Full CT scanning is essential for three-dimensional planning and is by far the best techniq ue, as it provides all the necessary information as well as a density map of the patient th at can be used for dose calculation. Magnetic resonance (MR) scanning can provide better diagnostic information than CT but prod uces geometrical distortions in the image that must be corrected. MR scanning is therefore only used in conjunction with CT planning. In all cases it is essential during the treatment planning process that patients consistent ly remain in the treatment position; immobiliza- tion devices can assist in this. The correct determination of the planning target volume (PTV) is obviously essential to the success of radiotherapy. The gross tumor volume (GTV) is that which is palpable or radiolo gically demonstra- ble, but must be surrounded by a margin to allow for microscopic spread, giving a clinical target volume (CTV). A further margin must be applied to the CTV to allow for geometri- cal inaccuracies in the treatment set-up and patient/organ movement OHO-08(93-134) 11/16/02 11:19 AM Page 113 TREATMENT PLANNING 113 during treatment, and this de \201nes the planning target volume. Progression from the GTV to the PTV is straightforward in two- dimensional planning. However, enlarging the CTV to the PTV, slice by slice on CT may not give correct margins in three dimensions when there i s a signi \201cant difference in the size of the CTV on adjoining slices. Further problems exist in de \201ning margins at the superior and inferior limits of the CTV due to the wi dth of the CT slice. Problems can be overcome by the use of three-dimensional volume-growin g algorithms that are available on computerized planning systems. Beam arrangements Optimum beam arrangements required to treat a particular site have been w idely investigated and adopted into protocols in each radio- therapy center, with little va riation from one center to another. However, some sites in the head and neck and the chest may require individualized beam arrangements. In general, co-planar beam arrangements are used, but the avail- ability of fully three-dim ensional treatment planning systems allows the placement of non-coplanar \201elds. The nu mber of beams required is less with a high-beam energy and a small depth to the center of t he target. In the pelvis, three or four beams are used at the highest avail- able energy, p referably 12 \200\22316 MV. Three beams are suf \201cient in the chest, using an energy of 6 \200\2238 MV, as at higher energies the range of the secondary electrons in lung tissue makes the calculation of the dose distribution uncertain. In the head and neck region, two \201elds are generally suf \201cient, using an energy 4 \200\2236 MV, as it may be neces sary to provide a high dose close to the entrance surface while minimizing the exit skin do se. The central axis of the beams pass through one point (known as the isocentre) which is plac ed at the center of the PTV, with the directions of the treatment beams chosen to avoid the irradiation of sensitive structures. Placing the beams uniformly around the patient is adv an- tageous in obtaining a uniform dose distribution over the target, and the selection of beam directions where the depth of the target is kept small reduces the overall dose to the patient. Beam size Beam sizes should be chosen so that the resulting high-dose volume encompasses th e PTV with a minimum dose not <95% of the iso- center dose. To achieve this, \201eld dime nsions must be larger than the PTV due to the fall off in dose towards the edge of the beam . The margins required are typically in the region of 6 \200\22310 mm and depend on how man y beams contribute to the fall off in dose. A development arising from three-dimensional treatment planning that assists greatly in the determination of beam size is the beam \200\231s eye OHO-08(93-134) 11/16/02 11:19 AM Page 114 PRINCIPLES OF RADIATION ONCOLOGY 114 view (BEV) approach. Here the observer is placed at the radiation source and the projection of any structure that has been outlined on a CT image set is displayed on a plane normal t o the central axis of the beam. A projection of the beam portal is superimposed and its siz e can be determined according to the projection of the PTV. The approach also assists in th e selection of the optimal beam direc- tions with respect to the separation of the target a nd vulnerable organs. The technique of conformal radiotherapy is increasingly used in which the beam shape is mat ched more closely to the PTV. This is achieved by the use of customized blocks or multi-lea f collimators (MLC) on individual beams, and in both cases the use of BEV is essential. Beam weight The relative contribution of a beam to the treatment plan is known as the beam weight. The de \201nition varies between centers and is de \201ned either as the relative contribution of the dose