Peter Mahler, MD, PhD

PURPOSE: Pulsed reduced-dose-rate radiotherapy (PRDR) is a reirradiation technique that reduces the effective dose rate and increases the treatment time, allowing sublethal damage repair during irradiation.

PATIENTS AND METHODS: A total of 103 patients with recurrent glioma underwent reirradiation using PRDR (86 considered to have Grade 4 at PRDR). PRDR was delivered using a series of 0.2-Gy pulses at 3-min intervals, creating an apparent dose rate of 0.0667 Gy/min to a median dose of 50 Gy (range, 20-60) delivered in 1.8-2.0-Gy fractions. The mean treatment volume was 403.5±189.4 cm3 according to T2-weighted magnetic resonance imaging and a 2-cm margin.

RESULTS: For the initial or upgraded Grade 4 cohort (n=86), the median interval from the first irradiation to PRDR was 14 months. Patients undergoing PRDR within 14 months of the first irradiation (n=43) had a median survival of 21 weeks. Those treated ≥14 months after radiotherapy had a median survival of 28 weeks (n=43; p=0.004 and HR=1.82 with a 95% CI ranging from 1.25 to 3.10). These data compared favorably to historical data sets, because only 16% of the patients were treated at first relapse (with 46% treated at the second relapse, 32% at the third or fourth relapse, and 4% at the fourth or fifth relapse). The median survival since diagnosis and retreatment was 6.3 years and 11.4 months for low-grade, 4.1 years and 5.6 months for Grade 3, and 1.6 years and 5.1 months for Grade 4 tumors, respectively, according to the initial histologic findings. Multivariate analysis revealed age at the initial diagnosis, initial low-grade disease, and Karnofsky performance score of ≥80 to be significant predictors of survival after initiation of PRDR.

CONCLUSION: PRDR allowed for safe retreatment of larger volumes to high doses with palliative benefit.

PMID:20472350 | DOI:10.1016/j.ijrobp.2009.11.058

PURPOSE: Reirradiation of breast cancer locoregional recurrence (LRR) in the setting of prior post-mastectomy radiation poses a significant clinical challenge due to the high risk for severe toxicity. In an attempt to reduce these toxicities, we have developed pulsed reduced dose-rate radiotherapy (PRDR), a reirradiation technique in which a series of 0.2 Gy pulses separated by 3-min time intervals is delivered, creating an apparent dose rate of 0.0667 Gy/min. Here we describe our early experience with PRDR.

PATIENTS AND METHODS: We reirradiated 17 patients with LRR breast cancer to the chest wall, axilla, or supraclavicular region using PRDR. The median prior radiation dose was 60 Gy. We delivered a median PRDR dose of 54 Gy (range 40-66 Gy) in 1.8-2.0 Gy per fraction. Eight patients received concomitant low dose capecitabine for radiosensitization. The median treatment volume was 2,084 cm(3) (range 843-7,881 cm(3)).

RESULTS: At a median follow-up of 18 months (range 4-75 months) only 2 patients have had tumor failure in the treatment region. Estimated 2-year local control rate is 92%. Treatment was well tolerated with 4 patients experiencing grade 3 acute skin toxicity. Despite a median cumulative dose of 110 Gy (range 80-236 Gy), there has been only one grade 3 and one grade 4 late toxicity.

CONCLUSIONS: With a median follow-up of 18 months, PRDR appears to be an effective method to reirradiate large volumes of previously irradiated tissue in selected patients with locoregional chest wall, axilla, and supraclavicular recurrences.

PMID:18389365 | DOI:10.1007/s10549-008-9995-3

BACKGROUND: Adjuvant postmastectomy radiotherapy (RT) decreases the risk of local recurrence of breast cancer and may increase overall survival (OS).

METHODS AND MATERIALS: After mastectomy, 656 premenopausal Vietnamese and Chinese women with clinical Stage II-IIIA breast cancer, in a clinical trial of adjuvant surgical oophorectomy and tamoxifen, were treated with adjuvant RT according to the availability in the institution. The short-term disease recurrence and OS experience of these 656 women were analyzed using univariate and multivariate methods.

