David Husband

Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy

Background:Epigenetic silencing of O6-methylguanine-DNA-methyltransferase (MGMT) by promoter methylation is associated with improved survival in glioblastomas treated with alkylating agents. In this study, we investigated MGMT promoter methylation in glioblastomas treated with temozolomide and radiotherapy in a single UK treatment centre.Methods:Quantitative methylation data at individual CpG sites were obtained by pyrosequencing for 109 glioblastomas.Results:Median overall survival (OS) was 12.4 months with 2-year survival of 17.9%. Pyrosequencing data were reproducible with archival samples yielding data for all glioblastomas. Variation in methylation patterns of discrete CpG sites and intratumoral methylation heterogeneity were observed. A total of 58 out of 109 glioblastomas showed average methylation >non-neoplastic brain in at least one clinical sample; 86% had homogeneous methylation status in multiple samples. Methylation was an independent prognostic factor associated with prolonged progression-free survival (PFS) and OS. Cases with methylation more than 35% had the longest survival (median PFS 19.2; OS 26.2 months, 2-year survival of 59.7%). Significant differences in PFS were seen between those with intermediate or high methylation and unmethylated cases, whereas cases with low, intermediate or high methylation all showed significantly different OS.Conclusions:These data indicate that MGMT methylation is prognostically significant in glioblastomas given chemoradiotherapy in the routine clinic; furthermore, the extent of methylation may be used to provide additional prognostic stratification.

Management of cerebral metastasis: Evidence-based approach for surgery, stereotactic radiosurgery and radiotherapy

Brain metastases constitute a significant disease burden and have a major impact on morbidity and mortality. This review discusses the relative merits of open surgery, whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS), which have been used alone and in combination with varying degrees of success for the treatment of newly diagnosed brain metastasis. Treatment aims to provide disease control with a good quality of life, although prolonged survival may not always be achieved. Decision to treat is based on several prognostic factors including age, performance status and control of the primary cancer. The recently developed disease-specific graded prognostic assessment (DS-GPA) scales can aid in clinical decision making for individual patients. Whole brain radiotherapy remains the mainstay of treatment and provides effective palliation. Omission of WBRT results in worse local and distant control, though not survival. Local tumour control can be achieved by either resection of stereotactic radiosurgery (SRS). In long-term survivors WBRT may cause cognitive decline and SRS is being explored as an alternative method of disease control. Increasingly, quality of life and neuro-cognitive function are being used as end-points in clinical trials.

Cerebral blood volume, genotype and chemosensitivity in oligodendroglial tumours.

IntroductionThe biological factors responsible for differential chemoresponsiveness in oligodendroglial tumours with or without the −1p/−19q genotype are unknown, but tumour vascularity may contribute. We aimed to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) could distinguish molecular subtypes of oligodendroglial tumour, and examined the relationship between relative cerebral blood volume (rCBV) and outcome following procarbazine, lomustine and vincristine (PCV) chemotherapy.MethodsPretherapy rCBV was calculated and inter- and intraobserver variability assessed. Allelic imbalance in 1p36, 19q13, 17p13, 10p12–15, and 10q22–26 and p53 mutation (exons 5–8) were determined. rCBV was compared with genotype and clinicopathological characteristics (n=37) and outcome following PCV chemotherapy (n=33).Results1p/19q loss was seen in 6/9 grade II oligodendrogliomas, 6/14 grade II oligoastrocytomas, 4/4 grade III oligodendrogliomas, and 3/10 grade III oligoastrocytomas. rCBV measurements had good inter- and intraobserver variability, but did not distinguish histology subtype or grade. Tumours with 1p/19q loss had higher rCBV values (Student’s t-test P=0.001). Receiver operating characteristic analysis revealed a cut-off of 1.59 for identifying genotype (sensitivity 92%, specificity 76%). Tumours with high and low rCBV showed response to chemotherapy. The −1p/−19q genotype, but not rCBV, was strongly associated with response, progression-free and overall survival following PCV chemotherapy. Tumours with high rCBV and intact 1p/19q were associated with shorter progression-free and overall patient survival than those with intact 1p/19q and low rCBV or high rCBV and 1p/19q loss.ConclusionrCBV identifies oligodendroglial tumours with 1p/19q loss, but does not predict chemosensitivity. The prognostic significance of rCBV may differ in oligodendroglial tumours with or without the −1p/−19q genotype.