to the isocentre or to the reference point. The adjustment of bea m weights is a method of achieving uniformity of dose over the PTV and giving approxi- mate ly the same dose to the isocentre from each beam will give good uniformity. Care should be taken to ensure that the entrance dose under the beam portals is not excessive. The inherent dose distribution of a beam can be altered by the insertion of a wedge-shaped \201lter that produces a dose gradient in one dimension across the beam. Wedges can be us ed to com- pensate for obliquity at the skin surface or to assist in obtaining dose uniform ity in the PTV when the beams are not uniformly spaced around the patient. Wedges are chara cterized by the angle through which the isodose lines are tilted and normally a selection a re available (or can otherwise be achieved), producing tilts of up to 60 . Selection of the optimum beam weights and wedges is assessed by the closeness of the result ing dose distribution to that required by the radiation oncologist. Modi \201cation of the inherent dose distribution over the beam in two dimensions is possible by the use of physi cal compensators or, more recently, by the dynamic movement of the leaves of an MLC. The use of the treatment simulator depends on the patient data used for planning. In three- dimensional CT planning, the radiation oncologist usually outlines the CTV on the relevant CT slices together with the outline of any vulnerable organs. The CT data represent the pat ient with computer graphics used to simulate the treatment beams. This can be thought of as virtual simulation and the patient only visits the treatment simulator at the end of the t reatment planning process to have the treatment veri \201ed. OHO-08(93-134) 11/16/02 11:19 AM Page 115 TREATMENT PLANNING 115 Treatment sheet The \201nal action of the treatment planning process is to produce a trea tment sheet that provides a set of instructions to allow the treat- ment radiographer to se t up the patient as planned and to deliver the correct dose distribution, including the num ber of monitor units to be applied to each beam. Accuracy has to be assured by a set of che cks at all stages of the planning process, and these should form part of a quality assuranc e system, such as ISO 9002, with fully documented procedures and work instructions. OHO-08(93-134) 11/16/02 11:19 AM Page 116 PRINCIPLES OF RADIATION ONCOLOGY 116 Total body irradiation (TBI) Treatment intensi \201cation with high doses of chemotherapy and/or radiotherapy is used t o try to improve cure rates for sensitive tumors. In some benign diseases such as aplastic anemia and thalassaemia, myelo-ablative therapy, usually with chemotherapy alone, precedes engraftment of normal donor marrow to overcome the underlying host problem. Aims (cid:2) To eliminate any residual malignant disease. (cid:2) To ablate residual marrow to p ermit engraftment of peripheral stem cells or bone marrow. (cid:2) To produce immune suppression (especially for non-haplotype identical grafts). Indications for high-dose therapy Acute lymphatic leukemia (cid:2) Patients at very high risk of relapse (such as those presenting with a white cell c ount of >100 000 or with speci \201c chromosome abnor- malities) may be treated in \201r st remission. (cid:2) Second or subsequent remission \200\224any patients who are not excluded by age or probability of complications. Acute myeloid leukemia High-dose consolidation therapy with chemotherapy, TBI, and bone mar row transplantation or stem cell rescue should be considered for all patients aged 2 \200 \22350 years with a compatible donor. Lymphoma Consider treatment for patients with high-grade non-Hodgkin \200\231s lym- phoma a fter a \201rst relapse; and for Hodgkin \200\231s disease patients with primary chemoresi stant disease or widespread disease after remission induction or after relapse. Myeloma Best tolerated in patients <50 years with good performance status and response to i nitial chemotherapy. Other malignancies These include advanced germ cell tumors, neuroblastoma. OHO-08(93-134) 11/16/02 11:19 AM Page 117 TOTAL BODY IRRADIATION (TBI) 117 Types of haemopoetic reconstitution (cid:2) Autologous Transplant may be peripheral stem cells or cryo- preserved marrow obtained before high-dose therapy. (cid:2) Allogeneic Matched or mismatched (1 haplotype identical) bone marrow is usually use d, and may be obtained from a family member or from a donor panel. Pre-treatment screening (cid:2) The patient \200\231s disease should be in remission. (cid:2) There should be adequ ate renal, cardiac, hepatic, and pulmonary function to cope with the toxicity of chemotherapy and TBI. (cid:2) Exposure to medication with the same side-effects as TBI, or likely to potentiate i ts side-effects, should be assessed. Common inter- actions: neurotoxicity with asparaginase , renal with platinum or ifosfamide, pulmonary with methotrexate