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Since 1978, the University of California San Francisco (UCSF) Ocular Tumor Program has been using particle therapy for treating ocular patients with malignant as well as benign eye disease. Helium ion beams were used initially and were produced by two synchrotron-based systems: first by the 184-inch synchro-cyclotron and later by the Bevalac, at the Lawrence Berkeley National Laboratory (LBNL). Since 1994, protons, produced by a cyclotron-based system at the Crocker Nuclear Laboratory (CNL) Eye Treatment Facility (ETF), have been used for this purpose. The CNL cyclotron produces a 67.5 MeV beam, allowing for a uniquely homogeneous beam for eye treatment, without degradation of the beam or manipulation of the beam line. This paper describes, in detail, the control system for beam delivery, as implemented for measuring and delivering the radiation to ocular tumors at CNL. The control system allows for optimal delivery and rapid termination of the irradiation after the desired dose is achieved. In addition, several safeguard systems are discussed, as these are essential for such a system in the event of failure of software, electronics, or other hardware. The QA analysis shows that the total range of the proton beam is 30.7 ± 1.0 mm in water at iso-center. The beam distal penumbra (80% - 20%) is 1.1 mm for a range-modulated beam at a collimator to iso-center distance of 50 mm. Daily QA checks confirm that the range and modulation is within 0.1 mm. The beam flatness and symmetry in a 25 mm diameter beam are ±1% - 2%. Variation in the daily dosimetry system, as compared to standard dosimetry, is within ±3.5%, with a mean variation of 0.72(±1.9)% and 0.85(±2.3)% for segmented transmission ionization chambers IC1 (upstream) and IC2 (downstream), respectively. From May 1994 to the end of 2015, UCSF has treated 1838 proton ocular patients at the Davis ETF. During this period, no treatments were missed due to any cyclotron or control system failures. The overall performance, maintenance, and quality assurance of the cyclotron and the ocular control system have been excellent.

Purpose Additional radiation following postmastectomy radiation (PMRT) has an undefined benefit. We investigate those likely to be selected for a chest wall boost (CWB) and its effect on breast cancer survival (BCS) and overall survival (OS). Methods and materials A total of 4747 women diagnosed from 2005 to 2009 were treated with PMRT identified from the California Cancer Registry (CCR); 2686 (57%) received a CWB. Univariate and multivariate analyses compared those receiving and not receiving a CWB for BCS and OS. Results With a median follow-up of 43.6 months, patients likely to receive a CWB were stage III ( P ≤ .001), grade 3/4 ( P = .03), positive nodes ( P = .04), HER 2+ ( P =.02). CWB was not related to BCS in the univariate (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.82-1.21), multivariate (HR, 1.04; 95% CI, 0.86 -1.26) analyses, and was not related OS for the univariate (HR, 0.92; 95% CI, 0.78-1.10), multivariate (HR, 0.95; 95% CI, 0.80-1.13) analyses. However, in multivariate analysis, patients not receiving chemotherapy who had a CWB had better BCS (HR, 1.77; 95% CI, 1.11-2.83). Conclusions The majority of patients were treated with a CWB. We found no difference in BCS or OS with the addition of a CWB.

Purpose To perform an in-depth temporal analysis of visual acuity (VA) outcomes after proton beam radiation therapy (PBRT) in a large, uniformly treated cohort of uveal melanoma (UM) patients, to determine trends in VA evolution depending on pretreatment and temporally defined posttreatment VA measurements; and to investigate the relevance of specific patient, tumor and dose-volume parameters to posttreatment vision loss. Methods and Materials Uveal melanoma patients receiving PBRT were identified from a prospectively maintained database. Included patients (n=645) received 56 GyE in 4 fractions, had pretreatment best corrected VA (BCVA) in the affected eye of count fingers (CF) or better, with posttreatment VA assessment at specified post-PBRT time point(s). Patients were grouped according to the pretreatment BCVA into favorable (≥20/40) or unfavorable (20/50-20/400) and poor (CF) strata. Temporal analysis of BCVA changes was described, and univariate and forward stepwise multivariate logistic regression analyses were performed to identify predictors for VA loss. Results Median VA follow-up was 53 months (range, 3-213 months). At 60-month follow up, among evaluable treated eyes with favorable pretreatment BCVA, 45% retained BCVA ≥20/40, whereas among evaluable treated eyes with initially unfavorable/poor BCVA, 21% had vision ≥20/100. Among those with a favorable initial BCVA, attaining BCVA of ≥20/40 at any posttreatment time point was associated with subsequent maintenance of excellent BCVA. Multivariate analysis identified volume of the macula receiving 28GyE ( P P =.0004) as independent dose-volume histogram predictors of 48-month post-PBRT vision loss among initially favorable treated eyes. Conclusions Approximately half of PBRT-treated UM eyes with excellent pretreatment BCVA assessed at 5 years after treatment will retain excellent long-term vision. 28GyE macula and optic nerve dose-volume histogram parameters allow for rational treatment planning optimization that may lead to improved visual outcomes. The detailed temporal analysis with intermediate as well as long-term functional prognosis, and the relationship of outcomes with clinical and treatment planning parameters, is critical for informed care of UM patients before and after PBRT.

The purpose of this study is to investigate the luminescence light output response in a plastic scintillator irradiated by a 67.5 MeV proton beam using various dosimetry parameters. The relationship of the visible scintillator light with the beam current or dose rate, aperture size and the thickness of water in the water-column was studied. The images captured on a CCD camera system were used to determine optimal dosimetry parameters for measuring the range of a clinical proton beam. The method was developed as a simple quality assurance tool to measure the range of the proton beam and compare it to (a) measurements using two segmented ionization chambers and water column between them, and (b) with an ionization chamber (IC-18) measurements in water. We used a block of plastic scintillator that measured 5×5×5 cm3 to record visible light generated by a 67.5 MeV proton beam. A high-definition digital video camera Moticam 2300 connected to a PC via USB 2.0 communication channel was used to record images of scintillation luminescence. The brightness of the visible light was measured while changing beam current and aperture size. The results were analyzed to obtain the range and were compared with the Bragg peak measurements with an ionization chamber. The luminescence light from the scintillator increased linearly with the increase of proton beam current. The light output also increased linearly with aperture size. The relationship between the proton range in the scintillator and the thickness of the water column showed good linearity with a precision of 0.33 mm (SD) in proton range measurement. For the 67.5 MeV proton beam utilized, the optimal parameters for scintillator light output response were found to be 15 nA (16 Gy/min) and an aperture size of 15 mm with image integration time of 100 ms. The Bragg peak depth brightness distribution was compared with the depth dose distribution from ionization chamber measurements and good agreement was observed. The peak/plateau ratio observed for the scintillator was found to be 2.21 as compared to the ionization chamber measurements of 3.01. The response of a scintillator block–CCD camera in 67.5 MeV proton beam was investigated. A linear response was seen between light output and beam current as well as aperture size. The relation between the thickness of water in the water column and the measured range also showed linearity. The results from the scintillator response was used to develop a simple approach to measuring the range and the Bragg peak of a proton beam by recording the visible light from a scintillator block with an accuracy of less than 0.33 mm. Optimal dosimetry parameters for our proton beam were evaluated. It is observed that this method can be used to confirm the range of a proton beam during daily treatment and will be useful as daily QA measurement for proton beam therapy.

