Methylenetetrahydrofolate reductase genetic polymorphisms and toxicity to 5-FU-based chemoradiation in rectal cancer.

BACKGROUND: There is a large degree of variation in tumour response and host toxicities associated with neoadjuvant chemoradiation for rectal cancer patients. We performed a complimentary pharmacogenetic study to investigate germline polymorphisms of genes involved in 5-fluorouracil (5-FU) and irinotecan pathways and their potential association with clinical outcomes and toxicities from neoadjuvant chemoradiation in patients with rectal cancer treated in a prospective genotype-directed study. METHODS: The germline DNA of 131 patients was genotyped for 10 variants in TYMS, MTHFR, DPYD, UGT1A1, ABCC1 and SLCO1B1 genes. Ninety-six patients were treated with 5-FU/radiotherapy (RT) and 35 received 5-FU/RT/irinotecan. Relationships between genetic variants and adverse events, tumour response, overall and disease-free survivals were assessed. RESULTS: MTHFR 1298A>C and MTHFR diplotypes (for 677C>T and 1298A>C) were associated with chemoradiation-related toxicity when 5-FU was used alone. MTHFR haplotypes (677C-1298C) and diplotypes (CA-TA and TA-TA) showed, respectively, a protective and a negative effect on the incidence of severe diarrhoea or mucositis. No association was observed between genetic markers and drug response. CONCLUSION: MTHFR polymorphisms can potentially predict toxicity in patients treated with 5-FU as a single chemotherapeutic drug.

The effects of 41 degrees C hyperthermia on the DNA repair protein, MRE11, correlate with radiosensitization in four human tumor cell lines.

PURPOSE: The goal of this study was to determine if reduced availability of the DNA repair protein, MRE11, for the repair of damaged DNA is a basis for thermal radiosensitization induced by moderate hyperthermia. To test this hypothesis, we measured the total amount of MRE11 DNA repair protein and its heat-induced alterations in four human tumor cell lines requiring different heating times at 41 degrees C to induce measurable radiosensitization. MATERIALS AND METHODS: Human colon adenocarcinoma cell lines (NSY42129, HT29 and HCT15) and HeLa cells were used as the test system. Cells were irradiated immediately after completion of hyperthermia. MRE11 levels in whole cell extract, nuclear extract and cytoplasmic extracts were measured by Western blotting. The nuclear and cytoplasmic extracts were separated by TX100 solubility. The subcellular localization of MRE11 was determined by immunofluorescence staining. RESULTS: The results show that for the human tumor cell lines studied, the larger the endogenous amount of MRE11 protein per cell, the longer the heating time at 41 degrees C required for inducing measurable radiosensitization in that cell line. Further, the residual nuclear MRE11 protein level, measured in the nuclear extract and in the cytoplasmic extract as a function of heating time, both correlated with the thermal enhancement ratio (TER). CONCLUSIONS: These observations are consistent with the possibility that delocalization of MRE11 from the nucleus is a critical step in the radiosensitization by moderate hyperthermia.

Experience with a small animal hyperthermia ultrasound system (SAHUS): report on 83 tumours.

An external local ultrasound (US) system was developed to induce controlled hyperthermia of subcutaneously implanted tumours in small animals (e.g., mice and rats). It was designed to be compatible with a small animal positron emission tomography scanner (microPET) to facilitate studies of hyperthermia-induced tumour re-oxygenation using a PET radiopharmaceutical, but it is applicable for any small animal study requiring controlled heating. The system consists of an acrylic applicator bed with up to four independent 5 MHz planar disc US transducers of 1 cm in diameter, a four-channel radiofrequency (RF) generator, a multiple thermocouple thermometry unit, and a personal computer with custom monitoring and controlling software. Although the system presented here was developed to target tumours of up to 1 cm in diameter, the applicator design allows for different piezoelectric transducers to be exchanged and operated within the 3.5-6.5 MHz band to target different tumour sizes. Temperature feedback control software was developed on the basis of a proportional-integral-derivative (PID) approach when the measured temperatures were within a selectable temperature band about the target temperature. Outside this band, an on/off control action was applied. Perfused tissue-mimicking phantom experiments were performed to determine optimum controller gain constants, which were later employed successfully in animal experiments. The performance of the SAHUS (small animal hyperthermia ultrasound system) was tested using several tumour types grown in thighs of female nude (nu/nu) mice. To date, the system has successfully treated 83 tumours to target temperatures in the range of 41-43 degrees C for periods of 65 min on average.

Transfection of human tumour cells with Mre11 siRNA and the increase in radiation sensitivity and the reduction in heat-induced radiosensitization.

