling the enhancement of fractionated radiotherapy by gene transfer to sensitize tumour cells to radiation.

BACKGROUND AND PURPOSE: Several strategies now exist for the use of gene transfer methodologies to sensitize tumour cells to radiation. These include the transfection of genes synthesizing cytokines, p53 gene replacement and methods based on the use of HSV-tk and gancyclovir. Very recently, the sequencing of radioprotector or repair genes, such as ATM, Ku80 and XRCC2, has made it possible to consider the design of gene transfer strategies resulting in protector gene knock-out. Selectivity of transfected gene expression might be achieved by use of tissue-specific promoters or by the trophism of viral vectors. The purpose of this study was to evaluate the probable efficacy of such strategies. METHODS: We have modelled gene transfer-mediated radiosensitization of tumour cells during radiotherapy, focusing on anti-protector gene strategies, to explore the role of transfection frequency, sensitizing efficacy, transfection stability, untransfectable subpopulations, the timing of gene therapy and the treatment schedule structure. RESULTS: We predict a substantial therapeutic benefit of gene transfer treatment (with at least weekly transfection) which modifies cellular radiosensitivity by a factor of 1.5 or more, despite modest efficiency of cellular transfection (e.g. 50%), transient retention of the transfected gene (e.g. 2-day half-life) and the existence of a small minority (e.g. 1%) of untransfectable cells. CONCLUSIONS: The analysis shows repeated administration of gene transfer treatment to be obligatory and implies that the existence of untransfectable minority subpopulations (i.e. cells inaccessible to the vector) will be the major limiting factor in therapy. Experimental work is needed to confirm these predictions before clinical studies begin.