Epidermal growth factor receptor (EGFR) is amplified or overexpressed in many malignant gliomas and other primary brain tumors but is low or undetectable in normal brain. In the present study, this differential expression has been exploited for targeted brain tumor therapy using a TGF-alpha-Pseudomonas exotoxin recombinant toxin, TGF-alpha-PE38. In vitro experiments demonstrate that the cytotoxicity of this fusion protein is primarily determined by tumor EGFR expression and that TGF-alpha-PE38 cytotoxicity is abolished by pretreatment with excess epidermal growth factor. Treatment with i.p. TGF-alpha-PE38 in nude mice bearing glioblastoma or medulloblastoma s.c. xenografts produced tumor regression and growth delay. For intracranial xenograft implants treated with i.p. TGF-alpha-PE38, significant increases in median survival were noted only for tumors with the highest EGFR expression. However, intracranial tumors treated with a single intratumoral injection of TGF-alpha-PE38 showed increased survival in all xenografts tested. These results indicate that TGF-alpha-PE38 is active against primary human brain tumors ranging from moderate to high EGFR expression. For intracranial tumors, however, the higher survival rates produced by intracranial injection of TGF-alpha-PE38 than by continuous i.p. administration suggest that increased drug clearance or impaired drug delivery reduces the efficacy of systemic TGF-alpha-PE38. Direct delivery of TGF-alpha-PE38 into brain tumors by controlled-release biodegradable polymers or intratumoral implanted catheters, or intrathecal administration into the colony stimulating factor of patients with leptomeningeal metastasis, may represent clinically useful applications of recombinant toxin therapy in tumors with high EGFR expression.

A l'occasion du 10eme anniversaire du departement de radiotherapie de l'universite d'Essen, un historique est fait sur la place de la neutrontherapie dans le traitement des cancers par radiations ionisantes

Since the Hammersmith cyclotron was removed, the earlier therapy results have been extensively re-examined. The overall experiences can be summarized as follows: 1. A total neutron dose of 1560 cGy given in twelve equally spaced fractions over 20 days seems to be the optimum. Neutrons, therefore, provide a treatment option with great advantage with respect to patient management. 2. Rapid tumour regression is an important often ignored effect, leading to a quick relief of pain and other serious symptoms in the patient. 3. Due to the high incidence of complete regression complicated surgery can be avoided in many cases. Tissue deficits can be often covered by modern methods of surgery repair. 4. Local control rates are as high as 60 to 80% of the advanced tumours. They improve the quality of life and reduce the cost of continuing patients' care.

Experimental results suggest advantages for neutrons where cells are hypoxic, in tumors which are slowly growing and also in a relative sparing of bone damage. The neutrons available at Hammersmith were of 7.5 MeV energy and produced a poorly penetrating beam, unsuitable for treating tumors in the pelvis and abdomen. Patients with locally advanced tumors in superficial sites were therefore selected to assess the effects of neutrons on normal and malignant tissues. One hundred and eight-nine patients had between them 191 locally advanced (T4 N0-3) tumors in the oral cavity, paranasal sinuses, salivary glands, and breast. Neutron therapy resulted in complete regression in 84% of which 13% subsequently recurred. Median survival for the whole group was 32 months. Twenty-eight other patients had advanced tumors of the head and neck which were recurrent after X ray therapy and other treatments; 82% of these completely regressed for more than 1 year. Complications appeared in 27% of patients not previously treated and in 46% who had already undergone X ray therapy. Seventy-four per cent of complications started in the skin. With neutrons of this energy there is minimal sparing of the skin and uneven distribution of dose resulting in "hot" spots. These affected skin, subcutis, and muscle. The high rates of control in these large tumors, the low incidence of bone necrosis, and the repair of some bones eroded by tumor correlate well with the experimental data. There was rapid regression of the tumor and close correlation between early and late effects on skin and subcutis. These two observations may relate to the fractionation, total dose, and overall time of treatment of 1560 cGy neutron dose given in 12 fractions over 28 days.

