Proton beam radiotherapy versus transarterial chemoembolization for hepatocellular carcinoma: Results of a randomized clinical trial.

BACKGROUND: This study compares survival rates, recurrence patterns, toxicity, and treatment cost in patients with hepatocellular carcinoma (HCC) treated with either transarterial chemoembolization (TACE) or proton beam radiotherapy (PBT). METHODS: Subjects with untreated HCC meeting Milan or San Francisco transplant criteria were recruited. Subjects were randomized to receive PBT (n = 36) or TACE (n = 40). Proton therapy was administered in 15 fractions over 3 weeks to a total dose of 70.2 Gy. TACE was repeated until complete or maximal response. The primary outcome measure was overall survival (OS). Secondary end points were progression-free survival (PFS), local control (LC), toxicity, and cost. RESULTS: Of the 76 randomized patients, 74 were assessed for outcome measures. The 2-year OS for PBT versus TACE was similar at 68%, 95% confidence interval (CI), 0.54-0.86, and 65%, 95% CI, 0.52-0.83 (p = .80), however, median PFS was improved for PBT versus TACE (not reached vs. 12 months, p = .002). LC was improved with PBT versus TACE (hazard ratio, 5.64; 95% CI, 1.78-17.9, p = .003). Days of posttreatment hospitalization were 24 for PBT and 166 for TACE (p < .001). Total mean cost per patient for treatment and posttreatment care revealed a 28% cost savings for PBT. CONCLUSIONS: PBT and TACE yielded similar OS for treatment of HCC, but PFS and LC were improved with PBT compared to TACE. Patients treated with PBT required fewer courses of treatment, fewer posttreatment hospitalization days, and reduced cost of treatment compared to TACE. These data support the use of PBT as a viable treatment alternative to TACE for patients with HCC within transplant criteria.

Association of Radiotherapy Duration With Clinical Outcomes in Patients With Esophageal Cancer Treated in NRG Oncology Trials: A Secondary Analysis of NRG Oncology Randomized Clinical Trials.

Importance: For many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes. Objective: To analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT). Design, Setting, and Participants: This study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy Oncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute-sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology Group). Enrolled patients with nonmetastatic esophageal cancer underwent definitive CRT in the trials between 1986 and 2013, with follow-up occurring through 2014. Data analyses were conducted between March 2022 to February 2023. Exposures: Treatment groups in the trials used standard-dose RT (50 Gy) and concurrent chemotherapy. Main Outcomes and Measures: The outcomes were local-regional failure (LRF), distant failure, disease-free survival (DFS), and overall survival (OS). Multivariable models were used to examine the associations between these outcomes and both RT duration and interruptions. Radiotherapy duration was analyzed as a dichotomized variable using an X-Tile software to choose a cut point and its median value as a cut point, as well as a continuous variable. Results: The analysis included 509 patients (median [IQR] age, 64 [57-70] years; 418 males [82%]; and 376 White individuals [74%]). The median (IQR) follow-up was 4.01 (2.93-4.92) years for surviving patients. The median cut point of RT duration was 39 days or less in 271 patients (53%) vs more than 39 days in 238 patients (47%), and the X-Tile software cut point was 45 days or less in 446 patients (88%) vs more than 45 days in 63 patients (12%). Radiotherapy interruptions occurred in 207 patients (41%). Female (vs male) sex and other (vs White) race and ethnicity were associated with longer RT duration and RT interruptions. In the multivariable models, RT duration longer than 45 days was associated with inferior DFS (hazard ratio [HR], 1.34; 95% CI, 1.01-1.77; P = .04). The HR for OS was 1.33, but the results were not statistically significant (95% CI, 0.99-1.77; P = .05). Radiotherapy duration longer than 39 days (vs ≤39 days) was associated with a higher risk of LRF (HR, 1.32; 95% CI, 1.06-1.65; P = .01). As a continuous variable, RT duration (per 1 week increase) was associated with DFS failure (HR, 1.14; 95% CI, 1.01-1.28; P = .03). The HR for LRF 1.13, but the result was not statistically significant (95% CI, 0.99-1.28; P = .07). Conclusions and Relevance: Results of this study indicated that in patients with esophageal cancer receiving definitive CRT, prolonged RT duration was associated with inferior outcomes; female patients and those with other (vs White) race and ethnicity were more likely to have longer RT duration and experience RT interruptions. Radiotherapy interruptions should be minimized to optimize outcomes.

