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.

Loss of chromosome 10 is an independent prognostic factor in high-grade gliomas.

Loss of heterozygosity (LOH) for chromosome 10 is the most frequent genetic abnormality observed in high-grade gliomas. We have used fluorescent microsatellite markers to examine a series of 83 patients, 34 with anaplastic astrocytoma (grade 3) and 49 with glioblastoma multiforme (grade 4), for LOH of chromosome 10. Genotype analysis revealed LOH for all informative chromosome 10 markers in 12 (35%) of patients with grade 3 and 29 (59%) grade 4 tumours respectively, while partial LOH was found in a further eight (24%) grade 3 and ten (20%) grade 4 tumours. Partial LOH, was confined to the long arm (10q) in six and the short arm (10p) in three cases, while alleles from both arms were lost in four cases. Five tumours (one grade 3 and four grade 4) showed heterogeneity with respect to loss at different loci. There was a correlation between any chromosome 10 loss and poorer performance status at presentation (chi2 P = 0.005) and with increasing age at diagnosis (Mann-Whitney U-test P = 0.034) but not with tumour grade (chi2 p= 0.051). A Cox multivariate model for survival duration identified age (proportional hazards (PH), P= 0.004), grade (PH, P= 0.012) and any loss of chromosome 10 (PH, P= 0.009) as the only independent prognostic variables. Specifically, LOH for chromosome 10 was able to identify a subgroup of patients with grade 3 tumours who had a significantly shorter survival time. We conclude that LOH for chromosome 10 is an independent, adverse prognostic variable in high-grade glioma.

Bilateral cerebellopontine metastases in a patient with an unknown primary.

We report the case history of a patient who presented with symptoms and signs suggestive of a left cerebellopontine tumour. He underwent an exploratory posterior fossa craniotomy, which revealed metastatic adenocarcinoma. Despite intensive investigation, a primary site was not located and the patient received cranial irradiation. The patient re-presented 2 years later with further symptoms from a metastasis in the right cerebellopontine angle. He refused further intervention.

In vitro evaluation of temozolomide combined with X-irradiation.

The in vitro cytotoxicity of 8-carbamoyl-3-methylimidazo [5,1-d]-1,2,3,5-tetrazine-4(3H)-one (temozolomide) with concurrent X-irradiation was examined in a human glioblastoma cell line (U373MG) as a potential radio-chemotherapeutic 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-irradiation (p < 0.035; unpaired two-tailed t-test). Temozolomide and X-irradiation proved largely additive in U373MG by isobologram analysis (50% iso-effect) and the addition of 10 microM 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 co-incubation with the AGT inhibitor O6-benzylguanine (O6-BG 1 microM; 24 h). O6-BG did not affect the radiation dose-response curve, but significantly increased temozolomide cytotoxicity (p < 0.015). In conclusion, the combination of temozolomide with radiation is at best additive, but could nonetheless by 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.

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.

Iodine seeds in the treatment of slowly proliferating tumours in the head and neck region.

Locally recurrent/persistent disease is a major cause of morbidity and mortality in patients suffering from tumours arising in the head and neck region. Iodine-125, with its long half-life of 60 days, is particularly suited for the treatment of slowly proliferating tumours (e.g. adenoidcystic carcinomas) of this site. We report our experience with 18 patients using iodine-125 seeds, placed at the time of surgery in patients with such tumours. Eleven of the patients were treated for recurrent disease following previous radical treatment. Disease free survival was 89% at 2 years and 53% at 5 years after treatment. These results are encouraging in a group of patients in whom achieving and maintaining local control can be extremely difficult.

An audit of the use of agreed treatment protocols at a major centre for cancer treatment.

The treatment that a patient with cancer receives may vary considerably, depending on where and by whom the treatment is given. Agreement on treatment protocols for patients undergoing cancer treatment is clearly a desirable aim. Within departments this will result in greater uniformity of treatment, lead to greater safety, facilitate the evaluation of treatment strategies, and improve cost effectiveness. We have examined prospectively the extent to which treatment protocols are being adhered to within a major cancer treatment centre. One hundred newly registered cancer patients were studied. The results are encouraging, with complete adherence to protocol for 84. Of the 16 occurrences of deviation from a protocol this was unavoidable for three and of minor importance for five, being relatively small changes in radiotherapy dose reflecting particular clinical situations. Thus, eight deviations represented serious departures from the protocols by the responsible clinicians. This study has shown that in a major cancer treatment centre the development of agreed treatment protocols is both feasible and practical.

Radioimmunotherapy of metastatic colorectal tumours with iodine-131-labelled antibody to carcinoembryonic antigen: phase I/II study with comparative biodistribution of intact and F(ab')2 antibodies.

Studies in animal tumour models of colorectal cancer suggest that F(ab')2 antibody fragments to carcinoembryonic antigen (CEA) labelled with iodine-131 give superior therapy compared with intact anti-CEA antibody. The purpose of this study was to investigate this hypothesis in patients. Ten patients received intact A5B7 IgG1 mouse monoclonal antibody (MAb) to CEA and nine patients received the F(ab')2 fragment of the same antibody. The biodistribution for each molecule was compared using quantitative single-photon emission computerised tomographic (SPECT) gamma-camera imaging. Tumour responses were seen in both groups and myelosuppression was the limiting toxicity. F(ab')2 localised more rapidly than intact antibody in tumour, giving a mean percentage injected activity per kg at 4.25 h after injection of 8.2% for F(ab')2 compared with 4.4% for intact antibody (P < 0.05). No significant difference in antibody clearance from, or cumulative dose per unit administered activity (cGy MBq-1) to, tumour was seen. Distribution in blood was similar for both the intact and fragment antibody. These findings are consistent with more rapid penetration of the smaller F(ab')2 into tumour masses. More efficient early uptake will give higher maximum dose rates to the tumour which is valuable for radioimmunotherapy (RIT) when low dose rates may limit effectiveness of treatment. F(ab')2 fragments may provide a substantially enhanced method of delivering RIT.

