Chung K. Lee

Implications of increased tumor blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment

In many past clinical studies in which hyperthermia enhanced the efficacy of radiotherapy, the tumor temperatures could be raised only to 40–42°C range in most cases. The heat-induced cell death, cellular radiosensitization, and vascular damage induced by such mild temperature hyperthermia (MTH) are likely to be insignificant despite the increased response of tumors to radiotherapy. Heating rodent tumors at 40–42°C was found to cause an enduring increase in blood flow and oxygenation in the tumors. Recent studies with canine soft tissue sarcoma and human tumor clinical studies also demonstrated that MTH improves tumor oxygenation, and enhances response of the tumors to radiotherapy or chemoradiotherapy. The increased blood flow and vascular permeability caused by MTH may also improve the delivery of various therapeutic agents such as chemotherapy drugs, immunotherapeutic agents and genetic constructs for gene therapy to tumor cells. MTH as a means to potentiate the efficacy of radiotherapy and others warrants further investigation.

Long-term cardiac mortality following radiation therapy for Hodgkin's disease: analysis with the relative seriality model☆

PURPOSE (a) To assess the increased risk of death due to ischemic heart disease (IHD) in a group of patients treated for Hodgkins disease (HD) with radiation therapy (RT) as the primary treatment. (b) To quantify the dose response of IHD using a biophysical model. MATERIALS AND METHODS Patient material consisted of 157 patients diagnosed for HD between 1972 and 1985 who received RT as the primary treatment at Radiumhemmet, Karolinska Hospital. The general population formed the control group. The RT treatments were reconstructed based on the individual treatment data and simulator films. Individual clinical and dosimetrical data were analyzed with the relative seriality model. The material was also analyzed grouping the material according to dose-volume constraints. RESULTS Of the 157 patients, 13 (8.3%) died due to IHD. The standardized mortality ratio (SMR) was 5.0 (95% CI, 2.7-8.6). Analysis of dose-volume histograms (DVH) showed an increasing risk with increasing dose to a larger volume fraction. The observed individual clinical complication data could not be modeled unambiguously. The group analysis resulted in the dose-response parameters: D(50)=71 Gy, gamma=0.96 and s=1.0. CONCLUSIONS A significantly increased risk of death due to IHD following RT for HD was found. The risk was found to increase with higher dose and larger volume fraction irradiated.

Evaluation of surface and superficial dose for head and neck treatments using conventional or intensity-modulated techniques

With increased use of intensity-modulated radiation therapy (IMRT) for head and neck treatment questions have arisen as to selection of an optimum treatment approach when either superficial sparing or treatment is desired. Other work has pointed out the increased superficial dose resulting from obliquity effects when multiple tangential beams are applied to head and neck treatment, as is the general case in IMRT planning. Helical tomotherapy might be expected to result in even further enhanced superficial dose compared with conventional bilateral field treatment. We have designed a typical right oropharynx target volume in an anthropomorphic head and neck phantom. Three different treatment techniques have been used to optimally treat this target, including bilateral static fields, eight-field IMRT and helical tomotherapy. The phantom was immobilized in a standard treatment position and treated on a Varian 2300cd linear accelerator and on a Hi-Art Helical Tomotherapy unit. 1 mm3 lithium-fluoride thermoluminescent dosimeters (TLDs) were placed on the surface of the phantom at a number of axial test positions. Film strips (Kodak EDR2) were either wrapped around the surface or sandwiched within the phantom. Measured doses at the surface and as a function of depth are compared with the planning system predictions for each treatment technique. The maximum surface doses on the proximal treatment side, averaged from TLDs and films, were measured to be 69-82% of the target dose with the bilateral fields yielding the lowest surface doses (69%), tomotherapy about 2% more than that (71%) and IMRT 13% more (82%). Anterior to the target volume, doses are always low for bilateral treatment. In this case the minimum anterior surface dose (chin area) was 6% of the prescription dose from that technique as compared with 26% and 35% from the IMRT and tomotherapy methods, respectively. The Eclipse and Tomotherapy planning systems both modelled deep and superficial doses well. Surface doses were better modelled by Eclipse at the test points, while the tomotherapy plans consistently overestimated the measured doses by 10% or more. Depth dose measurements, extracted from embedded films, indicated the depth of dose build-up to >99% to be the shallowest for IMRT (2-5 mm) followed by tomotherapy (5-8 mm) and bilateral fields (10-15 mm). The amount of surface dose is clearly technique dependent and should be taken into account in the planning stage.

