Cathryn S. Brock

Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials

*Department of Medical Oncology, Chafing Cross Hospital, Fulham Palace Road, London W6 8RF, U.K. t Cancer Research Campaign Experimental Cancer Chemotherapy Research Group, Cancer Research Laboratories, Department of Pharmaceutical Sciences, University of Nottingham, Nottingham NG7 ZRD, U.K.

The charing cross hospital experience with temozolomide in patients with gliomas

Drugs Dynamics Institute, College of Pharmacy, University of Texas at Austin, Austin, TX 78712-7074, U.S.A.

A New Model for Prediction of Drug Distribution in Tumor and Normal Tissues: Pharmacokinetics of Temozolomide in Glioma Patients

Temozolomide, a new oral cytotoxic agent, was given to 75 patients with malignant gliomas. The schedule used was for the first course 150 mg/m2 per day for 5 days (i.e. total dose 750 mg/m2), escalating, if no significant myelosuppression was noted on day 22, to 200 mg/m2 per day for 5 days (i.e. total dose 1000 mg/m2) for subsequent courses at 4-week intervals. There were 27 patients with primary disease treated with two courses of temozolomide prior to their radiotherapy and 8 (30%) fulfilled the criteria for an objective response. There were 48 patients whose disease recurred after their initial surgery and radiotherapy and 12 (25%) fulfilled the criteria for an objective response. This gave an overall objective response rate of 20 (27%) out of 75 patients. Temozolomide was generally well tolerated, with little subjective toxicity and predictable myelosuppression. However, the responses induced with this schedule were of short duration and had relatively little impact on overall survival. In conclusion, temozolomide given in this schedule has activity against high grade glioma. However, studies evaluating chemotherapy in primary brain tumours should include a quality-of-life/performance status evaluation in addition to CT or MRI scanning assessment.

Pharmacokinetic assessment of novel anti-cancer drugs using spectral analysis and positron emission tomography: A feasibility study

Difficulties in direct measurement of drug concentrations in human tissues have hampered the understanding of drug accumulation in tumors and normal tissues. We propose a new system analysis modeling approach to characterize drug distribution in tissues based on human positron emission tomography (PET) data. The PET system analysis method was applied to temozolomide, an important alkylating agent used in the treatment of brain tumors, as part of standard temozolomide treatment regimens in patients. The system analysis technique, embodied in the convolution integral, generated an impulse response function that, when convolved with temozolomide plasma concentration input functions, yielded predicted normal brain and brain tumor temozolomide concentration profiles for different temozolomide dosing regimens (75-200 mg/m(2)/d). Predicted peak concentrations of temozolomide ranged from 2.9 to 6.7 microg/mL in human glioma tumors and from 1.8 to 3.7 microg/mL in normal brain, with the total drug exposure, as indicated by the tissue/plasma area under the curve ratio, being about 1.3 in tumor compared with 0.9 in normal brain. The higher temozolomide exposures in brain tumor relative to normal brain were attributed to breakdown of the blood-brain barrier and possibly secondary to increased intratumoral angiogenesis. Overall, the method is considered a robust tool to analyze and predict tissue drug concentrations to help select the most rational dosing schedules.

Maintenance of fertility following treatment with temozolomide for a high grade astrocytoma

