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regional hyperthermia of deep seated malignancies: A comparison of annular phased array microwave, focused ultrasound, and interstitial RF devices
Proceedings of the 28th Annual ASTRO Meeting
153
119 ELECTRON Geraldine
ARC THERAPY: M. Jacobson,
Div. of Radiation
CHEST WALL M.D.,
Oncology,
IRRADIATION
Lee K. McNeely,
OF BREAST M.D.,
Dept. of Radiology,
CANCER
Dennis
PATIENTS
D. Leavitt,
Univ. of Utah Medical
Ph.D., and J. Robert Center,
Stewart,
M.D.
Salt Lake City, UT 84132
From November 1979 to August 1985 we treated forty-seven breast cancer patients with electron arc therapy. This technique was used in situations where optimal treatment with fixed photon or electron beams was technically difficult: long scars, recurrent tumor extending across midline or to the posterior thorax, or marked variation in depth of target tissues. Forty-six patients were treated following mastectomy: thirty-seven electively because of high risk of local failure and nine following local recurrence. One patient with advanced local regional disease was treated primarily. The target volume boundaries on the chest wall were defined by a foam lined cerrobend cast which conformed to the desired treatment field. Tine cast rested on the patient during treatment, functioning as a tertiary coilimator. A variable width secondary collimator was used to account for changes in the radius of the thorax from superior to inferior border. All patients had computerized tomography performed to determine IMC (Internal Mammary Chain) depth and chest wall thickness. Electron energies were selected based on these thicknesses and often varible energies over different segments of the arc were used because of changes in depth. The chest wall and regional node areas were irradiated to 45 Gy - 50 Gy in 5 - 6 weeks by this technique. The supraclavicular, low cervical, and upper axillary nodes were treated by a direct anterior photon field abutted to the superior edge of the electron arc field. Follow up is from 9 - 77 months with a median of _._ _L___._~ "_ I_ 57 months. IYO maJor complications were ooservea. Acute and iate effects and iocai controi are comparabie to standard chest wall irradiation. The disadvantages of this technique are that the preparation of the tertiary field defining cast and CT treatment planning are labor intensive and expensive. The advantage is that for specific clinical situations large areas of chest wall with marked topographical variation can be optimally, homogeneously irradiated while sparing normal uninvolved tissues.
120 HYPERTHERMIA D. Shimm, Dept.
IN THE TREATMENT
T. Cetas,
of Radiation
OF HUMAN
CANCERS
D. Sim, A. Fletcher, Oncology,
University
M. Bryson, of Arizona,
E. Gerner, Tucson,
J.R. Cassady
AZ 85724
Between 1977 and 1985, 244 patients were treated using hyperthermia + irradiation. These include 61 patients with head and neck tumors, 74 with pelvic tumors, 47 with tumors involving eccentric body wall sites, 31 with tumors involving the abdomen or thorax, and 13 with extremity tumors. Twenty-four patients were treated using the BSD APAS, 85 with other microwave techniques, 47 with the Magnetrode, 22 with other radiofrequency techniques, and 66 using interstitial techniques. Heating technique, tumor volume, and tumor site were all significant (p < 0.01) predictors of tumor heating; multivariate analysis indicated that heating technique and tumor volume were the most significant independent predictors of tumor heating. Tumor volume, heating technique, temperature achieved, radiation dose, and tumor site were all significant (p < 0.02) predictors of achieving a complete response; multivariate analysis indicated that temperature achieved, tumor volume, and radiation dose were the most significant independent predictors of complete response. Tumor site, heating technique, and temperature were the most significant predictors of response duration. In conclusion, experience over nine years in treating 244 patients with tumors involving varied sites of origin, using different hyperthermia techniques, confirms the importance of heating technique ,,,dL,,,r",r,Y . ..__I +L-^ i.....^."C.._.^^ ^L C^".n^u-.CI.u^4.. -^L;.-..*:r" - -,.."-1,.+r. 1_ .._L:_..:-^a therapeutic temperature, a,," l.,,rIll,p"rLarlLr "I LrlllpelaLurr 111a~lllrvllly a c"lllP1leL.e These findings provide a rationale for continued efforts to improve systems for heat delivery. response.
