Jerry D. Slater

Randomized Trial Comparing Conventional-Dose With High-Dose Conformal Radiation Therapy in Early-Stage Adenocarcinoma of the Prostate: Long-Term Results From Proton Radiation Oncology Group/American College of Radiology 95-09

PURPOSE To test the hypothesis that increasing radiation dose delivered to men with early-stage prostate cancer improves clinical outcomes. PATIENTS AND METHODS Men with T1b-T2b prostate cancer and prostate-specific antigen </= 15 ng/mL were randomly assigned to a total dose of either 70.2 Gray equivalents (GyE; conventional) or 79.2 GyE (high). No patient received androgen suppression therapy with radiation. Local failure (LF), biochemical failure (BF), and overall survival (OS) were outcomes. Results A total of 393 men were randomly assigned, and median follow-up was 8.9 years. Men receiving high-dose radiation therapy were significantly less likely to have LF, with a hazard ratio of 0.57. The 10-year American Society for Therapeutic Radiology and Oncology BF rates were 32.4% for conventional-dose and 16.7% for high-dose radiation therapy (P < .0001). This difference held when only those with low-risk disease (n = 227; 58% of total) were examined: 28.2% for conventional and 7.1% for high dose (P < .0001). There was a strong trend in the same direction for the intermediate-risk patients (n = 144; 37% of total; 42.1% v 30.4%, P = .06). Eleven percent of patients subsequently required androgen deprivation for recurrence after conventional dose compared with 6% after high dose (P = .047). There remains no difference in OS rates between the treatment arms (78.4% v 83.4%; P = .41). Two percent of patients in both arms experienced late grade >/= 3 genitourinary toxicity, and 1% of patients in the high-dose arm experienced late grade >/= 3 GI toxicity. CONCLUSION This randomized controlled trial shows superior long-term cancer control for men with localized prostate cancer receiving high-dose versus conventional-dose radiation. This was achieved without an increase in grade >/= 3 late urinary or rectal morbidity.

Methodologies and tools for proton beam design for lung tumors

PURPOSE Proton beams can potentially increase the dose delivered to lung tumors without increasing the dose to critical normal tissues because protons can be stopped before encountering the normal tissues. This potential can only be realized if tissue motion and planning uncertainties are correctly included during planning. This study evaluated several planning strategies to determine which method best provides adequate tumor coverage, minimal normal tissue irradiation, and simplicity of use. METHODS AND MATERIALS Proton beam treatment plans were generated using one or more of three different planning strategies. These strategies included designing apertures and boluses to the PTV, apertures to the PTV and boluses to the CTV, and aperture and bolus to the CTV. RESULTS The planning target volume as specified in ICRU Report 50 can be used only to design the lateral margins of beams, because the distal and proximal margins resulting from CT number uncertainty, beam range uncertainty, tissue motions, and setup uncertainties, are different than the lateral margins resulting from these same factors. The best strategy for target coverage with the planning tools available overirradiated some normal tissues unnecessarily. The available tools also made the planning of lung tumors difficult. CONCLUSIONS This study demonstrated that inclusion of target motion and setup uncertainties into a plan should be performed in the beam design step instead of creating new targets. New computerized treatment planning system tools suggested by this study will ease planning, facilitate abandonment of the PTV concept, improve conformance of the dose distribution to the target, and improve conformal avoidance of critical normal tissues.

Conformal proton radiation therapy for pediatric low-grade astrocytomas.

