t
Europ. J. Cancer Vol. 13, pp. 475-477. Pergamon Press 1977. Printed in Great Britain
A Preliminary Clinical Study of the Use of Mycophenolic Acid as a Radiosensitizer THELMA BATES Consultant Radiotherapist and Otwologist, St. Thomas' Hospital, London Abstta©t--Animal experiments have suggested that the drug Mycophenolic Acid may be a radiosensitizer. This brief communication describes a clinical trial of the drug in patients with two or more similar skin metastases or with bilateral lung metastases. The patients acted as their own controls, receiving two types of treatment on separate occasions using either Radiotherapy alone or Radiothera,~y with Mycophenolic Acid. The study failed to show synergism between radiotherapy and the drug in metastatic tumours of the breast, stomach, caecum and testes.
single treatment was used for pairs of small lesions up to 2 cm dia. Larger metastases were given 1200, 1300 or 1400 R in 2 treatments over 4-7 days. During the treatment of one of each pair of lesions oral Mycophenolic acid was given. The drug was started 2 full days before treatment and continued throughout the day or course of treatment. Daily doses ranging from 800 to 2400 mg were given for periods of 3-9 days. Bilateral lung metastases. Each lung was irradiated with a separate course of Cobalt 60 teletherapy (1.2 MeV, H.V.L. 10.4mm Pb), one with and one without concurrent intravenous sodium mycophenolate. Two patients were treated. One patient had metastases from a radiosensitive seminoma of testis. He received a maximum turnout dose of 1000P,. in 6 treatments over 9 days. The other had metastases from a radioresistant adenocarcinoma of the caecum. She received a maximum tumour dose of 2000 R in 7 treatments over 18 days. Both patients started intravenous sodium mycophenolate 4 g in 5 % Dextrose given over a period of 4 hr each day 2 days before treatment of their right lung. The patient with the seminoma continued this dose daily throughout the treatment course but the other patient, after the first two days, was only prepared to accept an intravenous drip on the day of treatment. Both patients completed the intravenous infusion of sodium mycophenolate
INTRODUCTION
BOTH animal experiments [1] and clinical experience [2] at the Lilly Research Centre have suggested that the drug Mycophenolic acid may be a radiosensitizer, i.e. a drug which improves the ratio of the damage of tumour cells to the damage of normal cells by ionising radiation. This preliminary clinical study of patients with metastatic tumours of the breast, stomach, caecum and testis did not confirm these findings. MATERIAL AND METHODS Selection of Patients Patients were selected because they had either two or more similar skin metastases or bilateral lung metastases from a histologically proven primary tumour. Thus, patients acted as their own controls. They were excluded from the trial if they were clinically unfit for radiotherapy or if the lesions under study were in a previously irradiated zone. Treatment Each patient received two types of treatment on separate occasions to similar skin or lung metastases, using either radiotherapy alone or radiotherapy with Mycophenolic acid. Metastatic skin nodules. Pairs of similar lesions were irradiated to the same dose with superficial X-ray therapy (70 kV, 9 mA, H.V.L. 1.5 m m A1.). A dose of 800, 900 or 1000 R in a
475
476
Thelma Bates
approximately 1 hr before each radiotherapy treatment. PATIENT RECORDS A detailed assessment of the present condition, including a description of the lesions to be treated was made before each treatment course. Haematological and biochemical findings were recorded together with diagrams, photographs and X-rays as appropriate. On completion of treatment and at 1 week, 1 month, 3 months and 6 months after treatment, changes in the treated lesions and in the adjacent irradiated normal tissues, e.g., skin, subcutaneous tissue and lung were observed, compared and recorded with photographs and X-rays if appropriate. A full blood count and biochemical examination were carried out and changes noted. RESULTS Skin metastases. Eighteen pairs of skin metastases were treated in 13 patients. Except for one patient who has a carcinoma of the stomach, the rest (17 pairs) had breast carcinoma. The tumour response with and without Mycophenolic acid was similar. The radiation effect on the skin ranged from a mild erythema to a dusky erythema and was similar in both treatment groups. No patient developed any late subcutaneous fibrosis. Bilateral lung metastases. The first patient treated was a co-operative male journalist aged 53 with metastases from a seminoma of the testis in his intra-abdominal lymph nodes and in both lungs. His left lung was irradiated first to 1000 R. On completion of treatment there had already been a dramatic improvement. His right lung was irradiated similarly but with daily intravenous sodium mycophenolate, again with a dramatic and similar improvement. At exactly one week and approximately 5 weeks after the completion of each course, regression was similar on both sides. He died soon after. The second patient was a frail elderly lady with bilateral lung metastases, worse on the left side, from an adenocarcinoma of the caecum which had been successfully excised 2½ years previously. Adenocarcinoma cells were present in her sputum. The left lung was irradiated first to a maximum tumour dose of 2000 R with little effect. Similar irradiation was delivered to the right lung with sodium mycophenolate. She received 4 g daily for two days before treatment and then 4 g on the
