Mark G. Glaser

The charing cross hospital experience with temozolomide in patients with gliomas

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.

IN VITRO EVALUATION OF TEMOZOLOMIDE COMBINED WITH X-IRRADIATION

The In vitro cytotoxicity of 8-carbamoyl-3-methylimldazo[ 5,1-d]-1,2,3,5-tetrazine-4(3 H)-one (temozolomide) with concurrent X-lrradiation was examined in a human glioblastoma cell line (U373MG) as a potential radio-chemotherapeutlc treatment for malignant glioma. The combination was also examined in a human colorectal adenocarcinoma (Mawi) which had 100-fold greater O6-alkylguanine-DNA alkyltransferase (AGT) activity, a DNA-repair protein which confers resistance to temozolomide. A comparison of IC50 values indicated U373MG to be over 32-fold more sensitive to temozolomide than Mawi, but slightly more resistant to X-irradlation (p < 0.035; unpaired two-tailed Mest). Temozolomide and X-irradiatlon proved largely additive in U373MG by Isobologram analysis (50% iso-effect) and the addition of 10 µ M temozolomide to 1-2 Gy of X-irradiation increased cell kill by 2.5- to 3.0-fold. However, the combination was antagonistic in Mawi: an effect attributed to AGT induction by X-irradiation as the antagonism was removed by coincubation with the AGT inhibitor O6-benzylguanine (O6-BG 1 µ M; 24 h). O6-BG did not affect the radiation doseresponse curve, but significantly increased temozolomide cytotoxicity (p < 0.015). In conclusion, the combination of temozolomide with radiation is at best additive, but could nonetheless be of considerable therapeutic benefit in glioma, particularly if administered for prolonged periods. If AGT induction compromises the efficacy of this therapy, it may be circumvented with an appropriate inhibitor such as O6-BG.

A medical research council randomized trial in patients with primary cerebral non-Hodgkin lymphoma

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.

Bony Metastasis in Carcinoma of the Uterine Cervix

The precise incidence of metastatic involvement of bone in carcinoma of the uterine cervix is unknown. The reported total incidence varies in different studies but tends to be low. In the authors experience bony metastasis occurs more frequently than is generally recognised. In this study all the cases of cervical cancer treated in one hospital over a period of two consecutive years have been analysed In this respect. Bone secondaries were discovered in 16%. The possible factors influencing secondary spread to bone are discussed, and of these the degree of histological differentiation was found to be the most important.

Carcinoma of the prostate: The treatment of bone metastases by radiophosphorus

Osseous deposits secondary to advanced carcinoma of the prostate are a common feature of the disease. These deposits are most often seen in the lumbar spine and pelvis and cause severe and intractable pain, often requiring large quantities of strong analgesia for alleviation of pain. Relief of pain can be achieved by external irradiation of these deposits, but this relief may not be permanent and the disease may be so widespread that it is impracticable to treat all the deposits by irradiation. Deposits from carcinoma of the prostrate are usually multiple and all may cause pain at the same time. A method of delivering the radiation to all the deposits at the same time has been sought. Previous studies have shown that radioactive phosphorus (P32) can be used to obtain this localisation of radioactivity at sites of osseous activity. In this study 24 patients with bone metastases from carcinoma of the prostate were treated with radiophosphorus and methyl testosterone, or radiophosphorus with parathormone and calcium. An overall response rate of 58% shows this to be an effective palliative treatment. The results suggest there is a greater response when P32 is used in conjunction with parathormone and calcium, than with methyl testosterone.

Quantitative distribution of 131I-labelled monoclonal antibodies administered by the intra-ventricular route

In a preliminary study in one patient [111In]DTPA was injected into the lateral ventricle and at the same time [99mT]DTPA into the lumbar sac. The 111In distributed freely throughout the CSF but the concentration of 99mTc in the ventricles remained consistently low. In the second phase of the study three patients with tumours confined to the neuraxis were treated with 20-50 mCi 131I-labelled monoclonal antibodies administered into the lateral ventricle via Ommaya reservoirs. Quantitative distribution of radio-labelled antibody was assessed at intervals up to 8 days post injection. In each case there was rapid distribution to all parts of the neuraxis with 38-68% of total CNS counts remaining in the head and 13-39% in each of the upper and lower half spine areas. The t1/2 for total CNS counts were 31.5, 19.8 and 15.5 h. There was no clear evidence of tumour localization and no neurological toxicity. These patients demonstrate that radiolabelled monoclonal antibodies can be given safely via Ommaya reservoirs and that in order to obtain optimal distribution throughout the CSF this should be the preferred method of administration. Further trials in patients with minimal disease are warranted.

