03&l-3016/91 53.M) + .oO Copyright B 1991 Pergamon Press plc
hr. J. Radiation Oncology Bid. Phys.. Vol. 21, pp. 1471-1478 Prmted in the U.S.A. All nghts reserved.
??Special Feature
THE IMPORTANCE OF OPTIMAL TREATMENT PLANNING IN RADIATION THERAPY HERMAN SUIT,M.D.D.
PHIL. (OXON) AND WILLEM DU Bars,
M.D.
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 There are two classes of failure in radiation therapy: local control not achieved and radiation-induced morhidity. Technical developments which permit the employment of treatment volumes which achieve a closer approximation to the target volume can confidently he asserted to yield clinical gains in terms of higher tumor control rates and/or reduced severity/frequency of radiation induced morbidity. The magnitude of the gains and the cost and effort to realize those gains may need to be assessed by the technique of the “clinical trial.” Such gains will be the consequence of a higher dose to the target and/or the irradiation of smaller volumes of non-target tissues. An important fact is that unirradiated tissues do not develop radiation-related injury. Selected categories of radiation injuries that appear in non-target tissues are here reviewed. Valuable advances in the technology of radiation therapy are virtually certain for the near term. This bodes well, indeed, for our future patients. Improved dose distribution, Tumor control probability, Radiation dose, ~50, Radiation complications. CLASSES OF FAILURE OF RADIATION THERAPY There are two classes of failure in radiation therapy: (a) local control not achieved and (b) radiation-induced morbidity. Strategies to improve the efficacy of radiation therapy are: (a) improve dose distribution; (b) increase the differential response between tumor and normal tissue; (c) develop the ability to predict the response of tumor and normal tissue in the individual patient; and (d) augment knowledge of the natural history of the various categories of tumor. This paper deals with the first listed strategy. The goal of treatment planning is to achieve the closest feasible approach of the treatment volume to the target volume. The clinical benefits will be due to the irradiation of reduced volumes of normal tissues/structures. This will be manifest as increased tolerance which will result in: lesser frequencies and severities of treatment-related morbidity; feasibility of higher doses to the target; and, hence, higher tumor control probabilities. Thus, efforts directed to enhance the technical quality of radiation treatment will decrease the frequency of each of the two classes of failure. The limit to improving dose distribution is, of course, the achievement of the treatment volume which conforms exactly to the target volume. The gains from the use of superior dose distributions are not limited to local effects. The higher probabilities of local control will also result in higher survival rates (14, 39, 40, 42, 43). Although clinical gains are certain of realization where technically improved treatments are used, their practical
importance is to be judged by assessments of the magnitude of those gains and their cost. With respect to the latter, our judgement is that there will be a rapidly decreasing willingness by the general public and the medical community to accept morbidity due to damage of non-target tissues which need not have been in the treatment volume had more technical effort gone into the treatment planning and execution. Further, there is likely to be less tolerance of local failures in patients who received comparatively low radiation doses because simple techniques were used which limited dose levels due to the inclusion of unnecessarily large volumes of non-target tissues. The public and our medical colleagues are increasingly better informed and interested in the details of our activities. This reflects an awareness that our treatment techniques do, indeed, matter. This means that our attitude as to what constitutes a reasonable cost can be expected to be regularly revised upwardly. This can be no cause for surprise, as it has been happening regularly throughout the history of radiation therapy. During the recent 40 years, there have been major and effective increments in the technical component of treatments, all of which added to the costs. These include portal films, simulators, %o units, linear accelerators, computer assisted treatment planning, large clinical physicist and dosimetry staff, new imaging techniques (CT, MRI), etc. Our future patients have good fortune in that there is a richness of entirely feasible proposals for additional improvements in the technical aspects of radiation therapy being tested at present. Prominent among these are
Reprint requests to: Herman D. Suit, M.D., Department of Radiation Oncology, Massachusetts General Hospital, Boston,
MA 02114. Accepted for publication 14 June 1991. 1471
1472
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Oncology
??Biology
0 Physics
further improved imaging techniques (CT, MRI, US, PET); 3D treatment planning and optimization software; on-line visual monitoring of the treatment field; use of non-coplanar beams; more effective and useable immobilization procedures; invasive procedures to place fiducial markers; conformal dynamic photon treatment; intra-operative radiation therapy; heavy charged particle beams; etc. There will not be clinical gains for every tumor/anatomic situation due to further developments in treatment planning. Rather, the evaluation of the potential gains needs to be considered for specific anatomic sites and clinical stages of disease. For example, significant gains cannot be expected in treatment results for the small and relatively superficial squamous cell carcinomas of the skin. Results for such patients are excellent and essentially unchanged since the 1930’s, as the techniques used then (50 KvP X rays and brachytherapy) obtained good conformation of treatment volumes with the target volumes. In contrast, for nearly all of the deeply sited lesions, many of the tumors of the head and neck region, and several other sites, the treatment volumes used today do encompass large volumes of non-target tissue despite the numerous technical improvements made over the past several decades. These are the sites for the future gains.