Strontium-89 chloride (Metastron) for palliative treatment of bony metastases : The University of Minnesota experience

Strontium-89 chloride (Metastron) is an FDA-approved treatment for palliation of cancer pain. We evaluated blood count changes and pain relief in 28 patients with widespread painful bony metastasis treated with strontium-89 at the University of Minnesota Hospital and Clinics. Eighteen patients had prostate cancer (all hormone-refractory cancer), seven patients had breast cancer, and three patients had lung cancer, all previously treated with either radiation, chemotherapy, or a combination of the two. Serial blood counts were performed weekly up to 8 weeks and at 12 weeks after administering Metastron. Pain scale and blood values were monitored simultaneously. The mean baselines of hemoglobin (Hgb), white blood count (WBC), and platelets (Plts) were 11.4, 5900, and 258,000, respectively. The mean dose of Metastron was 3 mCi (range 2.2-4.4). The median time (range) to nadir was about 6 weeks. The percentage reductions relative to baseline were 32% (range 0-72%) for WBC; 14% (range 0-50%) for Hgb; 15% (range 0-47%) for the red blood cell (RBC) count; and 40% (range 0-85%)for Plts. We did not find a close relationship among the baseline blood count, reduction of subsequent blood counts, or previously irradiated active bone marrow volume. The median time of survival was 23 weeks (range 2-66 weeks). At 12 weeks, 29% of patients had moderate to dramatic improvement of pain, 32% had some relief of pain, and 50% had no improvement in pain. Thirty-two percent of the treated patients required additional palliative external beam radiation to their bony lesions within the study period. Our results show that Metastron for palliation for bony metastases should be used with caution because of moderate to severe bone marrow toxicity, especially in platelets, associated with its use. Careful evaluation of patients given Metastron is needed to assess accurately its full benefit.

Clinical experience using 8 MHZ radiofrequency capacitive hyperthermia in combination with radiotherapy: Results of a phase I II study

PURPOSE Since 1985, the University of Minnesota Hospital and Clinic has investigated the efficacy and safety of 8 MHz radiofrequency (RF) capacitive hyperthermia using the Thermotron RF-8. This study reports the thermometric and clinical results of 119 patients treated with RF hyperthermia in combination with radiotherapy (RT). METHODS AND MATERIALS Of 119 patients, 69 received high-dose RT and 50 patients received low-dose RT because of previous irradiation to the treatment site. The most common anatomic sites treated were within the pelvic cavity or head and neck area. Thirty-three percent and 24% of tumors treated were > 7 cm and > 10 cm in largest diameter, respectively. Forty percent of the patients had deep-seated tumors (depth > 6 cm). Hyperthermia was given as soon as possible after RT twice weekly, allowing at least 72 h between treatments. The objective was to raise intratumoral temperatures to 42-43 degrees C or above for 30-50 min while keeping normal tissue temperatures below 40-41 degrees C. RESULTS Of 119 patients, 40% achieved a Tmax tumor temperature of > 42 degrees C and 40% achieved 40-42 degrees C Tmax. Higher Tmax) tumor temperatures were observed as tumor size increased. Tumors > 10 cm in largest diameter had a Tmax of 42.2 degrees C. Tumor depth was not a significant factor for the tumor temperatures achieved. Of 119 patients, 11% achieved complete response and 38% achieved partial response. Of the no-response patients, 34% had symptomatic palliation and 15% had stable disease for at least 12 months after treatment. We were able to treat tumors of patients with subcutaneous fat as thick as 3 cm by precooling the fat for 20 min with 10-15 degrees C saline-filled boluses prior to the initiation of heating. During treatment, 60% of patients complained of varying degrees of pain and 19% had pain that was a factor in limiting treatment. Vital signs were relatively stable and not a factor in limiting treatment. CONCLUSION The Thermotron RF-8 is a useful hyperthermia device that can raise tumor temperatures to a therapeutic level (i.e., 42 degrees C) in a significant proportion of patients with superficial, subsurface, and deep-seated tumors, with minimal adverse effects, complications, and systemic stress. Further clinical studies using improved thermometry systems are warranted.