Proton therapy for hepatocellular carcinoma.

Proton radiotherapy has seen an increasing role in the treatment of hepatocellular carcinoma (HCC). Historically, external beam radiotherapy has played a very limited role in HCC due to a high incidence of toxicity to surrounding normal structures. The ability to deliver a high dose of radiation to the tumor is a key factor in improving outcomes in HCC. Advances in photon radiotherapy have improved dose conformity and allowed dose escalation to the tumor. However, despite these advances there is still a large volume of normal liver that receives a considerable radiation dose during treatment. Proton beams do not have an exit dose along the beam path once they enter the body. The inherent physical attributes of proton radiotherapy offer a way to maximize tumor control via dose escalation while avoiding excessive radiation to the remaining liver, thus increasing biological effectiveness. In this review we discuss the physical attributes and rationale for proton radiotherapy in HCC. We also review recent literature regarding clinical outcomes of using proton radiotherapy for the treatment of HCC.

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

BACKGROUND: 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. METHODS: Patients with cirrhosis who had radiological features or biopsy-proven HCC were included in the study. Patients without cirrhosis and patients with extrahepatic metastasis were excluded. The mean age was 62.7 years. The mean tumor size was 5.5 cm. Eleven patients had multiple tumors, and 46% were within the Milan criteria. Patients received 63 Gy delivered over a 3-week period with PBT. RESULTS: Seventy-six patients were treated and followed prospectively for treatment outcomes at Loma Linda University Medical Center. Acute toxicity was minimal; all patients completed the full course of treatment. Radiation-induced liver disease was evaluated using liver enzyme, bilirubin, and albumin levels; no significant change supervened 6 months posttreatment. Median progression-free survival for the entire group was 36 months, with a 60% 3-year progression-free survival rate for patients within the Milan criteria. Eighteen patients subsequently underwent liver transplantation; 6 (33%) explants showed pathological complete response and 7 (39%) showed only microscopic residual. CONCLUSIONS: PBT was found to be a safe and effective local-regional therapy for inoperable HCC. A randomized controlled trial to compare its efficacy to a standard therapy has been initiated. Cancer 2011. © 2011 American Cancer Society.

Proton radiation therapy for lung cancer: is there enough evidence?

Proton radiation for cancer offers the ability to conform the high-dose region of radiation therapy to the tumor while reducing the dose of radiation to adjacent normal tissues. In lung cancer, this equates to greater sparing of uninvolved lung, heart, esophagus, and spinal cord. Sparing these normal tissues permits the delivery of higher-radiation doses to the tumor. Studies that compare the distribution of radiation doses for lung cancer show that proton radiation is superior, even when factors such as respiratory motion are considered. Clinical experience confirms the feasibility of proton radiation for early-stage non-small-cell lung cancers, and clinical trials are being conducted in locally advanced tumors: To date, evidence indicates that proton radiation should be further explored.

Hypofractionated Proton Therapy in Early Prostate Cancer: Results of a Phase I/II Trial at Loma Linda University.

PURPOSE: To determine whether a hypofractionated proton therapy regimen will control early-stage disease and maintain low rates of side effects similar to results obtained using standard-fraction proton therapy at our institution. MATERIALS AND METHODS: A cohort of 146 patients with low-risk prostate cancer according to National Comprehensive Cancer Network guidelines (Gleason score <7, prostate-specific antigen [PSA] <10, tumor stage of T1-T2a) received 60 Gy (cobalt Gy equivalent) of proton therapy (20 fractions of 3.0 Gy per fraction) in 4 weeks, a dose biologically equivalent to standard fractionation (44-45 fractions of 1.8 Gy to a total of 79.2 to 81 Gy in 0 weeks). Patients were evaluated at least weekly during treatment, at which time documentation of treatment tolerance and acute reactions was obtained. Follow-up visits were conducted every 3 months for the first 1 years, every 6 months for the next 3 years, then annually. Follow-up visits consisted of history and physical examination, PSA measurements, and evaluation of toxicity. RESULTS: The median follow-up time was 42 months (range, 3-96 months). Acute grade 2 urinary toxicity occurred in 16% (20/120) of the patients; acute grade 2 or higher gastrointestinal toxicity was seen in 1.7% (2/120). At 9 months, 1 patient had late grade 3 urinary toxicity, which resolved by 12 months; no grade 3 gastrointestinal toxicities occurred. The 3-year biochemical survival rate was 99.3% (144/145). The median time to PSA nadir was 30 months. CONCLUSION: Hypofractionated proton therapy of 60 Gy in 20 fractions was safe and effective for patients with low-risk prostate cancer.

