Roger Grove

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.

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.

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.

High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center

PURPOSE We update our previous reports on the use of hypofractionated proton beam radiation therapy for early-stage lung cancer patients. METHODS AND MATERIALS Eligible subjects had biopsy-proven non-small cell carcinoma of the lung and were medically inoperable or refused surgery. Clinical workup required staging of T1 or T2, N0, M0. Subjects received hypofractionated proton beam therapy to the primary tumor only. The dose delivered was sequentially escalated from 51 to 60 Gy, then to 70 Gy in 10 fractions over 2 weeks. Endpoints included toxicity, pulmonary function, overall survival (OS), disease-specific survival (DSS), and local control (LC). RESULTS One hundred eleven subjects were analyzed for treatment outcomes. The patient population had the following average characteristics; age 73.2 years, tumor size 3.6 cm, and 1.33 L forced expiratory volume in 1 second. The entire group showed improved OS with increasing dose level (51, 60, and 70 Gy) with a 4-year OS of 18%, 32%, and 51%, respectively (P=.006). Peripheral T1 tumors exhibited LC of 96%, DSS of 88%, and OS of 60% at 4 years. Patients with T2 tumors showed a trend toward improved LC and survival with the 70-Gy dose level. On multivariate analysis, larger tumor size was strongly associated with increased local recurrence and decreased survival. Central versus peripheral location did not correlate with any outcome measures. Clinical radiation pneumonitis was not found to be a significant complication, and no patient required steroid therapy after treatment for radiation pneumonitis. Pulmonary function was well maintained 1 year after treatment. CONCLUSIONS High-dose hypofractionated proton therapy achieves excellent outcomes for lung carcinomas that are peripherally or centrally located. The 70-Gy regimen has been adopted as standard therapy for T1 tumors at our institution. Larger T2 tumors show a trend toward improved outcomes with higher doses, suggesting that better results could be seen with intensified treatment.

Partial Breast Radiation Therapy With Proton Beam: 5-Year Results With Cosmetic Outcomes

PURPOSE We updated our previous report of a phase 2 trial using proton beam radiation therapy to deliver partial breast irradiation (PBI) in patients with early stage breast cancer. METHODS AND MATERIALS Eligible subjects had invasive nonlobular carcinoma with a maximal dimension of 3 cm. Patients underwent partial mastectomy with negative margins; axillary lymph nodes were negative on sampling. Subjects received postoperative proton beam radiation therapy to the surgical bed. The dose delivered was 40 Gy in 10 fractions, once daily over 2 weeks. Multiple fields were treated daily, and skin-sparing techniques were used. Following treatment, patients were evaluated with clinical assessments and annual mammograms to monitor toxicity, tumor recurrence, and cosmesis. RESULTS One hundred subjects were enrolled and treated. All patients completed the assigned treatment and were available for post-treatment analysis. The median follow-up was 60 months. Patients had a mean age of 63 years; 90% had ductal histology; the average tumor size was 1.3 cm. Actuarial data at 5 years included ipsilateral breast tumor recurrence-free survival of 97% (95% confidence interval: 100%-93%); disease-free survival of 94%; and overall survival of 95%. There were no cases of grade 3 or higher acute skin reactions, and late skin reactions included 7 cases of grade 1 telangiectasia. Patient- and physician-reported cosmesis was good to excellent in 90% of responses, was not changed from baseline measurements, and was well maintained throughout the entire 5-year follow-up period. CONCLUSIONS Proton beam radiation therapy for PBI produced excellent ipsilateral breast recurrence-free survival with minimal toxicity. The treatment proved to be adaptable to all breast sizes and lumpectomy cavity configurations. Cosmetic results appear to be excellent and unchanged from baseline out to 5 years following treatment. Cosmetic results may be improved over those reported with photon-based techniques due to reduced breast tissue exposure with proton beam, skin-sparing techniques, and the dose fractionation schedule used in this trial.

Randomized Clinical Trial Comparing Proton Beam Radiation Therapy with Transarterial Chemoembolization for Hepatocellular Carcinoma: Results of an Interim Analysis.

