ht. 1. Radiation Oncology Biol. Phys., Vol. 21, pp. 1479-1483 Pnnted m the U.S.A. All rights reserved.
Copyright
0360-3016/91 $3.00 + .oo 0 1991 Pergamon Press plc
??Special Feature
INTERSTITIAL BRACHYTHERAPY: PAST-PRESENT-FUTURE C. H. PAINE, D.M.,
FRCP,
FRCR’ ANDD. V. ASH, FRCP,
FRCR2
‘Radiotherapy and Oncology, Churchill Hospital, Headington, Oxford OX3 7LJ; and ’ Radiotherapy and Oncology, Cookridge
Hospital,
Leeds LS16 6QB UK
This article summarizes and reviews the development of brachytherapy from 1930 to 1990. Its purpose is to highlight the immense contribution made to its underlying science and clinical practice by Dr. Frank Ellis, who has been personally involved with it, in theory and in practice, for that whole half-century. A remarkable achievement in itself, but so much the more when it is seen beside his contributions to other aspects of radiation in the service of man. The early use of solid sources leads on to a discussion of manual afterloading and iridium. This leads on to a quick survey of the development of dosimetry. Thereafter clinical indications are briefly discussed and some published results tabulated. Lastly, some pointers to possible future development and beneflts are discussed. Mention is also made of some continuing unresolved problems where new work could help to establish the most appropriate use of brachytherapy. Brachytherapy, Interstitial therapy, _- Radium (substitutes), cross-line data, Afterloading, Dosimetry systems, Radiaiion protection. radon dosimetry that could be simply applied, and that would then permit comparisons of results between centers and replace pre-existing “rules of thumb” such as that used for the Finzi-Harmer laryngeal palisade (11). He was well on the way to achieving such a system himself when the Manchester school published their own Radium Dosage System in a series of articles (15). Frank Ellis at once saw the value of this system, and used it himself until, with the development of radium substitutes after 1945, he felt it insufficient to meet all the possible advantages of new technologies, and so asked his staff to provide him with the new approach of “cross-line” data. These data relate in simple graphical form the dose-rate at varying distance from the axis of standard activity tantalum-182 and iridium-192 wires of varying lengths (8). His individual system of dose calculation, using these basic data with some minor modem corrections, has been a mainstay of the Oxford department to this day. The Paris system of the French School (5) has indeed been the logical outcome of early crossline data-made possible by use of computers only available in more recent years. Frank Ellis’s other great contribution to brachytherapy over the years has been in the field of clinical practice. To every patient he treated, he gave individual consideration. He recognized the vital importance of accurate assessment of tumor extent and staging and of the part played by careful clinical examination in this. He did not hesitate to combine external beam and implant therapy where dose considerations seemed to favor this. He employed his own method to correct for the different biological effects of
INTRODUCTION Brachytherapy of human tumors is now approaching its Centenary. It was the first practical means of trying the effects of radiation on normal and abnormal tissues, and it is perhaps surprising that with all subsequent knowledge and technical developments it should still have an important place in cure of cancer. At various stages in this long period, Frank Ellis’s own understanding and experience of its value, his development of its practical physics, of its technology, and of novel and original clinical indications for its use have been a most significant factor in preventing its eclipse by other perhaps more fashionable and seemingly attractive alternatives. In this article, a brief review of some of his contributions is followed by an overview of the current status of brachytherapy and some thoughts on its future development. Reasons of space and cohesion confine this account to interstitial and mould therapy. However, their development and technology ran in parallel with intracavitary therapy for uterine cancer, to the theory and practice of which Frank Ellis also made significant contributions. Indeed, through an international Radium Substitutes Working Party, he continues now to give advice to those responsible for cancer treatment in many developing countries, on the most cost-effective and practical ways to treat their own patients most effectively by brachytherapy. When appointed as the first Radium Officer to the Sheffield Hospitals in 1930, he immediately saw the importance of establishing a practical system for radium and Reprint requests to: Dr. C. H. Paine.
