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Biomedical subjects

Brian D Kavanagh

Publications and source records attributed to Brian D Kavanagh.

17 recordsLinked to original sources
PubMed2006

Dose as a function of liver volume and planning target volume in helical tomotherapy, intensity-modulated radiation therapy-based stereotactic body radiation therapy for hepatic metastasis.

PURPOSE: Stereotactic body radiation therapy (SBRT) has been shown to be an effective, well-tolerated treatment for local control of tumors metastatic to the liver. Multi-institutional Phase II trials are examining 60 Gy in 3 fractions delivered by linac-based, 3D-conformal IMRT. HiArt Helical TomoTherapy is a treatment unit that delivers co-planar helical IMRT that is capable of image-guided SBRT. We hypothesized that the maximum tolerable dose (MTD) delivered to a lesion by Helical TomoTherapy-based SBRT could be predicted based on the planning target volume (PTV) and liver volume. METHODS AND MATERIALS: To test this, we performed inverse treatment planning and analyzed the dosimetry for multiple hypothetical liver gross tumor volumes (GTV) with conventional PTV expansions. Inverse planning was carried out to find the maximum tolerated SBRT dose up to 60 Gy to be delivered in 3 fractions based on the dose constraint that 700 cc of normal liver would receive less than 15 Gy. RESULTS: Regression analysis indicated a linear relationship between the MTD, the PTV and the liver volume, supporting our hypothesis. A predictive equation was generated, which was found to have an accuracy of +/-3 Gy. In addition, dose constraints based on proximity to other normal tissues were tested. Inverse planning for PTVs located at varying distances from the heart, small bowel, and spinal cord revealed a predictable decrease in the MTD as the PTV increased in size or approached normal organs. CONCLUSIONS: These data provide a framework for predicting the likely MTD for patients considered for Helical TomoTherapy liver SBRT.

Humans↗
PubMed2006

Stereotactic radiosurgery and stereotactic body radiation therapy: an overview of technical considerations and clinical applications.

SRS and SBRT have emerged as effective local treatment techniques for cranial and extracranial tumors, respectively. Clinical indications for SRS and SBRTcontinue to be redefined through ongoing clinical investigations. It will be especially interesting to investigate how SRS and SBRT might best be combined with new molecularly targeted systemic agents as the field of oncology progresses through the twenty-first century.

Humans↗
PubMed2006

Short-term tumor control and acute toxicity after stereotactic radiosurgery for glomus jugulare tumors.

OBJECTIVE: Glomus jugulare tumors (GJT) have traditionally been treated by surgery or fractionated external beam radiation therapy (XRT). This study evaluates acute toxicity and short-term efficacy of single-fraction stereotactic radiosurgery (SRS) for the treatment of GJT. STUDY DESIGN AND SETTING: Eight patients (age range 28-74) with GJT underwent SRS (Brainlab linear accelerator) as primary treatment. A nominal dose of 15-16 Gy was prescribed. RESULTS: After undergoing SRS, 7 of 8 patients (87.5%) reported complete resolution of presenting symptoms. Follow-up MRIs showed tumor stabilization in 100% of patients. Transient vertigo occurred in one patient. One patient suffered acute GI upset and transient lower cranial neuropathy. CONCLUSION: Stereotactic radiosurgery is an effective alternative for patients with GJT in achieving tumor control and resolution of symptoms. EBM RATING: C-4.

Adult↗
PubMed2006

Extracranial radiosurgery (stereotactic body radiation therapy) for oligometastases.

Extracranial radiosurgery, also known as stereotactic body radiation therapy (SBRT), is an increasingly used method of treatment of limited cancer metastases located in a variety of organs/sites including the spine, lungs, liver, and other areas in the abdomen and pelvis. The techniques used to perform SBRT were initially modeled after intracranial radiosurgery, although considerable evolution in technique and conduct has occurred for extracranial applications. Unlike intracranial radiosurgery, SBRT requires characterization and accounting for inherent organ movement including breathing motion. Potent dose hypofractionation schedules have been used with SBRT such that the treatment is generally both ablative and convenient. Because the treatment is severely damaging to tissues within and about the target, the volume of adjacent normal tissue must be strictly minimized to avoid toxic late effects. Outcomes in various sites show very high rates of local control with toxicity mostly related to tubular tissues like the airways and bowels. With proper conduct though, SBRT can be an extremely effective treatment option for oligometastases.

Clinical Trials as Topic↗
PubMed2006

Interim analysis of a prospective phase I/II trial of SBRT for liver metastases.