7 days she was irradiated. The left lung showed some improvement on X-ray at 1 and 2 months after the completion of treatment but then deteriorated. In the right lung which had been irradiated with sodium mycophenolate, the metastases were larger at each time interval. Neither patient developed a radiation pneumonitis or any other evidence of increased radiosensitivity of the normal tissues. DRUG TOXICITY Neither of the patients given sodium mycophenolate experienced toxic symptoms during or after administration. Oral Mycophenolic acid caused nausea in 8 of 13 patients. The incidence and severity of nausea was related to the daily dose. The experience of this trial suggested that a daily dose of 1200 mg is the maximum which patients will tolerate. Neither haematological nor iochemical changes were produced in any patient. DISCUSSION Perhaps with the exception of the development of Neutron therapy, radiotherapy alone is unlikely to offer any major contribution to cancer therapy in the forseeable future. The most likely major advances may be in the field of radiosensitizing drugs. A radiosensitizer is a chemical which increases the cell-killing effect of a given dose of radiotherapy, but to be of any value in radiotherapy a radiosensitizer must improve the therapeutic ratio (i.e., the ratio of the damage oftumour cells to the damage of normal cells)--, otherwise the same effect could be produced simply by increasing the dose of radiation. There are very few true radiosensitizers and most of the drugs for which this claim has been made have acted by addative rather than by synergistic effect with radiotherapy. Oxygen is the most effective radiosensitizer discovered so far and the most fruitful laboratory research at the moment appears to be in the use of electron-affmic compounds, as yet too toxic for use in man, which act in a similar way to oxygen. Preliminary work by Sweeney and his colleagues [1] showed synergism between Mycophenolic acid and X-ray therapy in the treatment of Gardner lymphosarcoma in mice. He was not able to show synergism in all tumour type and suggested that synergism was related to high/~ glucuronldase activity. This pilot study has failed to show a similar
Study of Mycophenolic Add as a Radiosensitizer
synergism in the treatment of four human tumours, i.e.,carcinoma of the breast, stomach and caecum and scminoma of the testis.It is suggested that this simple clinical experiment
477
could be used to test other possible radiosensitizing drugs. Aeimowledgement--~is trial was supported by a grant from Eli Lilly and Company.
~ G E S I. M.J. Swz~-Nxv, K. G~Rzotq, P. N. I-IARR~,R. E. HoT-~rr.s,G. A. POORZ and R. H. W ~ , Experimental antitumour activity and preclinical toxicology of mycophenolic acid. Cancer1~s. 32~ 1795 (1972). 2. R.W. DYvm,Personal Communication (1973).
Europ. J. Cancer Vol. 13, pp. 475-477. Pergamon Press 1977. Printed in Great Britain
A Preliminary Clinical Study of the Use of Mycophenolic Acid as a Radiosensitizer THELMA BATES Consultant Radiotherapist and Otwologist, St. Thomas' Hospital, London Abstta©t--Animal experiments have suggested that the drug Mycophenolic Acid may be a radiosensitizer. This brief communication describes a clinical trial of the drug in patients with two or more similar skin metastases or with bilateral lung metastases. The patients acted as their own controls, receiving two types of treatment on separate occasions using either Radiotherapy alone or Radiothera,~y with Mycophenolic Acid. The study failed to show synergism between radiotherapy and the drug in metastatic tumours of the breast, stomach, caecum and testes.
single treatment was used for pairs of small lesions up to 2 cm dia. Larger metastases were given 1200, 1300 or 1400 R in 2 treatments over 4-7 days. During the treatment of one of each pair of lesions oral Mycophenolic acid was given. The drug was started 2 full days before treatment and continued throughout the day or course of treatment. Daily doses ranging from 800 to 2400 mg were given for periods of 3-9 days. Bilateral lung metastases. Each lung was irradiated with a separate course of Cobalt 60 teletherapy (1.2 MeV, H.V.L. 10.4mm Pb), one with and one without concurrent intravenous sodium mycophenolate. Two patients were treated. One patient had metastases from a radiosensitive seminoma of testis. He received a maximum turnout dose of 1000P,. in 6 treatments over 9 days. The other had metastases from a radioresistant adenocarcinoma of the caecum. She received a maximum tumour dose of 2000 R in 7 treatments over 18 days. Both patients started intravenous sodium mycophenolate 4 g in 5 % Dextrose given over a period of 4 hr each day 2 days before treatment of their right lung. The patient with the seminoma continued this dose daily throughout the treatment course but the other patient, after the first two days, was only prepared to accept an intravenous drip on the day of treatment. Both patients completed the intravenous infusion of sodium mycophenolate
INTRODUCTION
BOTH animal experiments [1] and clinical experience [2] at the Lilly Research Centre have suggested that the drug Mycophenolic acid may be a radiosensitizer, i.e. a drug which improves the ratio of the damage of tumour cells to the damage of normal cells by ionising radiation. This preliminary clinical study of patients with metastatic tumours of the breast, stomach, caecum and testis did not confirm these findings. MATERIAL AND METHODS Selection of Patients Patients were selected because they had either two or more similar skin metastases or bilateral lung metastases from a histologically proven primary tumour. Thus, patients acted as their own controls. They were excluded from the trial if they were clinically unfit for radiotherapy or if the lesions under study were in a previously irradiated zone. Treatment Each patient received two types of treatment on separate occasions to similar skin or lung metastases, using either radiotherapy alone or radiotherapy with Mycophenolic acid. Metastatic skin nodules. Pairs of similar lesions were irradiated to the same dose with superficial X-ray therapy (70 kV, 9 mA, H.V.L. 1.5 m m A1.). A dose of 800, 900 or 1000 R in a
