Haruko Numajiri

Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer

INTRODUCTION This study was conducted to determine disease control rates and prognostic factors associated with recurrence of centrally and peripherally located stage I NSCLC treated using high-dose PBT. PATIENTS AND METHODS Seventy-four patients with 80 centrally or peripherally located stage I NSCLCs were treated with PBT. A protocol using 72.6 Gy (RBE) in 22 fractions was used for centrally located tumors, and 66 Gy (RBE) in 10 or 12 fractions was used for peripherally located tumors. Data were collected and control rates and prognostic factors for recurrence were evaluated retrospectively. RESULTS The median follow-up period was 31.0 months. The overall survival, disease-specific survival, and progression-free survival rates were 76.7%, 83.0%, and 58.6% at 3 years, respectively. Disease recurrence was noted in 30 patients and local recurrence of 11 tumors occurred. The 3-year local control rate was 86.2% for stage IA tumors and 67.0% for stage IB tumors. Radiation dose was identified as a significant prognostic factor for disease recurrence and local recurrence. Tumor diameter and age were only significantly associated with disease recurrence. The 3-year local control rate was 63.9% for centrally located tumors irradiated with 72.6 Gy (RBE) and 88.4% for peripherally located tumors irradiated with 66 Gy (RBE). CONCLUSION Radiation dose was shown to be the most significant prognostic factor for tumor control in stage I NSCLC treated using high-dose PBT. Tumor diameter was not significant for local control. Further evaluation of PBT for centrally located tumors is warranted.

Proton beam therapy for pediatric malignancies: a retrospective observational multicenter study in Japan

Recent progress in the treatment for pediatric malignancies using a combination of surgery, chemotherapy, and radiotherapy has improved survival. However, late toxicities of radiotherapy are a concern in long‐term survivors. A recent study suggested reduced secondary cancer and other late toxicities after proton beam therapy (PBT) due to dosimetric advantages. In this study, we evaluated the safety and efficacy of PBT for pediatric patients treated in Japan. A retrospective observational study in pediatric patients who received PBT was performed. All patients aged <20 years old who underwent PBT from January 1983 to August 2014 at four sites in Japan were enrolled in the study. There were 343 patients in the study. The median follow‐up periods were 22.6 months (0.4–374.3 months) for all patients and 30.6 months (0.6–374.3 months) for survivors. The estimated 1‐, 3‐, 5‐, and 10‐year survival rates were 82.7% (95% CI: 78.5–87.0%), 67.4% (61.7–73.2%), 61.4% (54.8–67.9%), and 58.7% (51.5–65.9%), respectively. Fifty‐two events of toxicity ≥ grade 2 occurred in 43 patients. Grade 4 toxicities of myelitis, visual loss (two cases), cerebral vascular disease, and tissue necrosis occurred in five patients. This study provides preliminary results for PBT in pediatric patients in Japan. More experience and follow‐up with this technique are required to establish the efficacy of PBT in this patient population.

Long-term follow-up after proton beam therapy for pediatric tumors: a Japanese national survey

Proton beam therapy (PBT) is a potential new alternative to treatment with photon radiotherapy that may reduce the risk of late toxicity and secondary cancer, especially for pediatric tumors. The goal of this study was to evaluate the long‐term benefits of PBT in cancer survivors. A retrospective observational study of pediatric patients who received PBT was performed at four institutions in Japan. Of 343 patients, 62 were followed up for 5 or more years. These patients included 40 males and 22 females, and had a median age of 10 years (range: 0–19 years) at the time of treatment. The irradiation dose ranged from 10.8 to 81.2 GyE (median: 50.4 GyE). The median follow‐up period was 8.1 years (5.0–31.2 years). The 5‐, 10‐ and 20‐year rates for grade 2 or higher late toxicities were 18%, 35% and 45%, respectively, and those for grade 3 or higher late toxicities were 6%, 17% and 17% respectively. Univariate analysis showed that the irradiated site (head and neck, brain) was significantly associated with late toxicities. No malignant secondary tumors occurred within the irradiated field. The 10‐ and 20‐year cumulative rates for all secondary tumors, malignant secondary tumors, and malignant nonhematologic secondary tumors were 8% and 16%, 5% and 13%, and 3% and 11%, respectively. Our data indicate that PBT has the potential to reduce the risk of late mortality and secondary malignancy. Longer follow‐up is needed to confirm the benefits of PBT for pediatric tumors.

Long-term outcomes of proton beam therapy in patients with previously untreated hepatocellular carcinoma.