REDUCTIONS OF ERRORS IN TREATMENT PLANNING The path to improved treatment planning is: think and think again about the difference between the target volume and the treatment volume in each treatment plan; define the magnitude of the errors in each step in treatment planning and execution; then devise the means for reduction of each of those errors to the smallest feasible level; employ treatment plans that display uncertainties around dose specifications; utilize the beam(s), number, quality, array, weighting, beam modifiers that achieve the minimum treatment volume while providing full coverage of the target; and use methods that permit confirmation of the position of the target in the beam. Major sources of error in treatment planning include: (a) definition of the boundaries in 3D of the target. This applies to the initial target, which includes those tissues suspected of involvement on a sub-clinical level as well as the gross disease, and the final target, which is the gross disease as determined on physical examination or on CT or MRI. The concept of the pattern and degree of the subclinical extensions of tumor are not well understood; hence, there is to be expected considerable inter-physician variation as to the definition of this component of the target. There is, on the other hand, likely to be close agreement as to many tissues and/or structures which are non-target. For example, there would be minimal disagreement that small bowel and the osseous pelvis are not target in the treatment of patients with carcinoma of the urinary blad-
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1991, Volume 21, Number 6
der, uterine cervix etc; (b) outlining the target or non-target tissues on the individual CT or MRI sections; (c) definition of the relationship of the surface of the target to the fiducial markers (anatomical landmarks or radio-opaque markers specially inserted into the tissues); (d) alignment of the fiducial markers with the beam; (e) inadequate immobilization of the patient such that there is motion during an individual treatment session and/or there is an inconstant positioning of the patient; (f) inadequate allowance for tissue heterogeneity in density; (g) failure to appreciate the uncertainties in the stated dose at any particular point. This latter is rarely emphasized; there is not a simple statement of the true dose at a point; (h) mis-alignment of beam modifiers, e.g., wedge or compensator filter; and (i) failure to confirm the target position in the beam. The measurement of the radiation output of the treatment machine is accurate to + 2%; this is not likely to be reduced in the near future, nor does that level of uncertainty constitute a practical problem for clinical radiation therapy. There is only a slight knowledge of these errors in a quantitative sense. In one particular radiation application, pertinent data are rapidly becoming available as to the feasible limit to reduction in the uncertainty of positioning of the target in the beam. That is, for the stereotactic radiation treatment of small intracranial vascular lesions by large single doses. The clinical importance of reductions in treatment volumes will be functions of these relationships: (a) slopes of the dose response curves for local control of tumor; (b) slope and relative position of dose response curves for normal tissue damage vis a vis that for tumor control; and (c) the dependence of the normal tissue tolerance on the exact anatomic region or structure (or portion thereof) in the treatment volume. These multiple factors mean that a detailed assessment of the positive impact of better treatment planning will be complex and at best encumbered with substantial margins of uncertainty. These problems have been considered previously by Brahme (5), Mijnheer et al. (22), and Thames et al. (45). Although assessment of the clinical value of superior dose distributions by the technique of the Phase III clinical trial is attractive, it surely is not essential. No truly informed patient would agree to have his/her normal tissues (non-target) irradiated when feasible technical means were available to exclude them from the treatment volume and could also be assured of coverage of the target in three dimensions on each treatment session. Further, were the frequency and severity of normal tissue damage to be low and approximately equivalent to those experienced after the conventional treatment, most patients would surely opt for a higher dose to the target and, hence, the confident expectation of a better tumor control probability. This has clearly been the practice with past developments, viz the introduction of 6oCo, linear accelerators, electron beams, etc. The use of a treatment plan which realizes a substantially smaller treatment volume does not necessarily need further justification, aside from cost consideration. Where
Optimal treatment planning 0 H. SUITAND W. Du BOIS
