A generalised method for calculating repopulation-corrected tumour EQD2 values in a wide range of clinical situations, including interrupted treatments.

Any radiotherapy schedule can be characterised by its 2 Gy per fraction equivalent dose (EQD2). EQD2s are easily calculated for late-responding normal tissues but for tumours significant errors may arise if no allowance is made for any repopulation which occurs in the reference and/or the derived EQD2 schedule. This article presents a systematic approach to calculating tumour EQD2 values utilising the concept of biologically effective dose (BED) with inclusion of repopulation effects. A factor (f) is introduced which allows the inter-dependence between EQD2 and its delivery time (and, hence, the amount of repopulation involved) to be embedded within the formulation without any additional assumptions. There exists a transitional BED below which simple methods of calculating tumour EQD2 remain valid. In cases where simpler approaches are inadequate, the correct EQD2 may be determined from the reference schedule BED (BEDref) by the relationship: EQD2 = A × BEDref - B, where A and B are constants which involve the same radiobiological parameters as are conventionally used in deriving tumour BED values. Some Worked Examples illustrate application of the method to fractionated radiotherapy and indicate that there can be substantial differences with results obtained from using over-simplified approaches. Since reference BEDs are calculable for other types of radiotherapy (brachytherapy, permanent implants, high-LET applications, etc) the methodology allows estimation of tumour EQD2 values in a wide range of clinical circumstances, including cases which involve interrupted treatments.

Ultrashort courses of adjuvant breast radiotherapy: wave of the future or a fool's errand?

In accelerated partial breast irradiation (APBI), the most commonly used fractionation schemes include 340 or 385 centigrays delivered in a twice daily administration. A further progression of the APBI literature has been the recent interest in extremely short courses of adjuvant radiotherapy, usually delivered by intraoperative radiotherapy techniques. This newer area of single-fraction radiotherapy approaches remains highly contentious. In particular, the recently reported TARGIT trial has been the subject of both praise and scorn, and a critical examination of the trial data and the underlying hypotheses is warranted. Short-term outcomes of the related Italian ELIOT approach have also been reported. Although the assumptions of linear quadratic formalism are likely to hold true in the range of 2 to 8 grays, equating different schedules beyond this range is problematic. A major problem of current single-fraction approaches is that the treatment doses are chosen empirically, or are based on tolerability, or on the physical dose delivery characteristics of the chosen technology rather than radiobiological rationale. This review article summarizes the current data on ultrashort courses of adjuvant breast radiotherapy and highlights both the promise and the potential pitfalls of the abbreviated treatment.

Is there a role for arcing techniques in proton therapy?

Proton arc therapy (PAT) has been proposed as a possible evolution for proton therapy. This commentary uses dosimetric and cancer risk evaluations from earlier studies to compare PAT with intensity modulated proton therapy. It is concluded that, although PAT may not produce better physical dose distributions than intensity modulated proton therapy, the radiobiological considerations associated with particular PAT techniques could offer the possibility of an increased therapeutic index.

Radiobiological effectiveness difference of proton arc beams versus conventional proton and photon beams.

This paper aims to demonstrate the difference in biological effectiveness of proton monoenergetic arc therapy (PMAT) compared to intensity modulated proton therapy (IMPT) and conventional 6 MV photon therapy, and to quantify this difference when exposing cells of different radiosensitivity to the same experimental conditions for each modality. V79, H1299 and H460 cells were cultured in petri dishes placed in the central axis of a cylindrical and homogeneous solid water phantom of 20 cm in diameter. For the PMAT plan, cells were exposed to 13 mono-energetic proton beams separated every 15° over a 180° arc, designed to deliver a uniform dose of higher LET to the petri dishes. For the IMPT plans, 3 fields were used, where each field was modulated to cover the full target. Cells were also exposed to 6 MV photon beams in petri dishes to characterize their radiosensitivity. The relative biological effectiveness of the PMAT plans compared with those of IMPT was measured using clonogenic assays. Similarly, in order to study the quantity and quality of the DNA damage induced by the PMAT plans compared to that of IMPT and photons, γ-H2AX assays were conducted to study the relative amount of DNA damage induced by each modality, and their repair rate over time. The clonogenic assay revealed similar survival levels to the same dose delivered with IMPT or x-rays. However, a systematic average of up to a 43% increase in effectiveness in PMAT plans was observed when compared with IMPT. In addition, the repair kinetic assays proved that PMAT induces larger and more complex DNA damage (evidenced by a slower repair rate and a larger proportion of unrepaired DNA damage) than IMPT. The repair kinetics of IMPT and 6 MV photon therapy were similar. Mono-energetic arc beams offer the possibility of taking advantage of the enhanced LET of proton beams to increase TCP. This study presents initial results based on exposing cells with different radiosensitivity to other modalities under the same experimental conditions, but more extensive clonogenic and in-vivo studies will be required to confirm the validity of these results.