PURPOSE To describe results of a planned interim analysis of a prospective, randomized clinical trial developed to compare treatment outcomes among patients with newly diagnosed hepatocellular carcinoma (HCC). METHODS AND MATERIALS Eligible subjects had either clinical or pathologic diagnosis of HCC and met either Milan or San Francisco transplant criteria. Patients were randomly assigned to transarterial chemoembolization (TACE) or to proton beam radiation therapy. Patients randomized to TACE received at least 1 TACE with additional TACE for persistent disease. Proton beam radiation therapy was delivered to all areas of gross disease to a total dose of 70.2 Gy in 15 daily fractions over 3 weeks. The primary endpoint was progression-free survival, with secondary endpoints of overall survival, local tumor control, and treatment-related toxicities as represented by posttreatment days of hospitalization. RESULTS At the time of this analysis 69 subjects were available for analysis. Of these, 36 were randomized to TACE and 33 to proton. Total days of hospitalization within 30 days of TACE/proton was 166 and 24 days, respectively (P<.001). Ten TACE and 12 proton patients underwent liver transplantation after treatment. Viable tumor identified in the explanted livers after TACE/proton averaged 2.4 and 0.9 cm, respectively. Pathologic complete response after TACE/proton was 10%/25% (P=.38). The 2-year overall survival for all patients was 59%, with no difference between treatment groups. Median survival time was 30 months (95% confidence interval 20.7-39.3 months). There was a trend toward improved 2-year local tumor control (88% vs 45%, P=.06) and progression-free survival (48% vs 31%, P=.06) favoring the proton beam treatment group. CONCLUSIONS This interim analysis indicates similar overall survival rates for proton beam radiation therapy and TACE. There is a trend toward improved local tumor control and progression-free survival with proton beam. There are significantly fewer hospitalization days after proton treatment, which may indicate reduced toxicity with proton beam therapy.

Dose response of rat retinal microvessels to proton dose schedules used clinically: a pilot study

PURPOSE This preclinical rat pilot study quantifies retinal microvessel, endothelial, and pericyte population changes produced by proton irradiation METHODS AND MATERIALS The left eyes of rats were irradiated with single doses of 8, 14, 20, and 28 Gy protons; right eyes, with two fractions. Animals were euthanized, and eyes were removed; elastase digests were prepared, and cell populations were counted in sample fields. Results were compared with unirradiated controls. RESULTS Progressive time- and dose-dependent endothelial cell loss occurred following all schedules. Cell loss was significantly different from control values (p < 0.001) following 28 Gy and following 20 Gy (p < 0.05) in a single dose. Endothelial cell loss was the same for single- and split-dose schedules. Progressive endothelial cell loss produced vessel collapse and acellular vessel strands. Endothelial cells were in the G(0) phase of the mitotic cycle. 28 Gy produced photoreceptor cell loss. CONCLUSION The retinal digest is an elegant bioassay to quantify the microvessel population response. Single- and split-dose schedules appear to yield similar outcomes, in terms of endothelial cell density.

Analysis of Intensity-Modulated Radiation Therapy (IMRT), Proton and 3D Conformal Radiotherapy (3D-CRT) for Reducing Perioperative Cardiopulmonary Complications in Esophageal Cancer Patients

Background. While neoadjuvant concurrent chemoradiotherapy has improved outcomes for esophageal cancer patients, surgical complication rates remain high. The most frequent perioperative complications after trimodality therapy were cardiopulmonary in nature. The radiation modality utilized can be a strong mitigating factor of perioperative complications given the location of the esophagus and its proximity to the heart and lungs. The purpose of this study is to make a dosimetric comparison of Intensity-Modulated Radiation Therapy (IMRT), proton and 3D conformal radiotherapy (3D-CRT) with regard to reducing perioperative cardiopulmonary complications in esophageal cancer patients. Materials. Ten patients with esophageal cancer treated between 2010 and 2013 were evaluated in this study. All patients were simulated with contrast-enhanced CT imaging. Separate treatment plans using proton radiotherapy, IMRT, and 3D-CRT modalities were created for each patient. Dose-volume histograms were calculated and analyzed to compare plans between the three modalities. The organs at risk (OAR) being evaluated in this study are the heart, lungs, and spinal cord. To determine statistical significance, ANOVA and two-tailed paired t-tests were performed for all data parameters. Results. The proton plans showed decreased dose to various volumes of the heart and lungs in comparison to both the IMRT and 3D-CRT plans. There was no difference between the IMRT and 3D-CRT plans in dose delivered to the lung or heart. This finding was seen consistently across the parameters analyzed in this study. Conclusions. In patients receiving radiation therapy for esophageal cancer, proton plans are technically feasible while achieving adequate coverage with lower doses delivered to the lungs and cardiac structures. This may result in decreased cardiopulmonary toxicity and less morbidity to esophageal cancer patients.

