The response of pig skin to single and fractionated high dose-rate and continuous low dose-rate 137Cs-irradiation-I: Experimental design and results.

A comparison of the radiation effect of single and fractionated irradiation at high dose rate (1.48 Gy/min) with continuous irradiation at low dose rate (1.2 Gy/hr) was performed on pig skin. Two identical plane ¹³⁷Cs-sources with similar geometrical arrangement were used, giving about the same field flatness and depth-dose distribution. Dose-response curves were established for the 3 irradiation modalities. The dose-rate factor between single doses given with high and low dose-rate irradiation was found to be 2.35 for the medium-term skin reaction. These experimental data also make it possible to establish an equivalent biological scale of radiation effect on normal tissue by the cumulative radiation effect (CRE) system over a wide range of irradiation techniques, including fractionated high dose-rate and continuous low dose-rate irradiation regimens. The value of normalizing factor in the CRE-formula for continuous low dose-rate regimens was found to be significantly lower than proposed.     

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.     

Radiobiological aspects of continuous low dose-rate irradiation and fractionated high dose-rate irradiation

The biological effects of continuous low dose-rate irradiation and fractionated high dose-rate irradiation in interstitial and intracavitary radiotherapy and total body irradiation are discussed in terms of dose-rate fractionation sensitivity for various tissues. A scaling between dose rate and fraction size was established for acute and late normal-tissue effects which can serve as a guideline for local treatment in the range of dose rates between 0.02 and 0.005 Gy/min and fraction sizes between 8.5 and 2.5 Gy. This is valid provided cell-cycle progression and proliferation can be ignored. Assuming that the acute and late tissue responses are characterised by alpha/beta values of about 10 and 3 Gy and a mono-exponential repair half-time of about 3 h, the same total doses given with either of the two methods are approximately equivalent. The equivalence for acute and late non-hemopoietic normal tissue damage is 0.02 Gy/min and 8.5 Gy per fraction; 0.01 Gy/min and 5.5 Gy per fraction; and 0.005 Gy/min and 2.5 Gy per fraction. A very low dose rate, below 0.005 Gy/min, is thus necessary to simulate high dose-rate radiotherapy with fraction sizes of about 2 Gy. The scaling factor is, however, dependent on the repair half-time of the tissue. A review of published data on dose-rate effects for normal-tissue response showed a significantly stronger dose-rate dependence for late than for acute effects below 0.02 Gy/min. There was no significant difference in dose-rate dependence between various acute non-hemopoietic effects or between various late effects. The consistent dose-rate dependence, which justifies the use of a general scaling factor between fraction size and dose rate, contrasts with the wide range of values for repair half-time calculated for various normal-tissue effects. This indicates that the model currently used for repair kinetics is not satisfactory. There are also few experimental data in the clinical dose-rate range, below 0.02 Gy/min. It is therefore necessary to verify further the presented scaling between fraction size and dose rate.     

The response of pig skin to single and fractionated high dose-rate and continuous low dose-rate 137Cs-irradiation-III. Re-evaluation of the CRE system and the TDF system according to the present findings

Application of the cumulative radiation effect (CRE) and time dose fractionation factors (TDF) systems on the dose-effect data from single and fractionated irradiation at high dose rate and continuous irradiation at low dose rate on pig skin revealed that significant corrections of these empirical models are necessary. There is evidence for modification of the CRE and TDF-formula for fractionated high dose-rate irradiation concerning late effects on normal tissue. The pig skin result indicated a value of the normalizing constant of 0.57 and 2.02 in the CRE and TDF-formulae for continuous irradiation instead of the proposed value of 0.80 and 1.57 respectively. The practical consequences for prediction of equivalent normal tissue reactions for fractionated high dose-rate and continuous low-dose-rate irradiation by the CRE and TDF systems will be elucidated.     

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.     

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.     

Recovery kinetics deduced from continuous low dose-rate experiments

Information on the rate of recovery from potentially lethal damage can be obtained from the analysis of the radiation dose-rate effect. Two mathematical models are useful in this respect: the Lethal-Potentially. Lethal (LPL) model of Curtis and the Incomplete Repair (IR) model of Thames. Full cell-survival curves are required at three or more dose rates in order to make a reliable analysis. Studies on human tumour cell lines yield values for recovery half-time in the range 0.1 to 0.9 h, and for each cell line the half-time found in this way is shorter than that obtained from a split-dose experiment. This result may imply that cellular recovery is a multi-component or a saturable process.     

