High-dose-rate brachytherapy may be radiobiologically superior to low-dose rate due to slow repair of late-responding normal tissue cells.

BACKGROUND AND PURPOSE: Recent analysis of morbidity for patients treated with the continuous hyperfractionated accelerated radiotherapy (CHART) regimen demonstrates that repair half-times for late-reacting normal tissue cells are of the order of 4-5 h, which is considerably longer than previously believed. This would reduce repair of these tissue cells during a course of low-dose rate (LDR) brachytherapy, but have no effect at high-dose-rate (HDR), where there is no repair during, and full repair between fractions, regardless of repair half-time. The effect this has upon radiobiologic comparison of LDR and HDR is the topic of this paper. METHODS AND MATERIALS: The linear-quadratic (L-Q) model is used to compare late-effect biologically effective doses (BEDs) of LDR and HDR, for constant BED (tumor). The effects of dose rate (for LDR), fractionation (for HDR), and geometrical sparing of normal tissues are all considered. Repair half-times observed in the CHART study are used to investigate the potential impact of long repair times on the comparison of LDR and HDR. RESULTS: It is demonstrated that, for a repair half-time of 1.5 h for tumor cells, if the half-time for repair of late-reacting normal tissue cells exceeds about 2.5 h, LDR becomes radiobiologically inferior to HDR. Even with the least HDR-favorable combinations of parameters, HDR at over about 5 Gy/fraction ought to be radiobiologically superior to LDR at 0.5 Gy/h, so long as the time between HDR fractions is long compared to the repair half time. It is also shown that any geometrical sparing of normal tissues will benefit HDR more than LDR. CONCLUSION: The previously held belief that LDR must be inherently superior radiobiologically to HDR is wrong if the long repair times demonstrated in the recent CHART study are applicable to other late-reacting normal tissues. This could explain why HDR has been so successful in clinical practice, especially for the treatment of cervical cancer, despite previous convictions of radiobiologic inferiority of this modality.

Medical physics: some recollections in diagnostic X-ray imaging and therapeutic radiology.

Medical physics has changed dramatically since 1895. There was a period of slow evolutionary change during the first 70 years after Roentgen's discovery of x rays. With the advent of the computer, however, both diagnostic and therapeutic radiology have undergone rapid growth and changes. Technologic advances such as computed tomography and magnetic resonance imaging in diagnostic imaging and three-dimensional treatment planning systems, stereotactic radiosurgery, and intensity modulated radiation therapy in radiation oncology have resulted in substantial changes in medical physics. These advances have improved diagnostic imaging and radiation therapy while expanding the need for better educated and experienced medical physics staff.

Pulsed brachytherapy: a formalism to account for the variation in dose rate of the stepping source.

Pulsed brachytherapy is an endeavor to mimic low dose rate (LDR) treatments using a single higher activity source (a medium dose rate) that is periodically introduced into the patient (i.e., pulsed) using a remote afterloader. It has been reported that by a careful choice of pulse length and frequency and using the ERD bioeffect dose model, therapeutic advantage (TA) values slightly less than unity can be achieved where TA has been defined as the ratio of tumor ERD for PB to tumor ERD for LDR treatments for constant late-reacting normal tissue ERD. These calculations are based upon a uniform average dose rate in each pulse and equal repair rate constants for both tumor and normal tissue. In this paper, it is demonstrated that TAs of greater than 1 might be possible, depending upon the repair rate constants assumed for the tissues involved. Furthermore, for PB treatments the dose rate at a point of interest during each pulse is not uniform, since the treatment involves a single stepping source. A generalized ERD equation based on the linear quadratic model has been developed to account for the variation in the dose rate and, subsequently, to maximize the TA. Our calculations indicate that PB performed with 40 pulses in 120 hours with an irradiation time of 30 minutes per pulse with a delay time of two and a half hours is the best replacement for a LDR treatment that delivers 60 Gy in 120 hours.

Study of lung density corrections in a clinical trial (RTOG 88-08). Radiation Therapy Oncology Group.

PURPOSE: To investigate the effect of lung density corrections on the dose delivered to lung cancer radiotherapy patients in a multi-institutional clinical trial, and to determine whether commonly available density-correction algorithms are sufficient to improve the accuracy and precision of dose calculation in the clinical trials setting. METHODS AND MATERIALS: A benchmark problem was designed (and a corresponding phantom fabricated) to test density-correction algorithms under standard conditions for photon beams ranging from 60Co to 24 MV. Point doses and isodose distributions submitted for a Phase III trial in regionally advanced, unresectable non-small-cell lung cancer (Radiation Therapy Oncology Group 88-08) were calculated with and without density correction. Tumor doses were analyzed for 322 patients and 1236 separate fields. RESULTS: For the benchmark problem studied here, the overall correction factor for a four-field treatment varied significantly with energy, ranging from 1.14 (60Co) to 1.05 (24 MV) for measured doses, or 1.17 (60Co) to 1.05 (24 MV) for doses calculated by conventional density-correction algorithms. For the patient data, overall correction factors (calculated) ranged from 0.95 to 1.28, with a mean of 1.05 and distributional standard deviation of 0.05. The largest corrections were for lateral fields, with a mean correction factor of 1.11 and standard deviation of 0.08. CONCLUSIONS: Lung inhomogeneities can lead to significant variations in delivered dose between patients treated in a clinical trial. Existing density-correction algorithms are accurate enough to significantly reduce these variations.