Molecular pathology and clinical characteristics of oligodendroglial neoplasms

To evaluate the role of molecular genetics in the routine clinic, we investigated allelic imbalance at 1p36, 19q13, 17p13, 10p12‐15, and 10q22‐26 and p53 mutation in 100 oligodendroglial neoplasms diagnosed at a single treatment center between 2000 and 2003. The ‐1p/‐19q genotype, seen in 64, 34, 77, and 30% of OII, OAII, OIII, and OAIII respectively, was inversely related to p53 mutation and 17p13 loss. Genotype was unrelated to tumor location and could not distinguish high‐grade tumors that presented de novo from those that progressed from a previous lower grade malignancy. Presentation with seizures was more common in cases with the ‐1p/‐19q genotype, and these remained stable for longer before treatment. In longitudinal samples, 74% retained their initial histological differentiation, whereas 29% showed new genetic alterations, the ‐1p/‐19q genotype being acquired in three cases. Loss of 1p36 and 19q13, 17p13, chromosome 10, and p53 mutation were significantly associated with survival from presentation in Kaplan–Meier analysis (p < 0.01), and loss of 1p36 and 19q13 and loss of 17p13 retained significance in multivariate analysis. In this recently diagnosed unselected series, clinical differences in tumors with and without the ‐1p/‐19q genotype support a genetic approach to aid diagnosis and prognostication for oligodendroglial neoplasms. Ann Neurol 2005;57:855–865

Correlation of Molecular Genetics with Molecular and Morphological Imaging in Gliomas with an Oligodendroglial Component

Purpose: Since the recognition that oligodendrogliomas may be chemosensitive, their diagnosis and clinical management has become highly controversial. Histopathology diagnosis remains challenging and new tools such as molecular genetics or molecular imaging require evaluation. Experimental Design: In a single-center, population-based prospective study, allelic imbalance in chromosomes 1p36, 19q13, 17p13, 10p12–15, and 10q22–26 has been investigated in 19 oligodendroglioma WHO grade 2 (OII), 20 oligoastrocytoma WHO grade 2 (OAII), 8 oligodendroglioma WHO grade 3 (OIII), and 12 oligoastrocytoma WHO grade 3 (OAIII), and compared with pretherapy histopathology, computed tomography and/or magnetic resonance (CT and/or MR), [fluorine-18]fluoro-2-deoxyglucose (18F-FDG), and thallium-201 single-photon emission computed tomography (201Tl SPECT). Results: In 50 cases, 18F-FDG uptake correlated with 201Tl uptake; however, 8 cases had increased 201Tl uptake but were hypometabolic for 18F-FDG, and 1 case was hypermetabolic with normal 201Tl uptake. Sixteen cases enhanced on CT/MR but failed to show 201Tl uptake; and 2 low-grade non-enhancing oligodendrogliomas had increased 201Tl uptake. Increased metabolism was more likely in high-grade cases, with 201Tl uptake more strongly correlated with grade than was 18F-FDG uptake. Tumors with 1p/19q loss were more likely to show increased 201Tl uptake and, to a lesser degree, increased 18F-FDG uptake than those without these losses. Elevated metabolism in 28% of low-grade tumors was significantly more common in tumors with 1p/19q loss, and increased uptake of both 18F-FDG and 201Tl in low-grade cases was found only in those with 1p/19q loss. Conclusions: In this study, dissociation of uptake of contrast agents and radiotracers suggests independent deregulation of the blood–brain barrier breakdown and metabolism during disease progression of oligodendroglial neoplasms, and the association of elevated metabolism with 1p/19q loss, particularly in low-grade tumors, may have implications for clinical management.

Ifosfamide encephalopathy: a reappraisal

Eighteen consecutive cases of encephalopathy occurring after ifosfamide/mesna chemotherapy were prospectively assessed. No relationship was found with tumour type or chemotherapy response. Onset was from 12 to 146 (mean 46) h after the start of the infusion and median duration was 3 days (range 1-12). In two patients recovery was incomplete. A confusional state and agitation were the major clinical features. Plasma potassium fell from a mean of 4.12 mmol/l before chemotherapy to 2.94 mmol/l at the onset of encephalopathy (P less than 0.001) with plasma potassium less than 3.0 mmol/l in 10 patients. Duration of hypokalaemia was not related to duration of encephalopathy. Median survival following encephalopathy was 25 days. The incidence of encephalopathy in 82 patients treated on two protocols was 11% and the sensitivity of a published nomogram was 18%. It is concluded that ifosfamide/mesna encephalopathy is a serious complication which may be irreversible and remains difficult to predict.

Clinical use of genotype to predict chemosensitivity in oligodendroglial tumors

Background: The −1p/−19q genotype has been associated with prolonged survival and chemosensitivity in oligodendroglial neoplasms, but the predictive and prognostic significance of genotype in the routine clinic is not established. Methods: The authors investigated allelic imbalance in 1p36, 19q13, 17p13, 10p12-15, and 10q22-26 and p53 mutation in a cohort representative of clinical practice at their center (50 primary, 26 recurrent cases) given PCV chemotherapy between 2000 and 2003 and compared with response and outcome following PCV. Results: 1p/19q loss was found in 12/19 OII, 10/23 OAII, 11/13 OIII, and 6/21 OAIII. Response, seen in 92% with 1p/19q loss, was associated with the −1p/−19q genotype (Fisher exact: p < 0.001) regardless of WHO grade or whether primary or recurrent. 1p/19q loss was an independent prognostic factor associated with longer progression-free (PFS) and overall survival (OS) (Cox regression: PFS and OS p < 0.001), with greater impact on PFS than OS in primary tumors, and OS at recurrence. 17p13 loss and p53 mutation were associated with poor prognosis in recurrent tumors and chromosome 10 loss was associated with short PFS and OS in primary tumors. Histologic subtype did not influence outcome in tumors of equivalent genotype. Genotype had greater association with response and outcome than conventional clinical factors. A total of 29% with intact 1p/19q and a variety of genetic or clinicopathologic characteristics responded in association with increased PFS and OS. Conclusions: The −1p/−19q genotype predicted response and favorable outcome following PCV chemotherapy corroborating genetic analysis to guide routine clinical management. However, some cases with intact 1p/19q also had clinical benefit.

