Phase I/II study of resection and intraoperative cesium-131 radioisotope brachytherapy in patients with newly diagnosed brain metastases.

OBJECT: Resected brain metastases have a high rate of local recurrence without adjuvant therapy. Adjuvant whole-brain radiotherapy (WBRT) remains the standard of care with a local control rate > 90%. However, WBRT is delivered over 10-15 days, which can delay other therapy and is associated with acute and long-term toxicities. Permanent cesium-131 ((131)Cs) implants can be used at the time of metastatic resection, thereby avoiding the need for any additional therapy. The authors evaluated the safety, feasibility, and efficacy of a novel therapeutic approach with permanent (131)Cs brachytherapy at the resection for brain metastases. METHODS: After institutional review board approval was obtained, 24 patients with a newly diagnosed metastasis to the brain were accrued to a prospective protocol between 2010 and 2012. There were 10 frontal, 7 parietal, 4 cerebellar, 2 occipital, and 1 temporal metastases. Histology included lung cancer (16), breast cancer (2), kidney cancer (2), melanoma (2), colon cancer (1), and cervical cancer (1). Stranded (131)Cs seeds were placed as permanent volume implants. The prescription dose was 80 Gy at a 5-mm depth from the resection cavity surface. Distant metastases were treated with stereotactic radiosurgery (SRS) or WBRT, depending on the number of lesions. The primary end point was local (resection cavity) freedom from progression (FFP). Secondary end points included regional FFP, distant FFP, median survival, overall survival (OS), and toxicity. RESULTS: The median follow-up was 19.3 months (range 12.89-29.57 months). The median age was 65 years (range 45-84 years). The median size of resected tumor was 2.7 cm (range 1.5-5.5 cm), and the median volume of resected tumor was 10.31 cm(3) (range 1.77-87.11 cm(3)). The median number of seeds used was 12 (range 4-35), with a median activity of 3.82 mCi per seed (range 3.31-4.83 mCi) and total activity of 46.91 mCi (range 15.31-130.70 mCi). Local FFP was 100%. There was 1 adjacent leptomeningeal recurrence, resulting in a 1-year regional FFP of 93.8% (95% CI 63.2%-99.1%). One-year distant FFP was 48.4% (95% CI 26.3%-67.4%). Median OS was 9.9 months (95% CI 4.8 months, upper limit not estimated) and 1-year OS was 50.0% (95% CI 29.1%-67.8%). Complications included CSF leak (1), seizure (1), and infection (1). There was no radiation necrosis. CONCLUSIONS: The use of postresection permanent (131)Cs brachytherapy implants resulted in no local recurrences and no radiation necrosis. This treatment was safe, well tolerated, and convenient for patients, resulting in a short radiation treatment course, high response rate, and minimal toxicity. These findings merit further study with a multicenter trial.

Sorafenib acts synergistically in combination with radiotherapy without causing intestinal damage in colorectal cancer.

AIMS AND BACKGROUND: Colorectal cancer is one of the commonest cancers. Chemoradiotherapy gives better results than radiotherapy or chemotherapy in colorectal cancer. To enhance radiosensitivity of tumor cells for chemoradiotherapy, targeted therapy drugs that act as radiosensitizers can be used. In the present study, we provide a scientific rationale for the clinical application of sorafenib as a radiosensitizer in colorectal cancer, without causing significant adverse effects on normal intestinal tissue. METHODS: Three human colorectal adenocarcinoma cell lines (HCT116, HT-29, and SW480) were treated with sorafenib alone, or radiation followed by sorafenib. In vitro tests were performed using colony forming assays, cell cycle analysis, and comet assays. In addition, the effects of sorafenib and radiation therapy on the inhibition HT-29 tumor growth and survival of intestinal jejunum crypts were examined in vivo. RESULTS: Sorafenib increased the radiosensitivity of tumor cells in human colon adenocarcinoma cell lines (HCT116, HT-29, and SW480), as well as in HT-29 xenograft animal models. Sorafenib, in combination with ionizing radiation, induced the accumulation of tumor cells in the G2-M phase and delayed the repair of DNA damage caused by ionizing radiation. The combination of sorafenib and ionizing radiation did not enhance the apoptosis of intestinal crypt cells, compared with the use of radiation alone. CONCLUSIONS: We provide a scientific rationale for the use of sorafenib in combination with radiotherapy in colorectal cancer.

