Purpose: Total body irradiation (TBI) has been used as part of the conditioning regimen before bone marrow transplantation or stem cell re-infusion for more than 30 years. A wide variety of regimens have been used, and no single one has emerged as the best. Experimental evidence suggests a diversity of radiosensitivities of leukaemia cells in culture, which may correlate with a significant variation of leukaemic cell radiosensitivities between patients. The purpose of this project was to compute leukaemic cell killing by different schedules and determine whether a ‘best treatment’ could be devised for individual patients. Methods: We have developed a mathematical model for leukaemic cell killing by alternative TBI schedules, applied to a patient population with diverse leukaemic radiosensitivities. We considered 13 schedules in clinical use, and 14 theoretical schedules calculated (by the linear–quadratic model) to be iso-effective for risk of radiation pneumonitis. When each schedule of treatment is applied to the patient population, a distribution of leukaemic cell kills (log cell kill values) can be obtained for that schedule. The leukaemic kill distribution was also computed for optimized individual scheduling, each individual being treated by the schedule that was most effective for that patient. Using available data on the clinically observed dose response relationship for acute myeloid leukaemia, the model was extended to provide leukaemia cure probabilities for each of the schedules and for the individualized strategy. Results: The computer simulations show that each schedule, applied to the treatment of a radiobiologically diverse patient population, results in a broad distribution of leukaemic log kill values, with a mean of 3–5 for most schedules (i.e. 10−3–10−5 surviving fraction of leukaemic cells), and a broad variation (1–10 log kill) amongst patients. The distributions generated by the various schedules were found to be overlapping, implying that many of the schedules would be difficult to distinguish reliably in clinical trials. Individualized optimum treatment is possible if radiobiological parameters are known for each patient and would improve the leukaemic log kill distribution by about 1 log on average, corresponding to an increase of leukaemia cure probability of several percent overall. For some individual patients, however, optimal scheduling could make a large difference to treatment outcome. Conclusions: The use of many different clinical treatment schedules may be continuing because outcomes are similar when these diverse schedules are applied to unselected patient populations. The measurement of individual leukaemic cell radiosensitivity would allow individualized scheduling, which could result in modest increases in overall curability, but substantial improvements in survival or duration of remission for individual patients.

Meta-iodobenzylguanidine conjugated to 131 I-iodine is an effective agent for the targeted radiotherapy of tumors of neural crest origin which express the noradrenaline transporter (NAT). The therapeutic application of 131 I MIBG is presently limited to the treatment of phaeochromocytoma, neuroblastoma, carcinoid and medullary thyroid carcinoma. To determine the feasibility of MIBG targeting for a wider range of tumor types, we employed plasmid-mediated transfer of the NAT gene into a human glioblastoma cell line (UVW) which does not express the NAT gene. This resulted in a 15-fold increase in uptake of MIBG by the host cells. A dose-dependent toxicity of 131 I MIBG to the transfectants was demonstrated using three methods: (1) survival of clonogens derived from monolayer culture; (2) survival of clonogens derived from disaggregated multicellular spheroids; and (3) spheroid growth delay. 131 I MIBG was twice as toxic to cells in spheroids compared with those in monolayers, consistent with a greater effect of radiation cross-fire (radiological bystander effect) from 131 I β-radiation in the three-dimensional tumor spheroids. The highest concentration of 131 I MIBG tested (1 MBq/ml) was nontoxic to UVW control cells or spheroids transfected with the NAT gene in reverse orientation. These findings are encouraging for the development of NAT gene transfer-mediated 131 I MIBG therapy.