Temozolomide: a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours.

Temozolomide, a new oral cytotoxic agent, has been given to 28 patients with primary brain tumours. Treatment was given at a dose of 150 mg/m2/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/day for 5 days (i.e. total dose 1000 mg/m2) for subsequent courses at 4 week intervals. A major improvement in computer tomography (CT) scan was noted in 5/10 patients with astrocytomas recurrent after radiotherapy, with a major clinical improvement but minor improvement on CT scan in one further patient. Reduction in the size of the CT lesion was also observed in 4/7 patients with newly diagnosed high grade astrocytomas given 2-3 courses of temozolomide prior to irradiation. 1 patient with recurrent medulloblastoma had a clinical response in bone metastases. Temozolomide was well tolerated with little subjective toxicity and usually predictable myelosuppression and is a promising new drug in the treatment of primary brain tumours.

Pneumothorax as a complication of tumour response to chemotherapy.

A patient with extensive pulmonary involvement by disseminated adenocarcinoma is presented. Response to chemotherapy resulted in the direct rupture of necrotic tumour tissue into the pleural cavity leading to a pneumothorax. The condition failed to improve with chest drainage and suction, necessitating surgical intervention. The development of the pneumothorax proved to be a fatal complication of treatment.

Weekly cisplatinum concomitant with radical radiotherapy in the treatment of advanced head and neck cancer.

A total of 36 patients with advanced head and neck cancer were treated with radical radiotherapy and weekly concomitant cisplatinum chemotherapy. Rapid tumour response of both primary tumours and nodes was notable and an initial complete response rate of 75% was obtained. The disease free survival was 64% at 1 year and 52% at 2 years. The protocol proved feasible with little increase in toxicity from the addition of chemotherapy. Considering the advanced stage of the tumours treated the initial results are promising and this approach would seem to warrant further investigation.

Impaired salivary gland function after radiotherapy compounded by commonly prescribed medications.

Impaired salivary gland function can be a major cause of late morbidity following the treatment of head and neck cancer with radiotherapy. A large number of commonly prescribed medications can also reduce salivary gland function. We report three patients with already impaired salivary gland function following successful radiotherapy in whom additional prescribed medication led to an increased reduction in salivary flow, thus further impairing the quality of life of these patients. Stopping the medication resulted in subjective and objective improvement in salivary gland function.

The spontaneous regression of lymphoma in AIDS.

Non-Hodgkin's lymphomas are an increasing problem in the AIDS population. They are generally aggressive, high-grade lymphomas and more commonly present at extranodal sites, particularly the central nervous system. Although chemo- and radiosensitive, the duration of response is generally short lived. Spontaneous remission of non-Hodgkin's lymphomas has been reported in immunocompetent individuals, but has not been reported in HIV disease. We would like to report the first such case.

Poor prognosis acute myeloid leukaemia treated by matched unrelated donor marrow transplant without preceding total body irradiation.

Two patients with acute myeloid leukaemia, one in relapse after autologous bone marrow transplantation (BMT) (aged 52 years) and the other with primary resistant disease secondary to previously treated malignancy, have received marrow transplants from matched unrelated donors. Cytoreductive conditioning in both cases was with high-dose combination chemotherapy alone. Engraftment was aided by the administration of total lymphoid irradiation together with in vivo antilymphocyte antibody prior to marrow infusion. Both patients survive in complete remission, currently at 12 and 15 months post-BMT respectively. The avoidance of total body irradiation in BMT patients at high risk of early treatment-related mortality may be advantageous.

Extradural metastases in a case of medulloblastoma.

Extradural metastases in medulloblastoma appear to be rare. We describe a case associated with use of a lumbar drain and propose that in this situation, adjuvant chemotherapy and possibly extension of the radiotherapy field to include the entire sacral epidural fat-space to the lower border of S5, should be considered.

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.

Antibody distribution and dosimetry in patients receiving radiolabelled antibody therapy for colorectal cancer.

The distribution of iodine-131 (131I) labelled antibody to carcinoembryonic antigen (CEA) has been studied in 16 patients with colorectal cancer. Levels of tumour and normal tissue radioactivity were measured by serial gamma-camera imaging and counting of blood and urine. Maximum concentrations were found in tumour 8 h after administration and varied up to 9-fold in different patients. Higher levels were found on average in tumour than in any other tissue. Liver, lung and blood were the other tissues in which antibody was concentrated relative to the rest of the body. Antibody cleared from all these tissues over 1 week. Second antibody directed against the antitumour (first) antibody was given 24 h after first antibody in order to accelerate clearance from the blood. This increased the tumour to blood ratio but had little effect on other tissues. Cumulative radiation dose to tumour and normal tissue was estimated. In patients with the most efficient localisation the tumour to body ratio was 20:1 and tumour to blood ratio 5:1. This may be sufficient for effective therapy of cancer in patients selected for efficient antibody localisation. The data may be used to estimate the effect of different therapeutic strategies. For instance, in the time after second antibody administration the average tumour to blood ratio of radiation dose was 11:1, suggesting that two phase systems in which the therapeutic modality is given after a good tumour to normal tissue ratio is obtained may be effective for the majority of patients.