Effects of paternal exposure to prolonged stress on the mental health of the spouse and children. Families of Canadian Army survivors of the Japanese World War II CAMPS

The dose in the build-up region for four different Cobalt-60 therapy units was measured. It was found that, for large collimator openings and relatively short SSDs, a new dose peak occurs at a depth very much smaller than 0.5 cm. The dose at this peak is a function of collimator openings and SSDs and, in some extreme case, could be 15% or more higher than the dose at the conventional peak dose of 0.5 cm. The new dose peak is probably due to electrons produced in the source capsule and the part of the collimator close to the source; it can be almost eliminated by a filter placed just below the collimator.     

Fetal dose estimates for electron-beam treatment to the chest wall of a pregnant patient

The purpose of this report is to discuss dosimetry and shielding for electron-beam radiotherapy of pregnant patients. Specifically, we have determined fetal dose for a pregnant patient considering electron radiotherapy for a chest wall recurrence of breast cancer. The treatment was simulated using an anthropomorphic phantom, and the measured dose to the unshielded fetus for this plan was 5.3 cGy, a level at which risk to the fetus is uncertain. Therefore abdominal shielding, consisting of 6.6 cm of lead, was used to reduce the dose to the fetus to less than 1.5 cGy, a level considered to be of little risk. We further found that using the lower (instead of upper) variable trimmer bars to define the field edge closest to the fetus resulted in approximately 30% lower dose to the fetus. These results show that it is possible to reduce fetal dose to acceptable limits in electron-beam radiotherapy of the chest wall using the general principles recommended for photon-beam radiotherapy.     

Quantalization of continuous data for benchmark dose estimation

Benchmark doses corresponding to low levels of noncancer disease risk have been proposed to replace the no-observed-adverse-effect level for establishing allowable daily intakes or reference doses. For quantal data each animal is classified with or without a disease. The proportion of animals with an adverse effect (risk) is observed as a function of dose of a toxic substance. The calculation of a benchmark dose is relatively straightforward. For continuous data a somewhat more complicated designation of risk is required. Because of the more direct procedures with quantal data, consideration could be given to converting continuous data to quantal data before estimating benchmark doses. The purpose of this paper is to compare the precision of the two approaches (use of continuous or quantalized data) for a number of sublinear dose-response curves ranging from low to high probabilities of risk at the highest dose. In these studies, five animals per dose were generally satisfactory to estimate the benchmark dose for continuous data, whereas the corresponding quantalized data generally do not perform as well even with 10 to 20 animals per dose. For quantalized data, the lower 95% confidence limits on the estimates of the benchmark dose were generally a factor of 3 to 4 below the true benchmark dose, whereas the confidence limits using the continuous data were generally within a factor of 2 of the true benchmark dose. Although the use of quantalized data for the estimation of risk is more direct, estimates of benchmark doses using the continuous data were more precise. Based on this study, converting continuous data to quantal data is not recommended.     

Vitamin E in the treatment of tardive dyskinesia: a preliminary study over 7 months at different doses

Vitamin E has been suggested to be a promising new treatment for tardive dyskinesia. However, little is known about the optimum dose. Twenty patients with tardive dyskinesia whose medication had been unchanged for at least 1 month were selected and randomly divided into a treatment group with 11 patients and a control group with nine patients. The treatment group was started on 600 mg of vitamin E per day, and this dose was increased over the 7 months of the trial to 1600 mg per day. The medication for the control group was unchanged. Severity of tardive dyskinesia was rated on the Abnormal Involuntary Movement Scale. Patients in the treatment group initially showed a significant response to the lower dose of 600 mg per day. However, this improvement was not maintained and differences between the two groups reached significant levels only after the dose of vitamin E was increased to 1600 mg per day. At this dose, there was a significant and sustained reduction in the severity of tardive dyskinesia. The results suggest that vitamin E is of value in the treatment of tardive dyskinesia and that the optimum dose for treating tardive dyskinesia is 1600 mg per day. In addition, there may be a dose related therapeutic effect of Vitamin E in tardive dyskinesia.     

