Biological Principles of Stereotactic Body Radiation Therapy (SBRT) and Stereotactic Radiation Surgery (SRS): Indirect Cell Death.

PURPOSE: To review the radiobiological mechanisms of stereotactic body radiation therapy stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). METHODS AND MATERIALS: We reviewed previous reports and recent observations on the effects of high-dose irradiation on tumor cell survival, tumor vasculature, and antitumor immunity. We then assessed the potential implications of these biological changes associated with SBRT and SRS. RESULTS: Irradiation with doses higher than approximately 10 Gy/fraction causes significant vascular injury in tumors, leading to secondary tumor cell death. Irradiation of tumors with high doses has also been reported to increase the antitumor immunity, and various approaches are being investigated to further elevate antitumor immunity. The mechanism of normal tissue damage by high-dose irradiation needs to be further investigated. CONCLUSIONS: In addition to directly killing tumor cells, high-dose irradiation used in SBRT and SRS induces indirect tumor cell death via vascular damage and antitumor immunity. Further studies are warranted to better understand the biological mechanisms underlying the high efficacy of clinical SBRT and SRS and to further improve the efficacy of SBRT and SRS.

The effect of electromagnetic field and local inductive hyperthermia on nonlinear dynamics of the growth of transplanted animal tumors.

AIM: To examine the effects of electromagnetic field with amplified magnetic component and local inductive hyperthermia (IH) on nonlinear dynamics of the growth of animal tumors. MATERIALS AND METHODS: Guerin carcinoma, Lewis lung carcinoma, sarcoma 45, Walker 256 carcinosarcoma and Pliss lymphosarcoma were studied. The animal tumors were exposed inside of loop aerial, 3 cm in diameter locally for 30 min. Parameters of electromagnetic irradiation (EI): frequency 40 MHz, magnetic intensity 72 A/m, electric intensity 200 V/m and the output power 50 W. The temperature measured by immersion of thermocouple inside the center of the tumor didn't exceed 38.5-39.5 degrees C. Nonlinear dynamics of the growth of animal tumors was analyzed by autocatalytic equation. The heterogeneity of ultrasonic image of the tumor was analyzed by Moran spatial autocorrelation. RESULTS: The strongest inhibition effect under the influence of EI was in Pliss lymphosarcoma and sarcoma 45. The growth stimulation of animal tumors after EI was recorded in Walker 256 carcinosarcoma. The use of mild IH increased the blood flow in the tumor of Guerin carcinoma. CONCLUSION: These results are important for clinical application because they testify the necessity of optimization of schemes for local EI during anticancer neoadjuvant therapy with the use of drugs or magnetic nanoparticles. The use of mild IH as a basis for the monotherapy of malignant tumors is not expedient.

Photodynamic therapy of Walker tumors by multiple laser irradiation.

OBJECTIVE: Photodynamic therapy of Walker tumor after subcutaneous administration of 5-ALA solution using a multiple laser irradiation scheme was monitored by the fluorescence imaging technique to investigate the effectiveness of 5-ALA-PDT. BACKGROUND DATA: Photodynamic therapy (PDT) is a localized cancer treatment based on the selective uptake and retention of photosensitizer at the tumoral level and on the activation of the photosensitizer by a specific wavelength of light, aiming to induce cytotoxic reactions. As a new photosensitizer, the heme precursor 5- aminolevulinic acid has been introduced recently for photodynamic therapy of tumors and precancerous lesions of the skin. It has been shown that the efficacy of topical 5-ALA-PDT is limited for deeper skin tumor by the depth of 5-ALA penetration through the skin. Oral or systemic administration of ALA or the use of different irradiation schemes may improve tumor response to PDT. METHODS: Laser irradiation parameters used in this study were lambda = 635 nm, P = 3 mW, t(exp) = 300 sec, and three sessions. The fluorescence was excitated by monochromatic light of 405 nm. The temporal behavior of PpIX fluorescence was studied by processing and analyzing the fluorescence images acquired just after applying 5-ALA, just before and just after three laser irradiations. RESULTS: The results demonstrate that PpIX is highly selective for tumors areas and a re-accumulation of PpIX appears between laser irradiations. During laser irradiation, the PpIX fluorescence intensity decreases rapidly, reflecting the photodegradation of PpIX. CONCLUSIONS: In conclusion, the use of a multiple laser irradiation scheme, for the activation of reaccumulation of Pp IX (with three steps) is effective for photodynamic therapy of Walker tumor.

