Simultaneous integrated intensity-modulated radiotherapy boost for locally advanced gynecological cancer: radiobiological and dosimetric considerations

PURPOSE: Whole-pelvis irradiation (WPI) followed by a boost to the tumor site is the standard of practice for the radiotherapeutic management of locally advanced gynecologic cancers. The boost is frequently administered by use of brachytherapy or, occasionally, external-beam radiotherapy (EBRT) when brachytherapy does not provide sufficient coverage because of the size of the tumor or the geometry of the patient. In this work, we propose using an intensity-modulated radiotherapy (IMRT) simultaneous integrated boost (SIB), which is a single-phase process, to replace the conventional two-phase process involving WPI plus a boost. Radiobiological modeling is used to design appropriate regimens for the IMRT SIB. To demonstrate feasibility, a dosimetric study is carried out on an example patient. METHODS AND MATERIALS: The standard linear-quadratic (LQ) model is used to calculate the biologically effective dose (BED) and equivalent uniform dose (EUD). A series of regimens that are biologically equivalent to those conventional two-phase treatments is calculated for the proposed SIB. A commercial inverse planning system (Corvus) was used to generate IMRT SIB plans for a sample patient case that used the newly designed fractionations. The dose-volume histogram (DVH) and EUD of both the target and normal structures for conventional treatments and the SIB are compared. A sparing factor was introduced to characterize the sparing of normal structures. RESULTS: Fractionation regimes that are equivalent to the conventional treatments and are suitable for the IMRT SIB are deduced. For example, a SIB plan with 25 x 3.1 Gy (77.5 Gy) to a tumor is equivalent to a conventional treatment of EBRT of 45 Gy to the whole pelvis in 25 fractions plus a high-dose rate (HDR) brachytherapy boost with 30 Gy in 5 fractions. The normal tissue BED is found to be lower for the SIB plan than for the whole-pelvis plus HDR scheme when a sparing factor for the critical structures is considered. This finding suggests that the IMRT SIB has a better therapeutic ratio. Three IMRT SIB plans with 25 x 1.8 Gy to the pelvic nodes and 25 x 2.4 Gy (60 Gy), 25 x 2.8 Gy (70 Gy), and 25 x 3.2 Gy (80 Gy) to the tumor site were generated for the example patient case. The target coverage ranged from 94% to 95.5%. The sparing of bladder and rectum is significantly improved with the 60 to 70 Gy SIB treatments, as compared with the conventional treatments. The proposed SIB treatment can reduce the treatment time to 5 weeks. CONCLUSIONS: An IMRT simultaneous integrated boost to replace the conventional two-phase treatments (whole pelvic irradiation followed by brachytherapy or EBRT boost) is radiobiologically and dosimetricaly feasible for locally advanced gynecological cancers that may not be amenable to brachytherapy for anatomic or medical reasons. In addition to its shorter treatment time, the proposed IMRT SIB can provide significant sparing to normal structures, which offers potential for dose escalation. Issues such as organ motion and changing anatomy as tumor responds still must be addressed.     

Pulsed reduced dose-rate radiotherapy: case report

The initial management of malignant gliomas is multimodality in nature, consisting of surgery, radiation therapy and chemotherapy. However, once progression has occurred, treatment options are limited both in terms of selection and efficacy. We report a case of a 37 year-old male diagnosed with a Grade II astrocytoma initially treated with surgery and external beam radiation therapy consisting of 54 Gy delivered in 1.8 Gy fractions that subsequently progressed to a Grade IV astrocytoma. This was managed with temozolomide chemotherapy until the patient exhibited further progression. Although the patient had received prior full dose radiotherapy, he was re-treated with external beam radiotherapy delivered at a substantially reduced dose-rate. This reduction in dose-rate is obtained by delivering treatment in a series of 0.2 Gy pulses separated by 3 min time intervals, creating an apparent dose rate of 0.0667 Gy/min. The region of recurrence was treated to a dose of 50 Gy delivered using 25 daily fractions of 2.0 Gy. The patient had both a radiographic response and clinical improvement following re-irradiation using pulsed reduced dose-rate radiotherapy with no apparent acute or late neurologic toxicities at a time when other treatment options were not available. Despite delivering 104 Gy to the tumor bed and the surrounding brain parenchyma, at no time was there radiographic evidence of radiation-induced normal tissue necrosis. The radiobiologic basis for the use of pulsed reduced dose-rate external beam radiotherapy in the management of recurrent glioma patients is discussed.     