121 LOCAL/REGIONAL HYPERTHERMIA OF DEEP SEATED MALIGNANCIES: A COMPARISON MICROWAVE, FOCUSED ULTRASOUND, AND INTERSTITIAL RF DEVICES.
OF ANNULAR
Peter Fessenden, Ph.D., Daniel S. Kapp, Ph.D., M.D., Sonja Schoeppel, John Meyer, M.D., Stavros V. Prionas, Ph.D., Allen W. Lohrbach
M.D.,
Division of Radiation Stanford, CA 94305
Therapy,
Department
of Radiology,
Stanford
University
PHASED
Thaddeus
School
ARRAY
V. Samulski,
Ph.D.,
of Medicine,
Improvement in local/regional control of advanced or recurrent deep seated malignancies would provide palliative and potentially curative therapy for a significant number of patients with solid tumors. The demonstrated improvement in local control rates in superficial tumors by the adjunct use of hyperthermia with radiation therapy strongly suggests that such an approach would be of benefit for
Radiation
154
Oncology
??
Biology
Physics
??
November
1986, Volume 12, Sup. 1
patients with deep seated malignancies as well. However, the delivery of relatively homogeneous heating at depth remains a difficult engineering challenge. In our Department over the past 5 years, 3 different techniques for the treatment of deep-seated tumors with hyperthermia have been employed. Electromagnetic heating, utilizing a connnercially available annular phased array (AA) operated in the frequency range of 60-100 MHz, was employed in 32 patients with deep-seated tumors involving the lower abdomen, pelvis, or extremities for a total of 106 treatment sessions. A custom designed focused six ultrasound transducer isospherical ultrasound device (IUD) operated at 350 kHz was utilized in the treatment of 20 patients mainly with deep-seated lower-abdominal and pelvic tumors. They received a total of 70 separate hyperthermia sessions. (Five of these patients were also treated in the AA device). An additional 11 patients, 6 with deep seated pelvic tumors and 5 with deep seated head and neck tumors, received a total of 22 heating sessions utilizing an interstitial RF heating system, operating at 5 kHz. The size and shape of the RF local current fields were determined by the number and conductive lengths of the interstitial electrodes. Invasive thermometry and thermal mapping were employed with all 3 devices in an attempt to characterize and regulate the intratumoral and adjacent normal tissue thermal distributions during treatments. A summary of the clinical material and a detailed comparison of the temperature distributions obtained will be presented for each of these 3 devices. Treatment limiting side-effects of these 3 approaches as well as the clinical responses to therapy will be discussed. The limitations of our current technology for the production of regional hyperthermia will be reviewed with consideration given to future directions in equipment development as well as alternative approaches to obtain more effective homogeneous regional heating for deep seated malignancies. This work was supported in part by NC1 grants CA-05838, CA-34680, CA-34686, and NC1 Contract CM-17480.
122 PHARMACOKINETICS E.L. Levine, J.R. Oleson,
AND TOXICITY
M.W. Dewhirst, M.D., Ph.D.