Low dose-rate interstitial brachytherapy in soft tissue sarcomas

Purpose. To assess the effectiveness of Ir-192 interstitial brachytherapy as an adjunct to wide local excision as a functionsaving strategy for soft tissue sarcomas.Subjects and methods. From September 1993 to April 1998, 20 consecutive patients diagnosed with soft tissue sarcomas were treated with a combination of wide local excision and interstitial brachytherapy. In 16 patients brachytherapy was done as an intraoperative procedure, while in four, the implant was performed post-operatively under local anesthesia. Eleven of the 20 patients also received external beam radiotherapy following the implant.Results. After a mean follow-up of 27 months (4-54) the local control rate for all 20 patients was 85% (17/20). In the 16 patients who had an intra-operative implant, local control was 94% (15/16). In the four patients who underwent a post-operative implant, local control was 50% (2/4). Actuarial 5-year survival was 90%. There were three cases (15%) of severe local complications.Conclusions. Wide local excision followed by low dose rate intersitital brachytherapy have yielded a 85% local control rate in 20 patients with soft tissue sarcomas. Local control rates were higher when the implants were done as an intra-operative procedure than as a post-operative one.     

Contemporary external beam radiotherapy boost or high dose-rate brachytherapy boost for cervical cancer: a propensity-score-matched,nationwide, population-based cohort study

To estimate the survival effects of contemporary external beam radiotherapy (EBRT) boost modalities (intensity-modulated radiation therapy or volumetric modulated arc therapy) and high dose-rate brachytherapy (HDR-BT) boost in patients with cervical cancer (CC). Patients who had been diagnosed as having CC were recruited from the Taiwan Cancer Registry Database. Propensity score matching was performed, and Cox proportional-hazards model curves were used to analyze the all-cause mortality of patients who received standard whole-pelvis irradiation with different boost modalities. The matching process yielded a final cohort of 1,630 patients (815 in the EBRT boost and HDR-BT boost groups, respectively) eligible for further analysis. The multivariate Cox regression analyses indicated that the adjusted hazard ratio (95% confidence intervals) for EBRT boost compared with HDR-BT boost was 1.62 (1.43-1.84). Multivariable analysis revealed that the independent poor prognostic factors of all-cause mortality among patients with CC were adenocarcinoma, no chemotherapy, Charlson comorbidity index score ≥ 1, age ≥ 60 years, and advanced International Federation of Gynecology and Obstetrics stage. HDR-BT boost may be more beneficial than contemporary EBRT boost in selected patients with CC.     

Postoperative endoscopic retrograde high dose-rate brachytherapy for cholangiocarcinoma

Cholangiocarcinoma typically presents with disease unlikely to be completely resected, and prognosis remains poor. Improvements in imaging, endoscopy, and stenting have given rise to renewed interest in brachytherapy. Several recent retrospective series suggest a benefit to intraluminal brachytherapy, most commonly delivered by the transhepatic route. We describe a case in which brachytherapy was delivered via the nasobiliary route to address positive margins at the common bile duct stump. A custom catheter was manufactured to make the procedure feasible. Pertinent literature is reviewed, which supports the view that these malignancies benefit from high doses of radiation, if this can be achieved respecting normal tissue tolerance.     

Elimination of dose-rate effects by mild hyperthermia.

PURPOSE: Preferential amplification of low dose-rate irradiation toxicity in tumor cells is one way of improving presently applied brachytherapy. Low temperature hyperthermia applied to a tumor volume during irradiation is one candidate for reaching this goal. The ranges of relevant temperatures and dose-rate have been determined in a tissue culture system. In addition, the role of inhibition of sublethal damage repair in inhibition of dose-rate sparing has been investigated. METHODS AND MATERIALS: Dose-rate modification by long duration, mild hyperthermia was investigated in rat 9L gliosarcoma cells at dose-rates between 0.0833 and 132 Gy/hr. Enhancement of toxicity was measured using the colony formation technique. RESULTS: A biphasic dose-rate effect curve was observed when cells were irradiated at 37 degrees C. The dose required to kill 99% of cells irradiated at 37 degrees C increased sharply between 20 and 5 Gy/hr and also below 1 Gy/hr. When cells were irradiated at 41 degrees C, dose-rate sparing disappeared from 132 to 0.0833 Gy/hr. Elimination of dose-rate sparing appeared to be caused by both inhibition of sublethal damage repair and blockage of cell proliferation. The temperature threshold for sensitizing low dose-rate irradiation was determined at temperatures between 24 degrees C and 41 degrees C during 0.5 Gy/hr irradiation. Temperature dependent sensitization occurred above 39 degrees C. The mechanisms by which low temperature hyperthermia sensitizes low dose-rate irradiation was investigated using split dose experiments. Survival curve shoulder recovery was inhibited when cells were incubated at 41 degrees C between acute irradiations. This effect appeared to be caused by both inhibition of recovery from sublethal damage from the first radiation and preheating sensitization of the second irradiation. In single acute dose experiments, sensitization from preheating at 41 degrees C increased gradually over a 6 hr period. CONCLUSIONS: The mechanism by which 41 degrees C hyperthermia sensitizes low dose-rate irradiation is inhibition of radiation repair at medium dose rates and inhibition of repair and proliferation at very low dose rates. If low temperature hyperthermia is able to sensitize human tumor cells to brachytherapy similar to what has been described with 9L gliosarcoma cells, the addition of this modality could potentially greatly improve presently applied therapy.     

