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This study investigated the appropriate dose prescription method in static multi-beam stereotactic body radiotherapy for lung tumors. Static multi-beam stereotactic body radiotherapy is a mainstream treatment in Japan. Based on the hypothesis that dose prescription to lower isodose lines may improve planning target volume dose coverage and decrease doses to organs at risk, we investigated changes in dose-volume histograms with prescription to various isodose lines for planning target volume in static multi-beam stereotactic body radiotherapy. In all treatment plans, 45 Gy in 4 fractions were prescribed to 95% of the planning target volume. By adjusting the leaf margins of each beam, various prescription isodose lines encompassing 95% volume of the planning target volume were generated. The prescription isodose lines investigated were 40, 50, 60, 70, 80 and 90% lines relative to the maximum dose of each planning target volume. The conformity index, homogeneity index, mean lung dose, and V5-V40 of the lung were evaluated. The dose was calculated by the adaptive convolve algorithm. The conformity index was lowest in the 70% or 80% isodose plan. The mean lung doses and V10-V40 of the lung decreased steeply from the 90% to the 70% isodose plan, and was lowest in the 60% and 70% isodose plans. These indices increased in the 40% and 50% isodose plans. The optimal stereotactic body radiotherapy plans appeared to be dose prescription to the 60% or 70% isodose line. Further investigation is warranted to clarify the advantage of using this method clinically.

Japanese national oncological experts convened to evaluate the efficacy and safety of particle beam therapy (PT) for pulmonary, liver and lymph node oligometastases (P-OM, L-OM and LN-OM, respectively) and to conduct a statistically comparative analysis of the local control (LC) rate and overall survival (OS) rate of PT versus those of X-ray stereotactic body radiotherapy (X-SBRT) and X-ray intensity-modulated radiotherapy (X-IMRT). They conducted [1] an analysis of the efficacy and safety of metastasis-directed therapy with PT for P-OM, L-OM and LN-OM using a Japanese nationwide multi-institutional cohort study data set; [2] a systematic review of X-ray high-precision radiotherapy (i.e. X-SBRT/X-IMRT) and PT for P-OM, L-OM and LN-OM; and [3] a statistical comparison between LC and OS of the cohort data set in PT and that of the extracted historical data set in X-SBRT/X-IMRT from the preceding systematic review. Safety was evaluated as the incidence of grade ≥ 3 adverse events, while statistical comparisons of LC and OS were conducted by estimating the incidence rate ratios (IRR) for local progression and mortality, respectively. This study demonstrated that PT provided durable LC (3-year LC rate: 72.8-83.2%) with acceptable OS (3-year OS rate: 38.5-68.1%) and risk of severe toxicity incidence of 0.8-3.5% in radical metastasis-directed therapy for P-OM, L-OM and LN-OM. Compared to LC with X-SBRT or X-IMRT, LC with PT was potentially superior for P-OM; superior for L-OM; and equivalent for LN-OM. In particular, this study demonstrated that PT may be a new treatment option for L-OM tumors measuring > 5 cm., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: This study evaluated the safety and efficacy of repeat SBRT for local recurrence of stage I non-small-cell lung cancer (NSCLC) and solitary lung metastasis., Methods: Thirty-one patients with in-field local relapse of NSCLC (n = 23) or lung metastasis (n = 8) underwent repeat SBRT. All patients had grade 2 or lower radiation pneumonitis after the first SBRT. Local recurrence was diagnosed with CT and FDG-PET in 17 patients and by biopsy in 14. The median interval between the first and second SBRT was 18 months (range, 4-80). The first SBRT dose was mainly 48-52 Gy in 4 fractions (n = 25) according to the institutional protocols. Second SBRT doses were determined based on the tumor size and distance to organs at risk, and were mostly 48-52 Gy in 4 fractions (n = 13) or 60 Gy in 8 fractions (n = 13)., Results: At 3 years, overall survival and local control rates were 36 and 53%, respectively, for all 31 patients. Four patients showed no further recurrence for > 5 years (63-111 months) after the second SBRT. Radiation pneumonitis after the second SBRT was grade 2 in 4 patients, and no grade 3 pneumonitis was observed., Conclusion: Repeat SBRT was safe. Local control and survival rates were higher than expected. SBRT should be an important treatment option for local recurrence of NSCLC or lung metastasis after previous local SBRT., Trial Registration: This retrospective study was approved by the ethics committee of our institution (September, 2017; approval number: 27-10).