The clinical investigation of fast neutrons at Hammersmith Hospital included 17 patients who between them had 20 T4 breast cancers. The majority of these tumours were ulcerated and all were painful. Ten had recurred after multiple other therapies. Complete local regression was achieved in all but one (95%) and no tumour recurred. Symptoms were relieved in all cases. Median survival was 26 months. Three patients developed small areas of skin necrosis following trauma of previous radiation. All the neutron treated breasts became fibrosed, but this was painless. Neutron treatment needed only 12 attendances over 28 days, in contrast to the best results from photon therapy which required 6-7 weeks followed by implant of radioactive wire and/or surgical excision. One patient who had bilateral tumours received neutrons to the left breast and X-ray therapy (photons) to the right. The photon treated tumour did not completely regress and recurred. The neutron treated one completely regressed and did not recur. Neutrons were also more effective than tamoxifen which causes complete regression in only about 30% of cases. It is suggested that neutron therapy is indicated for locally advanced tumours which do not respond to hormones. Since metastases were a common cause of death, there remains a need for an effective adjuvant treatment, acceptable to elderly patients.

In 1948, the Medical Research Council in the UK decided that data from radiobiological and physics experiments justified an investigation of neutron therapy for patients with malignant tumors. A cyclotron was therefore built and installed in Hammersmith Hospital in London, but it was not until 1969 that patients were treated on a regular basis. The MRC later put a second cyclotron for neutron therapy into the Western Hospital at Edinburgh and treatments were given from 1977 to 1985. Unfortunately both these machines were of inadequate energy (1516 MeV), the neutron beams being little better in penetration and penumbra than 250 KV X rays which became obsolete in the 1950’s with the advent of megavoltage X ray therapy. These inadequecies of the first 2 clinical cyclotrons were compounded by the collimators which were heavy and had to be changed manually and by the beam being fixed horizontally at Hammersmith. For the last 6 years, the Hammersmith collimators were changed to be fully adjustable by electronic means. From 1972, time was rented for neutron therapy on physics machines in the USA at Houston, Seattle, Cleveland, Fermi Laboratory, and Washington D.C. Although all of these were beams of higher energy (22 MeV-66 MeV) they were fixed in the horizontal plane, had manually changed collimators, were miles distant from a hospital and rates of hire by the hour were expensive. Machine inadequacies made the delivery of neutron dose to tumors uneven and risked giving normal tissues excessive radiation. The set-up of patients was very difficult. Each of these factors had a significantly deleterious effect on clinical results, cumulatively they produced a severe bias against neutron therapy. This bias was technical and mechanical and had nothing to do with the biological effects of neutrons on normal and malignant tissues. The two issues (the inadequacies of primitive machines and clinical effects of neutrons) have however constantly been confused. It was not until 1986 that the significance of neutron energy was demonstrated statistically. This was in an RTOG study which showed that low energy neutrons gave about 30% more complications than those of high energy.18 Funding authorities in the UK and the USA have not appreciated the contrast in quality of treatment between primitive neutron sources and modern megavoltage X ray therapy and since 1970 have insisted on or encouraged comparison in so-called controlled clinical trials. In this respect neutrons have been dealt with very differently from electrons, interstitial implants and most surgical procedures. The first such randomised “controlled” clinical trial was undertaken at Hammersmith Hospital from 1970 to 1975 on patients with advanced tumors of the head and neck. ‘,2Y6 The purpose of this trial was to compare neutron with photon effects on normal and malignant tissues in the localized area of treatment. Survival was not a primary interest. It was necessary to treat tumors superficial enough to measure, see and photograph the effects. The sites were oral cavity, oropharynx, larynx and hypopharynx, salivary glands, paranasal sinuses and neck nodes where the primary had already been controlled. Histological types were squamous cell, adenocarcinoma, adenoid cystic, and mucoepidermoid carcinoma. Many of the tumors were so advanced that they exceeded the TNM descriptions, 70% of the patients had fixed nodes. The neutron dose of 15.6 Gy in 12 fractions over 26 days gave a skin reaction equivalent in intensity and duration to photon doses of 48 Gy in the same fractionation and overall time. Because of the multicenter nature of this trial not all photon patients received this dose, but in all cases treatment was given with radical intent. The result of this trial was a highly significant advantage to the neutron treated patients in terms of local control (76% neutrons, 19% photons) and of local control without serious complications (42/70 (60%) neutron patients, lo/63 (16%) photon patients). Survival was slightly longer in the neutron treated patients, at 2 years 28% of neutron patients compared with 15% photon pa-