Radiobiologically derived biphasic fractionation schemes to overcome the effects of tumour hypoxia.

OBJECTIVE: As a fractionated course of radiotherapy proceeds tumour shrinkage leads to resolution of hypoxia and the initiation of accelerated proliferation of radioresistant cancer cells with better repair capacity. We hypothesise that, in tumours with significant hypoxia, improved tumour control could be achieved with biphasic fractionation schedules that either use acceleration after 3-4 weeks of conventional radiotherapy or deliver a higher proportional dose towards the end of a course of treatment. We conducted a modelling study based on the concept of biological effective dose (BED) comparing such novel regimens with conventional fractionation. METHODS: The comparator conventional fractionation schedule 70 Gy in 35 fractions delivered over 7 weeks was tested against the following novel regimens, both of which were designed to be isoeffective in terms of late normal tissue toxicity.40 Gy in 20 fractions over 4 weeks followed by 22.32 Gy in 6 consecutive daily fractions (delayed acceleration)30.4 Gy in 27 fractions over 4 weeks followed by 40 Gy in 15 fractions over 3 weeks (temporal dose redistribution)The delayed acceleration regimen is exactly identical to that of the comparator schedule over the first 28 days and the BED gains with the novel schedule are achieved during the second phase of treatment when reoxygenation is complete. For the temporal redistribution regimen, it was assumed that the reoxygenation fraction progressively increases during the first 4 weeks of treatment and an iterative approach was used to calculate the final tumour BED for varying hypoxic fractions. RESULTS: Novel fractionation with delayed acceleration or temporal fractionation results in tumour BED gains equivalent to 3.5-8 Gy when delivered in 2 Gy fractions. CONCLUSION: In hypoxic tumours, novel fractionation strategies result in significantly higher tumour BED in comparison to conventional fractionation. ADVANCES IN KNOWLEDGE: We demonstrate that novel biphasic fractionation regimens could overcome the effects of tumour hypoxia resulting in biological dose escalation.

Integrin αvß6 Positron Emission Tomography Imaging in Lung Cancer Patients Treated With Pulmonary Radiation Therapy.

PURPOSE: Post radiation therapy (RT) lung fibrosis is a major barrier to improved cure rate in lung cancer. Integrin αvß6 plays a key role in fibrogenesis by activating transforming growth factor-ß. Positron emission tomography (PET) studies with a fluorine-18 radiolabelled αvß6 radioligand, [18F]-FBA-A20FMDV2, were performed to assess uptake, and the relationship to RT dose parameters was explored. METHODS AND MATERIALS: Recently treated non-small cell lung cancer patients (<6 months after RT) had [18F]-FBA-A20FMDV2-PET scans, coregistered with the RT planning computed tomography and segmented to RT doses of >40 Gy (excluding tumor), 25 to 40 Gy, 15 to 25 Gy, 8 to 15 Gy, and <8 Gy. PET uptake (standardized uptake value; SUV) corrected for tissue density between 10 and 60 minutes (SUV10-60) was calculated and compared with RT dose, dose per fraction, and biological effective dose (BED). PET uptake was also evaluated in healthy volunteers. RESULTS: Six non-small cell lung cancer (3 male; 3 female) subjects scanned between 6 and 22 weeks after RT and 6 healthy volunteers (3 males; 3 females) were evaluated. Higher mean PET uptake (SUV10-60) was observed in the irradiated lung compared with the healthy lung (2.97 vs 1.99; P < .05). A significant and positive pharmacodynamic relationship was observed between radioligand uptake (SUV10-60) and dose per RT fraction (r2 = 0.63; P < .001) and with BED for fibrosis (r2 = 0.38; P < .001 for α/ß 3 Gy and r2 = 0.33; P < 0.001 for α/ß 5 Gy). CONCLUSIONS: Higher uptake in the irradiated lung and a pharmacodynamic relationship between αvß6 radioligand uptake versus RT dose per fraction and BED for lung fibrosis is consistent with RT induced activation of αvß6 integrin and supports a role for αvß6 in the induction of lung fibrosis after pulmonary RT. αvß6-PET imaging may potentially aid in the assessment and management of radiation-induced pulmonary fibrosis.