Definitive radiotherapy is an important alternative treatment for meningioma patients who are inoperable or refuse surgery. We evaluated the efficacy and toxicity of CyberKnife-based stereotactic radiosurgery (SRS) and hypofractionated stereotactic radiotherapy (hSRT) as first-line treatments for intracranial meningiomas that were diagnosed using magnetic resonance imaging (MRI) and/or computed tomography (CT). Between February 2005 and September 2015, 41 patients with intracranial meningiomas were treated with CyberKnife-based SRS or hSRT. Eleven of those tumors were located in the skull base. The median tumor volume was 10.4 ml (range, 1.4-56.9 ml). The median prescribed radiation dose was 17 Gy (range, 13-20 Gy to the 61-88% isodose line) for SRS (n = 9) and 25 Gy (range, 14-38 Gy to the 44-83% isodose line) for hSRT (n = 32). The hSRT doses were delivered in 2 to 10 daily fractions. The median follow-up period was 49 months (range, 7-138). The 5-year progression-free survival rate (PFS) for all 41 patients was 86%. The 3-year PFS was 69% for the 14 patients with tumor volumes of ≥13.5 ml (30 mm in diameter) and 100% for the 27 patients with tumor volumes of <13.5 ml (P = 0.031). Grade >2 toxicities were observed in 5 patients (all of them had tumor volumes of ≥13.5 ml). SRS and hSRT are safe and effective against relatively small (<13.5 ml) meningiomas.

The aim of this study was to describe our initial experience with a gold flexible linear fiducial marker and to evaluate the safety and technical and clinical efficacy of stereotactic body radiotherapy using this marker for malignant liver tumors. Between July 2012 and February 2015, 18 patients underwent percutaneous fiducial marker placement before stereotactic body radiotherapy for malignant liver tumors. We evaluated the technical and clinical success rates of the procedure and the associated complications. Technical success was defined as successful placement of the fiducial marker at the target site, and clinical success was defined as the completion of stereotactic body radiotherapy without the marker dropping out of position. All 18 fiducial markers were placed successfully, so the technical success rate was 100% (18/18). All 18 patients were able to undergo stereotactic body radiotherapy without marker migration. Thus, the clinical success rate was 100% (18/18). Slight pneumothorax occurred as a minor complication in one case. No major complications such as coil migration or bleeding were observed. The examined percutaneous fiducial marker was safely placed in the liver and appeared to be useful for stereotactic body radiotherapy for malignant liver tumors., (© The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: Recurrent ependymomas were retreated with stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT). The efficacy, toxicities, and differences between SRS and FSRT were analyzed., Methods: Eight patients with recurrent ependymomas fulfilling the criteria described below were evaluated. Inclusion criteria were: (1) the patient had previously undergone surgery and conventional radiotherapy as first-line treatment; (2) targets were located in or adjacent to the eloquent area or were deep-seated; and (3) the previously irradiated volume overlapped the target lesion., Results: FSRT was delivered to 18 lesions, SRS to 20 lesions. A median follow-up period was 23 months. The local control rate was 76 % at 3 years. No significant differences in local control were observed due to tumor size or fractionation schedule. Lesions receiving >25 Gy/5 fr or 21 Gy/3 fr did not recur within 1 year, whereas no dose-response relationship was observed in those treated with SRS. No grade ≥2 toxicity was observed., Conclusion: Our treatment protocol provided an acceptable LC rate and minimal toxicities. Because local recurrence of tumors may result in patient death, a minimum dose of 21 Gy/3 fr or 25 Gy/5 fr or higher may be most suitable for treatment of these cases.