Response of Breast Cancer Cells and Cancer Stem Cells to Metformin and Hyperthermia Alone or Combined

Metformin, the most widely prescribed drug for treatment of type 2 diabetes, has been shown to exert significant anticancer effects. Hyperthermia has been known to kill cancer cells and enhance the efficacy of various anti-cancer drugs and radiotherapy. We investigated the combined effects of metformin and hyperthermia against MCF-7 and MDA-MB-231 human breast cancer cell, and MIA PaCa-2 human pancreatic cancer cells. Incubation of breast cancer cells with 0.5–10 mM metformin for 48 h caused significant clonogenic cell death. Culturing breast cancer cells with 30 µM metformin, clinically relevant plasma concentration of metformin, significantly reduced the survival of cancer cells. Importantly, metformin was preferentially cytotoxic to CD44high/CD24low cells of MCF-7 cells and, CD44high/CD24high cells of MIA PaCa-2 cells, which are known to be cancer stem cells (CSCs) of MCF-7 cells and MIA PaCa-2 cells, respectively. Heating at 42°C for 1 h was slightly toxic to both cancer cells and CSCs, and it markedly enhanced the efficacy of metformin to kill cancer cells and CSCs. Metformin has been reported to activate AMPK, thereby suppressing mTOR, which plays an important role for protein synthesis, cell cycle progression, and cell survival. For the first time, we show that hyperthermia activates AMPK and inactivates mTOR and its downstream effector S6K. Furthermore, hyperthermia potentiated the effect of metformin to activate AMPK and inactivate mTOR and S6K. Cell proliferation was markedly suppressed by metformin or combination of metformin and hyperthermia, which could be attributed to activation of AMPK leading to inactivation of mTOR. It is conclude that the effects of metformin against cancer cells including CSCs can be markedly enhanced by hyperthermia.

Single dose versus fractionated stereotactic radiotherapy for meningiomas

OBJECTIVE To evaluate the safety and efficacy of stereotactic radiosurgery (SRS) compared to fractionated stereotactic radiation therapy (FSRT) for meningiomas treated over a seven year period. METHODS AND MATERIALS Of the 53 patients (15 male and 38 female) with 63 meningiomas, 35 were treated with SRS and the 18 patients with tumors adjacent to critical structures or with large tumors were treated with FSRT. The median doses for the SRS and the FSRT groups were 1400 cGy (500-4500 cGy) and 5400 cGy (4000-6000 cGy) respectively. Median target volumes for SRS and FSRT were 6.8 ml and 8.8 ml respectively. The median follow-up for the SRS and FSRT groups were 38 months (4.1-97 months) and 30.5 months (6.0-63 months) respectively. RESULTS The five-year tumor control probability (TC) for benign versus atypical meningiomas were 92.7% vs. 31% (P = .006). The three-year TC were 92.7% vs. 93.3% for SRS vs. FSRT groups respectively (P = .62). For benign meningiomas, the three-year TC were 92.9% vs. 92.3% for the SRS group (29 patients) vs. FSRT group (14 patients) respectively (P = .77). Two patients in the SRS group and one in the FSRT group developed late complications. CONCLUSION Preliminary data suggest that SRS is a safe and effective treatment for patients with benign meningiomas. Fractionated stereotactic radiation therapy with conventional fractionation appeared to be an effective and safe treatment alternative for patients not appropriate for SRS. A longer follow-up is required to determine the long-term efficacy and the toxicity of these treatment modalities.

Phase I/II study, combination of radiotherapy and hyperthermia in patients with deep-seated malignant tumors: Report of a pilot study by the Radiation Therapy Oncology Group

This is a report of a Phase I/II study activated in March 1984 and completed in October 1988 by the Radiation Therapy Oncology Group on the feasibility/toxicity of hyperthermia in patients with deep-seated malignant tumors. The main objective of this study was to evaluate the morbidity of regional hyperthermia (systemic and regional, acute and late effects); a secondary objective was to evaluate tumor response to combined irradiation and regional hyperthermia. A total of 54 patients with locally advanced abdominal or pelvic malignancy were accrued to this study; 42% were male and 58% female. Seventy-five of the patients had pelvic tumors and 25% abdominal tumors. Acute toxicities included grade 4 in three patients (1 cutaneous, 1 infection and 1 chemical peritonitis) one grade 3 (skin), and 12 grade 2 toxicities (6 skin and 6 gastrointestinal). With regard to late toxicities, grade 4 was noted in one patient (skin), grade 3 (GI) in one, and grade 2 (skin, peripheral neuropathy) in six patients. The prescribed course of hyperthermia was completed in 17 (32%) of patients. In 36 patients (68%) the course of hyperthermia was terminated, primarily because of patient discomfort. Tumor response was assessed by physical examination or radiological studies. Of 44 patients evaluable for response, there were 17 (39%) complete responses and 6 (14%) partial responders. Significant technical problems in heat delivery and thermometry remain.