Follow-up study of patients treated by x-ray epilation for tinea capitis. Estimation of the dose to the thyroid and pituitary glands and other structures of the head and neck

This study is a further investigation of radiation dose to various head structures in the children given X-ray therapy for tinea capitis (ringworm of the scalp). In this work, estimates of the dose to the thyroid and pituitary gland were obtained with lithium fluoride thermoluminescent dosemeters using a child's head phantom. Doses were also measured for the parotid gland and several skin sites where skin tumours developed in the irradiated cases. In a previous study, brain and scalp doses of 140 and 500-800 rad had been estimated for the treated group using this same head phantom. In this work dosemeters were also placed in the same brain locations so that comparisons could be obtained between the two studies. The thyroid dose was estimated to be 6 +/- 2 rad and the pituitary dose was 49 +/- 6 rad for the conventional tinea capitis treatment. The dose to the parotid gland was 39 rad and the dose to skin sites on the face and neck where tumours occurred ranged from 20 to 40 rad. The data for the thyroid adenoma response from this and other studies involving irradiation of children suggests a linear dose-response relationship within the first 30-40 years after exposure with a risk of about 0-04% per rad.     

Optimization of permanent 125I prostate implants using fast simulated annealing

PURPOSE: Treatment planning of ultrasound-guided transperineal 125I permanent prostatic implants is a time-consuming task, due to the large number of seeds used and the very large number of possible source arrangements within the target volume. The goal of this work is to develop an algorithm based on fast simulated annealing allowing consistent and automatic dose distribution optimization in permanent 125I prostatic implants. METHODS AND MATERIALS: Fast simulated annealing is used to optimize the dose distribution by finding the best seed distribution through the minimization of a cost function. The cost function includes constraints on the dose at the periphery of the planned target volume and on the dose uniformity within this volume. Adjustment between peripheral dose and the dose uniformity can be achieved by varying the weight factor in the cost function. RESULTS: Fast simulated annealing algorithm finds very good seed distributions within 20,000 iterations. The computer time needed for the optimization of a typical permanent implant involving 60 seeds and 14 needles is approximately 15 min. An additional 5 min are necessary for isodose distribution computations and miscellaneous outputs. CONCLUSION: The use of fast simulated annealing allows for an efficient and rapid optimization of dose distribution. This algorithm is now routinely used at our institution in the clinical planning of 125I permanent transperineal prostate implants for early stage prostatic carcinoma.     

A new genetic algorithm technique in optimization of permanent 125I prostate implants

Real time optimized treatment planning at the time of the implant is desirable for ultrasound-guided transperineal 125I permanent prostate implants. Currently available optimization algorithms are too slow to be used in the operating room. The goal of this work is to develop a robust optimization algorithm, which is suitable for such application. Three different genetic algorithms (sGA, sureGA and securGA) were developed and compared in terms of the number of function evaluations and the corresponding fitness. The optimized dose distribution was achieved by searching the best seed distribution through the minimization of a cost function. The cost function included constraints on the periphery dose of the planned target volume, the dose uniformity within the target volume, and the dose to the critical structure. Adjustment between the peripheral dose, the dose uniformity and critical structure dose can be achieved by varying the weighting factors in the cost function. All plans were evaluated in terms of the dose nonuniformity ratio, the conformation number and the dose volume histograms. Among these three GA algorithms, the securGA provided the best performance. Within 2500 function evaluations, the near optimum results were obtained. For a large target volume (5 cm x 4 cm x 4.5 cm) including urethra with 20 needles, the computer time needed for the optimization was less than 5 min on a HP735 workstation. The results showed that once the best set of parameters was found, they were applicable for all sizes of prostate volume. For a fixed needle geometry, the optimized plan showed much better dose distribution than that of nonoptimized plan. If the critical structure was considered in the optimization, the dose to the critical structure could be minimized. In the cases of irregular and skewed needle geometry, the optimized treatment plans were almost as good as ideal needle geometry. It is concluded that this new genetic algorithm (securGA) allows for an efficient and rapid optimization of dose distribution, which is suitable for real time treatment planning optimization for ultrasound-guided prostate implant.     