Purpose: The aim of this study was to investigate the feasibility of evaluating the pharmacokinetics of radiolabeled anti-cancer drugs using spectral analysis, a non-compartmental tracer kinetic modeling technique, and positron emission tomography (PET). Methods: Dynamic PET studies were performed on patients receiving tracer doses of 5-fluorouracil (5-[18F]-FU) and two developmental drugs – [11C]-temozolomide and [11C]-acridine carboxamide. Spectral analysis was then used to (a) determine individual and group average pharmacokinetics, (b) predict tumour handling in response to different drug administration regimens, and (c) produce functional parametric images describing regional pharmacokinetics. Results: Spectral analysis could distinguish tumour kinetics from normal tissue kinetics in an individual [11C]-temozolomide study and demonstrated a markedly greater volume of distribution (VD) in glioma than in normal brain, although there was no appreciable difference in mean residence time. Analysis of pooled acridine carboxamide data (n=22) revealed a relatively large VD (and prolonged retention) in the liver and spleen and a markedly lower VD (and initial uptake) in the brain. Continuous infusion of 5-[18F]-FU was predicted to achieve a concentration in colorectal metastases in liver approximately 10 times that achieved in plasma at 10 h after commencement of the infusion. Conclusions: We conclude that spectral analysis provides important pharmacokinetic information about radiolabeled anti-cancer drugs with relatively few model assumptions.

POMB/ACE chemotherapy for mediastinal germ cell tumours

Increasingly young patients with malignant diseases such as leukemias, lymphomas and germ cell tumours are being cured with combination chemotherapy. In addition individuals with incurable tumours are surviving longer. The short-term toxicities of chemotherapy are well defined however longer term toxicities such as infertility are poorly defined. In published studies the rate of male infertility following treatment for germ cell tumours has varied between 28–63% [1,2]. The accurate documentation of the effect of novel chemotherapy agents on fertility is vital if we are to be able to counsel patients accurately regarding the effect of treatment on this key area and if necessary to take the appropriate measures to try and preserve fertility. A 30 year old man presented in December 2001 with a history of headaches, parathesiae in his mouth and weakness in his legs a CT brain revealed a large cystic mass in the right frontal lobe. Craniotomy and debulking were carried out, histology revealing a grade III astrocytoma. He received concurrent radiotherapy and daily temozolomide 75 mg/m and after the completion of radiotherapy a further 6 cycles of temozolomide 200 mg/m days 1–5 every 28 days. He completed his treatment in October 2002 at which time all his symptoms had resolved. End of treatment MRI revealed a good response to treatment which has been maintained on subsequent repeated MRI brain scans the last being in June 2004. Thirteen months after completing treatment he fathered a child who was born fit and well in July 2004. Temozolomide is a novel oral imidazotetrazinone methylating agent which causes methylation at the O position of guanine with additional alkylation at the N position [3]. It has demonstrated efficacy as first-line therapy for patients with glioblastoma multiforme (GBM) and when given concomitantly and adjuvantly with radiotherapy in newly diagnosed GBM [4,5]. This is the first reported case in the literature of a patient successfully fathering a child following treatment with this agent. To date none of the reported GBM trials have commented on the effect of temozolomide on fertility, this could be due to a number of reasons firstly the high median age of the patients treated and therefore the likelihood that they have completed their families, in a recent trial the median age in the treatment group was 55.7 years [5]. Secondly, the aggressive nature of this disease with its potentially debilitating neurological problems and limited life expectancy reduces the opportunity to reproduce in this group of patients. However, with the promising activity seen with temozolomide in GBM and the increasing used in other tumour types the accurate monitoring of the effect of temozolomide on male and female fertility is important to determine the exact impact if any this drug has on reproductive ability.

A weekly alternating chemotherapy regimen with low toxicity for the treatment of aggressive lymphoma.

Mediastinal germ cell tumours (MGCT) are rare and most published series reflect the experiences of individual institutions over many years. Since 1979, we have treated 16 men (12 non-seminomatous germ cell tumours and 4 seminomas) with newly diagnosed primary MGCT with POMB/ACE chemotherapy and elective surgical resection of residual masses. This approach yielded complete remissions in 15/16 (94%) patients. The median follow-up was 6.0 years and no relapses occurred more than 2 years after treatment. The 5 year overall survival in the non-seminomatous germ cell tumours (NSGCT) is 73% (95% confidence interval 43-90%). One patient with NSGCT developed drug-resistant disease and died without achieving remission and 2 patients died of relapsed disease. In addition, 4 patients with bulky and/or metastatic seminoma were treated with POMB/ACE. One died of treatment-related neutropenic sepsis in complete remission and one died of relapsed disease. Finally, 4 patients (2 NSGCT and 2 seminomas) referred at relapse were treated with POMB/ACE and one was successfully salvaged. The combination of POMB/ACE chemotherapy and surgery is effective management for MGCT producing high long-term survival rates.