RESULTS: The 193 patients who did not receive RT differed from the 463 who did in that they had larger tumors and more frequently Grade 3 tumors. With a median follow-up of 3.6 years, in univariate analysis, RT was associated with improved disease-free survival (DFS) (relative risk 0.66; 95% confidence interval 0.49-0.89; p = 0.007) and OS (relative risk 0.71; 95% confidence interval 0.50-1.00; p = 0.051). In multivariate analysis, the relative risk for DFS and OS associated with RT was 0.78 and 0.94, respectively (p = not significant for both). Kaplan-Meier estimates showed better 5-year DFS (72% vs. 59%; p = 0.006) and OS (78% vs. 70%; p = 0.05) rates with RT.

CONCLUSION: In the absence of detailed CT planning capacity, adjuvant RT for premenopausal Vietnamese women was associated statistically with short-term improvement in DFS and OS in univariate, but not multivariate, analysis.

PMID:12788175 | DOI:10.1016/s0360-3016(03)00115-9

The objective of this study was to document the utility of computed tomography (CT) and a three-dimensional (3-D) radiotherapy treatment planning system for assessing the development of acute radiation pneumonitis in a canine model. Fourteen dogs were randomly assigned to a nonirradiated control group or one of three radiation dose groups receiving a single fraction of either 12, 15, or 18 Gy delivered to two-thirds of the right hemithorax. CT and survey radiographs were performed in all dogs prior to and at defined intervals for up to 13 weeks following irradiation. All images were subjectively evaluated for development of radiation pneumonitis and CT images were quantitatively analyzed. Radiation pneumonitis was detected earlier with CT images than with radiographs. Quantitatively, functional lung volume and radiation pneumonitis lesion volume on CT images changed over time in all irradiated dogs. However, there was no statistically significant difference between the three radiation dose groups, but a marked difference between irradiated dogs and nonirradiated controls. These data suggest that CT is superior to survey radiography for the evaluation and quantification of acute radiation pneumonitis in this canine model. Quantification of acute radiation pneumonitis suggests future promise for evaluating the efficacy of modifiers to lessen the effects of irradiating normal lung tissue in this canine model.

PMID:9652911 | DOI:<a href=https://doi.org/10.1002/(sici)1520-6823(1998)6:33.0.co;2-#>10.1002/(sici)1520-6823(1998)6:33.0.co;2-#

PMID:8598380 | DOI:10.1016/0360-3016(96)80687-0

In 33 healthy dogs, 66 bronchoalveolar lavage samples from the right and left caudal lung lobes were analyzed for volume of return, cellularity, differential cellularity, and immunophenotypic lymphocyte subpopulations. Lavage return was 64.8% (mean) following 3 sequential 25-ml lavages, for a total lavage volume of 75 ml. With this technique, 21.1 x 10(6) cells/sample (mean) were obtained. The cellular components of bronchoalveolar lavage samples, in decreasing order of frequency, were alveolar macrophages (79.4%), lymphocytes (13.5%), eosinophils (3.6%), mast cells (2.1%), epithelial cells (0.8%), and neutrophils (0.6%). Mean alveolar lymphocyte subpopulation frequencies, determined in 18 samples, for pan T, CD4, and CD8 cells were 52, 21.9, and 17.8%, respectively, with a CD4/CD8 ratio of 1.3. Variables analyzed did not vary between right and left caudal lung lobes, nor were they affected by body weight.