The aim of this study is to describe our initial experience with the VISICOIL, which is the first percutaneous fiducial marker approved for stereotactic body radiotherapy in Japan, and to evaluate its technical and clinical efficacy, and safety. Eight patients underwent this procedure under CT fluoroscopic guidance. One patient had two tumors, so the total number of procedures was nine. We evaluated the technical and clinical success rates of the procedure and the frequencies of complications. Technical success was defined as when the fiducial marker could be placed at the target site, and clinical success was defined as when stereotactic body radiotherapy could be performed without the marker dropping out of position. The technical success rate was 78% (7/9). In one of the two failed cases, we aimed to place the marker inside the tumor, but misplaced it beside the tumor. In the other failed case, we successfully placed the marker beside the tumor as planned; however, the marker migrated to near the pleura after the patient stopped holding their breath. None of the markers dropped out of place, so the clinical success rate was 100% (9/9). The complication rates were as follows: pneumothorax: 56% (5/9), pneumothorax necessitating chest tube placement: 44% (4/9), focal intrapulmonary hemorrhaging: 67% (6/9), hemoptysis: 11% (1/9), mild hemothorax 11% (1/9), air embolism 0% (0/9), and death 0% (0/9). In conclusion, this new percutaneous fiducial marker appears to be useful for stereotactic body radiotherapy due to its good stability.

Background: Organizing pneumonia (OP), so called bronchiolitis obliterans organizing pneumonia after postoperative irradiation for breast cancer has been often reported. There is little information about OP after other radiation modalities. This cohort study investigated the clinical features and risk factors of OP after stereotactic ablative radiotherapy of the lung (SABR)., Methods: Patients undergoing SABR between 2004 and 2010 in two institutions were investigated. Blood test and chest computed tomography were performed at intervals of 1 to 3 months after SABR. The criteria for diagnosing OP were: 1) mixture of patchy and ground-glass opacity, 2) general and/or respiratory symptoms lasting for at least 2 weeks, 3) radiographic lesion in the lung volume receiving < 0.5 Gy, and 4) no evidence of a specific cause., Results: Among 189 patients (164 with stage I lung cancer and 25 with single lung metastasis) analyzed, nine developed OP. The incidence at 2 years was 5.2% (95% confidence interval; 2.6-9.3%). Dyspnea were observed in all patients. Four had fever. These symptoms and pulmonary infiltration rapidly improved after corticosteroid therapy. Eight patients had presented with symptomatic radiation pneumonitis (RP) around the tumor 2 to 7 months before OP. The prior RP history was strongly associated with OP (hazard ratio 61.7; p = 0.0028) in multivariate analysis., Conclusions: This is the first report on OP after SABR. The incidence appeared to be relatively high. The symptoms were sometimes severe, but corticosteroid therapy was effective. When patients after SABR present with unusual pneumonia, OP should be considered as a differential diagnosis, especially in patients with prior symptomatic RP.

Since the dose delivery pattern in high-precision radiotherapy is different from that in conventional radiation, radiobiological assessment of the physical dose used in stereotactic irradiation and intensity-modulated radiotherapy has become necessary. In these treatments, the daily dose is usually given intermittently over a time longer than that used in conventional radiotherapy. During prolonged radiation delivery, sublethal damage repair takes place, leading to the decreased effect of radiation. This phenomenon is almost universarily observed in vitro. In in vivo tumors, however, this decrease in effect can be counterbalanced by rapid reoxygenation, which has been demonstrated in a laboratory study. Studies on reoxygenation in human tumors are warranted to better evaluate the influence of prolonged radiation delivery. Another issue related to radiosurgery and hypofractionated stereotactic radiotherapy is the mathematical model for dose evaluation and conversion. Many clinicians use the linear-quadratic (LQ) model and biologically effective dose (BED) to estimate the effects of various radiation schedules, but it has been suggested that the LQ model is not applicable to high doses per fraction. Recent experimental studies verified the inadequacy of the LQ model in converting hypofractionated doses into single doses. The LQ model overestimates the effect of high fractional doses of radiation. BED is particularly incorrect when it is used for tumor responses in vivo, since it does not take reoxygenation into account. For normal tissue responses, improved models have been proposed, but, for in vivo tumor responses, the currently available models are not satisfactory, and better ones should be proposed in future studies.

