RTOG quality assurance guidelines for clinical trials using hyperthermia

Dewhirst, Mark W.; Phillips, T.L.; Samulski, Thaddeus V.; Stauffer, Paul R.; Shrivastava, Prakash N.; Paliwal, Bhudatt R.; Pajak, Thomas F.; Gillim, M.; Sapozink, Michael D.; Myerson, Robert J.; Waterman, Frank M.; Sapareto, Stephen A.; Corry, Peter M.; Cetas, Thomas C.; Leeper, Dennis B.; Fessenden, Peter; Kapp, Daniel S.; Oleson, James R.; Emami, Bahman

doi:10.1016/0360-3016(90)90466-w

Cited by 128 publications

(35 citation statements)

References 12 publications

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“…Dogs were anesthetized with inhalational isoflurane anesthesia. Thermometry probes (Luxtron 3100 Fluoroptic thermometer, Santa Clara, CA) were placed according to the Radiation Therapy Oncology Group guidelines using computed tomography imaging (15). The tumors were heated with a scanning spiral or miniature annular-phased array microwave applicator operating between 140 and 433 mHz until the T 90 (lowest 10th percentile of temperatures) was 40.1jC, or the T 50 (median temperature) reached 44jC (8,16).…”

Section: Methodsmentioning

confidence: 99%

Phase I Trial of Doxorubicin-Containing Low Temperature Sensitive Liposomes in Spontaneous Canine Tumors

Hauck

LaRue

Petros

et al. 2006

Clinical Cancer Research

140

113

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Purpose: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. Experimental Design: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. Results: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the doselimiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received z2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 F 6.17 ng/mg tissue. Conclusion: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.Liposome-encapsulated chemotherapy was developed to improve selectivity of drug for tumor compared with normal tissue. Despite the achievement of tumor drug levels that are up to 10-fold higher than those achieved with unencapsulated drugs, particularly when given concurrently with hyperthermia, clinical efficacy of these agents has been only modestly improved (1 -4). Decreased toxicity, in particular the cardiotoxicity seen with doxorubicin, has been the most significant benefit derived from these formulations.One potential explanation for the lack of clinical benefit from liposomal drug delivery to the tumor tissue is the dependence of cytotoxicity on the presence of free drug. Although the liposomes may accumulate preferentially in tumors, the mechanisms by which traditional liposomes release their contents are not well understood (5). The development of liposomes engineered for triggered drug release is one approach that addresses this problem directly.The development of hyperthermia-mediated drug release from liposomes was first reported in 1978 (6). These early thermosensitive liposomes typically released their contents at temperatures > 42jC. Temperatures in this range are difficult to achieve uniformly in a clinical setting. In addition, drug release was slow, requiring 30 minutes to release 40% of the contents (7). Because of...

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Section: Methodsmentioning

confidence: 99%

Phase I Trial of Doxorubicin-Containing Low Temperature Sensitive Liposomes in Spontaneous Canine Tumors

Hauck

LaRue

Petros

et al. 2006

Clinical Cancer Research

140

113

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“…Tumors were imaged using computed tomography and thermometry catheters were placed according to Radiation Therapy Oncology Group guidelines (27,28). Hyperthermia was induced using scanning spiral or annular array microwave applicators operating between 140 and 433 MHz.…”

Section: Methodsmentioning

confidence: 99%

Thermal Dose Is Related to Duration of Local Control in Canine Sarcomas Treated with Thermoradiotherapy