Dosimetric characterization of model Cs-1 Rev2 cesium-131 brachytherapy source in water phantoms and human tissues with MCNP5 Monte Carlo simulation.

A recently developed alternative brachytherapy seed, Cs-1 Rev2 cesium-131, has begun to be used in clinical practice. The dosimetric characteristics of this source in various media, particularly in human tissues, have not been fully evaluated. The aim of this study was to calculate the dosimetric parameters for the Cs-1 Rev2 cesium-131 seed following the recommendations of the AAPM TG-43U1 report [Rivard et al., Med. Phys. 31, 633-674 (2004)] for new sources in brachytherapy applications. Dose rate constants, radial dose functions, and anisotropy functions of the source in water, Virtual Water, and relevant human soft tissues were calculated using MCNP5 Monte Carlo simulations following the TG-43U1 formalism. The results yielded dose rate constants of 1.048, 1.024, 1.041, and 1.044 cGy h(-1) U(-1) in water, Virtual Water, muscle, and prostate tissue, respectively. The conversion factor for this new source between water and Virtual Water was 1.02, between muscle and water was 1.006, and between prostate and water was 1.004. The authors' calculation of anisotropy functions in a Virtual Water phantom agreed closely with Murphy's measurements [Murphy et al., Med. Phys. 31, 1529-1538 (2004)]. Our calculations of the radial dose function in water and Virtual Water have good agreement with those in previous experimental and Monte Carlo studies. The TG-43U1 parameters for clinical applications in water, muscle, and prostate tissue are presented in this work.

Calibration of a TLD-100 powder dosimetric system to verify the absorbed dose to water imparted by 137Cs sources in low dose rate brachytherapy at the oncology unit in the Hospital General de Mexico.

A thermoluminescence dosimetry (TLD) system was characterised at SSDL-ININ to verify the air-kerma strength (S(K)) and dose-to-water (D(W)) values for (137)Cs sources used in low dose rate (LDR) brachytherapy treatments at the Hospital General de Mexico (HGM). It consists of a Harshaw 3500 reader and a set of TLD-100 powder capsules. The samples of TLD-100 powder were calibrated in terms of D(W) vs. nC or nC mg(-1), and their dose response curves were corrected for supralinearity. The D(W) was calculated using the AAPM TG-43 formalism using S(K) for a CDCSM4 (137)Cs reference source. The S(K) value was obtained by using a NE 2611 chamber, and with two well chambers. The angular anisotropy factor was measured with the NE 2611 chamber for this source. The HGM irradiated TLD-100 powder capsules to a reference dose D(W) of 2 Gy with their (137)Cs sources. The percent deviations between the imparted and reference doses were 1.2% < or = Delta < or = 6.5%, which are consistent with the combined uncertainties: 5.6% < or = u(c) < or = 9.8% for D(W).

Monte Carlo and experimental derivation of TG43 dosimetric parameters for CSM-type Cs-137 sources.

In this study, complete dosimetric datasets for the CSM2 and CSM3 Cs-137 sources were obtained using the Monte Carlo GEANT4 code. The application of this calculation method was experimentally validated with thermoluminescent dosimetry (TLD). Functions and parameters following the TG43 formalism are presented: the dose rate constant, the radial dose functional, and the anisotropy function. In addition, to aid the quality control process on treatment planning systems, a two-dimensional (2D) rectangular dose rate table (the traditional along-away table), coherent with the TG43 dose calculation formalism, is given. The data given in this study complement existing information for both sources on the following aspects: (i) the source asymmetries were considered explicitly in the Monte Carlo calculations, (ii) TG43 data were derived directly from Monte Carlo calculations, (iii) the radial range of the different tables was increased as well as the angular resolution in the anisotropy function, including angles close to the longitudinal source axis. The CSM2 source TG-43 data of Liu et al. [Med. Phys. 31, 477-483 (2004)] are not consistent with the Williamson 2D along-away data [Int. J. Radiat. Oncol., Biol., Phys. 15, 227-237 (1988)] at distances closer than approximately 2 cm from the source. The data presented here for this source are consistent with this 2D along-away table, and are suitable for use in clinical practice.

