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.

Non-Hodgkin's lymphoma presenting with spinal cord compression; a clinicopathological review of 25 cases.

The aim of this study was to retrospectively examine 25 patients with newly diagnosed non-Hodgkin's lymphoma (NHL) presenting with spinal cord or cauda equina compression as the first symptom that were referred to our department between 1985 and 1996. At presentation 17 patients were non-ambulatory; dual sphincter impairment was found in 9 patients with a further 8 patients having bladder dysfunction only. All patients had a tissue diagnosis. Five low-grade and 20 intermediate or high-grade tumours were identified. In this latter group 4 patients were treated palliatively and the remaining 16 patients received combination chemotherapy and/or radical radiation therapy. The overall survival at 5 years is 59%. The majority of patients became ambulatory, even if paretic at presentation. This is in marked contrast to reports of patients presenting in this fashion due to metastatic carcinoma. We urge this diagnosis be considered in all patients presenting with spinal cord compression attributed to malignancy.

Modelling the enhancement of fractionated radiotherapy by gene transfer to sensitize tumour cells to radiation.

BACKGROUND AND PURPOSE: Several strategies now exist for the use of gene transfer methodologies to sensitize tumour cells to radiation. These include the transfection of genes synthesizing cytokines, p53 gene replacement and methods based on the use of HSV-tk and gancyclovir. Very recently, the sequencing of radioprotector or repair genes, such as ATM, Ku80 and XRCC2, has made it possible to consider the design of gene transfer strategies resulting in protector gene knock-out. Selectivity of transfected gene expression might be achieved by use of tissue-specific promoters or by the trophism of viral vectors. The purpose of this study was to evaluate the probable efficacy of such strategies. METHODS: We have modelled gene transfer-mediated radiosensitization of tumour cells during radiotherapy, focusing on anti-protector gene strategies, to explore the role of transfection frequency, sensitizing efficacy, transfection stability, untransfectable subpopulations, the timing of gene therapy and the treatment schedule structure. RESULTS: We predict a substantial therapeutic benefit of gene transfer treatment (with at least weekly transfection) which modifies cellular radiosensitivity by a factor of 1.5 or more, despite modest efficiency of cellular transfection (e.g. 50%), transient retention of the transfected gene (e.g. 2-day half-life) and the existence of a small minority (e.g. 1%) of untransfectable cells. CONCLUSIONS: The analysis shows repeated administration of gene transfer treatment to be obligatory and implies that the existence of untransfectable minority subpopulations (i.e. cells inaccessible to the vector) will be the major limiting factor in therapy. Experimental work is needed to confirm these predictions before clinical studies begin.

A phase II study of oral piritrexim in recurrent high-grade (III, IV) glioma.

Piritrexim is a lipid-soluble drug which is as effective an inhibitor of dihydrofolate reductase as methotrexate. Phase I and II studies have indicated activity in some tumour types. Because of its lipophilicity we have conducted a phase II study in recurrent high-grade malignant glioma (grades III and IV). Twenty-seven patients were treated with 25 mg p.o. three times daily for five consecutive days, repeated weekly, with provision for dose escalation or reduction according to toxicity. Five patients received less than 4 weeks' treatment because of disease progression or death. Twenty-two patients were evaluable for response. One complete and one partial response was seen (duration 262+ and 241+ weeks) and 13 patients had static disease for a median duration of 13 weeks (range 7-35). The major toxicity was myelosuppression. This response rate of 9% of evaluable patients is much lower than that seen for some conventionally used drugs and we conclude that piritrexim is unlikely to be of value in the management of high-grade gliomas.

Combination chemotherapy for primitive neuroectodermal and other malignant brain tumours.

The toxicity and efficacy of a chemotherapy schedule comprising vincristine and cyclophosphamide, alternating with carboplatin and etoposide, has been assessed in a group of 15 patients with medulloblastoma, supratentorial primitive neuroectodermal tumours (PNET) or other malignant brain tumours. The patients comprised four adults and 11 children. Chemotherapy was given for palliation of recurrent disease (six patients), as an adjuvant to radiotherapy and surgery in five poor prognosis patients, or to delay the need for radiotherapy in four children aged 2 years or less. The treatment was generally well tolerated, with the principal toxicity being myelo-suppression. Among the ten assessable patients, there were six complete responders and one partial, an overall response rate of 70%. Three patients had progressive disease. Responses, although associated with good symptomatic improvement, were short lived, with two patients relapsing while still receiving chemotherapy. Three of four very young children relapsed within 7 months of completing chemotherapy and then received radiotherapy. It is concluded that this schedule merits further evaluation and comparison with more protracted and toxic schedules.

Psychiatric morbidity and platelet monoamine oxidase activity in cancer patients.

Psychometric ratings for both anxiety and depression in 30 cancer patients were significantly elevated compared with values in 16 controls. The scores were especially high in the 14 patients who did not have breast cancer. This group also had significantly greater platelet monoamine oxidase activity than either the breast cancer patients or controls. Platelet monoamine oxidase activity values correlated significantly with both depression and anxiety scores in the whole cancer group.

Biochemical investigation of human tumours in vivo with phosphorus-31 magnetic resonance spectroscopy.

The bioenergetic state of 15 human tumours was examined with phosphorus-31 magnetic resonance spectroscopy. A striking diversity in metabolic patterns was observed, and significant differences from normal tissue were seen in all cases. A common feature was an elevation of intracellular pH, which may be related to an increase in Na+/H+ exchange during cell activation. It is unlikely that the patterns observed directly correlate with malignancy, but characterisation of the energetic state of a given tumour in a given physiological environment may help in the design and evaluation of interventions for that specific case.

Fast neutron treatment as an alternative to radical surgery for malignant tumours of the facial area.

Thirty one patients with very advanced tumours of the maxillary sinus were treated with fast neutrons. Tumour regressed completely in 29 (94%) and subsequently recurred in four (14%). No surgical excision of bone, skin, or nerve was required, and an artificial eye was well tolerated in cases where the eye received the tumour dose and had to be removed. Complications occurred in 10 patients, two of whom had already received radical x ray treatment. The overall duration of neutron treatment was four weeks, and admission to hospital was usually unnecessary. These results compared well with those obtained with surgery. Surgery with curative intent for even moderately advanced tumours of the facial region, particularly the paranasal sinuses, results in deformity, which is often severe and always irreversible. Even so, the cure rate is only about 35%. The high rates of tumour control and the avoidance of severe cosmetic and functional defects after fast neutron treatment make it an alternative to radical surgery in the management of malignant tumours of the facial area.

Platelet monoamine oxidase and phenolsulphotransferase M and P in cancer.

Phenolsulphotransferase and monoamine oxidase inactivate a wide range of dietary and endogenous phenols/monoamines by sulphoconjugation and oxidative deamination respectively. In this study, both enzymes were measured in platelets from cancer patients and controls. Of the two variants of phenolsulphotransferase, activity of the P form was normal in all groups. Activity of the M form was, however, significantly less than control values in patients with cancer of the rectum and bowel but not in other cancer patient groups. If this finding reflects enzyme activity elsewhere in the body and is not merely a manifestation of an abnormal platelet population, the deficit could expose affected subjects to the action of potentially carcinogenic dietary phenols. Platelet monoamine oxidase activity was significantly raised in the cancer group as a whole, and in all sub-types investigated apart from breast cancer. The increase in the cancer group as a whole was independent of sex, age, drugs, radiotherapy, smoking or platelet count. Its mechanism and significance are unknown but there may be links with the patients' psychiatric state.