Radiation repair models for clinical application.

A number of newly emerging clinical techniques involve non-conventional patterns of radiation delivery which require an appreciation of the role played by radiation repair phenomena. This review outlines the main models of radiation repair, focussing on those which are of greatest clinical usefulness and which may be incorporated into biologically effective dose assessments. The need to account for the apparent "slowing-down" of repair rates observed in some normal tissues is also examined, along with a comparison of the relative merits of the formulations which can be used to account for such phenomena. Jack Fowler brought valuable insight to the understanding of radiation repair processes and this article includes reference to his important contributions in this area.

Three-Fraction Accelerated Partial Breast Irradiation (APBI) Delivered With Brachytherapy Applicators Is Feasible and Safe: First Results From the TRIUMPH-T Trial.

PURPOSE: Shorter courses of accelerated partial-breast irradiation delivered as single-fraction intraoperative therapy are now offered as an alternative to 4 to 6 weeks of whole-breast irradiation after lumpectomy. However, this approach has potential shortcomings in patient selection and target volume definition and in dosimetric, radiobiological, and logistical issues. We designed a prospective, phase 2, multi-institution clinical trial to study 2- or 3-day accelerated partial breast irradiation delivered with brachytherapy applicators. METHODS AND MATERIALS: This trial treats select breast cancers after breast-conserving surgery with brachytherapy applicators that deliver 22.5 Gy in 3 fractions of 7.5 Gy. The planning treatment volume was 1 to 1.5 cm beyond the surgical cavity. Eligible women were aged ≥45 years with unicentric invasive or in situ tumors ≤3.0 cm with positive estrogen or progesterone receptors and no metastasis to axillary nodes that have been excised with negative margins. Strict dosimetric parameters were required to be met before acceptance into the trial. RESULTS: A group of 200 patients was prospectively enrolled and followed for a minimum of 6 months. Two- or 3-day brachytherapy was associated with low acute or subacute toxicity, 97.25% excellent or good cosmetic outcomes, and excellent local control in select breast cancers. CONCLUSIONS: Ultrashort breast brachytherapy is dosimetrically feasible and can be delivered with excellent short-term tolerance and low toxicity.

MIRD pamphlet No. 20: the effect of model assumptions on kidney dosimetry and response--implications for radionuclide therapy.

UNLABELLED: Renal toxicity associated with small-molecule radionuclide therapy has been shown to be dose-limiting for many clinical studies. Strategies for maximizing dose to the target tissues while sparing normal critical organs based on absorbed dose and biologic response parameters are commonly used in external-beam therapy. However, radiopharmaceuticals passing though the kidneys result in a differential dose rate to suborgan elements, presenting a significant challenge in assessing an accurate dose-response relationship that is predictive of toxicity in future patients. We have modeled the multiregional internal dosimetry of the kidneys combined with the biologic response parameters based on experience with brachytherapy and external-beam radiation therapy to provide an approach for predicting radiation toxicity to the kidneys. METHODS: The multiregion kidney dosimetry model of MIRD pamphlet no. 19 has been used to calculate absorbed dose to regional structures based on preclinical and clinical data. Using the linear quadratic model for radiobiologic response, we computed regionally based surviving fractions for the kidney cortex and medulla in terms of their concentration ratios for several examples of radiopharmaceutical uptake and clearance. We used past experience to illustrate the relationship between absorbed dose and calculated biologically effective dose (BED) with radionuclide-induced nephrotoxicity. RESULTS: Parametric analysis for the examples showed that high dose rates associated with regions of high activity concentration resulted in the greatest decrease in tissue survival. Higher dose rates from short-lived radionuclides or increased localization of radiopharmaceuticals in radiosensitive kidney subregions can potentially lead to greater whole-organ toxicity. This finding is consistent with reports of kidney toxicity associated with early peptide receptor radionuclide therapy and (166)Ho-phosphonate clinical investigations. CONCLUSION: Radionuclide therapy dose-response data, when expressed in terms of biologically effective dose, have been found to be consistent with external-beam experience for predicting kidney toxicity. Model predictions using both the multiregion kidney and linear quadratic models may serve to guide the investigator in planning and optimizing future clinical trials of radionuclide therapy.