Estimation of the interindividual variability in the one-compartment pharmacokinetic model for methylmercury: implications for the derivation of a reference dose

A critical step in the U.S. EPA's derivation of an Reference Dose (RfD) for methylmercury is conversion of the maternal hair Hg concentration of 11 ppm to average daily intake using the one-compartment pharmacokinetic model. A default uncertainty factor (UF) adjustment of 3 for interindividual variability was then applied to this conversion. A probabilistic (Monte Carlo) analysis is presented estimating the interindividual variability inherent in this dose conversion for women 18-40 years old based on data in the scientific literature. The dose of 1.1 micrograms/kg/day, calculated by the U.S. EPA to correspond to 11 ppm Hg in hair, is estimated in this analysis to be larger than 94-99% of corresponding doses. The application of a UF of 3 to this U.S. EPA value gives a dose which is estimated to be larger than 28-73% of corresponding doses. This analysis suggests that if the dose conversion in the RfD is intended to be inclusive of 95-99% of women 18-40, the daily intake should be set at 0.1-0.3 microgram/kg/day. The RfD of 0.03-0.1 microgram/kg/day, derived from this dose by the U.S. EPA's application of an additional UF of 3 for additional toxicologic concerns, is somewhat smaller than the current RfD of 0.1 microgram/kg/day.     

Dosimetry of a blood irradiator

BACKGROUND: Blood and blood products are irradiated to avoid the graft-versus-host disease (GVHD) in immunosuppressed patients and to destroy tumor cells during the intra-operative autotransfusion in tumor surgery. For that purpose more and more dedicated gamma irradiators are used. In most cases the equipment is supplied with a dose calibration factor for a totally filled irradiation canister. As users handle different blood product volumes, it is necessary to investigate the influence of the irradiated blood volume on the absolute dose in a reference point and the dose distribution in the irradiation volume. MATERIAL AND METHODS: The dose rate in the center of an empty irradiation canister of an IBL 437C blood irradiator (CIS Diagnostic) was investigated by means of Fricke solution dosimeters from the Physikalisch-Technische Bundesanstalt (PTB). Using thermoluminescence dosimetry (TLD) this value could be transferred to a situation with an empty or completely filled respectively with 2 blood samples (270 ml each) filled canister. Also essential for the irradiation of blood is the knowledge of the dose distribution in the irradiated volume. The distributions in the empty and the realistic filled canister were measured by positioning the TLD on the plexiglas holder in a regular pattern. The case of a completely filled container was investigated by means of the MR Fricke gel dosimetry. All distributions are presented as dose-volume-histograms (DVH). RESULTS: The TLD-measurement in the center of the completely filled canister yielded a 4.8% higher dose rate value as compared to the suppliers certificate. From the investigations using the Fricke solution dosimeters in air combined with TLD-measurements values for the complete bandwidth of different container fillings could be derived. So the dose rate in the centre of the canister in the boundary conditions empty and full canister as compared to the values for the realistic filling condition (2 bags) are 117.5% and 94% respectively. Axial dose distributions and DVH have been determined for the 3 filling conditions. CONCLUSIONS: We recommend a dose calibration measurement of a blood irradiator to determine the irradiation times for the chosen filling condition, which is typical for the hospital. The DVH presented in this work can be used to derive a value for the dose variance within the irradiated blood.     