PURPOSE: The purpose of this study is to evaluate a novel approach for treatment planning using digital fundus image fusion in EYEPLAN for proton beam radiation therapy (PBRT) planning for ocular melanoma. The authors used a prototype version of EYEPLAN software, which allows for digital registration of high-resolution fundus photographs. The authors examined the improvement in tumor localization by replanning with the addition of fundus photo superimposition in patients with macular area tumors. METHODS: The new version of EYEPLAN (v3.05) software allows for the registration of fundus photographs as a background image. This is then used in conjunction with clinical examination, tantalum marker clips, surgeon's mapping, and ultrasound to draw the tumor contour accurately. In order to determine if the fundus image superimposition helps in tumor delineation and treatment planning, the authors identified 79 patients with choroidal melanoma in the macular location that were treated with PBRT. All patients were treated to a dose of 56 GyE in four fractions. The authors reviewed and replanned all 79 macular melanoma cases with superimposition of pretreatment and post-treatment fundus imaging in the new EYEPLAN software. For patients with no local failure, the authors analyzed whether fundus photograph fusion accurately depicted and confirmed tumor volumes as outlined in the original treatment plan. For patients with local failure, the authors determined whether the addition of the fundus photograph might have benefited in terms of more accurate tumor volume delineation. RESULTS: The mean follow-up of patients was 33.6 +/- 23 months. Tumor growth was seen in six eyes of the 79 macular lesions. All six patients were marginal failures or tumor miss in the region of dose fall-off, including one patient with both in-field recurrence as well as marginal. Among the six recurrences, three were managed by enucleation and one underwent retreatment with proton therapy. Three patients developed distant metastasis and all three patients have since died. The replanning of six patients with their original fundus photograph superimposed showed that in four cases, the treatment field adequately covered the tumor volume. In the other two patients, the overlaid fundus photographs indicated the area of marginal miss. The replanning with the fundus photograph showed improved tumor coverage in these two macular lesions. For the remaining patients without local failure, replanning with fundus photograph superimposition confirmed the tumor volume as drawn in the original treatment plan. CONCLUSIONS: Local control was excellent in patients receiving 56 GyE of PBRT for uveal melanomas in the macular region, which traditionally can be more difficult to control. Posterior lesions are better defined with the additional use of fundus image since they can be difficult to mark surgically. In one-third of treatment failing patients, the superposition of the fundus photograph would have clearly allowed improved localization of tumor. The current practice standard is to use the superimposition of the fundus photograph in addition to the surgeon's clinical and clip mapping of the tumor and ultrasound measurement to draw the tumor volume.

A new noninvasive monitoring system for fixing the eye has been developed to treat orbital and choroidal tumors with CyberKnife-based radiotherapy. This device monitors the eye during CT/MRI scanning and during treatment. The results of this study demonstrate the feasibility of the fixation light system for CyberKnife-based treatments of orbital and choroidal tumors and supports the idea that larger choroidal melanomas and choroidal metastases could be treated with CyberKnife without implanting fiducial markers.

In order to reduce the dose to surrounding critical tissues and also minimize the probability of recurrence of the tumor the placement of radiation fields relative to patient anatomy is very essential in proton beam therapy of ocular tumors. To achieve this objective, patient setup and field placement have been verified before treatment by analyzing the portal images obtained with Polaroid film-camera system. The Polaroid films are becoming expensive and obsolete, making new methods of verifying the patient treatment position essential. The objective of this study was to implement an orthogonal flat panel digital imaging (FPDI) system as a tool to image-guided radiation therapy (IGRT) on the UC Davis cyclotron proton beam therapy line and to use the system for patient setup verification. The image quality of the system is sufficient to see an air hole with a diameter of 0.5 mm at a depth of 9 mm, in a 10 cm Lucite phantom. The subject contrast of the FPDI system varied from 16% to 29% by varying the size of the air hole in the phantom from 1 to 5 mm and changing the depth from 9 to 15 mm. The subject contrast for 0.5 mm air hole was 11%. The comparison of the setup variations as measured from Polaroid port films and FPDI was 0.1±0.7 mm in the X -direction, 0.2±0.2 mm in the Y -direction and 0.04±0.1 mm in Z -direction, respectively. The day-to-day positional variations in-patient set-ups were studied for 30 patients using the FPDI system. The patient position set-up on first day of treatment [defined by the X , Y , Z coordinates of the chair and head holder] was registered as the reference image. The comparison of day-to-day patient position with reference image indicated net translation along the three orthogonal axes as 0.3±1.88 mm in right–left direction, −0.3±1.78 in superior–inferior direction and −0.6±2.8 mm in anterior–posterior direction. The image quality of the FPDI system was sufficient to clearly reveal the radio-opaque markers on the digital image. In conclusion a FPDI system can accurately replace the Polaroid system and will facilitate daily portal alignment and true electronic IGRT verification of patient position and tumor location relative to the proton beam.

BACKGROUND. Treatment outcomes for stage III and IV oropharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy without prior surgical resection were reviewed. METHODS. Between April 2000 and September 2004, 71 patients underwent IMRT concurrent with chemotherapy without prior surgical resection for stage III and IV oropharyngeal carcinoma. Chemotherapy was platinum based. The gross tumor volume (GTV) received 70 Gy in 2.12 Gy per fraction. The high-risk clinical tumor volume (CTV) received 59.4 Gy in 1.80 Gy per fraction, and the low-risk CTV received 54 Gy in 1.64 Gy per fraction. RESULTS. With a median follow-up of 33 months, the 3-year local, regional, and locoregional progression-free probabilities were 94%, 94%, and 90%, respectively. The 3-year overall survival estimate was 83%. Locoregional failures occurred in the GTV in 7 patients. Acute grade 3 or 4 toxicity developed in 35 patients. A feeding gastrostomy was placed in 25 patients. Late xerostomia was grade 0 in 16 patients, grade 1 in 31 patients, and grade 2 in 24 patients at last follow-up. No patients experienced grade 3 or 4 late toxicity, except for 1 who developed osteoradionecrosis of the mandible. CONCLUSIONS. Excellent local and regional control was achieved with IMRT and concurrent chemotherapy without prior surgical resection in the treatment of stage III and IV oropharyngeal carcinoma. Significant sparing of the parotid glands and other critical normal tissues was possible using IMRT with moderate acute toxicities and minimal severe late effects. Cancer 2008. © 2008 American Cancer Society.

Peripheral radiation can have deleterious effects on normal tissues throughout the body, including secondary cancer induction and cataractogenesis. The aim of this study is to evaluate the peripheral dose received by various regions of the body after ocular treatment delivered with the Model C Gamma Knife, proton radiotherapy with a dedicated ocular beam employing no passive-scattering system, or a CyberKnife unit before and after supplemental shielding was introduced. TLDs were used for stray gamma and x-ray dosimetry, whereas CR-39 dosimeters were used to measure neutron contamination in the proton experiments. Doses to the contralateral eye, neck, thorax and abdomen were measured on our anthropomorphic phantom for a 56 Gy treatment to a 588 mm(3) posterior ocular lesion. Gamma Knife (without collimator blocking) delivered the highest dose in the contralateral eye, with 402-2380 mSv, as compared with 118-234 mSv for CyberKnife pre-shielding, 46-255 mSv for CyberKnife post-shielding and 9-12 mSv for proton radiotherapy. Gamma Knife and post-shielding CyberKnife delivered comparable doses proximal to the treatment site, with 190 versus 196 mSv at the thyroid, whereas protons doses at these locations were less than 10 mSv. Gamma Knife doses decreased dramatically with distance from the treatment site, delivering only 13 mSv at the lower pelvis, comparable to the proton result of 4 to 7 mSv in this region. In contrast, CyberKnife delivered between 117 and 132 mSv to the lower pelvis. In conclusion, for ocular melanoma treatments, a proton beam employing no double scattering system delivers the lowest peripheral doses proximally to the contralateral eye and thyroid when compared to radiosurgery with the Model C Gamma Knife or CyberKnife. At distal locations in the pelvis, peripheral doses delivered with proton and Gamma Knife are of an order of magnitude smaller than those delivered with CyberKnife.