Stereotactic ablative radiotherapy (SABR) as primary, adjuvant, consolidation and re-treatment option in pancreatic cancer: scope for dose escalation and lessons for toxicity.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) offers an alternative treatment for pancreatic cancer, with the potential for improved tumour control and reduced toxicity compared with conventional therapies. However, optimal dose planning and delivery strategies are unelucidated and gastro-intestinal (GI) toxicity remains a key concern. METHODS: Patients with inoperable non-metastatic pancreatic cancer who received CyberKnife® SABR (18-36 Gy) in three fractions as primary, adjuvant, consolidation or re-treatment options were studied. Patient individualised planning and delivery variables were collected and their impact on patient outcome examined. Linear-quadratic (LQ) radiobiology modelling methods were applied to assess SABR parameters against a conventional fractionated radiotherapy schedule. RESULTS: In total 42 patients were included, 37 (88%) of whom had stage T4 disease. SABR was used > 6 months post-primary therapy to re-treat residual disease in 11 (26.2%) patients and relapsed disease in nine (21.4%) patients. SABR was an adjuvant to other primary therapy for 14 (33.3%) patients and was the sole primary therapy for eight (19.0%) patients. The mean (95% CI) planning target volume (PTV), prescription isodose, percentage cover, minimum dose to PTV and biological effective dose (BED) were 76.3(63.8-88.7) cc, 67.3(65.2-69.5)%, 96.6(95.5-97.7)%, 22.3(21.0-23.6) Gy and 50.3(47.7-53.0) Gy, respectively. Only 3/37 (8.1%) patients experienced Grade 3 acute toxicities. Two (4.8%) patients converted to resectable status and median freedom-from-local-progression (FFLP) and overall survival (OS) were 9.8 and 8.4 months, respectively. No late toxicity was experienced in 27/32 (84.4%) patients; however, four (12.5%) patients - of whom two had particularly large PTV, two had sub-optimal number of fiducials and three breached organ-at-risk (OAR) constraints-showed Grade 4 duodenal toxicities. Longer delivery time, extended treatment course and reduced percentage coverage additionally associated with late toxicity, likely reflecting parameters typically applied to riskier patients. Larger PTV size and longer treatment course associated with OS. Comparator regimen LQ modelling analysis indicated 50% of patients received minimum PTV doses less potent than a conventional radiotherapy regimen, indicating scope for dose escalation. CONCLUSION: The results demonstrate the value of SABR for a range of indications in pancreatic cancer. Dose escalation to increase BED may improve FFLP and OS in inoperable, non-metastatic disease: however concomitant enhanced stringency for duodenal protection is critical, particularly for patients where SABR is more challenging.

Radiobiologic modeling of cytoprotection effects in radiotherapy.

PURPOSE: To investigate the potential for mathematical modeling of the normal tissue-sparing effects of cytoprotective agents used in conjunction with radiotherapy and chemotherapy. METHODS AND MATERIALS: The linear quadratic model was modified to include a "cytoprotection factor," in two alternative ways. The published results on the incidence of treatment-related oral mucositis in patients treated for head-and-neck carcinoma using radiotherapy alone or combined with chemotherapy were assessed against the model to determine the likely values of the cytoprotection factor required to confer a reasonable degree of cytoprotection. RESULTS: In both of the model alternatives considered, a cytoprotection factor value of < or = 0.85 was required for a clinically detectable degree of cytoprotection to be realized. A cytoprotection factor value of 0.85 would mean that the radiation sensitivity coefficients would be effectively reduced by 15% on account of the action of the cytoprotector. CONCLUSION: The incorporation of a cytoprotection factor into an existing linear quadratic method would allow a quantitative assessment of cytoprotection and could be useful in the design of future clinical studies.

Further radiobiologic modeling of palliative radiotherapy: use of virtual trials.