Double-strand DNA breaks (DSBs) are potentially lethal DNA lesions induced by ionizing radiation. In eukaryotes, DSBs can be repaired by homologous recombination (HR) or non-homologous end-joining (NHEJ). DNA repair protein Mre11 participates in both the NHEJ and HR DNA repair pathways. Hyperthermia has been used clinically as a radiosensitizer. However, the mechanisms by which radiosensitization is induced by hyperthermia, especially moderate hyperthermia (41 degrees C) are not fully understood. Previous studies suggest that 41 degrees C reduces the nuclear Mre11 protein level in a manner that correlates with heat-induced changes in radiation sensitivity. Therefore, siRNA technology was used in the present study to reduce Mre11 gene expression to determine if reduced Mre11 protein levels induced radiosensitization and if such radiosensitization is similar to that induced by moderate hyperthermia. The results show that (1) the cellular level of the Mre11 protein was reduced about 60 +/- 18% by a 24-h treatment with siRNA. Results from the Mre11 protein turnover assay showed a half-life of 11.6 +/- 0.5 h for the Mre11 protein, which is consistent with reduction in protein level in 24 h after Mre11 siRNA treatment assuming a delay of 4-8 h to reduce RNA levels. After 48 h in siRNA, cellular Mre11 protein levels increased to approximately pretreatment levels. NSY cells were sensitized to ionizing radiation after 24 h of treatment with Mre11 siRNA. Two hours at 41 degrees C did not increase the radiation sensitivity of cells with a reduced Mre11 protein level following a 24-h siRNA treatment. These data support the conclusion that the DSB repair protein, Mre11, appears to be a target for radiosensitization by moderate hyperthermia.

Modelling heat-induced radiosensitization: clinical implications.

Clinically achievable minimum tumour temperatures are in the order of about 41 degrees C. Therefore, it is important to evaluate mechanisms by which temperatures in this range might enhance cytotoxicity. Previous in vitro studies have demonstrated that 1-4 h (depending on the sequencing of modalities) of heating at 41 degrees C produces substantial heat-induced radiosensitization with little or no cell killing by heat alone. The increased radiation sensitivity is best modelled as a change in the single hit, alpha, parameter (with no significant effect on the two-hit parameter, beta) of the cell survival curve. The implications of heat-induced radiosensitization being mediated by a change in alpha on the traditional thermal enhancement ratio (for various radiation doses/fraction and alpha/beta) are reviewed. Response rates for a cohort of 60 patients enrolled on a prospective thermal dose escalation study are modelled assuming that the thermal dose dependence of heat-induced radiosensitization is modulated by a heat-induced delta alpha. The clinical data are fitted with delta alpha about 0.05-0.1 Gy-1. Randomized trials reported in the literature and the implication for the design of future prospective trials are reviewed in light of these observations.

MicroPET-compatible, small animal hyperthermia ultrasound system (SAHUS) for sustainable, collimated and controlled hyperthermia of subcutaneously implanted tumours.

An external ultrasound system was developed for the heating of subcutaneously implanted tumours in small animals. This small animal hyperthermia ultrasound system (SAHUS) was designed to be compatible with a microPET (small animal positron emission tomography) scanner to facilitate studies of hyperthermia effects on tumour hypoxia. Collimation and localization of energy deposition, a specific goal for the new device to avoid regional and/or systemic heating of small animals, was demonstrated using thermoradiography following high-power short-time heating of a layered gel phantom. The in vivo heating capabilities of the SAHUS were tested using PC3 cell line tumours (2000-2700 mm(3)) grown in the lateral proximal thighs of Nu-/Nu- nuBR nude mice. Intratumour temperatures were recorded during heating trials with deep and superficial interstitial thermocouples. The experimental data showed that the SAHUS could produce hyperthermia in 8 +/- 2 mm diameter tumours in small animals to a target temperature of 41.5 degrees C and maintain it within a narrow temperature range (+/- 0.3 degrees C) for up to 4 h without raising the core temperature of the animals. PET imaging studies, data to be published separately, were conducted before and during SAHUS-induced hyperthermia. Both devices performed as expected and there was no significant decrease in image quality. In this paper, the new SAHUS is described and data from phantom and in vivo experiments presented.

Radiosensitization of heat resistant human tumour cells by 1 hour at 41.1 degrees C and its effect on DNA repair.