Fractionated Proton Beam Therapy for Acoustic Neuromas: Tumor Control and Hearing Preservation.

PURPOSE: This prospective cohort evaluated patients with acoustic neuroma treated with proton irradiation at Loma Linda University Medical Center. A dose of 50.4 Gy in 28 fractions was given to improve hearing preservation while maintaining tumor control. PATIENTS AND METHODS: Ninety-five patients were treated from March 1991 to March 2008. Fractionated proton radiotherapy at daily doses of 1.8 Gy was employed. Patients were treated to 1 of 3 total doses: 59.4 Gy, used initially for patients without serviceable hearing; 54 Gy, used for patients with serviceable hearing through October 2000; and 50.4 Gy used since 2001 for patients with serviceable hearing. Survival and local control were calculated using the Kaplan-Meier method. Logistic regression analysis was preformed comparing dose, tumor size, and tumor location with hearing preservation. RESULTS: Ninety-four patients were assessable; the median follow-up was 64 months. Five-year local control rates for the 59.4 Gy, 54 Gy, and 50.4 Gy groups were 95%, 97%, and 92%, respectively (P = .80); the overall 10-year actuarial control rate was 90%. Cranial nerve injuries occurred in <5% in all groups. Four-year actuarial rates of hearing preservation were maintained in 44% of patients treated with 54 Gy and 64% treated with 50.4 Gy (P = .284). On multivariate analysis, initial tumor diameter (≤1.5 cm) was found to be a prognostic factor for maintaining serviceable hearing in both groups (P = .011). CONCLUSIONS: Fractionated proton therapy of 50.4 Gy offers excellent local control and minimal cranial nerve toxicities. Improved rates of hearing preservation that are comparable with radiosurgery were seen with 50.4 Gy compared with higher doses, although this did not reach significance. Maintaining hearing was found to be associated with smaller initial tumor size.

Improved long-term patient-reported health and well-being outcomes of early-stage breast cancer treated with partial breast proton therapy.

BACKGROUND: Because early-stage breast cancer can be treated successfully by a variety of breast-conservation approaches, long-term quality of life (QoL) is an important consideration in assessing treatment outcomes for these patients. This study compares patient-reported QoL outcomes among women with stage 0-2 disease treated via lumpectomy followed by whole breast irradiation (WBI) or partial breast proton irradiation (PBPT). METHODS: In this cross-sectional study, 129 participants evaluated QoL several years post-treatment by responding to subjective instruments, including established scalar questionnaires and self-report measures. Responses were averaged between the two groups. RESULTS: At 6.5 years (median) postdiagnosis, participants' demographic, and clinical characteristics were similar. Patient-reported outcomes were reported as mean scale scores for the two groups, all displaying significant differences favoring PBPT, including: cosmetic breast cancer treatment outcome scale (BCTOS) (PBPT mean 1.45, WBI mean 1.88, P < 0.001); breast pain (PBPT mean 1.30, WBI mean 1.67, P < 0.05); breast texture (BPT mean 1.44, WBI mean 1.91, P < 0.001); clothing fit (PBPT mean 1.06, WBI 1.46, P < 0.001); fatigue (PBPT mean 2.24, WBI mean 3.77, P < 0.002); impact of daily life fatigue on personal relations (OBPT mean 0.83, WBI mean 2.15, P < 0.001); and self-consciousness (appearance dissatisfaction) (PBPT mean 1.38, WBI mean 1.77, P < 0.004). CONCLUSION: Patients' responses suggest that PBPT is associated with improved overall QoL compared to standard whole breast treatment. These self-perceptions are reported by patients who are 5-10 years post-treatment, and that PBPT may enhance QoL in a multitude of interrelated ways.

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.

Proton radiation for treatment of cancer of the oropharynx: early experience at Loma Linda University Medical Center using a concomitant boost technique.