Stereotactic Body Radiation Therapy (SBRT) is a potent means of systemic cytoreductive therapy for selected patients with metastatic cancer. We here report an interim analysis of a prospective Phase I/II study of SBRT for liver metastases. Eligible patients with liver metastases met these criteria: (1) maximum tumor diameter < 6 cm; (2) < or =3 discrete lesions; (3) treatment planning confirmed > or = 700 cm3 of normal liver receives < or =15 Gy. The gross tumor volume (GTV) was expanded 5-10 mm to yield the planning target volume, which received 60 Gy in 3 fractions of SBRT over 3-14 days in the Phase II component of the trial. As of July, 2006, 36 patients have been enrolled: 18 in Phase I, 18 in Phase II. The median age was 58 years (range 27-91); the M:F ratio was 20:16. The most common primary sites were lung (n = 10), colorectal (n = 9), and breast (n = 4). Among 21 pts with > or = 6 months post-SBRT follow-up (median 19 months, range 6-29), one instance of SBRT-related grade 3 toxicity occurred in subcutaneous tissue superficial to the liver. No grade IV toxicity occurred. For 28 discrete lesions treated (median GTV 14 cm3, range 1-98) the 18 month actuarial local control estimate is 93%. This interim analysis indicates that a very high rate of durable in-field tumor control can be safely achieved with SBRT to 1-3 liver lesions as administered in this protocol, to a prescription dose of 60 Gy in 3 fractions.

Adult↗
PubMed2006

The role of alpha-blockers in the management of lower urinary tract symptoms in prostate cancer patients treated with radiation therapy.

OBJECTIVE: Radiation therapy (RT) is commonly used for the treatment of prostate cancer, either via brachytherapy or external beam, and is often accompanied by dose-related obstructive and irritative lower urinary tract symptoms (LUTS). This review will analyze the current state of knowledge of LUTS secondary to RT for prostate cancer and review treatment options for this complication. METHODS: A review of the literature. RESULTS: Radiation-induced effects in the lower urinary tract that result in LUTS include injury to peripheral neurons, interstitial fibrosis of the bladder, and loss of muscle fibers in the muscularis propria. LUTS are associated with a diminished quality of life and impaired sexual function. Numerous nonrandomized studies and one randomized study support the proposition that the occurrence of LUTS secondary to RT is effectively mitigated by alpha1-adrenoreceptor blockade. CONCLUSIONS: Basic and clinical science studies as well as clinical guidelines relevant for LUTS secondary to RT suggest that the routine use of alpha1-adrenoreceptor antagonists should be considered in patients treated with RT, either prophylactically or at the earliest sign of LUTS.

Adrenergic alpha-Antagonists↗
PubMed2005

A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases.

PURPOSE: To determine the maximum tolerated dose (MTD) of stereotactic body radiation therapy (SBRT) for liver metastases. METHODS AND MATERIALS: A multicenter Phase I clinical trial was conducted. Eligible patients had one to three liver metastases, tumor diameter <6 cm, and adequate liver function. The first cohort received 36 Gy to the planning target volume (PTV) in three fractions (F). Subsequent cohorts received higher doses up to a chosen maximum of 60 Gy/3F. At least 700 mL of normal liver had to receive a total dose <15 Gy. Dose-limiting toxicity (DLT) included acute Grade 3 liver or intestinal toxicity or any acute Grade 4 toxicity. The MTD was exceeded if 2/6 patients in a cohort experienced DLT. RESULTS: Eighteen patients were enrolled (10 male, 8 female): median age, 55 years (range, 26-83 years); most common primary site, colorectal (6 patients); median aggregate gross tumor volume, 18 ml (range, 3-98 ml). Four patients had multiple tumors. No patient experienced a DLT, and dose was escalated to 60 Gy/3F without reaching MTD. CONCLUSIONS: Biologically potent doses of SBRT are well tolerated in patients with limited liver metastases. Results of this study form the basis for an ongoing Phase II SBRT study of 60 Gy over three fractions for liver metastases.

Adult↗
PubMed2004

Stereotactic body radiation therapy. Rationale, techniques, applications, and optimization.

Stereotactic body radiation therapy (SBRT) is a rapidly evolving cancer treatment method in which concepts and techniques previously developed for brain tumor radiosurgery are adapted to eradicate tumors elsewhere in the body. The spatial accuracy, conformality, and steep radiation dose gradients of radiosurgery, which have been critical to its success in the treatment of intracranial tumors, are applied in SBRT to treat a variety of extracranial tumors. Early results demonstrate excellent response rates and low toxicity with a variety of hypofractionated dose regimens and localization/immobilization techniques. This article provides an overview of the rationale and results of SBRT for specific indications, descriptions of some methods of treatment delivery, and discussion of potential areas of future investigation.

Brain Neoplasms↗
PubMed2003

Partial breast brachytherapy after lumpectomy: low-dose-rate and high-dose-rate experience.