A Monte Carlo investigation of the dosimetric characteristics of the CSM11 137Cs source from CIS.

The purpose of this study is to calculate basic dosimetry data for a CSM11 low dose rate 137Cs source in water. This source is widely used in afterloadable dome cylinders designed to homogeneously irradiate the vaginal cuff alone or additional areas of the vagina in hysterectomized patients. In this study, the Monte Carlo simulation code GEANT, incorporating in detail source geometry, is used to investigate the dosimetric characteristics of the source. The calculated data were analyzed using a fitting procedure that is described in detail. Absolute dose rate distributions in water were calculated around this source and are presented as conventional 2D Cartesian lookup tables (classically along-away tables). Also, the dose calculation formalism endorsed by the Interstitial Collaborative Working Group and the AAPM Task Group 43 have been calculated. The calculated dose rate constant for this source is lambda = 1.096 +/- 0.002 cGy h(-1) U(-1). The anisotropy function results in about 50% deviations from isotropy at positions near the long axis of the source. The radial dose function is given as a polynomial that reproduces the calculated data up to 20 cm. Best-fit values of attenuation coefficients suitable for use in Sievert integral calculations have been derived.

Radiation and chemotherapy instead of surgery for low infiltrative rectal adenocarcinoma: a prospective trial.

BACKGROUND: The objective of this prospective study was to determine the possibility of treatment based exclusively on chemotherapy and radiotherapy for patients with low infiltrative rectal tumors in an attempt to preserve sphincter function. METHODS: Sixteen patients with rectal adenocarcinoma up to 3 cm above the pectineal line with initial indications for abdominoperineal resection (APR) were submitted to a 5040-cGy (28 x 180 cGy) radiotherapy dose and chemotherapy during the first 3 and last 3 days of radiotherapy, using 425 mg/m2/day of 5-fluorouracil (5FU) and 20 mg/m2/day of folinic acid. Levamisole was used at 150 mg/day for 3 consecutive days at 2-week intervals throughout the period of therapy. Patients with a complete response were not submitted to APR, but received additional brachytherapy for curative purposes with doses from 2000 to 3000 cGy. Patients with recurrence after a complete response, with partial response, or with no response were submitted to APR. RESULTS: Six patients (37.5%) presented a complete response, five (31.25%) presented a partial response, and five (31.35%) did not respond. The disease-free interval ranged from 1 to 34 months (mean = 11 months) among the six patients with complete response, and only one patient not submitted to APR is currently asymptomatic. Among the 15 patients with an indication for APR, three refused surgery because of full improvement of clinical symptoms and currently have tumor activity in the rectum. Mean patient follow-up was 23.8 months (8 to 43 months), and ten patients (62.5%) showed no evidence of active disease at last follow-up. CONCLUSIONS: The therapeutic schedule used was not effective in preserving sphincter function in patients with low infiltrative rectal adenocarcinoma, because responses, although very frequent, were only temporary.

CT-simulator based brachytherapy planner: seed localization and incorporation of biological considerations.