High and low dose-rate brachytherapy for cervical carcinoma.

For the brachytherapy component of the radiation treatment of cervical carcinoma, high dose rate (HDR) is slowly replacing conventional low dose rate (LDR) due primarily to radiation safety and other physical benefits attributed to the HDR modality. Many radiation oncologists are reluctant to make this change because of perceived radiobiological disadvantages of HDR. However, in clinical practice HDR appears to be as effective as LDR but with a lower risk of late complications, as demonstrated by one randomized clinical trial and two comprehensive literature and practice surveys. The reason for this appears to be that the radiobiological disadvantages of HDR are outweighed by the physical advantages.

Hip stiffness following mixed conformal neutron and photon radiotherapy: a dose-volume relationship.

PURPOSE: To determine the relationship between dose, volume, and the incidence of hip stiffness in patients who received conformal neutron irradiation for prostate cancer. METHODS AND MATERIALS: A series of dose-searching studies using neutron irradiation for prostate cancer were performed to determine the optimal dose, fraction size, field size, technique, and proportions of photon and neutron dose. Neutron doses ranged from 9 to 20 Gy and photon doses ranged from 0 to 38 Gy. Data were analyzed by using a hip stiffness grading scale. RESULTS: Hip stiffness was recorded on follow-up examination in 30% of patients (40 out of 132) treated with fast neutrons or mixtures of fast neutron and photon radiation for prostate cancer. Hip stiffness was categorized as none (Grade 0, 92 patients), mild (Grade 1, 24 patients), moderate (Grade 2, 10 patients), or severe (Grade 3, 6 patients). The incidence of hip stiffness differed significantly by dose and volume in the five dose levels studied (p < 0.001). CONCLUSIONS: By using a mixture of conformal neutron and photon irradiation and limiting the total neutron dose to less than 13 Gy, hip stiffness toxicity could be reduced to acceptable levels.

Uses of therapeutic x rays in medicine.

Treatment of diseases with x rays began within months of Roentgen's discovery, and within four years x rays were being used successfully for the treatment of skin cancers. Deep-seated cancers began to be treated successfully in the 1920's with the advent of "deep" x-ray units and, especially, once supervoltage therapy machines became available in the 1930's. The 1940's and 1950's saw significant growth of megavoltage therapy, initially with Van de Graaff generators and betatrons, and later with linear accelerators. Linear accelerators became popular during the 1960's and 1970's and, by the 1980's they began to replace 60Co units as the most common form of treatment machine. With high-energy linear accelerators, computerized treatment planning, and ingenious fractionation schemes, modern radiotherapy has become a vital component of cancer treatment.

Is radiation-induced ovarian failure in rhesus monkeys preventable by luteinizing hormone-releasing hormone agonists?: Preliminary observations.

With the advent of cancer therapy, increasing numbers of cancer patients are achieving long term survival. Impaired ovarian function after radiation therapy has been reported in several studies. Some investigators have suggested that luteinizing hormone-releasing hormone agonists (LHRHa) can prevent radiation-induced ovarian injury in rodents. Adult female rhesus monkeys were given either vehicle or Leuprolide acetate before, during, and after radiation. Radiation was given in a dose of 200 rads/day for a total of 4000 rads to the ovaries. Frequent serum samples were assayed for estradiol (E2) and FSH. Ovariectomy was performed later. Ovaries were processed and serially sectioned. Follicle count and size distribution were determined. Shortly after radiation started, E2 dropped to low levels, at which it remained, whereas serum FSH level, which was low before radiation, rose soon after starting radiation. In monkeys treated with a combination of LHRHa and radiation, FSH started rising soon after the LHRHa-loaded minipump was removed (after the end of radiation). Serum E2 increased after the end of LHRHa treatment in the nonirradiated monkey, but not in the irradiated monkey. Follicle counts were not preserved in the LHRHa-treated monkeys that received radiation. The data demonstrated no protective effect of LHRHa treatment against radiation-induced ovarian injury in this rhesus monkey model.

Comparison of high and low dose rate remote afterloading for cervix cancer and the importance of fractionation.