Long‐term efficacy of proton beam therapy (PBT) remains unclear for patients with previously untreated hepatocellular carcinoma (HCC). We aimed to study the long‐term outcomes of PBT according to Barcelona Clinic Liver Cancer (BCLC) staging classifications in patients with previously untreated HCC. The major eligibility criteria of this observational study were an Eastern Cooperative Oncology Group performance status (PS) 0–2, Child–Pugh grade A or B, previously untreated HCC covered within an irradiation field, and no massive ascites. A total of 66.0–77.0 GyE was administered in 10–35 fractions. Local tumor control (LTC), defined as no progression in the irradiated field, progression‐free survival (PFS), and overall survival (OS) were assessed according to BCLC staging. From 2002 to 2009 at our institution, 129 patients were eligible. The 5‐year LTC, PFS, and OS rates were 94%, 28%, and 69% for patients with 0/A stage disease (n = 9/21), 87%, 23%, and 66% for patients with B stage disease (n = 34), and 75%, 9%, and 25% for patients with C stage disease (n = 65), respectively. The 5‐year LTC and OS rates of 15 patients with tumor thrombi in major vessels were 90% and 34%, respectively. Multivariate analyses revealed that PS (0 versus 1–2) was a significant prognostic factor for OS. No grade 3 or higher adverse effects were observed. PBT showed favorable long‐term efficacies with mild adverse effects in BCLC stage 0 to C, and can be an alternative treatment for localized HCC especially when accompanied with tumor thrombi. This study was registered with UMIN Clinical Trials Registry (UMIN000025342).

Dose distribution resulting from changes in aeration of nasal cavity or paranasal sinus cancer in the proton therapy.

BACKGROUND AND PURPOSE Aeration in the nasal cavity and paranasal sinus (NCPS) was investigated during the course of proton therapy (PT), and the influence of aeration on the dose distribution was determined. MATERIAL AND METHODS Twenty patients with NCPS cancer (10 nasal cavity, 10 paranasal sinus) were analyzed. All the patients received a total proton beam irradiation dose of 38-78.4 Gray equivalents (GyE). Two to five CT examinations were performed during the course of treatment. The aeration ratio inside the cavity/sinus was calculated for each CT observation. Moreover, a simulation study supposing that the first treatment plan had been continued until the end of treatment was performed using the subsequent CT findings. RESULTS The aeration ratio was increased in 18 patients. The largest increase was from 15% to 82%. Three patients had a simulated maximum cumulative dose in the brainstem of beyond 60 GyE, while 10 patients had a simulated maximum cumulative dose in the optic chiasm of beyond 50 GyE. The shortest simulated time period to reach the dose limitation was 21 days. CONCLUSIONS Aeration in the NCPS is altered during the course of PT treatment and can greatly alter the dose distribution in the brainstem and optic chiasm.

Proton beam therapy for metastatic liver tumors

PURPOSE The purpose of this study was to investigate the safety and efficacy of proton beam therapy (PBT) for the treatment of metastatic liver tumors. MATERIAL AND METHODS A total of 140 patients with liver metastasis who received PBT were retrospectively investigated. The main primary tumor sites were the colorectum (60) and the pancreas (19). RESULTS One hundred thirty-three patients (95%) completed treatment. Two patients experienced late adverse effects (rib fracture and cholangitis). The 5-year overall survival (OS) rate was 24%. In the 85 patients with lesions confined to the liver, the 5-year OS rate of was 28%, and in the 55 patients with lesions both inside and outside the liver, it was 16% (P=0.007). Among the patients with lesions confined to the liver, the 5-year OS rate of the 62 patients who received curative treatment was 30%, and that of the 23 patients who received palliative treatment, 23% (P=0.016). Multivariate analysis showed that the treatment strategy (curative and palliative) alone was associated with the OS rate (P=0.02). CONCLUSION PBT is a potentially safe and effective treatment for metastatic liver tumors.

Association between pretreatment retention rate of indocyanine green 15 min after administration and life prognosis in patients with HCC treated by proton beam therapy.

PURPOSE The Child-Pugh score is often used to judge the outcome of radiotherapy for hepatocellular carcinoma (HCC). The retention rate of indocyanine green 15 min after administration (ICG R15) can also be used to predict prognosis after liver resection. We evaluated the utility of ICG R15 for prediction of outcomes after proton beam therapy (PBT) for HCC. METHODS AND MATERIALS A retrospective evaluation was performed in 250 patients who received PBT between 2002 and 2007. The patients (178 males and 72 females) had a median age of 71 years (range: 43-88). Child-Pugh categories were A (score 5-6), B (7-9), and C (10-15) in 197, 51, and 2 patients, respectively. ICG scores were 0-<10, 10-<20, 20-<30, 30-<40 and ⩾40 in 27, 99, 59, 28 and 37 patients, respectively; including 26, 92, 45, 16 and 18 Child-Pugh A patients and 1, 8, 14, 11, and 17 Child-Pugh B patients, respectively. Survival times from the start of PBT were compared between Child-Pugh A and B patients, and among each ICG group. RESULTS The median survival times were 61 months (95% CI: 50-72 months) in all patients, and 64 and 20 months in Child-Pugh A and B patients, respectively (p=0.001), The 3-year survival rates were 72%, 72%, 75%, 63%, and 26% in patients with ICG scores of 0-<10, 10-<20, 20-<30, 30-<40, and ⩾40 (p=0.001); 70%, 75%, 77%, 65%, and 38% in these respective groups in Child-Pugh A patients (p=0.02); and 100%, 57%, 67%, 36%, and 14% in Child-Pugh B patients (p=0.173, not significant). Multivariate analysis showed that low ICG R15 and the absence of portal vein tumor thrombus were associated with good survival. CONCLUSIONS Pretreatment ICG R15 is a useful prognostic factor for prediction of outcome of PBT in HCC patients, especially in those with Child-Pugh A liver function.

