Clinical implications of incomplete repair parameters for rat spinal cord: the feasibility of large doses per fraction in PDR and HDR brachytherapy.

PURPOSE: To evaluate the clinical implications of the repair parameters determined experimentally in rat spinal cord and to test the feasibility of large doses per fraction or pulses in daytime high-dose-rate (HDR) or pulsed-dose-rate (PDR) brachytherapy treatment schedules as an alternative to continuous low-dose-rate (CLDR) brachytherapy. METHODS AND MATERIALS: BED calculations with the incomplete repair LQ-model were performed for a primary CLDR-brachytherapy treatment of 70 Gy in 140 h or a typical boost protocol of 25 Gy in 50 h after 46-Gy conventional external beam irradiation (ERT) at 2 Gy per fraction each day. Assuming biphasic repair kinetics and a variable dose rate for the iridium-192- (192Ir) stepping source, the LQ-model parameters for rat spinal cord as derived in three different experimental studies were used: (a) two repair processes with an alpha/beta ratio = 2.47 Gy and repair half-times of 0.2 h (12 min) and 2.2 h (Pop et. al.); (b) two repair processes with an alpha/beta ratio = 2.0 Gy and repair half-times of 0.7 h (42 min) and 3.8 h (Ang et al.); and (c) two repair processes with an alpha/beta ratio = 2.0 Gy and repair half-times of 0.25 h (15 min) and 6.4 h (Landuyt et al.). For tumor tissue, an alpha/beta ratio of 10 Gy and a monoexponential repair half time of 0.5 h was assumed. The calculated BED values were compared with the biologic effect of a clinical reference dose of conventional ERT with 2 Gy/day and complete repair between the fractions. Subsequently, assuming a two-catheter implant similar to that used in our experimental study and with the repair parameters derived in our rat model, BED calculations were performed for alternative PDR- and HDR-brachytherapy treatment schedules, in which the irradiation was delivered only during daytime. RESULTS: If the repair parameters of the study of Pop et al., Ang et al., or Landuyt et al. are used, for a CLDR-treatment of 70 Gy in 140 h, the calculated BED values were 117, 193, or 216 Gy(sc) (Gy(sc) was used to express the BED value for the spinal cord), respectively. These BED values correspond with total doses of conventional ERT of 65, 96, or 104 Gy. The latter two are unrealistic high values and illustrate the danger of a straightforward comparison of BED values if repair parameters are used in situations quite different from those in which they were derived. For a brachytherapy boost protocol, the impact of the different repair parameters is less, due to the fact that the percentage increase in total BED value by the brachytherapy boost is less than 50%. If a primary treatment with CLDR brachytherapy delivering 70 Gy in 140 h has to be replaced, high doses per fraction or pulses (> 1 Gy) during daytime can only be used if the overall treatment time is prolonged with 3-4 days. The dose rate during the fraction or pulse should not exceed 6 Gy/h. For a typical brachytherapy boost protocol after 46 Gy ERT, it seems to be safe to replace CLDR delivering a total dose of 25 Gy in 50 h by a total dose of 24 Gy in 4 days with HDR or PDR brachytherapy during daytime only. Total dose per day should be limited to 6 Gy, and the largest time interval as possible between each fraction or pulse should be used. CONCLUSION: Extrapolations based on longer repair half-times in a CLDR reference scheme may lead to the calculation of unrealistically high BED values and dangerously high doses for alternative HDR and PDR treatment schedules. Based on theoretical calculations with the IR model and using the repair parameters derived in our rat spinal cord model, it is estimated that with certain restrictions, large doses per fraction or pulses can be used during daytime schedules of HDR or PDR brachytherapy as an alternative to CLDR brachytherapy, especially for those treatment conditions in which brachytherapy is used after ERT for only less than 50% of the total dose.

Post-radiotherapy contrast enhancement changes in fast dynamic MRI of cervical carcinoma.