the reduction in treatment volume is small and the resultant permitted increment in dose is modest, say 120 cm*, respectively, among 110 patients treated at M.D. Anderson Hospital to -70 Gy (not indicating a field size dependence of complication frequency). Shipley et al. (38) reported their experience at the Massachusetts General Hospital with 121 patients treated by external photon beam therapy alone: 50.4 Gy in 5.5 weeks via contoured four-field box technique followed by small field boost to 64.8 - 68.4 Gy. The one major complication was severe hemorrhagic cystitis which required cystectomy. There is variability in rates of morbidity, treatment volumes, pattern of field reduction during treatment, dose level, and beam quality among the cancer centers. By use of smaller treatment volumes there should, as a minimum, be significant reductions in damage to the small intestine, acute and late (mild, moderate and severe). Importantly, the smaller treatment volume would permit an increment in dose that would effect a reduction in local failure rate. This latter is a significant concern, especially for T3 lesions. There are many other classes of treatment-related morbidity which are unarguably the consequence of irradiation of non-target tissues. An important example is spinal cord damage after treatment of patients with epithelial tumors of the head-neck region, thorax, and upper abdomen. Modem radiation treatment practice sets the limit on dose to the spinal cord at -44 Gy (1.8 Gy per fraction). This means that in many instances the dose to the target is not effec-
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radiation techniques that exclude the spinal cord from the treatment volume would avoid the present low frequency of cord damage but also increase the frequency of control of the tumor. Further documentation of the clinical verity that much of the treatment-related morbidity is the result of the irradiation of uninvolved tissue is not essential in this brief review. tive. Hence,
SLOPE OF THE DOSE RESPONSE CURVE FORLOCALCONTROL The clinical importance of the increment in dose due to improved treatment planning will depend heavily upon the slope of the dose response curve for local control of tumor. As advances in treatment planning yield progressively smaller treatment volumes, while still providing full coverage of the target at each treatment session, the critical questions become: (a) what increment in dose to the target does the improved tolerance permit; and (b) what increase in tumor control probability does that augmented dose yield? This is a subject that has elicited much interest, as it is clearly of central importance to much of the current investigative work in radiation therapy (5, 11, 22, 25, 45, 50). The uncertainties on this subject are to a substantial degree due to the large impact of heterogeneity of the patient populations that have been available for assessment of the dose response relationships. Were all tumors in the population under consideration to be exactly equivalent with respect to number of tumor clonogens, distribution of radiation sensitivities, proliferation kinetics, tumor-host immune relationship, etc., the dose response curve would be steep, and be determined by the random cell killing and Poisson statistics. For example, the tumor control probability [TCP] would be expected to increase by 2 percent points for each increment in dose by 1%, for TCPs in the mid-
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range, e.g., 30-70% (44). As the control TCP is moved to
the extremes of the dose response curves, the effect of dose increments would rapidly decrease. Heterogeneity with respect to one or several of the above-mentioned parameters progressively flattens the dose response curve. Hence, considerations of the slope of dose response curves should be made only with respect to homogenous patient populations which have been treated according to a relatively standard protocol, with dose as the major variable and with employment of a reasonably wide range of doses. The complimentary consideration is the dependence of morbidity on the proportion of a structure irradiated to full dose and the effect of inclusion of large volumes of tissue in the low dose sectors of the treatment volume. There are few clinical data on this point. This is an important area for future laboratory and clinical research. In summary, to the extent that treatment-related morbidity occurs in tissue not involved by tumor, there will be clinically important gains by the use of treatment volumes that more closely conform to the target volume. In parallel with the reductions in morbidity, there will, in many anatomic situations, be permitted higher doses and consequently higher tumor control probabilities. This statement is powerfully supported by the history of radiation therapy, which clearly documents that when technical developments made the employment of improved dose distributions, there have been gains in clinical results. These have come about through the important achievements in radiologic imaging as well as the advances in design and power of x-ray generators, and variety of the beams and sources available to the clinician (electrons, protons, and a variety of radioactive isotopes). There are many and important advances in progress and soon to be initiated which will continue this series of advances. The new and more costly treatment procedures will need careful evaluation to provide assessments of the gains versus cost.
