Lilia N. Loredo

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.

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.

Phase I/II study of proton beam irradiation for the treatment of subfoveal choroidal neovascularization in age-related macular degeneration : Treatment techniques and preliminary results

PURPOSE Age-related macular degeneration is the prevalent etiology of subfoveal choroidal neovascularization (CNV). The only effective treatment is laser photocoagulation, which is associated with decreased visual acuity following treatment in most patients. This study assessed both the response of subfoveal CNV to proton beam irradiation and treatment-related morbidity. We evaluated preliminary results in patients treated with an initial dose of 8 Cobalt Gray Equivalents (CGE) using a relative biological effectiveness (RBE) of 1.1. METHODS AND MATERIALS Twenty-one patients with subfoveal CNV received proton irradiation to the central macula with a single fraction of 8 CGE; 19 were eligible for evaluation. Treatment-related morbidity was based on Radiation Therapy Oncology Group (RTOG) criteria; response was evaluated by Macular Photocoagulation Study (MPS) guidelines. Fluorescein angiography was performed; visual acuity, contrast sensitivity, and reading speed were measured at study entry and at 3-month intervals after treatment. Follow-up ranged from 6 to 15 months. RESULTS No measurable treatment-related morbidity was seen during or after treatment. Of 19 patients evaluated at 6 months, fluorescein angiography demonstrated treatment response in 10 (53%); 14 (74%) patients had improved or stable visual acuity. With a mean follow-up of 11.6 months, 11 (58%) patients have demonstrated improved or stable visual acuity. CONCLUSION A macular dose of 8 CGE yielded no measurable treatment morbidity in patients studied. Fluorescein angiography demonstrated that regressed or stabilized lesions were associated with improved visual acuity as compared with MPS results. In the next phase, a dose of 14 CGE in a single fraction will be used to further define the optimal dose fractionation schedule.

Combined proton and photon conformal radiation therapy for locally advanced carcinoma of the prostate: Preliminary results of a phase I II study

PURPOSE A study was developed to evaluate the use of combined photons and protons for the treatment of locally advanced carcinoma of the prostate. This report is a preliminary assessment of treatment-related morbidity and tumor response. METHODS AND MATERIALS One hundred and six patients in stages T2b (B2), T2c (B2), and T3 (C) were treated with 45 Gy photon-beam irradiation to the pelvis and an additional 30 Cobalt Gray Equivalent (CGE) to the prostate with 250-MeV protons, yielding a total prostate dose of 75 CGE in 40 fractions. Median follow-up time was 20.2 months (range: 10-30 months). Toxicity was scored according to the Radiation Therapy Oncology Group (RTOG) grading system; local control was evaluated by serial digital rectal examination (DRE) and prostate specific antigen (PSA) measurements. RESULTS Morbidity evaluation was available on 104 patients. The actuarial 2-year rate of Grade 1 or 2 late morbidity was 12% (8% rectal, 4% urinary). No patients demonstrated Grade 3 or 4 late morbidity. Treatment response was evaluated on 100 patients with elevated pretreatment serum PSA levels. The actuarial 2-year rate of PSA normalization was 96%, 97%, and 63% for pretreatment PSAs of > 4-10, > 10-20, and > 20, respectively. The 13 patients with rising PSA demonstrated local recurrence (3 patients), distant metastasis (8 patients), or no evidence of disease except increasing PSA (2 patients). CONCLUSIONS The low incidence of side effects, despite the tumor dose of 75 CGE, demonstrates that conformal protons can deliver higher doses of radiation to target tissues without increasing complications to surrounding normal tissues. The initial tumor response, as assessed by the high actuarial rate of normalization with pretreatment PSA < or = 20, and the low rate of recurrences within the treatment field (2.8%), are encouraging.

Proton therapy for pediatric cranial tumors: Preliminary report on treatment and disease-related morbidities

PURPOSE Accelerated protons were used in an attempt to limit treatment-related morbidity in children with tumors in or near the developing brain, by reducing the integral dose to adjacent normal tissues. METHODS AND MATERIALS Children treated with protons at Loma Linda University Medical Center between August 1991 and December 1994 were analyzed retrospectively. Twenty-eight children, aged 1 to 18 years, were identified as at risk for brain injury from treatment. Medical records, physical examinations, and correspondence with patients, their parents, and referring physicians were analyzed. The investigators tabulated post-treatment changes in pre-treatment signs and symptoms and made judgments as to whether improvement, no change, or worsening related to disease or treatment had supervened. Magnetic resonance images were correlated with clinical findings and radiographic impressions were tabulated. RESULTS Follow-up ranged from 7 to 49 months (median 25 months). Four instances of treatment-related morbidity were identified. Forty-one instances of site-specific, disease-related morbidity were identified: 15 improved or resolved and 26 remained unchanged after treatment. Four patients had radiographic evidence of local failure. Three of these patients, including two with high-grade glioma, have died. CONCLUSION Early treatment-related morbidity associated with proton therapy is low. Tumor progression remains a problem when treating certain histologies such as high-grade glioma. Escalating the dose delivered to target volumes may benefit children with tumors associated with poor rates of local control. Long-term follow-up, including neurocognitive testing, is in progress to assess integral-dose effects on cognitive, behavioral and developmental outcomes in children with cranial tumors.