475
476
Thelma Bates
approximately 1 hr before each radiotherapy treatment. PATIENT RECORDS A detailed assessment of the present condition, including a description of the lesions to be treated was made before each treatment course. Haematological and biochemical findings were recorded together with diagrams, photographs and X-rays as appropriate. On completion of treatment and at 1 week, 1 month, 3 months and 6 months after treatment, changes in the treated lesions and in the adjacent irradiated normal tissues, e.g., skin, subcutaneous tissue and lung were observed, compared and recorded with photographs and X-rays if appropriate. A full blood count and biochemical examination were carried out and changes noted. RESULTS Skin metastases. Eighteen pairs of skin metastases were treated in 13 patients. Except for one patient who has a carcinoma of the stomach, the rest (17 pairs) had breast carcinoma. The tumour response with and without Mycophenolic acid was similar. The radiation effect on the skin ranged from a mild erythema to a dusky erythema and was similar in both treatment groups. No patient developed any late subcutaneous fibrosis. Bilateral lung metastases. The first patient treated was a co-operative male journalist aged 53 with metastases from a seminoma of the testis in his intra-abdominal lymph nodes and in both lungs. His left lung was irradiated first to 1000 R. On completion of treatment there had already been a dramatic improvement. His right lung was irradiated similarly but with daily intravenous sodium mycophenolate, again with a dramatic and similar improvement. At exactly one week and approximately 5 weeks after the completion of each course, regression was similar on both sides. He died soon after. The second patient was a frail elderly lady with bilateral lung metastases, worse on the left side, from an adenocarcinoma of the caecum which had been successfully excised 2½ years previously. Adenocarcinoma cells were present in her sputum. The left lung was irradiated first to a maximum tumour dose of 2000 R with little effect. Similar irradiation was delivered to the right lung with sodium mycophenolate. She received 4 g daily for two days before treatment and then 4 g on the
7 days she was irradiated. The left lung showed some improvement on X-ray at 1 and 2 months after the completion of treatment but then deteriorated. In the right lung which had been irradiated with sodium mycophenolate, the metastases were larger at each time interval. Neither patient developed a radiation pneumonitis or any other evidence of increased radiosensitivity of the normal tissues. DRUG TOXICITY Neither of the patients given sodium mycophenolate experienced toxic symptoms during or after administration. Oral Mycophenolic acid caused nausea in 8 of 13 patients. The incidence and severity of nausea was related to the daily dose. The experience of this trial suggested that a daily dose of 1200 mg is the maximum which patients will tolerate. Neither haematological nor iochemical changes were produced in any patient. DISCUSSION Perhaps with the exception of the development of Neutron therapy, radiotherapy alone is unlikely to offer any major contribution to cancer therapy in the forseeable future. The most likely major advances may be in the field of radiosensitizing drugs. A radiosensitizer is a chemical which increases the cell-killing effect of a given dose of radiotherapy, but to be of any value in radiotherapy a radiosensitizer must improve the therapeutic ratio (i.e., the ratio of the damage oftumour cells to the damage of normal cells)--, otherwise the same effect could be produced simply by increasing the dose of radiation. There are very few true radiosensitizers and most of the drugs for which this claim has been made have acted by addative rather than by synergistic effect with radiotherapy. Oxygen is the most effective radiosensitizer discovered so far and the most fruitful laboratory research at the moment appears to be in the use of electron-affmic compounds, as yet too toxic for use in man, which act in a similar way to oxygen. Preliminary work by Sweeney and his colleagues [1] showed synergism between Mycophenolic acid and X-ray therapy in the treatment of Gardner lymphosarcoma in mice. He was not able to show synergism in all tumour type and suggested that synergism was related to high/~ glucuronldase activity. This pilot study has failed to show a similar
Study of Mycophenolic Add as a Radiosensitizer
synergism in the treatment of four human tumours, i.e.,carcinoma of the breast, stomach and caecum and scminoma of the testis.It is suggested that this simple clinical experiment
477
could be used to test other possible radiosensitizing drugs. Aeimowledgement--~is trial was supported by a grant from Eli Lilly and Company.
~ G E S I. M.J. Swz~-Nxv, K. G~Rzotq, P. N. I-IARR~,R. E. HoT-~rr.s,G. A. POORZ and R. H. W ~ , Experimental antitumour activity and preclinical toxicology of mycophenolic acid. Cancer1~s. 32~ 1795 (1972). 2. R.W. DYvm,Personal Communication (1973).