Biodistribution of 10B in a rat liver tumor model following intra-arterial administration of sodium borocaptate (BSH)/degradable starch microspheres (DSM) emulsion.

We reported that intra-arterial administration of borocaptate sodium (BSH)/lipiodol emulsion provided selectively high (10)B concentrations (approximately 200 ppm 6 h after administration) in experimental liver tumors. In the present study, we investigated the pharmacokinetics of BSH following intra-arterial administration of BSH with other embolizing agent, degradable starch microspheres (DSM). The (10)B concentration in the tumor at 1 h after administration of BSH with DSM was 231 ppm. At 6 h, the (10)B concentration in the tumor in BSH with DSM group was 81.5 ppm. The (10)B concentration in the liver at 1 h after administration of BSH with DSM was 184 ppm. At 6 h, the(10)B concentration in the liver in BSH with DSM group was 78 ppm. The tumor/liver (10)B concentration ratios (T/L ratio) in the "BSH+DSM" group were significantly smaller than those in the "BSH+lipiodol" group at 1 h (1.4 vs. 3.6) and 6h (1.1 vs. 14.9). BSH/DSM-boron neutron capture therapy (BNCT) was not suitable for treatment of multiple liver tumors due to the low T/L (10)B concentration ratio. However, the high (10)B accumulation in the liver tumors following intra-arterial administration of BSH/DSM emulsion suggests that BSH/DSM-BNCT has the potential for application to malignant tumors in other sites.

Intra-arterial administration of sodium borocaptate (BSH)/lipiodol emulsion delivers B-10 to liver tumors highly selectively for boron neutron capture therapy: experimental studies in the rat liver model.

PURPOSE: Boron neutron capture therapy (BNCT) is particle radiotherapy with alpha ((4)He) particle and recoiled lithium nucleus ((7)Li) derived from a reaction of boron ((10)B) and thermal neutron. We investigated applying BNCT to malignant liver tumors. The purpose of the present study was to reveal the efficacy for administration of emulsion of a boron compound (sodium borocaptate; BSH) and lipiodol via a hepatic artery using a rat liver tumor model. METHODS AND MATERIALS: Rat liver tumors were developed by direct injection of Walker 256 cells into the liver parenchyma. BSH (75 mg/kg)/lipiodol (0.3 mL/kg) emulsion was administered via the hepatic artery. Boron concentrations in the tumors, liver, and blood were measured at 1, 6, and 12 h after administration. Neutron capture radiography (NCR) was taken to confirm the selective accumulation of (10)B in the liver tumors. RESULTS: Boron concentrations in the liver tumors and the tumor/liver (T/L) boron concentration ratio at 1, 6, and 12 h after administration of BSH/lipiodol emulsion (concentration: T/L ratio) were 479.2 ppm: 4.0, 197.3 ppm: 14.9, and 96.5 ppm: 6.6, respectively. Highly selective irradiation was clearly demonstrated by the NCR images. CONCLUSIONS: Intra-arterial administration of BSH/lipiodol emulsion is effective method for delivering high concentration of (10)B selectively to the liver tumors.

[18F]Fluoroazomycinarabinofuranoside (18FAZA) and [18F]Fluoromisonidazole (18FMISO): a comparative study of their selective uptake in hypoxic cells and PET imaging in experimental rat tumors.