The present study was undertaken to determine if short duration (1-2 h), moderate hyperthermia (41.1 degrees C) could radiosensitize human tumour cells. It was found that moderate hyperthermia (41.1 degrees C), for as little as 1 h, can radiosensitize heat resistant human adenocarcinoma cells, NSY42129 (NSY), provided the cells are irradiated 15 min prior to the end of the heat exposure. Analysis of the survival data showed a 2.5-3-fold increase in the alpha parameter with no significant change in the beta parameter of the survival curve, implying that the cells had become more susceptible to killing by single radiation energy deposition events as opposed to lethal events that require an interaction between two separate energy deposition events. 41.1 degrees C hyperthermia did not affect the induction or repair of alkaline labile DNA damage in a way that correlated with radiosensitivity. In contrast, heat-induced changes in the induction of micronuclei by radiation correlated with changes in cell killing. Therefore, the effect of 41.1 degrees C hyperthermia on the intracellular localization of the DNA double strand break repair protein, Mre11, was measured using in situ immunofluorescence and immunoblotting of soluble and insoluble cellular fractions. The results showed that Mre11 delocalizes from the nucleus as a function of time at 41.1 degrees C. It was then determined if 41.1 degrees C hyperthermia altered the association of Mre11 with its functional partner, Rad50. A significant decrease in the amount of Rad50 recovered with Mre11 occurred under the experimental conditions that produced significant radiosensitization. These results are consistent with the possibility that the heat-induced perturbation in Mre11 localization and its radiation-induced association with Rad50 contributes to an increase in radiosensitivity.

A phase I/II trial of three-dimensionally planned concurrent boost radiotherapy and protracted venous infusion of 5-FU chemotherapy for locally advanced rectal carcinoma.

BACKGROUND: Improving the response to preoperative therapy may increase the likelihood of successful resection of locally advanced rectal cancers. Historically, the pathologic complete response (pCR) rate has been < approximately 10% with preoperative radiation therapy alone and < approximately 20% with concurrent chemotherapy and radiation therapy. METHODS AND MATERIALS: Thirty-seven patients were enrolled on a prospective Phase I/II protocol conducted jointly at Washington University, St. Louis and the Catholic University of the Sacred Heart, Rome evaluating a three-dimensionally (3D) planned boost as part of the preoperative treatment of patients with unresectable or recurrent rectal cancer. Preoperative treatment consisted of 4500 cGy in 25 fractions over 5 weeks to the pelvis, with a 3D planned 90 cGy per fraction boost delivered once or twice a week concurrently (no time delay) with the pelvic radiation. Thus, on days when the boost was treated, the tumor received a dose of 270 cGy in one fraction while the remainder of the pelvis received 180 cGy. When indicated, nonaxial beams were used for the boost. The boost treatment was twice a week (total boost dose 900 cGy) if small bowel could be excluded from the boost volume, otherwise the boost was delivered once a week (total boost dose 450 cGy). Patients also received continuous infusion of 5-fluorouracil (1500 mg/m(2)-week) concurrently with the radiation as well as postoperative 5-FU/leucovorin. RESULTS: All 37 patients completed preoperative radiotherapy as planned within 32--39 elapsed days. Twenty-seven underwent proctectomy; reasons for unresectability included persistent locally advanced disease (6 cases) and progressive distant metastatic disease with stable or smaller local disease (4 cases). Actuarial 3-year survival was 82% for the group as a whole. Among resected cases the 3-year local control and freedom from disease relapse were 86% and 69%, respectively.Twenty-four of the lesions (65%) achieved an objective clinical response by size criteria, including 9 (24%) with pCR at the primary site (documented T0 at surgery). The most important factor for pCR was tumor volume: small lesions with planning target volume (PTV) < 200 cc showed a 50% pCR rate (p = 0.02). There were no treatment associated fatalities. Nine of the 37 patients (24%) experienced Grade 3 or 4 toxicities (usually proctitis) during preoperative treatment. There were an additional 7 perioperative and 2 late toxicities. The most important factors for small bowel toxicity (acute or late) were small bowel volume (> or = 150 cc at doses exceeding 4000 cGy) and large tumor (PTV > or = 800 cc). For rectal toxicity the threshold is PTV > or = 500 cc. CONCLUSION: 3D planned boost therapy is feasible. In addition to permitting the use of nonaxial beams for improved dose distributions, 3D planning provides tumor and normal tissue dose-volume information that is important in interpreting outcome. Every effort should be made to limit the treated small bowel to less than 150 cc. Tumor size is the most important predictor of response, with small lesions of PTV < 200 cc most likely to develop complete responses.

Dosimetry and techniques for simultaneous hyperthermia and external beam radiation therapy.