Accepted for publication 1479
24 May 1991.
1480
I. J. Radiation Oncology 0 Biology 0 Physics
varying dose rate. He also gave much consideration to the advantages that brachytherapy might have for tumors of unusual site and histology, for instance, soft tissue sarcomas, and devised techniques to treat suitable cases (2). Recognizing the hazards of handling active radionuclides during long surgical procedures, he was the first to devise afterloading methods with radium needles and tubes, which led directly to use of the flexible Ta 182 and then Ir 192 wire or ribbon techniques used in several centers almost simultaneously from the early 1960’s (8, 9, 20). These methods rapidly led to his enthusiasm for intra-operative radiotherapy: the implantation of a tumor bed at the time of excision, so giving a high dose where needed while sparing normal structures that an external beam would have had to irradiate to significant dosage (7). Now that radiation hazard in brachytherapy has been nearly overcome, and published local cure rates clearly demonstrate effectiveness, the firm start based on careful dosimetry and his own vast clinical experience brought to this subject by Frank Ellis gives an excellent prospect for further advances in the future (6, 18). METHODS AND MATERIALS Available radionuclides and techniques Iridium 192 either as wire or seed ribbons is now the isotope in most common use for removable implants. Radium can no longer be recommended because of the radiation protection problems to which it gives rise. Many centers have replaced their radium needles with equivalent needles containing caesium 137. As the stock of caesium needles reaches the end of its useful life, however, more and more centers are moving to the use of iridium because it can be incorporated in manual or remote afterloading techniques. In developing countries where the supply of iridium may prove difficult to ensure, however, caesium may be retained. Permanent implants are commonly performed with iodine 125 seeds and gold 198 grains. The promised radiobiological advantages of califomium 252, which emits neutrons, have not yet been realized in practice. Because of its expense and the difficulties of ensuring proper protection during handling and after loading, califomium has been largely abandoned for interstitial therapy. Newer nuclides such as palladium-103 and ytterbium169 are under investigation to see whether they have useful advantages over presently used isotopes. Increasing recognition of the exposure hazard from handling radioactive sources has led to a continuing move toward afterloading systems, which should be used whenever possible (17, 18, 22). Although manual afterloading systems reduce exposure hazard substantially compared with the previous conventional radium and caesium needle implants, they do not eliminate it completely. Newly developed remote afterloading machines now make it possible to perform interstitial therapy with almost no exposure hazard, and these are being increasingly
November 1991, Volume 21, Number 6
adopted. Most manual afterloading techniques can be adapted to remote afterloading, but in some instances techniques have to be modified to make them suitable for remote afterloading. The availability of iridium wire in high specific activity now makes it possible to consider brachytherapy at high dose rate. For interstitial implants this will lead to investigation of the usefulness of fractionated implant therapy. For brachytherapy of bronchial and esophageal cancer, high dose rate treatment permits a useful therapeutic dose to be given in a single outpatient procedure. Dosimetry Over the years considerable experience has been gained with the use of standard systems such as those described by the Manchester (15), Memorial Hospital (9, 24), and Paris (22) schools of brachytherapy. Each system consists of a set of rules for implantation that are directed towards achieving a dose distribution having particular attributes. The implantation rules are used in conjunction with a system of dose calculation and prescription. If these implant systems are strictly followed, experience shows they can be used with efficiency and safety. All of the above implant systems were developed before the general availability of computer dosimetry. Computer derived isodoses now permit prescribing doses even in instances (less accessible sites, for example) where it may not have been possible to follow an established system. This new latitude can make it difficult to compare the dosimetry of implants performed in one center with that in another and it should be applied with caution. A need is evident for more complete and more uniform reporting of implant dose, with better characterization of the dose throughout the implant in relation to the dose at the periphery (perhaps a ratio of average to peripheral dose or even a dose-volume histogram). Recommendations for a uniform system of reporting dose and volume in interstitial therapy are currently under study by a report committee of the I. C. R. U. There remains controversy about whether it is necessary to apply a dose rate correction factor for removable implants. Considerable experience with the Paris system suggests that provided that the dose rate at the prescription isodose is within the range 30 to 60 cGy per hour (4-8 days for a radical dose of 60 Gy) there is no need to apply a dose rate correction factor (21). For the high dose rate afterloading techniques, however, considerable work remains to be done to identify the optimum dose/time/volume parameters. There is also a need for further data on fractionation of brachytherapy and on its combination with external beam therapy. Clinical indications Brachytherapy may be used for accessible tumors whose extent has been very carefully determined, and where anatomy permits a proper geometry to be constructed. Its strongest indication is in head and neck cancer, especially
Interstitial brachytberapy 0 C. H.
PAINEAND D.
1481
V. ASH
Table 1. Suitable for brachytherapy Site
Local control rate (%)
Source
Advantages
Owen et al., 1981 (14)
90
Salivation intact, normal anatomy preserved Ditto
Owen et al., 1981 (14)
95 93
Normal contours preserved Ditto
Pigneux et al., 1979 (21) Mazeron er al., 1989 (12)
Ditto Avoids Colostomy
Mazeron et al., 1986 (10) Papillon, 1982 (17)
Preserves penis and potency Avoids cystectomy; low morbidity Low morbidity; potency often retained
Daly er al., 1982 (2)
Mobile tongue
90
Floor of Mouth Lower alveolus Lip Shin: nose and nasal vestibule Pinna Anal canal (Papillon technique without chemotherapy) Penis Bladder
88
Prostate
80-90
98 68 (5year
survival rate)
95
Mazeron et al., 1988 (11) De Blasio et al., 1988 (3)
Note: This table gives a guide to published results of some tumors where treatment by brachytherapy holds special advantage. The sources are shown. The local control rates are at varying times after treatment. The tumor sizes are those selected by the authors as suitable for brachvtheranv: __ usually Tl and small T2. More advanced tumors can sometimes be similarly treated but not of course with so high a chance of local cure.