The present study compares the uptake of [(18)F]Fluoroazomycinarabinofuranoside ((18)FAZA), a recently developed hypoxia tracer for PET imaging of tissue hypoxia, with an established tracer [(18)F]Fluoromisonidazole ((18)FMISO) both in vitro, using Walker 256 rat carcinosarcoma cells, and in vivo in experimental rat tumors eleven to twelve days after tumor cell implantation. In vitro studies indicated that hypoxia-selective uptake of both (18)FAZA and (18)FMISO in tumor cells, 20 and 100 minutes post-incubation was of the same magnitude (20 min: 1.24 +/- 0.4% ((18)FAZA); 1.19 +/- 0.7% ((18)FMISO); 100 min: 3.6 +/- 1.6% ((18)FAZA); 3.3 +/- 1.7% ((18)FMISO)). PET imaging reflected a similar radiotracer distribution in rat tumors for (18)FAZA and (18)FMISO one h after radiotracer injection. The concentration of (18)FAZA in the tumors as measured by PET, however, was lower in comparison to (18)FMISO (SUV(FAZA) = 0.61 +/- 0.2 vs. SUV(FMISO) = 0.92 +/- 0.3, p < 0.05) although the tumor to muscle ratios for (18)FAZA and (18)FMISO did not differ in the PET images that were obtained after one h (SUV(FAZA) = 2.5 +/- 0.5 vs. SUV(FMISO) = 2.9 +/- 0.7). A comparison of PET data three h post-injection (SUV(FAZA) = 3.0 +/- 0.5 vs. SUV(FMISO) = 4.6 +/- 1.8, p < 0.05) demonstrated a lower (18)FAZA uptake that indicates a lower sensitivity of (18)FAZA in comparison to (18)FMISO in detecting hypoxic regions at a longer time in this animal model. However, these data also show a faster elimination of (18)FAZA from blood, viscera and muscle tissue, via the renal system. This advantage of a faster reduction of unspecific binding, in light of similar or marginally lower tumor uptake, warrants further investigation of (18)FAZA as a marker of regional hypoxia in tumors.

[Inhibitory effect of samarium-153-labeled ethylenediaminetetramethylene phosphonate (EDTMP) on bone invasion and osteolysis in Walker 256 carcinoma bearing rats].

OBJECTIVE: To investigate the inhibitory effect of samarium-153 EDTMP on bone invasion and osteolysis in Walker 256 carcinoma bearing rats. METHODS: Invasion and resorption of tibia by Walker 256 carcinoma in rats were evaluated by X-ray and histological examination. RESULTS: Intravenous administration of 153Sm-EDTMP at a dose of 74 or 148 MBq/kg, the rat numbers with tibia invasion and bone resorption were reduced by fifty percent. 153Sm-EDTMP at a dose of 37 MBq/kg still exhibited inhibitory effect on bone invasion and osteolysis as compared with the control group. However, there was no indication of change in the weight of primary tumor even at the highest dose utilized. CONCLUSION: Samarium-153 EDTMP can inhibit bone invasion and osteolysis by Walker 256 carcinoma in rats, but it has no effect on the growth of the transplanted tumor. Therefore, that the effect of 153Sm-EDTMP is due to a reduction in tumor growth leading to decreased bone invasion and osteolysis can be reasonably ruled out.

Effect of recombinant human granulocyte colony-stimulating factor on efficacy of radiation therapy in tumor-bearing rats.

The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on radiation-induced neutropenia and on growth of transplanted tumors treated by irradiation was investigated using tumor-bearing rats as a model for radiation therapy. In a preliminary study using normal rats, neutropenia induced by upper hemi-body irradiation at 3 Gy/day 5 times a week for 3 weeks was prevented by consecutive subcutaneous injections of rhG-CSF at 100 micrograms/kg/day. Rats bearing Walker-256, a mammary tumor, were scheduled to receive upper hemibody irradiation at 3 Gy/day for 15 times in 3 weeks if white blood cell (WBC) counts were maintained above 3,000/microliters. In control tumor-bearing rats not receiving rhG-CSF, irradiation was often withheld because of the decrease in WBC counts below 3,000/microliters. In contrast, a decrease in WBC counts below 3,000/microliters was rarely found in tumor-bearing rats injected daily with rhG-CSF. The average number of radiation treatments in control rats and rats treated with rhG-CSF was about 8 and 14, respectively, out of the scheduled 15 treatments in 3 weeks. Treatment with rhG-CSF made it possible to complete the radiation therapy regimen and thus inhibit the growth of the transplanted tumor more effectively. These results suggest that rhG-CSF may be useful to ensure radiation therapy on schedule in cancer patients.

[Combined effect of hyperglycemia and chemo- and radiation action on the status of metabolic processes in certain experimental sarcomas in rats]. / Kombinirovannoe vliianie giperglikemii s khimio- i luchevym vozdeistviem na sostoianie metabolicheskikh protsessov v nekotorykh éksperimental'nykh sarkomakh krys.

A number of metabolic parametres were studied in subcellular fractions of rat sarcoma 45, M-1 and carcinosarcoma Worker 256. Administration of high doses of glucose amplified some effects of chemotherapeutic drugs and X-ray therapy, which were manifested as follows: a decrease in glycolysis rate, alteration in the rate of redox reactions, shifts in the ratio between glycolysis and biological oxidation in mitochondria. These alterations were determined by the type of sarcoma, by sequence of operations in the procedure and by cytostatic used. The most effective procedure proved to be simultaneous administration of drugs and X-ray therapy followed by hyperglycemia. Distinct inhibition of glycolysis defected under these conditions may contribute to inhibition of energy metabolism during the sarcoma growth and regression.