This pilot study determines fast dynamic gadolinium enhanced MRI contrast enhancement parameters (onset of enhancement and time to peak enhancement) before and after radiotherapy in 10 cervical carcinoma patients. Before radiotherapy, onset of enhancement and time to peak enhancement were early, with a median of 4.5 and 5.2 seconds, respectively. High-grade tumors showed early enhancement, compared with low-grade. After radiotherapy, contrast enhancement patterns differed. In survivors, onset of enhancement after radiotherapy was later than before radiotherapy. In non-survivors, onset of enhancement after radiotherapy was still early. The median difference in onset of enhancement before and after radiotherapy in survivors and non-survivors was an increase of 3.2 and a decrease of 1.1 seconds, respectively. Early onset of enhancement after radiotherapy was a better predictor for survival than a high-signal intensity zone on post radiotherapy unenhanced T1/T2-weighted MRI. It is concluded that enhancement parameters from fast dynamic Gd-enhanced MR images can provide additional functional information with regard to tumor vascularization, and may have prognostic significance. It complements clinical examination and unenhanced MRI in determining the effectiveness of radiotherapy treatment in cervical carcinoma. Future studies will focus on the clinical utility and improvements of the estimation of contrast-enhanced parameters with this new technique.

HDR brachytherapy applied to cervical carcinoma with moderate lateral expansion: modified principles of treatment.

BACKGROUND AND PURPOSE: In order to meet the deficiencies of endocavitary applications, a combined technique was introduced with the aim of achieving better target coverage for improvement of loco-regional tumour control. In high dose rate (HDR) endocavitary applications with tandem and ovoids, enlargement of the distance between the ovoids, shifting of dwell times and also optimization often fail to achieve sufficient expansion of the cervical parametrial area encompassed by the reference isodose. MATERIALS AND METHODS: The Deventer method, whereby HDR endocavitary and HDR interstitial brachytherapy are applied in the same session, was applied for tumours with a lateral expansion of 25 mm or more from the axis of the cervical canal. For the addition of HDR interstitial brachytherapy, each ovoid was provided with a channel which allowed insertion of an afterloading needle into the cervix up to a fixed depth. The dose specifications and dosimetry in neighbouring organs are presented in detail. RESULTS: Seventy-six combined applications were given to 41 patients. The follow-up averaged at 23 months, with a maximum of 59 months. No severe early or persistent late complications were observed. In stage IIB tumours, the most important evaluation of the merits of this technique, the disease-free 3-year survival determined with the Kaplan-Meier method was 75% (n=20). CONCLUSIONS: The Deventer method of HDR endocavitary and HDR interstitial brachytherapy applied in the same session is a feasible method for enlargement of the reference isodose envelope in the cervical parametrial area. The 3-year disease-free survival in stage IIB patients and the low complication rates in all stages together, justify its continuation.

Radiation tolerance of rat spinal cord to pulsed dose rate (PDR-) brachytherapy: the impact of differences in temporal dose distribution.

PURPOSE: To investigate the impact of a time-variable dose rate during a high dose rate (HDR-) or pulsed dose rate (PDR-) brachytherapy fraction with the HDR-microSelectron and to compare this with the biological effect of a constant dose rate treatment with the same average dose rate (as in the case of (192)Ir-wires). Moreover, the kinetics of repair in rat spinal cord are investigated using a wide spectrum of temporal dose distributions. MATERIALS AND METHODS: Two parallel catheters are inserted on each side of the vertebral bodies of the rat spinal column (Th(10)-L(4)) and connected to the HDR-microSelectron. Interstitial irradiation (IRT) is performed with a stepping (192)Ir-point source, varying the activity of the point source between 0.3 and 6.5 Ci. Three different groups of experiments are defined, varying the overall treatment time and average dose rates in the range of 3-8, 28-53 and 82-182 min and 312-489 Gy/h, 32-56 Gy/h and 13-15 Gy/h, respectively. Difference in temporal dose distribution (dose rate variation) during almost the same overall treatment time is obtained by varying the number of pulses per dwell position in either one or ten runs through the implant. For reasons of comparison, previously reported results of continuous irradiation at a constant dose rate obtained with two (192)Ir-wires in a fixed position are reanalyzed. Paralysis of the hindlegs after 5-6 months and histopathological examination of the spinal cord of each animal are used as experimental endpoints. RESULTS: During one run of the (192)Ir-point source, the peak dose rate is at least 25 times higher as compared with the minimum local dose rate and almost four times higher as compared with the average dose rate. For the three different groups of varying overall treatment times and average dose rates there is a significant difference in biological effect, with an ED(50)-value of 23.1-23.6 Gy (average dose rate 312-489 Gy/h), 25.4-27.9 Gy (average dose rate 312-489 Gy/h) and 29.3-33 Gy (average dose rate 13-15 Gy/h). For these range of single doses, difference in temporal dose distribution with either one or ten runs is only significant for treatment times less then 1 h. For the prolonged treatment times at lower average dose rates, the difference between one or ten run is no longer significant. However, the results with the (192)Ir-point source at an average dose rate/run of 13-15 Gy/h are significantly different from the ED(50)-value of 33 Gy using (192)Ir-wires at the same but constant dose rate. Using different types of analysis to estimate the repair parameters, the best fit of the data is obtained assuming biphasic repair kinetics and a variable dose rate (geometrically dependent) for the (192)Ir-point source. On the basis of the incomplete repair LQ model, two repair processes with an alpha/beta ratio=2.47 Gy and repair halftimes of 0.19 and 2.16 h are detected. The partition coefficient for the longer repair process is 0.98. This results in the proportion of total damage associated with the longer repair halftime being 0.495 for short sharp fractions with complete repair in between. CONCLUSIONS: Even in the range of high dose rates of 15-500 Gy/h, spinal cord radiation tolerance is significantly increased by a reduction in dose rate. For larger doses per fraction in PDR-brachytherapy dose rate variation is important, especially for tissues with very short repair half times (components). In rat spinal cord the repair of sublethal damage (SLD) is governed by a biphasic repair process with repair halftimes of 0.19 and 2.16 h.

