Andrew J. Milligan

Predictions of blood flow from thermal clearance during regional hyperthermia

In order to provide a method for estimation of regional blood flow during hyperthermia, a mathematical model has been developed which employs thermal clearance to measure this physiologic parameter. Limbs of mongrel dogs were heated with 2450 megaHertz microwaves to temperatures of 43 degrees C, 45 degrees C, or 47 degrees C and thermal washout was measured at five minute intervals throughout each treatment period. Calculated blood flow indicates that in response to heat challenge, normal tissue compensates by increasing regional blood flow within the treatment volume. This increase in blood flow continues to a maximum value after which the blood flow begins to decrease. Data indicate that the time for maximum increase in blood flow (induction time) decreases as treatment temperature increases. These induction times were 40 minutes, 25 minutes, and 15 minutes for treatment temperatures of 43 degrees, 45 degrees, and 47 degrees C, respectively. The data also show that the calculated value of peak blood flow is directly related to treatment temperature. Calculated peak blood flow values reached 37.8, 59.0, and 183.0 ml/minute/100 grams of tissue during 43 degrees, 45 degrees, and 47 degrees C, hyperthermia, respectively. It is suggested that a therapeutic advantage could be gained by treating tumors for a specific length of time during which the blood flow in adjacent normal tissues continues to increase. This would take maximum advantage of normal tissues ability to compensate for increased temperature, and would exploit any decreased ability of tumor tissue to perform this same function.

Conformal microwave array (CMA) applicators for hyperthermia of diffuse chest wall recurrence

Purpose: This article summarises the evolution of microwave array applicators for heating large area chest wall disease as an adjuvant to external beam radiation, systemic chemotherapy, and potentially simultaneous brachytherapy. Methods: Current devices used for thermotherapy of chest wall recurrence are reviewed. The largest conformal array applicator to date is evaluated in four studies: (1) ability to conform to the torso is demonstrated with a CT scan of a torso phantom and MR scan of the conformal water bolus component on a mastectomy patient; (2) specific absorption rate (SAR) and temperature distributions are calculated with electromagnetic and thermal simulation software for a mastectomy patient; (3) SAR patterns are measured with a scanning SAR probe in liquid muscle phantom for a buried coplanar waveguide CMA; and (4) heating patterns and patient tolerance of CMA applicators are characterised in a clinical pilot study with 13 patients. Results: CT and MR scans demonstrate excellent conformity of CMA applicators to contoured anatomy. Simulations demonstrate effective control of heating over contoured anatomy. Measurements confirm effective coverage of large treatment areas with no gaps. In 42 hyperthermia treatments, CMA applicators provided well-tolerated effective heating of up to 500 cm2 regions, achieving target temperatures of Tmin = 41.4 ± 0.7°C, T90 = 42.1 ± 0.6°C, Tave = 42.8 ± 0.6°C, and Tmax = 44.3 ± 0.8°C as measured in an average of 90 points per treatment. Conclusion: The CMA applicator is an effective thermal therapy device for heating large-area superficial disease such as diffuse chest wall recurrence. It is able to cover over three times the treatment area of conventional hyperthermia devices while conforming to typical body contours.

Canine normal and tumor tissue estimated blood flow during fractionated hyperthermia

Time-temperature relationships are of critical importance in hyperthermia effects on tumors. Knowledge of temperature distributions within tumors is necessary to achieve maximal tumor response, and because blood flow is the major determinant of heat dissipation within tissue, knowledge of blood flow parameters is equally important. A mathematical model has been developed which estimates a parameter that may be related to regional tissue blood flow and is readily adaptable to clinical observations. Eight canine mast cell tumors were heated with interstitial radiofrequency (100 mHz) hyperthermia to a temperature range of 44 degrees C, +/- 0.5 degrees C, for 40 minutes. Estimated blood flow increased over the 40-minute treatment interval from 81 ml/min/100 gm of tissue at 10 minutes post-initiation of treatment to a maximum of 101.2 ml/min/100 gm of tissue at 30 minutes post-initiation of treatment. Over a 9-day period, during which both tumor and normal tissues were treated four times, values increased within the volume of interest. Maximum estimated blood flow within normal tissue increased from 115.7 ml/min/100 gm of tissue after 10 minutes of heating to a maximum of 121.7 ml/min/100 gm of tissue at 40 minutes. In contrast to normal tissue, eight canine mast cell sarcomas showed little change in estimated blood flow during 40 minutes of treatment. However, tumor tissue appears to undergo compensatory changes over the 9-day treatment interval with increases occurring in blood flow over that time period. These data underscore the importance of knowing blood flow characteristics within tumor and normal tissue.