An increased biological effect is realized when hyperthermia and radiation therapy are combined simultaneously. To take advantage of this effect, techniques have been developed that combine existing hyperthermia devices with a linear accelerator. This allows concomitant delivery of either ultrasound or microwave hyperthermia with photon radiation therapy. Two techniques have been used clinically: the orthogonal technique, in which the microwave or ultrasound beam and the radiation beam are orthogonal to one another, and the en face technique, in which the ultrasound or microwave beam and the radiation beam travel into the tumour through the same treatment window. The en face technique has necessitated the development of special attachments so that the hyperthermia device can be mounted to the linear accelerator and so that non-uniform portions of the hyperthermia device can be removed from the radiation beam. For microwave therapy, applicators are mounted onto the linear accelerator using the compensating filter tray holder. For ultrasound, special reflector devices are mounted to a frame that is mounted onto the compensating filter tray holder of the linear accelerator. Because the linear accelerator is an isocentric device, the height of the radiation source is fixed, and this has necessitated specially designed devices so that the ultrasound support system is compatible with the linear accelerator. The treatment setups for both the en face technique and the orthogonal technique require the interaction of both hyperthermia and radiation therapy personnel and equipment. The dosimetry and day-to-day operations for each technique are unique. The simulation for the en face technique is much different from the simulation of a normal radiation treatment and requires the presence of a hyperthermia physicist. Also, for the en face technique, the attenuation of the microwave applicator and the thickness and attenuation of the ultrasound reflector system are taken into account for radiation dosimetry. This paper presents details of the dosimetry and logistics of the techniques for simultaneous thermoradiotherapy based on 7 years of experience treating more than 50 patients.

The impact of ultrasonic parameters on chest wall hyperthermia.

A transient, three-dimensional acousto-thermal numerical model for chest wall anatomies was developed to evaluate the impact of ultrasonic parameters on thermal coverage. The following independent variables were considered: (1) the relative output intensities of the low and high frequency components of an unfocused dual-frequency ultrasonic beam (xi1); (2) the depths of the soft-tissue bone (d(b)) and soft-tissue-lung (d(u)) interfaces; (3) the intensity reflectivities of these interfaces; and (4) the intensity attenuation coefficient of bone. Several important results were obtained. First, acoustic reflections from the underlying bone and lung surfaces may contribute significantly to heating of the overlying soft-tissue. Secondly, a strong dependence of optimal xi1 values on d(b) and d(u) values was found. Chest wall volumes with 2-3 cm of soft-tissue overlying the ribs were optimal targets for unfocused ultrasound hyperthermia. Thirdly, the maximum steady state temperature in bone also strongly depended on xi1. Finally, the largest difference between the maximum temperature in bone and the maximum temperature in soft-tissue during initial transient heating was between -1.4 degrees C and 0.8 degrees C. That is, the maximum temperature in the field, either during the transient period or at steady state, did not always occur in bone. It is concluded that control of power deposition penetrability offers great potential for improving hyperthermia to chest wall targets in real time.

A multi-user networked database for analysis of clinical and temperature data from patients treated with simultaneous radiation and ultrasound hyperthermia.

A database was developed using commercially available development software that allows the entry of clinical data and automatically analyses temperature and power data from a commercial ultrasound hyperthermia system. The database can be accessed via network connections by more than one authorized user, thus facilitating the entry, management, and analysis of clinical data. The software automatically estimates ultrasound induced temperature artifacts and calculates thermal dose parameters such as T90s, equivalent minutes at 43 degrees, and time at or above index temperatures using the corrected temperatures. These parameters also become part of the database. Digital photographs of treatment setup, probe placement, and tumour or normal tissue response can be included in the database for documentation and reference. Ultrasound diagnostic images that document the depth and reproducibility of probe placement can be scanned into the PC and included in the database as well. This short communication documents experiences developing this tool that may be useful to other investigators.

Simultaneous superficial hyperthermia and external radiotherapy: report of thermal dosimetry and tolerance to treatment.

