Mary Catterall

The treatment of advanced cancer by fast neutrons from the Medical Research Council's Cyclotron at Hammersmith Hospital, London

Abstract Patients continue to be treated regularly three times weekly on the Medical Research Councils cyclotron. A standard dose of 1440 rad in 12 treatments over 26 days is given. All the patients have had such advanced or “radioresistant” tumours that it was thought that other methods of treatment would not be satisfactory, or the tumours had recurred. Two hundred and thirty-eight patients completed their treatment by January 1973 and 58 lived with no sign of tumour in the neutron treated area for more than one year. One hundred and thirty-five who survived for less than one year, died of metastases but with regressing or completely regressed tumours in the neutron treated area. Forty-five tumours probably recurred and were all associated with doses which were lower than the standard dose. Necrosis of the skin appeared in 11 of 97 patients surviving more than 6 months, but in each of these cases, there was a precipitating factor and the necrosis was never unexpected or unexplained. Noteworthy results have been achieved in tumours of the salivary glands, buccal cavity, oropharynx, nasopharynx, stomach and in sarcoma and fixed glands invaded with adenocarcinoma, melanoma and squamous cell carcinoma. The effects of neutron therapy on the normal tissues which are unavoidably irradiated are being carefully observed. The eye is a uniquely good site for recording basic radiation changes and valuable information is being collected.

Re-irradiation of advanced tumors of the head and neck with fast neutrons

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).

The treatment of malignant salivary gland tumors with fast neutrons.

The results of fast neutron therapy for malignant tumors of the salivary glands are very satisfactory and on present evidence, fast neutrons are the treatment of first choice for tumors in these sites, when compared with the results from surgery and conventional radiotherapy. In this article, confirmation of results of neutron therapy already published from Hammersmith are given by workers at the Fermi Laboratory.

A comparison of clinical and laboratory data on neutron therapy for locally advanced tumors.

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 results of randomised and other clinical trials of fast neutrons from the medical research council cyclotron, London

Abstract In all centres using fast neutrons for the treatment of cancer, marked differences exist between neutron sources and modern megavoltage machines and neutron treated patients are at significant disadvantages in terms of treatment techniques. Improvements in the machines producing neutrons for clinical use are very urgently needed. The controlled clinical trial into the treatment of advanced tumors of the head and neck was carried out with such clinical inequalities that any but the most marked advantages of neutrons could have been masked. 134 patients were randomised, prospectively, to treatment with neutrons or photons. Complete regression of tumors was seen much more frequently and recurrences much less frequently in the neutron series. These differences were highly statistically significant, p = 0.001. The benefit to the neutron treated patients was seen in all sites of the head and neck and was not dependent on a greater quantity of radiation being given in the group where TDFs were equal. There were more complications in the neutron patients in the larynx and oropharynx, but this may have been due to curing tumors which, themselves, had caused irreparable damage to normal tissues. The cosmetic and functional results of neutrons in the floor of mouth and salivary gland tumors were good and contrast with radical surgical approaches in these sites. In other comparative studies, of two primary tumors in the same patient, an advamtege to the neutron treated tumor was seen in each of 2 such patients. For the same acute and late normal tissue reactions, there was complete regression without recurrence in the neutron tumors whereas both photon treated tumors did recur. Extreme care is taken in planning and in all stages of treatment and follow up. We are convinced that it is essential to have a highly trained medical and scientific team and a neutron source within the grounds of a first class hospital. A more energetic beam of neutrons, clinically comparable with modern megavoltage (cobalt) machines is essential before a proper assessment can be made of the place of neutrons in oncology. The good results already obtained suggest that the longer these machines are In coming, the greater may be the delay in significantly improving the treatment of some tumors which are, at present, lethal to the patient.

Results of neutron therapy: differences, correlations and improvements

Abstract All machines that have given neutron therapy over the past 12 years are so unsatisfactory that they closely resemble the now obsolete X ray machines of the 1950s. Present day neutron machines increase complications and reduce the chance of giving adequate doses to tumors through mechanical deficiencies; these may dominate the biological effects of neutrons. Comparisons with modern megavoltage X rays in valid controlled clinical trials are impossible in most sites of the body, although such trials are being attempted. Despite the inadequacies of the neutron machines, most trials are showing no difference between the neutrons and X rays. The only completed trial of advanced tumors of the head and neck showed a significant advantage to the neutron-treated patients. Clinical data correlate closely with laboratory data from the MRC cyclotron at Hammersmith Hospital, London, where special treatment techniques have been developed and tumors are specially selected for neutron therapy. These correlations are seen in the lack of damage to normal bone (because of the low kerma of neutrons for bone), the lack of vomiting and the high rate of control of advanced tumors, presumably a result at the greater effect of neutrons on hypoxic cells. The Hammersmith dose is higher than that given in most other centers; this is possible because the special techniques used protect the normal tissues and deliver the dose as precisely as possible to the tumor. Where adenocarcinomas have been treated in superficial sites, a high rate of local control is achieved, but local control is significantly less when these tumors are deeply sited in the :abdomen and pelvis, presumably because of the impossibility of delivering an adequate dose from the low energy neutrons. Modern high energy cyclotrons are now available, and only when these machines treat patients adequately can the place of neutrons in the treatment of cancer be accurately assessed.