Purpose: To review a single-institutional experience with the use of intraoperative radiation therapy (IORT) for recurrent head-and-neck cancer. Methods and Materials: Between 1991 and 2004, 137 patients were treated with gross total resection and IORT for recurrence or persistence of locoregional cancer of the head and neck. One hundred and thirteen patients (83%) had previously received external beam radiation as a component of definitive therapy. Ninety-four patients (69%) had squamous cell histology. Final surgical margins were microscopically positive in 56 patients (41%). IORT was delivered using either a modified linear accelerator or a mobile electron unit and was administered as a single fraction to a median dose of 15 Gy (range, 10‐18 Gy). Median follow-up among surviving patients was 41 months (range, 3‐122 months). Results: The 1-year, 2-year, and 3-year estimates of in-field control after salvage surgery and IORT were 70%, 64%, and 61%, respectively. Positive margins at the time of IORT predicted for in-field failure (p 0.001). The 3-year rates of locoregional control, distant metastasis-free survival, and overall survival were 51%, 46%, and 36%, respectively. There were no perioperative fatalities. Complications included wound infection (4 patients), orocutaneous fistula (2 patients), flap necrosis (1 patient), trismus (1 patient), and neuropathy (1 patient). Conclusions: Intraoperative RT results in effective disease control with acceptable toxicity and should be considered for selected patients with recurrent or persistent cancers of the head and neck. © 2007 Elsevier Inc. Intraoperative radiation, Head and neck, Cancer.

Background. The optimal treatment for patients with locally recurrent carcinomas of the salivary glands is unclear. Methods. Ninety-nine patients underwent salvage surgery for locally recurrent salivary gland carcinomas. Eighty-one (82%) had previously received radiation. Thirty-seven patients (37%) received intraoperative radiation therapy (IORT) to a median dose of 15 Gy (range, 12–18 Gy) at the time of salvage. Results. The 1-, 3-, and 5-year estimates of local control after salvage surgery were 88%, 75%, and 69%, respectively. A Cox proportional hazard model identified positive margins (0.01) and the omission of IORT (p = .001) as independent predictors of local failure. The 5-year overall survival was 34%. Distant metastasis was the most common site of subsequent failure, occurring in 42% of patients. Conclusions. IORT significantly improves disease control for patients with locally recurrent carcinomas of the salivary glands. The high rate of distant metastasis emphasizes the need for effective systemic therapies. © 2007 Wiley Periodicals, Inc. Head Neck, 2008

Major progress has been made during the last decade in the safety and results of partial liver resection for metastatic cancer. Survival rates of 20% to more than 40% for five or more years can now be achieved.

Purpose: This study sought to review a single-institution experience with the management of adenoid cystic carcinoma of the head and neck. Methods and Materials: Between 1960 and 2004, 140 patients with adenoid cystic carcinoma of the head and neck were treated with definitive surgery. Ninety patients (64%) received postoperative radiation to a median dose of 64 Gy (range, 54–71 Gy). Distribution of T stage was: 26% T1, 28% T2, 20% T3, and 26% T4. Seventy-eight patients (56%) had microscopically positive margins. Median follow-up was 66 months (range, 7–267 months). Results: The 5- and 10-year rate estimates of local control were 88% and 77%, respectively. A Cox proportional hazards model identified T4 disease ( p = 0.0001), perineural invasion ( p = 0.008), omission of postoperative radiation ( p = 0.007), and major nerve involvement ( p = 0.02) as independent predictors of local recurrence. Radiation dose lower than 60 Gy ( p = 0.0004), T4 disease ( p = 0.005), and major nerve involvement ( p = 0.02) were predictors of local recurrence among those treated with surgery and postoperative radiation. The 10-year overall survival and distant metastasis-free survival were 64% and 66%, respectively. Conclusion: Combined-modality therapy with surgery followed by radiation to doses in excess of 60 Gy should be considered the standard of care for adenoid cystic carcinoma of the head and neck.

The aim of this study is to (1) compare the delineation of the tumor volume for ocular melanoma on high-resolution three-dimensional (3D) T2-weighted fast spin echo magnetic resonance imaging (MRI) images with conventional techniques of A- and B-scan ultrasound, transcleral illumination, and placement of tantalum markers around tumor base and (2) to evaluate whether the surgically placed marker ring tumor delineation can be replaced by 3D MRI based tumor delineation. High-resolution 3D T2-weighted fast spin echo (3D FSE) MRI scans were obtained for 60 consecutive ocular melanoma patients using a 1.5 T MRI (GE Medical Systems, Milwaukee, WI), in a standard head coil. These patients were subsequently treated with proton beam therapy at the UC Davis Cyclotron, Davis, CA. The tumor was delineated by placement of tantalum rings (radio-opaque markers) around the tumor periphery as defined by pupillary transillumination during surgery. A point light source, placed against the sclera, was also used to confirm ring agreement with indirect ophthalmoscopy. When necessary, intraoperative ultrasound was also performed. The patients were planned using EYEPLAN software and the tumor volumes were obtained. For analysis, the tumors were divided into four categories based on tumor height and basal diameter. In order to assess the impact of high-resolution 3D T2 FSE MRI, the tumor volumes were outlined on the MRI scans by two independent observers and the tumor volumes calculated for each patient. Six (10%) of 60 patients had tumors, which were not visible on 3D MRI images. These six patients had tumors with tumor heights < or = 3 mm. A small intraobserver variation with a mean of (-0.22 +/- 4)% was seen in tumor volumes delineated by 3D T2 FSE MR images. The ratio of tumor volumes measured on MRI to EYEPLAN for the largest to the smallest tumor volumes varied between 0.993 and 1.02 for 54 patients. The tumor volumes measured directly on 3D T2 FSE MRI ranged from 4.03 to 0.075 cm3. with a mean of 0.87 +/- 0.84 cm3. The tumor shapes obtained from 3D T2 FSE MR images were comparable to the tumor shapes obtained using EYEPLAN software. The demonstration of intraocular tumor volumes with the high-resolution 3D fast spin echo T2 weighted MRI is excellent and provides additional information on tumor shape. We found a high degree of accuracy for tumor volumes with direct MRI volumetric measurements in uveal melanoma patients. In some patients with extra large tumors, the tumor base and shape was modified, because of the additional information obtained from 3D T2 FSE MR images.

The advances brought about by research in radiation medicine over the past 50 years are presented. The era began with the atomic explosions in Hiroshima and Nagasaki and the establishment of the Atomic Bomb Casualty Commission to understand what damage was caused by exposure of a large population to radiation. A better understanding of the effects of whole-body exposure led to the development of whole-body radiation treatment techniques and to bone marrow transplantation in the treatment of leukemias. The field of diagnostic imaging was revolutionized by a series of inventions that included angiography, mammography, computed tomography, magnetic resonance imaging, magnetic resonance spectroscopy, and ultrasound imaging. The field of nuclear medicine came of age through new man-made radionuclides and the invention of scanning and imaging techniques including positron emission tomography. Radiotherapy, a minor sideline of radiology, developed into radiation oncology, an extremely important component of modern cancer therapy. The advances in clinical radiotherapy were made possible by discoveries and inventions in physics and engineering and by insights and discoveries in radiobiology. The result of the last 50 years of progress is a very powerful set of clinical tools.