BACKGROUND: In vitro and animal studies indicate that a moderate temperature of 41 degrees C maintained for approximately 1 h will provide radiosensitization if radiation (RT) and hyperthermia (HT) are delivered simultaneously, but not with sequential treatment. A minimum tumour temperature of 41 degrees C is a more feasible goal than the goal of >42 degrees C needed for sequential treatment. METHODS AND MATERIALS: Forty-four patients with 47 recurrent superficial cancers received simultaneous external beam radiotherapy and superficial hyperthermia on successive IRB approved phase I/II studies. All lesions had failed previous therapy, 35 were previously irradiated (mean dose 52.7 Gy). Hyperthermia was delivered with 915 MHz microwave or 1-3.5 MHz ultrasound using commercially available applicators. The average dimensions of 19 lesions treated with microwave were 4.7 x 3.6 x 1.7 cm and the average dimensions of 28 lesions treated with ultrasound were 8.0 x 6.1 x 2.9 cm. The most common sites were chest wall (15 cases) and head and neck (21 cases). Temperatures were monitored at an average of six intratumoral locations using multisensor probes. The median number of hyperthermia treatments was three and the median radiation dose 30 Gy. Radiation dose per fraction was 4 Gy with hyperthermia and 2 Gy or 4 Gy (depending on protocol) on non-hyperthermia days. RESULTS: Six different measures of minimum monitored temperature and duration were found to be highly correlated with each other. There was nearly a one-to-one correspondence between minimum tumour time at or above 41 degrees C (Min t41) and minimum tumour Sapareto Dewey equivalent time at 42 degrees C (Min teq42). After four sessions 63% of cases had a per session average Sapareto Dewey equivalent time at 41 degrees C which exceeded 60 min in all monitored tumour locations. The complete and partial response rate in evaluable lesions were respectively 21/41 (51%) and 7/41 (17%) and were best correlated with site (chest wall showing best response). Toxicity consisted of 10/47 (21%) slow healing soft tissue ulcers which healed in all cases but required a median of 7 months. The most important predictors for chronic ulceration were cumulative radiation dose >80 Gy and complete response to treatment. CONCLUSIONS: Minimum tumour temperatures maintained for durations compatible in vitro with thermal radiosensitization (if RT and HT are delivered simultaneously) are clinically feasible and tolerable for broad but superficial lesions amenable to externally applied ultrasound or microwave hyperthermia. The current in-house protocol is evaluating the impact of more than four hyperthermia sessions on the overall thermal dose distribution and toxicity.

Five fractions of preoperative radiotherapy for selected cases of rectal carcinoma: long-term tumor control and tolerance to treatment.

BACKGROUND: Randomized Swedish studies demonstrate the efficacy of a 5-fraction course of preoperative radiotherapy for rectal carcinoma. The present study evaluates the results in a single U.S. institution over a 20-year period with a similar regimen. METHODS AND MATERIALS: During the period of 1975-1995, 83 patients received pelvic radiotherapy of 20 Gy/5 fractions, followed by immediate surgery for rectal cancer. These patients represented 21% of cases receiving preoperative treatment; the remainder received 45-50 Gy preoperatively. The 5-fraction course was used for lesions deemed readily resectable but too bulky for conservative endocavitary treatment. Since 1990, it has been our policy to administer postoperative chemotherapy to medically fit patients who prove to have pathologic Stage II or III disease. Patient characteristics including age (mean 65 years, range 23-90), gender (45% male), and location within the rectum were comparable to our previously reported cases that received 45 Gy/25 fractions preoperatively. However, the group selected for 5 fractions preoperatively had relatively fewer lesions that were tethered (20% vs. 61%), circumferential (11% vs. 20%), or near obstructing (1% vs. 16%). RESULTS: With a post treatment follow-up of 1-15 years (mean 4.7), there have been 3 local failures and 12 distant failures, with an actuarial local control of 95%, and disease-specific survival of 77% at 5 and 10 years. Grade > or = 3 perioperative or late toxicity occurred in 11 cases (13%), including 3 (3.5%) late bowel obstructions. Stage II or III disease was found in 56% of the cases, 74% of which were free of disease at last follow-up. However, patients with Stage II or III lesions that were significantly tethered or fixed had a 40% greater likelihood of recurring than similar stage lesions that were, at most, slightly tethered. Sphincter-preserving surgery was possible in 60% of the patients. In recent years, postoperative chemotherapy has been administered to 16 patients with Stage II or III disease; this has been well tolerated, with only 1 late toxicity (cystitis managed medically). When compared with a matched group of cases receiving conventionally fractionated preoperative radiation, there were no significant differences in perioperative morbidity and nonradiotherapeutic cost generating factors (length of hospital stay, duration of postoperative antibiotics, blood loss at surgery). CONCLUSION: Patients with resectable rectal cancer who received 20 Gy/5 fractions preoperative radiotherapy to the pelvis had excellent local and distant control of disease. These patients were able to undergo sphincter-preserving surgery and postoperative chemotherapy. It would be of interest to conduct a randomized trial comparing short course with longer course (45 or 50 Gy) preoperative radiotherapy for resectable T3 lesions. The results of this study suggest that, in general, differences in toxicity, local control, and disease-free survival would probably be < 10%. However, since the results of this study suggest that patients with significantly tethered lesions may be better served with the higher dose and longer duration course of radiation, clinical degree of fixation should be included as a stratification parameter, and stopping criteria should be included for tethered lesions.

Numerical and in vitro evaluation of temperature fluctuations during reflected-scanned planar ultrasound hyperthermia.