Quantification of Rat Retinal Growth and Vascular Population Changes after Single and Split Doses of Proton Irradiation: Translational Study Using Stereology Methods

Abstract Mao, X. W., Archambeau, J. O., Kubínová, L., Boyle, S., Petersen, G. and Grove, R. Quantification of Rat Retinal Growth and Vascular Population Changes after Single and Split Doses of Proton Irradiation: Translational Study Using Stereology Methods. Radiat. Res. 160, 5–13 (2003). This study quantified architectural and population changes in the rat retinal vasculature after proton irradiation using stereology. A 100 MeV conformal proton beam delivered 8, 14, 20 and 28 Gy as single and split doses to the whole eye. The vascular networks were prepared from retinal digests. Stereological methods were used to obtain the area of the retina and unbiased estimates of microvessel/artery/vein endothelial, pericyte and smooth muscle population, and vessel length. The retinal area increased progressively in the unirradiated, age-matched controls and in the retinas irradiated with 8 and 14 Gy, indicating uniform progressive retinal growth. No growth occurred after 20 and 28 Gy. Regression analysis of total endothelial cell number in all vessels (arteries, veins and capillaries) after irradiation documented a progressive time- and dose-dependent cell loss occurring over 15 to 24 months. The difference from controls was significant (P < 0.01) after 28 Gy given in single and split doses and after 20 Gy given as a split dose (P < 0.05). Total vessel length in microvessel was significantly shortened at 20 and 28 Gy compared to that of controls (P < 0.05). No evident dose recovery was observed in the endothelial populations after split doses. At 10 Gy, the rate of endothelial cell loss, a dose parameter used to characterize the time- and dose-dependent loss of the endothelial population, was doubled.

Evaluation of normal tissue exposure in patients receiving radiotherapy for pancreatic cancer based on RTOG 0848

BACKGROUND Pancreatic cancer is a highly aggressive malignancy. Chemoradiotherapy (CRT) is utilized in many cases to improve locoregional control; however, toxicities associated with radiation can be significant given the location of the pancreas. RTOG 0848 seeks to evaluate chemoradiation using either intensity-modulated radiation therapy (IMRT) or 3D conformal photon radiotherapy (3DCRT) modalities as an adjuvant treatment. The purpose of this study is to quantify the dosimetric changes seen when using IMRT or 3D CRT photon modalities, as well as proton radiotherapy, in patients receiving CRT for cancer of the pancreas treated per RTOG 0848 guidelines. MATERIALS Ten patients with pancreatic head adenocarcinoma treated between 2010 and 2013 were evaluated in this study. All patients were simulated with contrast-enhanced CT imaging. Separate treatment plans using IMRT and 3DCRT as well as proton radiotherapy were created for each patient. All planning volumes were created per RTOG 0848 protocol. Dose-volume histograms (DVH) were calculated and analyzed in order to compare plans between the three modalities. The organs at risk (OAR) evaluated in this study are the kidneys, liver, small bowel, and spinal cord. RESULTS There was no difference between the IMRT and 3DCRT plans in dose delivered to the kidneys, liver, or bowel. The proton radiotherapy plans were found to deliver lower mean total kidney doses, mean liver doses, and liver D1/3 compared to the IMRT plans. The proton plans also gave less mean liver dose, liver D1/3, bowel V15, and bowel V50 in comparison to the 3DCRT. CONCLUSIONS For patients receiving radiotherapy per ongoing RTOG 0848 for pancreatic cancer, there was no significant difference in normal tissue sparing between IMRT and 3DCRT treatment planning. Therefore, the choice between the two modalities should not be a confounding factor in this study. The proton plans also demonstrated improved OAR sparing compared to both IMRT and 3DCRT treatment plans.