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.

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.

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.

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.

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.

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.

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.

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.

Assessment of the radiation-equivalent of chemotherapy contributions in 1-phase radio-chemotherapy treatment of muscle-invasive bladder cancer.

PURPOSE: To estimate the radiation equivalent of the chemotherapy contribution to observed complete response rates in published results of 1-phase radio-chemotherapy of muscle-invasive bladder cancer. METHODS AND MATERIALS: A standard logistic dose-response curve was fitted to data from radiation therapy-alone trials and then used as the platform from which to quantify the chemotherapy contribution in 1-phase radio-chemotherapy trials. Two possible mechanisms of chemotherapy effect were assumed (1) a fixed radiation-independent contribution to local control; or (2) a fixed degree of chemotherapy-induced radiosensitization. A combination of both mechanisms was also considered. RESULTS: The respective best-fit values of the independent chemotherapy-induced complete response (CCR) and radiosensitization (s) coefficients were 0.40 (95% confidence interval -0.07 to 0.87) and 1.30 (95% confidence interval 0.86-1.70). Independent chemotherapy effect was slightly favored by the analysis, and the derived CCR value was consistent with reports of pathologic complete response rates seen in neoadjuvant chemotherapy-alone treatments of muscle-invasive bladder cancer. The radiation equivalent of the CCR was 36.3 Gy. CONCLUSION: Although the data points in the analyzed radio-chemotherapy studies are widely dispersed (largely on account of the diverse range of chemotherapy schedules used), it is nonetheless possible to fit plausible-looking response curves. The methodology used here is based on a standard technique for analyzing dose-response in radiation therapy-alone studies and is capable of application to other mixed-modality treatment combinations involving radiation therapy.

Radio-chemotherapy for bladder cancer: Contribution of chemotherapy on local control.

The purpose of this study was to review the magnitude of contribution of chemotherapy (CT) in the local control of muscle invasive bladder carcinoma in the studies where a combined radio-chemotherapy (RCT) was used (how much higher local control rates are obtained with RCT compared to RT alone). Studies on radiotherapy (RT) and combined RCT, neo-adjuvant, concurrent, adjuvant or combinations, reported after 1990 were reviewed. The mean complete response (CR) rates were significantly higher for the RCT studies compared to RT-alone studies: 75.9% vs 64.4% (Wilcoxon rank-sum test, P = 0.001). Eleven of the included RCT studies involved 2-3 cycles of neo-adjuvant CT, in addition to concurrent RCT. The RCT studies included the one-phase type (where a full dose of RCT was given and then assessment of response and cystectomy for non-responders followed) and the two-phase types (where an assessment of response was undertaken after an initial RCT course, followed 6 wk later by a consolidation RCT for those patients with a CR). CR rates between the two subgroups of RCT studies were 79.6% (one phase) vs 71.6% (two-phase) (P = 0.015). The average achievable tumour control rates, with an acceptable rate of side effects have been around 70%, which may represent a plateau. Further increase in CR response rates demands for new chemotherapeutic agents, targeted therapies, or modified fractionation in various combinations. Quantification of RT and CT contribution to local control using radiobiological modelling in trial designs would enhance the potential for both improved outcomes and the estimation of the potential gain.

Equivalent uniform dose for accelerated partial breast irradiation using the MammoSite applicator.

INTRODUCTION: This study aims to quantify the radiobiology of the MammoSite applicator and examine whether there is a relationship between equivalent uniform dose (EUD) and radiotherapy-associated toxicity. METHODS AND MATERIALS: A previously-published version of the linear quadratic (LQ) model, designed to address the impact of dose-gradients in brachytherapy applications, was used to determine the biological effective dose (BED), equivalent dose in 2 Gray per fraction (EQD2) and EUD for the most common fractionation scheme for the MammoSite catheter (34 Gy in 10 fractions prescribed to 1cm from the balloon surface), using a range of balloon sizes in a series of patients treated with single or multiple dwell positions. Toxicity from the MammoSite catheter was assessed and statistical associations with the calculated EUDs were investigated. RESULTS: The acute- and late-toxicity EUDs respectively range from 34.8-39.4 Gy and 33.4-37.6 Gy, with EUD decreasing as balloon diameter increases and/or the number of dwell positions increases. There was a positive association between EUD and hyperpigmentation and telangiectasia. CONCLUSIONS: For APBI using the Mammosite applicator, EUD is higher than the marginal prescription dose and, for the dose-fractionation patterns considered here, was associated with acute and late skin toxicity. EUD is a potentially useful parameter to characterize non-uniform dose distributions related to brachytherapy treatments. Further evaluation in future studies is warranted.

Use of the concept of equivalent biologically effective dose (BED) to quantify the contribution of hyperthermia to local tumor control in radiohyperthermia cervical cancer trials, and comparison with radiochemotherapy results.

PURPOSE: To express the magnitude of contribution of hyperthermia to local tumor control in radiohyperthermia (RT/HT) cervical cancer trials, in terms of the radiation-equivalent biologically effective dose (BED) and to explore the potential of the combined modalities in the treatment of this neoplasm. MATERIALS AND METHODS: Local control rates of both arms of each study (RT vs. RT+HT) reported from randomized controlled trials (RCT) on concurrent RT/HT for cervical cancer were reviewed. By comparing the two tumor control probabilities (TCPs) from each study, we calculated the HT-related log cell-kill and then expressed it in terms of the number of 2 Gy fraction equivalents, for a range of tumor volumes and radiosensitivities. We have compared the contribution of each modality and made some exploratory calculations on the TCPs that might be expected from a combined trimodality treatment (RT+CT+HT). RESULTS: The HT-equivalent number of 2-Gy fractions ranges from 0.6 to 4.8 depending on radiosensitivity. Opportunities for clinically detectable improvement by the addition of HT are only available in tumors with an alpha value in the approximate range of 0.22-0.28 Gy(-1). A combined treatment (RT+CT+HT) is not expected to improve prognosis in radioresistant tumors. CONCLUSION: The most significant improvements in TCP, which may result from the combination of RT/CT/HT for locally advanced cervical carcinomas, are likely to be limited only to those patients with tumors of relatively low-intermediate radiosensitivity.

Biologically effective dose-response relationship for breast cancer treated by conservative surgery and postoperative radiotherapy.

PURPOSE: To find a biologically effective dose (BED) response for adjuvant breast radiotherapy (RT) for initial-stage breast cancer. METHODS AND MATERIALS: Results of randomized trials of RT vs. non-RT were reviewed and the tumor control probability (TCP) after RT was calculated for each of them. Using the linear-quadratic formula and Poisson statistics of cell-kill, the average initial number of clonogens per tumor before RT and the average tumor cell radiosensitivity (alpha-value) were calculated. An alpha/beta ratio of 4 Gy was assumed for these calculations. RESULTS: A linear regression equation linking BED to TCP was derived: -ln[-ln(TCP)] = -ln(No) + alpha(*) BED = -4.08 + 0.07 (*) BED, suggesting a rather low radiosensitivity of breast cancer cells (alpha = 0.07 Gy(-1)), which probably reflects population heterogeneity. From the linear relationship a sigmoid BED-response curve was constructed. CONCLUSION: For BED values higher than about 90 Gy(4) the radiation-induced TCP is essentially maximizing at 90-100%. The relationship presented here could be an approximate guide in the design and reporting of clinical trials of adjuvant breast RT.