Yukimasa Aoki

Megavoltage CT-assisted stereotactic radiosurgery for thoracic tumors: original research in the treatment of thoracic neoplasms.

PURPOSE The aim of the study was to evaluate the efficacy of stereotactic radiosurgery (SRS) for thoracic tumors with megavoltage computed tomography (MVCT) from the point of view of symptom palliation as well as local control. METHODS AND MATERIALS MVCT-assisted positioning verification and real-time monitoring for a multileaf collimator (MLC) were used to enhance the accuracy of the thoracic SRS. Twenty-two thoracic tumors in 15 patients underwent the present treatment. All but 1 tumor were metastases from various primary malignancies. Eleven patients were symptomatic. The treatment site was the chest wall/pleura in 10 tumors, and the lung in 12 tumors. The median volume of the clinical target was 4.5 cc and the median peripheral dose was 20 Gy, for the lung tumors. For the chest wall/pleura tumors, the median volume of the clinical target was 40 cc and the median peripheral dose was 20 Gy. Conventional fractionated conformal radiation therapy (CRT) followed SRS in 10 tumors. RESULTS Of 21 tumors eligible for evaluation, there were 13 with complete responses, 6 with partial responses, and 2 without response. Duration of local control ranged from 0.6 to 82 months with a median of 8 months, with only one local recurrence seen. Immediate palliation was obtained in most symptomatic patients. Interstitial changes in the lung were limited. Autopsy performed for a patient revealed remarkable histologic effects with minimal injuries to the lung. CONCLUSION The geometric accuracy of MVCT-assisted SRS appeared to enhance the clinical efficacy and safety of treatment to thoracic malignancies.

Radiation therapy in early glottic carcinoma: uni- and multivariate analysis of prognostic factors affecting local control.

PURPOSE The purpose of this report is to clarify prognostic factors affecting local control of T1 and T2 glottic tumors and to define an optimal regimen for radiation therapy. METHODS AND MATERIALS Two hundred and ten patients (199 males, 11 females, age range 30 to 86 years with an average of 62 years) with previously untreated invasive squamous cell carcinoma of the glottis were treated with radiation therapy at the University of Tokyo between January 1972 and December 1989. Endoscopic microsurgery was introduced as an integral part of treatment in 1974. From 1974 to 1979 the radiation dose was gradually reduced, reaching a mean of 20 Gy in 2 weeks in 1979. From 1980 to 1983, the total dose increased to 50.4 Gy, with a fraction size of 1.8 Gy, over a mean of 5.6 weeks. From 1984 onward, the mean total radiation dose increased to 60 Gy with a fraction of 2 Gy. RESULTS Recurrence-free 5 year survival rates for T1a, T1b, and T2 were 79%, 73%, and 67%, respectively. When the relationship between radiation dose and local control rates was analyzed for each year from 1974 to 1989, total doses were strongly associated with local control for patients with T1a disease. Age, sex, daily dose, total dose, radiation machine (Co-60 or 10 MV Lineac), treatment technique (anterior wedged pair or parallel opposed fields), treatment volume, use of endoscopic microsurgery, and involvement of the anterior commissure were examined for effects upon relapse-free survival in T1a disease by uni- and multivariate analysis. Total dose was the only significant factor for T1a disease (p < 0.02). The effect of these variables upon relapse-free survival in T2 disease as well as the effect of cord mobility, and number of involved sites was examined by multivariate analysis. Total dose (p < 0.03), cord mobility (p < 0.05), and number of involved sites (p < 0.04) significantly affected relapse-free survival in T2 disease. CONCLUSION At least 50 Gy is required for treatment of T1 disease when 2 Gy is used as a daily dose, even if endoscopic microsurgery is performed. Better local control of T2 disease in patients with impaired cord mobility or more than three involved sites leads to an improved prognosis; we recommend doses of at least 70 Gy or use of hyperfractionation in such patients with these factors. Although the daily dose did not significantly affect prognosis in multivariate analyses, 1.8 Gy is not recommended for treatment of T2 tumors instead of 2 Gy.