PMID:7771692

Late radiation injury to muscles and peripheral nerves is infrequently observed. However, the success of radiation oncology has led to longer patient survival, providing a greater opportunity for late effects to develop, increase in severity and, possibly, impact the quality of life of the patient. In addition, when radiation therapy is combined with surgery and/or chemotherapy, the risk of late complications is likely to increase. It is clear that the incidence of complications involving muscles and nerves increases with time following radiation. The influence of volume has yet to be determined; however, an increased volume is likely to increase the risk of injury to muscles and nerves. Experimental and clinical studies have indicated that the alpha/beta ratio for muscle is approximately 4 Gy and, possibly, 2 Gy for peripheral nerve, indicating the great influence of fractionation on response of these tissues. This is of concern for intraoperative radiation therapy, and for high dose rate brachytherapy. This review of clinical and experimental data discusses the response of muscle and nerves late after radiation therapy. A grading system has been proposed and endpoints suggested.

PMID:7713790 | DOI:10.1016/0360-3016(94)00422-H

Concern about radiation induced nephropathy results in a dose limiting constraint in some applications of radiation therapy. An understanding of the etiology of radiation therapy. An understanding of the etiology of radiation nephropathy is essential if attempts to alter the time course or extent of the pathology are to be successful. In an attempt to gain a better understanding of this disease process, and to see if it could be altered by dietary manipulation, young adult male Sprague-Dawley rats were unilaterally nephrectomized, after which the remaining kidney was exteriorized and exposed to 14 Gy of X rays. Non-irradiated control animals had their remaining kidney exteriorized for a comparable length of time. Five days after irradiation, the animals were switched from standard lab rations to isocaloric diets of differing protein content. Diets used included 4%, 20% and 50% protein and the 4% and 20% diets given in combination with 0.9% NaCl drinking water. For all the diet groups, irradiated animals had median survival times shorter than their corresponding non-irradiated controls. Within the irradiated groups, the ranking of the median survival times was: 4% + 0.9% NaCl greater than 4% greater than 20% + 0.9% NaCl = 20% greater than 50%. The differences in survival among the irradiated groups were significant at the 0.01 level. These data indicate that kidney response to irradiation can be altered by manipulation of dietary protein levels. Such information may have clinical application.

PMID:7107425 | DOI:10.1016/0360-3016(82)90103-1

PMID:7100399

PMID:7063629

We have previously reported a technique for the quantitative transplantation of monodispersed rat thyroid cells. In this study, the influence of the age and sexual status of the donor and recipient animals on the transplantation process has been examined using the number of cells required for the growth of 1 or more follicular units in 50% of the transplantation sites (follicular dose 50% or FD50) as the end point. The number of multifollicular clusters per 1000 inoculated cells was also explored. FD50 values in 5-week-old intact male recipients increased as the donor's age increased over the range of 4 weeks to 12 months. FD50 values in 5-week-old thyroidectomized male recipients were similar when donors were 4-8 weeks old, but were increased for cells from 52-week-old donors. The FD50 values of cells from 5-week-old donors was higher in 4-week-old intact recipients than in the 5- or 6-week-old recipients. In male recipients, the FD50 values were lower than in female recipients of 5 and 8 weeks of age. This sex-related effect was reduced by orchiectomy and ovariectomy. Generally, the frequency of multifollicular clusters per 1000 inoculated cells increased as the FD50 decreased. These results are discussed in the light of measurements of thyroidal DNA synthesis and TSH levels reported by others.

PMID:6847815 | DOI:10.1210/endo-112-1-172

The kinetics of in situ repair (ISR) was investigated in normal rat mammary epithelial cells exposed in vivo to 8 Gy 137 Cs gamma rays. ISR as measured by transplantation assay was completed by 4 hours after exposure. Although ISR in the three normal epithelial cell types thus far tested differs from repair of potentially lethal damage in tumour cells and cultured fibroblasts in that it affects the shoulder and not the slope of the survival curve, the current study shows that the time course of ISR resembles that for repair of potentially lethal damage in both tumours and fibroblasts.