Temperature fluctuations inside a target volume during reflected-scanned planar ultrasound hyperthermia were investigated numerically and in vitro. The numerical approach consisted of integrating an ultrasonic power deposition model for a scanning ultrasound reflector linear array system (SURLAS) designed for simultaneous thermoradiotherapy, and a three-dimensional transient version of Pennes' bioheat transfer equation. The in vitro approach consisted of delivering hyperthermia to a fixed-perfused canine kidney phantom using a SURLAS prototype. Both approaches allowed the study of temperature fluctuations for several important clinically relevant parameters: scan time, scan distance, perfusion rate and skin cooling. The simulation results showed that the largest temperature fluctuations were located at the opposite ends of the scan window where the scanning reflector comes to a sudden and complete stop and reverses direction. The smallest fluctuations were located at the centre of the scan window. For a given scan distance, the magnitude of the temperature fluctuations increased linearly with increasing scan time, and increased almost linearly as a function of blood perfusion rate. For a scan window of 10 cm x 10 cm and a blood perfusion rate of 5 kg/m3 s, the simulated temperature fluctuations were within +/- 0.5 degree C from the average temperature for scan times less than or equal to 20 s. The in vitro results agreed well with the numerical findings. The measured temperature fluctuations were less than 1.0 degree C for flow rates into the renal artery of less than 200 ml/min and scan times less than 20 s.

Superficial hyperthermia and irradiation for recurrent breast carcinoma of the chest wall: prognostic factors in 196 tumors.

PURPOSE: To correlate patient-, tumor-, and treatment-related factors with subsequent local tumor control. METHODS AND MATERIALS: From 1977 to 1990, 196 subcutaneous/superficial lesions (179 measurable, 17 microscopic) in 151 patients with recurrent breast carcinoma of the chest wall were treated with superficial 915-MHz microwave hyperthermia and irradiation. The definition of min t43 > or = 10 min is that all monitored tumor catheters had a minimum of 1 hyperthermia session with temperatures > 43 degrees C for at least 10 min. RESULTS: Factors correlating with local control on univariate analysis included length of survival (> or = 1 year vs. < 1 year) (p < 0.0001), specific absorption rate (SAR) (> or = 25% vs. < 25%) (p = 0.0001), minimum t43 > 10 min (p < 0.0001), tumor volume (p < 0.0001), tumor surface area (p < 0.0001), tumor depth (p = 0.0002), number of hyperthermia sessions (p = 0.0003), and current radiation dose (p = 0.0012). On multivariate analysis, the factors best correlated with ultimate local control were SAR (p < 0.001) and number of hyperthermia sessions (p = 0.003). CONCLUSIONS: Multivariate analysis supports the importance of adequate specific absorption rate (SAR) coverage as a better predictor of local control than tumor volume, surface area, or depth. The explanation is that SAR can be correlated with the tumor surface area and depth, depending on the hyperthermia applicator characteristics. It is recommended that future clinical trials stratify study lesions into either SAR > or = 25% or < 25% because this can be readily estimated prior to initiating treatment. It is also recommended that future clinical trials attempt to have adequate lengths of follow-up after therapy to assess the results in long-term survivors.

An ultrasound system for simultaneous ultrasound hyperthermia and photon beam irradiation.

PURPOSE: An existing ultrasound system has been adapted for simultaneous use with external photon beam irradiation. The system is being used to investigate the potential for increased biological benefit of simultaneously combined hyperthermia and external beam irradiation with currently achievable temperature distributions. METHODS AND MATERIALS: An existing clinical ultrasound system has been modified for simultaneous operation with a 60Co teletherapy machine. The generator, thermometry system, computer, and applicators are located inside the treatment room, while the monitor and system control are located at the control console. Two approaches have been used clinically to combine the two modalities. In the first approach, an en-face setup is used in which the ultrasound beam and the photon beam travel through the same window of entry to the tumor. This is acheived by a reflecting system designed to deflect the ultrasound to the tumor while positioning the ultrasound transducer outside the radiation beam. The reflecting system consists of water and water-equivalent materials except for a 1 mm sheet of polished brass that is used as the reflector. The relative pressure fields were measured in water at the same distance from the ultrasound source using a scanning hydrophone with and without the reflector at the two operating frequencies of the device (1.0 and 3.4 MHz) for two applicators. Radiation dosimetry measurements were performed to determine the relationship between 60Co irradiation through the reflector and absorbed dose. In the second approach the ultrasound and the radiation beam travel into the tumor from different windows of entry such that the radiation beam passes through no portion of the water bolus prior to entering the patient. We have termed this approach the orthogonal approach. For both approaches, the radiation fraction is given in the middle of an uninterrupted 60-min hyperthermia treatment. RESULTS: The system modifications did not impair the ability to effectively deliver ultrasound hyperthermia or 60Co teletherapy. With the en-face approach the ultrasonic patterns generated with and without the reflector demonstrated that the ultrasound system maintained both a uniform and controllable heating pattern. The 60Co beam had no effect on the performance of the thermocouple thermometers. The radiation beam is attenuated nearly uniformly by the reflector system. To date, 10 patients have been treated with the en-face approach and 12 have been treated with the orthogonal approach (90 treatments). CONCLUSIONS: The clinical implementation of ultrasound hyperthermia simultaneous with 60Co irradiation is technically and clinically feasible without any complications or hazards to the patient. The implementation of a reflecting device allows en-face delivery of both the ultrasound and 60Co irradiation. Temperatures obtained during simultaneous treatments are comparable to those historically obtained during sequential treatments with the same commercial ultrasound device.