PURPOSE: The use of partial breast brachytherapy (PBB) after lumpectomy for selected patients with early-stage breast cancer reduces the adjuvant radiotherapy treatment time to <1 week. Despite the advantages of accelerated treatment, maintaining an acceptable cosmetic outcome is important. In a cohort of patients who received low-dose-rate (LDR) or high-dose-rate (HDR) PBB after lumpectomy, the clinical characteristics and treatment parameters were analyzed to identify predictors for an unfavorable cosmetic outcome. METHODS AND MATERIALS: Early-stage breast cancer patients with clear resection margins and 0-3 positive lymph nodes were eligible for PBB. Uniform guidelines for target definition and brachytherapy catheter placement were applied. The HDR PBB dose was 34 Gy in 10 fractions within 5 days, and the LDR dose was 45 Gy given at a rate of 50 cGy/h. The end points included incidence of radiation recall reaction, telangiectasias, and cosmetic-altering fibrosis. RESULTS: Between 1995 and 2000, 44 patients with early-stage breast cancer received PBB without adjuvant external beam radiotherapy after lumpectomy (31 HDR PBB, 13 LDR PBB). After a median follow-up of 42 months (range 18-86), all patients remained locally controlled. The overall rate of good/excellent cosmetic outcome was 79.6% overall and 90% with HDR PBB. Radiation recall reactions occurred in 43% of patients (6 of 14) who received adriamycin. LDR PBB and adriamycin were significant predictors for late unfavorable cosmetic changes in univariate analysis (p = 0.003 and p = 0.005, respectively). CONCLUSION: Although a high rate of local control and good/excellent cosmetic outcome is provided with HDR PBB, the risk of unfavorable cosmetic changes when treated with both LDR PBB and adriamycin is noteworthy. This suggests that HDR PBB is preferred in patients for whom adriamycin is indicated.

Adult↗
PubMed2002

The effects of pentoxifylline on the survival of human glioma cells with continuous and intermittent stereotactic radiosurgery irradiation.

PURPOSE: In linac-based stereotactic radiosurgery, treatment is delivered intermittently via multiple individual small radiotherapy arcs. The time lapses between the individual arcs permit greater damage repair and increased tumor cell survival in comparison with continuous irradiation. Because pentoxifylline (PTX) has been reported to prevent radiation-induced cell cycle arrest at the G2/M checkpoint, where damage repair is critically linked to cell survival, we hypothesized that PTX would exert a favorable radiosensitization effect by reducing the recovery observed during intermittent stereotactic radiosurgery. METHODS AND MATERIALS: The human glioma cell line T98G was used to study the effects of continuous vs. intermittent irradiation with or without PTX. Cell cycle patterns were studied using flow cytometry. Clonogenic assays of single cells and spheroid outgrowth assays provided a quantitative measure of PTX-mediated radiosensitization. The PTX effect upon cells in low oxygen conditions was also studied in vitro after enzymatic oxygen scavenging. RESULTS: Flow Cytometry: T98G cells exposed to both continuous and intermittent irradiation exhibit similar arrest at the G2/M checkpoint. The addition of 2 mM PTX significantly reduced the radiation-induced G2/M block in both irradiation schemes. Clonogenic Assays: The same PTX concentration applied before a continuous dose of 12 Gy, two intermittent doses of 6 Gy, or three intermittent doses of 4 Gy, all given within a 1-h interval, consistently caused radiosensitization. The drug enhancement ratios for PTX were 1.5, 2.7, and 6.0 for the continuous and two different intermittent dose schedules, respectively. Adding PTX after irradiation yielded lower enhancement ratios than pre-irradiation application. A similar pattern was observed after total doses of 4, 6, 9, or 12 Gy, as well. In low oxygen conditions, PTX was seen to have the same effects as in normoxic conditions. Spheroid Outgrowth Assays: The in vitro PTX effects were replicated in the spheroid outgrowth assays. CONCLUSION: In human glioma cells, PTX abrogates the radiation-induced G2/M block observed after either continuous radiation exposure or intermittent exposures modeling clinical linac-based radiosurgery. The PTX-mediated reduction of the G2/M block translates into radiosensitization, most notably during intermittent exposures, and is presumably a consequence of diminished DNA damage repair at the G2/M checkpoint, though other contributing effects cannot be ruled out. The radiosensitization effect of PTX is sustained under low oxygen conditions. These results support consideration of the clinical evaluation of PTX to enhance the efficacy of linac-based radiosurgery involving intermittent irradiation through multiple arcs.

Cell Survival↗
PubMed2002

A theoretical model for the effects of reduced hemoglobin-oxygen affinity on tumor oxygenation.