PMID:6605948 | DOI:10.1080/09553008314551421

Radiation survival curves are presented for several normal parenchymal cell types irradiated in situ or in vitro. The data presented indicate that the in situ survival parameters for a specific cell type cannot be simply extrapolated from the results of either in vitro assays or rapid in vivo clonal transplantation assays. The data suggest that the D0 and terminal slope of in vitro survival curves can reflect those parameters for cells left in situ, but the shoulder width and the n value cannot. This appears to be due to the inability of the in vitro environment to support two major forms of repair that occur in situ, i.e. the "contact effect" and in situ repair (ISR). ISR is a form of potentially lethal damage repair (PLDR) that occurs when certain cells are allowed to remain in situ following irradiation. ISR is characterized by an increased shoulder in the survival curve without a change in slope and it has been observed in rat mammary, thyroid and liver epithelia.

PMID:6582905 | PMC:PMC2149172

PMID:6515664

Studies with WR-2721 and related compounds have been hindered by the lack of a suitable assay for the drug and its major metabolites. We have developed a chromatographic method which requires no derivatization for the separation and detection of WR-2721, the free thiol, its symmetrical disulfide and other mixed disulfides. Our procedure involves ion-pairing for separation of ionizable compounds by causing polar molecules to become more lipophilic and hence separable using reverse phase HPLC. Detection is based upon liquid scintillation counting of S-35 incorporated during the synthesis of the parent compound. This method requires no pre-column preparation of samples and, by detecting the S-35 label, eliminates the chance that a coeluting species could interfere with detection, as might occur with post-column derivatization. Chromatography was done using a 10 micron C8RP column and 35% MeOH/65% 0.0113M NaH2PO4, 0.005 M hexanesulfonate, pH 5.9, flowing at 1 ml/min. Half-minute fractions were collected into scintillation vials for counting. Retention volumes for the various compounds were: column breakthrough (3.5 ml), WR-2721 (4.5 ml), WR-1065 (9 ml), and WR-33278 (24 ml). This analytical technique employing radiotracers can be used to study radioprotective mechanisms by time dependent measurements of the tissue distribution and chemical form of labeled drug. Such chemical information can then be correlated with biological measures of radiation protection.

PMID:6090353 | DOI:10.1016/0360-3016(84)90492-9

Immediately following unilateral nephrectomy the remaining kidney of juvenile male Sprague-Dawley rats was sham irradiated or irradiated to doses of 14-30 Gy. Following irradiation the animals were placed on isocaloric diets of either 20 or 4% protein. Median life spans for the animals on the low protein diet were significantly increased compared to the median life spans on the 20% protein diet. Serum urea nitrogen (SUN) levels were periodically measured in rats from each of the experimental groups. SUN levels in the irradiated rats fed the 20% protein diet increased significantly over unirradiated controls as a function of time. In contrast animals fed the 4% protein diet showed no significant changes in SUN levels irrespective of the size of radiation dose and time post irradiation. Renal protective factors calculated as the ratio of 80% survival times for animals fed the 20% protein diet compared to animals fed the 4% protein diet can be calculated to be 2.3 at 18 Gy and 2.8 at 22 Gy. Likewise, a SUN protective factor calculated as the ratio of percentage of nonirradiated control SUN values for the two diets (SUN 20% irradiated) (SUN 20% nonirradiated) (SUN 4% irradiated) (SUN 4% nonirradiated) is 2.4 for 18 Gy and 3.9 for 22 Gy.

PMID:3809396

A double isotope technique was used to measure changes in the vascular permeability surface area product (PS) for albumin after irradiation. PS was measured in several tissues of the rat during the first 38 days following 11, 13.5, 18, or 25 Gy whole thorax irradiation. After 18 and 25 Gy most irradiated and nonirradiated (shielded) tissues showed elevated permeability at 1 day after radiation, which declined to control levels by Day 4. All irradiated tissues showed a second wave of increased permeability between 14 and 38 days after radiation that varied in onset and extent depending upon tissue and dose. Lung and heart showed a direct response to dose between 11 and 18 Gy during this period. Peak lung values averaged three times control values at 19 days after 18 Gy. Peak heart values averaged twice control values at the same time and dose. The double isotope technique has proven to be a reliable means of quantitatively determining vascular permeability response to radiation over time.