Potential for power deposition conformability using reflected-scanned planar ultrasound.

Specialized heating devices for the simultaneous delivery of hyperthermia and ionizing radiation are being developed by several investigators in an effort to increase thermal radiosensitization in clinical treatment. One particular device is the SURLAS (Scanning Ultrasound Refléctor-Linear Array System), which was designed specifically to operate concomitantly with medical linear accelerators. The technical feasibility of the SURLAS has been demonstrated, and a design optimization study has been performed. The main objective of this paper is to demonstrate the potential for power deposition conformability of the SURLAS. This has been done using a thermographic technique which provides qualitative, high spatial-resolution measurements of power deposition distributions. The technique consists of normally insonating one surface of a 1 cm layer of a Polyurethane phantom while the temperature field on the opposite air-exposed surface is recorded using an infrared camera during the first few minutes after power insult. The thermal fields measured in this way are good qualitative estimates of relative power deposition. To demonstrate conformability, a region of 10 cm (the length of the array) by 12 cm (the scanning distance) on the air-exposed phantom surface was divided into 24 sectors (24 subregions with independent power control). Each sector was 2.5 x 2 cm across and long the scanning direction respectively. Several sector insonation patterns were synthesized in an open-loop fashion by properly adjusting power levels to each of the elements of an array as a function of reflector position as the reflector was scanned continuously in a reciprocating fashion at a constant speed. The array was made of a single piezoelectric crystal with resonant frequency of 2.2 MHz and electrically segmented into four 2.5 x 2.5 cm elements. The reflector was made of a 0.5 mm thick Brass plate. Sufficient power was supplied to the array to induce peak temperature elevations of about 10 degrees C in 60s at a scanning speed of 2.4 cm/s. The results show that measured relative power deposition patterns agreed well with programmed insonation patterns demonstrating that the SURLAS possesses great potential for power conformability, and thus, for temperature feedback power deposition control.

A phase I/II study to evaluate radiation therapy and hyperthermia for deep-seated tumours: a report of RTOG 89-08.

The purpose of this paper is to evaluate the safety and efficacy of deep hyperthermia in conjunction with radiation therapy. This study employed 'second generation' electromagnetic devices which were felt to be better able to confine heating and spare normal tissue than the devices evaluated in a previous study (RTOG 84-01). Sixty six patients at six institutions were enrolled on a prospective Phase I/II study. Eligible deep seated tumours were treated with a combination of external hyperthermia and radiation therapy. Radiation consisted of 1.7-2 Gy per fraction, 4-5 fractions per week, to > 20 Gy (previously irradiated lesions) or > 50 Gy (no previous radiation). Deep hyperthermia was delivered with electromagnetic devices: BSD 2000 for 92% of cases, Thermotron for 5% of cases, other low frequency electromagnetic for 4% of cases. Hyperthermia was delivered < or = twice weekly. Overall complete and partial response rates were 34% and 16% respectively. Response was not correlated with maximum tumour temperature or disease site. There was, however, a strong association with radiation dose: 54% CR with > or = 45 Gy versus 7% with < 45 Gy (p < 0.0001). The achieved temperatures were less than ideal. Although the average maximum tumor temperature was 41.9 degrees C (range 35.7 degrees C-46.7 degrees C), the minimum tumour temperatures were low. The average minimum tumour temperature was 38.5 degrees C and was never > 41.8 degrees C. Treatment was well tolerated with no fatalities. There were four acute grade 3 or 4 toxicities (6% of patients). Patient discomfort resulted in interruption or discontinuation of sessions in 30% of the sessions. In 12 cases (18% of patients) the planned course of hyperthermia was discontinued due to acute discomfort. The devices used in this study were better tolerated than the devices used in the previous Phase I/II deep hyperthermia trial (RTOG 84-01) with less patient discomfort and no problems with severe systemic cardiovascular stress. In the previous study 68% of the hyperthermia courses were prematurely terminated primarily due to patient discomfort and toxicity; in the present study 18% were prematurely terminated. However, as indicated by the low minimum tumour temperature, fundamental problems with achieving acceptable temperature distributions remain.