or bleomycin, cardiac with cyclosphosphamide or anthracyclines. (cid:2) The need for additional therapy to sites such as the central nervous system, testes , mediastinum i.e. areas of sanctuary or bulk disease. Informed consent must be obtained. (cid:2) Preparation TBI is usually preceded by high-dose cyclophosphamide given 48 \200\22372 hours before treatment. Experimental results suggest the poss- ible bene \201t of giving cyclop hosphamide after TBI as used in the Memorial Sloan Kettering protocol. Other combinations o f chemotherapy may also be used before TBI. Anti-emetics, including a 5HT antagonist, are given with dexa- methasone, intravenously, 1 hour before treatment starts. If addition- al sedation is required phenobarbitone or diazep am may be used. For very young children, anesthesia with ketamine may be necessary. Technique (cid:2) Linear accelerator or cobalt unit \200\224optimum energy around 6 MV. (cid:2) Fract ionated TBI is preferred for reasons of convenience. (cid:2) Patient lies on couch behind a perspex sheet (to provide full skin bolus) either on their side or back and side alternately. (cid:2) Treatment is given by opposed \201elds for half each treatment time. (cid:2) The couch is placed at an extended distance from the machine to obtain the \201eld size required to cover the whole body. (cid:2) The dose distribution will be inhomogenous because of variation in AP/PA separation along the body and because of density differ- ences (especially the lung). This can be com pensated for by using OHO-08(93-134) 11/16/02 11:19 AM Page 118 PRINCIPLES OF RADIATION ONCOLOGY 118 bolus or lung shielding but is unnecessary using schedules described here, where doses do n ot exceed tolerance for any normal tissues. (cid:2) The maximum risk of damage is to the lung. Calculation of dose Paired lithium \202uoride dose meters or diodes are used to measure d ose distribution throughout the body. These are placed on the skin at de \201ned sites in the upper and lower lung, mediastinum, abdomen, and pelvis. Midline doses are taken as the average of AP and PA dose meter readings or CT scanning of the whole body can be used with a planning computer to calculate doses throughout the body. Dose schedules Adults The optimum fractionated doses are determined as 13.2 Gy \200\22314.4 Gy depending o n the point of dose prescription. The maximum lung dose is preferred, as this is the dose l imiting toxicity, and should not exceed l4.4 Gy. Children May tolerate slightly higher doses than adults. In the MRC protocol, treatment is given in 8 fractions of 1.8 Gy over 4 days. Many other dose schedules are in common use and have been found by experience to be satisfactory. Toxicity of treatment Acute effects (cid:2) Nausea and vomiting commonly starts about 6 hours after the \201rst fraction. (cid:2) Parotid swelling \200\224occurs in the \201rst 24 hours and then resolves spontaneously, although often leaving dry mouth. (cid:2) Hypotension. (cid:2) Fever \200\224abolished by steroids. (cid:2) Diarrhea \200\224 occurs at day 5 as a result of gastrointestinal mucositis. Delayed toxicity (cid:2) Pneumonitis presenting with dyspnoea and characteristic X-ray appearances. (cid:2) Somnolence due to transient demyelination occurs at 6 \200\2238 weeks and is charac terized by sleepiness, anorexia, and in some cases nausea which settles spontaneously withi n 7 \200\22310 days. OHO-08(93-134) 11/16/02 11:19 AM Page 119 TOTAL BODY IRRADIATION (TBI) 119 Late toxicity (cid:2) Cataracts occur in <20% of patients, incidence increases at 2 \200\2236 years, but then appears to plateau. (cid:2) Hormonal changes \200\224azoospermia and amenorrhoea with conse- quent sterility ar e the norm; very occasionally fertility has been maintained leading to normal pregnancies w ith no increased inci- dence of abnormalities in the offspring (cid:2) Hypothyroidism may result from damage to the thyroid alone or in combination with pituitary damage. In children, there may be impaired production of growth hormone which, added to the effect of early epiphyseal fusion from TBI, results in stunting of growth. Induction of second malignancy \200\224there is a 5-fold increase in the risk o f second malignancies. Brain tumors may be attributed to the TBI and oral and rectal carcin omas have been reported. (cid:2) (cid:2) (cid:2) Malignancy of the lymphoid system may result from the prolonged immune suppression. Clinical outcome Clinical trials have shown better survival after high-dose therapy with ap propriate rescue than after conventional chemotherapy for selected patients with acute myel oid and acute lymphatic leukemia. Some bene \201t has been shown for patients with high-ri sk node-positive breast cancer, stage IV neuroblastoma, and high-grade lymphoma, but the ro le of high-dose therapy in these settings needs further clari \201cation. Comparisons of chemotherapy with and without TBI for condition- ing