M. Bower

Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma

Purpose: Patients with progressive or recurrent supratentorial high-grade gliomas were entered into a multicentre phase II trial to evaluate the efficacy and toxicity of temozolomide. Methods: The treatment schedule was 150–200 mg/m2 per day orally for 5 days repeated every 28 days. Response evaluation was by a combination of neurological status evaluation (MRC scale) and imaging. Results: Of 103 eligible patients enrolled, 11 (11%) achieved an objective response and a further 48 (47%) had stable disease. The median response duration was 4.6 months. Response rates were similar for anaplastic astrocytomas (grade III) and glioblastoma multiforme (grade IV) tumours. Predictable myelosuppression was the major toxicity. Conclusions: The observation of objective responses and tolerable side effects in this heterogeneous population of patients supports the further investigation of this agent in high-grade gliomas.

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.

Chemotherapy for gestational trophoblastic tumours hastens menopause by 3 years

Chemotherapy may induce acute ovarian failure, but in women who retain gonadal function throughout chemotherapy, the late effects upon ovarian function are unknown. A retrospective controlled survey was performed to ascertain whether chemotherapy for gestational trophoblastic tumours (GTT) results in premature menopause. Questionnaires were sent to 1,489 women diagnosed between 1971 and 1990 with GTT, including 1089 who had received chemotherapy and 400 who had not received chemotherapy (controls). Responses were obtained from 972 chemotherapy-treated patients and 327 controls. 124 women were not evaluable for menopause date as they had undergone hysterectomy as part of the treatment for GTT or had developed permanent amenorrhoea during chemotherapy. Overall, 172 women reported that they were postmenopausal, including 157 women who had received chemotherapy. The median age at menopause for the evaluable population was 50 years (range 25-56 years). The age at menopause was significantly earlier in the treated arm (median 50, range 25-56 years) than in the controls (median 53, range 40-57 years) (logrank test chi 2 = 12.6, P = 0.0004). Menopause occurred significantly earlier in women treated with combination chemotherapy (median 49, range 25-56 years) compared with single agent methotrexate (median 51, range 25-56 years) (logrank test chi 2 = 8.3, P = 0.004). However, the age at completion of chemotherapy in the treated arm did not influence the age of menopause (proportional Hazards chi 2 = 1.99, P = 0.16). Chemotherapy for GTT induces menopause 3 years earlier than it occurs in women with GTT who do not receive chemotherapy. Although the difference is statistically significant, the magnitude is modest and most women can be reassured that neither fertility nor postmenopausal osteoporosis will be greatly affected.

Influence of chemotherapy for gestational trophoblastic disease on subsequent pregnancy outcome.

The aim of this study was to determine the influence of cytotoxic chemotherapy on subsequent reproductive performance. Details of post‐treatment reproductive intent and outcome were requested from 1211 survivors registered at The Charing Cross Hospital gestational trophoblastic disease centre; a response rate of 96% was achieved. Seven hundred and twenty‐eight women had tried to become pregnant; 607 reported at least one live birth, 73 conceived but had not registered a live birth, and 48 did not conceive. No differences were apparent between the 392 women who received methotrexate as single agent chemotherapy and the 336 treated with multi‐agent chemotherapy. Women who had registered a live birth were younger (P < 0.0001) and the duration of follow up was significantly less among those who did not achieve pregnancy at all (P < 0.0003). A higher than expected rate of caesarean section and stillbirth was recorded. The chemotherapy protocols used by this unit have minimal impact on the subsequent ability to reproduce.