of the oral cavity, where results in terms of cure equal or exceed those of surgery or external beam therapy and are accompanied by excellent preservation of structure and function (Table 1). In breast cancer, brachytherapy is widely used as a boost after beam therapy following local excision. Although there is little evidence that it improves local control rates above those of other methods, it spares further dosage to overlying skin and so improves the cosmetic result. It is also useful as a palliative for advanced and recurrent breast cancer on the chest wall or in the lymph nodes. In genitourinary sites, leaving aside intracavitary therapy for uterine cancer, it plays a useful part in treatment of localised tumors of the vagina, vulva, bladder, and prostate, where centers with experience have published good results in carefully selected cases. Perhaps of special importance to the patient are the good results achieved in small rectal, anal, and penile cancers, which can allow excellent preservation of structure and function of these organs, while not prejudicing radical surgery if treatment fails (Table 1). Tumors at many other sites have been treated with success by brachytherapy. They include the skin (with preservation of the pinna, lip, or nasal contours, for example: Table 1); palliation of metastatic lymph node recurrence at various sites; apical lung cancer, with good pain relief; the brain, for inoperable tumors; and the nasopharynx, for small residual tumors or recurrence. Implantation of the tumor bed after surgical excision of various primary and recurrent tumors, soft tissue sarcomas, and mixed salivary adenomas has also been held by some to improve local control (2). Good palliation can also result from use of in-
tracavitary high dose rate treatments for some bronchial and oesophageal turnouts (25). Details of the common clinical applications of brachytherapy and their outcome have been reviewed in detail elsewhere (1, 10, 18, 22). The less common applications mentioned in the previous paragraph have, however, except for skin cancer, usually been in regular planned use in only a few centers. This has meant that the number of patients treated has generally been small, and not subject to randomized, controlled study. Other modalities of therapy have also changed and developed, as has the application of brachytherapy itself, during the period over which such series have been collected. Further work therefore now needs to be done to determine the value of brachytherapy in some of these clinical situations. DISCUSSION The future of brachytherapy
In the days when Frank Ellis and others were pioneering the use of interstitial implantation, identification of the volume to be treated was a matter of clinical judgment and implantation of the sources a manual skill that required development by experience. Computation of dose was largely by hand and the whole clinical procedure was attended by considerable radiation exposure, both for the operator and other staff. Great technical developments in tumor localization by computed tomography, magnetic resonance imaging, and ultrasound have now revolutionized the accuracy with which the target volume can be identified. Integration of these techniques with afterloading now
1482
I. J. Radiation
Oncology
0 Biology 0 Physics
makes it possible to be more certain that the target volume is adequately covered and evenly irradiated by the implanted sources. This can be checked by a reconstruction in several planes and can be linked with demonstration of isodoses to confirm that adequate doses have been delivered to all parts of the target volume. This does not, of course, render clinical judgment obsolete, but provides invaluable assistance in achieving clinical aims by improving case selection for brachytherapy. Where once implantations of sources had to be done at speed to minimize exposure, afterloading with inactive source carriers can now be done with time for sufficient care to ensure optimum geometry. In difficult sites source placement can now be aided by the use of templates and even stereotactic frames, permitting custom planning from 3D imaging data to enhance the likelihood of achieving a satisfactory implant. Good and effective implants to once difficult sites, such as the CNS and the prostate, can now regularly be achieved using these new techniques, and their development can be expected to continue. The application of computers to dosimetry and the linkage with CT localization, both of tumor and implanted sources, now makes it possible to gain very accurate data on dose distribution within the target volume and the adjacent normal tissues. If agreement can be reached on a uniform method of recording such data, there is the potential for learning a great deal about the tolerance of tumors and normal tissues to interstitial irradiation. Manual afterloading techniques have already reduced radiation exposure to low levels, and they are consequently being taken up by those who were previously using radium or caesium needles. Remote afterloading will however reduce exposure to even lower levels and as its technology improves, it, too, will be used increasingly. High dose rate afterloading has already taken brachytherapy into areas where it has been little used in the past. Much experience has been gained in the palliation of esophageal and bronchial carcinomas with high dose rate remote afterloading, and this experience will be extended as these treatments are used as part of radical therapy for some cases. High dose rate remote afterloading also makes it possible to consider intra-operative brachytherapy. Instead of placing catheters in the tumor bed and only irradiating later at continous low dose rate, the catheters can be used as well at the time of operation to give a single fraction of high dose rate irradiation similar to that received during intra-operative electron therapy. New afterloading machines now offer the possibility of using a single high activity source to service several channels in a multi-source volume implant. By automatically stepping the single source along each channel and transferring from channel to channel over the space of a few days, a continuous low dose rate volume implant can be simulated with a single high activity source. Computer-assisted planning can optimize dose distribution by specifying the