OF INTRAPERITONEAL
D.V.M.,
Ph.D.,
CISPLATIN
J.E. Riviere,
PLUS REGIONAL
D.V.M.,
Division of Radiation Oncology, Duke university Medical Center, *North Carolina State University School of Veterinary Medicine,
Ph.D.*,
HYPERTHERMIA P.J. Hoopes,
D.V.M.,
Ph.D.*,
Durham, NC 27710 Raleigh, NC 27606
Since hyperthermia (HT) potentiates effects of cisplatin, there is rationale for combining regional HT with intraperitoneal (IP) cisplatin as a possible therapeutic approach for advanced ovarian carcinoma. Cisplatin is biotransformed in a series of aquation and protonation reactions which may be altered by heat and are clinically important because the chemical form of the drug influences its efficacy and toxicity. This study (1) characterizes the IP and systemic temperature distributions achieved in Beagle dogs using an IP fluid instillation and a microwave annular phased array to maintain elevated temperature, (2) defines pharmacokinetic parameters of IP cisplatin as a function of regional temperature elevation, and (3) assesses L_-.z_~L__ :_ _____*l.__i_ _.^ ".*hj,,,tc IlypC1LLICLIYILDUYJSLLY. LonlcsLy 111 LI"‘ll,"LLleL‘IIIC YJ. I.....__c?.~__i^ Cisplatin (65 mg/m2) in 800-1500 cc of normal saline (NS) was administered IP with a dwell time of two Five dogs were concurrently given 60 minutes of regional abdominal HT. Blood, hours in nine Beagle dogs. urine, and instillate samples were collected over 24 hours and then processed for atomic absorption free cisplatin spectrophotometry to determine total (serum, urine, instillate) as well as ultrafilterable Normal in serum. In vitro, cisplatin was incubated with NS at 380, 400, 420, and 440C for 15-120 minutes. dog serum was then added for one hour to determine the amount of reactive drug generated. IP temperatures were maintained at 40°-43OC while systemic temperatures (thoracic aorta) remained There was a The initial cisplatin concentrations were 10-22x higher IP than the serum levels. <38.5OC. significant difference (p=.O16) in the IP half-lives (tl/Z); which were longer in the dogs receiving HT Total amounts of cisplatin (t1/2 = 119min + 24min) compared with the euthermic dogs (t1/2 = 62min + 12min). appearing in blood and urine were the same for the HT and euthermic dogs; however, the area under the (pz.006) concentration versus time curve (AUC) for the percentage of free drug in the serum was significantly lower in the dogs receiving HT (40% + 8%) as compared with the euthermic dogs (60% + 7%) for the initial six No serious organ toxicities were found by necropsy on day 21 post hours, with the same trend over 24 hours. and liver enzyme studies remained within normal limits IP cisplatin. Blood cell counts, serum electrolytes, In vitro studies showed that with except for a transient increase in BUN in two dogs (one from each group). -increasing temperatures from 38 o-44OC there was a linear increase in the rate of formation of reactive cisplatin metabolites that can bind to serum proteins. In summary, with IP temperature elevation there is an increased rate of generation of reactive This coupled with the lower free drug serum AUC indicate that metabolites and a longer tl/2 of cisplatin. the reactive metabolites are being retained in the peritoneal cavity with less free drug available in the serum. This process appears to occur without systemic complications.
153
119 ELECTRON Geraldine
ARC THERAPY: M. Jacobson,
Div. of Radiation
CHEST WALL M.D.,
Oncology,
IRRADIATION
Lee K. McNeely,
OF BREAST M.D.,
Dept. of Radiology,
CANCER
Dennis
PATIENTS
D. Leavitt,
Univ. of Utah Medical
Ph.D., and J. Robert Center,
Stewart,
M.D.
Salt Lake City, UT 84132
From November 1979 to August 1985 we treated forty-seven breast cancer patients with electron arc therapy. This technique was used in situations where optimal treatment with fixed photon or electron beams was technically difficult: long scars, recurrent tumor extending across midline or to the posterior thorax, or marked variation in depth of target tissues. Forty-six patients were treated following mastectomy: thirty-seven electively because of high risk of local failure and nine following local recurrence. One patient with advanced local regional disease was treated primarily. The target volume boundaries on the chest wall were defined by a foam lined cerrobend cast which conformed to the desired treatment field. Tine cast rested on the patient during treatment, functioning as a tertiary coilimator. A variable width secondary collimator was used to account for changes in the radius of the thorax from superior to inferior border. All patients had computerized tomography performed to determine IMC (Internal Mammary Chain) depth and chest wall thickness. Electron energies were selected based on these thicknesses and often varible energies over different segments of the arc were used because of changes in depth. The chest wall and regional node areas were irradiated to 45 Gy - 50 Gy in 5 - 6 weeks by this technique. The supraclavicular, low cervical, and upper axillary nodes were treated by a direct anterior photon field abutted to the superior edge of the electron arc field. Follow up is from 9 - 77 months with a median of _._ _L___._~ "_ I_ 57 months. IYO maJor complications were ooservea. Acute and iate effects and iocai controi are comparabie to standard chest wall irradiation. The disadvantages of this technique are that the preparation of the tertiary field defining cast and CT treatment planning are labor intensive and expensive. The advantage is that for specific clinical situations large areas of chest wall with marked topographical variation can be optimally, homogeneously irradiated while sparing normal uninvolved tissues.