Purpose: To investigate the relationship between waiting time (WT) and disease progression in patients undergoing stereotactic body radiotherapy (SBRT) for lung adenocarcinoma (AD) or squamous cell carcinoma (SQ)., Methods and Materials: 201 patients with Stage I AD or SQ undergoing SBRT between January 2004 and June 2010 were analyzed. The WT was defined as the interval between diagnostic computed tomography before referral and computed tomography for treatment planning or positioning before SBRT. Tumor size was measured on the slice of the longest tumor diameter, and tumor volume was calculated from the longest diameter and the diameter perpendicular to it. Changes in tumor volume and TNM stage progression were evaluated, and volume doubling time (VDT) was estimated., Results: The median WT was 42 days (range, 5-323 days). There was a correlation between WT and rate of increase in volume in both AD and SQ. The median VDTs of AD and SQ were 170 and 93 days, respectively. Thirty-six tumors (23%) did not show volume increase during WTs >25 days. In 41 patients waiting for ≤4 weeks, no patient showed T stage progression, whereas in 25 of 120 (21%) patients waiting for >4 weeks, T stage progressed from T1 to T2 (p = 0.001). In 10 of 110 (9.1%) T1 ADs and 15 of 51 (29%) T1 SQs, T stage progressed (p = 0.002). N stage and M stage progressions were not observed., Conclusion: Generally, a WT of ≤4 weeks seems to be acceptable. The WT seems to be more important in SQ than in AD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the compliance of linear-quadratic (LQ) model calculations in the high-dose range as used in stereotactic irradiation in a murine tumor model., Methods and Materials: Female 10-week-old Balb/c mice bearing 1-cm-diameter EMT6 tumors in the hind legs were used. Single doses of 10-25 Gy were compared with 2-5 fractions of 4-13 Gy given at 4-hour intervals. Cell survival after irradiation was determined by an in vivo-in vitro assay. Using an α/β ratio determined for in vitro EMT6 cells and the LQ formalism, equivalent single doses for the hypofractionated doses were calculated. They were then compared with actually measured equivalent single doses for the hypofractionated doses. These fractionation schedules were also compared simultaneously to investigate the concordance/divergence of dose-survival curves plotted against actual radiation doses and biologically effective doses (BED)., Results: Equivalent single doses for hypofractionated doses calculated from LQ formalism were lower than actually measured doses by 21%-31% in the 2- or 3-fraction experiments and by 27%-42% in the 4- or 5-fraction experiments. The differences were all significant. When a higher α/β ratio was assumed, the discrepancy became smaller. In direct comparison of the 2- to 5-fraction schedules, respective dose-response curves almost overlapped when cell survival was plotted against actual radiation doses. However, the curves tended to shift downward by increasing the fraction number when cell survival was plotted against BED calculated using an α/β ratio of 3.5 Gy for in vitro EMT6 cells., Conclusion: Conversion of hypofractionated radiation doses to single doses using the LQ formalism underestimated the in vivo effect of hypofractionated radiation by approximately 20%-40%. The discrepancy appeared to be larger than that seen in the previous in vitro study and tended to increase with the fraction number. BED appeared to be an unreliable measure of tumor response., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The treatment schedules for stereotactic body radiotherapy (SBRT) for lung cancer vary from institution to institution. Several reports have indicated that stage IB patients had worse outcomes than stage IA patients when the same dose was used. We evaluated the clinical outcomes of SBRT for stage I non-small cell lung cancer (NSCLC) treated with different doses depending on tumor diameter., Methods: Between February 2004 and November 2008, 124 patients with stage I NSCLC underwent SBRT. Total doses of 44, 48, and 52 Gy were administered for tumors with a longest diameter of less than 1.5 cm, 1.5-3 cm, and larger than 3 cm, respectively. All doses were given in 4 fractions., Results: For all 124 patients, overall survival was 71%, cause-specific survival was 87%, progression-free survival was 60%, and local control was 80%, at 3 years. The 3-year overall survival was 79% for 85 stage IA patients treated with 48 Gy and 56% for 37 stage IB patients treated with 52 Gy (p = 0.05). At 3 years, cause-specific survival was 91% for the former group and 79% for the latter (p = 0.18), and progression-free survival was 62% versus 54% (p = 0.30). The 3-year local control rate was 81% versus 74% (p = 0.35). The cumulative incidence of grade 2 or 3 radiation pneumonitis was 11% in stage IA patients and 30% in stage IB patients (p = 0.02)., Conclusions: There was no difference in local control between stage IA and IB tumors despite the difference in tumor size. The benefit of increasing the SBRT dose for larger tumors should be investigated further.