Hematoporphyrin Derivative Photochemotherapy of Experimental Bladder Tumors

Recent studies have shown that disruption of tumor blood flow is a major consequence of hematoporphyrin derivative photochemotherapy. A series of experiments was undertaken on the transplantable N-(4-(5-nitro-2-furyl)-2-thiazolyl)-formamide induced urothelial tumor in Fischer 344 rats to determine a dose response for both hematoporphyrin derivative and light. Tumor blood flow was used as the biologic criteria of response. Hematoporphyrin derivative doses of 10 micrograms./gm. body weight or above were necessary to cause a significant decrease in tumor blood flow when the tumors were illuminated with 360 joules/cm.2 of noncoherent red light (greater than 590 nm.). With a constant hematoporphyrin derivative dose of 20 micrograms./gm. body weight, significantly lower tumor blood flows were observed with fluences of 240 joules/cm.2 and above. In order to correlate dose response to tumor regression, experiments were done in which tumor dry weights were determined 3 weeks after completion of photochemotherapy (360 joules/cm.2). Hematoporphyrin derivative doses of 10 micrograms./gm. body weight or above were necessary to induce tumor regression. These studies support the hypothesis that disruption of tumor blood flow is a tumoricidal mechanism of hematoporphyrin derivative photochemotherapy.

Radiation Dosimetry of a Conformal Heat-brachytherapy Applicator

The purpose of this paper is to report the radiation dosimetric characteristics of a new combination applicator for delivering heat and radiation simultaneously to large area superficial disease <1.5 cm deep. The applicator combines an array of brachytherapy catheters (for radiation delivery) with a conformal printed circuit board microwave antenna array (for heat generation), and a body-conforming 5–10 mm thick temperature-controlled water bolus. The rationale for applying both modalities simultaneously includes the potential for significantly higher response rate due to enhanced synergism of modalities, and lower peak toxicity due to temporal extension of heat and radiation induced toxicities. Treatment plans and radiation dosimetry are calculated with IPSA (an optimization tool developed at UCSF) for 15 × 15 cm2 and 35 × 24 cm2 applicators, lesion thicknesses of 5 to 15 mm, flat and curved surfaces, and catheter separation of 5 and 10 mm. The effect on skin dose of bolus thickness and presence of thin copper antenna structures between radiation source and tissue are also evaluated. Results demonstrate the ability of the applicator to provide conformal radiation dose coverage for up to 15 mm deep target volumes under the applicator. For clinically acceptable plans, tumor coverage is > 98%, homogeneity index > 0.95 and the percentage of normal tissue irradiated is < 20%. The dose gradient at the skin surface varies from 3 to 5 cGy/mm depending on bolus thickness and lesion depth. Attenuation of the photon beam by the printed circuit antenna array is of the order 0.25% and secondary electron emissions are absorbed completely within 5 mm of water bolus and plastic layers. Both phenomena can then be neglected in dose calculations allowing commercial software to be used for treatment planning. This novel applicator should prove useful for the treatment of diffuse chestwall disease located over contoured anatomy that may be difficult to treat with single field external beam therapy. By delivering heat and radiation simultaneously, increased synergism is expected with a TER in the range of 2–5. Lowering radiation dose by an equivalent factor may produce lower radiation toxicity with similar efficacy, while preserving the option of subsequent retreatment(s) with thermoradiotherapy in order to further extend patient survival.

Treatment of cancer of the pancreas by intraoperative electron beam therapy: physical and biological aspects

Radiation therapy has had a significant and an expanded role in the management of cancer of the pancreas during the last decade. In particular, for locally advanced disease, radiation therapy has improved the median survival of patients to 1 year. Intraoperative electron beam therapy has been applied to unresectable and resectable pancreatic cancer in an attempt to enhance local control of disease and to improve patient survival. This paper presents a survey of the role of radiation therapy in treatment of cancer of the pancreas, provides information on the radiobiological aspects of this treatment modality and details the physical and dosimetric characteristics of intraoperative radiation therapy with electrons. Presented are the design specifics of an applicator system, central axis beam data, applicator parameters, dose distribution data, shielding, treatment planning and means of verification. Emphasis is placed on the collaboration and cooperation necessary for all members of the intraoperative radiation therapy team including surgeons, radiation therapists, medical physicists, anesthesiologists, technologists, and nurses.

Canine muscle blood flow during fractionated hyperthermia

Blood flow is an important parameter for obtaining uniform thermal distributions in tumour and normal tissue. This study investigated the effect of fractionated hyperthermia on muscle blood flow in 30 dogs treated interstitially. These animals were divided into five groups, each group receiving either 0 (control), 1, 2, 3, or 4 hyperthermia fractions separated by 72 h. Each animal was treated for 40 min at 45 degrees C. Blood flow was measured with four different radioactive microspheres at either 10, 20, 30, or 40 min of heating. During the first treatment, blood flow increased from control of 7.5 +/- 1.1 ml min-1/100 g of tissue to 39.6 +/- 5.8 ml min-1/100 g of tissue at 20 min of heating. Blood flow decreased over the next 20 min to 24.4 +/- 4.8 ml min-1/100 g of tissue. This pattern was repeated for all hyperthermia treatments and peak blood flows were observed for all groups between 20 and 30 min of heating. Peak blood flows reached 20.0, 16.5 and 11.0 ml min-1/100 g of tissue for animals treated with 2, 3, or 4 hyperthermia fractions, respectively. These data suggest that peak blood flow in normal tissue decreased with increasing numbers of hyperthermia fractions. Blood flow response to hyperthermia changes from fraction to fraction and description of the kinetics of these changes is important for understanding the response of normal tissue to heat.

