Radiotherapy and adjuvant chemotherapy for childhood medulloblastoma. The Royal Marsden Hospital experience.

PURPOSE: We reviewed the outcome of children with medulloblastoma treated from 1970 to 1985 with combined radiotherapy and chemotherapy. PATIENTS AND METHODS: Fifty-seven children with a median age of 8 years (range 1 to 16 years) at diagnosis were analyzed regarding survival, site and time of recurrence, treatment toxicity, prognostic factors and performance status. RESULTS: The overall 5- and 10-year-survival was 66% and 54%, respectively. Patients with subarachnoid metastases or positive cerebrospinal fluid cytology (M1-3) had a shorter survival compared with those without it (p < 0.1). Furthermore, survival appeared to improve with the addition of lomustine (CCNU) to vincristine chemotherapy with a 5-year-survival of 70% versus 31% (relative risk 3.4, 95% confidence interval 1.4 to 8.1) although it should be noted that these were consecutive not randomized patients treated. Of the 52 patients achieving remission, 17 relapsed either in primary (2), spine (5) or a combination of these (10). Two patients developed bone metastases without central nervous system recurrence. Performance status measured crudely appeared to be good in long-term survivors. Of 31 patients that survived for long-term follow-up and had their performance evaluated, 28 had no or minor residual neurological signs and the remaining 3 were disabled. CONCLUSION: Combined modality treatment for medulloblastoma in childhood was able to cure 54% of patients with a good performance status in the majority of survivors.

Craniopharyngioma--a long-term results following limited surgery and radiotherapy.

Between 1950 and 1986 173 patients with craniopharyngioma were treated at the Royal Marsden Hospital with external beam radiotherapy either alone or following surgery. Four patients had complete tumour excision, 21 subtotal and 78 partial resection, 14 had biopsy alone, 34 aspiration alone and 22 had no surgery directed at tumour eradication. Seventy-seven (45%) were children (aged < 16 years). The 10 and 20 year progression-free survival (PFS) rates were 83% and 79%. There were no independent prognostic factors for PFS. The 10 and 20 year survival rates were 77% and 66% at a median follow-up of 12 years. After adjustment for mortality in the normal population, age and technique of radiotherapy (which corresponded with era of treatment) were significant independent prognostic factors for survival. The risk of death (corrected for mortality from natural causes and controlling for radiotherapy technique) for age groups 16-39 and > or = 40 was 0.58 and 0.40 respectively, relative to a risk of 1.0 for the age group < 16 years. Survival and PFS were not influenced by the extent of surgical excision. Visual field defect improved after radiotherapy in 36% of patients (38/106) and visual acuity in 30% (27/91). No patient developed radiation optic neuropathy. We conclude that limited surgery and radiotherapy achieve excellent long-term tumour control and survival with low morbidity.

Intracranial ependymoma: long-term results of a policy of surgery and radiotherapy.

Ninety-three patients with primary intracranial ependymoma were treated at the Royal Marsden Hospital, between 1952 and 1988, with postoperative radiotherapy. The survival probability at 5, 10, and 15 years was 51%, 42% and 31%, respectively, and the corresponding progression free survival (PFS) probability, 41%, 38%, and 30%. Tumor grade was the single most important prognostic factor for survival and PFS with gender of lesser prognostic significance. Treatment parameters were stratified for grade. In patients with low grade tumors survival and PFS were better following complete macroscopic excision compared to incomplete surgery. The extent of resection had no significant influence on survival or PFS in patients with high grade tumors. Extent of irradiation did not influence PFS, irrespective of tumor grade, while patients with high grade tumors had marginally better survival following extensive irradiation compared to more limited radiotherapy. The main problem in the treatment of ependymoma remains local progression which was the cause of death in all but two patients. New treatment strategies should focus on improvement of local control, especially in incompletely resected low grade tumors and all high grade tumors. The use of spinal irradiation is unlikely to significantly improve treatment results.

Postoperative radiotherapy in the management of spinal cord ependymoma.