Purpose: At our institution, we have been using intracavitary brachytherapy as a boost in selected cases of both primary and recurrent nasopharyngeal carcinoma. The local control, distant metastasis–free rate, overall survival, and morbidity are presented. Methods and Materials: Between January 1, 1955, and August 2000, 576 patients with a diagnosis of nasopharyngeal carcinoma were seen at the department of radiation oncology, University of California–San Francisco, and 55 patients received intracavitary brachytherapy as one part of their treatment. All patients were treated with megavoltage external beam radiation, including 43 patients treated for initial disease and 12 for recurrence. Brachytherapy was routinely used for early cases of T1 and T2 lesions and selected cases of more advanced lesions, as well as recurrent lesions. The median age was 48 years (range 22–85 years); there were 17 women and 38 men, and 39 patients were ethnic Chinese, 13 were white, and 3 were other races. Stage at treatment (primary and recurrent) was I (n = 13), II (n = 18), III (n = 19), and IV (n = 5); 18 patients had concurrent chemotherapy. The brachytherapy applicators used were Rotterdam (n = 24), balloon (n = 16), ovoid (n = 14), and ribbon (n = 1). The dose rate was high (n = 24), low (n = 29), or pulsed (n = 2). External beam doses ranged from 54 to 72 Gy for primary disease and 30 to 42 Gy for recurrent disease. Brachytherapy doses ranged from 5 to 7 Gy for high dose rate and 10 to 54 Gy for low dose rate. Results: With a median follow-up of 36 months in those who were treated for primary carcinoma, the 5-year estimate of local control was 89%, the distant metastasis–free rate was 75%, and the overall survival estimate was 86%. Recurrent patients had a median follow-up of 50 months; the 5-year estimate of local control was 64%, the distant metastasis–free rate was 100%, and the overall survival estimate was 91%. Patients with Stage I or II disease had a longer overall survival compared with those with Stage III or IV (p = 0.05). There was a significant difference in the rate of distant metastases due to nodal status (N0 vs. N1–N3, p = 0.02) or to overall stage (I/II vs. III/IV, p = 0.005). Conclusions: Intracavitary boost brachytherapy was found to be effective and well tolerated in selected cases of both primary and recurrent nasopharyngeal carcinoma.

Relevant clinical data are needed given the increasing national interest in charged particle radiation therapy (CPT) programs. Here we report long-term outcomes from the only randomized, stratified trial comparing CPT with iodine-125 plaque therapy for choroidal and ciliary body melanoma.From 1985 to 1991, 184 patients met eligibility criteria and were randomized to receive particle (86 patients) or plaque therapy (98 patients). Patients were stratified by tumor diameter, thickness, distance to disc/fovea, anterior extension, and visual acuity. Tumors close to the optic disc were included. Local tumor control, as well as eye preservation, metastases due to melanoma, and survival were evaluated.Median follow-up times for particle and plaque arm patients were 14.6 years and 12.3 years, respectively (P=.22), and for those alive at last follow-up, 18.5 and 16.5 years, respectively (P=.81). Local control (LC) for particle versus plaque treatment was 100% versus 84% at 5 years, and 98% versus 79% at 12 years, respectively (log rank: P=.0006). If patients with tumors close to the disc (2 mm) were excluded, CPT still resulted in significantly improved LC: 100% versus 90% at 5 years and 98% versus 86% at 12 years, respectively (log rank: P=.048). Enucleation rate was lower after CPT: 11% versus 22% at 5 years and 17% versus 37% at 12 years, respectively (log rank: P=.01). Using Cox regression model, likelihood ratio test, treatment was the most important predictor of LC (P=.0002) and eye preservation (P=.01). CPT was a significant predictor of prolonged disease-free survival (log rank: P=.001).Particle therapy resulted in significantly improved local control, eye preservation, and disease-free survival as confirmed by long-term outcomes from the only randomized study available to date comparing radiation modalities in choroidal and ciliary body melanoma.

Objectives. To report the toxicity profile of patients treated with three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) receiving doses of 82 Gy or more to portions of their prostate. Methods. Forty-four patients treated with radiation therapy for prostate cancer between June 1992 and August 1998 at the University of California, San Francisco received a maximal dose within the target volume (Dmax) of 82 Gy or more. Eighteen patients were boosted selectively to a limited portion of their prostate using IMRT, whereas 26 patients were treated with 3D-CRT and had unselected “hot spots” within their prostate. The Radiation Therapy Oncology Group (RTOG) acute and late toxicity scales were used to score gastrointestinal (GI) and genitourinary (GU) morbidity. Results. Median follow-up and Dmax were 23.1 months (range 10.0 to 84.7) and 84.5 Gy (range 82.0 to 96.7), respectively. Of the patients, 59.1% and 34.1% developed some level of acute GU and GI toxicity, respectively. One patient experienced grade 3 acute GI toxicity. No other grade 3 or greater acute toxicity was observed. The 2-year actuarial rates for freedom from late GI and GU morbidity were 77.1% (95% confidence interval [CI] 60.4% to 87.5%) and 79.5% (95% CI 62.7% to 89.3%), respectively. Although no grade 3 or greater late GU morbidity has been observed to date, 3 patients experienced grade 3 late GI morbidity. However, these cases involved rectal bleeding and were effectively managed with laser coagulation/fulguration. Conclusions. Doses of 82 Gy or more to a portion of the prostate gland can be tolerated with acceptable morbidity. This observation supports the continued investigation of IMRT as a means for improving disease control in prostate cancer.

Purpose: The optimal fractionation schedule for radiotherapy of head and neck cancer has been controversial. The objective of this randomized trial was to test the efficacy of hyperfractionation and two types of accelerated fractionation individually against standard fractionation. Methods and Materials: Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1.2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. Of the 1113 patients entered, 1073 patients were analyzable for outcome. The median follow-up was 23 months for all analyzable patients and 41.2 months for patients alive. Results: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better local-regional control (p = 0.045 and p = 0.050 respectively) than those treated with standard fractionation. There was also a trend toward improved disease-free survival (p = 0.067 and p = 0.054 respectively) although the difference in overall survival was not significant. Patients treated with accelerated fractionation with split had similar outcome to those treated with standard fractionation. All three altered fractionation groups had significantly greater acute side effects compared to standard fractionation. However, there was no significant increase of late effects. Conclusions: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased.

Purpose: The purpose of this study was to evaluate tumor response, progression-free survival, local tumor control, patterns of relapse, and toxicity in patients with Stages IIIb and IVa squamous cell carcinoma of the uterine cervix treated with irradiation or irradiation and misonidazole. This is a report of the final results of the study. Methods: This study was a prospective randomized Phase III trial performed by the Radiation Therapy Oncology Group (RTOG). Between August 1980 and November 1984, 120 patients with Stages IIIb and IVa squamous cell carcinoma of the cervix were randomized to receive either standard irradiation or standard irradiation and misonidazole. Irradiation consisted of 46 Gy to the pelvis plus a 10 Gy parametrial boost followed by intracavitary brachytherapy or external irradiation boost to the primary tumor. Misonidazole was administered at 400 mg/m 2 daily, 2–4 h before irradiation. Patients in the 2 treatment groups were evenly distributed by stage, Karnofsky Performance Status, and positive para-aortic lymph nodes. Results: Sixty-one patients were treated with irradiation alone, and 59 patients received irradiation and misonidazole. Complete response in the pelvis occurred in 44 (75%) of those treated with irradiation and in 38 (64%) of those treated with irradiation and misonidazole. The progression-free survivals were 22% at 5 years for the control group, and 29% at 5 years for the misonidazole group. At the time of last follow-up, 18 patients in the control arm were free of disease, and in the experimental arm, 19 were free of disease. The patterns of failure for those treated with irradiation alone were local-only in 9 patients, distant-only in 8 patients, and local and distant in 11 patients. The patterns of failure for those receiving irradiation and misonidazole were local-only in 3 patients, distant-only in 8 patients, and local and distant in 8 patients. The maximum toxicity experienced per patient was grade 3 in 18%, grade 4 in 8%, and no grade 5 toxicity for those treated with irradiation alone compared to 8%, 2%, and 2%, respectively, for the experimental arm. Conclusion: There were no statistically significant differences in pelvic response, disease-free survivals, patterns of failure, or toxicity for the irradiation alone group or for the irradiation and misonidazole group as administered in this study for patients with Stages IIIb and IVa squamous cell carcinoma of the uterine cervix.