The dose-rate effect in human tumour cells

The radiation response of 12 cell lines derived from a variety of human tumours has been investigated over the dose-rate range from 150 to 1.6 cGy/min. As the dose rate was lowered, the amount of sparing varied widely; in 2 cell lines it was zero, in the other cell lines the dose required for 10(-2) survival ranged up to twice the value at high dose rate. Low dose-rate irradiation discriminates better than high dose rate between tumour cell lines of differing radiosensitivity. The data are equally well fitted by two mathematical models of the dose-rate effect: the LPL model of Curtis and the Incomplete Repair model of Thames. Analysis by the LPL model leads to the conclusion that the theoretical radiosensitivity in the total absence of repair was rather similar among the 7 cell lines on which this analysis was possible. What differs among these cell lines is the extent of repair and/or the probability of direct infliction of a non-repairable lesion. Recovery from radiation damage was also examined by split-dose experiments in a total of 17 human tumour cell lines. Half-time values ranged from 0.36 to 2.3 h and there was a systematic tendency for split-dose halving times to be longer than those derived from analysis of the dose-rate effect. This could imply that cellular recovery is a two-component process, low dose-rate sparing being dominated by the faster component. The extent of low dose-rate sparing shows some tendency to correlate with the magnitude of split-dose recovery; in our view the former is the more reliable measure of cellular recovery. The clinical implication of these studies is that some human tumour types may be well treated by hyperfractionation or low dose-rate irradiation, while for others these may be poor therapeutic strategies.     

Late radiation-induced heart disease after radiotherapy. Clinical importance, radiobiological mechanisms and strategies of prevention

The clinical importance of radiation-induced heart disease, in particular in post-operative radiotherapy of breast cancer patients, has been recognised only recently. There is general agreement, that a co-ordinated research effort would be needed to explore all the potential strategies of how to reduce the late risk of radiation-induced heart disease in radiotherapy. This approach would be based, on one hand, on a comprehensive understanding of the radiobiological mechanisms of radiation-induced heart disease after radiotherapy which would require large-scale long-term animal experiments with high precision local heart irradiation. On the other hand – in close co-operation with mechanistic in vivo research studies – clinical studies in patients need to determine the influence of dose distribution in the heart on the risk of radiation-induced heart disease. The aim of these clinical studies would be to identify the critical structures within the organ which need to be spared and their radiation sensitivity as well as a potential volume and dose effect. The results of the mechanistic studies might also provide concepts of how to modify the gradual progression of radiation damage in the heart by drugs or biological molecules. The results of the studies in patients would need to also incorporate detailed dosimetric and imaging studies in order to develop early indicators of impending radiation-induced heart disease which would be a pre-condition to develop sound criteria for treatment plan optimisation.     

The role of radiotherapy in recurrent and metastatic malignant melanoma: a clinical radiobiological study

A review of the literature and our data has been completed to analyze the clinical radiobiology of malignant melanoma. Six hundred eighteen radiotherapy-treated malignant melanoma lesions were analyzed with regard to radiobiological parameters such as total dose, dose per fraction, treatment time, tumor volume, and various fractionation models. Forty-eight per cent of the treated tumors achieved complete response, which was persistent in 87% after 5 years. Neither total dose, treatment time, nor various modifications of the NSD concept showed any well-defined correlation with response. There was, however, a significant relationship between dose per fraction and response, and a high dose per fraction yielded a significantly better response (59% CR for doses greater than 4 Gy versus 33% CR for doses per fraction less than or equal to 4 Gy). The lack of treatment time influence allowed analysis of the data according to the linear-quadratic model, resulting in an alpha/beta ratio of 2.5 Gy. Using this ratio, an iso-effect for different fractionation schedules could be estimated by the extrapolated total-dose (ETD). The ratio was further improved when corrected for the tumor volume. Thus, an iso-effect formula for malignant melanoma could be calculated as: ETDvol (Gy) = D X [d + 2.5)/2.5) X M-.33, where D and d are total dose and dose per fraction in Gy, respectively, and M is the mean tumor diameter in cm. Based on a logit analysis, a complete response level of 50% appeared at an ETDvol value of 83 Gy. The formula is currently the best way to determine an optimal radiation schedule for an effective radiation treatment of malignant melanoma. The tumor response was further improved in 134 additional cases receiving adjuvant hyperthermia. Here, a thermal enhancement ratio (TER) of 2.0 was observed. In a group of 131 patients with only local or regional disease, a 5 year survival rate of 49% was observed in 77 patients with persistent local tumor control, but only 3% survived among the 54 patients in whom local therapy failed. It is therefore, highly important to the probability of survival in recurrent melanoma that proper local treatment be performed.     