November
1991, Volume 21. Number 6
time for which the source rests within each channel. The radiobiology of high dose rate brachytherapy, particularly when applied to interstitial therapy, is however largely unexplored and considerable experimental, and clinical work will be necessary in the future to define optimum dose rates and fractionation patterns, and to avoid under- or overdosage in biological terms. The new imaging and computer technology that is being brought to bear opens an exciting future for brachytherapy. The ability to implant source carrying tubes accurately into tumors is also being linked to delivery of new nonionizing forms of treatment for tumors such as hyperthermia and photodynamic therapy. Fractionation of brachytherapy applications and their proper combination with external beam therapy would seem to merit further planned investigation. The advantages already apparent in rectal and anal canal cancers (19) and in some mouth cancers should be confirmed and perhaps extended. Further work is needed too on dose-rate. At present, the radiobiological and clinical views do not wholly coincide (16). Patients naturally prefer shorter treatments. If tumor control and normal tissue results are as good with them, sources of suitable activity are now available. Lastly, further work is needed on the varied group of tumors referred to above, where good results have been claimed, but only by a few workers. The difficulty here, as indeed with assessment of new techniques, is in the collection by different centers of like cases, and in the carrying through of comparable treatment protocols in these relatively rare clinical situations. This has to be done alongside other constantly changing treatment modalities like chemotherapy and surgery. Randomized controlled studies do become very hard to achieve in such circumstances, but these problems must be overcome if we are to develop gradually more effective cancer therapy.
CONCLUSION Brachytherapy has come a long way since Frank Ellis began more than 60 years ago to confirm and define the advantages of its uses discovered by the earliest workers. It must be our target and that of our successors to build upon the advances made, to define further its indications and to bring the greatest possible benefits of its use to future patients. It must also be realized, as stressed years ago by Dr. Ellis himself (6), that work by health education upon the social factors which are the cause of a good proportion of the cancers most suitable for brachytherapy is still of the utmost importance both in developed and developing countries. Governments have an important part to play in this work, by providing funds for education to discourage causative factors such as alcohol and tobacco, and by promoting early detection of small cancers still having a high chance of cure of brachytherapy or by other means.
Interstitial brachytherapy ??C. H. PAINEANDD. V. ASH
1483
REFERENCES 1. Anderson, L. L.; Nath, R.; Weaver, K. A.; Nori, D.; Phillips, T. L.; Son, Y. H.; Chiu-Tsao, S. T.; Meigooni, A. S.; Meli, J. A.; Smith, V. Interstitial brachytherapy: physical, biological and clinical considerations. New York: Raven Press; 1990: 360. 2. Collins, J. E.; Paine, C. H.; Ellis, F. The treatment of connective tissue sarcomas by local excision followed by radioactive implant. Clin. Radiol. 27:3941; 1976. 3. Daly, N. J.; Douchez, J.; Coombes, P. M. Treatment of carcinoma of the penis by iridium-192 wire implant. Int. J. Radiat. Oncol. Biol. Phys. 8:1239-1243; 1982. 4. DeBlasio, D. S.; Hilaris, B. S.; Nori, D.; Fuks, Z.; Whitmore, W. F.; Anderson, L. L. Permanent interstitial implantation of prostatic cancer in the 1980’s. Endocur. Hyperther. Oncol. 4:193-201; 1988. 5. Dutreix, A.; Marinello, G.; Wambersie, A. Dosimetrie en Curietherapie. Paris: Masson; 1982. 6. Ellis, F. My philosophy of radiotherapy. Brit. J. Radiol. 36: 627-644; 1963. 7. Ellis, F.; Patterson, T. J. S. The treatment of malignant disease by radiotherapy and surgery. Brit. J. Plastic Surg. 21: 321-328; 1968. 8. Hall, E. J.; Oliver, R.; Shepstone, B. J. Routine dosimetry with Tantalum-182 and Iridium-192 wire. Acta. Radiol. (Ther. Phys. Biol.) 4:155-160; 1966. 9. Henschke, U. K.; Hilaris, B. S.; Mahan, G. D. After-loading in interstitial and intracavitary radiotherapy Am. J. Roentgenol. 90:38&395; 1963. 10. Hilaris, B. S.; Nori, D.; Anderson, L. L. Atlas of brachytherapy. New York: Macmillan; 1988: 326. 11 Lederman, M. 1975. History of radiotherapy in the treatment cancer of the larynx, 18961939. Laryngoscope 85:661-667; 1975. 12 Mazeron, J. J.; Ghalie, R.; Zeller, J.; Marinello, G.; Martin, L.; Raynal, M.; Le Bourgeois, J. P.; Pierquin, B. Radiation therapy for carcinoma of the pinna using iridium 192 wires: a series of 70 patients. Int. J. Radiat. Oncol. Biol. Phys. 12: 1757-1733; 1986.