Fractionated high dose-rate versus low dose-rate regimens for intracavitary brachytherapy of the cervix: equivalent regimens for combined brachytherapy and external irradiation

The conventional treatment for carcinoma of the uterine cervix is a combination of external teletherapy and low dose-rate (LDR) intracavitary brachytherapy. Recently, however, there has been an increasing trend toward the use of high dose-rate (HDR) brachytherapy, in combination with external irradiation. The question is addressed of designing HDR treatments that will produce equivalent results to the more conventional protocols. We argue that for the unique case of radiotherapeutic treatment of carcinoma of the cervix, the criterion for producing an equivalent treatment should be based on the matching of early, not late, effects. In essence, this is because the dose to the tissues at risk for late effects is usually significantly smaller than the prescribed dose. When this effect is factored in with the different shape of dose-response curves for early and late effects, we conclude that, in the majority of cases, late effects will be no worse in a HDR regimen than a LDR regimen, provided that the corresponding doses have been matched to produce equal early effects. We provide a formalism whereby equivalent protocols can be designed for combined "external + HDR brachytherapy" regimens to match current "external + LDR brachytherapy" schedules. Using extensive basic radiobiological in vitro data derived from various cells of human origin, we provide specific examples of equivalent "external + HDR brachytherapy" regimens for 23 current "external + LDR brachytherapy" commonly-used schedules.     

Repair in the mouse lung during low dose-rate irradiation

The thorax of CBA mice was exposed to 60Co gamma-rays at dose rates ranging from 100 to 2 cGy/min. Iso-effect doses (ED50) were calculated for early and late lung damage from dose-response curves for breathing rate and lethality. A continuous increase in tolerance for early radiation pneumonitis was seen as the dose rate was reduced, reaching a dose recovery factor (DRF) of 2.6 at 2 cGy/min. There was significantly less dose sparing with 2 cGy/min for the rise in breathing rate during expression of late damage (DRF = 2.1). The lower DRF compared well with that obtained from late measurements of pleural fluid levels. Comparison with fractionation experiments indicated incomplete repair at 2 cGy/min with further dose recovery expected at even lower dose rates or at doses per fraction below 200 cGy. Since the dose-rate dependence of damage to haemopoietic tissue is less marked, this study predicts an advantage of employing low dose-rate total-body irradiation (TBI) in the treatment of bone-marrow transplant patients. A further gain in the therapeutic index may be expected using a hyperfractionated regime with small doses per fraction.     