Compensation for changes in dose-rate in radical low-dose-rate brachytherapy: a radiobiological analysis of a randomised clinical trial.

BACKGROUND AND PURPOSE: This study reanalysed the results of the Cs-137 low-dose-rate brachytherapy trials for stage I and II cervix carcinoma at the Christie Hospital, Manchester, UK, in order to quantify the clinical outcome as a function of dose, and to extract radiobiological parameter values by modelling the data for local control and morbidity. PATIENTS AND METHODS: Kaplan-Meier survival curves and Cox regression analyses were used to analyse the time to event data. Linear-quadratic (LQ) analysis was also used in a mixture model, incorporating a half-time for repair, a time factor, and a heterogeneity function between patients. Full 5-year follow-up data were available for 339 patients receiving Cs-137 doses between 60 and 75 Gy delivered at 1.4-1.8 Gy/h, and 178 patients receiving a Ra-226 dose of 75 Gy at 0.5 Gy/h, using two insertions 7-10 days apart. RESULTS: With the increased dose-rate, a dose reduction between 20 and 25% was required to achieve a similar morbidity rate. This reduction had a detrimental effect on tumour control, by about 15% points. Unexpectedly, this loss in local control did not lead to a decrease in cancer-specific survival. For both tumour control and complications a high alpha/beta and short half-time for repair best fitted the data, suggesting that consequential late reactions may be responsible for much of the bowel and urinary morbidity after these short treatments. The variability in response between patients was greater (CV 40%) for morbidity than for tumour control (CV 17%), probably reflecting the greater variation in dose at the target tissue. There was no significant dependence on overall treatment time detected over the 7-10-day range of these treatments. CONCLUSIONS: The therapeutic ratio was somewhat less for the higher dose-rate, in agreement with radiobiological expectations, although cancer-specific survival was inexplicably unchanged. The LQ-parameter analysis suggests that high alpha/beta ratios and/or short repair half-times are applicable for both tumour and normal tissue responses in these treatments.     

The radiation dose-rate effect in two human neuroblastoma cell lines

The current use of targeted radiotherapy in the treatment of neuroblastoma has generated a requirement for further information on the radiobiology of these cells. Here we report on studies of the dose-rate effect in two human neuroblastoma cell lines (HX138 and HX142) and the recovery that they demonstrate in split-dose experiments. The sensitivity of the two cell lines to high dose-rate irradiation was confirmed. Surviving fractions at 2 Gy were 0.083 for HX138 and 0.11 for HX142. There was little evidence of a dose-rate effect above 2 cGy min-1 but significant sparing was seen at lower dose rates. Substantial recovery was seen in split-dose experiments on both cell lines, to an extent that was consistent with the linear quadratic equation. The data were used to derive values for the beta parameter of the linear-quadratic equation; the values for the neuroblastomas were higher than for any of the other human tumour cell lines that we have investigated to date. Thus, despite their high sensitivity to ionising radiation HX138 and HX142 do exhibit substantial levels of cellular recovery, suggesting that they may have a significant capacity for repair of radiation-induced lesions.     

3D radiobiological evaluation of combined radiotherapy and hyperthermia treatments

Purpose: Currently, clinical decisions regarding thermoradiotherapy treatments are based on clinical experience. Quantification of the radiosensitising effect of hyperthermia allows comparison of different treatment strategies, and can support clinical decision-making regarding the optimal treatment. The software presented here enables biological evaluation of thermoradiotherapy plans through calculation of equivalent 3D dose distributions.

Methods: Our in-house developed software (X-Term) uses an extended version of the linear-quadratic model to calculate equivalent radiation dose, i.e. the radiation dose yielding the same effect as the thermoradiotherapy treatment. Separate sets of model parameters can be assigned to each delineated structure, allowing tissue specific modelling of hyperthermic radiosensitisation. After calculation, the equivalent radiation dose can be evaluated according to conventional radiotherapy planning criteria. The procedure is illustrated using two realistic examples. First, for a previously irradiated patient, normal tissue dose for a radiotherapy and thermoradiotherapy plan (with equal predicted tumour control) is compared. Second, tumour control probability (TCP) is assessed for two (otherwise identical) thermoradiotherapy schedules with different time intervals between radiotherapy and hyperthermia.