Fifty-eight patients with histologically verified spinal cord ependymomas were treated at the Royal Marsden Hospital and Atkinson Morley's Hospital between 1950 and 1987. The median age in this series was 40 years (range 1 to 79 years) and the male:female ratio was 1.8:1. Ten patients had tumors in the cervical cord and 10 in the thoracic cord; 14 tumors involved the conus medullaris and 24 the cauda equina. Forty ependymomas were grade I and 13 were grades II to IV (in five patients there was insufficient material for grading). Eleven patients underwent biopsy only, 33 had partial or subtotal resection, and 14 had complete resection. Forty-three patients received postoperative radiotherapy. The median follow-up period was 70 months (range 3 to 408 months). Cause-specific survival rates were 74% and 68% at 5 and 10 years, respectively. On univariate analysis, age, histological grade, postoperative neurological function, and era of treatment were significant prognostic factors for survival. The histological grade was the only significant independent prognostic factor. The relative risk of death from ependymoma was 9.0 for patients with tumor grades II to IV compared to grade I (p less than 0.005, 95% confidence interval 2.7 to 30). The survival rates of patients following complete excision were significantly better compared to those after incomplete surgery (p less than 0.025). The majority of completely resected neoplasms were low-grade cauda equina tumors. Despite incomplete surgery, 5- and 10-year progression-free survival rates following radical radiotherapy were both 59%, and cause-specific survival rates were 69% at 5 years and 62% at 10 years. This suggests that radiotherapy may achieve long-term tumor control in over half of those patients with residual spinal ependymoma.

The role of radiotherapy in the management of intracranial meningiomas: the Royal Marsden Hospital experience with 186 patients.

One hundred and eighty-six patients with intracranial meningiomas were treated at the Royal Marsden Hospital between 1963 and 1983 with megavoltage photon irradiation (60Co gamma rays and 6-8 Mv. X rays). Survival parameters were measured from the time of referral for radiotherapy. The 10-year actuarial cause-specific survival was 67% for all cases and the actuarial disease-free survival was 61%. Both malignant and also "aggressive benign" histologies were associated with poor long-term survival. Benign angioblastic meningioma was associated with lower actuarial cause specific and disease-free survival compared with other benign histological sub-groups. Prognosis was related to the extent of initial surgical resection. Of those who underwent subtotal or partial tumor resection with post-operative radiotherapy the 10-year actuarial cause-specific survival was 77%, and in inoperable patients treated by radiotherapy alone it was 46%. Radiotherapy alone resulted in improvement of neurological performance (Karnofsky) in 12 out of the 32 (38%) patients with inoperable disease. The 10-year survival of patients referred for irradiation following "complete" surgical resection was only 34% owing to the high incidence of adverse histological sub-types in this treatment sub-group. Based upon univariate analysis, performance status of less than 60 (Karnofsky) and also age greater than 50 years at the time of referral for radiotherapy were adverse prognostic factors. Multivariate analysis revealed that histological type, extent of surgical resection and performance status at the time of presentation for radiotherapy were independent prognostic variables. However age at the time of referral lost significance as an independent variable when analyzed using this method. Patients undergoing complete surgical resection for the typical benign non-aggressive meningioma do not require adjuvant irradiation. The results of this study support the role of radiotherapy for treatment of incompletely resected and inoperable meningioma of all 3 histological types (benign, "aggressive benign", malignant).

Endocrine disorders following treatment of childhood brain tumours.

We have studied the long-term endocrine effects of treatment on 144 children treated for brain tumours. All received cranial irradiation, 86 also received spinal irradiation and 34 chemotherapy. Almost all patients (140 of 144) had evidence of growth hormone insufficiency. Treatment with growth hormone was effective in maintaining normal growth but could not restore a deficit incurred by delay in instituting treatment. The effect of spinal irradiation on spinal growth was not corrected by growth hormone. As spinal growth makes the major contribution to the pubertal growth spurt and limb length the major contribution to childhood growth, treatment with GH will have maximal effect on leg length if instituted before the onset of puberty. Primary thyroid dysfunction was found in 11 of 47 children (23%) treated with craniospinal irradiation but in none treated with cranial irradiation alone. The incidence rose to 69% of 29 children treated with spinal irradiation and chemotherapy and to 50% of four children treated with cranial irradiation and chemotherapy. This effect of chemotherapy has not previously been reported and was detected by us through measurement of serum TSH concentration. Primary thyroid dysfunction requires treatment with thyroxine to prevent increasing the risk of secondary thyroid tumours. Seven of 20 girls (35%) treated with spinal irradiation had primary ovarian dysfunction as determined by raised gonadotrophin levels. Chemotherapy increased this, but not significantly. Three of 15 boys (20%) treated with chemotherapy had primary testicular dysfunction. Gonadotrophin deficiency occurred in seven boys. Four of 90 children had deficiency of cortisol secretion in response to hypoglycaemia. These results confirm the requirement for long-term follow-up of children treated for brain tumours from the endocrine point of view. Anticipation of hormone deficiencies and replacement treatment can improve the quality of life of survivors.