Background: To evaluate the safety and efficacy of proton radiation therapy (PRT) for intracranial low-grade astrocytomas, the authors analyzed the first 27 pediatric patients treated at Loma Linda University Medical Center (LLUMC). Patients and Method: Between September 1991 and August 1997, 27 patients (13 female, 14 male) underwent fractionated proton radiation therapy for progressive or recurrent low-grade astrocytoma. Age at time of treatment ranged from 2 to 18 years (mean: 8,7 years). Tumors were located centrally (diencephalic) in 15 patients, in the cerebral and cerebellar hemispheres in seven patients, and in the brainstem in five patients. 25/27 patients (92%) were treated for progressive, unresectable, or residual disease following subtotal resection. Tissue diagnosis was available in 23/27 patients (85%). Four patients with optic pathway tumors were treated without histologic confirmation. Target doses between 50.4 and 63.0 CGE (Cobalt Gray Equivalent, mean: 55.2 CGE) were prescribed at 1.8 CGE per fraction, five treatments per week. Results: At a mean follow-up period of 3.3 years (0.6–6.8 years), 6/27 patients experienced local failure (all located within the irradiated field), and 4/27 patients had died. By anatomic site these data translated into rates of local control and survival of 87% (13/15 patients) and 93% (14/15 patients) for central tumors, 71% (5/7 patients) and 86% (6/7 patients) for hemispheric tumors, and 60% (3/5 patients) and 60% (3/5 patients) for tumors located in the brainstem. Proton radiation therapy was generally well tolerated. All children with local control maintained their performance status. One child with associated neurofibromatosis, Type 1, developed Moyamoya disease. All six patients with optic pathway tumors and useful vision maintained or improved their visual status. Conclusions: This report on pediatric low-grade astrocytomas confirms proton radiation therapy as a safe and efficacious 3-D conformal treatment modality. Results are encouraging for central tumors as well as large optic pathway tumors, where dose conformity is of particular importance; yet it is difficult to achieve. Longer follow-up time is needed to fully evaluate the benefits of normal tissue sparing.Hintergrund: Mittels dieser Studie soll die Sicherheit und Effizienz der Protonentherapie (PRT) für niedrigmaligne Astrozytome bei Kindern (LGA) untersucht werden. Dabei wurden von den Autoren die ersten 27 pädiatrischen Patienten, die am Loma Linda University Medical Center (LLUMC) behandelt wurden, ausgewertet. Patienten und Methode: Zwischen September 1991 und August 1997 wurden 27 Patienten (13 Mädchen, 14 Jungen) wegen eines progredienten oder rezidivierenden niedriggradigen Astrozytoms mittels einer fraktionierten Protonentherapie behandelt. Zum Zeitpunkt der Behandlung variierte das Alter der Patienten zwischen 2 und 18 Jahren (Mean: 8,7 Jahre). Bei 15 Patienten lag der Tumor im Dienzephalon, bei sieben Patienten in den zerebralen oder zerebellaren Hemisphären und bei fünf Patienten im Hirnstamm. 25 der 27 Patienten (92%) wurden wegen Progress, Irresektabilität oder Resttumor nach subtotaler Entfernung behandelt. Die Diagnose war bei 23 von 27 Patienten histologisch verifiziert. Vier Patienten mit einem Tumor, der von den Sehnerven oder Sehbahnen ausging, wurden ohne histologische Diagnosesicherung behandelt. Im Zielvolumen wurden Dosen zwischen 50,4 und 63,0 CGE (Cobalt Gray Equivalent, Mean: 55,2 CGE) in Einzeldosen von 1,8 CGE verwendet. Die Behandlung erfolgte fünfmal pro Woche. Ergebnisse: Die mittlere Nachbeobachtungszeit betrug 3,3 Jahre (0,6–6,8 Jahre) Bei sechs von 27 Patienten trat ein lokales Tumorrezidiv auf (der Progress lag im Zielvolumen), und vier der Patienten verstarben an Tumorprogression. Aufgeschlüsselt nach der anatomischen Lage betrugen die lokale Kontrolle und das Überleben für die Patienten mit im Dienzephalon gelegenen Tumoren 87% (13/15 Patienten) und 93% (14/15 Patienten), für die mit in den Hemisphären gelegenen Tumoren 71% (5/7 Patienten) und 86% (6/7 Patienten) und für die mit im Hirnstamm gelegenen Tumoren 60% (3/5 Patienten) und 60% (3/5 Patienten). Die Protonentherapie wurde insgesamt gut von den Patienten toleriert. Keiner der lokal kontrollierten Patienten wies eine Verschlechterung des klinischen Zustands nach Bestrahlung auf. Ein Kind mit einer assoziierten Neurofibromatose Typ 1 entwickelte eine Moyamoya-Krankheit. Alle sechs Patienten mit einem Tumor des Sehnervs oder der Sehbahnen zeigten eine Stabilisierung oder Verbesserung ihrer Sehfähigkeit. Schlussfolgerung: Diese Studie belegt, dass die Protonentherapie eine sichere und effiziente 3 D-geplante konformale Therapiemöglichkeit darstellt. Die Ergebnisse sind vor allem bei zentral liegenden und ausgedehnten Tumoren, die vom Sehnerv oder den Sehbahnen ausgehen, ermutigend. Gerade bei diesen Tumoren ist eine hohe Konformalität der Dosisverteilung wichtig, die mit konventionellen strahlentherapeutischen Therapiemöglichkeiten nur schwer zu erreichen. Eine längere Nachbeobachtungszeit ist zur Untersuchung der Reaktion des Normalgewebes bei besserer Schonung desselben notwendig.