A report on three years' fast neutron therapy from the Medical Research Council's cyclotron at Hammersmith Hospital, London.

All of the patients in 3 years of fast neutron therapy at Hammersmith Hospital have had such advanced or radioresistant tumors that they were thought unlikely to respond to low L.E.T. radiation. Twenty percent of those referred have been too ill to be treated or have been unable to complete the course of treatment. Of 238 patients who completed their treatment by January, 1973, 180 died less than 1 year after treatment of metastases or other causes, but in 135 of these, the tumors were either regressing or had completely regressed at the time of death. Fifty‐eight patients survived for more than a year with no sign of tumor in the treated area, including 20 with adenocarcinoma, 14 with well‐differentiated squamous cell carcinoma, 9 with sarcomas, and 7 with salivary gland tumors. Twenty‐two tumors definitely recurred or were residual, but all these received a dose which was less than the standard of 1440 rads in 12 treatments over 26 days. Eleven of the 97 patients who survived more than 6 months after treatment developed necrosis, but a precipitating factor was present in every case. Details of the results of 26 patients with buccal cavity tumors and of 31 patients with inoperable carcinoma of the stomach are given. Early results of a randomized clinical trial of the treatment of advanced tumors of the head and neck show that a greater number of tumors completely regressed with neutron than with supervoltage treatment. The results are statistically significant, but more patients are required and the trial is continuing. The techniques of fast neutron therapy are much more demanding than those of low L.E.T. radiation; the margin is narrow between the dose leading to recurrence and that resulting in necrosis. Scrupulous attention to planning and treatment is necessary in every case.

Clinical experience with fast neutrons from the Medical Research Council's cyclotron at Hammersmith Hospital

Abstract Forty patients suffering from advanced malignant tumours of the breast, head, neck and skin have been treated with 7 MeV fast neutrons from the M.R.C.s cyclotron at Hammersmith Hospital. This machine has an output of 40 rads/min and treatment times did not exceed 4 min. Ten of the patients had multiple or very large tumours and were treated also with low LET radiations. The responses of the skin in the treated areas to the two types of radiation have been observed and the reactions quantitated in order to obtain the RBE of fast neutrons for effects on skin. From the data available this appears to be approximately 2 · 9 . A skin sparing effect has been demonstrated. The tumours have been measured as objectively as possible and rates of regression have been recorded. These have varied among different histological types and also in the same patient when multiple nodules have been treated with both types of radiation. All the tumours treated with neutrons showed a favourable response which was not qualitatively different from that seen with low LET radiation.

The regression of tumors of the head and neck treated with neutrons.

Measurements were made of the exponential regression of cervical nodes from 44 patients with squamous carcinoma of the head and neck and of 20 salivary gland tumors treated with neutrons (7.5 MeV). In 80% of patients, the tumor regressed exponentially from the first day of treatment; in 20% of patients there was an initial shoulder followed by exponential regression. The volume-halving times were calculated and found to vary widely for each histological type. There was no correlation of the volume-halving time either with the differentiation of the squamous carcinomas or with the initial tumor volume. The mean volume-halving time for squamous carcinoma of the head and neck was 20.8 days; for malignant pleomorphic adenomas of the parotid gland the mean volume-halving time was 122.6 days.

The assessment of the results of neutron therapy

The control of tumors and the incidence of complications are major criteria for assessing the effectiveness of neutrons in the treatment of cancer. However, both of these are seriously affected by the neutron machines available at present. These have beams with poor penetration, wide penumbras, fixed field sizes and fixed positions. Undesirably large volumes of skin and normal tissues are therefore irradiated through the multiplicity of beams used and side scatter of radiation. Even machines with high energy neutrons are fixed in position and restricted in the sizes of fields available. Complications are therefore caused by inferior machines and compromised treatment plans independently of the biological effects of neutrons. The incidence of complications has caused some centers to reduce the dose of neutrons to a level where tumor control is not maintained and the recurrence rate is fairly high. The Hammersmith experience shows, however, that by improving treatment techniques and the care of early and late reactions, complications have been reduced from 18% to 5%, while maintaining the standard dose. There is close correlation between the clinical and laboratory data which show biological and physical advantages for neutron therapy. Higher energy machines with isocentric heads, mechanically adjustable collimators and the ability to use shields and wedges concurrently are now available and should be used to extend the investigation of neutrons, especially to tumors of the abdomen and pelvis.