Biochemical and cellular effects of radiofrequency intuced interstitial hyperthermia on normal canine liver

Interstitial hyperthermia (44.0 +/- 0.5 degrees C for 40 minutes) was delivered to the livers of 16 dogs to determine acute effects of treatment on blood chemistry, histology, and cellular appearance of normal liver. SGOT in treated animals peaked immediately at 300 +/- 21 U/L (within 2 hrs) and returned to control value within 7 days. LDH levels peaked at 1 day post-treatment and again at 2 weeks (300 +/- 16 U/L and 340 +/- 25 U/L respectively) and returned to pre-treatment values by week 4. SGPT remained elevated for 6 to 7 days following hyperthermia, but returned to control value at 2 weeks. There was also a rise in alkaline phosphatase (200 +/- 14 U/L 1 day post-treatment), which returned to a pre-treatment level by week 3. Changes in serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, lactate dehydrogenase, and alkaline phosphatase were attributed to both liver parenchymal damage induced by hyperthermia and to surgery. Other deviations in the blood chemistries and hematological parameters measured were ascribed to the stress response from surgical intervention, or to the resultant hemodilution from fluids during surgery. Microscopic examination upon necropsy, performed 4 weeks post-operatively, displayed limited fibrosis with some alteration of liver architecture, generalized sinusoidal dilation and red blood cells in the space of Disse. Cellular ultrastructure changes showed an increase of myelin figures, but mitochondria and other cellular organelles remained essentially normal. Localized tissue inflammation and some loss of function occurred in response to localized hyperthermia for this volume of tissue at therapeutic temperatures. This study showed that the technique was feasible and confirmed that the parenchymal damage caused by interstitial hyperthermia did not produce the severe loss of function that might have been expected.

Progress on conformal microwave array applicators for heating chestwall disease

Previous studies have reported the computer modeling, CAD design, and theoretical performance of single and multiple antenna arrays of Dual Concentric Conductor (DCC) square slot radiators driven at 915 and 433 MHz. Subsequently, practical CAD designs of microstrip antenna arrays constructed on thin and flexible printed circuit board (PCB) material were reported which evolved into large Conformal Microwave Array (CMA) sheets that could wrap around the surface of the human torso for delivering microwave energy to large areas of superficial tissue. Although uniform and adjustable radiation patterns have been demonstrated from multiple element applicators radiating into simple homogeneous phantom loads, the contoured and heterogeneous tissue loads typical of chestwall recurrent breast cancer have required additional design efforts to achieve good coupling and efficient heating from the increasingly larger conformal array applicators used to treat large area contoured patient anatomy. Thus recent work has extended the theoretical optimization of DCC antennas to improve radiation efficiency of each individual aperture and reduce mismatch reflections, radiation losses, noise, and cross coupling of the feedline distribution network of large array configurations. Design improvements have also been incorporated into the supporting bolus structure to maintain effective coupling of DCC antennas into contoured anatomy and to monitor and control surface temperatures under the entire array. New approaches for non-invasive monitoring of surface and sub-surface tissue temperatures under each independent heat source are described that make use of microwave radiometry and flexible sheet grid arrays of thermal sensors. Efforts to optimize the clinical patient interface and move from planar rectangular shapes to contoured vest applicators that accommodate entire disease in a larger number of patients are summarized. By applying heat more uniformly to large areas of contoured anatomy, the CMA applicator resulting from these enhancements should expand the number of patients that can benefit from effective heating of superficial disease in combination with radiation or chemotherapy.

Correlation Of Tumor Blood Flow To Tumor Regression After Hematoporphyrin Derivative (HPD) Photodynamic Therapy To Transplantable Bladder Tumors

Hematoporphyrin derivative (HPD) photodynamic therapy (PDT) has proved effective in the treatment of selected neoplasms (1). The effectiveness of this form of therapy rests on the retention of the systemically administered HPD in neoplastic tissue and its photoactivation with visible light resulting in ‘photodynamic’ tumor destruction. Although it is generally agreed that singlet oxygen liberated during HPD-photodynamic therapy is responsible for the biologic damage created by PDT, the mechanisms of cell death have not been clearly defined (2). Previous studies in our laboratory have demonstrated a rapid and sustained decrease in tumor blood flow after HPD-photodynamic therapy (3,4). The present study was undertaken to correlate changes in tumor blood flow with tumor regression after HPD-PDT.