are not conclusive. TBI is preferred where more immune suppres- sion is needed (e.g. mismatched grafts). Chemother apy is preferred for benign disease because of the increased risk of second tumor induction with TBI. Otherwise, choices are based on the differing patterns of toxicity of the modali ties of conditioning. TBI may be considered for more frequent use in adults where growth and developmental problems are less important. OHO-08(93-134) 11/16/02 11:19 AM Page 120 PRINCIPLES OF RADIATION ONCOLOGY 120 Brachytherapy A form of radiation treatment where the radiation sources are placed within or close to the target volume i.e. the sources are placed at the heart of the tumor. Indications (cid:2) The extent of the neoplasm must be known precisely, as treatment is often given to a relatively small volume and \200\230geographic miss \200\231 of tumor is a signi \201ca nt risk. (cid:2) The site should be accessible for both inserting and removing sources and allowing satisfactory geometric positioning of those sources. Advantages (cid:2) The probability of local tumor control increases with increasing radiation dose, bu t so does the probability of normal tissue damage. Brachytherapy allows the delivery of a l ocalized high radiation dose to a small tumor volume, increasing the chance of local contro l. There is a sharp fall-off of radiation dose in the surrounding normal tissue, therefore the risks of complication are reduced. (cid:2) The overall duration of brachytherapy is short, generally between 2 \200\2237 days. The constant low-dose irradiation takes advantage of the different rates of repair and re- population of normal and malig- nant tissue to produce differential cell killing, enhancing the thera- peutic ratio. (cid:2) Hypoxic cells are relatively resistant to radiation treatment. Re- oxygenation may occur during low-dose-rate radiotherapy, with initially resistant hypoxic cells becoming we ll aerated and sensitive. (cid:2) The dose distribution within the tumor volume is often no t homogeneous. Treatment is often prescribed to the minimum dose received around the periph ery of the treated volume. Areas close to the radiation sources in the center of the tumor volume often receive up to twice this dose. Hypoxic cells are situated in avascular, someti mes necrotic areas in the center of tumors and the higher doses received in the center help to compensate for the relative radio-resistance of these hypoxic cells. Irregular-shaped t umors can be treated by judicious positioning of radiation sources and critical surrounding normal tissues can be avoided. (cid:2) OHO-08(93-134) 11/16/02 11:19 AM Page 121 BRACHYTHERAPY 121 Disadvantages (cid:2) Many sources emit gamma rays and nursing and medical staff may be exposed to low bu t signi \201cant doses of radiation from the patient. Staff exposure can be minimized by a fter-loading tech- niques or the use of low-energy radionuclides. (cid:2) Large tumors are usually unsuitable, although brachytherapy may be employed as a bo ost treatment following reduction in size by external beam radiotherapy and/or chemotherapy . (cid:2) Radiation dose falls off rapidly from the sources according to the inverse square l aw. In order to treat the required tissue volume adequately, accurate geometric positioning is critical. The spatial arrangement of sources used varies, depending on the type of sour ce applicator, the anatomical position of the tumor, and the surrounding dose-limiting norm al tissue. Accurate positioning of sources or applicators requires special skill and traini ng and this is not universally available. (cid:2) Surrounding structures such as lymph nodes that may contain overt or microscopic ca ncer will not be irradiated by the implant or intracavity treatment. Types Intracavity \200\224radioactive material into body cavities (cid:2) Uses \200\224gynae cancers \200\224bronchial cancers \200\224oesophageal cancers \200\224bile duct cancer Interstitial \200\224radioactive material in tissues (cid:2) Uses \200\224breast cancer \200\224tongue cancer \200\224 \202oor of mouth cancer \200 \224anal cancer (cid:2) Surface of tumor \200\224skin \200\224eye Implants can be classi \201ed as manually inserted, after-loading, or remote after-loading . Manual insertion of radiation sources should be avoided if possible owing to the radiatio n hazards to operating staff and nurses. After-loading is when radioactive material is load ed into hollow needles, catheters, or applicators that have been inserted into the tumor ar ea previously. Manipulation of these \200\230cold \200\231 applicators carries no radiatio n hazard to medical and nursing staff, so that time can safely be taken to ensure optimal s ource geometry. OHO-08(93-134) 11/16/02 11:19 AM Page 122 PRINCIPLES OF RADIATION ONCOLOGY 122 After-loading with radioactive material can be manual or remote (using machines such as the Selectron, commonly used to