Results: The examples demonstrate that our software can be used for individualised treatment decisions (first example) and treatment optimisation (second example) in thermoradiotherapy. In the first example, clinically acceptable doses to the bowel were exceeded for the conventional plan, and a substantial reduction of this excess was predicted for the thermoradiotherapy plan. In the second example, the thermoradiotherapy schedule with long time interval was shown to result in a substantially lower TCP.

Conclusions: Using biological modelling, our software can facilitate the evaluation of thermoradiotherapy plans and support individualised treatment decisions.     

Animation and radiobiological analysis of 3D motion in conformal radiotherapy.

PURPOSE: To allow treatment plans to be evaluated against the range of expected organ motion and set up error anticipated during treatment. METHODS: Planning tools have been developed to allow concurrent animation and radiobiological analysis of three dimensional (3D) target and organ motion in conformal radiotherapy. Surfaces fitted to structures outlined on CT studies are projected onto pre-treatment images or onto megavoltage images collected during the patient treatment. Visual simulation of tumour and normal tissue movement is then performed by the application of three dimensional affine transformations, to the selected surface. Concurrent registration of the surface motion with the 3D dose distribution allows calculation of the change in dose to the volume. Realistic patterns of motion can be applied to the structure to simulate inter-fraction motion and set-up error. The biologically effective dose for the structure is calculated for each fraction as the surface moves over the course of the treatment and is used to calculate the normal tissue complication probability (NTCP) or tumour control probability (TCP) for the moving structure. The tool has been used to evaluate conformal therapy plans against set up measurements recorded during patient treatments. NTCP and TCP were calculated for a patient whose set up had been corrected after systematic deviations from plan geometry were measured during treatment, the effect of not making the correction were also assessed. RESULTS: TCP for the moving tumour was reduced if inadequate margins were set for the treatment. Modelling suggests that smaller margins could have been set for the set up corrected during the course of the treatment. The NTCP for the rectum was also higher for the uncorrected set up due to a more rectal tissue falling in the high dose region. CONCLUSION: This approach provides a simple way for clinical users to utilise information incrementally collected throughout the whole of a patient's treatment. In particular it is possible to test the robustness of a patient plan against a range of possible motion patterns. The methods described represent a move from the inspection of static pre-treatment plans to a review of the dynamic treatment.     

The response of pig skin to single and fractionated high dose-rate and continuous low dose-rate 137Cs-irradiation--II. Theoretical considerations of the results.

The result of a comparison of single and fractionated irradiation at high dose rate with continuous irradiation at low dose rate on pig skin is discussed from a radiobiological point of view. A short review is given of other fractionation and dose-rate investigations. Some dose-rate experiments have resulted in an increased therapeutic gain for continuous irradiation at low dose rate, compared to single acute irradiation. However, there is a lack of data comparing fractionated high dose-rate irradiation with continuous low dose-rate irradiation on normal tissues as well as malignant tumors.     

Salvage radiotherapy for prostate cancer: Finding a way forward using radiobiological modeling

Purpose: Recent modeling efforts, based on reported outcomes following salvage radiotherapy (SRT) for prostate cancer, predict the likelihood of biochemical control (tumor control probability, TCP) as a function of pre-treatment prostate specific antigen (PSA) and SRT dose. Similar instruments predict the risk of grade ≥ 3 late toxicity (normal tissue complication probability, NTCP) as a function of SRT dose. Here we explore how changes in the parameters of those models might affect the optimal SRT dose and clinical outcomes. Materials and Methods: Baseline TCP and NTCP model parameters were established in a previous report. Pre-treatment PSA was set at 0.4 ng/mL. Model parameters were modified to explore four scenarios: (1) improving the safety of SRT, (2) increasing tumor cell radiosensitivity, (3) increasing the cure rate achievable with SRT and (4) adoption of hypofractionated SRT schedules. The “optimal” SRT dose, defined as the dose that maximized the likelihood of achieving biochemical control without causing late toxicity, was identified for each scenario. Results: Improving the safety of SRT increased the optimal SRT dose, while radiosensitization decreased the optimal dose. Both changes were predicted to increase the probability of biochemical control and decrease late toxicity rates. Increasing the cure rate achievable with SRT (eg: improving patient selection or combining SRT with effective systemic therapy) provided the greatest gains in TCP. Adoption of a hypofractionated SRT schedule was predicted to improve both biochemical control and late toxicity. Conclusions: Modeling exercises demonstrate the significant gains that may be achieved with improved implementation of SRT for prostate cancer. Strategies to realize the effects modeled in this report should be explored in clinical trials.