Jean-François Chatal and Cornelis Hoefnagel (Sept 11, p 931)1Chatal J-F Hoefnagel CA Radionuclide therapy..Lancet. 1999; 354: 931-935Summary Full Text Full Text PDF PubMed Scopus (86) Google Scholar have provided a valuable review of current practice and future prospects in radionuclide therapy. However, they omit from their list of new developments innovative approaches to radionuclide therapy that make use of the technology of gene therapy. At present, treatment of malignant disease with radionuclides is effective in a small number of disorders in which targeting agents, or the isotopes themselves, are selectively taken up by tumour cells in sufficient quantity; but even in these situations, radionuclide therapy alone is seldom curative. Laboratory studies have shown the feasibility of engineering tumour cells, by transfection of appropriate genes, to increase cellular uptake of radionuclides. Raben and colleagues2Raben D Buschbaum DJ Khazaeli MB et al.Enhancement of radiolabelled binding and tumour localization through adenoviral transduction of the human carcinoembryonic antigen gene..Gene Ther. 1996; 3: 567-580PubMed Google Scholar have reported greatly enhanced targeting by antibodies against the carcinoembryonic antigen (CEA) after transfection of the human CEA gene, and Buschbaum and colleagues3Buschbaum DJ Raben D Stackhouse MA et al.Approaches to enhance cancer radiotherapy employing gene transfer methods..Gene Ther. 1997; 3: 1042-1068Google Scholar have reviewed a range of related possibilities. Mandel and colleagues4Mandell RB Mandell LZ Link Jr., CJ Radioisotope concentrator gene therapy using the sodium/iodide symporter gene..Cancer Res. 1999; 59: 661-668PubMed Google Scholar have shown that non-thyroid tumour cells can be induced to take up radioactive iodine after transfection of the sodium iodide symporter gene. Our research group has focused on genetic enhancement of uptake of the radiopharmaceutical metaiodobenzylguanidine (MIBG), which featured in the review by Chatel and Hoefnagel. We genetically modified the uptake of MIBG in cultured human glioma cells, for which MIBG uptake is otherwise very poor. Active cellular uptake of MIBG depends on the norepinephrine transporter molecule, the gene for which is known and sequenced. By plasmid-mediated transfection of the human norepinephrine transporter gene, we obtained 15-fold enhancement of 131I-MIBG uptake in malignant glioma cells and multicellular tumour spheroids, resulting in a pronounced steepening of the dose-response curve for cell death (figure).5Boyd M Cunningham SH Brown MM Mairs RJ Wheldon TE Noradrenaline transporter gene transfer for radiation kill by 131I-meta-iodobenzylguanidine..Gene Ther. 1999; 6: 1147-1152Crossref PubMed Scopus (69) Google Scholar We expect that uptake of the analogous α-emitting radiopharmaceutical (astatine-211) meta-astatobenzylguanidine (MABG) will be similarly enhanced by transfection of the noradrenaline transporter gene, and could lead to very potent cell killing. As with sodium iodide, MIBG and MABG are small molecules for which tumour penetration ought not to be an obstacle. An additional advantage is the built-in bystander effect in the form of radiation crossfire between transfected cells and cells that have escaped transfection. Clinical application now requires both the transfection of uptake-enhancing genes under the control of tissue-specific or cycle-specific promoters, and the development of vectors suitable for in-vivo transfection of each tumour type. These studies raise the prospect that gene-therapy techniques could be used to enable the treatment of a wide-range of tumours with radiopharmaceuticals of established clinical acceptability.

Childhood leukaemia presenting at a young age has been suspected of resulting from a leukaemogenic mutation in parental germ cells, either spontaneously or due to the exposure of a parent to leukaemogenic environmental hazards, particularly ionizing radiation. Mathematical modelling of leukaemogenesis suggests that any such patient would be especially prone to multiple independent leukaemogenic events leading to multiclonality in terms of cell of origin (analogous to bilaterality in familial retinoblastoma). To test this hypothesis we have carried out a search for multiclonal leukaemogenesis in infant and childhood acute lymphoblastic leukaemia (ALL). We used a polymerase chain reaction-based analysis of the X-linked monoamine oxidase A (MAOA) gene locus to study the clonality of marrow samples obtained from female paediatric ALL patients at the time of disease presentation. We obtained presentation samples from 102 patients of whom 72 were found to be informative at the MAOA locus. These included 20 infant leukaemias (< 1 year at diagnosis). Sixty-six samples were found to be unequivocally monoclonal while the remaining six could not, with certainty, be assigned a clonal origin. We also obtained bone marrow aspirates at first relapse as well as at presentation from eight patients. In each case the same pattern of X-linked allelic inactivation was observed at both time points of the course of the disease. No evidence was found for leukaemic multiclonality in any age group at presentation or for leukaemic 'clone-switching' in relapse. These findings suggest that both infant and childhood ALL is of single-cell origin and implies that leukaemic predisposition resulting from germ cell mutation is unlikely to have a major role in their pathogenesis.