treat gynae- cological cancer). For remote after-loading stain less steel pellets con- taining, for example, caesium in glass, are moved pneumatically fro m a computer-controlled lead-lined safe into intrauterine and vaginal applicators. This com pletely eliminates irradiation of theater and nursing staff. Some remote after-loading devices work at a very high dose rate e.g. the Microselectron (hi gh-intensity iridium sources) or the Cathetron (high-intensity cobalt sources) and treatmen t is over in a matter of minutes. Most implants are of the removable type \200\224the radiation sources are removed after the delivery of the prescribed treatment dose. However, permanent implantations can be perform ed using relatively short half-life isotopes such as 125I or 198Au, which are implanted int o the tumors in the form of seeds which remain after the radiation has decayed virtually co mpletely. Radionuclides Gamma emitters Radium was used for many years as the major source of gamma rays for brachyt herapy. This is now obsolete. The major source of gamma rays is the gaseous daughter produc t, radon. Radium tubes and nee- dles must be gas-tight and frequently checked for leaks. Th e gamma rays used are very penetrating and very thick lead shields are required to provide adequate radiation protection. Caesium-137 has no gaseous daughter products, a very useful half-life of 30 years, and a somewhat less penetrating 660 KeV gamma ray \200\224it has lar gely replaced radium, especially for gynecological work. Iridium-192 is manufactured in the form of \202exible wire and has many advantages over t raditional radium or caesium needles for interstitial brachytherapy. Thin wires (0.3 mm in diameter) can be inserted into \202exible nylon tubes or after-loading needles previously implanted into the tumor. Thicker wires (0.6 mm diameter), in the form of hairpins, can be inserted directly into a tumor through suit- able introducers. In the USA, iridium is also available in the form of seeds sealed in thin plastic coating. Iridium produces a gamma ra y of 330 KeV and lead shields 2 cm in thickness provide good protection. The only major dis advantage of iridium is the relatively short half-life (74 days), so that fresh material sh ould be used for each implant. Iodine-125 has a half-life of 59.6 days and is used for permanent implants of the prostate. As well as having a relatively short half-life, the gamma rays produced by this radionucli de (27 \200\22335 KeV) are of very low energy and very little radiation is emitted from a p atient following the implant, allowing early discharge from hospital. OHO-08(93-134) 11/16/02 11:19 AM Page 123 BRACHYTHERAPY 123 Beta emitters The major use of plaques emitting beta-ray radiation is in the treat- ment of eye tumors. Plaques can be made of Strontium-90 or Ruthenium-106/Rhodium-106. Neutron emitters Californium-252 has been used in the past to treat gynecological tumors. T he advantage of neutron-emitting sources is that they are more effective against hypoxic tu mors. The radiation hazards involved have restricted the use of such sources. Dosimetry Radioactive material is implanted into tissues according to distribu- tion rules that vary according to the system used. In Europe the classical Parker \200\223Paterson and Quimby systems have largely been superseded by the Paris system which is particularly suit able for iridi- um wire implants. Wire of the same linear intensity is used and sources are arranged in parallel, straight, equidistant lines, 8 \200\22320 mm apart. To compensate fo r \200\230uncrossed \200\231 ends, the wires are 20 \200\22330% longer than the length req uired to treat the tumor. In a volume implant, sources in cross-section should be arranged in either equi- lateral triangles or squares. The dose to the tumor can be calculated manually, using graphs such as Oxford cross line cu rves, or by computer. The basal dose rate (the mean of minimum values between sources) is \201rst calculated. The treatment dose (e.g. 65 Gy in 7 days) is prescribed to the referen ce dose line (85% of the basal dose). The prescription point for surface applicators such as molds and some intracavity treatment is usually 0.5 \200\2231 cm from the applicator. A special case is intracavitary gynecolog ical treatment. The most fre- quently used prescribing point is the Manchester A point, de \201ned as a point 2 cm lateral to the uterine canal and 2 cm above the cervical os. The d ose calculated at this point is a good predictor of late radiation damage to the ureter, bl adder, rectum, and other pelvic organs. The International Commission of Radiation Units (IC RU) Report 381 has proposed that the volume (de \201ned in height, thickness, and width en closed by a 60 Gy isodose line) should be used for reporting absorbed dose following gyneco logical treatments. Future developments There is increasing use of sophisticated three-dimensional planning