REFERENCES 1 Austin-Seymour, M.; Munzenrider, J.; Goitein, M.; Verhey, L.; Urie, M.; Gentry, R.; Bimbaum, S.; Ruotolo, D.; McManus, P.; Skates, S.; Ojemann, R.; Rosenberg, A.; Schiller, A.; Koehler, A.; Suit, H. Fractionated proton radiation therapy of chordoma and low grade chondrosarcoma of the base of skull. J. Neurosurg. 70:13-17; 1989. 2. Bagshaw, M. A.; Cox, R. S.; Ray, G. R. Status of radiation treatment of prostate cancer at Stanford University. NC1 Monog. 7:47-60; 1988. 3. BJR Supplement 22. Megavoltage radiotherapy 1937-1987. In: Plowman, P. N.; Hamett, A. N., eds. London:Brit.Inst.Radiol.; 1988. 4. Boise, J. D.; Engholm, G.; Kleinerman, R. A.; Blettner, M.; Stovall, M. et al. Radiation dose and second cancer risk in patients treated for cancer of the cervix. Radiat. Res. 116: 3-5s; 1988. 5. Brahme, A. Dosimetric precision requirements in radiation therapy. Acta Radiol. Oncol. 23:379-391; 1984. 6. Cheng, V. S. T.; Downs, J.; Herbert, D.; Aramany, M. The function of the parotid gland following radiation therapy for
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13. Forman, J. D.; Zinreich, E.; Lee, D. J.; Wharam, M. D.; Baumgardner, R. A.; Order, S. E. Improving the therapeutic ratio of external beam irradiation for carcinoma of the prostate. Int. J. Radiat. Oncol. Biol. Phys. 11:2073-2080; 1985. 14. Fuks, Z.; Lievel, S.; Wallner, K. E.; Begg, C. B.; Fair, W. R.; Anderson, L. L.; Hilaris, B. S.; Whitmore, W. F. The effect of local control on metastatic dissemination in carcinoma of the prostate: long term results. Int. J. Radiat. Oncol. Biol. Phys. (In press), 1991. 15. Hamberger, A. D.; Unal, A.; Gershenson, D. M.; Fletcher, G. H. Analysis of the severe complications of irradiation of carcinoma of the cervix: whole pelvis irradiation and intracavitary radium. Int. J. Radiat. Oncol. Biol. Phys. 9:367371; 1983. 16. Hatfield, P. M.; Schulz, M. D. Post irradiation sarcoma: including 5 cases after X-ray therapy of breast carcinoma. Radiol. 96:593-602; 1970. 17. Heyman, J. The so-called Stockholm method and the results of treatment of the uterine cancer of the radiumhemmet. Acta Radiol. 16:129; 135. 18. Hilaris, B., ed. Handbook of interstitial brachytherapy, Acton, MA: Publishing Science Group; 1975: xiii. 19. Kim, J. H.; Chu, F. C.; Woodward, H. Q.; Melamed, M. D.; Huvos, A.; Cantin, J. Radiation-induced soft-tissue and bone sarcoma. Radiol. 129501-508; 1978. 20. Kuten, A.; Sapir, D.; Cohen, Y.; Haim, N.; Borovik, R.; Robinson, E. Postirradiation soft tissue sarcoma occurring in breast cancer patients: report of seven cases and results of combination chemotherapy. J. Surg. Oncol. 28:168-171; 1985. 21. Loeffler, J. S.; Alexander, E., III; Wen, P. Y.; Shea, W. M.; Coleman, C. N.; Kooy, H. N.; Fine, H. A.; Nedzi, L. A.; Silver, B.; Rese, N. E. et al. Results of stereotactic brachytherapy used in the initial management of patients with glioblastoma. JNCI 82:1918-1921; 1990. 22, Mijnheer, G. B.; Batterman, J. J.; Wambersie, A. What degree of accuracy is required and can be achieved in photon and neutron therapy? Radiother. Oncol. 8:237-252; 1987. 23. Mira, J. G.; Wescott, W. B.; Starcke, E. N.; Shannon, I. L. Some factors influencing salivary function when treating with radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 7:535541; 1981. 24. Montano, G. S.; Fowler, W. C. Carcinoma of the cervix: analysis of bladder and rectal radiation dose and complications. Int. J. Radiat. Oncol. Biol. Phys. 16:95-100; 1989. 25. Moore, J. M.; Hendry, J. H.; Hunter, R. D. Dose-incidence curves for tumor control and normal tissue injury, in relation to response of clonogenic cells. Radiother. Oncol. 11:143157; 1983. 26. Munzenrider, J. E.; Verhey, L. J.; Gragoudas, E. S.; Seddon, J.M.; Urie, M.; Gentry, R.; Bimbaum, S.; Ruotolo, D. M.; Crowell, C.; McManus, P.; Finn, S.; Sisterson, J.; Johnson, K.; Egan, K.; Lento, D.; Bassin, P. Conservative treatment of uveal melanoma: local recurrence after proton beam therapy. Int. J. Radiat. Oncol. Biol. Phys. 17:493498; 1989. 27. Neglia, W. J.; Hussey, D. H.; Johnson, D. E. Megavoltage radiation therapy for carcinoma of the prostate. Int. J. Radiat. Oncol. Biol. Phys. 2:873-882; 1977. 28. Parsons, J. T.; Mendenhall, W. M.; Mancuso, A. A.; Cassisi, N. J.; Million, R. R. Malignant tumors of the nasal cavity and ethmoid and sphenoid sinuses. Int. J. Rad. Oncol. Biol. Phys. 14:11-22; 1988. 29. Paterson, R. The treatment of malignant disease by radium and X-rays. London: Edward Arnold & Co; 1948. 30. Perez, C. A.; Breaux, S.; Madoc-Jones, H.; Camel, H. M.; Purdy, J.; Sharma, S.; Powers, W. E. Correlation between