The proton treatment center at Loma Linda University Medical Center: Rationale for and description of its development

Proton radiation, a continuation of radiation oncologys historic search for an optimum dose distribution, offers superior characteristics for clinical radiation therapy. A complete facility for clinical proton radiation therapy has been designed for and constructed at Loma Linda University Medical Center. To bring about this achievement, a consortium of engineers, physicists, and physicians interested in the clinical applications of protons was necessary. The accelerator, the beam transport and delivery systems, the building, and the personnel who operate the system were all brought together to fully exploit the properties of protons for patient treatments, which are now underway.

Proton radiation therapy (prt) for pediatric optic pathway gliomas: comparison with 3d planned conventional photons and a standard photon technique

PURPOSE Following adequate therapy, excellent long-term survival rates can be achieved for patients with optic pathway gliomas. Therefore, avoidance of treatment-related functional long-term sequelae is of utmost importance. Optimized sparing of normal tissue is of primary concern in the development of new treatment modalities. The present study compares proton radiation therapy (PRT) with a three-dimensional (3D)-planned multiport photon and a lateral beam photon technique for localized and extensive optic pathway tumors. METHODS AND MATERIALS Between February 1992 and November 1997, seven children with optic pathway gliomas underwent PRT. For this study, we computed proton, 3D photon, and lateral photon plans based on the same CT data sets, and using the same treatment planning software for all plans. Radiation exposure for normal tissue and discrete organs at risk was quantified based on dose-volume histograms. RESULTS Gross tumor volume (GTV) ranged from 3.9 cm3 to 127.2 cm3. Conformity index (relation of encompassing isodose to GTV volume) was 2.3 for protons, 2.9 for 3D photons, and 7.3 for lateral photons. The relative increase of normal tissue (NT) encompassed at several isodose levels in relation to NT encompassed by the 95% proton isodose volume was computed. Relative NT volume of proton plan isodoses at the 95%, 90%, 80%, 50%, and 25% isodose level increased from 1 to 1.6, 2.8, 6.4, to a maximum of 13.3. Relative volumes for 3D photons were 1.6, 2.4, 3.8, 11.5, and 34.8. Lateral plan relative values were 6, 8.3, 11.5, 19.2, and 26.8. Analysis for small (<20 cm3) and larger (> 80 cm3) tumors showed that protons encompassed the smallest volumes of NT at all isodose levels. Comparable conformity and high-dose gradient were achieved for proton and 3D photon plans in small tumors. However, with increasing tumor volume and complexity, differences became larger. At the 50% isodose level, 3D photons were superior to lateral photons for small tumors; this advantage was equalized for larger tumors. At the lowest isodose level, 3D photons encompassed the highest amount of NT. Analysis of organs at risk showed that PRT reduced doses to the contralateral optic nerve by 47% and 77% compared to 3D photons and lateral photons, respectively. Reductions were also seen for the chiasm (11% and 16%) and pituitary gland (13% and 16%), with differences at clinically relevant tolerance levels. Furthermore, reduced dose exposure of both temporal lobes (sparing 39% and 54%) and frontal lobes was achieved with PRT. CONCLUSION PRT offered a high degree of conformity to target volumes and steep dose gradients, thus leading to substantial normal tissue sparing in high- and low-dose areas. It is expected that this will result in decreased long-term toxicity in the maturing child. Advantages of proton versus 3D photon plans became increasingly apparent with increasing target size and tumor complexity. Even in small tumors, conformity of 3D photon irradiation came at the expense of a larger amount of NT receiving moderate to low radiation doses. Lateral photons resulted in inferior dose distribution with high radiation exposure of clinically relevant normal tissues.