[Radionuclide study of blood flow in tumor and normal tissues of rats in induced hyperglycemia]. / Radionuklidnoe issledovanie krovotoka v opukholevoi i normal'noi tkaniakh krys pri iskusstvennoi giperglikemii.

Radionuclide angiography was performed in rats with transplantable tumors (sarcoma 45 and Walker carcinosarcoma 256). Induced hyperglycemia was shown to result in blood flow inhibition in tumor and normal tissues of tumor-bearing rats. Some differences were revealed in a degree of reversibility of blood flow disorders in tissues of the above strains. The results obtained confirmed the advisability of radiation therapy at the height of a decrease in tumor blood flow.

Estudo do metronidazol no tumor de Walker 256 previamente submetido a radioterapia: avaliaçäo polarográfica / Study of metronidazol on Walker 256 tumor previously submitted to radioterapy: polarografic evaluation

E estudo polarográfico do oxigênio e metronidazol foi realizado em 52 ratos inoculados com tumor de Walker 256, implantando-se eletrodos de platina no músculo da coxa e no tumor. O objetivo da presente pesquisa foi o estudo das alteraçöes polarográficas, no tumor de Walker 256, com diâmetro aproximado de 20 mm e após evoluçäo de 48 horas, com e sem radioterapia, obtendo-se curvas polarográficas com oxigênio e metronidazol. Foram estudados os atributos: intensidade basal (ib), intensidade máxima i max) e intervalo (I). Da pesquisa constam quatro grupos experimentais: G1 - polarografia do tumor, com diâmetro de 20 mm; G2 - polarografia do tumor, 48 horas após ter atingido o diâmetro de 20 mm; G3 - tumor irradiado com 1000 rad ao apresentar 20 mm de diâmetro e polarografia 48 horas após; G4 - idem ao G3, mas com irradiaçäo de 2000 rad. O método polarográfico permitiu, na presente pesquisa, as conclusöes a seguir enumeradas: 1. A polarografia realizada no músculo, evidenciou näo existir diferença significativa entre os grupos, em todos os atributos (ib, imax e I), demonstrando a boa reprodutividade do método. 2. Os atributos ib e imax foram sempre maiores no músculo do que no tumor. 3. O atributo imax obtido no músculo, com oxigênio, foi maior do que auqle resultante com metronidazol, em todos os grupos, näo havendo diferença no tumor. 4. O atributo I nas curvas polarográficas, com oxigênio, foi menor do que com metronidazol, no músculo (em todos os grupos) e no tumor (G1 e G3). 5. A evoluçäo de 48 horas (G2) ocasionou, no tumor, uma diminuiçäo do imax (significativa) e do ib (tendência), quando obtido com oxigênio, e uma diminuiçäo do imax (näo significativa), quando obtido com metronidazol. 6. A radioterapia (G3 e G4) determinou aumento (näo significativo) do ib e imax (com oxigênio) e imax (com metronidazol). 7. O estudo do número de respostas (obtençäo da curva polarográfica) mostrou que esse número foi: - Com metronidazol, maior no tumor do que no músculo, no grupo G1. - Com oxigênio, maior no músculo do que no tumor, em todos os grupos. - No tumor, menor no grupo G2 do que nos demais grupos, tanto com oxigênio como com metronidazol. - No músculo, maior com oxigênio do que com metronidazol, ocorrendo o inverso no tumor.

[The effect of whole-body and local irradiation, modified by hyperglycemia, on the metastasis of Walker carcinosarcoma 256 in rats]. / Vliianie obshchego i lokal'nogo oblucheniia, modifitsirovannogo giperglikemiei, na metastazirovanie kartsinosarkomy Uoker 256 u krys.

It has been shown that the local radiation therapy, and also radiation therapy modified by the short-term hyperglycemia really increase the life-span of rats with Walker 256 carcinosarcoma. At the same time the metastatic process also increases, especially after the modified radiation therapy. The total irradiation of experimental animals in a dose of 50 sGy before the modified radiation therapy considerably decreases the frequency of metastatic process. A conclusion is drawn that the total irradiation has a prophylactic influence on metastases under conditions of modified radiation therapy.