Accelerated radiotherapy with carbogen and nicotinamide (ARCON) for laryngeal cancer.

BACKGROUND AND PURPOSE: Tumor hypoxia and tumor cell repopulation are known factors determining radiation response. Accelerated radiotherapy as a method to counteract cellular repopulation was combined with carbogen (95% O2 + 5% CO2) breathing and oral administration of nicotinamide as a means to improve tumor perfusion and oxygenation. The feasibility, toxicity and clinical effectiveness of this approach as a voice-preserving treatment for carcinoma of the larynx was assessed in a prospective study. PATIENTS AND METHODS: Sixty-two patients with stage III-IV laryngeal carcinoma were treated with a schedule of accelerated radiotherapy. The total radiation dose to the primary tumor was 64 Gy and that to the metastatic nodes was 68 Gy delivered in fractions of 2 Gy over 35-37 days. Radiotherapy was combined with carbogen breathing in the initial 11 patients and with both carbogen and nicotinamide administration in the subsequent 51 patients. RESULTS: After a median follow-up of 24 months, the actuarial local control rate at 2 years was 92%. This is higher than any previous report in the literature for this category of patients. Five patients had a local tumor recurrence and underwent laryngectomy. There was one regional recurrence. Including salvage surgery the loco-regional control rate was 100%. Four patients developed distant metastases and died. The actuarial overall survival rate at 2 years was 85%. Toxicity was increased relative to conventional radiotherapy but was considered as acceptable. One patient underwent laryngectomy for radiation-induced cartilage necrosis. CONCLUSION: These preliminary results indicate that advanced laryngeal cancer can be controlled in a high proportion of patients when treated with accelerated radiotherapy combined with carbogen and nicotinamide. This approach offers excellent possibilities for larynx preservation.

Tolerance of rat spinal cord to continuous interstitial irradiation.