Thermoradiotherapy in the treatment of locally advanced nonsmall cell lung cancer

PURPOSE To improve the treatment results of locally advanced non-small cell lung cancer (NSCLC), we have been conducting a clinical trial using regional hyperthermia combined with radiotherapy. METHODS AND MATERIALS Between 1985 and 1990, 19 patients were treated. All cases except one were regarded as initially unresectable. There were 10 Stage IIIA cases and nine Stage IIIB cases. In 10 cases thermoradiotherapy was used definitively, and in the other nine cases preoperatively. Radiotherapy was administered with conventional fractionation. Total dose ranged from 42 to 80 Gy (mean 62.9 Gy) for definitive treatment cases, and 38 to 47 Gy (mean 40.6 Gy) for preoperative cases. Radiofrequency (RF) capacitive hyperthermia was administered twice weekly, immediately after radiotherapy. Total sessions of hyperthermia ranged from 5 to 16 times (mean 9.0) for definitive treatment cases and 3 to 8 times (mean 6.7) for preoperative cases. RESULTS The results of thermoradiotherapy group (HTRT group) were compared with our historical control group (RT group); initially unresectable Stage III NSCLC irradiated definitively with 50 Gy or more (26 cases), or became resectable after radiotherapy and operated (4 cases). As for initial response, there were 5 complete responses (CRs), 13 partial responses (PRs), and 1 no change (NC) (CR rate 26%, response rate 95%) in the HTRT group, whereas there were no CR, 21 PRs, and 9 NCs in the RT group (CR rate 0%, p < 0.005, response rate 70%, p < 0.05). Overall 3-year local relapse-free survival and survival rate for the HTRT group was 73% and 37%, respectively, and 20% and 6.7%, respectively, for the RT group (p < 0.01, p < 0.01). The rate of death from uncontrolled primary disease for the HTRT group was significantly lower than for the RT group (21% vs. 53%, p < 0.03). CONCLUSION Although the number of cases is rather small, thermoradiotherapy in the treatment of locally advanced NSCLC is promising in raising resectability, local control, and, thus, long-term survival.

A single institutional outcome analysis of Gamma Knife radiosurgery for single or multiple brain metastases

Although Gamma Knife stereotactic radiosurgery (SRS) is widely used for metastatic brain tumors, optimal patient selection and treatment strategy continue to be investigated. The aim of this study was to provide treatment results with Gamma Knife SRS and to establish prognostic factors. Of the 54 patients treated from 1990 to 1997, 51 patients were evaluable. There were 28 males and 23 females, with a median age of 60 years. Median Karnofsky Index was 80. There were 19 non-small cell lung cancers, eight colon cancers, six renal cell cancers, five ovarian cancers, four gastric cancers, three breast cancers, and six others. Primary tumors were controlled in 33 patients, and extracranial tumors were absent in 25 patients. Sixty-eight metastatic brain tumors in 37 patients underwent SRS as an initial treatment for the brain metastasis. Brain metastasis was solitary in 32 patients. Conventional radiation was combined with SRS in 29 patients, 24 of whom received whole brain radiotherapy. Eight patients had some form of surgical resection. Median survival time was 7.4 months. Five-year actuarial survival and local control rates were 16 and 52%, respectively. Median duration time of keeping pretreatment quality of life was 6.9 months. On a multivariate analysis, uncontrolled primary tumor, combined conventional radiotherapy, and performance status were statistically significant prognostic factors. Four patients who underwent whole brain radiation developed low grade dementia.

Real-time beam monitoring in dynamic conformation therapy

PURPOSE Although portal imaging is a promising method of verification during static multiport irradiation, it cannot be applied directly to dynamic irradiation such as rotational conformation with multileaf collimator movement. A real-time beam monitoring system based on megavoltage computed tomography scanning has been developed to establish a verification method for the rotational conformation technique. METHODS AND MATERIALS Exit beam through the patient is extracted by the same detector unit as used for megavoltage scanning during the actual treatment. Beam edge is defined as the 50% level of the maximum dose of the detector array. Megavoltage computed tomography is done after patient setup and just prior to the actual irradiation. Detected beam pathways are overlaid on this image approximately every 1 s. Therapists can monitor correlation between the target and actual beam pathways on a real-time computer display. RESULTS The accuracy of field edge detection has been proven to be less than 2 mm from various measurements. Real-time monitoring is more useful in rotational conformation than in static multiport irradiation due to dynamic movement of the collimator. Field errors were identified in two of 54 sessions using this method. CONCLUSIONS Although several limitations remain to be solved, the method presented is a useful tool for treatment verification of high accuracy radiation therapy, particularly rotational conformation irradiation.