13. Mazeron, J. J.; Crook, J.; Chopin, D.; Abbou, C. C.; Le Bourgeois, J. P.; Auvert, J.; Pierquin, B. Conservative treatment of bladder carcinoma by partial cystectomy and interstitial Iridium-192. Int. J. Radiat. Oncol. Biol. Phys. 14: 1323-1330; 1988. 14. Mazeron, J. J.; Chassagne, D.; Crook, J.; Bachelot, F.; Brune, D.; (and 13 others). Radiation therapy of carcinomas of the skin, nose and nasal vestibule: a report of 1676 cases to the Group Europeen de Curietherapie. Rad. Oncol. 13: 165-173; 1989. 15. Meredith, W. J., ed. Radium dosage: The Manchester system. Edinburgh: E and F Livingstone; 1949. 16. Owen, J. R.; Maylin, B.; LeBourgeois, J. P.; Baillet, F.; Sabatini, B.; Pierquin, B. Iridium 192 implantation of tumours of the anterior two thirds of the tongue and floor of mouth. A retrospective analysis of treatment results and sites and causes of failure. J. Eur. Radiother. 2:92-103; 1981. 17. Paine, C. H. Modem after-loading methods for interstitial therapy. Clin. Radiol. 23:263-272; ~1972. 18. Paine, C. H.; Ash, D. V. Interstitial radiation therapy. Oxford textbook of oncology. Oxford: Oxford University Press; 1991 (In press). 19. Papillon, J. Rectal and anal cancers. Berlin: Springer; 1982. 20. Pierquin, B. P&is de Curietherapie. Paris: Masson; 1964. 21. Pierquin, B.; Chassagne D.; Baillet F.; Paine C. H. Clinical observations on the time factor in interstitial radiotherapy using Iridium-192. Clin. Radiol. 24:50&509; 1973. 22. Pierquin, B.; Wilson, J. F.; Chassagne, D. Modem brachytherapy. New York: Masson; 1987. 23. Pigneux, J.; Richard, P.; Lagarde, C. The place of interstitial therapy using Iridium-192 in the management of carcinoma of lip. Cancer 43:1073-1077; 1979. 24. Quimby, E. H. Dosage calculations in radium therapy. Am. J. Roentgenol. 57:622-627; 1947. 25. Rowland, C. G.; Pagliero, K. M. Intracavitary irradiation in palliation of carcinoma of the oesophagus and cardia. Lancet 2:981-983; 1985.
Copyright
0360-3016/91 $3.00 + .oo 0 1991 Pergamon Press plc
??Special Feature
INTERSTITIAL BRACHYTHERAPY: PAST-PRESENT-FUTURE C. H. PAINE, D.M.,
FRCP,
FRCR’ ANDD. V. ASH, FRCP,
FRCR2
‘Radiotherapy and Oncology, Churchill Hospital, Headington, Oxford OX3 7LJ; and ’ Radiotherapy and Oncology, Cookridge
Hospital,
Leeds LS16 6QB UK
This article summarizes and reviews the development of brachytherapy from 1930 to 1990. Its purpose is to highlight the immense contribution made to its underlying science and clinical practice by Dr. Frank Ellis, who has been personally involved with it, in theory and in practice, for that whole half-century. A remarkable achievement in itself, but so much the more when it is seen beside his contributions to other aspects of radiation in the service of man. The early use of solid sources leads on to a discussion of manual afterloading and iridium. This leads on to a quick survey of the development of dosimetry. Thereafter clinical indications are briefly discussed and some published results tabulated. Lastly, some pointers to possible future development and beneflts are discussed. Mention is also made of some continuing unresolved problems where new work could help to establish the most appropriate use of brachytherapy. Brachytherapy, Interstitial therapy, _- Radium (substitutes), cross-line data, Afterloading, Dosimetry systems, Radiaiion protection. radon dosimetry that could be simply applied, and that would then permit comparisons of results between centers and replace pre-existing “rules of thumb” such as that used for the Finzi-Harmer laryngeal palisade (11). He was well on the way to achieving such a system himself when the Manchester school published their own Radium Dosage System in a series of articles (15). Frank Ellis at once saw the value of this system, and used it himself until, with the development of radium substitutes after 1945, he felt it insufficient to meet all the possible advantages of new technologies, and so asked his staff to provide him with the new approach of “cross-line” data. These data relate in simple graphical form the dose-rate at varying distance from the axis of standard activity tantalum-182 and iridium-192 wires of varying lengths (8). His individual system of dose calculation, using these basic data with some minor modem corrections, has been a mainstay of the Oxford department to this day. The Paris system of the French School (5) has indeed been the logical outcome of early crossline data-made possible by use of computers only available in more recent years. Frank Ellis’s other great contribution to brachytherapy over the years has been in the field of clinical practice. To every patient he treated, he gave individual consideration. He recognized the vital importance of accurate assessment of tumor extent and staging and of the part played by careful clinical examination in this. He did not hesitate to combine external beam and implant therapy where dose considerations seemed to favor this. He employed his own method to correct for the different biological effects of