Management of primary cerebral lymphoma with initial chemotherapy: preliminary results and comparison with patients treated with radiotherapy alone.

Between 1986 and 1988 10 patients with primary cerebral lymphoma (PCL) were treated with initial MACOP-B chemotherapy followed by radiotherapy. All demonstrated radiological response to chemotherapy but this did not predict final clinical outcome. The overall median survival was 14 months. Patients with poor MRC neurological performance status (NPS) 2-4 had a median survival of 5 months. Three of 7 patients with NPS 0-1 died and the median survival is 18 months with a median follow-up of 13 months (10-35 months). The results were compared to 25 patients with primary cerebral lymphoma treated between 1963 and 1986 with radiotherapy as the main treatment modality. The overall median survival was 16 months. Patients presenting with poor NPS (2 and 3) had worse survival (median survival 8 months) compared to patients with good NPS (median survival 22 months; p less than 0.025). Patients diagnosed and treated from 1982 to 1986 also had significantly worse prognosis when compared to earlier treated patients. The preliminary results of combined modality therapy are so far not significantly different when compared to historical series and we have to await long-term outcome before recommending combined modality therapy as the treatment of choice.

Long-term psychological effects in children treated for intracranial tumors.

The results are reported of the psychological assessment of 62 children who presented with primary intracranial tumors and who received radiotherapy at the Royal Marsden Hospital between 1963 and 1973. Evaluations were carried out 3-20 years after treatment. All patients were free from progressive tumor at testing. The average IQ of the total series was within the normal range (Full-Scale IQ 92) but 23% of the patients were functioning at an educationally subnormal level of intelligence (IQ less than 80). Sex, tumor type, tumor location and the radiotherapy volume and site of maximum dose were not found to have a significant effect on intellectual outcome. A significant correlation was found between intelligence and age at the time of treatment. Children who received treatment under the age of 5 years were more adversely affected (average IQ 72) than those who were aged 6-10 (average IQ 93) and those aged 11-15 years (average IQ 107). The incidence of neurological abnormalities and physical disability was significantly greater among patients with supratentorial tumors (72% of cases), compared with patients with infratentorial lesions (44% of cases). The results were discussed in terms of the management of young patients with intracranial tumors.

The treatment and long-term prognosis of children with intracranial tumors: a study of 610 cases, 1950-1981.

Six hundred and ten children aged under 16 years with intracranial tumors were referred for radiotherapy between 1950 and 1981: 579 were new cases and 31 had recurrent disease after primary treatment elsewhere. Radiotherapy was completed in 93% of all cases. The actuarial survival rate for all new cases was 53% at 5 years, 46% at 10 years, 40% at 20 years, and 39% at 30 years. The oldest children (10-15 years) had the best survival and the youngest (0-2 years) had the worst survival. Children treated with megavoltage x-ray equipment (1970 to 1981) had a significantly greater survival than those treated with orthovoltage X rays (1950-1969). Overall, a direct correlation was found between survival and maximum radiotherapy dose. Children having a total excision of the tumor prior to radiotherapy showed a greater survival than those treated by a subtotal or partial tumor removal. Children treated by radiotherapy alone had a survival comparable to those treated by sub-total excision and radiotherapy. There is a striking difference in survival expectation depending on initial functional category (I to III). The overall survival rates of 428 children completing treatment for glioma were 49% at 5 years, 43% at 10 years, and 40% at 15 years. The results according to certain specific tumor sites within the cerebral hemispheres are reported. Age is an important prognostic factor in low grade and also high grade astrocytomas, children having longer survivals than adults. Sub-total or partial excision of craniopharyngiomas combined with radical radiotherapy appears to give the best long-term results. Of 73 new cases, the 5-, 10-, and and 15-year survival rates were 92%, 84%, and 79%. Recurrent craniopharyngiomas treated by surgery alone can be salvaged by further conservative surgery and radical radiotherapy. Optic gliomas are slow growing low grade astrocytomas. Survival rates at 5, 10, and 15 years for 20 children with mostly chiasmal lesions were 89%, 89%, and 78%, respectively. In 73 children with brain stem tumors, 17% remained alive for up to 15 years. The risk of CNS seeding from intracranial ependymomas depends on site of origin and grade of malignancy, with 50% incidence occurring in cases with high grade lesions situated in the posterior fossa. Survivals at 5, 10, and 15 years in 51 children were 51%, 40%, and 31%. Adjuvant chemotherapy improves survival.(ABSTRACT TRUNCATED AT 400 WORDS)

Medulloblastoma in adults: a review of 47 patients treated between 1952 and 1981.