Heat-Induced Up-Regulation of NAD(P)H:Quinone Oxidoreductase Potentiates Anticancer Effects of β-Lapachone

Purpose: The purpose of the present study was to evaluate the efficacy of mild hyperthermia to potentiate the anticancer effects of β-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione) by up-regulating NAD(P)H:quinone oxidoreductase (NQO1) in cancer cells. Experimental Design: Effects of β-lapachone alone or in combination with mild heating on the clonogenic survival of FSaII fibrosarcoma cells of C3H mice and A549 human lung tumor cells in vitro was determined. Effects of heating on the NQO1 level in the cancer cells in vitro were assessed using Western blot analysis for NQO1 expression, biochemical determination of NQO1 activity, and immunofluorescence microscopy for NQO1 expression. Growth of FSaII tumors in the hind legs of C3H mice was determined after treating the host mice with i.p. injection of 45 mg/kg β-lapachone followed by heating the tumors at 42°C for 1 hour every other day for four times. Results: Incubation of FSaII tumor cells and A549 tumor cells with β-lapachone at 37°C reduced clonogenic survival of the cells in dose-dependent and incubation time–dependent manner. NQO1 level in the cancer cells in vitro increased within 1 hour after heating at 42°C for 1 hour and remained elevated for >72 hours. The clonogenic cell death caused by β-lapachone increased in parallel with the increase in NQO1 levels in heated cells. Heating FSaII tumors in the legs of C3H mice enhanced the effect of i.p.-injected β-lapachone in suppressing tumor growth. Conclusion: We observed for the first time that mild heat shock up-regulates NQO1 in tumor cells. The heat-induced up-regulation of NQO1 enhanced the anticancer effects of β-lapachone in vitro and in vivo.

A phase I feasibility study of multi-modality imaging assessing rapid expansion of marrow fat and decreased bone mineral density in cancer patients ☆

PURPOSE Cancer survivors are at an increased risk for fractures, but lack of effective and economical biomarkers limits quantitative assessments of marrow fat (MF), bone mineral density (BMD) and their relation in response to cytotoxic cancer treatment. We report dual energy CT (DECT) imaging, commonly used for cancer diagnosis, treatment and surveillance, as a novel biomarker of MF and BMD. METHODS We validated DECT in pre-clinical and phase I clinical trials and verified with water-fat MRI (WF-MRI), quantitative CT (QCT) and dual-energy X-ray absorptiometry (DXA). Basis material composition framework was validated using water and small-chain alcohols simulating different components of bone marrow. Histologic validation was achieved by measuring percent adipocyte in the cadaver vertebrae and compared with DECT and WF-MRI. For a phase I trial, sixteen patients with gynecologic malignancies (treated with oophorectomy, radiotherapy or chemotherapy) underwent DECT, QCT, WF-MRI and DXA before and 12months after treatment. BMD and MF percent and distribution were quantified in the lumbar vertebrae and the right femoral neck. RESULTS Measured precision (3mg/cm(3)) was sufficient to distinguish test solutions. Adiposity in cadaver bone histology was highly correlated with MF measured using DECT and WF-MRI (r=0.80 and 0.77, respectively). In the clinical trial, DECT showed high overall correlation (r=0.77, 95% CI: 0.69, 0.83) with WF-MRI. MF increased significantly after treatment (p<0.002). Chemotherapy and radiation caused greater increases in MF than oophorectomy (p<0.032). L4 BMD decreased 14% by DECT, 20% by QCT, but only 5% by DXA (p<0.002 for all). At baseline, we observed a statistically significant inverse association between MF and BMD which was dramatically attenuated after treatment. CONCLUSION Our study demonstrated that DECT, similar to WF-MRI, can accurately measure marrow adiposity. Both imaging modalities show rapid increase in MF following cancer treatment. Our results suggest that MF and BMD cannot be used interchangeably to monitor skeletal health following cancer therapy.