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radiation dose and tumor recurrence and complications in carcinoma of the uterine cervix: Stages I and IIA. Int. J. Radiat. Oncol. Biol. Phys. 5:373-382; 1979. Perez, C. A.; Walz, B. J.; Zivnuska, F. R., Pilepich, M.; Prasad, K.; Bauer, W. Irradiation of carcinoma of the prostate localized to the pelvis: analysis of tumor response and prognosis. Int. J. Radiat. Oncol. Biol. Phys. 6:555-563; 1980. Pettersson, F.; Fotiou, S.; Einhom, N.; Silfversward, C. Cohort study of the long-term effect of irradiation for carcinoma of the uterine cervix. Acta Radio1 Oncol 24 (Fasc.2):145151; 1985. Regaud, C. Traitmant des cancers du co1 de l’uterus par le radiation: idee sommaire des methodes et des resultats; indications therapeutiques. Rapp. VIIE Cong. Sot. Int. Chirug. 1:35; 1926. Robinson, E.; Neugut, A. I.; Wylie, P. Clinical aspects of postirradiation sarcomas. JNCI 80:233-240; 1988. Rosen, E.; Cassady, J. R.; Connlly, J.; Chaffey, J. T. Radiotherapy for prostate carcinoma: the JCRT experience (1968-1978). II. Factors related to tumor control and complications. Int. J. Radiat. Oncol. Biol. Phys. 11:725-730; 1985. Schulz, M. D. The supervoltage story. Janeway lecture, 1974. Am. J. Roentgenol. 124:541-559; 1975. Senyszyn, J. J.; Johnston, A. D.; Jacox, H. W.; Chu, F. C. H. Radiation-induced sarcoma after treatment of breast cancer. Cancer 26:39-3; 1970. Shipley, W. U.; Prout, G. R.; Coachman, N. M.; McManus, P. L.; Healey, E. A.; Althausen, A. F.; Heney, N. M.; Parkhurst, E. C.; Young, H. H.; Shipley, J. W.; Kaufman, S. D. Radiation therapy for localized prostate carcinoma: experience at the Massachusetts General Hospital (1973-l 98 1). Natl. Cancer Inst. Monog. 7:67-73; 1988. Suit, H. D.; Miralbell, R. Potential impact of improvements in radiation therapy on quality of life and survival. Int. J. Radiat. Oncol. Biol. Phys. 16:891-895; 1989. Suit, H. D.; Becht, J.; Leong, J.; Stracher, M.; Wood, W. C.; Verhey, L.; Goitein, M. Potential for improvement in radiation therapy. The first Gilbert H. Fletcher lecture at Univ. of Texas M.D. Anderson Cancer Center, April 1986. Int. J. Radiat. Oncol. Biol. Phys. 14:777-786; 1988. Suit, H. D.; Sedlacek, R.; Fagundes, L.; Goitein, M.; Rothman, K. Time distribution of recurrences of an immunogenic and non-immunogenic tumor following local irradiation. Radiat. Res. 73:251-266; 1978. Suit, H. D.; Westgate, S. J. Impact of improved local control on survival. Int. J. Radiat. Oncol. Biol. Phys. 12:453458; 1986. Suit, H. D. Potential for improving survival rates for the cancer patient by increasing the efficacy of treatment of the primary lesion. Cancer 50:1227-1234; 1982. Suit, H. D.; Verhey, L. J. Precision in megavoltage radiotherapy. Br. J. Radiol. 22, (Suppl):17-24; 1988. Thames, H. D.; Schultheiss, T. E.; Tucker, S. L.; Dubray, B. M.; Hendry, J. H.; Brock, W. A. Can modest escalations of dose be detected as increased tumor control? NC1 Workshop, April, 1989; potential clinical gains by use of superior radiation dose distributions. Int. J. Radiat. Oncol. Biol. Phys., (In press). Tod, M. C.; Meredith, W. J. A dosage system for use in the treatment of cancer of the uterine cervix. Brit. J. Radiol. 11: 809-824; 1938. Tountas, A. A.; Fomasier, V. L.; Harwood, A. R.; hung,
P. M. Post-irradiation sarcoma of the bone: a prespective. Cancer 43(1):182-187; 1979. 48. Tucker, M. A.; D’Angia, G. J.; Boice, J. D.; Strong, L. C.; Li, F. P.; Stoval, M.; Stone, B. J.; Green, D. M.; Lombardi,
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F.; Newton, W.; Hoover, R. N.; Fraumeni, J. F. Bone sarcomas linked to radiotherapy and chemotherapy in children. N. Eng. J. Med. 316599-593; 1987. 49. Willett, C. G.; Shellito, P. C.; Tepper, J. E.; Eliseo, R.; Convery, K.; Wood, W. C. Intraoperative electron beam ra-
November 1991, Volume 2 1, Number 6 diation therapy for primary locally advanced rectal and rectosigmoid carcinoma. J. Clin. Oncol. 9843-849; 1990. 50. Zagars, G. K.; Schultheiss, T. E.; Peters, L. .I. Inter-tumor heterogeneity and radiation dose-control curves. Radiother. Oncol. 8353-362; 1987.