120 HYPERTHERMIA D. Shimm, Dept.
IN THE TREATMENT
T. Cetas,
of Radiation
OF HUMAN
CANCERS
D. Sim, A. Fletcher, Oncology,
University
M. Bryson, of Arizona,
E. Gerner, Tucson,
J.R. Cassady
AZ 85724
Between 1977 and 1985, 244 patients were treated using hyperthermia + irradiation. These include 61 patients with head and neck tumors, 74 with pelvic tumors, 47 with tumors involving eccentric body wall sites, 31 with tumors involving the abdomen or thorax, and 13 with extremity tumors. Twenty-four patients were treated using the BSD APAS, 85 with other microwave techniques, 47 with the Magnetrode, 22 with other radiofrequency techniques, and 66 using interstitial techniques. Heating technique, tumor volume, and tumor site were all significant (p < 0.01) predictors of tumor heating; multivariate analysis indicated that heating technique and tumor volume were the most significant independent predictors of tumor heating. Tumor volume, heating technique, temperature achieved, radiation dose, and tumor site were all significant (p < 0.02) predictors of achieving a complete response; multivariate analysis indicated that temperature achieved, tumor volume, and radiation dose were the most significant independent predictors of complete response. Tumor site, heating technique, and temperature were the most significant predictors of response duration. In conclusion, experience over nine years in treating 244 patients with tumors involving varied sites of origin, using different hyperthermia techniques, confirms the importance of heating technique ,,,dL,,,r",r,Y . ..__I +L-^ i.....^."C.._.^^ ^L C^".n^u-.CI.u^4.. -^L;.-..*:r" - -,.."-1,.+r. 1_ .._L:_..:-^a therapeutic temperature, a,," l.,,rIll,p"rLarlLr "I LrlllpelaLurr 111a~lllrvllly a c"lllP1leL.e These findings provide a rationale for continued efforts to improve systems for heat delivery. response.
121 LOCAL/REGIONAL HYPERTHERMIA OF DEEP SEATED MALIGNANCIES: A COMPARISON MICROWAVE, FOCUSED ULTRASOUND, AND INTERSTITIAL RF DEVICES.
OF ANNULAR
Peter Fessenden, Ph.D., Daniel S. Kapp, Ph.D., M.D., Sonja Schoeppel, John Meyer, M.D., Stavros V. Prionas, Ph.D., Allen W. Lohrbach
M.D.,
Division of Radiation Stanford, CA 94305
Therapy,
Department
of Radiology,
Stanford
University
PHASED
Thaddeus
School
ARRAY
V. Samulski,
Ph.D.,
of Medicine,
Improvement in local/regional control of advanced or recurrent deep seated malignancies would provide palliative and potentially curative therapy for a significant number of patients with solid tumors. The demonstrated improvement in local control rates in superficial tumors by the adjunct use of hyperthermia with radiation therapy strongly suggests that such an approach would be of benefit for
Radiation
154
Oncology
??
Biology
Physics
??
November
1986, Volume 12, Sup. 1
patients with deep seated malignancies as well. However, the delivery of relatively homogeneous heating at depth remains a difficult engineering challenge. In our Department over the past 5 years, 3 different techniques for the treatment of deep-seated tumors with hyperthermia have been employed. Electromagnetic heating, utilizing a connnercially available annular phased array (AA) operated in the frequency range of 60-100 MHz, was employed in 32 patients with deep-seated tumors involving the lower abdomen, pelvis, or extremities for a total of 106 treatment sessions. A custom designed focused six ultrasound transducer isospherical ultrasound device (IUD) operated at 350 kHz was utilized in the treatment of 20 patients mainly with deep-seated lower-abdominal and pelvic tumors. They received a total of 70 separate hyperthermia sessions. (Five of these patients were also treated in the AA device). An additional 11 patients, 6 with deep seated pelvic tumors and 5 with deep seated head and neck tumors, received a total of 22 heating sessions utilizing an interstitial RF heating system, operating at 5 kHz. The size and shape of the RF local current fields were determined by the number and conductive lengths of the interstitial electrodes. Invasive thermometry and thermal mapping were employed with all 3 devices in an attempt to characterize and regulate the intratumoral and adjacent normal tissue thermal distributions during treatments. A summary of the clinical material and a detailed comparison of the temperature distributions obtained will be presented for each of these 3 devices. Treatment limiting side-effects of these 3 approaches as well as the clinical responses to therapy will be discussed. The limitations of our current technology for the production of regional hyperthermia will be reviewed with consideration given to future directions in equipment development as well as alternative approaches to obtain more effective homogeneous regional heating for deep seated malignancies. This work was supported in part by NC1 grants CA-05838, CA-34680, CA-34686, and NC1 Contract CM-17480.