Radioiodinated iododeoxyuridine (IUdR) is a novel, cycle-specific agent that has potential for the treatment of residual malignant glioma after surgery. As only cells in S-phase incorporate IUdR into DNA, a major limitation to this therapy is likely to be proliferative heterogeneity of the tumour cell population. Using a clonogenic end point, we have compared the toxicities of three radioiodoanalogues of IUdR--[123I]IUdR, [125I]IUdR and [131I]IUdR--to the human glioma cell line UVW, cultured as monolayers in the exponential and the plateau phase of growth and as multicellular spheroids. Monolayers treated in the exponential growth phase were most efficiently sterilized by [125I]IUdR (concentration resulting in 37% survival (C37) = 2.36 kBq ml(-1)), while [123I]IUdR and [131I]IUdR were less effective eradicators of clonogens (C37 = 9.75 and 18.9 kBq ml(-1) respectively). Plateau-phase monolayer cultures were marginally more susceptible to treatment with [123I]IUdR and [125I]IUdR (40% clonogenic survival) than [131I]IUdR (60% clonogenic survival). In cells derived from glioma spheroids, both [125I]IUdR and [123I]IUdR were again more effective than [131I]IUdR at concentrations up to and including 20 kBq ml(-1). However, the survival curve for [131I]IUdR crossed the curves for the other agents, resulting in lower survival for [131I]IUdR than [123I]IUdR and [125I]IUdR at concentrations of 40 kBq ml(-1) and higher, the clonogenic survival values at 100 kBq ml(-1) were 13%, 45% and 28% respectively. It was concluded that IUdR incorporating the Auger electron emitters 123I and 125I killed only cells that were in S-phase during the period of incubation with the radiopharmaceutical, whereas the superior toxicity to clonogenic cells in spheroids of [131I]IUdR at higher concentration was due to cross-fire beta-irradiation. These findings suggest that [131I]IUdR or combinations of [131I]IUdR and [123I]IUdR or [125I]IUdR may be more effective than Auger electron emitters alone for the treatment of residual glioma, if proliferative heterogeneity exists.

Radiation myelopathy (RM) is an uncommon but serious late effect of thoracic radiotherapy (RT), which oncologists try to avoid by careful planning and dose selection. Five patients with RM are described from among 1048 with inoperable non-small cell lung cancer treated with palliative RT in three randomized trials conducted by the Medical Research Council Lung Cancer Working Party. Seven RT regimens were used in these trials: 10 Gy in a single fraction on one day (10/1/1) (114 patients), 17/2/8 (524 patients), 27/6/11 (47 patients), 30/6/11 (36 patients), 30/10/12 (88 patients), 36/12/16 (86 patients) and 39/13/17 (153 patients). Of the five instances of RM, three occurred in the 524 patients treated with 17 Gy in two fractions, and two in the 153 treated with 39 Gy in 13 fractions. The estimated cumulative risks of RM by 2 years were 2.2% for the 17 Gy group, 2.5% for the 39 Gy group, and 0% for the remainder, but the annual risks had wide 95% confidence intervals, indicating that the distribution of episodes among the seven regimens could have been random. Nevertheless, calculation of cord doses in terms of the total doses that would have an equivalent biological effect if given in 2 Gy fractions (LQED2 values) from our data for different values of the ratio of the linear quadratic parameters of the cell survival curve (alpha/beta), suggest that the best estimate of alpha/beta is less than 3 Gy, and possibly close to 2 Gy. This emphasizes the sensitivity of human spinal cord to changes in fraction size. We recommend that, when the computed LQED2 for a schedule of treatment that includes the thoracic spinal cord (assuming alpha/beta = 2 for cord) exceeds 48 Gy, oncologists should consider reducing the dose to the cord.

UNLABELLED:Targeted radionuclide therapy is a new form of radiotherapy that differs in some important respects from external beam irradiation. One of the most important differences is due to the finite range of ionizing beta particles emitted as a result of radionuclide disintegration. The effects of particle range have important implications for the curability of tumors.METHODS:We used a mathematical model to examine tumor curability and its relationship to tumor size for 22 beta-emitting radionuclides that may have therapeutic potential. The model assumed a uniform distribution of radionuclide throughout.RESULTS:For targeted radionuclide therapy, the relationship between tumor curability and tumor size is different from that for conventional external beam radiotherapy. With targeted radionuclides, there is an optimal tumor size for cure. Tumors smaller than the optimal size are less vulnerable to irradiation from radionuclides because a substantial proportion of the disintegration energy escapes and is deposited outside the tumor volume.CONCLUSION:We found an optimal tumor size for radiocurability by each of the 22 radionuclides considered. Optimal cure diameters range from less than 1 mm for short-range emitters such as 199Au and 33P to several centimeters for long-range emitters such as 90Y and 188Re. The energy emitted per disintegration may be used to predict optimal cure size for uniform distributions of radionuclide.