PURPOSE: To study the kinetics of repair in rat spinal cord during continuous interstitial irradiation at different dose rates and to investigate the impact of a rapid dose fall off over the spinal cord thickness. MATERIAL AND METHODS: Two parallel catheters were inserted on each side of the vertebral bodies from the level of T10 to L4. These catheters were afterloaded with two 192Ir- wires of 4 cm length each (activity 1-10 mCi/cm) or connected to the HDR- microSelectron. Experiments have been carried out to obtain complete dose response curves at 7 different dose rates: 0.53, 0.90, 1.64, 2.56, 4.4, 9.9 and 120 Gy/h. Paralysis of the hindlegs after 5 - 6 months and histopathological examination of the spinal cord of each animal were used as experimental endpoints. RESULTS: The distribution of the histological damage was a good reflection of the rapid dose fall - off over the spinal cord, with white matter necrosis or demyelination predominantly seen in the dorsal tracts of the spinal cord or dorsal roots. With each reduction of the dose rate, spinal cord tolerance was significantly increased, with a maximum dose rate factor of 4.3 if the dose rate was reduced from 120 Gy/h to 0.53 Gy/h (ED50 of 17.3 Gy and 75.0 Gy, respectively). Estimates of the repair parameters using different types of analysis are presented. For the direct analysis the best fit of the data was obtained if a biexponential function for repair was used. For the 100% dose prescribed at the ventral side of the spinal cord the alpha/beta ratio is 1.8 Gy (0.8 - 2.8) and two components of repair are observed: a slow component of repair of 2.44 h (1.18 - infinity) and a fast component of 0.15 h (0.02 - infinity). The proportion of the damage repaired with the slow component is 0.59 (0.18 - 1). For the maximum of 150% of the prescribed dose at the dorsal side of the spinal cord the alpha/beta ratio is 2.7 Gy (1.5 - 4.4); the two components for the kinetics of repair remain the same. CONCLUSIONS: Spinal cord radiation tolerance is significantly increased by a reduction in dose rate. Depending on the dose prescription, the alpha/beta ratio is 1.8 or 2.7 Gy for the 100% and 150% of the reference dose (rate), respectively; for the kinetics of repair a biphasic pattern is observed, with a slow component of 2.44 hours and a fast component of 0.15 hours, which is independent of the dose prescription.

High dose rate (HDR) and low dose rate (LDR) interstitial irradiation (IRT) of the rat spinal cord.

PURPOSE: To describe a newly developed technique to study radiation tolerance of rat spinal cord to continuous interstitial irradiation (IRT) at different dose rates. MATERIAL AND METHODS: Two parallel catheters are inserted just laterally on each side of the vertebral bodies from the level of Th10 to L4. These catheters are afterloaded with two 192Ir wires of 4 cm length each (activity 1-2.3 mCi/cm) for the low dose rate (LDR) IRT or connected to the HDR micro-Selectron for the high dose rate (HDR) IRT. Spinal cord target volume is located at the level of Th12-L2. Due to the rapid dose fall-off around the implanted sources, a dose inhomogeneity across the spinal cord thickness is obtained in the dorso-ventral direction. Using the 100% reference dose (rate) at the ventral side of the spinal cord to prescribe the dose, experiments have been carried out to obtain complete dose response curves at average dose rates of 0.49, 0.96 and 120 Gy/h. Paralysis of the hind-legs after 5-6 months and histopathological examination of the spinal cord of each irradiated rat are used as experimental endpoints. RESULTS: The histopathological damage seen after irradiation is clearly reflected the inhomogeneous dose distribution around the implanted catheters, with the damage predominantly located in the dorsal tract of the cord or dorsal roots. With each reduction in average dose rate, spinal cord radiation tolerance is significantly increased. When the dose is prescribed at the 100% reference dose rate, the ED50 (induction of paresis in 50% of the animals) for the HDR-IRT is 17.3 Gy. If the average dose rate is reduced from 120 Gy/h to 0.96 or 0.49 Gy/h, a 2.9- or 4.7-fold increase in the ED50 values to 50.3 Gy and 80.9 Gy is observed; for the dose prescribed at the 150% reference dose rate (dorsal side of cord) ED50 values are 26.0, 75.5 and 121.4 Gy, respectively. Using different types of analysis and in dependence of the dose prescription and reference dose rate, the alpha/beta ratio varies between 1.46 (0.06-3.08 CL) and 2.17 Gy (0.08-4.61). The half time of repair during continuous irradiation is 1.76 h (1.33-2.64), while no indication is found for a biphasic pattern of the kinetics of repair. CONCLUSION: The implantation technique in our study has shown to be a reliable model to compare the effectiveness of HDR- and LDR-interstitial continuous irradiation at different dose rates.

Constraints in the use of repair half times and mathematical modelling for the clinical application of HDR and PDR treatment schedules as an alternative for LDR brachytherapy.