tec hniques incorporating CT or MRI scans to determine the dosage to the whole tumor and to cri tical normal tissues. As well as de \201ning the dose in purely physical terms, the biolog ical effects in different tissues may be expressed as biological effective doses. OHO-08(93-134) 11/16/02 11:19 AM Page 124 PRINCIPLES OF RADIATION ONCOLOGY 124 Radiation exposure to staff has been reduced by the increased use of high-dose-rate remote after-loading machines. The complication rate following fractionated high-dose gynecologica l insertions is less than that following manually inserted low-dose sources. Continuous low - dose-rate implants may be replaced by high-dose \200\230pulsed \200\231 insertions with optimization of the dose distribution and more homogeneous irradiation of the target volume . OHO-08(93-134) 11/16/02 11:19 AM Page 125 INTRA-OPERATIVE RADIOTHERAPY 125 Intra-operative radiotherapy A fundamental problem with radiotherapy is targeting diseased tis- sues while avoiding unaf fected normal structures. Various approaches are possible including: Increasing sophisticated planning and treatment delivery for exter- nal beam radiotherapy ( EBRT) (cid:2) (cid:2) Brachytherapy (cid:2) Radio-immunotherapy (cid:2) Boron neutron capture therapy (BN CT) Intra-operative radiotherapy (IORT) (cid:2) There is some overlap between these techniques e.g. implantation of brachytherapy sources w ill be done under general anesthetic for a variety of diseases, including prostate cancer, and can thus be termed \200\230intra-operative \200\231. The attraction of IORT is that affected tissues can be surgically exposed and selectively t reated with reduced morbidity to non-affected tissues The principal drawback is the need fo r specialist additional equipment in the operating theater. Also, there is a consequent inc reased need for radiation protection for staff in the presence of therapeutic (as opposed t o diagnostic) radiation exposure. The need for the radiation oncologist to be present throu ghout imposes a further constraint on IORT com- pared to EBRT where patients can be treated without this requirement. Surveys Long-term follow-up data are limited but animal studies suggest that IORT exposures up to 30 Gy carry little risk of long-term sequelae as long as sensitive structures such a s major nerves, blood vessels, the spinal cord, or the small bowel are kept out of the irra diation \201eld. The thresh- old for nerve damage is 20 \200\22325 Gy with a latent perio d of 6 \200\2239 months with little damage seen below 10 \200\22315 Gy in large animal mode ls. A further factor to be considered is late malignancy \200\224a number of studies in dogs ha ve reported a high incidence of sarcomas induced by IORT compared to other treatment modali ties. Issues such as treatment planning are clearly complex, as only limited advanced data can be available.2 Speci \201c tumors Rectal cancer (cid:2) May be helpful in both primary and recurrent tumors (cid:2) Complex treatment OHO-08(93-134) 11/16/02 11:19 AM Page 126 PRINCIPLES OF RADIATION ONCOLOGY 126 (cid:2) High cost (cid:2) Little hard data Stomach and esophagus (cid:2) Dose of up to 20 Gy \200\224safe (cid:2) Higher doses \200\224signi \201cant compl ications (cid:2) No randomized data Bile duct (cid:2) Limited bene \201t in unresectable bile duct tumors (cid:2) Complex treatment (cid :2) May be role in minimal residual disease Pancreas (cid:2) Technique feasible (cid:2) Toxicity acceptable (cid:2) Little (no) bene \201t Head and neck cancer (cid:2) Safe, tolerated (cid:2) Encouraging results from limited number of centers (cid:2) Little hard data (cid:2) May be helpful if minimal residual disease or recurrent disease Brain (cid:2) Poor results (cid:2) Tumors spread along white tracts (cid:2) Boron neutron capture therapy (BNCT) Boron compounds exposed to a low-energy neutron beam undergo neutron captur e, releasing lithium 7 nuclei and alpha particles \200\224range less than 1 cell diameter. Early useful results; 15% long-term survival in Japan. Other tumors (cid:2) May be of value in pediatric and soft-tissue sarcomas (cid:2) No randomized trials Conclusions IORT is a promising technique but limited by the technical and logistic problem s already outlined. The continued development of conformal planning and delivery techniques for EBRT will reduce the therapeutic gain that can be obtained from intra-operative treatm ent. In addition, conformal radiotherapy (CRT) is more reproducible in OHO-08(93-134) 11/16/02 11:19 AM Page 127 INTRA-OPERATIVE RADIOTHERAPY 127 set-up and dosimetry and poses no special radiobiological problems as in most cases fractio nation is not changed signi \201cantly. The lack of phase III data is likely to limit the development of IORT and restrict its use to specialist centers with a research base for evalu- ation of long-term results. At presen t, IORT cannot be regarded as part of mainstream