Two patient groups have been identified from a data base of 965 patients with carcinoma of the larynx. One group of 393 patients had squamous cell carcinoma of the larynx arising in the glottis—no nodal involvement; the other group of 163 patients had tumours arising in the supraglottic region. The second group was a more heterogenous group some patients had nodal involvement at the time of presentation. All patients were treated on a linear accelerator. Patients were treated using a variety of dose-fraction-time schedules. Mathematical modelling using linear quadratic equation was carried out. This shows that a break in treatment if a week reduces the local tumour rate for glottic tumours by 12% or about 25 per day. Local tumour control rates increased as the effective dose was increased. The data for tumours arising in the supraglottic region is not so convincing though it does show that prolongation of treatment time reduces local tumour control rates. The effects of longer tittles can be nullified by increasing the effective dose. The supraglottic subject, however, is very heterogenous, and the groups within the subset are small. Two patient groups have been identified from a data base of 965 patients with carcinoma of the larynx. One group of 393 patients had squamous cell carcinoma of the larynx arising in the glottis—no nodal involvement; the other group of 163 patients had tumours arising in the supraglottic region. The second group was a more heterogenous group some patients had nodal involvement at the time of presentation. All patients were treated on a linear accelerator. Patients were treated using a variety of dose-fraction-time schedules. Mathematical modelling using linear quadratic equation was carried out. This shows that a break in treatment if a week reduces the local tumour rate for glottic tumours by 12% or about 25 per day. Local tumour control rates increased as the effective dose was increased. The data for tumours arising in the supraglottic region is not so convincing though it does show that prolongation of treatment time reduces local tumour control rates. The effects of longer tittles can be nullified by increasing the effective dose. The supraglottic subject, however, is very heterogenous, and the groups within the subset are small.

International Journal of CancerVolume 63, Issue 6 p. 881-882 Letter To The Editor Clonal analysis of phenacetin-implicated urothelial carcinoma Frank Rinaldi, Frank Rinaldi Department of Radiation Oncology, Beatson CRC Laboratories, Glasgow G61BDSearch for more papers by this authorRobert Mairs, Robert Mairs Department of Radiation Oncology, Beatson CRC Laboratories, Glasgow G61BDSearch for more papers by this authorThomas Wheldon, Thomas Wheldon Department of Radiation Oncology, Beatson CRC Laboratories, Glasgow G61BDSearch for more papers by this authorGeorge Smith, George Smith Department of Pathology, Slobhill General Hospital, Glasgow G21 3UWSearch for more papers by this authorAntony Yates, Antony Yates Department of Pathology, Slobhill General Hospital, Glasgow G21 3UWSearch for more papers by this authorPaul Symonds, Paul Symonds Beatson Oncology Centre, Western Infirmary, Glasgow G11 6NT, UKSearch for more papers by this author Frank Rinaldi, Frank Rinaldi Department of Radiation Oncology, Beatson CRC Laboratories, Glasgow G61BDSearch for more papers by this authorRobert Mairs, Robert Mairs Department of Radiation Oncology, Beatson CRC Laboratories, Glasgow G61BDSearch for more papers by this authorThomas Wheldon, Thomas Wheldon Department of Radiation Oncology, Beatson CRC Laboratories, Glasgow G61BDSearch for more papers by this authorGeorge Smith, George Smith Department of Pathology, Slobhill General Hospital, Glasgow G21 3UWSearch for more papers by this authorAntony Yates, Antony Yates Department of Pathology, Slobhill General Hospital, Glasgow G21 3UWSearch for more papers by this authorPaul Symonds, Paul Symonds Beatson Oncology Centre, Western Infirmary, Glasgow G11 6NT, UKSearch for more papers by this author First published: 11 December 1995 https://doi.org/10.1002/ijc.2910630621Citations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume63, Issue611 December 1995Pages 881-882 RelatedInformation