Radiation dose prescription, interpretation, and planning can be problematic for brachytherapy due to high spatial heterogeneity, varying and various dose rates, absence of superimposed calculated isodose distributions onto affected tissues, and lack of dose volume histograms. A new treatment planner has been developed to reduce these limitations in brachytherapy planning. The PC-based planning system uses a CT-simulator to sequentially scan the patient to generate orthogonal images (to localize seed positions) and subsequently axially scan the patient. This sequential scanning procedure avoids using multiple independent patient scans, templates, external frames, or fiducial markers to register the reconstructed seed positions with patient contours. Dose is computed after assigning activity to (low dose rate) Ir192, linear Cs137, or I125 seeds or dwell times (high dose rate) to the Ir192 source. The planar isodose distribution is superimposed onto axial, coronal, or sagittal views of the tissues following image reconstruction. The treatment plan computes (1) direct and cumulative volume dose histograms for individual tissues, (2) the average, standard deviation, and coefficient of skewness of the dose distribution within individual tissues, (3) an average (over all tissue pixels) survival probability (S) and average survival dose DASD for a given radiation treatment, (4) normal tissue complication probability (NTCP) delivered to a given tissue. All four computed quantities account for dose heterogeneity. These estimates of the biological response to radiation from laboratory-based studies may help guide the evaluation of the prescribed low- or high-dose rate therapy in retrospective and prospective clinical studies at a number of treatment sites.

Radiosensitization of human T-cell leukemia by thymidine and 41.8 degrees C hyperthermia in vitro.

This study tested whether thymidine, a naturally occurring nucleoside metabolite, could increase the sensitivity of human T-cell neoplasms to ionizing irradiation and whether adding 41.8 degrees C hyperthermia (X 1 h) to the combination of thymidine and irradiation would further enhance killing of cells by radiation. The magnitude of cytotoxicity induced directly by thymidine was also evaluated. Finally, the ability of 2'-deoxycytidine to prevent thymidine-induced cytotoxicity and radiosensitization was studied. Using JM and MOLT3, two human T-cell acute lymphoblastic leukemias, it was found that thymidine itself was cytotoxic and the toxicity appeared rapidly upon exposure to the drug (i.e., at 4 h). Thymidine caused significant radiosensitization, and thymidine plus 1 h of 41.8 degrees C hyperthermia enhanced radiation-induced killing significantly more than did thymidine or hyperthermia separately. The addition of 2'-deoxycytidine only partly reversed thymidine-induced killing and did not prevent thymidine-induced radiosensitization. The applicability of these results to the clinical management of T- and null-cell malignancies is discussed, as is the presumed mechanistic basis for these observations relative to deoxyribonucleoside metabolism, NAD metabolism, and inhibition of poly(ADP-ribose) polymerase.

31P NMR spectroscopic study of bioenergetic changes in radiation-induced fibrosarcoma-1 after radiation therapy.

The effects of localized gamma-irradiation on the in vivo 31P NMR spectra of RIF-1 tumors grown subcutaneously in C3H/HeN mice have been examined before and during the week after treatment. Increases in the ratio of phosphocreatine (PCr) to inorganic phosphate (Pi) and in tumor pH, and decreases in the ratio of Pi to the beta phosphorus resonance of the nucleotide triphosphates (beta NTP) were observed in irradiated tumors. The time course of changes in the 31P spectrum following treatment was the opposite of the pattern during untreated growth, and the magnitude and duration of the changes increased with increasing radiation dose, decreasing clonogenic cell survival and increasing growth delay. To examine the possibility that nontherapeutic systemic effects of the tumor irradiation were responsible for the changes observed, a number of animals bearing two tumors were examined. One tumor on each mouse was selectively irradiated. Changes in tumor volume, Pi/beta NTP, PCr/Pi, the ratio of phosphomonoesters to beta NTP, and tumor pH were all significantly different in the treated compared to the untreated tumor on each animal, indicating that these changes in 31P NMR spectra were a response to radiation therapy and not a systemic response to radiation toxicity.

[Results in combined hyperthermia/radiotherapy of adenoid cystic carcinomas compared with conventional treatment]. / Erfahrungen mit der kombinierten Hyperthermie/Strahlentherapie adenoidzystischer Karzinome im Vergleich mit herkömmlicher Behandlung.