Purpose: To review the results and evaluate the prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma. Methods and Materials: We reviewed the records of 74 patients with locally recurrent nasopharyngeal carcinoma treated at the University of California, San Francisco between 1957 and 1995. The histologic types included squamous cell carcinoma in 6 (8.1%), nonkeratinizing carcinoma in 48 (64.9%), and undifferentiated carcinoma in 20 (27%) cases. The site of recurrence was in the primary in 46 (62.2%), in the neck nodes in 20 (27%), and in both sites in 8 (10.8%) patients. The recurrent disease was Stage I in 10 (13.5%), Stage II in 16 (21.6%), Stage III in 20 (27%), and Stage IV in 28 (37.9%) patients. Thirty-seven (50%) patients developed recurrence within 2 years and 58 (78.4%) within 5 years after initial treatment. Radiotherapeutic techniques used in the retreatment of primary recurrence consisted of external beam radiotherapy (EBRT), intracavitary brachytherapy, heavy-charged particle beam, and gamma knife, alone or in combination. Reirradiation doses ranged from 18 to 108 Gy, with a median dose of 60 Gy. Treatment of recurrent neck nodes consisted of radical neck dissection (RND) ± intraoperative radiotherapy (IORT), or EBRT ± hyperthermia, or chemotherapy ± hyperthermia. Chemotherapy was used in 22 (30%) patients. Median follow-up was 20 months (range: 2 to 308 months). Results: The 3-, 5-, and 10-year actuarial overall survival following retreatment were 49, 37, 18%, respectively. Thirty-six patients (49%) were free of further local-regional recurrence after retreatment. The 3-, 5-, and 10-year local-regional progression-free rates were 52, 40, and 38%, respectively. On univariate analysis, histologic type (p < 0.0001), interval to recurrence (p = 0.034), and treatment modality for early-stage disease (p = 0.01) were significant prognostic factors for overall survival, with age being marginally significant (p = 0.053). For local-regional progression-free rate, only histology was significant (p = 0.035). On multivariate analysis, age (p = 0.026), histology (p = 0.015), and interval to recurrence (p = 0.030) were significant for overall survival, and only histology (p = 0.002) and presence of complications (p = 0.016) were significant for local-regional progression-free rate. Of the 64 reirradiated patients, late complications were documented in 29 (45%) patients. The late complications were permanent in 21 (33%) and severe in 15 (23%) patients. Conclusion: Retreatment using radiotherapy alone or in combination with other treatment modalities can achieve long-term local-regional control and survival in a substantial proportion of patients witb locally recurrent nasopharyngeal carcinoma. Age, histology, and interval to recurrence were independent prognostic factors for overall survival, but only histology and presence of complications were significant for local-regional progression-free rate.

Purpose: This study was designed to evaluate a combined modality treatment for malignant gliomas using radiation therapy with a radiosensitizer and an adjuvant chemotherapy regimen designed to modify resistance to BNCU. Methods and Materials: Patients were eligible if they were 15 years of age or older, and had newly diagnosed glioblastoma multiforme (GBM), or anaplastic glioma (AG). Treatment consisted of external beam radiotherapy given to a dose of 60 Gy using a single daily fraction Monday to Friday. Concurrent hydroxyurea at a dose of 300 mg/m2 every 6 h every other day was given during radiation. Following radiotherapy, patients were then treated with BCNU and 6-Thioguanine (6TG). The 6-TG was given by mouth every 6 h for 12 doses prior to BCNU. Patients were initially treated with 60 mg/m2/dose of 6TG, with escalation to a maximum dose of 100 mg/m2/dose. The primary study end points were time to tumor progression and survival. Results: A total of 245 eligible patients were enrolled from 1/18/88 to 12/26/91. The histologic subtypes included 135 GBM, and 110 with AG (103 with anaplastic astrocytoma, 7 with high-grade mixed oligoastrocytoma). For the GBM group, the median time to tumor progression (TTP) and median survival were 33 (95% CI 26, 39) and 56 (95% CI 49, 69) weeks, respectively. For the AG group the median TTP was 282 weeks (95% lower confidence bound = 155 weeks). Median survival for this group has not been reached (95% lower confidence bound = 284 weeks) with a median follow-up for surviving patients of 298 weeks. A proportional hazards model was used to look at potential prognostic factors for survival, including initial Karnofsky Performance Scale (KPS), age, and extent of surgery, as well as dose of 6TG. Higher KPS, and lower age, predicted for longer survival (p < 0.01, < 0.001) in GBM patients; lower age was significant (p = 0.05) for AG cases. A higher (greater than 95 mg/m2) or lower dose of 6TG was not statistically significant in this model. Conclusions: This therapy was no more effective in patients with GBM than other reported series. In patients with malignant gliomas other than GBM, prolonged progression-free and overall survival is noted, without a median survival reached at the time of this report. In this subset of AG patients, survival is comparable to recent studies using halogenated prymidines during radiation and Procarbazine, CCNU, and Vincristine (PCV) as adjuvant chemotherapy.

Purpose Many cancer chemotherapeutic agents interact with radiation to enhance the amount of radiation damage observed in both tumor and normal tissues. It is important to predict this interaction and to determine the effect of drug on sublethal damage repair. To evaluate for effects in rapid renewing normal tissues, the intestinal crypt cell in vivo assay is an excellent one to employ. These studies investigate the effect of eleven cancer chemotherapeutic drugs on split-dose repair in the intestinal crypt cell of the mouse. Methods and materials LAF1 male mice, age 10-12 weeks, were exposed to whole-body irradiation with orthovoltage x-rays delivered as a single dose or as equally divided doses delivered with intervals between the two exposures of 2 to 24 h. In the experimental group, the cancer chemotherapeutic agent was administered intraperitoneally 2 h before the first radiation dose. At 3.6 days after the second irradiation, the mice were sacrificed; the jejunum was removed, fixed, and sectioned for light microscopy. The number of regenerating crypts were counted and corrected to represent the number of surviving cells per circumference. Results Of the eleven drugs tested, only carmustine eliminated split-dose repair. Cisplatin delayed repair, and methotrexate caused marked synchronization obliterating the observation of split-dose repair. Conclusions Most cytotoxic chemotherapeutic agents do not inhibit sublethal damage repair in intestinal crypt cells when given 2 h before the first radiation exposure. Absence of the initial increase in survival seen with split-dose radiation is noted with carmustine and high-dose methotrexate.

To evaluate the influence of fraction size, overall time, total dose, and other prognostic factors on local control of T1 and T2 glottic carcinomas.Between 1956 and 1995, 398 consecutive patients with early glottic carcinoma (315 T1 and 83 T2) were treated with once-a-day definitive radiotherapy at the University of California, San Francisco, and associated institutions. Treatment was delivered 5 days per week. Minimum tumor dose ranged from 46.6 to 77.6 Gy (median: 63 Gy). The fraction size was1.8 Gy in 146; 1.8-1.99 Gy in 128; 2.0-2.24 Gy in 62, andor = 2.25 Gy in 62 patients. Overall time ranged from 34 to 75 days (median: 50 days). The majority of patients treated with a fraction size of 2.25 Gy completed therapy within 43 days. Median follow-up of all alive patients was 116 months (range 3-436 months).Five-year local control was 85% for T1 and 70% for T2 glottic carcinomas (p = 0.0004). For T1 lesions, within the dose and time range evaluated, there was no apparent relationship between fraction size, overall time, total dose, and local control on multivariate analysis. Treatment era was the only significant prognostic factor (p = 0.02), and anterior commissure (AC) involvement was of borderline significance (p = 0.056). Five-year local control was 77% for patients treated between 1956-1970, 89% for between 1971-1980, and 91% for between 1981-1995; 80% for patients with AC involvement and 88% for those without. For T2 lesions, prognostic factors for local control on multivariate analysis were: overall time (p = 0.003), fraction size (p = 0.003), total dose (p = 0.01), impaired vocal cord mobility (p = 0.02), and subglottic extension (p = 0.04). Five-year local control was 100% for T2 lesions treated with overall timeor = 43 days vs. 84% for overall time43 days; 100% for fraction sizeor = 2.25 Gy vs. 44% for fraction size1.8 Gy; 78% for total dose65 Gy vs. 60% for total doseor = 65 Gy; 79% for normal cord mobility vs. 45% for impaired cord mobility, and 58% for lesions with subglottic extension vs. 77% for those without. The severe complication rate for the entire group was low: 1.8%.Total dose, fraction size, and overall time were significant factors for local control of T2 but not T1 glottic carcinomas. Anterior commissure involvement was associated with decreased local control for T1 but not T2 lesions. For T1 lesions, local control improved over the treatment era. For T2 lesions, local control decreased with impaired cord mobility and subglottic extension.