hr. J. Radiation Oncology Bid. Phys.. Vol. 21, pp. 1471-1478 Prmted in the U.S.A. All nghts reserved.
??Special Feature
THE IMPORTANCE OF OPTIMAL TREATMENT PLANNING IN RADIATION THERAPY HERMAN SUIT,M.D.D.
PHIL. (OXON) AND WILLEM DU Bars,
M.D.
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 There are two classes of failure in radiation therapy: local control not achieved and radiation-induced morhidity. Technical developments which permit the employment of treatment volumes which achieve a closer approximation to the target volume can confidently he asserted to yield clinical gains in terms of higher tumor control rates and/or reduced severity/frequency of radiation induced morbidity. The magnitude of the gains and the cost and effort to realize those gains may need to be assessed by the technique of the “clinical trial.” Such gains will be the consequence of a higher dose to the target and/or the irradiation of smaller volumes of non-target tissues. An important fact is that unirradiated tissues do not develop radiation-related injury. Selected categories of radiation injuries that appear in non-target tissues are here reviewed. Valuable advances in the technology of radiation therapy are virtually certain for the near term. This bodes well, indeed, for our future patients. Improved dose distribution, Tumor control probability, Radiation dose, ~50, Radiation complications. CLASSES OF FAILURE OF RADIATION THERAPY There are two classes of failure in radiation therapy: (a) local control not achieved and (b) radiation-induced morbidity. Strategies to improve the efficacy of radiation therapy are: (a) improve dose distribution; (b) increase the differential response between tumor and normal tissue; (c) develop the ability to predict the response of tumor and normal tissue in the individual patient; and (d) augment knowledge of the natural history of the various categories of tumor. This paper deals with the first listed strategy. The goal of treatment planning is to achieve the closest feasible approach of the treatment volume to the target volume. The clinical benefits will be due to the irradiation of reduced volumes of normal tissues/structures. This will be manifest as increased tolerance which will result in: lesser frequencies and severities of treatment-related morbidity; feasibility of higher doses to the target; and, hence, higher tumor control probabilities. Thus, efforts directed to enhance the technical quality of radiation treatment will decrease the frequency of each of the two classes of failure. The limit to improving dose distribution is, of course, the achievement of the treatment volume which conforms exactly to the target volume. The gains from the use of superior dose distributions are not limited to local effects. The higher probabilities of local control will also result in higher survival rates (14, 39, 40, 42, 43). Although clinical gains are certain of realization where technically improved treatments are used, their practical
importance is to be judged by assessments of the magnitude of those gains and their cost. With respect to the latter, our judgement is that there will be a rapidly decreasing willingness by the general public and the medical community to accept morbidity due to damage of non-target tissues which need not have been in the treatment volume had more technical effort gone into the treatment planning and execution. Further, there is likely to be less tolerance of local failures in patients who received comparatively low radiation doses because simple techniques were used which limited dose levels due to the inclusion of unnecessarily large volumes of non-target tissues. The public and our medical colleagues are increasingly better informed and interested in the details of our activities. This reflects an awareness that our treatment techniques do, indeed, matter. This means that our attitude as to what constitutes a reasonable cost can be expected to be regularly revised upwardly. This can be no cause for surprise, as it has been happening regularly throughout the history of radiation therapy. During the recent 40 years, there have been major and effective increments in the technical component of treatments, all of which added to the costs. These include portal films, simulators, %o units, linear accelerators, computer assisted treatment planning, large clinical physicist and dosimetry staff, new imaging techniques (CT, MRI), etc. Our future patients have good fortune in that there is a richness of entirely feasible proposals for additional improvements in the technical aspects of radiation therapy being tested at present. Prominent among these are
Reprint requests to: Herman D. Suit, M.D., Department of Radiation Oncology, Massachusetts General Hospital, Boston,
MA 02114. Accepted for publication 14 June 1991. 1471
1472
I. J. Radiation
Oncology
??Biology
0 Physics
further improved imaging techniques (CT, MRI, US, PET); 3D treatment planning and optimization software; on-line visual monitoring of the treatment field; use of non-coplanar beams; more effective and useable immobilization procedures; invasive procedures to place fiducial markers; conformal dynamic photon treatment; intra-operative radiation therapy; heavy charged particle beams; etc. There will not be clinical gains for every tumor/anatomic situation due to further developments in treatment planning. Rather, the evaluation of the potential gains needs to be considered for specific anatomic sites and clinical stages of disease. For example, significant gains cannot be expected in treatment results for the small and relatively superficial squamous cell carcinomas of the skin. Results for such patients are excellent and essentially unchanged since the 1930’s, as the techniques used then (50 KvP X rays and brachytherapy) obtained good conformation of treatment volumes with the target volumes. In contrast, for nearly all of the deeply sited lesions, many of the tumors of the head and neck region, and several other sites, the treatment volumes used today do encompass large volumes of non-target tissue despite the numerous technical improvements made over the past several decades. These are the sites for the future gains.