Fractionated proton beam radiotherapy for acoustic neuroma.

OBJECTIVE This study evaluated proton beam irradiation in patients with acoustic neuroma. The aim was to provide maximal local tumor control while minimizing complications such as cranial nerve injuries. METHODS Thirty-one acoustic neuromas in 30 patients were treated with proton beam therapy from March 1991 to June 1999. The mean tumor volume was 4.3 cm3. All patients underwent pretreatment neurological evaluation, contrast enhanced magnetic resonance imaging, and audiometric evaluation. Standard fractionated proton radiotherapy was used at daily doses of 1.8 to 2.0 cobalt Gray equivalent: patients with useful hearing before treatment (Gardner-Robertson Grade I or II) received 54.0 cobalt Gray equivalent in 30 fractions; patients without useful hearing received 60.0 cobalt Gray equivalent in 30 to 33 fractions. RESULTS Twenty-nine of 30 patients were assessable for tumor control and cranial nerve injury. Follow-up ranged from 7 to 98 months (mean, 34 mo), during which no patients demonstrated disease progression on magnetic resonance imaging scans. Eleven patients demonstrated radiographic regression. Of the 13 patients with pretreatment Gardner-Robertson Grade I or II hearing, 4 (31%) maintained useful hearing. No transient or permanent treatment-related trigeminal or facial nerve dysfunction was observed. CONCLUSION Fractionated proton beam therapy provided excellent local control of acoustic neuromas when treatment was administered in moderate doses. No injuries to the Vth or VIIth cranial nerves were observed. A reduction in the tumor dose is being evaluated to increase the hearing preservation rate.

Surgery and radiotherapy: complementary tools in the management of benign intracranial tumors

Historically, radiation therapy has been used extensively in the treatment of malignant and aggressive intracranial tumors, and the importance of its role has been repeatedly verified by prolonged patient survival rates and increased tumor control. As more modern capabilities are employed in surgery and radiotherapy, attention is being directed to the utility of radiation as either primary or secondary treatment of benign tumors. Specifically, primary treatment encompasses irradiation of small benign tumors without biopsy confirmation of tumor type; secondary treatment involves postoperative radiation therapy, with the possibility that less-aggressive tumor resection may be performed in areas that have a higher probability of resultant neurological deficit. Current literature suggests that this is not only a possible treatment strategy, but that it may be superior to more radical resection in some cases, for example, in vestibular schwannomas and meningiomas. This article provides an overview of factors to consider in the use of radiation therapy and reviews the relationships between radiation and surgery, notably the unique complementary role each plays in the treatment of benign intracranial tumors.

Fractionated proton radiotherapy for benign cavernous sinus meningiomas.

PURPOSE To evaluate the efficacy of fractionated proton radiotherapy for a population of patients with benign cavernous sinus meningiomas. METHODS AND MATERIALS Between 1991 and 2002, 72 patients were treated at Loma Linda University Medical Center with proton therapy for cavernous sinus meningiomas. Fifty-one patients had biopsy or subtotal resection; 47 had World Health Organization grade 1 pathology. Twenty-one patients had no histologic verification. Twenty-two patients received primary proton therapy; 30 had 1 previous surgery; 20 had more than 1 surgery. The mean gross tumor volume was 27.6 cm(3); mean clinical target volume was 52.9 cm(3). Median total doses for patients with and without histologic verification were 59 and 57 Gy, respectively. Mean and median follow-up periods were 74 months. RESULTS The overall 5-year actuarial control rate was 96%; the control rate was 99% in patients with grade 1 or absent histologic findings and 50% for those with atypical histology. All 21 patients who did not have histologic verification and 46 of 47 patients with histologic confirmation of grade 1 tumor demonstrated disease control at 5 years. Control rates for patients without previous surgery, 1 surgery, and 2 or more surgeries were 95%, 96%, and 95%, respectively. CONCLUSIONS Fractionated proton radiotherapy for grade 1 cavernous sinus meningiomas achieves excellent control rates with minimal toxicities, regardless of surgical intervention or use of histologic diagnosis. Disease control for large lesions can be achieved by primary fractionated proton therapy.

Dose Response in the Treatment of Subfoveal Choroidal Neovascularization in Age-Related Macular Degeneration: Results of a Phase I/II Dose-Escalation Study Using Proton Radiotherapy

Approximately 20% of patients with subfoveal choroidal neovascularization qualify for laser photocoagulation, a treatment associated with both disease control and reduced visual acuity. No proved treatment exists for other patients. Single-fraction proton therapy was investigated as an alternative for two groups of patients: 21 patients received 8 GyE; 27 received 14 GyE. Follow-up by fluorescein angiography, visual acuity, contrast sensitivity, and reading speed were done (mean duration: 16 months). Actuarial lesion control at 21 months was 36% for 8-GyE patients and 89% for 14-GyE patients; 77% of patients with controlled lesions achieved improved/stable visual acuity, compared to 44% with uncontrolled lesions. Actuarial mean visual loss for proton-treated maculas was zero at 24 months. No treatment-related morbidity supervened, based on Radiation Therapy Oncology Group criteria. Proton therapy of 14 GyE in one fraction appears to be more effective in controlling neovascular macular degeneration than 8 GyE in one fraction, for both laser-ineligible and -eligible patients.