Proton radiotherapy in management of pediatric base of skull tumors

PURPOSE Primary skull base tumors of the developing child are rare and present a formidable challenge to both surgeons and radiation oncologists. Gross total resection with negative margins is rarely achieved, and the risks of functional, structural, and cosmetic deficits limit the radiation dose using conventional radiation techniques. Twenty-nine children and adolescents treated with conformal proton radiotherapy (proton RT) were analyzed to assess treatment efficacy and safety. MATERIALS AND METHODS Between July 1992 and April 1999, 29 patients with mesenchymal tumors underwent fractionated proton (13 patients) or fractionated combined proton and photon (16 patients) irradiation. The age at treatment ranged from 1 to 19 years (median 12); 14 patients were male and 15 female. Tumors were grouped as malignant or benign. Twenty patients had malignant histologic findings, including chordoma (n = 10), chondrosarcoma (n = 3), rhabdomyosarcoma (n = 4), and other sarcomas (n = 3). Target doses ranged between 50.4 and 78.6 Gy/cobalt Gray equivalent (CGE), delivered at doses of 1.8-2.0 Gy/CGE per fraction. The benign histologic findings included giant cell tumors (n = 6), angiofibromas (n = 2), and chondroblastoma (n = 1). RT doses for this group ranged from 45.0 to 71.8 Gy/CGE. Despite maximal surgical resection, 28 (97%) of 29 patients had gross disease at the time of proton RT. Follow-up after proton RT ranged from 13 to 92 months (mean 40). RESULTS Of the 20 patients with malignant tumors, 5 (25%) had local failure; 1 patient had failure in the surgical access route and 3 patients developed distant metastases. Seven patients had died of progressive disease at the time of analysis. Local tumor control was maintained in 6 (60%) of 10 patients with chordoma, 3 (100%) of 3 with chondrosarcoma, 4 (100%) of 4 with rhabdomyosarcoma, and 2 (66%) of 3 with other sarcomas. The actuarial 5-year local control and overall survival rate was 72% and 56%, respectively, and the overall survival of the males was significantly superior to that of the female patients (p = 0.002). Of the patients with benign tumors, 1 patient (giant cell tumor) had local failure at 10 months. The other 8 patients continued to have local tumor control; all 9 patients were alive at last follow-up (actuarial 5-year local control and overall survival rate of 89% and 100%, respectively). Severe late effects (motor weakness and sensory deficits) were observed in 2 (7%) of 29 patients. CONCLUSION Proton RT for children with aggressively recurring tumors after major skull base surgery can offer a considerable prospect of tumor control and survival. Longer follow-up is necessary to assess the real value of protons, in particular with regard to bone growth and cosmetic outcome.

Reducing toxicity from craniospinal irradiation: using proton beams to treat medulloblastoma in young children.