REDUCTIONS OF ERRORS IN TREATMENT PLANNING The path to improved treatment planning is: think and think again about the difference between the target volume and the treatment volume in each treatment plan; define the magnitude of the errors in each step in treatment planning and execution; then devise the means for reduction of each of those errors to the smallest feasible level; employ treatment plans that display uncertainties around dose specifications; utilize the beam(s), number, quality, array, weighting, beam modifiers that achieve the minimum treatment volume while providing full coverage of the target; and use methods that permit confirmation of the position of the target in the beam. Major sources of error in treatment planning include: (a) definition of the boundaries in 3D of the target. This applies to the initial target, which includes those tissues suspected of involvement on a sub-clinical level as well as the gross disease, and the final target, which is the gross disease as determined on physical examination or on CT or MRI. The concept of the pattern and degree of the subclinical extensions of tumor are not well understood; hence, there is to be expected considerable inter-physician variation as to the definition of this component of the target. There is, on the other hand, likely to be close agreement as to many tissues and/or structures which are non-target. For example, there would be minimal disagreement that small bowel and the osseous pelvis are not target in the treatment of patients with carcinoma of the urinary blad-
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der, uterine cervix etc; (b) outlining the target or non-target tissues on the individual CT or MRI sections; (c) definition of the relationship of the surface of the target to the fiducial markers (anatomical landmarks or radio-opaque markers specially inserted into the tissues); (d) alignment of the fiducial markers with the beam; (e) inadequate immobilization of the patient such that there is motion during an individual treatment session and/or there is an inconstant positioning of the patient; (f) inadequate allowance for tissue heterogeneity in density; (g) failure to appreciate the uncertainties in the stated dose at any particular point. This latter is rarely emphasized; there is not a simple statement of the true dose at a point; (h) mis-alignment of beam modifiers, e.g., wedge or compensator filter; and (i) failure to confirm the target position in the beam. The measurement of the radiation output of the treatment machine is accurate to + 2%; this is not likely to be reduced in the near future, nor does that level of uncertainty constitute a practical problem for clinical radiation therapy. There is only a slight knowledge of these errors in a quantitative sense. In one particular radiation application, pertinent data are rapidly becoming available as to the feasible limit to reduction in the uncertainty of positioning of the target in the beam. That is, for the stereotactic radiation treatment of small intracranial vascular lesions by large single doses. The clinical importance of reductions in treatment volumes will be functions of these relationships: (a) slopes of the dose response curves for local control of tumor; (b) slope and relative position of dose response curves for normal tissue damage vis a vis that for tumor control; and (c) the dependence of the normal tissue tolerance on the exact anatomic region or structure (or portion thereof) in the treatment volume. These multiple factors mean that a detailed assessment of the positive impact of better treatment planning will be complex and at best encumbered with substantial margins of uncertainty. These problems have been considered previously by Brahme (5), Mijnheer et al. (22), and Thames et al. (45). Although assessment of the clinical value of superior dose distributions by the technique of the Phase III clinical trial is attractive, it surely is not essential. No truly informed patient would agree to have his/her normal tissues (non-target) irradiated when feasible technical means were available to exclude them from the treatment volume and could also be assured of coverage of the target in three dimensions on each treatment session. Further, were the frequency and severity of normal tissue damage to be low and approximately equivalent to those experienced after the conventional treatment, most patients would surely opt for a higher dose to the target and, hence, the confident expectation of a better tumor control probability. This has clearly been the practice with past developments, viz the introduction of 6oCo, linear accelerators, electron beams, etc. The use of a treatment plan which realizes a substantially smaller treatment volume does not necessarily need further justification, aside from cost consideration. Where