PURPOSE: To study duration of response in palliative radiotherapy in a population of tumors. METHODS AND MATERIALS: Models of dynamic changes in cell number with time were used to develop a function for the remission time (T(rem)) after palliative radiotherapy: [See Equation], where BED is the biologically effective dose, t(1) the duration of symptoms (i.e., the time between the onset of symptoms and the initiation of radiotherapy), K the daily BED repopulation equivalent, alpha the linear radiosensitivity parameter in the linear-quadratic model, and z the tumor regression rate. RESULTS: Simulations of clinical trials show marked variations in remission statistics depending on the tumor characteristics and are highly compatible with the results of clinical trials. Dose escalation produces both a higher proportion and extended duration of remissions, especially in tumors with high alpha/beta ratios and K values, but the predicted dose responses of acute and late side effects show that caution is necessary. The prospect of using particle beam therapy to reduce normal tissue radiation exposures or using hypoxic sensitizers to improve the tumor cell kill might significantly improve the results of palliative radiotherapy in carefully selected patients and could also be used for safer palliative re-treatments in patients with the potential for prolonged survival. The effect of tumor heterogeneity in determining palliative responses probably exceeds that in radical radiotherapy; as few as 100 patients in each treatment arm produce statistically unreliable results. CONCLUSIONS: Virtual trials of palliative radiotherapy can be useful to test the effects of competing schedules and better determine future strategies, including improved design of clinical trials as well as combinations of radiotherapy with other anticancer modalities.

The incorporation of the concept of minimum RBE (RbEmin) into the linear-quadratic model and the potential for improved radiobiological analysis of high-LET treatments.

PURPOSE: The formulation of relative biological effectiveness (RBE) for high linear energy transfer (high-LET) radiation treatments is revisited. The effects of changed production of sub-lethal damage with varying LET is now considered via the RBEmin concept, where RBEmin represents the lower limit to which RBE tends at high doses per fraction. MATERIALS AND METHODS: An existing linear-quadratic formulation for calculating RBE variations with fractional dose for high-LET radiations is modified to incorporate the twin concepts of RBEmax (which represents the value of RBE at an effective dose-per-fraction of 0 Gy) and RBEmin. RESULTS: Fits of the model to data showed RBEmin values in the range of 0.1- 2.27. In all cases the raw data was a better statistical fit to the model which included RBEmin, although this was only very highly significant in one case. In the case of the mouse oesophagus it is shown that, if change in the beta-radiosensitivity coefficient with LET is considered as trivial, an underestimation > 5% in RBE can be expected at X-ray doses of 2 Gy/fraction if RBEmin is not considered. To ensure that the results were not biased by the statistical method used to obtain the parameter values relevant to this analysis (i.e., using fraction-size effect or Fe-plots), an alternative method was used which provided very similar correlation with the data. CONCLUSIONS: If the production of sublethal damage is considered independent of LET, there will be a risk that non-corrected evaluation of RBE will lead to an over- or under-estimate of RBE at low doses per fractions (the clinically relevant region).

Linear quadratic modeling of increased late normal-tissue effects in special clinical situations.

PURPOSE: To extend linear quadratic theory to allow changes in normal-tissue radiation tolerance after exposure to cytotoxic chemotherapy, after surgery, and in elderly patients. METHODS: Examples of these situations are analyzed by use of the biologic effective dose (BED) concept. Changes in tolerance can be allowed for by: estimation of either the contribution of the additional factor as an equivalent BED or the equivalent dose in 2-Gy fractions or by the degree of radiosensitization by a mean dose-modifying factor (x). RESULTS: The estimated x value is 1.063 (95% confidence limits for the mean, 1.056 to 1.070) for subcutaneous fibrosis after cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy and radiotherapy in breast cancer. The point estimate of x is 1.18 for the additional risk of gastrointestinal late-radiation effects after abdominal surgery in lymphoma patients (or 10.62 Gy at 2 Gy per fraction). For shoulder fibrosis in patients older than 60 years after breast and nodal irradiation, x is estimated to be 1.033 (95% confidence limits for the mean, 1.028 to 1.0385). The equivalent BED values were CMF chemotherapy (6.48 Gy3), surgery (17.73 Gy3), and age (3.61 Gy3). CONCLUSIONS: The LQ model can, in principle, be extended to quantify reduced normal-tissue tolerance in special clinical situations.

The radiobiology of conventional radiotherapy and its application to radionuclide therapy.