POMB/ACE chemotherapy in non-seminomatous germ cell tumours: outcome and importance of dose intensity.

This study reports the outcome of POMB/ACE (cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, etoposide) chemotherapy in 53 male patients with metastatic non-seminomatous germ cell tumour (NSGCT) treated between 1983 and 1989 in one centre. The overall complete response (CR) rate was 62% [95% confidence interval (CI) 49-75%), and for patients with large or very large volume disease (L/VL, MRC criteria), the CR rate was 56% (95% CI 41-71%). The overall 5 year survival was 61%, and for L/VL volume disease 67%. Comparison with previous studies suggests that POMB/ACE chemotherapy is not superior to BEP, even in patients with adverse prognostic factors. Increased average relative dose intensity and increased relative dose intensity of cisplatin over the first seven courses were not associated with improved survival. However, in patients receiving a relative dose intensity of etoposide greater than or equal to 0.75, survival at 5 years was significantly improved compared with those in whom this parameter was less than 0.75 (79% vs. 44%, P less than 0.05), suggesting that dose intensity of etoposide may be an important determinant of outcome in the chemotherapy of metastatic NSGCT.

Treatment of Squamous Cell Carcinoma of the Tongue Base: Irradiation, Surgery, or Palliation?

Objectives: Squamous cell carcinoma of the tongue base has a poor prognosis, and treatment is accompanied by a number of major problems. In view of this, it is important to recognize which patients will benefit from treatment with curative intent and which treatment method to use. Methods: One hundred sixty-five patients with squamous cell carcinoma of the tongue base were identified on our database. Eighty-two patients were treated by radical irradiation, and 41 by surgery. A further 42 patients were considered unsuitable for curative treatment. Results: The 5-year cause-specific survival rate was 41% for those treated by irradiation, 58% for those treated by surgery, and 9% for untreated patients. There was no difference in the efficacy of treatment methods (p = .5362), but a highly significant difference was seen in survival rate between treated and untreated patients (p = .0028). The decision regarding administration of curative treatment was based on the extent of locoregional involvement at the primary site (p = .0139; odds ratio, 0.43) and in the neck (p = .0078; odds ratio, 0.23). No factors affected the decision to treat by irradiation or surgery. When the observed survival rate was calculated, there was no significant difference in 5-year survival rate between treated and untreated patients (p = .2762). Those with early (T1-2) disease at the primary site had an improved survival rate from 0.5 to 4 years compared with those who were untreated (T3-4; p = .0081; odds ratio, 2.2). In addition, those with early (T1-2) disease had a better survival rate than those with advanced cancers (p = .0139; odds ratio, 2.09). There was, however, no difference in survival rate at 5 years. Those with early disease compared with those with advanced disease were twice as likely to be alive at 2 years; however, all survival advantages had disappeared by 5 years. Conclusions: In terms of observed survival, treating tongue base squamous cell carcinoma that is locally advanced (T3-4) at presentation offers no survival advantage over palliation alone. Treating early disease (T1-2) doubles the survival rate for up to 4 years, but by 5 years this survival advantage is lost. The present study finds radiotherapy and surgery to be equivalent at controlling this disease.

Extensive neck node metastases (N3) in head and neck squamous carcinoma: is radical treatment warranted?

Objective. Head and neck squamous cell carcinoma (HNSCC) patients with N3 neck disease at presentation are the minority. Prognosis for such patients is poor, but there is disagreement about which treatment policy is best adopted. The aim of this study was to identify which groups of patients are best offered radical treatment, examining factors of association, prognosis, and survival. Study Design. Prospective cohort study. Setting. Regional tertiary head and neck cancer unit. Subjects and Methods. Data were collected prospectively from patients treated for HNSCC with N3 nodal disease between 1975 and 2005. The data collected included age, sex, tumor TNM stage, histological grade, treatment, and survival. Odds ratio was used to calculate whether each parameter was statistically significant. Tumor-specific and observed survival curves were also calculated. Results. A total of 275 patients had N3 disease. Multivariate analysis confirmed that advanced disease at the primary site (odds ratio = 4.6, P = .0261) mitigated against curative treatment. Comparison of tumor-specific survival between curative and palliative treatment strategies suggests that aggressive treatment is associated with greatly improved survival (median survival = 1.45 years, 95% confidence interval [CI] = 1.23-1.67 years; 5-year survival = 26.6%, CI = 17.14%-36.06%) compared with those treated palliatively (median survival = 3.18 months, CI = 3.06-3.30 months; no 5-year survivors; P < .0001). Conclusion. A major factor in determining treatment strategies for N3 disease HNSCC is the extent of disease at the primary site. These data suggest that aggressive treatment of the neck improves survival and should be considered in these patients.