Polarography of Walker tumor submitted to radiotherapy.

A polarographic study of oxygen was done in 57 rats inoculated with Walker 256 tumor and platinum electrode implanted in muscle and in tumor. The goal of the research was the study of oxygen in tumor before and after irradiation. Tumor growth caused a decrease in tumoral oxygen. Oxygen was always lower in the tumor than in the muscle. Radiotherapy with 2000 rad (but not with 1000 rad) increased oxygen in the tumor.

Tumor oxygenation using direct injection of oxygenated saline.

Direct injection of oxygen into an in-vivo tumor system was performed using saline lavage through a double-lumen catheter inserted into a Walker 256 carcinoma implanted in the flank of a rat. Ten extremely hypoxic tumors (core pO2 0 to 1 mm Hg) were examined. The mean pO2 in these tumors increased from 66 to 112 mm Hg after 5 minutes of lavage with oxygenated saline. These results indicate a substantial increase in tumor pO2 can be obtained with this system, possibly resulting in improved radioresponsiveness. More general applications of this system may also be feasible.

Nitrogen-13 glutamate uptake and perfusion in Walker 256 carcinosarcoma before and after single-dose irradiation.

Nitrogen-13 (13N) glutamate uptake was recorded in 18 anesthetized rats, both before and at least once after intervention. Each investigation was immediately followed by imaging of blood flow distribution using [11C]butanol. All animals had Walker 256 carcinosarcoma implants in one hind leg. Tumors were locally irradiated with a dose of 800 rad in 14 rats; in four rats, the vasoactive substance 5-hydroxytryptamine (5-HT) was administered. Prior to interventions, the [13N]glutamate tumor-to-muscle uptake showed a linear correlation with blood flow close to identity (y = 0.117 + 0.915x, r = 0.97). After irradiation, a discordant pattern was observed: blood flow tended to increase, while [13N]glutamate tumor-to-muscle uptake dropped from 4.30 +/- 0.66 (s.e.m.) to 3.06 +/- 0.36 (p less than 0.005) during 30 min and attained 4.04 +/- 0.67 2 days later. If [13N]glutamate tumor-to-muscle uptake was related to that of [11C] butanol in each individual animal, this index dropped from 0.93 +/- 0.03 (s.e.m.) to 0.62 +/- 0.04 (p less than 0.001) 30 min after irradiation and attained 0.90 +/- 0.09 after 2 days. In animals treated with 5-HT, [13N]glutamate and [11C]butanol showed a parallel drop from 6.60 +/- 0.84 to 2.10 +/- 0.60 (p less than 0.05) and from 6.8 +/- 0.78 to 2.08 +/- 0.74 (p less than 0.05), respectively. Thus, single-dose irradiation causes [13N]glutamate uptake to be uncoupled with respect to flow, while [13N]glutamate uptake in untreated tumors is flow-limited and responds together with flow on vasomotion.

Effect of dihydroxyanthraquinone on the response of a rat solid tumor to radiation therapy.

Dihydroxyanthraquinone (DHAQ, NSC 279836, a new cancer chemotherapeutic agent presently in clinical trials) was tested, alone and in combination with radiation, for therapeutic effectiveness in a rat solid tumor model. The Walker 256 fibrosarcoma was implanted subcutaneously in the leg via trochar so as to yield palpable tumors within 7-11 days. When tumor diameters reached 1 cm, the animals were treated as follows: as controls; with DHAQ (3.0 mg/kg, i.p.); with 300 KVP x-rays (15 Gy to the tumor-burdened leg); or with a combination of DHAQ and radiation. Tumor diameters were measured three times a week to monitor the response to therapy. DHAQ alone had no effect on tumor growth rate. Radiation alone produced a delay in tumor growth. The combination of DHAQ and radiation resulted in a consistently better therapeutic response than did radiation only, but at only a marginal level of statistical significance (0.05 less than p less than 0.10). However, there were 3/10 long-term survivors (greater than 80 days post treatment) without evidence of tumor in the combination therapy group; whereas all animals in the radiation group died or were sacrificed because of progressive tumor growth by day 71. These results suggest that even though DHAQ is only minimally effective against this rat solid tumor when used alone, there may still be some added therapeutic benefit derived from a combination of DHAQ and radiation therapy.