In vitro performance of three combinations of spacers and pressurized metered dose inhalers for treatment in children

The performance of pressurized metered dose inhalers (pMDIs) and spacers in correct dose recommendations is important, but limited information on dose delivery and fine-particle dose from different combinations of spacers and pMDIs is available. In this study, three combinations of spacers and pMDIs were investigated: NebuChamber and AeroChamber with budesonide pMDI and Babyhaler with fluticasone propionate pMDI. Doses were withdrawn onto a filter either with a breathing simulator (dose to ventilator) or with constant flow (maximal dose). The fine-particle dose was assessed with a cascade impactor (Andersen Sampler). The effect of repeated use and cleaning of the spacers on the passive fallout of aerosol within the spacers was determined by evacuating the dose on a filter 2, 5, 10 and 30 s after actuating the spray. The drugs were quantified by liquid chromatography. The NebuChamber delivered the highest doses, both maximal dose and dose to ventilator. The recovered doses (means+/-SD) were 55+/-6% and 51+/-2%, respectively, of the delivered dose from the pMDI. The corresponding results for the Babyhaler were 41+/-7% and 24+/-4% and for the Aerochamber 27+/-3% and 17+/-3%. The passive fallout of aerosol, determined as half-life (t1/2) was around approximately 30 s for the NebuChamber, 9-15 s for the Babyhaler and approximately 10 s for the AeroChamber. The present study confirms that there are significant differences in dose output from different combinations of pressurized metered dose inhalers and spacers, with the NebuChamber giving the highest dose, both as delivered dose and in droplets <4.7 microm. Interactions with the spacer material, dead space in the inspiratory line and entrainment of air during inhalation due to inefficient valve control could account for these differences.     

Management of primary postpartum haemorrhage

BACKGROUND AND PURPOSE: The use of new materials in radiotherapy requires an investigation of the effects of these materials on the relevant beam parameters. The high strength and low density of carbon fibre suggest an excellent material for table inserts with minimal attenuation, without changing the skin sparing effect in the build-up zone. MATERIALS AND METHODS: In this paper three different carbon fibre plates and two conventionally table top materials are studied in Co-60, 6 MV and 23 MV photon beams. RESULTS AND CONCLUSIONS: From depth dose measurements it is clear that the dose in the build-up zone is influenced in the qualities of the beams. The mutual differences for the three carbon plates are minimal. For Co-60 the depth of the maximum dose is decreased by carbon from 5 to 2 mm and the surface dose is increased from 18 to 76%. For 6 and 23 MV the surface dose is increased from 21 to 52% and 20 to 32%, respectively, as well as the dose in the build-up region. A transmission of 99% was measured for two carbon plates out of three in Co-60 and for one out of three in 6 MV.     

Conversion of ionization measurements to radiation absorbed dose in non-water density material

The radiation absorbed dose to non-water equivalent materials of interest in radiotherapy is the dose to lung and the dose to bone. The measurement and calculation of dose to the lung has been of great interest and much effort has gone into the development of accurate lung dose calculation methods. The radiation absorbed dose to the bone is usually not calculated and most absorbed dose calculations have been done without correcting for the presence of bone. For the lower megavoltage photon beams this may be appropriate, however, as the energy of the photon beam increases, the region of electronic disequilibrium becomes larger and pair production which depends on the atomic number of the material becomes significant. Therefore the bone will produce greater perturbations of the dose distribution. The dose to lung-equivalent material is uniquely obtained from ionization measurements. However, in bone-equivalent materials two different calculations of absorbed dose are possible: the absorbed dose to soft tissue plastic (polystyrene) within bone-equivalent material and the dose to the bone-equivalent material itself. Both can be calculated from ionization measurements in phantoms. These two calculations result in significantly different doses in a heterogeneous phantom composed of polystyrene and aluminium (a bone substitute). The dose to a thin slab of polystyrene in aluminium is much higher than the dose to the aluminium itself at the same depth in the aluminium. Monte Carlo calculations confirm that the calculation of dose to polystyrene in aluminium can be accurately carried out using existing dosimetry protocols. However, the conversion of ionization measurements to absorbed dose to high atomic number materials cannot be accurately carried out with existing protocols and appropriate conversion factors need to be determined.     