radiation oncology practice. OHO-08(93-134) 11/16/02 11:19 AM Page 128 PRINCIPLES OF RADIATION ONCOLOGY 128 The role of unsealed radionuclides Nuclear medicine in oncology is used to localize the primary tumor, to determine tumor size , and to detect metastases. Radioactive tracers may also be used to monitor the response to therapy and detect recurrences. Radio-labeled tracers A radiopharmaceutical consists of a pharmaceutical attached to a radi onuclide that emits gamma rays. The kinetics or distribution of the radiopharmaceutical may vary from the normal because of a pathological process e.g. a malignant tumor. Biochemical changes in tumors cannot be detected by morphology. In this respect scintigra- phy, re \202ecting regional biochemistry, is unique compared with other imaging modalities. Anatomi cal and functional information are often complementary. Several radiopharmaceuticals are used for both diagnosis and treatment; well-known examples are iodine123 and 131I which local- ize avidly in functioning thyroid tissue. Other simple radio- pharmaceuticals are thallium-201 (201T1) and gallium-67 (67Ga). The ideal radionucl ide for scintigraphic imaging does not exist, but technetiuin-99m (99mTc) has many favorabl e characteris- tics. Scintigraphic methods Traditionally, gamma cameras are used for scintigraphic imaging. Plan ar images and whole-body images are acquired during a period of several minutes by a statio nary gamma camera. With single photon emission tomography (SPET), cross-sectional images ca n be obtained using computer techniques similar to those in CT. The main advan- tages of SP ET are greater sensitivity and accurate three-dimensional localization of lesions. Positron emission tomography (PET) PET employs radionuclides that emit positrons and provid es quanti- tative tomographic images. Glucose utilization is measured with 18F-labeled \202uorodeoxyglucose and cerebral blood \202ow has been studied with 15O-labeled water. P ET scanning may be useful to identi- fy primary tumors and metastases, and to study tumor v itality, cell turnover rates, and metabolic response to therapy. OHO-08(93-134) 11/16/02 11:19 AM Page 129 THE ROLE OF UNSEALED RADIONUCLIDES 129 Applications in diagnosis and follow-up Bone scintigraphy Bone scintigraphy is normally performed 2 \200\2234 hours after the injec tion of 550 MBq of 99mTc-labeled methylene disphosphonate (99mTc- medronate, MDP) or hydrox ymethylene disphosphonate (99mTc- oxidronate, HDP). Multiple planar images or a whole-body survey of the skeleton are obtained. Skeletal scintigraphy has high sensitivity for the det ection of primary and metastatic bone lesions. In the absence of reactive osteoblastic acti vity, the lesion itself may appear on the bone scan as a \200\230cold \200\231 defect. High sensitivity (80 \200\223100%) has been reported in patients with breast carcinoma, pro static carcinoma, bronchogenic carcinoma, gastric carcinoma, osteogenic sarcoma, cervix car cinoma, Ewing \200\231s sar- coma, head and neck carcinomas, neuroblastoma, and ovarian car ci- noma. Lower sensitivity, around 75%, has been found in melanoma, small-cell lung tumors , Hodgkin \200\231s disease, renal-cell carcinoma, rhabdomyosarcoma, multiple myeloma, and bladder carcinoma. Liver scintigraphy The conventional liver scintigram is performed after IV administra- tion of 50 \200\223100 MBq of 99mTc-labeled colloidal particles varying in size from 0.3 \200 \2231.0 mm. The radioactive agent accumulates in the cells of the reticulo-endothelial syst em by phagocytosis. The reticulo- endothelial system cells are homogeneously distributed in the liver and spleen, and to a lesser extent in bone, marrow, and lungs. The most common indication for liver scintigraphy used to be the detection of space-occupyi ng lesions. Nowadays, ultrasonography and CT are generally considered to be more effective modalities than scintigraphy. The solitary non-cystic lesion may pose a clinical problem. Non- invasive differentiation b etween haemangioma and metastasis or between hepatoma, hepatocellular carcinoma, follicular nodular hyperplasia, and metastasis is important for the clinical management of the patien t. Scintigraphic studies with 99mTc-labeled erythrocytes, iminodiacetic acids (IDA), or wit h 67Ga can be used as non-invasive methods for a more speci \201c characterization of the tumor in addi- tion to colloid scintigraphy. Thyroid scintigraphy 131I as radioiodine, 123I as sodium iodide, and 99mTc as sodium pertec hnetate are the radionuclides used for scintigraphic visualiza- tion of the thyroid gland. Although 131I is cheap and readily available, its major disadvantages are its long physical half-life and (cid:2)-emissions, resulting in a considerable radiation dose to the thyroid and the gastrointestinal tract. 