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the reduction in treatment volume is small and the resultant permitted increment in dose is modest, say 120 cm*, respectively, among 110 patients treated at M.D. Anderson Hospital to -70 Gy (not indicating a field size dependence of complication frequency). Shipley et al. (38) reported their experience at the Massachusetts General Hospital with 121 patients treated by external photon beam therapy alone: 50.4 Gy in 5.5 weeks via contoured four-field box technique followed by small field boost to 64.8 - 68.4 Gy. The one major complication was severe hemorrhagic cystitis which required cystectomy. There is variability in rates of morbidity, treatment volumes, pattern of field reduction during treatment, dose level, and beam quality among the cancer centers. By use of smaller treatment volumes there should, as a minimum, be significant reductions in damage to the small intestine, acute and late (mild, moderate and severe). Importantly, the smaller treatment volume would permit an increment in dose that would effect a reduction in local failure rate. This latter is a significant concern, especially for T3 lesions. There are many other classes of treatment-related morbidity which are unarguably the consequence of irradiation of non-target tissues. An important example is spinal cord damage after treatment of patients with epithelial tumors of the head-neck region, thorax, and upper abdomen. Modem radiation treatment practice sets the limit on dose to the spinal cord at -44 Gy (1.8 Gy per fraction). This means that in many instances the dose to the target is not effec-
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radiation techniques that exclude the spinal cord from the treatment volume would avoid the present low frequency of cord damage but also increase the frequency of control of the tumor. Further documentation of the clinical verity that much of the treatment-related morbidity is the result of the irradiation of uninvolved tissue is not essential in this brief review. tive. Hence,
SLOPE OF THE DOSE RESPONSE CURVE FORLOCALCONTROL The clinical importance of the increment in dose due to improved treatment planning will depend heavily upon the slope of the dose response curve for local control of tumor. As advances in treatment planning yield progressively smaller treatment volumes, while still providing full coverage of the target at each treatment session, the critical questions become: (a) what increment in dose to the target does the improved tolerance permit; and (b) what increase in tumor control probability does that augmented dose yield? This is a subject that has elicited much interest, as it is clearly of central importance to much of the current investigative work in radiation therapy (5, 11, 22, 25, 45, 50). The uncertainties on this subject are to a substantial degree due to the large impact of heterogeneity of the patient populations that have been available for assessment of the dose response relationships. Were all tumors in the population under consideration to be exactly equivalent with respect to number of tumor clonogens, distribution of radiation sensitivities, proliferation kinetics, tumor-host immune relationship, etc., the dose response curve would be steep, and be determined by the random cell killing and Poisson statistics. For example, the tumor control probability [TCP] would be expected to increase by 2 percent points for each increment in dose by 1%, for TCPs in the mid-
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range, e.g., 30-70% (44). As the control TCP is moved to
the extremes of the dose response curves, the effect of dose increments would rapidly decrease. Heterogeneity with respect to one or several of the above-mentioned parameters progressively flattens the dose response curve. Hence, considerations of the slope of dose response curves should be made only with respect to homogenous patient populations which have been treated according to a relatively standard protocol, with dose as the major variable and with employment of a reasonably wide range of doses. The complimentary consideration is the dependence of morbidity on the proportion of a structure irradiated to full dose and the effect of inclusion of large volumes of tissue in the low dose sectors of the treatment volume. There are few clinical data on this point. This is an important area for future laboratory and clinical research. In summary, to the extent that treatment-related morbidity occurs in tissue not involved by tumor, there will be clinically important gains by the use of treatment volumes that more closely conform to the target volume. In parallel with the reductions in morbidity, there will, in many anatomic situations, be permitted higher doses and consequently higher tumor control probabilities. This statement is powerfully supported by the history of radiation therapy, which clearly documents that when technical developments made the employment of improved dose distributions, there have been gains in clinical results. These have come about through the important achievements in radiologic imaging as well as the advances in design and power of x-ray generators, and variety of the beams and sources available to the clinician (electrons, protons, and a variety of radioactive isotopes). There are many and important advances in progress and soon to be initiated which will continue this series of advances. The new and more costly treatment procedures will need careful evaluation to provide assessments of the gains versus cost.
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