Analysis of the data obtained from a survey of 56 institutions treating a total of over 17,000 cervix cancer patients with high dose rate (HDR) remote afterloading, shows that the average fractionation regimen is about 5 fractions of 7.5 Gy each to Point A, regardless of stage of disease. Comparison with historical controls treated by the same clinicians at low dose rate (LDR), showed that 5-year survival was statistically significantly better for HDR versus LDR for Stage III patients (47.2% compared to 42.6%, P = 0.005) and for all patients pooled together (60.8% vs. 59.0% P = 0.045). Morbidity rates were considerably lower for HDR versus LDR for both severe (2.23% vs. 5.34%, P less than 0.001) and moderate plus severe complications (9.05% vs. 20.66%, P less than 0.001). There is an apparent geometrical advantage of HDR intracavitary therapy in that there is a reduction in the "hot-spot" rectal and bladder doses relative to Point A of, on average, (13 +/- 4)% for the HDR compared to the LDR treatments. Fractionation of the HDR treatments significantly influenced toxicity: morbidity rates were highly significantly lower for Point A doses/fraction less than or equal to 7 Gy compared with greater than 7 Gy for both severe injuries (1.28% vs. 3.44%, P less than 0.001) and moderate plus severe (7.58% vs. 10.51%, P less than 0.001). The effect of dose/fraction on cure rates was equivocal. Finally, the data showed that for conversion from LDR to HDR the total dose to Point A was reduced on average by a factor 0.54 +/- 0.06.

Recent developments in time-dose modelling.

Two recent innovations in time-dose models are reviewed: the linear-quadratic (L-Q) and the variable-exponent Time-Dose Factor (TDF) models. The basic L-Q equations for fractionated and continuous (brachytherapy) regimes are presented as well as those for incomplete repair and short half life radionuclides. None of these equations has provision for a repopulation factor, so a "wasted ERD" parameter is introduced, which is a linear function of overall treatment time, with incorporation of a lag time if desired. For low dose rate therapy, an effective treatment time is defined, at which the ERD reaches its maximum value when the rate of increase due to irradiation equals the rate of decrease due to repopulation. The variable-exponent TDF model has a volume-effect parameter and scaling factors which make TDFs of 100 correspond to tolerance for all volumes of tissue treated, for both fractionated and continuous therapy. These, as well as the exponents, are all tissue-specific. Volume-effect and scaling factors are also appropriate for the L-Q equations. With these it is possible to apply the TDF and L-Q models to problems which involve inhomogeneous dose distributions. Several examples of the use of these models are presented.

Survival and complications in stage I carcinoma of corpus uteri receiving post-operative irradiation.

243 patients with carcinoma of corpus uteri were seen between 1980 and 1985, of which 175 Stage I cases were treated by one of six treatment protocols. The survivals of all six groups were comparable. Their complications are correlated with treatment and the time-dose factor (TDF) and extrapolated response dose (ERD) units for rectal radiation dose. As a result, a treatment policy has been adopted for Stage I disease. Total hysterectomy and bilateral salpingo-oophorectomy is followed by radiotherapy, based on the pathology report. Patients with well differentiated (Grade I) adenocarcinoma infiltrating only as far as the inner third of the myometrium have 33 Gy at 0.5 cm depth from the surface of the upper 3 cm of a vaginal applicator as a single treatment, at a dose rate of l Gy/h. in 48 patients there has to date been no significant reaction nor recurrent carcinoma. Fifty-three patients with more aggressive or invasive tumours were treated by external telecobalt irradiation to the pelvis, 45 Gy in 5 weeks, followed by intravaginal application of 15 Gy at 0.5 cm depth. Six percent had significant reactions, 94% are alive at 1-3 years and none had had a pelvic recurrence.

A unified approach to dose-effect relationships in radiotherapy. I: Modified TDF and linear quadratic equations.

A linear quadratic factor analogue (LQF) to the variable-exponent TDF model is introduced. In both of these models, account is taken of the volume of tissue irradiated. Scaling factors are used such that an LQF or a TDF of 100 represents tolerance for each volume or partial volume of each tissue or organ irradiated. These models are sufficient for tissues which are irradiated fairly homogeneously. Examples illustrate the use of these models.

A unified approach to dose-effect relationships in radiotherapy. II: Inhomogeneous dose distributions.

Conventional dose-effect relationships, such as those based upon the NSD or linear-quadratic concepts, do not account for dose inhomogeneities. Only a single "dose" value can be used in these equations and this can give rise to significant errors in the estimation of the "tolerance" dose in situations where dose distributions are inhomogeneous. This paper presents a method of "integrating" the biologically effective dose over the entire volume of each organ or tissue irradiated. Integral forms of the variable-exponent TDF and linear quadratic factor (LQF) models (ITDF and ILQF, respectively) can be used to determine whether or not any organ or tissue in an irradiated volume has exceeded tolerance, regardless of dose distribution non-uniformity. Several examples are given with comparisons to solutions obtained by conventional dose-effect models.