PURPOSE: To assess accelerated fractionation using photon and proton radiation to improve local control and reduce complications in treating locally advanced oropharyngeal cancer. METHODS AND MATERIALS: Twenty-nine patients with localized Stage II-IV oropharyngeal cancer received accelerated photon and proton radiation, 75.9 GyE in 45 fractions/5.5 weeks, to the primary disease, involved lymph nodes, and potential areas of subclinical spread. Follow-up ranged from 2 to 96 months. RESULTS: Five-year actuarial control for local disease was 88%, and for neck node disease, 96%; yielding a 84% locoregional control rate at 5 years. Four patients developed distant metastases. The 5-year actuarial locoregional control rate was 84%. The actuarial 2-year disease-free survival rate was 81%; at 5 years, it was 65%. All patients completed the prescribed treatment; though aggressive nutritional and anesthetic support was necessary. Late Grade 3 toxicity was seen in 3 patients. CONCLUSIONS: Protons used as a concomitant boost with photons effectively delivered an accelerated time-dose schedule to the cancer with a more tolerable schedule to surrounding normal tissues. Preliminary results reveal increased locoregional control without increased toxicity. Future studies must evaluate the optimum time-dose schedule.

Clinical immobilization techniques for proton therapy.

Proton therapy through the use of the Bragg peak affords clinicians a tool with which highly conformal dose can be delivered to the target while minimizing integral dose to surrounding healthy tissue. To gain maximum benefit from proton therapy adequate patient immobilization must be maintained to ensure accurate dose delivery. While immobilization in external beam radiation therapy is designed to minimize inter- and intra-fraction target motion, in proton therapy there are other additional aspects which must be considered, chief of which is accurately determining and maintaining the targets water-equivalent depth along the beam axis. Over the past 23 years of treating with protons, the team at the James M. Slater Proton Treatment and Research Center at Loma Linda University Medical Center have developed and implemented extensive immobilization systems to address the specific needs of protons. In this publication we review the immobilization systems that are used at Loma Linda in the treatment of head and neck, prostate, upper GI, lung and breast disease, along with a description of the intracranial radiosurgery immobilization system used in the treatment of brain metastasis and arteriovenous malformations (AVM's).

Time course of serum cytokines in patients receiving proton or combined photon/proton beam radiation for resectable but medically inoperable non-small-cell lung cancer.

PURPOSE: We prospectively measured the levels of basic fibroblast growth factor (bFGF), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, IL-10, and procollagen III peptide (P III P) in serum from non-small-cell lung cancer patients treated with photons combined with protons or protons alone. These factors were quantified because they may be extremely important in the development of side effects, and the treated volume integral dose may be crucial in inducing them. METHODS: Of the 12 participating patients, 6 with squamous cell carcinoma (SCC) and 3 with adenocarcinoma received combined photon/proton beam radiation, whereas 2 with SCC and 1 with large-cell carcinoma (LCC) received only proton radiation. Mean age was 73.6 years. There were 4 male and 8 female patients with a mean smoking history of 87.0 packyears. Nine patients had Stage I, 2 had Stage II, and 1 had stage IIIA lung cancer. Serum samples were obtained at baseline and on Days 15, 30, 45, 60, 90, 120, 150, 180, and 210 after initiation of radiation therapy. Injury scores for pneumonitis and fibrosis based on computed tomography (CT) scans were assigned. RESULTS: The percentage of lung volume irradiated was significantly less for patients treated with protons alone compared with those receiving photon plus proton therapy (p < 0.001). Injury scores were also lower for proton only treatment (p = 0.039). When evaluated collectively, bFGF, TNF-alpha, and IL-6 concentrations were significantly higher in the photon/proton group (p < 0.05 or less); radiation regimen, but not time after treatment initiation, was a significant factor in their levels. P III P level was also higher in the photon/proton patients (p < 0.001) and both radiation regimen (p = 0.027) and time after treatment (p = 0.019) had an impact. CONCLUSIONS: Although significant changes occurred in some of the measured cytokines and P III P, it was the difference in the volume integral dose that occurred when protons were used alone vs. mixed photon/proton therapy that correlated with the incidence of pneumonitis and/or fibrosis. However, it cannot be ruled out that differences in cytokine levels before radiotherapy initiation may have contributed to the outcome.

Proton therapy for prostate cancer: the initial Loma Linda University experience.

PURPOSE: We analyzed results of conformal proton radiation therapy for localized prostate cancer, with emphasis on biochemical freedom from relapse. METHODS AND MATERIALS: Analyses were performed for 1255 patients treated between October 1991 and December 1997. Outcomes were measured on primarily in terms of biochemical relapse and toxicity. RESULTS: The overall biochemical disease-free survival rate was 73%, and was 90% in patients with initial PSA

Hypofractionated proton beam radiotherapy for stage I lung cancer.