158 patients with advanced malignancies of the head and neck area were treated by a combined hyperthermia/radiotherapy since 1972. 16 were adenoid cystic carcinoma (ACC). Their treatment results are compared with 28 ACC after radiotherapy alone. All 16 patients with hyperthermia achieved a complete remission. CR in 28 ACC-patients without hyperthermia was 61%. 113 patients with hyperthermia-treated squamous cell carcinomas had a comparatively low CR-rate of 49%. Five-year-survival on the other hand was 50% for ACC after hyperthermia, 57% after a planned postoperative radiation without hyperthermia and 37.5% after a radiotherapy alone in cases of inoperability. The combination of hyperthermia and radiotherapy is indicated in cases of advanced inoperable ACC and leads to a high percentage of local tumour control.

Advanced stage IIIB cancer of the cervix treatment by hyperthermia and radiation.

Treatment records of patients with primary untreated Stage IIIB carcinoma of the cervix treated at Indiana University Department of Radiation Oncology from November 1964 through January 1979 were reviewed. During this period, 79 patients were treated; 46 received external therapy using cobalt-60, 15 received a 25-MV photon beam, and 18 received a 25-MV photon beam followed by 45 min of 434-MHz microwave hyperthermia producing central tumor core temperatures of 39.5 to 41.5 degrees C. All patients received similar doses of radiation using combination intracavitary radioactive isotopes and external therapy. Patients who received heat therapy in combination with radiation therapy did not have increased acute or chronic complications of normal tissues. Local tumor control was superior when regional heat therapy was given; however, long-term absolute survival rates were not affected as the survival rate at 5 years was not statistically different in any of the three treatment groups.

[Reduced-dose adjuvant CMF-chemotherapy combined with postoperative irradiation in breast cancer with lymphatic metastases. A prospective study of 45 patients]. / Adjuvante CMF-Chemotherapie mit reduzierter Dosis kombiniert mit postoperativer Bestrahlung beim lymphogen metastasierten Mammakarzinom. Eine prospektive Studie an 45 Patientinnen.

From 1978 to 1982, 45 postoperative cases of breast cancer with lymphatic spread received radiation to the chestwall and axillary, supra- and infraclavicular lymph nodes up to 40 Gy. In addition, we gave 600 mg cyclophosphamide, 50 mg methotrexate and 750 mg 5-fluorouracil intravenously on day 1 of altogether nine 21-day cycles. The median follow-up is 37 months, and we calculate a 5-year over-all actuarial survival-rate which was 83% in the premenopausal and 77% in the postmenopausal patients. The disease-free 5-year survival-rate was 74% for the premenopausal and 61% for the postmenopausal women. There were twice as many patients with stage N2 in the postmenopausal group. No severe side-effects were observed. These promising preliminary results and the good tolerance of the above-mentioned combined therapy recommend it for future randomized studies.

The change in hypoxic and chronically hypoxic cell fraction in murine tumors treated with hyperthermia.

The effect of hyperthermia on the size of hypoxic and chronically hypoxic cell fractions in murine tumors was studied. The chronically hypoxic cell fraction was defined as a fraction of tumor cells which were not oxygenated under hyperbaric oxygen. Animals were C3Hf/Sed mice derived from our defined flora mouse colony. Tumors were FSa-II and MCa which were early generation isotransplants of a spontaneous fibrosarcoma and a mammary carcinoma, respectively. TCD50 (50% tumor control dose) or the radiation dose which yields a local tumor control in half the treated animals and TG (tumor growth) time or the time required for half the treated tumors to reach 1000 mm3 from the first treatment day were experimental end points. Hyperthermia was given by immersing animal feet into a water bath maintained at 43.5 +/- 0.1 degrees C. Animal tumors were irradiated with a 137Cs unit under hypoxic conditions, in air or under O2 30 psi. The hypoxic cell fraction increased immediately after hyperthermia in both MCa and FSa-II tumors. The chronically hypoxic cell fraction was, on the other hand, decreased following hyperthermia. The decrease was more substantial in the MCa than in FSa-II.