Surgery, chemotherapy and whole abdominal radiotherapy in the management of advanced ovarian carcinoma

A pilot study on 35 women was performed to determine the feasibility of giving whole abdominal radiotherapy after surgery and chemotherapy for Stage III and IV ovarian adenocarcinoma. The planned duration of therapy was only 6 months from diagnosis. Chemotherapy consisted of four courses of cis-platinum 100 mg/m2 alternating every 10-12 days with four courses of methotrexate 300 mg/m2 and cyclophosphamide 500 mg/m2 followed by folinic acid rescue. Twenty-nine of 35 (83%) patients were shown at second look surgery after chemotherapy to have residual tumour deposits no more than 2 cm in diameter. The usual radiotherapy dose was 2400 cGy in 20 fractions over approximately 4 to 5 weeks, with kidney shielding, and was generally well tolerated. Three patients failed to complete radiotherapy, two because of progressive disease and one because of persistent nausea and vomiting. During radiotherapy the white blood count fell below 2.0 X 10(9)/litre in seven patients (26%), and in eight patients (30%) the platelet count fell below 75 X 10(9)/litre. However, the white blood count nadir of 1.5 X 10(9)/litre was reached by 1300 cGy and the platelet nadir of 45 X 10(9)/litre was reached by 1400 cGy and both then levelled or recovered despite continuing radiotherapy. The median follow up since diagnosis is 26 months. Four of 12 patients with no tumour detected at second look operation have relapsed compared with 13 of 15 patients who had detectable tumour. Toxicity of this multi-modality therapy was acceptable.

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

AbstractBackground and aim:In the UK, the current management of high-grade gliomas consists of maximal surgical debulking, where possible, followed by radiotherapy. A large, randomized, multicenter trial assessing the addition of temozolomide to radiotherapy found a significant increase in median survival of the order of 2.5 months in favor of the combined treatment (14.6 vs 12.1 months; p < 0.001). Our center has considerable experience with temozolomide and has treated patients with a regimen similar to that used in the above trial. The aim of this study was to confirm whether these results are translated into a benefit when used in clinical practice in the UK. Material and methods:We present a retrospective study of 86 patients treated for glioblastoma with radiotherapy with or without temozolomide between 1998 and 2003. A search of our radiotherapy database was undertaken and patient records were accessed for histopathology, chemotherapy, and radiotherapy information. Patients who were diagnosed with glioblastoma and who did not receive radiotherapy or only received a palliative dose were excluded from the study. Radiotherapy was administered at a dosage of 60–65Gy in 30–37 fractions over 6 weeks. Temozolomide was administered orally at a dosage of 75 mg/m2daily for 6 weeks throughout the radiotherapy, followed by adjuvant temozolomide given for 6 cycles on days 1–5 of a 28-day cycle (150–200 mg/m2/day). Results:Eighty-six patients (59 male and 27 female; mean age = 55.1 years, range 25–72) with glioblastoma were planned to receive treatment with a radical dosage of radiotherapy. Forty-eight patients (56%) underwent surgical debulking. Forty-nine patients (57%) received concurrent temozolomide and radiotherapy followed by adjuvant temozolomide (median number of cycles received was three). Thirty-seven patients (43%) initially received radiotherapy alone, although nine of those received chemotherapy on further disease progression. Three patients died before treatment was completed. The decision to treat with temozolomide was influenced by the availability of the drug. There were no identifiable patient factors influencing the decision for radical radiotherapy alone or combined radiotherapy and temozolomide. Patients treated with concurrent temozolomide and radiotherapy had a significantly better median survival of 13 months compared with 8 months for those treated with radiotherapy alone (p < 0.003). Conclusion:The addition of temozolomide to the standard treatment of radiotherapy for glioblastoma improved overall survival. This study shows that the published phase III results in a selective group of patients can be replicated in everyday practice and that the combined regimen is both practical and effective.

Treatment of small cell lung cancer by eight weeks chemotherapy.

Eighty-two patients with small cell lung cancer (SCLC), 32 with limited disease, were treated with alternating chemotherapy. Eight courses were administered at weekly intervals, and responding patients received radiotherapy to sites of bulk disease. Overall response rate was 76.8%. Overall median survival was 265 days, 408 days in patients with limited disease. The median symptom free period after chemotherapy was completed was 123 days. These results are comparable with those in reports of chemotherapy of longer duration and warrant the further investigation of short duration treatment in this disease.

EMOP/CA chemotherapy for the treatment of aggressive non-Hodgkin's lymphomas

From October 1983 to June 1987, 32 patients with aggressive non-Hodgkins lymphomas (diffuse centroblastic, lymphoblastic and Burkitt type) were treated with the weekly alternating EMOP/CA schedule, total duration 12 weeks. There were six bulky stage II, nine stage III and 17 stage IV patients, median age 54 years (range 19-75). The complete remission rate was 59% (95% confidence limits 40-76%) and the partial remission rate 28% providing an overall response rate of 87%. With a median follow up time of 33 months (range 18-56) the relapse-free survival of those patients achieving a complete remission is 52% and the overall survival for the 32 patients treated is 27%. The CR rate for patients with stage IV disease was 47% and for those with stage II and III disease was 73% of whom 81% remain in remission. EMOP/CA chemotherapy produces acceptable results in stage II and III aggressive non-Hodgkins lymphomas but is inadequate therapy for stage IV disease.