Radiotherapy during pregnancy : Effects on fetuses and neonates

To optimize the efficacy of radiotherapy for cancer patients who are pregnant, the following factors must be considered: the potential effects of the therapy on fetuses and neonates, the stage and prognosis of the mothers disease, and the possible risks to the patient of restricting cancer treatment. Malformations and mental retardation are the most serious consequences of fetal exposure to radiation that are observed after birth. The sensitivity to radiation is high from 2 to 8 weeks after conception for malformations and from 8 to 25 weeks (particularly up to week 15) for mental retardation; the risk of mental retardation declines rapidly after the 25th week of gestation. When a pregnant patient requires radiation therapy, the physician should consider fetal sensitivity to radiation in light of gestational age and the expected dose of radiation and should then calculate the risk to the fetus versus the benefits to the mother. The risk is negligible if fetal exposure does not exceed 0.1 Gy, preferably remaining below 0.05 Gy, during gestation. Furthermore, it is safest to administer radiotherapy during or after the 25th week of gestation.

Enhancer-promoter activity of human papillomavirus type 16 long control regions isolated from cell lines SiHa and CaSki and cervical cancer biopsies.

Expression of human papillomavirus 16 (HPV‐16) oncogenes is markedly higher in cervical cancer cells than in precancerous cells, and the elevated expression is believed to be required for the malignant phenotypes. We compared cancer cell lines CaSki (with 200 to 400 copies of HPV‐16 DNA per cell) and SiHa (with one to two copies of HPV‐16 DNA per cell) for the E7 expression in cells and the enhancer‐promoter activity of the isolated viral long control region (LCR). Although these parameters per cell were 10‐fold higher in CaSki than in SiHa, the levels of the E7 mRNA and protein per HPV DNA copy were 10‐ to 20‐fold higher in SiHa than in CaSki. Characterization of the isolated LCRs showed that, whereas the LCR from CaSki resembled the prototype in structure and activity, the LCR from SiHa, with a deletion of 38 base pairs, enhanced transcription from P97 as assayed by using a plasmid capable of expressing luciferase. The upregulation appeared to be due to removal of one of the silencer YY1‐binding sites. Furthermore, we isolated and characterized LCRs from 51 cervical cancer patients’ biopsies. Among them, one with a deletion including YY1‐binding sites and the other with a substitution in a YY1‐motif were found to enhance the transcription. These findings suggest that mutation affecting YY1‐motifs in the LCR is one of the mechanisms enhancing the viral oncogene expression in the course of progression of cancer cells.

Technological features and clinical feasibility of megavoltage CT scanning

Megavoltage CT scanning using 4-MV and 6-MV radiotherapy beams has been developed and applied to verify errors in patient positioning. A detect or system composed of 120 pairs of cadmium tungstate scintillators with photodiodes is mounted to the treatment unit at a distance of 160 cm from the beam source. Image reconstruction is performed with a standard filtered back-projection algorithm. Scanning time and reconstruction time for a slice is approximately 35 s and 60 s respectively. Although spatial resolution is as large as 4 mm, it has sufficient image quality to be applied for treatment planning and verification. The delivered dose with 4 MV and 6 MV is about 1.4 cGy and 28. cGY respectively. When a megavoltage CT image is taken in treatment position, the positioning errors are easily detected by comparing it with diagnostic CT sections for treatment planning. Several clinical examples are presented.

Immediate neurological deterioration after gamma knife radiosurgery for acoustic neuroma. Case report.