INTRODUCTION Brachytherapy of human tumors is now approaching its Centenary. It was the first practical means of trying the effects of radiation on normal and abnormal tissues, and it is perhaps surprising that with all subsequent knowledge and technical developments it should still have an important place in cure of cancer. At various stages in this long period, Frank Ellis’s own understanding and experience of its value, his development of its practical physics, of its technology, and of novel and original clinical indications for its use have been a most significant factor in preventing its eclipse by other perhaps more fashionable and seemingly attractive alternatives. In this article, a brief review of some of his contributions is followed by an overview of the current status of brachytherapy and some thoughts on its future development. Reasons of space and cohesion confine this account to interstitial and mould therapy. However, their development and technology ran in parallel with intracavitary therapy for uterine cancer, to the theory and practice of which Frank Ellis also made significant contributions. Indeed, through an international Radium Substitutes Working Party, he continues now to give advice to those responsible for cancer treatment in many developing countries, on the most cost-effective and practical ways to treat their own patients most effectively by brachytherapy. When appointed as the first Radium Officer to the Sheffield Hospitals in 1930, he immediately saw the importance of establishing a practical system for radium and Reprint requests to: Dr. C. H. Paine.
Accepted for publication 1479
24 May 1991.
1480
I. J. Radiation Oncology 0 Biology 0 Physics
varying dose rate. He also gave much consideration to the advantages that brachytherapy might have for tumors of unusual site and histology, for instance, soft tissue sarcomas, and devised techniques to treat suitable cases (2). Recognizing the hazards of handling active radionuclides during long surgical procedures, he was the first to devise afterloading methods with radium needles and tubes, which led directly to use of the flexible Ta 182 and then Ir 192 wire or ribbon techniques used in several centers almost simultaneously from the early 1960’s (8, 9, 20). These methods rapidly led to his enthusiasm for intra-operative radiotherapy: the implantation of a tumor bed at the time of excision, so giving a high dose where needed while sparing normal structures that an external beam would have had to irradiate to significant dosage (7). Now that radiation hazard in brachytherapy has been nearly overcome, and published local cure rates clearly demonstrate effectiveness, the firm start based on careful dosimetry and his own vast clinical experience brought to this subject by Frank Ellis gives an excellent prospect for further advances in the future (6, 18). METHODS AND MATERIALS Available radionuclides and techniques Iridium 192 either as wire or seed ribbons is now the isotope in most common use for removable implants. Radium can no longer be recommended because of the radiation protection problems to which it gives rise. Many centers have replaced their radium needles with equivalent needles containing caesium 137. As the stock of caesium needles reaches the end of its useful life, however, more and more centers are moving to the use of iridium because it can be incorporated in manual or remote afterloading techniques. In developing countries where the supply of iridium may prove difficult to ensure, however, caesium may be retained. Permanent implants are commonly performed with iodine 125 seeds and gold 198 grains. The promised radiobiological advantages of califomium 252, which emits neutrons, have not yet been realized in practice. Because of its expense and the difficulties of ensuring proper protection during handling and after loading, califomium has been largely abandoned for interstitial therapy. Newer nuclides such as palladium-103 and ytterbium169 are under investigation to see whether they have useful advantages over presently used isotopes. Increasing recognition of the exposure hazard from handling radioactive sources has led to a continuing move toward afterloading systems, which should be used whenever possible (17, 18, 22). Although manual afterloading systems reduce exposure hazard substantially compared with the previous conventional radium and caesium needle implants, they do not eliminate it completely. Newly developed remote afterloading machines now make it possible to perform interstitial therapy with almost no exposure hazard, and these are being increasingly
November 1991, Volume 21, Number 6
adopted. Most manual afterloading techniques can be adapted to remote afterloading, but in some instances techniques have to be modified to make them suitable for remote afterloading. The availability of iridium wire in high specific activity now makes it possible to consider brachytherapy at high dose rate. For interstitial implants this will lead to investigation of the usefulness of fractionated implant therapy. For brachytherapy of bronchial and esophageal cancer, high dose rate treatment permits a useful therapeutic dose to be given in a single outpatient procedure. Dosimetry Over the years considerable experience has been gained with the use of standard systems such as those described by the Manchester (15), Memorial Hospital (9, 24), and Paris (22) schools of brachytherapy. Each system consists of a set of rules for implantation that are directed towards achieving a dose distribution having particular attributes. The implantation rules are used in conjunction with a system of dose calculation and prescription. If these implant systems are strictly followed, experience shows they can be used with efficiency and safety. All of the above implant systems were developed before the general availability of computer dosimetry. Computer derived isodoses now permit prescribing doses even in instances (less accessible sites, for example) where it may not have been possible to follow an established system. This new latitude can make it difficult to compare the dosimetry of implants performed in one center with that in another and it should be applied with caution. A need is evident for more complete and more uniform reporting of implant dose, with better characterization of the dose throughout the implant in relation to the dose at the periphery (perhaps a ratio of average to peripheral dose or even a dose-volume histogram). Recommendations for a uniform system of reporting dose and