STUDY OBJECTIVES: To determine the efficacy and toxicity of high-dose hypofractionated proton beam radiotherapy for patients with clinical stage I lung cancer. DESIGN: A prospective phase 2 clinical trial. SETTING: Loma Linda University Medical Center. PATIENTS: Subjects with clinical stage I non-small cell lung cancer who were medically inoperable or refused surgery. INTERVENTIONS: All patients were treated with proton beam radiotherapy. The target included the gross tumor volume as seen on CT scan, with additional margin to allow for respiratory motion. A multibeam treatment plan was generated. Delivered treatment was 51 cobalt Gray equivalent (CGE) in 10 fractions over 2 weeks to the initial 22 patients; the subsequent 46 patients received 60 CGE in 10 fractions over 2 weeks. RESULTS: Sixty-eight patients were analyzed for this report, with a median follow-up time of 30 months. No cases of symptomatic radiation pneumonitis or late esophageal or cardiac toxicity were seen. The 3-year local control and disease-specific survival rates were 74%, and 72%, respectively. There was significant improvement in local tumor control in T1 vs T2 tumors (87% vs 49%), with a trend toward improved survival. Cox regression analysis revealed that patients with higher performance status, female gender, and smaller tumor sizes had significantly improved survival. CONCLUSION: High-dose hypofractionated proton beam radiotherapy can be administered safely, with minimal toxicity, to patients with stage I lung cancer. Local tumor control appears to be improved when compared to historical results utilizing conventional radiotherapy, with a good expectation of disease-specific survival 3 years following treatment.

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 cm(3). 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.

The prognostic value of percentage of positive biopsy cores, percentage of cancer volume, and maximum involvement of biopsy cores in prostate cancer patients receiving proton and photon beam therapy.

UNLABELLED: The purpose of this study was to compare the prognostic value of the percentage of positive biopsy cores (PPBC), the percentage of cancer volume (PCV), and the maximum involvement of biopsy cores (MIBC) as a prognostic factor in low- and intermediate-risk patients with clinically localized prostate cancer who received proton or photon beam therapy. Four hundred and fifty-nine patients with clinically localized prostate carcinoma who were treated with proton or photon beam therapy at Loma Linda University Medical Center were used for this analysis. Patients were treated with a median dose of 74.0 Gy (range 70.2-79.2) proton or combined proton/photon beam radiotherapy. Pathology reports were reviewed and PPBC, PCV, and MIBC were recorded. Analysis of biochemical no evidence of disease (bNED) outcome was assessed using Kaplan-Meier analyses. Cox regression multivariate analyses were performed to assess the impact of the biopsy factors on survival. RESULTS: 285, 291, and 291 patients had biopsy information available for analysis, respectively. Survival analysis showed that a higher PPBC, PCV, and MIBC were each individually associated with an increased risk of biochemical failure on univariate analysis (p < 0.01). Only PPBC and PCV were associated with an increased risk of biochemical failure on multivariate analysis, adjusting for age, NCCN risk group, and dose (p < 0.01). When isolating the intermediate-risk group, only PPBC and PCV were statistically significant on multivariate analysis. Multivariate analysis of the intermediate-risk group comparing PPBC and PCV showed that PPBC was not a significant predictor of biochemical failure, while PCV was a significant predictor of biochemical failure (p = 0.37 and p = 0.03, respectively). CONCLUSION: PPBC and PCV can potentially be used for additional risk stratification of intermediate-risk patients with PCV potentially being the most clinically relevant predictor bNED survival. MIBC was not found to have utility in the prognosis of low- and intermediate-risk patients.

Immobilization considerations for proton radiation therapy.

Proton therapy is rapidly developing as a mainstream modality for external beam radiation therapy. This development is largely due to the ability of protons to deposit much of their energy in a region known as the Bragg peak, minimizing the number of treatment fields and hence integral dose delivered to the patient. Immobilization in radiation therapy is a key component in the treatment process allowing for precise delivery of dose to the target volume and this is certainly true in proton therapy. In proton therapy immobilization needs to not only immobilize the patient, placing them in a stable and reproducible position for each treatment, but its impact on the depth dose distribution and range uncertainty must also be considered. The impact of immobilization on range is not a primary factor in X-ray radiation therapy, but it is a governing factor in proton therapy. This contribution describes the immobilization considerations in proton therapy which have been developed at Loma Linda over twenty plus years of clinical operation as a hospital based proton center.

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.

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.

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.