Chemotherapy for ovarian germ cell tumours

59 patients were treated for newly diagnosed metastatic ovarian germ cell tumours with POMB/ACE chemotherapy (which contains cisplatinum, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide and etoposide). The median follow-up was 7.7 years. The 3 year survival is 87.8% (95% confidence interval 76.9-93.9%) and no relapses occurred more than 3 years after treatment. 4 (7%) patients had primary drug resistance to POMB/ACE and 4 (7%) have relapsed. One patient in complete remission developed secondary acute myeloid leukaemia after receiving a total of 1.3 g/m2 etoposide. 6 of 12 (50%) patients referred at relapse were salvaged by POMB/ACE. 14 of 33 (42%) women (> 18 years old) have had successful pregnancies after fertility conserving surgery and chemotherapy with no congenital abnormalities reported. The POMB/ACE regimen is as efficacious as other published regimens for ovarian germ cell tumours (OGCT) and balances a low incidence of life-threatening toxicity with a high success rate.

An evolutionary approach to constructing prognostic models

A prognostic model is sought to determine whether or not patients suffering from an uncommon form of cancer will survive. Given a set of case histories, we attempt to find the relative weightings of the different variables that are used to describe the cases. Our first innovation is to use a diffusion genetic algorithm (DGA) to find weightings which will give optimal survival predictions. The DGA enables a number of criteria to be satisfied simultaneously, making it particularly suitable for model building. A further innovation is a method of representing synergies between interacting factors. The evolved model correctly predicts 90% of the survivors and 87% of deaths, an improvement over the current model. More significantly, the method enables a simple model to be evolved, one that produces well-balanced predictions, and one that is relatively easy for clinicians to use. The method was validated by running it on a training set made up of 90% of the original database and then studying the performance of the generated models on a test set consisting of the remaining 10% of the cases.

POMB/ACE chemotherapy for mediastinal germ cell tumours

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.

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

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.

MANAGEMENT OF RESISTANT GESTATIONAL TROPHOBLASTIC TUMORS

OBJECTIVE To analyze the causes of therapeutic success and failure in the management of patients with high-risk gestational trophoblastic tumors (GTTs). STUDY DESIGN Analysis of 272 consecutive high-risk patients treated at the trophoblastic disease center at the Charing Cross Hospital between 1979 and 1995. RESULTS EMA (etoposide, methotrexate, actinomycin D)/CO (cyclophosphamide, vincristine) chemotherapy is our treatment of choice for patients with high-risk GTT. In 272 consecutive patients the cumulative five-year survival was 86.2% (95% confidence interval, 81.9-90.5%). No deaths occurred from GTT more than two years after the start of treatment. In patients whose disease became resistant to EMA/CO or relapsed after receiving EMA/CO, the majority (70%) could be salvaged with further chemotherapy (usually with the EP (etoposide, cisplatin)/EMA chemotherapy with or without surgery. Multivariate analysis identified the following adverse prognostic factors: presence of liver metastases (P < .0001), prolonged interval from antecedent pregnancy (P < .0001), presence of brain metastases (P = .0008) and term delivery of antecedent pregnancy (P = .045). Intensive chemotherapy for treating high-risk GTT carries a small risk of inducing second malignancies, and two patients developed acute myeloid leukemia, 2 cervical malignancy and 1 gastric adenocarcinoma after receiving EMA/CO chemotherapy. CONCLUSION EMA/CO is an effective and well-tolerated regimen for high-risk GTT. Salvage chemotherapy with EP/EMA is effective in the majority of patients whose disease is resistant to EMA/CO and should be combined with surgery when the dominant site of resistant disease is known. Major adverse prognostic variables have been identified, and patients with combinations of these factors should be considered for innovative therapeutic approaches from the outset.

Current Management of AIDS Related Non Hodgkin's Lymphoma.

Non Hodgkin’s lymphoma is the AIDS defining illness in 3-3.5% of patients and is increasing in incidence as the survival of HIV infected people improves. The incidence of these intermediate/high grade B cell malignancies is sixty times higher than in the general population. The most important prognostic factors are a CD4 positive lymphocyte count of <100 cells/mm3, a prior AIDS defining diagnosis, an ECOG performance status >2 and primary cerebral origin. Patients with any of these factors are most likely to benefit from palliative rather than radical treatment. Good prognosis patients have a 30-40% chance of cure from their lymphoma with carefully administered intensive chemotherapy.