Purpose: To investigate the reliability of the linear-quadratic (LQ) formalism and the magnitude of errors associated with its use in assessing biologic equivalence between single, high radiation doses and hypofractionated radiation doses., Methods and Materials: V79 and EMT6 single cells received single doses of 2-12 Gy or two or three fractions of 4 or 5 Gy, each at 4-h intervals. Single and fractionated doses to actually reduce the cell survival to the same level were determined by a colony assay. The alpha/beta ratio was obtained from the cell survival curves. Using the alpha/beta ratio and the LQ formalism, equivalent single doses for the hypofractionated doses were calculated. They were then compared with the actually determined equivalent single doses for the hypofractionated doses. The V79 spheroids received single doses of 5-26 Gy or two to five fractions of 5-12 Gy at 2 or 4-h interval, and then were assayed for cell survival. Next, equivalent single doses for the hypofractionated doses were determined, as were done for the single cells., Results: The alpha/beta ratio was 5.1 Gy for the V79 single cells and 0.36 Gy for EMT6. In V79, the equivalent single doses for the hypofractionated doses calculated using the LQ formalism were 12-19% lower than the actually measured biologically equivalent single doses. In the EMT6 cells, this trend was also seen, but the differences were not significant. In the V79 spheroids, the calculated doses were 18-30% lower than the measured doses., Conclusion: Conversion of hypofractionated radiation doses to single doses using the LQ formalism could underestimate the effect of hypofractionated radiation by < or =30%.

Background: In stereotactic body radiotherapy (SBRT) for lung tumors, reducing tumor movement is necessary. In this study, we evaluated changes in tumor movement and percutaneous oxygen saturation (SpO2) levels, and preliminary clinical results of SBRT using the BodyFIX immobilization system., Methods: Between 2004 and 2006, 53 consecutive patients were treated for 55 lesions; 42 were stage I non-small cell lung cancer (NSCLC), 10 were metastatic lung cancers, and 3 were local recurrences of NSCLC. Tumor movement was measured with fluoroscopy under breath holding, free breathing on a couch, and free breathing in the BodyFIX system. SpO2 levels were measured with a finger pulseoximeter under each condition. The delivered dose was 44, 48 or 52 Gy, depending on tumor diameter, in 4 fractions over 10 or 11 days., Results: By using the BodyFIX system, respiratory tumor movements were significantly reduced compared with the free-breathing condition in both craniocaudal and lateral directions, although the amplitude of reduction in the craniocaudal direction was 3 mm or more in only 27% of the patients. The average SpO2 did not decrease by using the system. At 3 years, the local control rate was 80% for all lesions. Overall survival was 76%, cause-specific survival was 92%, and local progression-free survival was 76% at 3 years in primary NSCLC patients. Grade 2 radiation pneumonitis developed in 7 patients., Conclusion: Respiratory tumor movement was modestly suppressed by the BodyFIX system, while the SpO2 level did not decrease. It was considered a simple and effective method for SBRT of lung tumors. Preliminary results were encouraging.