PURPOSE: To develop a theoretical model for oxygen delivery to tumors, and to use the model to simulate the effects of changing the affinity of hemoglobin for oxygen on tumor oxygenation. METHODS AND MATERIALS: Hemoglobin affinity is expressed in terms of P(50), the partial pressure of oxygen (Po(2)) at half saturation. Effects of changing P(50) on arterial Po(2) are predicted using an effective vessel approach to describe diffusive oxygen transport in the lungs, assuming fixed systemic oxygen demand and fixed blood flow rate. The decline in oxygen content of blood as it flows through normal tissue before entering the tumor region is assumed fixed. The hypoxic fraction of the tumor region is predicted using a three-dimensional simulation of diffusion from a network of vessels whose geometry is derived from observations of tumor microvasculature in the rat. RESULTS: In air-breathing rats, predicted hypoxic fraction decreases with moderate increases in P(50), but increases with further increases of P(50), in agreement with previous experimental results. In rats breathing hyperoxic gases, and in humans breathing either normoxic or hyperoxic gases, increased P(50) is predicted to improve tumor oxygenation. CONCLUSIONS: The results support the administration of synthetic agents to increase P(50) during radiation treatment of tumors.

Animals↗
PubMed2002

The effect of high-dose-rate brachytherapy dwell sequence on cell survival.

PURPOSE: During a high-dose-rate (HDR) brachytherapy treatment, as the source steps through different dwell positions, the dose rate at any fixed point within the implant varies, because the distance between the point and the source continually changes. The instantaneous dose rate may vary by a factor of 100 or more, in a complex dwell position sequence. Two different points which receive the same total dose may have received that dose with a very different sequence of dose rates. Any effects due to the complex changes in dose rate, including the sequence of dose delivery, are ignored. We investigated the possible effects of the sequence in which dose is delivered at two different dose rates, representative of dose rates that occur during an HDR treatment. METHODS AND MATERIALS: The target consisted of a tube containing a 1.0 cm(3) suspension of V-79 Chinese hamster cells. Two fixed source dwell positions near and far from the target, representing high and intermediate dose rates, were considered. The experiments compared the survival of V-79 cells exposed to an irradiation sequence consisting of either an HDR component followed by an intermediate-dose-rate component (H-I arm), or the reverse (I-H arm). In either case, the total dose and the dose ratio were the same, only the order in which the high- or intermediate-dose-rate components of the dose were delivered was changed. RESULTS: When the intermediate-dose-rate component was given before the HDR component, there was increased survival. All data pairs from three experiments showed greater survival for the I-H arm than the H-I arm by amounts ranging from 4% to 24%. Simple linear-quadratic models such as the Lea-Catchside model, which is invariant to time reversal of irradiation sequence, do not predict these results. CONCLUSIONS: These results suggest that targets receiving the same total dose of radiation during an HDR implant may not experience the same biological effect. This may be related to induced radioresistance or sublethal damage repair.

Animals↗
PubMed2002

Technical considerations in the application of intensity-modulated radiotherapy as a concomitant integrated boost for locally-advanced cervix cancer.

The technical aspects of IMRT applied to cervix cancer are discussed in this paper, as well as issues related to tumor delineation, target volume definitions, inverse planning, and IMRT delivery. A theoretical example illustrating how IMRT can accurately mimic dose distributions obtained using conventional planning plus HDR brachytherapy is also shown. The notion of clinical optimization parameters is introduced to account for the radiation delivery variables, which affect the overall treatment time. This is especially relevant to the possible introduction of intrafractional movement and resulting inaccuracy, as well as facility efficiency.

Brachytherapy↗
PubMed2002

Clinical application of intensity-modulated radiotherapy for locally advanced cervical cancer.

Intensity-modulated radiotherapy (IMRT) offers technical advantages over conventional external beam radiotherapy (CXRT) that might prove clinically advantageous in the management of gynecologic malignancies. Especially in the case of locally advanced cervical cancer, IMRT provides an opportunity to improve the therapeutic ratio by allowing a selective combination of normal tissue dose reduction and/or concomitant integrated boost dose to the tumor. The clinical and biologic rationale for IMRT in this setting is presented here, and pertinent technical considerations such as the delineation of relevant clinical and planning target volumes are discussed. The capacity for IMRT-mediated normal tissue sparing is illustrated by example and review of the literature. Furthermore, for a small cohort of patients with locally advanced or recurrent cervical cancer treated with concomitant integrated boost IMRT and concurrent chemotherapy, preliminary clinical observations of toxicity and tumor response are presented. Concomitant integrated boost IMRT appears clinically tolerable and efficacious in this setting, and formal clinical investigation is warranted as a means of exploiting the fraction-size dependence of radiosensitizers in common clinical use.

Female↗