Simultaneous delivery of electron beam therapy and ultrasound hyperthermia using scanning reflectors: a feasibility study.

PURPOSE: The feasibility of simultaneously delivering external electron beam radiation and superficial hyperthermia using a scanning ultrasound reflector-array system (SURAS) was experimentally investigated and demonstrated. METHODS AND MATERIALS: A new system uses a scanning reflector to distribute the acoustic energy from a planar ultrasound array over the surface of the target volume. External photon/electron beams can be concurrently delivered with hyperthermia by irradiating through the scanning reflectors. That is, this system enables the acoustic waves and the radiation beams to enter the target volume from the same direction. Reflectors were constructed of air-equivalent materials for maximum acoustic reflection and minimum radiation attenuation. Acoustically, the air reflectors were compared to brass reflectors (assumed ideal) for reflectivity and specular quality using several single transducers ranging in frequency from 0.68 to 4.8 MHz. The relative reflectivity was determined from acoustic power measurements using a force-balance technique. The specular quality was assessed by comparing the acoustic pressure fields reflected by air reflectors with those reflected by brass reflectors. Also, acoustic pressure fields generated by a SURAS prototype for two different arrays (2.24 and 4.5 MHz) were measured to investigate field distribution variations as a function of the distance separating the array and the scanning reflector. All pressure fields were measured with a hydrophone in a degassed water tank. Finally, to determine the effect of the air reflectors on electron dose distributions, these were measured using film in a water-equivalent solid phantom after passage of a 20 MeV electron beam through the SURAS. These measurements were performed with the reflector scanning continuously across the electron beam and at rest within the electron beam. RESULTS: The measurements performed using single ultrasound transducers showed that the air reflectors had power reflectivities of 87-96% that of brass, and that for smooth surfaces the reflections from air reflectors were as specular as those from brass reflectors. Acoustic pressure fields measurements of the SURAS for two different arrays showed that the 50% pressure amplitude contours were well-distributed across the projected surface area of the array for different distances separating the array and the reflector. Finally, film dosimetry showed that the electron dose distribution was not affected by the air reflector of the SURAS either for the scanning case or the stationary case. This indicates that the reflectors as made are basically water-equivalent in terms of high energy ionizing radiation. The measured isodoses also indicate that the constructed SURAS prototype would allow the delivery of adequate radiation (90% isodose) to a depth of 2.0 cm. CONCLUSIONS: The results presented show that the SURAS design has the potential to deliver hyperthermia to large superficial tumors, while allowing simultaneous irradiation with 20 MeV electron beams without adverse effects on the radiation dose delivery.

Clinical system for simultaneous external superficial microwave hyperthermia and cobalt-60 radiation.

A system for simultaneous thermoradiotherapy was devised to investigate the possible benefits and/or complications of thermal radiosensitization in human superficial tumours. The system combines the well-known treatment modalities of external 915 MHz microwave hyperthermia and cobalt-60 teletherapy. Single waveguide applicators are utilized either attached to blocking trays, so that the gamma beam travels through a waveguide and into the patient (en face setup), or in a conventional way with the microwave propagation vector orthogonal to the gamma beam (orthogonal setup). With these setups a radiation fraction can be delivered in the middle of a 60-min, non-interrupted hyperthermia treatment. Temperatures and power level are remotely monitored and recorded outside the Cobalt room. Extensive measurements and testing showed that the operation of the hyperthermia system (generator, applicators, thermometry unit and temperature sensors) was not disrupted by irradiation and that the microwaves were confined to the treatment room and did not interfere with the operation of the Cobalt unit, of an adjacent linear accelerator or of an adjacent radiotherapy simulator. For the en face setup the dose distributions induced in solid water phantoms were uniform with the exception of a narrow (< 0.5 cm) region under the applicators' internal probes where 10-18% reduction exists. This dose defect is clinically smoothed using feathering techniques. The system has been successfully used without technical problems in 51 treatments in 15 patients (18 lesions) in a phase I/II clinical trial. An analysis of the thermal data showed that the temperature distributions achieved during simultaneous delivery have the same general characteristics of those achieved in conventional sequential hyperthermia with microwaves, and that the steady state distributions are maintained during the time of simultaneous irradiation. The tests performed in addition to the preliminary clinical experience clearly indicate that this type of combined therapy is technically feasible and safe. Here the system for simultaneous, external, superficial thermoradiotherapy and the implementation tests performed are described in detail. Preliminary clinical experience and results are also reported.