The conventional treatment for cancer of the salivary glands is surgery, with or without X ray therapy. In advanced tumors (Stage III and IV), local control and 5-year survival rates are less than 35%. Radical surgery severs the facial nerve in the majority of operations on parotid gland tumors. Local control of unresectable salivary gland tumors was achieved, in 74% of cases, by fast neutron therapy. From the MRC cyclotron at Hammersmith Hospital neutrons were given to 65 patients, with locally advanced or recurrent tumors, 89% of which were Stage IV. Local control and 5-year survival rates were 72% and 50%, respectively. The facial nerve was not damaged by neutron therapy. In patients with parotid gland tumors, 77% regained or maintained function. Function was lost in 14% through recurrence and 9% remained paralyzed. The results were achieved using beams from primitive machines with serious disadvantages. The results from neutrons implicate improvements for locally advanced tumors of non-epidermal origin in other sites of the body, especially with the high energy neutrons now available from modern cyclotrons.

Seventy of 104 patients with advanced oral cancer lived more than one year after neutron therapy and a local control rate of 74% was obtained. Eighty-nine per cent of these tumours were stage 3 or 4. There were 24 adverse late effects of which 20 involved soft tissues and four involved bone. Thirty eight of 40 mandibles which were normal before treatment remained so despite the curative dose which was given. Seven of 15 mandibles eroded by tumour became clinically normal after treatment. Eight per cent variation in dose was easily discernible in the skin and subcutis. These clinical findings correlated with the low energy of the neutrons and with the relative sparing of bone by neutrons.

The treatment of malignant parotid gland tumours by either surgery or X-radiotherapy alone results in unacceptably high rates of local recurrence. This has led to a combined management, with radiation given either before or after surgery. In the best series this gives an 85% control rate but with severance of the facial nerve in a high proportion of cases. Fast neutron therapy was given for much more advanced tumours and gave the same control rate. Where the facial nerve had been damaged by the tumour, paralysis was lessened substantially in four of nine cases. However neutrons were the apparent course of damage to the nerve in three cases. Two of these had previously received surgery and X-ray therapy.

The reader of the paper by Pointon et al (1985) might well infer from the discussion section that the Hammersmith trials included carcinoma of the bladder. In fact, we have treated no patients with bladder cancer because the penetration of our neutron beam was inadequate and its penumbra too wide. The beam of 15 MeV neutrons used by Dr. Pointon had similar penetration and an even worse penumbra. In addition, we had the problem of a beam fixed in a horizontal direction.

The incidence of malignant mesothelioma of the pleura is rising-there were 254 deaths from this cause in England and Wales in 1982.' Despite the fact that isolated claims have been made for radical surgery,2 chemotherapy,3 and megavoltage therapy4 5 there is no good evidence that any of these forms of treatment improve the outlook in mesothelioma and most clinicians would subscribe to the view that those patients who have the least active treatment do best.6 We report a patient who has done well with fast neutron therapy.

Twenty-eight patients who had received radical treatment with X rays to tumors of the head and neck presented with advanced recurrent tumors, 23 of them had also undergone surgery and 10 had more than one operation. Seven had also received chemotherapy. They were treated with neutrons to a tumor dose of 1560 cGy in 12 fractions over 26 days using the techniques of the Hammersmith Unit. Twenty-three of the tumors (82%) underwent complete regression that was maintained in 15 for at least 12 months. Despite the damage done by the previous radiation and surgery to the normal tissues, 15 patients had no complications following neutron therapy. In six patients, there was major necrosis, in seven others, this was minor. Eight tumors recurred. Five patients responded with partial regression of their tumors. The median survival was 20 months (range 4-69 months).

Fast neutron therapy has been used to treat 87 tumours of primary, recurrent or metastatic melanoma in 48 patients. Complete regression has been obtained in 71 percent of tumours and 91 per cent of all tumours were controlled for the remainder of the patients, lives. Median survival was 14.5 months; 30 of the 34 deaths were due to metastases. Complications arose in 22 per cent of sites and were either fibrosis, which was related to large treated areas, previous surgery or a higher than standard dose, or necrosis which was related to sites with poor circulation, such as in the lower limb. It is suggested that for the treatment of advanced local disease fast neutron therapy is more effective than X-ray treatment and has a local control rate similar to that of surgery.