Promising results from new approaches such as radiosurgery or stereotactic surgery of brain metastases have recently been reported. Are these results due to the therapy alone or can the results be attributed in part to patient selection? An analysis of tumor/patient characteristics and treatment variables in previous Radiation Therapy Oncology Group (RTOG) brain metastases studies was considered necessary to fully evaluate the benefit of these new interventions.The database included 1200 patients from three consecutive RTOG trials conducted between 1979 and 1993, which tested several different dose fractionation schemes and radiation sensitizers. Using recursive partitioning analysis (RPA), a statistical methodology which creates a regression tree according to prognostic significance, eighteen pretreatment characteristics and three treatment-related variables were analyzed.According to the RPA tree the best survival (median: 7.1 months) was observed in patients65 years of age with a Karnofsky Performance Status (KPS) of at least 70, and a controlled primary tumor with the brain the only site of metastases. The worst survival (median: 2.3 months) was seen in patients with a KPS less than 70. All other patients had relatively minor differences in observed survival, with a median of 4.2 months.Based on this analysis, we suggest the following three classes: Class 1: patients with KPSor = 70,65 years of age with controlled primary and no extracranial metastases; Class 3: KPS70; Class 2- all others. Using these classes or stages, new treatment techniques can be tested on homogeneous patient groups.

To determine neovascular glaucoma (NVG) incidence and identify contributing tumor and dosing factors in uveal melanoma patients treated with proton beam radiation therapy (PBRT).A total of 704 PBRT patients treated by a single surgeon (DHC) for uveal melanoma (1996-2010) were reviewed for NVG in our prospectively maintained database. All patients received 56 GyE in 4 fractions. Median follow-up was 58.3 months. Analyses included the Kaplan-Meier method to estimate NVG distributions, univariate log-rank tests, and Cox's proportional hazards multivariate analysis using likelihood ratio tests to identify independent risk factors of NVG among patient, tumor, and dose-volume histogram parameters.The 5-year PBRT NVG rate was 12.7% (95% confidence interval [CI] 10.2%-15.9%). The 5-year rate of enucleation due to NVG was 4.9% (95% CI 3.4%-7.2%). Univariately, the NVG rate increased significantly with larger tumor diameter (P.0001), greater height (P.0001), higher T stage (P.0001), and closer proximity to the disc (P=.002). Dose-volume histogram analysis revealed that if30% of the lens or ciliary body received ≥50% dose (≥28 GyE), there was a higher probability of NVG (P.0001 for both). Furthermore, if 100% of the disc or macula received ≥28 GyE, the NVG rate was higher (P.0001 and P=.03, respectively). If both anterior and posterior doses were above specified cut points, NVG risk was highest (P.0001). Multivariate analysis confirmed significant independent risk factors to include tumor height (P.0001), age (P.0001), %disc treated to ≥50% Dose (100% vs 100%) (P=.0007), larger tumor diameter (P=.01), %lens treated to ≥90% Dose (0 vs0%-30% vs30%) (P=.01), and optic nerve length treated to ≥90% Dose (≤1 mm vs1 mm) (P=.02).Our current PBRT patients experience a low rate of NVG and resultant enucleation compared with historical data. The present analysis shows that tumor height, diameter, and anterior as well as posterior critical structure dose-volume parameters may be used to predict NVG risk.

Purpose: We defined the efficacy of radiotherapy for the treatment of high grade (Gleason scores 8 to 10) adenocarcinoma of the prostate.Materials and Methods: A total of 50 patients underwent radiotherapy with curative intent for clinically localized prostate cancer with Gleason scores of 8 to 10 at 1 of 4 facilities affiliated with the University of California San Francisco. Patients were considered to have biochemical failure if they had a significant increase in prostate specific antigen (PSA) of 0.5 ng./ml. per year, an increase in PSA to greater than 1.0 ng./ml. or a positive biopsy.Results: Among the 50 patients median PSA was 22.7 ng./ml. (range 1.3 to 93.4). Tumors were clinical stage T1 or T2 in 46 percent of the cases and stage T3 or T4 in 54 percent. The overall actuarial probability of freedom from biochemical failure at 4 years was 23 percent. In a multivariate analysis including all patients pretreatment PSA was the only predictor of PSA failure, with 64 percent free of progression ...

A retrospective review including long-term follow-up (4.6–12.0 years) was performed of all 28 pediatric patients who underwent high-activity 125I brachytherapy at the University of Californ

Purpose: To conduct a Phase II study to evaluate the long-term efficacy and safety of radiotherapy combined with intravenous bromodeoxyuridine for patients with anaplastic glioma tumors. Methods and Materials: Between 1983 and 1987, study patients received 1.7–1.8 Gy radiation once a day, Monday through Friday, to a toatl dose of 60 Gy. On the Thursday prior to beginning radiotherapy and for the next 5 weeks (6 weeks total), patients received a continuous 96 h intravenous infusion of bromodeoxyuridine at 0.8 g/m 2 /24 h; following radiotherapy, patients received procarbazine, lomustine (CCNU), and vincristine (PCV) for 1 year or until tumor progressed. Results: One-hundred thirty eight patients (median age, 43 years) were evaluated for analysis. Estimated 4-year survival for the anaplastic astrocytoma (AA) stratum ( n = 116) is 46%. For the astrocytoma (ASTRO) stratum ( n = 22), the 6-year survival is estimated at 79%. Estimated 4-year progression-free survival for AAs is 42%, and for ASTROs, 68%. Whole brain irradiation was used in 23% and limited-field irradiation in 77%; patients receiving limited-field irradiation had a better survival rate ( p = 0.07). Total tumor resection was performed in 15%, partial resection in 53%, and biopsy only in 32%. For the 81 patients with tumor recurrence, 34 (42%) are known to have received additional treatment(s). For AA, fits of the Cox proportional hazards regression model showed that covariates individually predictive of survival were younger age ( p p = 0.04), and extent of surgery ( p = 0.04); limited-field irradiation was not significant ( p = 0.10). Major toxicities were rash during Weeks 1 through 6 requiring dose modification in 14%, Garde ≥III leukopenia in 18%, and Grad ≥III thrombocytopeni in 9%. Conclusion: The study suggests that the bromodeoxyuridine-radiotherapy-PCV, compared with other published therapies, can improve progression-free survival, and aggressive treatment of ASTRO patients can lead to substantial increases in survival compared to published survival data.

One hundred patients, recently treated at the University of California, San Francisco (UCSF) with radiotherapy for lung and esophageal cancer, were studied. Three subsets of these patients were defined based on tumor location to test how commonly the use of three-dimensional (3D) conformal radiotherapy (3DCRT) could improve significantly the delivery of high dosages. Comparisons were made between isodose distributions and dose volume histograms (DVHs) of patients' prior computed tomography (CT)-based treatment plans and newly generated 3D-based treatment plans. The use of beam angles outside the conventional horizontal plane did not significantly improve the dose distribution for patients if a peripheral mass was the target volume. Patients with a target volume involving the central thorax represented a subset (>40% of the patients) who would have benefited the most from the use of nonconventional beam angles. In these patients, sagittal coplanar beams (sagittal Y technique) reduced the dose to 30% of the lung volume from 30% to 5%. Doses to the spinal cord and heart were slightly higher than with conventional techniques but were within the tolerance of normal tissues. The sagittal Y technique allows an escalation in total dose to the tumor without increasing dose to normal tissues beyond their tolerance.