Comparison of dose–volume histograms between proton beam and X-ray conformal radiotherapy for locally advanced non-small-cell lung cancer

The purpose of this study was to compare the parameters of the dose–volume histogram (DVH) between proton beam therapy (PBT) and X-ray conformal radiotherapy (XCRT) for locally advanced non-small-cell lung cancer (NSCLC), according to the tumor conditions. A total of 35 patients having NSCLC treated with PBT were enrolled in this analysis. The numbers of TNM stage and lymph node status were IIB (n = 3), IIIA (n = 15) and IIIB (n = 17), and N0 (n = 2), N1 (n = 4), N2 (n = 17) and N3 (n = 12), respectively. Plans for XCRT were simulated based on the same CT, and the same clinical target volume (CTV) was used based on the actual PBT plan. The treatment dose was 74 Gy-equivalent dose (GyE) for the primary site and 66 GyE for positive lymph nodes. The parameters were then calculated according to the normal lung dose, and the irradiation volumes of the doses (Vx) were compared. We also evaluated the feasibility of both plans according to criteria: V5 ≥ 42%, V20 ≥ 25%, mean lung dose ≥ 20 Gy. The mean normal lung dose and V5 to V50 were significantly lower in PBT than in XCRT. The differences were greater with the more advanced nodal status and with the larger CTV. Furthermore, 45.7% of the X-ray plans were classified as inadequate according to the criteria, whereas 17.1% of the proton plans were considered unsuitable. The number of inadequate X-ray plans increased in cases with advanced nodal stage. This study indicated that some patients who cannot receive photon radiotherapy may be able to be treated using PBT.

Registration error of the liver CT using deformable image registration of MIM Maestro and Velocity AI

BackgroundUnderstanding the irradiated area and dose correctly is important for the reirradiation of organs that deform after irradiation, such as the liver. We investigated the spatial registration error using the deformable image registration (DIR) software products MIM Maestro (MIM) and Velocity AI (Velocity).MethodsImage registration of pretreatment computed tomography (CT) and posttreatment CT was performed in 24 patients with liver tumors. All the patients received proton beam therapy, and the follow-up period was 4–14 (median: 10) months. We performed DIR of the pretreatment CT and compared it with that of the posttreatment CT by calculating the dislocation of metallic markers (implanted close to the tumors).ResultsThe fiducial registration error was comparable in both products: 0.4–32.9 (9.3 ± 9.9) mm for MIM and 0.5–38.6 (11.0 ± 10.0) mm for Velocity, and correlated with the tumor diameter for MIM (r = 0.69, P = 0.002) and for Velocity (r = 0.68, P = 0.0003). Regarding the enhancement effect, the fiducial registration error was 1.0–24.9 (7.4 ± 7.7) mm for MIM and 0.3–29.6 (8.9 ± 7.2) mm for Velocity, which is shorter than that of plain CT (P = 0.04, for both).ConclusionsThe DIR performance of both MIM and Velocity is comparable with regard to the liver. The fiducial registration error of DIR depends on the tumor diameter. Furthermore, contrast-enhanced CT improves the accuracy of both MIM and Velocity.Institutional review board approvalH28-102; July 14, 2016 approved.

Proton beam therapy for a patient with a giant thymic carcinoid tumor and severe superior vena cava syndrome

Surgical resection is the first choice for treatment of a thymic carcinoid tumor and radiotherapy is often performed as adjuvant therapy. Here, we report a case of an unresectable and chemoresistant thymic carcinoid tumor that was treated successfully using standalone proton beam therapy (PBT). The patient was a 66-year-old woman in whom surgical resection of the tumor was impossible because of cardiac invasion. Therefore, chemotherapy was administered. However, the tumor grew to 15 cm in diameter and she developed severe superior vena cava (SVC) syndrome. She was referred to our hospital and received PBT at a dose of 74 GyE in 37 fractions. PBT was conducted without severe early toxicities. After PBT, the tumor mildly shrunk to 13 cm in diameter and SVC syndrome almost disappeared. Subsequently, the tumor has continued to decrease in size slowly over the last 2 years and late toxicities have not been observed. Our experience with this case suggests that PBT may be effective for an unresectable thymic carcinoid tumor.