Implementation and evaluation of patient-specific three-dimensional internal dosimetry

Current methods for calculating the absorbed dose in a target region from a source region rely on a standard "reference man" geometry and assume an uniform distribution of radiolabel. While this approach is acceptable at the low levels of radioisotope administered for most diagnostic purposes, the generality of the calculations is not adequate for doses at the higher levels required for therapy and is not easily extendible to tumor dosimetry. METHODS: We have developed an integrated system which utilizes patient anatomy and radionuclide distribution in the calculation of absorbed dose rate or total dose to any user-defined target region. Images of radionuclide distribution (PET/SPECT) are registered to anatomic images (CT/ MRI) and then entered into a three-dimensional internal dosimetry software system (3D-ID) where regions of interest are defined. Dose calculations are performed by the mathematical convolution between a user-specified, dose-point kernel with the activity in the source volume over the target volume. The resulting dose rate distribution may be scaled by cumulated activity to yield absorbed dose. In addition to calculating the mean dose, dose-volume histograms may be generated which plot absorbed dose with respect to percent of volume. The method was evaluated using selected standard man phantom organs. RESULTS: Dose estimates for two patient studies are included to illustrate differences between patient-specific and MIRD-based calculations. The package provides an alternative approach to image display and three-dimensional internal dose calculations. CONCLUSION: The dose-volume histogram representation of absorbed dose to a target volume provides valuable information in assessing tumor control probability and normal tissue toxicity.     

Effect of guarana on exercise in normal and epinephrine-induced glycogenolytic mice

For cells irradiated by alpha particles in suspension, there is presently no simple test to show that the cell killing can be attributed to alpha-particle passages through the nuclei. In this communication, for a uniform distribution of alpha-particle sources and spherical nuclei, a D0 is calculated such that at least 63% of the cell nuclei have at least one alpha-particle passage. For a uniform distribution of alpha-particle sources and spherical nuclei, it is shown that the average dose for 63% of the cell nuclei to be hit (37% not hit) is equal to the average dose per hit. For this condition an energy deposition of any size would result in cell death and the average dose is the minimum D0 possible. Minimum D0 values are calculated using a Monte Carlo treatment for nuclear diameters from 4 to 10 microm and initial alpha-particle energies between 3.18 and 8.38 MeV.     

PC-assisted three-dimensional description of organs containing tubular structures, applied on the epididymis of the rat