PURPOSEWe report on a radiation treatment technique that has reduced the dose to critical normal structures in children with medulloblastoma. PATIENTS AND METHODSThree children between the ages of 3 and 4 with stage M2 or M3 medulloblastoma were treated between 2001 and 2003 with craniospinal irradiation using protons. Patients received 36 cobalt gray equivalent to the craniospinal axis, then 18 cobalt gray equivalent to the posterior fossa. The cranium was treated with opposed lateral fields. The spine was treated with three matched posteroanterior fields, with the beam stopping just beyond the thecal sac. The posterior fossa was then treated with alternating posteroanterior, right posterior oblique, and left posterior oblique fields, with the beam stopping just proximal to the cochlea. The use of general anesthesia and pre-porting with diagnostic-quality x-rays allowed precise patient positioning. RESULTSCraniospinal irradiation delivered via conformal proton irradiation substantially reduced the dose to the cochlea and vertebral bodies and virtually eliminated the exit dose through thorax, abdomen, and pelvis. Despite concurrent chemotherapy, a clinically significant lymphocyte count reduction was not seen. Patients tolerated treatment well; acute side effects (e.g., nausea, decreased appetite, and odynophagia) were mild. All patients completed therapy without interruption. CONCLUSIONOur proton-beam technique for craniospinal irradiation of pediatric medulloblastoma has successfully reduced normal-tissue doses and acute treatment-related sequelae. This technique may be especially advantageous in children with a history of myelosuppression, who might not otherwise tolerate irradiation.

Proton radiation therapy for medium and large choroidal melanoma: preservation of the eye and its functionality

PURPOSE Evaluation of efficacy and safety of proton radiation therapy (PRT) for medium- and large-size choroidal melanoma with focus on preservation of the eye and its function. METHODS Retrospective review of 78 patients with 60 medium and 18 large-size choroidal melanomas at a median follow-up of 34 months. RESULTS The 5-year data for local control, metastases-free survival, and disease-specific survival were estimated to be 90.5 +/- 3.7%, 76.2 +/- 6.7%, and 75.6 +/- 7.6%, respectively. Eye preservation was achieved in 75.3% of patients, with useful (better than 20/200) visual acuity (VA) in 49.1% of surviving patients. Both local failure and complications led to enucleation. Prognosticators were tumor close to the optic disc (p = 0.003), large tumors involving the ciliary body (p = 0.041), and local failure (p < 0.001). Prognostic factors for VA following PRT were initial VA (p = 0.001), doses to optic disc (p = 0.001) and fovea (p = 0.022) higher than 35 CGE (Cobalt Gray equivalent), tumor close to the optic disc (p = 0.034), and retinal detachment (p < 0.001). Tumor basis diameter was significantly related to metastases free survival (p = 0.02), overall survival (p = 0.033), and disease specific survival (p = 0.017), but did not impair local tumor control, rate of enucleation, and VA. CONCLUSION The present data suggest that PRT is an effective and safe treatment for medium and large size choroidal melanoma. PRT can preserve the eye and its function in a reasonable percentage of patients. Further evaluation in controlled clinical trials comparing PRT to plaque radiotherapy and enucleation is required.

Conformal proton radiation therapy of the posterior fossa: a study comparing protons with three-dimensional planned photons in limiting dose to auditory structures

PURPOSE Conventional radiation therapy for pediatric posterior fossa tumors can cause sequelae such as hearing loss and impairments in language and learning. Modern three-dimensional (3D) treatment techniques have improved dose conformity to the posterior fossa. This report compares the normal tissue dose-sparing capabilities of proton radiation therapy (PRT) with 3D conformal photon plans. METHODS AND MATERIALS Nine children underwent previous PRT for primary CNS malignancies. Using original planning CT scans, the posterior fossa, inner and middle ear, and temporal lobes were delineated. Three-dimensional treatment plans were generated for protons and photons. Normal tissue exposures were calculated by averaging mean doses received and by analysis of dose-volume histogram. RESULTS The 95% isodose encompassed the posterior fossa in all plans. Normal structures received markedly less radiation from PRT plans than from 3D photon plans. The cochlea received an average mean of 25 +/- 4% of the prescribed dose from PRT, and 75 +/- 6% from photons. Forty percent of temporal lobe volume was completely excluded using protons; with photons 90% of the temporal lobe received 31% of the dose. CONCLUSION PRT resulted in increased dose sparing of normal structures analyzed. Posterior fossa conformity of 3D photons came at the expense of increasing amounts of normal tissue receiving low to moderate doses.

The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma: a phase 2 prospective trial

Proton beam therapy (PBT) may provide useful local‐regional treatment for hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the safety and efficacy of PBT for HCC.