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Fast neutron therapy: Its promise and its past
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Inr. J. Rodiarion oncology Biol. Phys.. Vol. 6. pp. 387-388 0 Pergamon Press Ltd., 1980. Printed in the: U.S.A.
??Editorial FAST NEUTRON THERAPY: THOMAS
W.
ITS PROMISE AND ITS PAST GRIFFIN,
M.D.
Chairman, Department of Radiation Oncology, University of Washington Hospital, Seattle, WA 98 105 Fast neutron beam radiati’on therapy began over forty years ago when Stone began a research program to investigate the effects of cyclotron-generated fast neutron beams on patients who had advanced cancersi Between 1939 and 1944, he treated 250 patients, most of whom had extensive tumors that were considered incurable by conventional treatment. blany of these patients had previously been unsuccessfully treated by X-rays. Dr. Stone reported impressive tumor responses; however, nearly ail of his few long-term survivors suffered severe radiation-produced sequelae in normal tissues.’ He interpreted these distressing late changes to be a consequence of an increased relative bilological effectiveness (RBE) for late effects compared to early effects; his discouraging report deterred further clinical trials of fast neutron teletherapy for approximately twenty years. Following the development of mammalian cell culture techniques in the mid-1950’s,” it was noted that the shapes of post-irradiation cell survival curves were different for fast neutrons than for X-ray photons. These varying shaped survival curves provided evidence that RBE’s for fast neutrons are larger for the small dose increments that are used clinically, than for the large dose increments that are usually used in the laboratory.’ Stone had inadvertently given nearly all of his patients, inordinantly high doses, reflected by calculated Nominal Standard Doses of 2000-3200 ret.’ Although an “oxygen elfect” was acknowledged in clinical radiation therapy dating at least to Hahn’s observations in 1904,9 recent increased interest dates to the work of Gray et a1.6 in 1953. It was recognized that “high linear energy transfer (LET)” radiations are influenced less adversely by sub-physiological cellular oxygen levels than are conventional photon radiations. This led to speculation that hypoxic cellular foci might be controlled more frequently by high LET radiations than by low LET photons. Reduced variation of radiosensitivity related to cell age and differences in post-irradiation recovery were also recognized as possible advantages for high LET particles over low LET photons.” A second clinical trial of fast neutron radiation therapy was initiated at the Hamrnersmith Hospital, London,
England, in November 1969.2 It was prompted by the important radiobiological findings of RBE variation with dose increment size as an explanation of the adverse treatment sequelae reported by Stone, and the lessening influence of tumor cell hypoxia as a reasonable explanation of the failure to erradicate some cancers with photon irradiation. After several hundred patients with extensive cancers were treated, it was concluded that fast neutron beam teletherapy was well tolerated and that extensive cancers responded remarkably well,’ better than one would have expected from photon irradiation. Enthusiasm generated by this and other preliminary reports led to the establishment of nineteen additional clinical fast neutron cancer therapy centers in Europe, Japan, the United Kingdom, and in the United States. The National Cancer Institute has recently embarked on an ambitious research program to investigate the value of high LET radiation in the treatment of human malignancies. While heavy ion and negative pi meson research will continue on equipment located in physics laboratories, four hospital based clinically dedicated neutron generators will be installed over the next three years to definitively test the potential of fast neutrons. Unlike their fixed-beam, laboratory-based predecessors, these rotational isocentric machines are capable of depth doses and field arrangements that are comparable to modern linear accelerators. These advantages will avoid the limitations imposed by low energy fixed horizontal beam physics machines and will assure the comparability of results obtained from randomized prospective clinical trials that compare neutrons to photons. The goal of the fast neutron beam research program is to increase local tumor control, and hopefully subsequent survival, while minimizing normal tissue side effects. Although publications from several of the physics based neutron projects have reported impressive local tumor control,3.7*‘0 the price has often been high in terms of normal tissue effects. Many of these normal tissue side effects (such as extensive subcutaneous fibrosis) result from the poor depth dose characteristics and non versatile field arrangements associated with the physics machines. However, a number of them, (such as the effects of
Accepted for publication
2 January 1980. Reprint requests to: Thomas W. Griffin, M.D. 387
388
Radiation
Oncology
Physics 0 Biology ??
neutrons on brain tissue reported in this journal)4 are based on a repetition of Dr. Stone’s error, an inaccurate assessment of normal tissue RBE. The experience gained and methods developed for neutron treatment with physics equipment stongly suggest that the goal of significantly improved tumor
January
1980, Volume 6, Number
2
response with acceptable normal tissue reactions can be attained at least for some tumors.3*7*8.‘0 Hopefully, this can be translated into an improved survival rate for the estimated 70,000 people who die each year from uncontrolled local cancers.
REFERENCES 1. Brennan, J.T., Phillips, T.L.: Evaluation
2.
3.
4.
5.