The linear-quadratic (LQ) model of radiobiological effect is well established in conventional, i.e., external beam, radiotherapy. Because the model is derived from sound biophysical principles, it is also emerging as the standard formalism for assessing biological responses for the whole range of radiotherapy treatments. A central feature of LQ methodology is the quantity known as the biologically effective dose (BED), which may be used to quantify the radiobiological impact of a treatment on both tumors and normal tissues. The BEDs commonly associated with conventional therapy may thus be compared to those expected from novel radiotherapy treatments, such as targeted radionuclide therapy. This approach also provides a mechanism for designing targeted treatments which are therapeutically equivalent to external beam treatments. In this paper the LQ methodology is outlined and worked examples are provided which demonstrate the tentative link between targeted radiotherapy doses and those used in conventional radiotherapy. The incorporation of an allowance for relative biological effectiveness (RBE) effects is also discussed. The complexity of the subject and the potentially large number of variables does place a restriction on overall predictive accuracy and the necessary caveats are outlined.

Application of biological effective dose (BED) to estimate the duration of symptomatic relief and repopulation dose equivalent in palliative radiotherapy and chemotherapy.

PURPOSE: To investigate the potential for mathematic modeling in the assessment of symptom relief in palliative radiotherapy and cytotoxic chemotherapy. METHODS: The linear quadratic model of radiation effect with the overall treatment time and the daily dose equivalent of repopulation is modified to include the regrowth time after completion of therapy. RESULTS: The predicted times to restore the original tumor volumes after treatment are dependent on the biological effective dose (BED) delivered and the repopulation parameter (K); it is also possible to estimate K values from analysis of palliative treatment response durations. Hypofractionated radiotherapy given at a low total dose may produce long symptom relief in slow-growing tumors because of their low alpha/beta ratios (which confer high fraction sensitivity) and their slow regrowth rates. Cancers that have high alpha/beta ratios (which confer low fraction sensitivity), and that are expected to repopulate rapidly during therapy, are predicted to have short durations of symptom control. The BED concept can be used to estimate the equivalent dose of radiotherapy that will achieve the same duration of symptom relief as palliative chemotherapy. CONCLUSION: Relatively simple radiobiologic modeling can be used to guide decision-making regarding the choice of the most appropriate palliative schedules and has important implications in the design of radiotherapy or chemotherapy clinical trials. The methods described provide a rationalization for treatment selection in a wide variety of tumors.

The determination of radiobiologically optimized half-lives for radionuclides used in permanent brachytherapy implants.

PURPOSE: To use tumor growth kinetics and other biologic parameters in an extended version of the linear-quadratic (LQ) formulation to determine radiobiologically optimized half-lives of radionuclides which might be used in permanent brachytherapy implants. METHODS AND MATERIALS: A version of the LQ model suitable for the analysis of permanent brachytherapy implants has been modified to investigate the radionuclide half-lives that will maximize the biologically effective dose (BED) delivered to tumors with repopulation rates (K values) in the range 0.01-1.1 Gyday(-1). The method assumes that part of the physical dose delivered to the tumor may be radiobiologically wasted because of the repopulation phenomenon, whereas adjacent normal tissues will exhibit little or no wastage. To perform the analysis, it is necessary to stipulate alpha/beta ratios and sublethal damage recovery rates together with the normal tissue tolerance BED. The analysis also takes into account a range of likely relative biological effectiveness (RBE) values. RESULTS: Rapidly growing tumors require the shortest radionuclide half-lives, but even slow-growing tumors such as prostate adenocarcinomas can be satisfactorily treated with radionuclides possessing half-lives substantially less than that associated with I(125). The likelihood that prostate tumors possess an alpha/beta value which is comparable with, or lower than, that associated with late-responding normal tissues would also mitigate against the use of long-lived radionuclides. Although a number of parameter assumptions are involved, the results suggest that, for a wide range of tumor types, shorter-lived radionuclides are more versatile for achieving reasonable clinical results. The theoretically derived optimum half-lives typically range from around 0-5 days for fast-repopulating tumors (K 1.1 Gyday(-1)) to approximately 14-50 days for slow-growing tumors (K approximately 0.1 Gyday(-1) or less). For prostate implantation, 103Pd is overall a better choice than 125I. CONCLUSION: With so many variables and parameter uncertainties, it is not appropriate to attempt to define optimum radionuclide half-lives too closely. However, this study suggests that half-lives in the approximate range 4-17 days are likely to be significantly better for a wide range of tumor types for which the radiobiologic characteristics may not be precisely known in advance.