The results of treatment of 47 adults with medulloblastoma are reviewed. For those treated with ortho-voltage radiotherapy between 1952 and 1963 the actuarial 5- and 10-year survival rates were 38% and 23%, respectively. Of those treated with megavoltage radiotherapy between 1964 and 1981, the corresponding 5- and 10-year survival rates were 59% and 53%, respectively. Of patients treated with megavoltage radiotherapy and adjuvant chemotherapy between 1971 and 1981, 76% were alive at 5 years and also at 10 years. Treatment factors associated with an increased survival were complete or subtotal resection of the primary tumor, as opposed to partial removal, a radiation dose to the posterior fossa of 55 Gy or more and the administration of adjuvant chemotherapy. Neither the quality of life, nor the fertility of the surviving patients, have been impaired by the treatment. Six patients (13%) developed metastatic disease outside the central nervous system.

Low grade glioma of the cerebral hemispheres in adults: a retrospective analysis of 88 cases.

Eighty-eight adult patients with histologically verified cerebral low grade gliomas (grades 1 and 2) treated with post-operative radiotherapy at the Royal Marsden Hospital between 1960 and 1985 were reviewed. Survival of oligodendroglioma patients was greater than those with astrocytoma (64% vs 36% at 5 years) but the difference was less marked in the long term (35% vs 26% at 10 years). Previous studies have identified prognostic factors important in these tumors: age, extent of surgery, grade, performance status, and duration of symptoms. In this study of low grade astrocytomas and oligodendrogliomas, age (highly significant in the former and significant in the latter), extent of surgery (oligodendrogliomas), and performance status have been demonstrated as factors influencing outcome. The precise role of radiotherapy including the optimal radiation dose and timing of treatment remains unclear. The information, given by a retrospective analysis such as this, helps in the design of prospective, randomized studies looking at radiation dose and time of surgical and radiotherapeutic interventions, always with careful assessment needed of quality of life and treatment morbidity.

Pineal and CNS germ cell tumors: Royal Marsden Hospital experience 1962-1987.

A retrospective analysis has been made of all patients with pineal and CNS germ cell tumors who were treated at The Royal Marsden Hospital between 1962-1987. A total of 67 new cases were seen: 17 had initial histological verification of tumor type and the remainder were tested for radiosensitivity with a dose of 20 Gy following a shunting procedure. Patients with germ cell or radiosensitive tumors were treated with a uniform policy of whole neuraxis radiotherapy giving 50 Gy to the local tumor and 30 Gy to the remaining brain and spinal cord. Nonresponding lesions continued with local fields to a dose of 50 Gy. Patients were divided into three groups (a) germinoma and radiosensitive tumours, 34 cases; (b) malignant teratoma, 12 cases; (c) non-germ cell, 21 cases. Median follow-up is 83 months (range 2-246 months). Overall and cause specific actuarial 5/10 year survival were for group 1, 81.7%/69.4% and 86.5%;/86.5%; group 2, 18.2%/18.2% and 18.2%/18.2%, and group 3, 64.3%/46.8% and 64.3%/52.6%, respectively. No patient in group 1 treated during the last 12 years has recurred. Univariate analysis of factors at presentation, showed that neurological performance status (p less than .001) as well as tumor type (p less than .001) correlated with outcome. Recurrence was confined to the primary site in only 1 of 4 patients in group 1 compared to 6 of 9 patients in group 2 and 9 of 10 patients in group 3. No isolated spinal recurrence occurred in group 1 patients. A total of eight patients have received platinum containing chemotherapy for recurrence (6 cases) or adjuvant therapy (4 cases). Germinomas appear to respond better than teratomas, all of which have recurred rapidly following initial partial response. Shunting and radiosensitivity testing remains the treatment of choice for tumors compatible with germinoma. Craniospinal irradiation is associated with low morbidity providing spinal growth is complete and is recommended in older patients as salvage following spinal recurrence is unsatisfactory. Aggressive combined modality approaches with surgery, radiotherapy and chemotherapy need to be investigated to improve results in CNS teratoma.

Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I).

Two hundred and eighty-six patients with medulloblastoma from 46 centres in 15 countries were treated in a prospective randomized trial designed to assess the value of adjuvant chemotherapy. All patients were treated by craniospinal irradiation. Those randomly allocated to receive adjuvant chemotherapy were given vincristine during irradiation and maintenance CCNU and vincristine, given in 6-weekly cycles, for 1 year. The overall survival was 53% at 5 years and 45% at 10 years. At the close of the trial in 1979, the difference between the disease-free survival rate for the chemotherapy and control groups was statistically significant (P = 0.005). Since then, late relapses have occurred in the chemotherapy arm and the statistically significant difference between the two groups has been lost. Although there is now no statistical difference between the two arms of the trial, a benefit for chemotherapy persists in a number of sub-groups; partial or sub-total surgery (P = 0.007), brainstem involvement (P = 0.001), and stage T3 and T4 disease (P = 0.002). A number of prognostic factors for medulloblastoma have emerged; sub-total resection, extent of disease and being male sex carry a poor prognosis.

Adjuvant chemotherapy in T3 carcinoma of the bladder. A prospective trial: preliminary report.

We report the early results of a multi-centre, randomised prospective trial of neoadjuvant and maintenance chemotherapy with methotrexate (MTX) in 376 patients with advanced (T3) carcinoma of the bladder. In patients under 65 years of age, treatment consisted of radical radiotherapy (64 Gy) or, in some centres, pre-operative radiotherapy (44 Gy) and elective cystectomy. All patients over 65 had radical radiotherapy. MTX was administered to 188 patients. There was no increase in toxicity attributable to the MTX. MTX did not significantly increase the proportion of patients whose tumours responded to radiotherapy; 50% (70/141) responded to radiotherapy and 56% (76/136) to MTX radiotherapy. The development of metastases and survival was also similar in both groups (3-year survival: radiotherapy 37.3%, MTX + radiotherapy 38.6%). We report the logistic difficulties of the administration of prolonged courses of maintenance chemotherapy. Further controlled trials of neo-adjuvant chemotherapy in advanced bladder cancer are required, involving more active regimes.

High dose BCNU chemotherapy with autologous bone marrow transplantation and full dose radiotherapy for grade IV astrocytoma.

In a series of 22 patients, high dose BCNU (800-1,000mg m-2) with autologous bone marrow transplantation was given as the first post-surgical treatment for grade IV astrocytoma and followed by full dose radiotherapy. When compared to historical experience and matched to control patients in national studies, there appeared to be a small prolongation of survival but no increase in the proportion of long survivors. Acute myelosuppression was mild but toxicity to lung and liver was substantial and limited further dose escalation. Late bone marrow failure was seen in 4 patients. Pharmacokinetic studies were performed and suggested that the late marrow failure was due to persistence of BCNU at the time of marrow return. Despite the suggestion of a prolongation of survival this approach is not routinely recommended and a randomised trial is probably not justified.

Renal impairment following the combined use of high-dose methotrexate and procarbazine.

A major side-effect of high-dose methotrexate is renal toxicity, which may develop unexpectedly despite adequate standard precautions such as hydration and alkalinisation of the urine. The pathogenesis is unclear. Recent reports suggest that the combination of high-dose methotrexate with non-chemotherapeutic agents may cause such renal impairment. Three cases of unexpected renal impairment following the combined use of high-dose methotrexate and another cytotoxic agent, procarbazine, are reported. Possible mechanisms of this interaction are discussed, as are recommendations for future combined administration.

Percutaneous renal surgery and local radiotherapy in the management of renal pelvic transitional cell carcinoma.