Thrall

LaRue

Yu³

et al. 2005

Clinical Cancer Research

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Purpose:To test that prospective delivery of higher thermal dose is associated with longer tumor control duration. Experimental Design: 122 dogs with a heatable soft tissue sarcoma were randomized to receive a low (2-5 CEM43jCT90) or high (20-50 CEM43jCT90) thermal dose in combination with radiotherapy. Most dogs (90%) received four to six hyperthermia treatments over 5 weeks. Results: In the primary analysis, median (95% confidence interval) duration of local control in the low-dose group was1.2 (0.7-2.1) years versus1.9 (1.4-3.2) years in the high-dose group (log-rank P = 0.28). The probability (95% confidence interval) of tumor control at 1 year in the low-dose versus high-dose groups was 0.57 (0.43-0.70) versus 0.74 (0.62-0.86), respectively. Using multivariable procedure, thermal dose group (P = 0.023), total duration of heating (P = 0.008), tumor volume (P = 0.041), and tumor grade (P = 0.027) were significantly related to duration of local tumor control. When correcting for volume, grade, and duration of heating, dogs in the low-dose group were 2.3 times as likely to experience local failure. Conclusions: Thermal dose is directly related to local control duration in irradiated canine sarcomas. Longer heating being associated with shorter local tumor control was unexpected. However, the effect of thermal dose on tumor control was stronger than for heating duration. The heating duration effect is possibly mediated through deleterious effects on tumor oxygenation. These results are the first to show the value of prospectively controlled thermal dose in achieving local tumor control with thermoradiotherapy, and they establish a paradigm for prescribing thermoradiotherapy and writing a thermal prescription.

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“…Hyperthermia treatment was then administered. Two closed-end catheters (Flexineedles, Best Medical International, Springfield, VA) were placed in the tumor under computer-assisted tomography scan guidance, following the Radiation Therapy Oncology Group guidelines (18). Precalibrated fiberoptic thermometers were placed in these catheters to provide temperature measurements during hyperthermia treatment.…”

Section: Gene Injectionsmentioning

confidence: 99%

A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas

Siddiqui¹,

LaRue³

et al. 2007

Molecular Cancer Therapeutics

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Interleukin-12 (IL-12), a proinflammatory cytokine, shows anticancer properties. Systemically administered IL-12 causes dose-dependent toxicity. To achieve localized intratumoral gene expression, an adenoviral gene therapy vector with IL-12 controlled by a heat-inducible promoter (heat shock promoter 70B) was developed and tested in a phase I clinical trial in cats with spontaneously arising soft tissue sarcoma. A feasibility study was done in 16 cats with soft tissue sarcoma using murine IL-12 and/or enhanced green fluorescent protein adenoviral vectors under cytomegalovirus or heat shock promoter 70 control. Subsequently, we conducted a phase I clinical trial using an adenoviral feline IL-12 construct in 13 cats with soft tissue sarcoma. The soft tissue sarcomas were irradiated (48 Gy/16 fractions) followed by intratumoral injection of adenovirus. Twenty-four hours postinjection, tumors were heated (41°C, 60 min). Tumor expression of feline IL-12 and IFN-; was determined. Cats were monitored for systemic toxicity. For the murine IL-12 construct, an association was noted between viral dose and murine IL-12 levels within tumor, whereas serum levels were minimal. Mild toxicity was noted at 10 11 plaque-forming units (pfu). With the feline IL-12 construct, high levels of feline IL-12 mRNA were detected in tumor biopsies with low or absent IFN-; mRNA following gene therapy. Hematologic and hepatic toxicities were noted at the highest viral doses and were associated with detection of IFN-; mRNA in tumor. It is possible to localize gene expression and limit systemic toxicity of IL-12 using the hyperthermia-induced gene therapy approach. The maximum tolerated dose of the feline IL-12 adenoviral vector was 10

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RTOG quality assurance guidelines for clinical trials using hyperthermia

Cited by 128 publications

References 12 publications

Phase I Trial of Doxorubicin-Containing Low Temperature Sensitive Liposomes in Spontaneous Canine Tumors

Phase I Trial of Doxorubicin-Containing Low Temperature Sensitive Liposomes in Spontaneous Canine Tumors

Thermal Dose Is Related to Duration of Local Control in Canine Sarcomas Treated with Thermoradiotherapy

A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas

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