122 PHARMACOKINETICS E.L. Levine, J.R. Oleson,
AND TOXICITY
M.W. Dewhirst, M.D., Ph.D.
OF INTRAPERITONEAL
D.V.M.,
Ph.D.,
CISPLATIN
J.E. Riviere,
PLUS REGIONAL
D.V.M.,
Division of Radiation Oncology, Duke university Medical Center, *North Carolina State University School of Veterinary Medicine,
Ph.D.*,
HYPERTHERMIA P.J. Hoopes,
D.V.M.,
Ph.D.*,
Durham, NC 27710 Raleigh, NC 27606
Since hyperthermia (HT) potentiates effects of cisplatin, there is rationale for combining regional HT with intraperitoneal (IP) cisplatin as a possible therapeutic approach for advanced ovarian carcinoma. Cisplatin is biotransformed in a series of aquation and protonation reactions which may be altered by heat and are clinically important because the chemical form of the drug influences its efficacy and toxicity. This study (1) characterizes the IP and systemic temperature distributions achieved in Beagle dogs using an IP fluid instillation and a microwave annular phased array to maintain elevated temperature, (2) defines pharmacokinetic parameters of IP cisplatin as a function of regional temperature elevation, and (3) assesses L_-.z_~L__ :_ _____*l.__i_ _.^ ".*hj,,,tc IlypC1LLICLIYILDUYJSLLY. LonlcsLy 111 LI"‘ll,"LLleL‘IIIC YJ. I.....__c?.~__i^ Cisplatin (65 mg/m2) in 800-1500 cc of normal saline (NS) was administered IP with a dwell time of two Five dogs were concurrently given 60 minutes of regional abdominal HT. Blood, hours in nine Beagle dogs. urine, and instillate samples were collected over 24 hours and then processed for atomic absorption free cisplatin spectrophotometry to determine total (serum, urine, instillate) as well as ultrafilterable Normal in serum. In vitro, cisplatin was incubated with NS at 380, 400, 420, and 440C for 15-120 minutes. dog serum was then added for one hour to determine the amount of reactive drug generated. IP temperatures were maintained at 40°-43OC while systemic temperatures (thoracic aorta) remained There was a The initial cisplatin concentrations were 10-22x higher IP than the serum levels. <38.5OC. significant difference (p=.O16) in the IP half-lives (tl/Z); which were longer in the dogs receiving HT Total amounts of cisplatin (t1/2 = 119min + 24min) compared with the euthermic dogs (t1/2 = 62min + 12min). appearing in blood and urine were the same for the HT and euthermic dogs; however, the area under the (pz.006) concentration versus time curve (AUC) for the percentage of free drug in the serum was significantly lower in the dogs receiving HT (40% + 8%) as compared with the euthermic dogs (60% + 7%) for the initial six No serious organ toxicities were found by necropsy on day 21 post hours, with the same trend over 24 hours. and liver enzyme studies remained within normal limits IP cisplatin. Blood cell counts, serum electrolytes, In vitro studies showed that with except for a transient increase in BUN in two dogs (one from each group). -increasing temperatures from 38 o-44OC there was a linear increase in the rate of formation of reactive cisplatin metabolites that can bind to serum proteins. In summary, with IP temperature elevation there is an increased rate of generation of reactive This coupled with the lower free drug serum AUC indicate that metabolites and a longer tl/2 of cisplatin. the reactive metabolites are being retained in the peritoneal cavity with less free drug available in the serum. This process appears to occur without systemic complications.