volume in interstitial therapy are currently under study by a report committee of the I. C. R. U. There remains controversy about whether it is necessary to apply a dose rate correction factor for removable implants. Considerable experience with the Paris system suggests that provided that the dose rate at the prescription isodose is within the range 30 to 60 cGy per hour (4-8 days for a radical dose of 60 Gy) there is no need to apply a dose rate correction factor (21). For the high dose rate afterloading techniques, however, considerable work remains to be done to identify the optimum dose/time/volume parameters. There is also a need for further data on fractionation of brachytherapy and on its combination with external beam therapy. Clinical indications Brachytherapy may be used for accessible tumors whose extent has been very carefully determined, and where anatomy permits a proper geometry to be constructed. Its strongest indication is in head and neck cancer, especially
Interstitial brachytberapy 0 C. H.
PAINEAND D.
1481
V. ASH
Table 1. Suitable for brachytherapy Site
Local control rate (%)
Source
Advantages
Owen et al., 1981 (14)
90
Salivation intact, normal anatomy preserved Ditto
Owen et al., 1981 (14)
95 93
Normal contours preserved Ditto
Pigneux et al., 1979 (21) Mazeron er al., 1989 (12)
Ditto Avoids Colostomy
Mazeron et al., 1986 (10) Papillon, 1982 (17)
Preserves penis and potency Avoids cystectomy; low morbidity Low morbidity; potency often retained
Daly er al., 1982 (2)
Mobile tongue
90
Floor of Mouth Lower alveolus Lip Shin: nose and nasal vestibule Pinna Anal canal (Papillon technique without chemotherapy) Penis Bladder
88
Prostate
80-90
98 68 (5year
survival rate)
95
Mazeron et al., 1988 (11) De Blasio et al., 1988 (3)
Note: This table gives a guide to published results of some tumors where treatment by brachytherapy holds special advantage. The sources are shown. The local control rates are at varying times after treatment. The tumor sizes are those selected by the authors as suitable for brachvtheranv: __ usually Tl and small T2. More advanced tumors can sometimes be similarly treated but not of course with so high a chance of local cure.
of the oral cavity, where results in terms of cure equal or exceed those of surgery or external beam therapy and are accompanied by excellent preservation of structure and function (Table 1). In breast cancer, brachytherapy is widely used as a boost after beam therapy following local excision. Although there is little evidence that it improves local control rates above those of other methods, it spares further dosage to overlying skin and so improves the cosmetic result. It is also useful as a palliative for advanced and recurrent breast cancer on the chest wall or in the lymph nodes. In genitourinary sites, leaving aside intracavitary therapy for uterine cancer, it plays a useful part in treatment of localised tumors of the vagina, vulva, bladder, and prostate, where centers with experience have published good results in carefully selected cases. Perhaps of special importance to the patient are the good results achieved in small rectal, anal, and penile cancers, which can allow excellent preservation of structure and function of these organs, while not prejudicing radical surgery if treatment fails (Table 1). Tumors at many other sites have been treated with success by brachytherapy. They include the skin (with preservation of the pinna, lip, or nasal contours, for example: Table 1); palliation of metastatic lymph node recurrence at various sites; apical lung cancer, with good pain relief; the brain, for inoperable tumors; and the nasopharynx, for small residual tumors or recurrence. Implantation of the tumor bed after surgical excision of various primary and recurrent tumors, soft tissue sarcomas, and mixed salivary adenomas has also been held by some to improve local control (2). Good palliation can also result from use of in-
tracavitary high dose rate treatments for some bronchial and oesophageal turnouts (25). Details of the common clinical applications of brachytherapy and their outcome have been reviewed in detail elsewhere (1, 10, 18, 22). The less common applications mentioned in the previous paragraph have, however, except for skin cancer, usually been in regular planned use in only a few centers. This has meant that the number of patients treated has generally been small, and not subject to randomized, controlled study. Other modalities of therapy have also changed and developed, as has the application of brachytherapy itself, during the period over which such series have been collected. Further work therefore now needs to be done to determine the value of brachytherapy in some of these clinical situations. DISCUSSION The future of brachytherapy
In the days when Frank Ellis and others were pioneering the use of interstitial implantation, identification of the volume to be treated was a matter of clinical judgment and implantation of the sources a manual skill that required development by experience. Computation of dose was largely by hand and the whole clinical procedure was attended by considerable radiation exposure, both for the operator and other staff. Great technical developments in tumor localization by computed tomography, magnetic resonance imaging, and ultrasound have now revolutionized the accuracy with which the target volume can be identified. Integration of these techniques with afterloading now