123I has excellent physical properties for imaging OHO-08(93-134) 11/16/02 11:19 AM Page 130 PRINCIPLES OF RADIATION ONCOLOGY 130 and a physical half-life of 13 hours, but its use is limited due to its cost. 99mTc is trap ped in the thyroid, but is not organi \201ed and washes out from the gland over time. The indications for thyroid scintigraphy in oncology are: (cid:2) Evaluation of a solitary or dominant nodule. (cid:2) Follow-up after surgery for di fferentiated thyroid cancer. Thyroid scintigraphy with 99mTc and 123I can be used to assign prob- ability of malignant disease on the basis of the functional status of the nodule. Hy perfunctioning nodules are almost always benign, but malignancy can be found in 4% of the h ot nodules. The ma- jority of non-functioning nodules represent benign cysts and adeno- mas ; l6 \200\22320% of solitary non-functioning nodules contain thyroid cancer. Scintigraphy of medullary thyroid cancer is possible with 201T1, 99mTc-DMSA-V, 131I- or 123 I-labeled m-iodobenzylguanidine (MIBG), and 111In- or 123I-labeled somatostatin analogs. Th e sensitivity of these methods in detecting the primary tumor or its metastases is generall y low. For the new tracer, 111In-octreotide, the sensitivity for the detection of medullary thyroid cancer is 66%, compared with 35% for 131I-MIBG. The value of 131I-MIBG scintigraph y is to determine whether a patient may bene \201t from therapy with this radiopharmaceuti cal. Imaging of neuroendocrine tumors Phaeochromocytoma and other neural crest tumors can succes sfully be detected with 123I or 131I-MIBG. The molecular structure of MIBG has some similar ity to noradrenaline. The scintigraphic study is done at intervals of 24, 48, and occasiona lly 72 hours after intravenous injections of 370 MBq of 123I-MIBG or 37 MBq of 131I-MIBG. W ith a sensitivity of 92% and speci \201city of nearly 100% in neuroblastoma, MIBG scintigr aphy is a useful technique for the detection, staging, and follow-up of this disease. Addit ionally, it serves as an indicator for potential therapy using 131I-MIBG. Somatostatin is a polypeptide hormone with a short biological half- life. Receptors for thi s hormone are present on many cells of neuroen- docrine origin. A long-acting analog, octre otide, was synthesized for therapy. 111In-octreotide was developed for imaging, performed 2 4 and 48 hours after injection of 111 MBq. The potential clinical value of somatostatin rec eptor scintigraphy is in the detection of occult primary tumors, screening of metastases fo r staging, follow-up of therapy, and selection of patients who might bene \201t from palli ative treatment with unlabelled octreotide. The cumulative sensitivity of 111In-octreotide scintigraphy for the detection of endocrine pancreatic tumors is around 75%, and for carcinoid tumors, around 85%. These tumors are oft en small and not easily recognized on CT or MRI. OHO-08(93-134) 11/16/02 11:19 AM Page 131 THE ROLE OF UNSEALED RADIONUCLIDES 131 Monoclonal antibodies The development of monoclonal antibodies that recognize human tumor-a ssociated antigens has implications for nuclear medicine. Antibodies and fragments (Fab) ca n be labeled with 131I, 123I, 111In, and 99mTc for scintigraphy. In colorectal cancer, scin tigraphy with monoclonal antibodies is potentially valuable in detecting occult disease, lo calizing recurrent disease when serum markers are elevated, and differentiating between via ble tumor and post-surgical \201brosis. The potential roles for radio-immunoscintigraphy in ovarian cancer are in the evaluation of chemotherapy, of pelvic masses after therapy for the presence of viable tumor, and of raised serum markers. Imaging of tumor tissue Nuclear medicine techniques have a limited role in the characteriza - tion of tumors. Modalities such as plain X-ray radiography, ultra- sound, CT, and MRI off er superior anatomical detail. The value of tumor-seeking radiopharmaceuticals lies in the capability of distinguishing viable tumor tissue from a speci \201c residual mass after th erapy and in convenient screening for additional lesions using whole-body imaging. Gallium scintigraphy is usually done 48 \200\22372 hours after the IV administration of 180 MBq 67Ga-citrate. It is of limited value in the initial staging of Hodgkin \200\231s and n on-Hodgkin \200\231s lymphoma, because of the dif \201culty of detecting lesions in the ab domen. In patients with Hodgkin \200\231s disease and other lymphomas, 67Ga scintigraphy, i ncluding SPET is an indicator of residual viable tumor tissue with a better pre- dictive va lue than CT. Thallium-201 is widely used for myocardial perfusion imaging. Over the past few years there has been growing interest in the use of 201T1 in oncology. It may be useful in the differe ntiation between low- and high-grade glial tumors and between tumor recurrence and scar tis sue. Thallium-201 scintigraphy can assess residual tumor via- bility after chemotherapy in bone and soft-tissue sarcomas. Assessment of organ and tissue damage related to cancer therapy