PMID:3749461

A quantitative measure of the vascular permeability surface area product (PS) for albumin has been made using a double isotope technique. PS was significantly elevated in irradiated rat lung, heart, skin, and muscle, between 19 and 26 days following 18 or 25 Gray thorax irradiation. Administration of dexamethasone from 2 days before irradiation through the day of measurement suppressed the expected increase in PS in lung, heart, and muscle, but not in skin. Shorter periods of steroid administration were not as effective in suppressing this response to radiation exposure. Increased vascular permeability following radiation may be an essential element in the development of radiation fibrosis. We hypothesize that the ability to suppress this response could result in a long term reduction in the incidence of fibrosis.

PMID:3558047 | DOI:10.1016/0360-3016(87)90072-1

Diets containing hydrolyzed casein have been observed to enhance post-irradiation intestinal mucosal recovery. The intake and the composition of such diets were not carefully controlled. This study attempted to do so. Male specific pathogen-free Sprague-Dawley rats were randomized to receive either an enzymatically hydrolyzed casein semi-purified diet (EHC), a whole casein semi-purified diet (WC), or powdered lab chow (C). All diets were isonitrogenous, and the WC and C rats were pair-fed to the ad libitum fed EHC rats. Seven days after initiation of feeding, the rats were abdominally irradiated with a single 9.0 Gy dose of 137Cs gamma rays. The rats were continued on the diets for another 5 days. Intestinal mucosa from transverse segments at the duodenum, jejunum, proximal ileum, and distal ileum were measured for incorporation of (3H methyl) Thymidine 1 hour after interperitoneal injection. Incorporation reached a maximum by day 4 post-irradiation regardless of diet or segment. Incorporation in the duodenum was enhanced by the EHC diet compared to the C diet, while the incorporation in the jejunum was initially suppressed by the EHC diet compared to the WC diet. In the jejunum, the number of mitoses per crypt of 25 anti-mesenteric crypts post-irradiation was increased by the EHC diet. Prior to irradiation, all groups gained similar amounts of weight. After irradiation, the C rats lost weight, while the EHC and WC rats remained the same or gained weight. Guaiac tests for occult blood were negative prior to irradiation, but positive for all rats on days 1-5 postirradiation. When calorie and protein intakes were controlled, different areas of the small intestine responded differently to EHC.

PMID:3558029 | DOI:10.1016/0360-3016(87)90013-7

The role of endothelial cell damage in the development of radiation injury in the lung was investigated in rats. Vascular permeability-surface area product (PS) was measured as an indicator of the degree of endothelial cell damage in lungs of rats exposed to single dose hemithorax irradiation. Hemithorax irradiation was chosen to simulate clinical radiotherapy, in which only a portion of the lung is irradiated. In addition, it provided a control lung to compare to the irradiated lung. Radiation is postulated to lead to activation of several different biochemical pathways that result in lung injury and fibrosis. Many of these pathways can be specifically blocked with drugs. Thirteen different drugs were studied. Dexamethasone, indomethacin, cromolyn, cyproheptadine, Vitamin D3, theophylline, and diethylcarbamazine were all effective at reducing lung PS on the irradiated side. Dexamethasone, Vitamin D3, and indomethacin also significantly reduced lung PS in the unirradiated lungs and in sham-irradiated rats. Captopril, cobra venom factor, penicillamine, trapidil, epsilon-amino caproic acid, and dapsone had no significant effect on lung PS after hemithorax irradiation. We conclude that the major pathways involved in early post-radiation lung injury involve prostaglandin, leukotriene, and histamine release from macrophages and mast cells. Complement activation, proteolytic enzymes, and neutrophil migration do not seem to be important mediators of early post-radiation lung injury.

PMID:2168354 | DOI:10.1016/0360-3016(90)90541-q