Six patients with a history of bladder carcinoma and a radiographic filling defect of the pelvicaliceal system have been investigated or treated percutaneously. In two cases of doubtful diagnosis, percutaneous pyeloscopy showed that no pelvicaliceal tumour was present. In four patients with multifocal or recurrent transitional cell carcinoma and difficult clinical problems, intrarenal tumours were cauterised or resected percutaneously. Radioactive iridium wire (192Ir) was inserted into the surgical track to deliver prophylactic irradiation (4500 cGy) to prevent tumour seeding. Follow-up was from 7 to 36 months. One operated patient developed early wide-spread multifocal disease throughout the urothelium, including the operated kidney, and died of uraemia. The other three patients have shown no recurrence in the operated kidney, though two have developed recurrences in the bladder or ureter. There have been no track recurrences.

Optic gliomas: radiation therapy and prognosis.

A retrospective study was performed of 30 patients with optic gliomas referred to the Royal Marsden Hospital between 1951 and 1981. Twenty-nine of these had progressive disease, and were treated with radiotherapy. At presentation 12 (41%) had visual deficit to the extent of at least one blind eye. Visual acuity improved following treatment in 10 (43%) of 23 evaluable patients, was stable in 11 (48%) and deteriorated in 2 (9%). There was increase in visual fields in 4 (18%) of 22 evaluable patients, and no change in the remaining 18 (82%). Overall 26/29 (90%) of irradiated patients remained free from disease progression at a median follow-up period of 10 years. The probability of survival was 100% at five years following radiotherapy, and 93% at 10 years and also at 15 years. In view of the substantial morbidity and mortality in reported series, and the tendency for referral of more serious cases to a radiotherapy center, we conclude from our results that radiotherapy is effective in preventing progression of optic glioma, and that treatment early in the course of the disease is indicated to minimize the associated visual deficit.

Primitive neuroectodermal tumours of the cerebrum. Pathology and treatment.

Eighteen cases of cerebral tumour composed partly or totally of primitive embryonal cells are reported. These lesions comprise 2.8% of all primary cerebral hemisphere tumours in the histopathology files of The Royal Marsden Hospital between 1971 and 1980 inclusive. Most exhibited some degree of differentiation towards neuronal or glial elements and, as more than one type of differentiation was often present in the same lesion, we agree with others that the term primitive neuroectodermal tumour (PNET) is more appropriate to describe these lesions than terms based on histogenesis. The extent of the primitive component varied, but usually accounted for more than 80% of the tumour. Although the tumours bear some similarities to posterior fossa medulloblastomas, they exhibit important differences in histology, immunohistology, natural history and response to treatment. Nearly all PNETs examined expressed some glial fibrillary acidic (GFAP) both in primitive areas and zones of astrocytic differentiation. GFAP staining may thus be of value in distinguishing PNETs from undifferentiated non-neurogenic tumours. Of 14 patients referred for radiotherapy, the survival rate at 3 years was 29% (4/14) and 5 years 25% (3/12). Patients with tumours in which at least 90% of the tissue was undifferentiated exhibited an extremely poor prognosis with none of 9 patients still alive at 3 years in contrast to 3 of 5 patients (60%) with tumours showing less than 90% undifferentiation. Radical tumour removal, where feasible, followed by irradiation of the whole cerebrospinal axis is recommended. Adjuvant chemotherapy with such agents as CCNU and Vincristine may be of value: the 3 long term survivors in the present series (7-11 years), including one who presented disseminated intracranial disease, received such adjuvant treatment.

Malignant mesothelioma of the pleura: a study of 52 treated and 64 untreated patients.

We have carried out sequential prospective studies of treatment with surgery alone, chemotherapy, and radiotherapy in malignant mesothelioma of the pleura. The survival of treated patients was contrasted with that of 64 contemporary untreated patients whose clinical condition at presentation was comparable with that of the treated patients. Non-radical surgery alone (28 patients) was of palliative benefit, particularly for the control of recurrent pleural effusions, and may have prolonged survival in one patient with localised malignant mesothelioma. Chemotherapy with doxorubicin, vincristine, and cyclophosphamide (12 patients, with preceding surgery in eight) was without objective benefit. Megavoltage radiotherapy by an off axis beam rotational technique (12 patients, with preceding surgery in eight) abolished pain and dyspnoea and may have prolonged survival in one patient and terminated recurrent pleural effusions in three, but it was of no value in the other patients. There was no significant difference in survival between treatment groups or between treated and untreated patients, and no difference when mesotheliomas of epithelial, sarcomatous, and mixed cell types were examined separately. Treatment of this disease appeared to fail because of the unresponsiveness of the tumour to existing forms of treatment and the advanced stage of the disease at clinical presentation.