6.
of past experience with fast neutron teletherapy and its implications for future applications. Europ. J. Cancer 7: 2 19-225, 197 1. Catterall, M.: Clinical experience with fast neutrons from the Medical Research Council’s cyclotron at Hammersmith Hospital. Europ. J. Cancer 7: 227-229, 197 1. Catterall, M.: Clinical experience in particle therapy. Current experiences and prospects in Britain. Particle Radiation Therapy: Proceedings of an International Workshop, Key Biscayne. Fla.. 1975. Published by the American College of Radiology, July 1976, Vivian P. Smith, Ed. Catterall, M. Bloom, H.J.G., Ash, D.V., Walsh, L., Richardson, A., Uttley, D., Cowing, N.F.C., Lewis, P., Chaucer, B.: Fast neutrons compared with megavoltage X-rays in the treatment of patients with supratentorial glioblastoma: A controlled pilot study. Int. J. Radiat. Oncol. Biol. Phys. 6: 261-266, 1980. Fowler, J.F., Morgan, R.L.: Pretherapeutic experiments with the fast neutron beam from the Medical Research Council cyclotron. VIII. General review. Brit. J. Rad. 36: 115-121, 1963. Gray, L.H., Conger, A.D., Ebert, M., Hornsey, S., Scott, O.C.A.: The concentration of oxygen dissolved in tumor at
7.
8.
9. 10.
11. 12. 13.
the time of ionization as a factor in radiotherapy. Brit. J. Rad. 26: 638-648, 1953. Griffin, T.W., Laramore, G.E., Parker, R.G., Gerdes, A.J., Heberd, D.W., Blasko, J.C., Groudine, M.: An evaluation of fast neutron beam teletherapy of metastatic cervical adenopathy from squamous cell carcinomas of the head and neck region. Cancer 42: 25 17-2520,1978. Griffin, T.W., Weisberger, E.C., Laramore, G.E., Tong, D., Blasko, J.C.: Complications of combined surgery and neutron radiation therapy in patients with advanced carcinoma of the head and neck. Radiology 132: 177-178, 1979. Hahn, R.: Ein beitrag zur rontgentherapie. Fortshr. Beg. Rontgenstruhlen. 8: 120-l 2 1, 1904. Peters, L.J., Hussey, D.H., Fletcher, G.H., Baumann, P.A., Olson, M.H.: Preliminary report of the M.D. Anderson Hospital/Texas A & M variable energy cyclotron fastneutron therapy pilot study. AJR 132: 637-642, 1979. Puck, T.T., Marcus, P.T., Cieciera, J.J.: Clonal growth of mammalian cells in vitro. J. Exp. Med. 103: 372, 1956. Stone, R.S.: Neutron therapy and specific ionization. Amer. J. Roentgenol. 59: 77 l-785, 1948. Withers, H.R.: Biological basis for high LET radiotherapy. Radiology 108: 131-137, 1973.
Inr. J. Rodiarion oncology Biol. Phys.. Vol. 6. pp. 387-388 0 Pergamon Press Ltd., 1980. Printed in the: U.S.A.
??Editorial FAST NEUTRON THERAPY: THOMAS
W.
ITS PROMISE AND ITS PAST GRIFFIN,
M.D.
Chairman, Department of Radiation Oncology, University of Washington Hospital, Seattle, WA 98 105 Fast neutron beam radiati’on therapy began over forty years ago when Stone began a research program to investigate the effects of cyclotron-generated fast neutron beams on patients who had advanced cancersi Between 1939 and 1944, he treated 250 patients, most of whom had extensive tumors that were considered incurable by conventional treatment. blany of these patients had previously been unsuccessfully treated by X-rays. Dr. Stone reported impressive tumor responses; however, nearly ail of his few long-term survivors suffered severe radiation-produced sequelae in normal tissues.’ He interpreted these distressing late changes to be a consequence of an increased relative bilological effectiveness (RBE) for late effects compared to early effects; his discouraging report deterred further clinical trials of fast neutron teletherapy for approximately twenty years. Following the development of mammalian cell culture techniques in the mid-1950’s,” it was noted that the shapes of post-irradiation cell survival curves were different for fast neutrons than for X-ray photons. These varying shaped survival curves provided evidence that RBE’s for fast neutrons are larger for the small dose increments that are used clinically, than for the large dose increments that are usually used in the laboratory.’ Stone had inadvertently given nearly all of his patients, inordinantly high doses, reflected by calculated Nominal Standard Doses of 2000-3200 ret.’ Although an “oxygen elfect” was acknowledged in clinical radiation therapy dating at least to Hahn’s observations in 1904,9 recent increased interest dates to the work of Gray et a1.6 in 1953. It was recognized that “high linear energy transfer (LET)” radiations are influenced less adversely by sub-physiological cellular oxygen levels than are conventional photon radiations. This led to speculation that hypoxic cellular foci might be controlled more frequently by high LET radiations than by low LET photons. Reduced variation of radiosensitivity related to cell age and differences in post-irradiation recovery were also recognized as possible advantages for high LET particles over low LET photons.” A second clinical trial of fast neutron radiation therapy was initiated at the Hamrnersmith Hospital, London,