AIM: Although the relationship between the dose delivered to adjacent organs (urinary bladder and rectum) and the frequency and severity of treatment complications has been reported in many series, the factors influencing pelvic dose distribution are not well defined. The aim of the study was to assess retrospectively the influence of the size of cervical cancer brachytherapy applicators (ovoids and uterine tandems) on pelvic dose distribution and the impact of various therapy-dependent factors on patient anatomy and on dose distribution in particular applications. PATIENTS AND METHOD: The subject of this study were 356 cervical cancer patients treated with Selectron LDR as a part of their radical radiotherapy. Analysed factors included preceding external beam radiotherapy (EBRT) or brachytherapy applications, use of general anaesthesia for application and the system of pellet loading. RESULTS: Significant correlation was found between the size of applicators and doses to bladder, rectum and points B: larger vaginal applicators produced lower dose in bladder and rectum and higher dose in point B (all p < 0.0001), longer uterine tandems produced lower dose in rectum and higher dose in point B (both p < 0.0001). Significant decrease in the frequency of use of large applicators (ovoids: p < 0.0001, tandems: p = 0.055) and worsening of dose distribution, i.e. higher doses to critical organs (respectively: bladder p = 0.0012, rectum p = 0.02) and lower point B dose (p = 0.0001) were observed at consecutive brachytherapy applications. Similar situation occurred in patients, who received EBRT prior to brachytherapy (ovoids: p < 0.001, tandem: p = 0.04, bladder dose: p = 0.009, rectal dose: p = 0.073, point B dose: p = 0.059). Vaginal applicators were larger (p = 0.026) and the dose distribution was better (bladder: p = 0.023, rectum: p = 0.002, point B: p = 0.0001) in patients who had their insertions performed under general anaesthesia. The comparison of 2 consecutively used systems of pellet loading revealed more favourable dose distribution: lower dose for bladder (p = 0.014) and higher dose for point B (p < 0.0001) for the system, which utilised more sources in ovoids and in the distal part of the uterine tandem, in spite of more frequent use of smaller applicators in this group of patients. In multivariate analysis ovoid size was related to preceding external beam radiotherapy (p = 0.025). Uterine tandem length was dependent on the number of preceding intracavitary applications (p < 0.001) and preceding external beam radiotherapy (p = 0.007). Bladder dose was related to preceding brachytherapy (p = 0.011) and the pattern of pellet loading (p = 0.031). Rectal dose was dependent only on the use of general anaesthesia during application (p = 0.001) and point B dose was dependent on the pattern of pellet loading (p < 0.001) and marginally-on the use of preceding external beam radiotherapy (p = 0.06). CONCLUSIONS: The results of this study allow for identification of treatment-related factors determining pelvic dose distribution in cervical cancer brachytherapy and may potentially enable optimisation of this distribution in particular clinical situation.     

Expression of p21(waf1/cip1) protein in transitional cell bladder tumours and its prognostic value

Selective antagonists to the Type 3 serotonin receptor (5HT3) in combination with corticosteroids are now considered the standard of care for the prevention of emesis from moderately to highly emetogenic chemotherapy. Here we address issues of optimal dose, schedule and route of administration of four currently available selectable 5HT3 antagonists. This paper utilizes an evidence based medicine approach to the literature regarding this class of drugs, emphasizing the results large, randomized, controlled trials to make formal recommendations concerning optimal use of this important new class of anti-emetic agents. We conclude that for each drug there is a plateau in therapeutic efficacy at a definable dose level above which further dose escalation does not improve outcome. Furthermore, a single dose is as effective as multiple doses or continuous infusion, and finally, emerging data demonstrate that the oral route is equally efficacious as the intravenous route of administration, even with highly emetogenic chemotherapy.     

Effect of motilin on the lower esophageal sphincter of the opossum

We have studied the effect of Yajima's synthetic motilin on the lower esophageal sphincter (LES) of the opossum and compared its potency to that of gastrin and its interaction with secretin. Dose-response curves for the LES were constructed from the intravenous bolus injection of graded doses of motilin and gastrin alone and motilin given against a background infusion of secretin. The smallest dose of motilin that elicited a significant response was 0.05 microng/kg, and the highest response was observed with the highest dose used in this study (1.0 microng/kg). Over a wide dose range, both motilin and gastrin were found to be equally potent in stimulating the LES of the opposum, and secretin caused inhibition of the LES pressure to motilin. Therefore, we conclude that (1) motilin is a potent stimulant of the LES; (2) this response is dose dependent; (3) motilin's potency is similar to that of gastrin; and (4) secretin counteracts the effect of motilin on the LES.     