PURPOSE: To assess whether laser-induced hyperthermia in conjunction with proton irradiation of choroidal melanoma may more rapidly decrease exudative retinal detachments. DESIGN: Case-control study. METHODS: This was a single-center prospective phase 1 study of choroidal melanoma patients with exudative retinal detachments. These tumors did not overhang the optic disc, involve the fovea, or have greater than 40% involvement of the ciliary body. Patients were treated with laser-induced hyperthermia and proton radiation; results were compared with those of similar patients treated at the same institution with only proton radiation. Patients were followed up in an identical manner for loss of subretinal fluid, visual acuity change, and visual field alterations. RESULTS: All 11 patients treated with combined laser and proton therapy had resorption of subretinal fluid with a mean duration of retinal detachment of 193 days, compared with 263 days in the group treated with only proton therapy (P

EBV genotypes of first- and second-generation Chinese diagnosed with nasopharyngeal carcinoma in the United States were analyzed by PCR techniques. Previous studies showed a geographical distribution of genotypically distinct sub-types of EBV. Viruses detected at a higher frequency among Chinese NPC patients (Cf) were distinguished from those found in the majority of Caucasian NPC patients (DF) in the United States by polymorphisms in the BamHI F and I regions. Exploiting this distinction, we analyzed the biopsies of Chinese immigrants in the United States for their C/D and F/f genotypes to evaluate the importance of retention of the Cf virus among Chinese NPC patients in a geographical area where the DF virus prevails. This study shows that approximately 45.5 to 50% of first- and second-generation Chinese NPC patients in California harbor the Cf virus, which is present in only 8% of Caucasian NPC patients in California. It is interesting that, while only 48% of the viral isolates from immigrant Chinese to California harbor the "f" variant, 96% harbor the type-C viruses.

Purpose: To study patterns of recurrence in patients with focal primary glioblastoma treated on Northern California Oncology Group protocol 6G-82-2 including surgery, focal external beam radiotherapy (59.4–60 Gy) with oral hydroxyurea followed by temporary brain implant with high-activity iodine-125 sources (50 Gy), and six cycles of chemotherapy with procarbazine, lomustine, and vincristine. Methods and Materials: Serial brain imaging scans were available for review in 25 of 34 patients with glioblastoma who underwent brain implant boost. Of 381 scans performed between the date of diagnosis and the date of death or last follow-up, 362 (95%) were re-reviewed. Disease progression was scored as local (within 2 cm of the implant site), separate within the brain parenchyma (⩾ 2 cm from the implant site), subependymal, or systemic. Both initial and subsequent failures were scored. Results: Three patients are 5-year survivors, without evidence of disease, at 267, 292, and 308 weeks. Of the 22 initial sites of failure, 17 (77%) were local, three (14%) were separate brain lesions (one of which was due in retrospect to multicentric disease at diagnosis), one (5%) subependymal, and one (5%) systemic. Five patients with local failure later had other sites of failure, including a separate brain lesion in 1, subependymal spread in 3, and both in 1. One patient with separate brain failure later had local progression and then subependymal spread. Conclusion: Although there was a significant risk of separate brain lesions or subependymal spread over time, local tumor progression was the predominant pattern of failure.

OBJECTIVE: The authors investigated the combined experience of a single institution in treating bile duct carcinoma during the modern era. SUMMARY BACKGROUND DATA: Bile duct carcinomas are notoriously difficult to cure, with locoregional recurrence the rule, even after radical resection. Adjuvant efforts have included various radiation modalities, with limited success. Recently, charged-particle radiotherapy has also been used in these patients. METHODS: The authors performed a retrospective chart analysis of 129 patients with bile duct adenocarcinomas treated between 1977 and 1987 through the University of California at San Francisco, including 22 patients treated at Lawrence Berkeley Laboratory with the charged particles helium and neon. The minimum follow-up was 5 years. Survival, outcome, and complication results were analyzed. RESULTS: Sixty-two patients were treated with surgery alone (S), 45 patients received conventional adjuvant x-ray radiotherapy (S + X), and 22 were treated with charged particles (S + CP). The median survival times were 6.5, 11, and 14 months, respectively, for the entire group, and 16, 16, and 23 months in patients treated with curative intent. There was a survival difference in patients undergoing total resection compared with debulking (p = 0.05) and minor resections (p = 0.0001). Patients with microscopic residual disease had increased median survival times when they were treated with adjuvant irradiation, most markedly after CP (p = 0.0005) but also with conventional X (p = 0.0109). Patients with gross residual disease had a less marked but still statistically significant extended survival (p = 0.05 for S + X and p = 0.0423 for S + CP) after irradiatio CONCLUSIONS: The mainstay of bile duct carcinoma management was maximal surgical resection in these patients. Postoperative radiotherapy gave patients with positive microscopic margins a significant survival advantage and may be of value in selected patients with gross disease.

Purpose : Although thermotolerance may be an important variable in clinical hyperthermia, few means have been described to measure its effect or duration in the clinical setting. This study was undertaken to determine if heat shock protein 70 could be used as an assay to predict the presence of retained thermotolerance in human tumors. Methods and Materials : Tissue samples were obtained from patients undergoing hyperthermia and assayed for heat shock protein 70 synthesis. Eight patients having advanced, persistent, or recurrent malignant tumors had open-ended thermometry catheters placed into the lesion being heated. Through these catheters, tissue samples were obtained using a fine needle aspiration technique. Attempts were made to obtain samples before and after the first three heat treatments. Some samples were labeled immediately with radioactive methionine (35S) at 37°C for 4–8 hr, others were given a test heat dose in vitro and then labeled. Protein synthesis profiles were analyzed by gel electrophoresis and autoradiography. Results : Preliminary results show that it is possible to obtain tissue from hyperthermia patients in a safe and practical manner, that the rate of heat shock protein 70 synthesis can be measured in a variety of tumors, and that the persistence of thermotolerance in the clinical setting can be shown by the inability to reinduce heat shock protein 70 synthesis. Conclusion : The measurement of heat shock protein 70 using the described technique may provide an assay for retained thermotolerance in clinical hyperthermia. Technical difficulties which need to be addressed include obtaining sufficient tissue in all patients, confirming the presence of tumor in the obtained tissue, and obtaining tissue at more frequent intervals to best determine the kinetics of thermotolerance.

Purpose: Evaluate the use of helium charged particle radiotherapy in the treatment of residual or unresectable meningioma adjacent to critical structures. Methods and Materials: Twenty-nine patients with meningioma of the skull base or spine were irradiated with helium charged particle radiotherapy at the University of California Lawrence Berkeley Laboratory (UCLBL) during the period 1981–1992. Twenty-six patients were treated for intracranial and three for spinal tumors. Total doses of 53.0–80.4 Gray equivalent (GyE) with a mean of 63 GyE were delivered using the helium ion beam. Results: Ten-year local control and survival rates calculated by the Kaplan-Meier product limit method were 84% and 80% respectively. Doses of 60.0 GyE were delivered with a low rate of complications. The only failures were in massive, recurrent tumors. Conclusion: High doses using helium charged particle radiotherapy can be safely and effectively delivered to large residual or unresectable meningioma near radiosensitive structures.