New therapeutic approaches are needed for advanced neuroblastoma as few patients are currently curable. We describe an innovative strategy combining [131I]meta-iodobenzylguanidine ([131I]mIBG) therapy with high dose chemotherapy and total body irradiation. The aim of combining these treatments is to overcome the specific limitations of each when used alone to maximise killing of neuroblastoma cells. Five children received combined therapy with [131I]mIBG followed by high dose melphalan and fractionated total body irradiation. Autologous bone marrow transplantation was undertaken in 3 patients and allogeneic in 2 patients. One patient received additional localised radiotherapy to residual bulk disease. One patient is alive without relapse 32 months after treatment. 4 patients relapsed after remissions of 9, 10, 14 and 21 months. These results indicate that this combined modality approach is feasible and safe, but further evaluation is necessary to establish whether it has advantages over conventional megatherapy using melphalan alone.

PURPOSE:Radiobiological modeling was used to explore optimum combination strategies for treatment of disseminated malignancies of differing radiosensitivity and differing patterns of metastatic spread. The purpose of the study was to derive robust conclusions about the design of combination strategies that incorporate a targeting component. Preliminary clinical experience of a neuroblastoma treatment strategy, which is based upon general principles obtained from modelling, is briefly described. METHODS AND MATERIALS:The radiobiological analysis was based on an extended (dose-rate dependent) formulation of the linear quadratic model. Radiation dose and dose rate for targeted irradiation of tumors of differing size was in part based on microdosimetric considerations. The analysis was applied to several tumor types with postulated differences in the pattern of metastatic spread, represented by the steepness of the slope of the relationship between numbers of tumors present and tumor diameter. The clinical pilot study entailed the treatment of five children with advanced neuroblastoma using a combination of 131I metaiodobenzylguanidine (mIBG) and total body irradiation followed by bone marrow rescue. RESULTS:The theoretical analysis shows that both intrinsic radiosensitivity and pattern of metastatic spread can influence the composition of the ideal optimum combination strategy. High intrinsic radiosensitivity generally favors a high proportion of targeting component in the combination treatment, while a strong tendency to micrometastatic spread favors a major contribution by total body irradiation. The neuroblastoma patients were treated using a combination regimen with an initially low targeting component (2 Gy whole body dose from targeting component plus 12 Gy from total body irradiation). The treatment was tolerable and resulted in remissions in excess of 9 months in each of these advanced neuroblastoma patients. CONCLUSIONS:Radiobiological analysis, which incorporates simple models of metastatic spread, emphasizes the importance of the total body irradiation component in a targeting/total body irradiation combination strategy. However, the analysis favors a larger targeting component than is used in clinical practice at present. A cautious escalation of the 131I mIBG component in the combination treatment of advanced neuroblastoma appears justified.

Biologically targeted radiotherapy entails the preferential delivery of radiation to solid tumours or individual tumour cells by means of tumour-seeking delivery vehicles to which radionuclides can be conjugated. Variant forms of this are the binary strategies (neutron capture therapy, photodynamic therapy) in which cell killing by the targeting moiety is dependent on activation by an external radiation beam. Monoclonal antibodies have attracted attention for some years as potentially selective targeting agents, but advances in tumour and molecular biology are now providing a much wider choice of molecular species. General radiobiological principles may be derived which are applicable to most forms of targeted radiotherapy. These principles provide guidelines for the appropriate choice of radionuclide in specific treatment situations and its optimal combination with other treatment modalities. In the future, the availability of gene targeting agents will focus attention on the use of Auger electron emitters whose high potency and short range selectivity makes them attractive choices for specific killing of cancer cells whose genetic peculiarities are known.