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makes it possible to be more certain that the target volume is adequately covered and evenly irradiated by the implanted sources. This can be checked by a reconstruction in several planes and can be linked with demonstration of isodoses to confirm that adequate doses have been delivered to all parts of the target volume. This does not, of course, render clinical judgment obsolete, but provides invaluable assistance in achieving clinical aims by improving case selection for brachytherapy. Where once implantations of sources had to be done at speed to minimize exposure, afterloading with inactive source carriers can now be done with time for sufficient care to ensure optimum geometry. In difficult sites source placement can now be aided by the use of templates and even stereotactic frames, permitting custom planning from 3D imaging data to enhance the likelihood of achieving a satisfactory implant. Good and effective implants to once difficult sites, such as the CNS and the prostate, can now regularly be achieved using these new techniques, and their development can be expected to continue. The application of computers to dosimetry and the linkage with CT localization, both of tumor and implanted sources, now makes it possible to gain very accurate data on dose distribution within the target volume and the adjacent normal tissues. If agreement can be reached on a uniform method of recording such data, there is the potential for learning a great deal about the tolerance of tumors and normal tissues to interstitial irradiation. Manual afterloading techniques have already reduced radiation exposure to low levels, and they are consequently being taken up by those who were previously using radium or caesium needles. Remote afterloading will however reduce exposure to even lower levels and as its technology improves, it, too, will be used increasingly. High dose rate afterloading has already taken brachytherapy into areas where it has been little used in the past. Much experience has been gained in the palliation of esophageal and bronchial carcinomas with high dose rate remote afterloading, and this experience will be extended as these treatments are used as part of radical therapy for some cases. High dose rate remote afterloading also makes it possible to consider intra-operative brachytherapy. Instead of placing catheters in the tumor bed and only irradiating later at continous low dose rate, the catheters can be used as well at the time of operation to give a single fraction of high dose rate irradiation similar to that received during intra-operative electron therapy. New afterloading machines now offer the possibility of using a single high activity source to service several channels in a multi-source volume implant. By automatically stepping the single source along each channel and transferring from channel to channel over the space of a few days, a continuous low dose rate volume implant can be simulated with a single high activity source. Computer-assisted planning can optimize dose distribution by specifying the
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time for which the source rests within each channel. The radiobiology of high dose rate brachytherapy, particularly when applied to interstitial therapy, is however largely unexplored and considerable experimental, and clinical work will be necessary in the future to define optimum dose rates and fractionation patterns, and to avoid under- or overdosage in biological terms. The new imaging and computer technology that is being brought to bear opens an exciting future for brachytherapy. The ability to implant source carrying tubes accurately into tumors is also being linked to delivery of new nonionizing forms of treatment for tumors such as hyperthermia and photodynamic therapy. Fractionation of brachytherapy applications and their proper combination with external beam therapy would seem to merit further planned investigation. The advantages already apparent in rectal and anal canal cancers (19) and in some mouth cancers should be confirmed and perhaps extended. Further work is needed too on dose-rate. At present, the radiobiological and clinical views do not wholly coincide (16). Patients naturally prefer shorter treatments. If tumor control and normal tissue results are as good with them, sources of suitable activity are now available. Lastly, further work is needed on the varied group of tumors referred to above, where good results have been claimed, but only by a few workers. The difficulty here, as indeed with assessment of new techniques, is in the collection by different centers of like cases, and in the carrying through of comparable treatment protocols in these relatively rare clinical situations. This has to be done alongside other constantly changing treatment modalities like chemotherapy and surgery. Randomized controlled studies do become very hard to achieve in such circumstances, but these problems must be overcome if we are to develop gradually more effective cancer therapy.
CONCLUSION Brachytherapy has come a long way since Frank Ellis began more than 60 years ago to confirm and define the advantages of its uses discovered by the earliest workers. It must be our target and that of our successors to build upon the advances made, to define further its indications and to bring the greatest possible benefits of its use to future patients. It must also be realized, as stressed years ago by Dr. Ellis himself (6), that work by health education upon the social factors which are the cause of a good proportion of the cancers most suitable for brachytherapy is still of the utmost importance both in developed and developing countries. Governments have an important part to play in this work, by providing funds for education to discourage causative factors such as alcohol and tobacco, and by promoting early detection of small cancers still having a high chance of cure of brachytherapy or by other means.
Interstitial brachytherapy ??C. H. PAINEANDD. V. ASH
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