Purpose: In stereotactic irradiation using a linear accelerator, the effect of radiation may be reduced during intermittent exposures owing to recovery from sublethal damage in tumor cells. After our previous in vitro study suggesting this phenomenon, we investigated the issue in murine tumors., Methods and Materials: We used EMT6 and SCCVII tumors approximately 1 cm in diameter growing in the hind legs of syngeneic mice. Three schedules of intermittent radiation were investigated. First, 2 fractions of 10 Gy were given at an interval of 15-360 min to investigate the pattern of recovery from sublethal damage. Second, 5 fractions of 4 Gy were given with interfraction intervals of 2.5-15 min each. Third, 10 fractions of 2 Gy were given with interfraction intervals of 1-7 min each. Doses of 15-20 Gy were also given without interruption to estimate the dose-modifying factors. Tumors were excised 20 h later, and tumor cell survival was determined by an in vivo-in vitro assay., Results: In the 2-fraction experiment, the increase in cell survival with elongation of the interval was much less than that observed in our previous in vitro study. In the 5- and 10-fraction experiments, no significant increase in cell survival was observed after the intermittent exposures. Moreover, cell survival decreased at most points of the 5-fraction experiments by interruption of radiation in both EMT6 and SCCVII tumors. In the 10-fraction experiment, cell survival also decreased when the interruption was 3 or 7 min in EMT6 tumors., Conclusion: The results of the present in vivo studies were different from those of our in vitro studies in which cell survival increased significantly when a few minutes or longer intervals were posed between fractions. This suggests that recovery from sublethal damage in vivo may be counterbalanced by other phenomena such as reoxygenation that sensitizes tumor cells to subsequent irradiation.

Purpose: In stereotactic irradiation using a linear accelerator and intensity-modulated radiation therapy (IMRT), radiation is administered intermittently, and 30 min or longer is often required in one treatment session. The purpose of the present study was to determine how different the dose delivered with such intermissions is from that delivered continuously and to estimate dose-modifying factors., Methods and Materials: Murine EMT6 and SCCVII cells in culture were used. First, two doses of 4 Gy were given with an interruption of 15 min to 6 h or 1-10 min, or without interruption. Next, five fractions of 1.6 Gy were given with interfraction intervals of 1 to 5 min each. Doses of 6.5-8 Gy were also given without interruption to estimate dose-modifying factors. Cell survival was determined by a colony assay. Furthermore, a total dose of 2 Gy was given in 5 or 10 even fractions at intervals of 1-5 min or 30 s-3 min each, respectively, and the results were compared with those obtained after 1.6-2 Gy delivered continuously by using a cytokinesis-block micronucleus assay., Results: In the two-fraction experiments, a significant increase in cell survival resulting from recovery from sublethal damage (SLDR) was observed when the interruption time was 2 min or longer in EMT6 cells and 3 min or longer in SCCVII. With a 5-min interval, cell survival increased by 13% in EMT6 and by 18% in SCCVII. In the five-fraction experiments, SLDR was evident when the interfraction interval was 2 min or longer in both 8-Gy and 2-Gy dose experiments. In the 10-fraction experiment using a dose of 2 Gy, SLDR was evident when the interfraction interval was 1 min or longer. In the 5-fraction and 10-fraction experiments, the dose-modifying factors were between 1.08 and 1.16 when the total time for irradiation was between 20 and 30 min., Conclusions: The effects of stereotactic radiosurgery and IMRT that require considerably long beam interruption (e.g., 8 min or longer in total) may be less than those of the same dose administered continuously. In treatments that take 20 min or longer, dose modification appears necessary based on biologically estimated dose-modifying factors.