A spatio-temporal simulation model of the response of solid tumours to radiotherapy in vivo: parametric validation concerning oxygen enhancement ratio and cell cycle duration.

Advanced bio-simulation methods are expected to substantially improve radiotherapy treatment planning. To this end a novel spatio-temporal patient-specific simulation model of the in vivo response of malignant tumours to radiotherapy schemes has been recently developed by our group. This paper discusses recent improvements to the model: an optimized algorithm leading to conformal shrinkage of the tumour as a response to radiotherapy, the introduction of the oxygen enhancement ratio (OER), a realistic initial cell phase distribution and finally an advanced imaging-based algorithm simulating the neovascularization field. A parametric study of the influence of the cell cycle duration Tc, OER, OERbeta for the beta LQ parameter on tumour growth. shrinkage and response to irradiation under two different fractionation schemes has been made. The model has been applied to two glioblastoma multiforme (GBM) cases, one with wild type (wt) and another one with mutated (mt) p53 gene. Furthermore, the model has been applied to a hypothetical GBM tumour with alpha and beta values corresponding to those of generic radiosensitive tumours. According to the model predictions, a whole tumour with shorter Tc tends to repopulate faster, as is to be expected. Furthermore, a higher OER value for the dormant cells leads to a more radioresistant whole tumour. A small variation of the OERbeta value does not seem to play a major role in the tumour response. Accelerated fractionation proved to be superior to the standard scheme for the whole range of the OER values considered. Finally, the tumour with mt p53 was shown to be more radioresistant compared to the tumour with wt p53. Although all simulation predictions agree at least qualitatively with the clinical experience and literature, a long-term clinical adaptation and quantitative validation procedure is in progress.

Use of the linear-quadratic radiobiological model for quantifying kidney response in targeted radiotherapy.

This paper reviews the generalized application of the linear quadratic (LQ) model of radiobiological effect to targeted radiotherapy. Special attention is given to formulations for normal tissue responses and these are applied, in particular, to the kidney. Because it is derived from self-consistent bio-physical principles, the LQ model currently remains the standard formalism for assessing biological responses for the whole range of radiotherapy treatments. A central feature of the model is the derivation of biologically effective doses (BEDs), which may be used to quantify the impact of a treatment on both tumors and normal tissues. BEDs are routinely derived for conventional external-beam treatments. The likely limits of targeted radiotherapy may, thus, be assessed by comparing the expected normal-tissue BEDs for such treatments with those known to be just tolerable in conventional therapy. The main parameters required in the model are defined, and data are provided which demonstrate the tentative link between targeted radiotherapy doses and those used in conventional radiotherapy. The extension of the LQ method to targeted radiotherapy involves using parameters for which the numerical values may not be accurately known at present. This places a restriction on the overall predictive accuracy of the model and the necessary caveats are, therefore, outlined.

A theoretical radiobiological assessment of the influence of radionuclide half-life on tumor response in targeted radiotherapy when a constant kidney toxicity is maintained.

The potential of targeted radionuclide therapy may be limited if the antibody affinity to the tumor is relatively low and if significant normal tissue damage occurs while the tumor is sterilized. One way to increase the efficiency of the antibody-radionuclide complex might be to use knowledge of the radiobiological processes to select a near-optimal radionuclide half-life. In this paper, the role of physical half-life in targeted radiotherapy optimization is investigated using the linear quadratic (LQ) radiobiological model in conjunction with a range of radiobiological parameters relevant to the tumor. Five radionuclides ((211)At, (90)Y, (131)I, (86)Rb, and (114m)In) were selected, providing a half-life range from 0.3-49.5 days. The dose-limiting organ was assumed to be the kidney, with a simple fractional link between the initial (extrapolated) dose-rate to the tumor and the initial dose-rate to the kidney. The results suggest that short-lived radionuclides (half-life in the range of 1-10 days) have an advantage over medium- and long-lived radionuclides. Furthermore, for very rapid tumor uptake (uptake half-time of a few hours), very short-lived radionuclides (half-life of less than 1 day) could be efficiently employed. Ultimately, however, treatment outcome (in terms of tumor cell kill) is limited by the antibody affinity to the tumor.