Using theoretical models based on radiobiological principles for the design of new treatment schedules for HDR and PDR brachytherapy, it is important to realise the impact of assumptions regarding the kinetics of repair. Extrapolations based on longer repair half times in a continuous LDR reference scheme may lead to the calculation of dangerously high doses for alternative HDR and PDR treatment schedules. We used the clinical experience obtained with conventional ERT and LDR brachytherapy in head and neck cancer as a clinical guideline to check the impact of the radiobiological parameters used. Biologically equivalent dose (BED) values for the in clinical practice of LDR brachytherapy recommended dose of 65-70 Gy (prescribed at a dose rate between 30-50 cGy/h) are calculated as a function of the repair half time. These BED values are compared with the biological effect of a clinical reference dose of conventional ERT with 2 Gy/day and complete repair between the fractions. From this comparison of LDR and ERT treatment schedules, a range of values for the repair half times of acute or late responding tissues is demarcated with a reasonable fit to the clinical data. For the acute effects (or tumor control) the best fits are obtained for repair half times of about 0.5 h, while for late effects the repair half times are at least 1 h and can be as high as 3 h. Within these ranges of repair half times for acute and late effects, the outcome of "alternative' HDR or PDR treatment schedules are discussed. It is predominantly the late reacting normal tissue with the longer repair half time for which problems will be encountered and no or only marginal gain is to be expected of decreasing the dose rate per pulse in PDR brachytherapy.

Radiotherapy with carbogen breathing and nicotinamide in head and neck cancer: feasibility and toxicity.

The feasibility and early toxicity of radiotherapy with carbogen breathing and nicotinamide was tested in 74 head and neck cancer patients. Forty patients with laryngeal and hypopharyngeal tumors were treated with an accelerated schedule combined with carbogen alone (16) or with carbogen and nicotinamide (24). Thirty-four patients with far advanced unresectable tumors of the oral cavity and oropharynx received conventional radiotherapy with carbogen [16] or with carbogen and nicotinamide (18). Some enhancement of skin reaction was observed with nicotinamide but this remained well within limits of tolerance. With the accelerated regimen there was increased severity of mucosal damage expressed as confluent mucositis in 95% of patients which required healing times of 3-4 months in four patients. Eventually restoration of the mucosal lining was complete in all cases. Nausea and vomiting are the most frequent side effects of nicotinamide and were reported by 60% and 36% of the subjects, respectively. In 26% this was reason to discontinue drug intake. Severe renal dysfunction was associated with nicotinamide intake in two patients of this study and in one other patient who presented later. It is our conclusion that radiotherapy combined with carbogen and nicotinamide is a safe treatment with manageable side effects. We recommend not to give nicotinamide concomitantly with nephrotoxic medication or to patients who have impaired renal function. Preliminary tumor control rates are encouraging and clinical testing will be continued.

High dose rate intracavitary brachytherapy of early and superficial carcinoma of the nasal vestibule as an alternative to low dose rate interstitial radiation therapy.

A new technique of high dose rate intracavitary brachytherapy is introduced for treating patients with early and superficial squamous cell carcinoma of the nasal vestibule. This method is illustrated by a case report. A customized intranasal mould was fabricated in which afterloading catheters were placed. These catheters were loaded with a high activity 192Ir pointsource, using the HDR-microSelectron. In this way the patient was treated twice daily over 5 days without hospitalization. The indications for the use of this technique and the advantages in comparison with low dose rate interstitial irradiation are discussed.

Evaluation of treatment results of squamous cell carcinoma of the buccal mucosa.

Of the 49 patients with squamous cell carcinoma of the buccal mucosa referred to the Rotterdam Radio-Therapeutic Institute (RRTI) and Universital Hospital Dijkzigt Rotterdam (AZD) during 1970-1984, 31 patients had an advanced stage of disease, 21 patients had clinical evidence of lymph node metastasis. Forty patients were treated with curative intention. Treatment modalities were: radiation therapy, preoperative radiation followed by surgery, and primary surgery. Eighteen of the 40 patients (45%) developed a local tumor recurrence; nearly all recurrences occurred within 2 years. The incidence was equal in all treatment groups. Of the 22 patients with initial clinically negative neck, regional relapse occurred in 3 of the 14 patients, of whom the neck was not treated electively by radiation therapy; all three in combination with a local recurrence. None of the 8 patients with electively irradiated necks developed a regional relapse. Eight of the 18 patients with initial clinically enlarged lymph nodes treated either by radiotherapy or surgery, developed a regional relapse, 5 in combination with a local recurrence. Treatment of the clinically positive neck by neck dissection was superior to radiotherapy. Local recurrence carried a poor prognosis. Almost 70% died of their disease. The overall and corrected 5-year survival was 38% and 52% respectively.