Characterization of the minimal lethal dose of gamma irradiation for Penicillium citrinum

The use of nuclear power through radiation for the destruction of microorganisms which cause food decay, and toxicosis, is specifically for peaceful purposes. Penicillium citrinum is a fungus which produce mycotoxins responsible for intoxication in humans and animals as a result of eating contaminated food. There is little informations on the resistance of P. citrinum to radiation. The objective of this research is to determine the lethal dose of gama radiation for these microorganisms. Seventy six suspensions containing approximately 100,000 spores/ml received a dose of radiation between 0.2 and 2.2 KGy (KiloGray), being one sample still alive re-irradiated with doses up to 3.0 KGy. The fungus were totally destroyed with a 2.2 KGy. Seventy six suspensions containing approximately 100,000 spores/ml received a dose of radiation between 0.2 and 2.2 KGy, being one sample still alive re-irradiated with doses up to 3.0 KGy. The fungus were totally destroyed with a 2.2 KGy dose. An increase in the resistance to lower dose levels of radiation was observed, in relation to the fungus which had not received irradiation. Conclusion: the Minimum Lethal Dose (MLD) of gamma irradiation, for P. citrinum is 2.2 KGy; the re-irradiation of the surviving fungus demonstrate that occur appearance of radio-resistant mutants.     

Quality assurance of the dose delivered by small radiation segments

The use of intensity modulation with multiple static fields has been suggested by many authors as a way to achieve highly conformal fields in radiotherapy. However, quality assurance of linear accelerators is generally done only for beam segments of 100 MU or higher, and by measuring beam profiles once the beam has stabilized. We propose a set of measurements to check the stability of dose delivery in small segments, and present measured data from three radiotherapy centres. The dose delivered per monitor unit, MU, was measured for various numbers of MU segments. The field flatness and symmetry were measured using either photographic films that are subsequently scanned by a densitometer, or by using a diode array. We performed the set of measurements at the three radiotherapy centres on a set of five different Philips SL accelerators with energies of 6 MV, 8 MV, 10 MV and 18 MV. The dose per monitor unit over the range of 1 to 100 MU was found to be accurate to within +/-5% of the nominal dose per monitor unit as defined for the delivery of 100 MU for all the energies. For four out of the five accelerators the dose per monitor unit over the same range was even found to be accurate to within +/-2%. The flatness and symmetry were in some cases found to be larger for small segments by a maximum of 9% of the flatness/symmetry for large segments. The result of this study provides the dosimetric evidence that the delivery of small segment doses as top-up fields for beam intensity modulation is feasible. However, it should be stressed that linear accelerators have different characteristics for the delivery of small segments, hence this type of measurement should be performed for each machine before the delivery of small dose segments is approved. In some cases it may be advisable to use a low pulse repetition frequency (PRF) to obtain more accurate dose delivery of small segments.     

The relationship between high-dose treatment and combination chemotherapy: the concept of summation dose intensity

The most important variables for the clinical use of antitumor agents (AAs) are dose and combination chemotherapy. The objectives of this study were to analyze the relationship between these two variables and to propose a unified conceptual framework for the construct and interpretation of clinical trials. Definitions and variables with respect to dose include potency, therapeutic index, standard dose, efficacy, relative efficacy, dose-limiting toxicity (DLT), dose rate, dose density, dose intensity, and fractional dose intensity. Our overarching concept, that is, summation dose intensity (SDI), was calculated in several ways, depending upon the nature of the data, and included the relative efficacy method, the unit regimen method, and the high dose method. The SDI concept was then applied to disease categories and strategies to determine its usefulness and effectiveness in integrating dose and combinations. The tumors and settings were: mustargen-vincristine-procarbazine-prednisone in Hodgkin's disease, combination chemotherapy for acute lymphocytic leukemia in children, metastatic breast cancer including dose and combinations, selected other solid tumors, alternating chemotherapy, and high dose studies in the leukemias and lymphomas. SDI was effective in integrating and quantifying dose and combination chemotherapy. For classical AAs, the implication of SDI for the construct and analysis of clinical trials was emphasized. In addition to new drug development, emphasis should be given to reducing or eliminating DLTs, such as those of the marrow, now and, in the future, those of the gastrointestinal tract toxicity and other DLTs. The above was derived from and applies to the classical AAs. Whether they will apply to, with appropriate adjustment, agents with significantly different dose-response curves, such as biotherapeutics and hormonal agents, remains to be determined.