High dose-rate brachytherapy for elderly patients with uterine cervical cancer

BACKGROUND: The need for radiotherapy (RT) in cancer treatment for the elderly patient is growing. The purpose of this study was to analyze the efficacy and complication rate for radiotherapy, using external-beam irradiation (EBRT) and high dose-rate intracavitary brachytherapy (HDRICB), for patients aged 70 years or older with carcinoma of the uterine cervix. METHODS: From September 1992 to December 1997, 295 patients diagnosed with uterine cervical cancer completed RT at the Shin Kong Memorial Hospital and China Medical College Hospital. Two hundred and fifty-eight patients [International Federation of Gynecology and Obstetrics (FIGO) stage distribution: 35 Ib, 26 IIa, 122 IIb, 10 IIIa, 58 IIIb, 7 IVa] who had undergone at least two courses of HDRICB and a minimum of 3 years of follow-up, were evaluated. A retrospective analysis was conducted to compare the outcome of radiation therapy for the 179 patients under 70 years of age (younger group) and the 79 patients aged 70 years or older (older group). The RT consisted of EBRT followed by HDRICB. After a total EBRT dose of 40-45 Gy/20 in 25 fractions, irradiating the whole pelvis over 4-5 weeks, dosage for patients diagnosed as FIGO stage IIb-IVa bilateral parametrial disease was boosted to 54-58 Gy, with central shielding. HDRICB was administered at 1-week intervals using an Ir-192 remote after-loading technique. Ninety-nine patients (38.4%) received three fractions of HDRICB, while 156 patients (60.5%) had four fractions. Total prescribed Point A dosages (EBRT + HDRICB) ranged from 58 to 71.6 Gy (median, 65.6 Gy) for stage IB-IIA, while for larger lesions (stage IIB-IVA) analogous dosages were 59-75.6 Gy (median, 65.6 Gy). Median follow-up durations for the older and younger groups were 56/55 months, respectively. RESULTS: The respective 5-year actuarial survivals (AS) for the older and younger groups were 82/85% for stage Ib, 65/65% for IIa, 61/71% for IIb and 35/59% for IIIa-b. The 5-year cause-specific survivals (CSS) for the older and younger groups were 100/95% for stage Ib, 85/75% for IIa, 78/72% for IIb and 42/61% for IIIa-b. The 5-year pelvic relapse-free survivals (PRFS) for the older and younger groups were 100/100% for stage Ib, 91/93% for IIa, 91/90% for IIb and 67/80% for IIIa-b. The 5-year distant metastasis-free survivals (DMFS) for older and younger groups were 100/100% for stage Ib, 92/88% for IIa, 84/73% for IIb and 55/75% for IIIa-b. There was no statistically significant survival difference on comparing the two groups according to stage. The gross tumor-free ratios after EBRT (NRT) for the older and younger groups were 44.3/24.5% (P = 0.001). The 5-year CSS for the 35 NRT patients was 88% for the older group, while for the 44 patients diagnosed with gross residual tumor after EBRT (GRT) it was 64% (P = 0.001). Twelve (15.0%) of the 79 older patients and 14 (7.8%) of the 179 younger patients developed RTOG grade 3-4 rectal complications (P = 0.12), while seven (8.9%) of the 79 older patients and 10 (5.6%) of the 179 younger patients developed RTOG grade 3-4 small bowel complications (P = 0.34). CONCLUSION: Radiation therapy, consisting of a combination of EBRT and three or four fractions of HDRICB, proved to be effective for older patients. Further optimization of treatment policy is essential by changing the HDRICB fractionation strategy, shortening the treatment time and designing combination drug regimens that are both effective and tolerable during radiotherapy.     

Beta dose-rate distributions in microscopic spherical tumors for intraperitoneal radioimmunotherapy

PURPOSE: This work was designed to calculate the radial beta dose-rate profiles through microscopic spherical tumors. Its application is in the treatment of micrometastases in the peritoneal cavity by the intraperitoneal administration of radiolabeled immunoliposomes. METHODS AND MATERIALS: Using previously published data for the dose-rate as a function of distance from a point source of activity, dose-rate profiles through five sizes of tumors (radii: 10 microm, 50 microm, 100 microm, 500 microm, 1 mm) for six different radionuclides ((188)Re, (186)Re, (32)P, (90)Y, (67)Cu, (131)I) were calculated. Dose-rate profiles were calculated for two source geometries: (1) a large bath of radioactivity in which the tumor is submerged, and (2) surface-bound radioactivity that results from tumor targeting. RESULTS: The bath geometry produced profiles that were uniform for sufficiently small tumors. For high-energy emitters (i.e., (90)Y and (188)Re), uniformity was maintained up to a tumor radius of 100 microm. For lower energy emitters (i.e., (67)Cu and (131)I) deviations from uniformity start to appear at a tumor radius of 50 microm. Surface-bound radioactivity produced a much greater range of dose-rates within tumors of all sizes. Lower energy emitters bound to the surface of tumors produce higher dose-rates for very small micrometastases compared with high-energy emitters. Upon consideration of the simultaneous contributions from both source geometries, we believe that liposome-mediated radioimmunotherapy would benefit from the inclusion of a high-energy beta emitter, possibly as a component of a cocktail of radionuclides. CONCLUSIONS: The calculated dose-rate profiles provide a tool for making tumor control probability estimations for micrometastases and for assessing the potential benefit offered by a targeted approach over a nontargeted approach. These calculations also suggest that the inclusion of a high-energy beta emitter is appropriate for this treatment modality.     

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.