The purpose of this paper was to note a potential source of error in magnetic resonance (MR) imaging. Magnetic resonance images were acquired for stereotactic planning for GKS of a vestibular schwannoma in a female patient. The images were acquired using three-dimensional sequence, which has been shown to produce minimal distortion effects. The images were transferred to the planning workstation, but the coronal images were rejected. By examination of the raw data and reconstruction of sagittal images through the localizer side plate, it was clearly seen that the image of the square localizer system was grossly distorted. The patient was returned to the MR imager for further studies and a metal clasp on her brassiere was identified as the cause of the distortion.A-60-year-old man with medically intractable left-sided maxillary division trigeminal neuralgia had severe cardiac disease, was dependent on an internal defibrillator and could not undergo magnetic resonance imaging. The patient was successfully treated using computerized tomography (CT) cisternography and gamma knife radiosurgery. The patient was pain free 2 months after GKS. Contrast cisternography with CT scanning is an excellent alternative imaging modality for the treatment of patients with intractable trigeminal neuralgia who are unable to undergo MR imaging.The authors describe acute deterioration in facial and acoustic neuropathies following radiosurgery for acoustic neuromas. In May 1995, a 26-year-old man, who had no evidence of neurofibromatosis Type 2, was treated with gamma knife radiosurgery (GKS; maximum dose 20 Gy and margin dose 14 Gy) for a right-sided intracanalicular acoustic tumor. Two days after the treatment, he developed headache, vomiting, right-sided facial weakness, tinnitus, and right hearing loss. There was a deterioration of facial nerve function and hearing function from pretreatment values. The facial function worsened from House-Brackmann Grade 1 to 3. Hearing deteriorated from Grade 1 to 5. Magnetic resonance (MR) images, obtained at the same time revealed an obvious decrease in contrast enhancement of the tumor without any change in tumor size or peritumoral edema. Facial nerve function improved gradually and increased to House-Brackmann Grade 2 by 8 months post-GKS. The tumor has been unchanged in size for 5 years, and facial nerve function has also been maintained at Grade 2 with unchanged deafness. This is the first detailed report of immediate facial neuropathy after GKS for acoustic neuroma and MR imaging revealing early possibly toxic changes. Potential explanations for this phenomenon are presented.In clinical follow-up studies after radiosurgery, imaging modalities such as computerized tomography (CT) and magnetic resonance (MR) imaging are used. Accurate determination of the residual lesion volume is necessary for realistic assessment of the effects of treatment. Usually, the diameters rather than the volume of the lesion are measured. To determine the lesion volume without using stereotactically defined images, the software program VOLUMESERIES has been developed. VOLUMESERIES is a personal computer-based image analysis tool. Acquired DICOM CT scans and MR image series can be visualized. The region of interest is contoured with the help of the mouse, and then the system calculates the volume of the contoured region and the total volume is given in cubic centimeters. The defined volume is also displayed in reconstructed sagittal and coronal slices. In addition, distance measurements can be performed to measure tumor extent. The accuracy of VOLUMESERIES was checked against stereotactically defined images in the Leksell GammaPlan treatment planning program. A discrepancy in target volumes of approximately 8% was observed between the two methods. This discrepancy is of lesser interest because the method is used to determine the course of the target volume over time, rather than the absolute volume. Moreover, it could be shown that the method was more sensitive than the tumor diameter measurements currently in use. VOLUMESERIES appears to be a valuable tool for assessing residual lesion volume on follow-up images after gamma knife radiosurgery while avoiding the need for stereotactic definition.This study was conducted to evaluate the geometric distortion of angiographic images created from a commonly used digital x-ray imaging system and the performance of a commercially available distortion-correction computer program. A 12 x 12 x 12-cm wood phantom was constructed. Lead shots, 2 mm in diameter, were attached to the surfaces of the phantom. The phantom was then placed inside the angiographic localizer. Cut films (frontal and lateral analog films) of the phantom were obtained. The films were analyzed using GammaPlan target series 4.12. The same procedure was repeated with a digital x-ray imaging system equipped with a computer program to correct the geometric distortion. The distortion of the two sets of digital images was evaluated using the coordinates of the lead shots from the cut films as references. The coordinates of all lead shots obtained from digital images and corrected by the computer program coincided within 0.5 mm of those obtained from cut films. The average difference is 0.28 mm with a standard deviation of 0.01 mm. On the other hand, the coordinates obtained from digital images with and without correction can differ by as much as 3.4 mm. The average difference is 1.53 mm, with a standard deviation of 0.67 mm. The investigated computer program can reduce the geometric distortion of digital images from a commonly used x-ray imaging system to less than 0.5 mm. Therefore, they are suitable for the localization of arteriovenous malformations and other vascular targets in gamma knife radiosurgery.

ANALYSIS OF DOSE DISTRIBUTION IN GAMMA KNIFE RADIOSURGERY FOR MULTIPLE TARGETS

PURPOSE The aim of this study is to evaluate the actual effect of irradiation for other targets in dose planning for the treatment of multiple metastases with Gamma Knife. METHODS AND MATERIALS We analyzed dose distributions for 51 targets in 10 patients with metastatic brain tumors who underwent radiosurgery with Gamma Knife for the treatment of more than one target in one session. We made dose plans with every attempt to include as many targets as possible and calculate dose distributions separately for each dose matrix. We also calculated the composite dose distribution by including the effect of all shots used. We compared these noncomposite and composite dose distributions. RESULTS The differences in the mean target dose between the noncomposite dose distribution and the composite one ranged from 0.0 to 4.5 Gy with a mean of 1.5 Gy and was more than 2 Gy in 12 (24%) targets. The difference tended to be larger when targets were small in volume and/or the number of targets was large. CONCLUSIONS The effect of irradiation from the shots for other targets was not negligible in some cases. This difference of dose distribution should be considered in the analysis of clinical outcomes of cases with multiple targets treated in one session.