England, in November 1969.2 It was prompted by the important radiobiological findings of RBE variation with dose increment size as an explanation of the adverse treatment sequelae reported by Stone, and the lessening influence of tumor cell hypoxia as a reasonable explanation of the failure to erradicate some cancers with photon irradiation. After several hundred patients with extensive cancers were treated, it was concluded that fast neutron beam teletherapy was well tolerated and that extensive cancers responded remarkably well,’ better than one would have expected from photon irradiation. Enthusiasm generated by this and other preliminary reports led to the establishment of nineteen additional clinical fast neutron cancer therapy centers in Europe, Japan, the United Kingdom, and in the United States. The National Cancer Institute has recently embarked on an ambitious research program to investigate the value of high LET radiation in the treatment of human malignancies. While heavy ion and negative pi meson research will continue on equipment located in physics laboratories, four hospital based clinically dedicated neutron generators will be installed over the next three years to definitively test the potential of fast neutrons. Unlike their fixed-beam, laboratory-based predecessors, these rotational isocentric machines are capable of depth doses and field arrangements that are comparable to modern linear accelerators. These advantages will avoid the limitations imposed by low energy fixed horizontal beam physics machines and will assure the comparability of results obtained from randomized prospective clinical trials that compare neutrons to photons. The goal of the fast neutron beam research program is to increase local tumor control, and hopefully subsequent survival, while minimizing normal tissue side effects. Although publications from several of the physics based neutron projects have reported impressive local tumor control,3.7*‘0 the price has often been high in terms of normal tissue effects. Many of these normal tissue side effects (such as extensive subcutaneous fibrosis) result from the poor depth dose characteristics and non versatile field arrangements associated with the physics machines. However, a number of them, (such as the effects of
Accepted for publication
2 January 1980. Reprint requests to: Thomas W. Griffin, M.D. 387
388
Radiation
Oncology
Physics 0 Biology ??
neutrons on brain tissue reported in this journal)4 are based on a repetition of Dr. Stone’s error, an inaccurate assessment of normal tissue RBE. The experience gained and methods developed for neutron treatment with physics equipment stongly suggest that the goal of significantly improved tumor
January
1980, Volume 6, Number
2
response with acceptable normal tissue reactions can be attained at least for some tumors.3*7*8.‘0 Hopefully, this can be translated into an improved survival rate for the estimated 70,000 people who die each year from uncontrolled local cancers.
REFERENCES 1. Brennan, J.T., Phillips, T.L.: Evaluation
2.
3.
4.
5.
6.
of past experience with fast neutron teletherapy and its implications for future applications. Europ. J. Cancer 7: 2 19-225, 197 1. Catterall, M.: Clinical experience with fast neutrons from the Medical Research Council’s cyclotron at Hammersmith Hospital. Europ. J. Cancer 7: 227-229, 197 1. Catterall, M.: Clinical experience in particle therapy. Current experiences and prospects in Britain. Particle Radiation Therapy: Proceedings of an International Workshop, Key Biscayne. Fla.. 1975. Published by the American College of Radiology, July 1976, Vivian P. Smith, Ed. Catterall, M. Bloom, H.J.G., Ash, D.V., Walsh, L., Richardson, A., Uttley, D., Cowing, N.F.C., Lewis, P., Chaucer, B.: Fast neutrons compared with megavoltage X-rays in the treatment of patients with supratentorial glioblastoma: A controlled pilot study. Int. J. Radiat. Oncol. Biol. Phys. 6: 261-266, 1980. Fowler, J.F., Morgan, R.L.: Pretherapeutic experiments with the fast neutron beam from the Medical Research Council cyclotron. VIII. General review. Brit. J. Rad. 36: 115-121, 1963. Gray, L.H., Conger, A.D., Ebert, M., Hornsey, S., Scott, O.C.A.: The concentration of oxygen dissolved in tumor at
7.
8.
9. 10.
11. 12. 13.
the time of ionization as a factor in radiotherapy. Brit. J. Rad. 26: 638-648, 1953. Griffin, T.W., Laramore, G.E., Parker, R.G., Gerdes, A.J., Heberd, D.W., Blasko, J.C., Groudine, M.: An evaluation of fast neutron beam teletherapy of metastatic cervical adenopathy from squamous cell carcinomas of the head and neck region. Cancer 42: 25 17-2520,1978. Griffin, T.W., Weisberger, E.C., Laramore, G.E., Tong, D., Blasko, J.C.: Complications of combined surgery and neutron radiation therapy in patients with advanced carcinoma of the head and neck. Radiology 132: 177-178, 1979. Hahn, R.: Ein beitrag zur rontgentherapie. Fortshr. Beg. Rontgenstruhlen. 8: 120-l 2 1, 1904. Peters, L.J., Hussey, D.H., Fletcher, G.H., Baumann, P.A., Olson, M.H.: Preliminary report of the M.D. Anderson Hospital/Texas A & M variable energy cyclotron fastneutron therapy pilot study. AJR 132: 637-642, 1979. Puck, T.T., Marcus, P.T., Cieciera, J.J.: Clonal growth of mammalian cells in vitro. J. Exp. Med. 103: 372, 1956. Stone, R.S.: Neutron therapy and specific ionization. Amer. J. Roentgenol. 59: 77 l-785, 1948. Withers, H.R.: Biological basis for high LET radiotherapy. Radiology 108: 131-137, 1973.