Emerging targeted treatments for malignant glioma.

Abstract A total of 50 consecutive adult patients with newly diagnosed aggressive non-Hodgkin’s lymphoma were treated with a weekly alternating combination chemotherapy schedule, BEMOP/CA, including bleomycin, etoposide, methotrexate, vincristine, cyclophosphamide and Adriamycin. Two-thirds of the patients were over 60 years old or had stage 4 disease. Clinical remission was achieved in 56% of cases. The 3-year survival is 53% (95% confidence interval, 39 – 66%). The presence of B symptoms and a serum albumin value of <33 g/l at presentation were poor prognostic indicators for survival in a multivariate proportional-hazards model. Overall, the response rate and survival for this group of patients with intermediate- and high-grade lymphomas is similar to results previously reported. The BEMOP/CA treatment was brief (16 weeks) and associated with a low fatal toxicity (one early death and one late fatality from Pneumocystis pneumonia), and the drug costs are equivalent to those for eight cycles of CHOP.

Metastatic ductal eccrine adenocarcinoma masquerading as an invasive ductal carcinoma of the male breast.

This paper focuses on the medical management of malignant gliomas, which is currently undergoing change. It suggests that as surgery and radiotherapy are of limited benefit in the treatment of these tumours, medical therapies may have the potential to offer a better alternative. The current therapies for glioma and the targeted agents in clinical trials are reviewed. There is a general acceptance that temozolomide in combination with radiotherapy is replacing radiotherapy alone as first-line therapy in high-grade astrocytic gliomas. Within the realms of clinical research, it can be seen that there is a shift away from therapies targeting the end effect of deregulated cell-cycle control, to targeting specific and individual genetic aberrations in tumours. Finally, the paper questions current clinical trial methodology and tentatively suggests ways in which this may be improved.

Treatment of Newly Diagnosed Glioblastoma with Concomitant and Adjuvant Temozolomide and Radiotherapy

We report the case of a 38‐year‐old man with metastatic ductal eccrine adenocarcinoma (DEA) of the left breast responding to 5‐flourouracil, epirubicin and cyclophosphamide (FEC) chemotherapy. He initially presented with a 2‐week history of difficulty walking because of bilateral hip and lower back pain. Examination showed an ulcerating cutaneous mass over the left anterior chest wall, left axillary lymphadenopathy and tenderness over the spine. A punch biopsy of the breast lesion resulted in a diagnosis of metastatic invasive ductal carcinoma (IDC) of the breast. He received palliative radiotherapy to the spine and also received six cycles of FEC chemotherapy and was subsequently commenced on tamoxifen and ibandronate. There was a symptomatic and radiological response to the FEC chemotherapy. Referral was subsequently made to our institution where the original punch biopsy was reviewed. This showed tumor cells that were polygonal with darkly stained pleomorphic nuclei and abundant eosinophilic cytoplasm and were also localized to areas of fibrotic stroma containing eccrine glands and ducts but did not appear to involve mammary tissue. Immunohistochemical studies showed the tumors to be cytokeratin 7 and gross cystic disease fluid protein‐15/prolactin inducible protein negative and estrogen receptor alpha positive. Both the morphological and the immunohistochemical characteristics of the tumor were consistent with a revised diagnosis of DEA rather than IDC. When last reviewed, the patient remains pain free and his disease stable 17 months after his original presentation. This case emphasizes the challenge in discriminating histopathologically between two rare tumors of the male breast, namely DEA and IDC. In addition, clinical response to FEC by metastatic DEA has not been previously documented, and this therapeutic regimen warrants further investigation.