Laryngeal tumours, especially T1N0M0 and T2N0M0 lesions, are readily controlled by radiotherapy. Studies have shown that control varies with the dose of radiotherapy delivered to the tumour. Other factors, including the dose per fraction and the time over which the treatment schedule is delivered are also important. The varying biological effectiveness of a number of different dose fraction time schedules used in the management of laryngeal tumours of different stages are considered, the end points being tumour control and associated morbidity. Special attention has been given to the length of time over which the schedule is delivered. Of the schedules examined the results would suggest that a dose of 60 Gy given in 25 fractions over a period of 35 days is the best of the six schedules studied for T1, T2, T3 and T4 lesions with minimal associated morbidity. It is possible, however, that the poor results shown on the Kaplan-Meier curves for patients treated with the schedule of 60 Gy in 30 fractions over a period of 42 days could be due to geographical misses of the tumours as 56% were treated without a beam directed shell. The poor result obtained when patients were treated with the schedule of 60 Gy given in 30 fractions over 49+ days may be due to tumour repopulation occurring during the rest period though the possibility of geographical misses may contribute to the poor tumour control results. Mathematical modelling using linear quadratic analysis suggests that the shorter the period of time over which the treatment is given the better chance of achieving tumour control irrespective of the stage of the disease. These models were developed for patients treated with a beam directed shell thus excluding those patients who are most likely to be at risk from a geographic miss of the tumour. Linear quadratic analysis of the treatment data suggests that the ratio alpha/beta for tumour cells is estimated in the region of 13 Gy. For T1 lesions the tumour doubling time is in the order of 6 days, with longer doubling times for the more advanced stages. The analysis provides some support for investigative use of accelerated treatment schedules. This analysis also shows the importance of using beam directed shells when treating small fields especially in the head and neck region.

131I is the radionuclide most commonly used in biologically targeted radiotherapy at the present time. Microdosimetric analysis has shown that microtumors whose diameters are less than the β-particle maximum range absorb radiation energy inefficiently from targeted radionuclides. Micrometastases of diameters <1 mm are likely to be spared if targeted131I is used as a single modality. Because of this, combined modality therapy incorporating targeted131I, external beam total-body irradiation (TBI), and bone marrow rescue has been proposed. In this study, the minimum necessary TBI component is shown to depend on the radiosensitivity of the tumor cells. The analysis shows that the TBI component, to achieve radiocurability, increases directly with tumor radioresistance. For the most radiosensitive tumors, a whole-body TBI treatment dose 2×2 Gy is calculated to be obligatory, whereas practical tumors, the analysis implies that a TBI treatment delivery of 5×2 Gy is obligatory. In all situation, external beam TBI appears to be an essential factor in providing reasonable probability of cure of disseminated malignant disease. Reasonable prospects of tumor cure by combination strategies incorporating131I exist for the more radiosensitive tumor types (e.g., neuroblastoma, lymphoma, leukemia, myeloma, seminoma), but more resistant tumors are unlikely to be curable at present. Superior targeting agents, and the possible use of panels of different radionuclides, may be necessary to achieve high cure probabilities for less radiosensitive tumor types.

Targeted radiotherapy consists of biologically selective irradiation of malignant cells by means of radionuclides attached to tumour-seeking molecules. A variety of clinical strategies for targeted radiotherapy may be used, for which different normal tissues will be critical. A large number of radionuclides exist, emitting nuclear particles with a range of path lengths from nanometres to millimetres. An important feature of normal-tissue radiobiology is the dose-rate effect, which is especially marked for late-responding tissues. Radiobiological calculations imply that tolerance dose for targeted radiotherapy using low-LET emitters will depend strongly on the effective half-life of the radionuclide, which will be affected by pharmacokinetics and may vary between patients. Some strategies designed to improve the therapeutic radio (e.g. accelerated clearance of radionuclide) may have modulating effects on the tolerance dose. Tumour response will be governed by the 'four Rs' (repair, repopulation, reoxygenation, redistribution) as well as by mechanisms peculiar to targeted radiotherapy. Analysis based on the extended linear quadratic model predicts that dose-rate effects will be of major importance for only a minority of tumours. Most of the radiation dose to tumour will usually be delivered over a time-scale of a few days. This might give insufficient time for tumour reoxygenation, making the use of hypoxic sensitizers appropriate. A special feature of targeted radiotherapy is the complex relationship between tumour curability and tumour size for different radionuclides. For long-range beta-emitters, microscopic tumours may be operationally resistant because of inefficient absorption of radionuclide disintegration energy in small volumes. Short-range emitters will be more efficient in sterilization of micrometastases but sterilization of larger tumours may require an unattainable degree of homogeneity of radionuclide distribution. Optimal use of targeted radiotherapy may require it to be combined with external-beam irradiation or chemotherapy. Experimental studies will be necessary to investigate those features of targeted radiotherapy which differ from external-beam irradiation. Future directions may include targeted radiotherapy of minimal numbers of tumour cells detected by use of molecular probes. Such applications call for use of short-range alpha-emitters and Auger emitters whose radiobiology will become increasingly important.

Isolated limb perfusion (ILP) has now been practised for years [1], but many fundamental issues remain to resolved. This paper summarises three studies we have performed.