Background To investigate the safety and tolerability of ranibizumab combined with proton beam irradiation in treating exudative age-related macular degeneration. Methods Six eyes (6 subjects) with exudative age-related macular degeneration (4 newly diagnosed; 2 previous treated with ranibizumab) were treated with 4 monthly ranibizumab and 24 GyE proton beam irradiation (2 fractions, 24 hours apart) and seen monthly thereafter and retreated with ranibizumab for decrease in best-corrected visual acuity of ≥2 lines, new macular hemorrhage or fluid noted on optical coherence tomography. Results Follow-up ranged from 12 months to 36 months (mean, 28 months). Baseline best-corrected visual acuity ranged from 20/40 to 20/250. Final best-corrected visual acuity ranged from 20/25 to 20/400. No radiation retinopathy was noted in any eye. Calculated radiation distribution dose curves indicate that ≤10% of retina received ≥90% of radiation dose in all eyes. Two subjects lost ≥3 lines of best-corrected visual acuity during follow-up, 1 subject in both eyes from enlarging geographic atrophy and the other from worsening fibrovascular pigment epithelial detachment, which was refractory to multiple ranibizumab treatments before enrollment. Among 4 eyes with newly diagnosed exudative age-related macular degeneration, 3 had no fluid on optical coherence tomography at month 12 without further treatment. Conclusion No safety concerns were noted after 3 years in eyes with exudative age-related macular degeneration treated with ranibizumab combined with proton beam irradiation in this small pilot study. A larger randomized prospective study is under way to further evaluate this combination therapy.

Purpose: Optimal radiation therapy for uveal melanoma is uncertain, and the relative efficacies of radioactive plaques and charged particles are unclear. Methods: The authors prospectively studied helium-ion irradiation and iodine 125 ( 125 I) brachytherapy in a randomized, dynamically balanced trial. Of the 184 patients who met the eligibility criteria, 86 were treated with helium ions and 98 with 125 1 brachytherapy. Results: No patients with uveal melanoma had a history of systemic malignancy. Tumors were less than 15 mm in maximum diameter and less than 10 mm in thickness. A minimum tumor dose of 70 GyE was delivered to the tumor apex. There was a significantly higher local recurrence rate after 125 1 brachytherapy than after helium-ion irradiation. Enucleations occurred more frequently after brachytherapy (relative risk=1.99; 95% confidence interval, 0.78–5.78). More anterior segment complications occurred after helium-ion irradiation. To date, there has been no measurable impact on survival. Conclusions: Most uveal melanomas can be managed with radiation with retention of the eye. There was better tumor control with helium-ion irradiation; however, there were more anterior segment complications.

Purpose: To determine the rates of survival and local control in patients with bile duct adenocarcinomas treated with post-operative photons and/or charged particles. Methods and Materials: A retrospective study was performed analyzing all patients with bile duct adenocarcinomas who received radiotherapy through the University of California San Francisco and at Lawrence Berkeley Laboratory between 1977 and 1987, a total of 62 patients. University of California San Francisco patients received photon therapy (median dose 5400 cGy), and Lawrence Berkeley Laboratory patients were treated with the charged particles helium and/or neon (median dose 6000 cGyE). Forty-eight patients were treated post-operatively with curative intent, 30 with photons and 18 paticles. Thirty-six patients in the study had gross residual disease; none had microscopically negative margins. Results: The overall two-year actuarial survival was 28%: 44% for particle-treated patients and 18% for patients treated with photons ( p = .048). Median actuarial survival was 23 months in particle patients and 12 months in photon patients. Local control was also improved, though less significantly, in patients treated with particles (median disease-free survival 20 months vs. 4.5 months, p = .054). A univariate and multivariate analysis was performed and revealed that only extent of residual disease predicted local failure and overall survival; no other prognostic factors were identified. Conclusion: Compared to conventional photon radiotherapy, treatment with post-operative charged particle irradiation at Lawrence Berkeley Laboratory appeared to offer a survival advantage in this non-randomized series. Additional investigation into protection of surrounding normal tissue with better dose localization through the use of charged particles is planned.

Purpose: Episcleral 125I plaque therapy of uveal melanoma is an important treatment modality to control tumor, salvage the globe, and potentially preserve vision. We retrospectively analyzed our experience in 239 patients to assess treatment outcome with this technique. Methods and Materials: Between 1983 and 1990, 239 uveal melanoma patients were treated with 125I plaques at the University of California, San Francisco. High intensity 125I seeds in the range of 3–20 mCi were used to give a minimum tumor dose of 70 Gy in 4 days. Initial mean tumor size was 10.9 mm × 9.2 mm × 5.5 mm with a range in tumor diameter from 4 to 18 mm and tumor height from 1.9 to 11.1 mm. Best corrected pre-treatment visual acuity was 20/200 or better in 92% of patients. Results: Local tumor control was maintained in 91.7% of patients with a mean follow-up of 35.9 months; 19 patients had local tumor progression; mean time to progression was 27.3 mo (1.8 to 60.1 mo). Actuarial local control is 82% at 5 years. Multivariate analysis demonstrates significant correlation of local failure with larger maximum tumor diameter (p = 0.0008), closer proximity to the fovea (p = 0.0001), lower radiation dose (p = 0.0437), and smaller ultrasound height (p = 0.0034). The actuarial incidence of distant metastases is 12% at 5 years with multivariate analysis showing significant correlation only with maximum tumor diameter (p = 0.0064). Visual outcome is 20200 or better in 58% of patients. Conclusion: While the tumor control rates appear favorable, ocular morbidity is significant. A current randomized trial comparing 125I plaque with Helium ion therapy is in progress with specific comparison of tumor control, survival, and visual outcome.

Purpose: We tested the role of lipid peroxidation in the demyelination and white matter necrosis associated with radiation injury of the central nervous system. Methods and Materials: We irradiated the cervical spinal cords of female F344 rats (23 Gy) and assayed for the accumulation of the peroxidation byproducts malondialdehyde and hydroxyeicosatetraenoic acids, and for the consumption of the endogenous free radical scavengers vitamins E and C. We further tested the role of lipid peroxidation in radiation injury of the central nervous system by determining the sensitivity of the cervical spinal cord to radiation in rats on diets containing deficient, normal, and supplemental levels of the antioxidant vitamin E. Rats were placed on these diets at 4 weeks of age and irradiated (18.5-21.5 Gy) 16 weeks later. Results: During the 5 months between irradiation and the onset of paralysis, no accumulation of peroxidation byproducts or consumption of endogenous scavengers was seen in the cervical spinal cords of the irradiated rats. The cervical spinal cords of some of the rats placed on the diets with deficient, normal, and supplemental levels of vitamin E were analyzed at the time of irradiation and contained 197 ± 57, 501 ± 19, and 717 ± 35 pmol vitamin E/mg protein, respectively. Despite the statistical differences in these levels, the radiation sensitivity of the cervical spinal cord (ED5 50 for white matter necrosis) in rats receiving the three diets was not different (20.4, 20.7, and 20.6 Gy). Conclusion: These data do not support a role for free radical-induced lipid peroxidation in the white matter damage seen in radiation injury of the central nervous system.

The search continues for a favorable subgroup of patients with brain metastases in whom testing of new modalities might show a benefit in overall survival. Complete pre- and post-treatment CT evaluation of the brain was performed in 779 of the 859 patients entered into RTOG protocol 7916, a phase III study of the role of misonidazole combined with radiation therapy in the treatment of brain metastases. Pretreatment scan findings of mass effect, midline shift, massive edema, central necrosis, location of sentinel lesion, and number of lesions were correlated with length of survival for all patients as well as for each treatment group. The only characteristics that showed a statistically significant difference in survival in the overall group were the presence ofor = 3 lesions and the presence of a midline shift. The actual benefit in overall survival, however, was found to be only 3 weeks. The volume of the largest lesion prior to treatment did not correlate well with survival, nor did location of lesions. The time to response, number of responders and absolute decrease in number of lesions were similar for the four treatment arms. Patients who responded to cranial treatment had a significantly prolonged survival over those who did not respond. No CT characteristic evaluated in this study showed value as a clinically relevant prognosticator for patients with brain metastases for the overall group. Patients who fulfilled three of the four favorable clinical characteristics previously described by Diener-West (ageor = 60, KPSor = 70, primary lesion absent or controlled and brain as sole site of metastasis), were analyzed separately. Those withor = three lesions had a statistically significantly prolonged survival over those with four or more lesions.