H. Iwata

Stereotactic body radiotherapy using a radiobiology-based regimen for stage I nonsmall cell lung cancer: a multicenter study.

The most common regimen of stereotactic body radiotherapy (SBRT) for stage I nonsmall cell lung cancer in Japan is 48 grays (Gy) in 4 fractions over 4 days. Radiobiologically, however, higher doses are necessary to control larger tumors, and interfraction intervals should be >24 hours to take advantage of reoxygenation. In this study, the authors tested the following regimen: For tumors that measured <1.5 cm, 1.5 to 3.0 cm, and >3.0 cm in greatest dimension, radiation doses of 44 Gy, 48 Gy, and 52 Gy, respectively, were given in 4 fractions with interfraction intervals of ≥3 days.

Hypofractionated stereotactic radiotherapy with CyberKnife for nonfunctioning pituitary adenoma: high local control with low toxicity

The aim was to evaluate the clinical outcome of hypofractionated stereotactic radiotherapy (SRT) with CyberKnife for nonfunctioning pituitary adenoma. From October 2000 to March 2009, 100 patients with nonfunctioning pituitary adenoma were treated with hypofractionated SRT. Forty-three patients were male, and 57 were female. The patients ages ranged from 16 to 82 years (median, 59 years). Five patients were medically inoperable, and 1 refused surgery; the remaining 94 were recurrent cases or those receiving postoperative adjuvant SRT. No patients had a history of previous cranial radiotherapy. Tumor volume ranged from 0.7 to 64.3 mL (median, 5.1 mL). The marginal doses were 17.0 to 21.0 Gy for the 3-fraction schedule and 22.0 to 25.0 Gy for the 5-fraction schedule. Toxicities were evaluated with the Common Terminology Criteria for Adverse Events version 4.0. The median follow-up period for living patients was 33 months (range, 18-118.5 months). The 3-year overall survival and local control rates were 98% and 98%, respectively. In-field and out-field tumor regrowth were observed in 3 and 2 patients, respectively. Transient cyst enlargement occurred in 3 cases. A post-SRT grade 2 visual disorder occurred in 1 patient. Symptomatic post-SRT hypopituitarism was observed in 3 of 74 patients who had not received hormone replacement therapy after surgery. CyberKnife SRT involving 21 Gy in 3 fractions or 25 Gy in 5 fractions is safe and effective for surgical treatment of nonfunctioning pituitary adenoma. Hypofractionated SRT appears useful for protecting the visual nerve and neuroendocrine function, especially for tumors located near the optic pathways and large tumors.

High‐dose proton therapy and carbon‐ion therapy for stage I nonsmall cell lung cancer

A study was undertaken to evaluate the clinical outcome of particle therapy for stage I nonsmall cell lung cancer (NSCLC).

Clinical outcomes of stereotactic body radiotherapy for stage I non-small cell lung cancer using different doses depending on tumor size

BackgroundThe 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.MethodsBetween 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.ResultsFor 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).ConclusionsThere 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.

Invasive Thymoma: Postoperative Mediastinal Irradiation, and Low-Dose Entire Hemithorax Irradiation in Patients with Pleural Dissemination

Introduction: We evaluated the results of postoperative mediastinal radiotherapy (MRT) for invasive thymoma and low-dose entire hemithorax radiotherapy (EHRT) for pleural dissemination. Methods: Sixty patients were treated with a nearly uniform policy. Generally, we administered 30 to 40 Gy MRT after surgery at 2 Gy daily fractions for Masaoka stage II tumors or suspected residual diseases, and 50 to 55 Gy MRT for stage III tumors and for highly-suspected or macroscopic residual diseases. Since 1992, we have administered EHRT in patients with pleural dissemination, with 11.2 Gy in 7 fractions or 15 to 16 Gy in 10 fractions after removal of disseminated lesions in addition to MRT. We treated 52 patients with MRT alone and 8 with EHRT and MRT. In addition, we gave EHRT to four patients who developed pleural dissemination later. Results: For all 60 patients, the overall and cause-specific survival and local and pleural-dissemination control rates at 5 years were 79, 87, 86, and 69%, respectively. Both Masaoka stage and tumor resectability were associated with prognosis. In stage IVa patients, pleural dissemination control rate was 71% at 3 years after EHRT, whereas it was 49% in patients receiving MRT alone (p = 0.38). Grade 2 or higher radiation pneumonitis was observed in only 3 of 52 patients (5.8%) undergoing MRT initially. In 12 patients who underwent EHRT, 3 patients (25%) experienced grade 2 or 4 pneumonitis. Conclusions: Postoperative MRT appeared to prevent local recurrence with acceptable toxicity. EHRT is generally safe and may contribute to control of pleural dissemination.

Estimation of Errors Associated With Use of Linear-Quadratic Formalism for Evaluation of Biologic Equivalence Between Single and Hypofractionated Radiation Doses: An In Vitro Study

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%.

Hypofractionated Stereotactic Body Radiotherapy for Primary and Metastatic Liver Tumors Using the Novalis Image-Guided System: Preliminary Results regarding Efficacy and Toxicity

The purpose of this study was to evaluate the efficacy and toxicity of stereotactic body radiotherapy (SBRT) for primary and metastatic liver tumors using the Novalis image-guided radiotherapy system. After preliminarily treating liver tumors using the Novalis system from July 2006, we started a protocol-based study in February 2008. Eighteen patients (6 with primary hepatocellular carcinoma and 12 with metastatic liver tumor) were treated with 55 or 50 Gy, depending upon their planned dose distribution and liver function, delivered in 10 fractions over 2 weeks. Four non-coplanar and three coplanar static beams were used. Patient age ranged from 54 to 84 years (median: 72 years). The Child-Pugh classification was Grade A in 17 patients and Grade B in 1. Tumor diameter ranged from 12 to 35 mm (median: 23 mm). Toxicities were evaluated according to the Common Terminology Criteria of Adverse Events version 4.0, and radiation-induced liver disease (RILD) was defined by Lawrences criterion. The median follow-up period was 14.5 months. For all patients, the 1-year overall survival and local control rates were 94% and 86%, respectively. A Grade 1 liver enzyme change was observed in 5 patients, but no RILD or chronic liver dysfunction was observed. SBRT using the Novalis image-guided system is safe and effective for treating primary and metastatic liver tumors. Further investigation of SBRT for liver tumors is warranted. In view of the acceptable toxicity observed with this protocol, we have moved to a new protocol to shorten the overall treatment time and escalate the dose.

Long-Term Outcome of Proton Therapy and Carbon-Ion Therapy for Large (T2a–T2bN0M0) Non–Small-Cell Lung Cancer

Introduction: Although many reports have shown the safety and efficacy of stereotactic body radiotherapy (SBRT) for T1N0M0 non–small-cell lung cancer (NSCLC), it is rather difficult to treat T2N0M0 NSCLC, especially T2b (>5 cm) tumor, with SBRT. Our hypothesis was that particle therapy might be superior to SBRT in T2 patients. We evaluated the clinical outcome of particle therapy for T2a/bN0M0 NSCLC staged according to the 7th edition of the International Union Against Cancer (UICC) tumor, node, metastasis classification. Methods: From April 2003 to December 2009, 70 histologically confirmed patients were treated with proton (n = 43) or carbon-ion (n = 27) therapy according to institutional protocols. Forty-seven patients had a T2a tumor and 23 had a T2b tumor. The total dose and fraction (fr) number were 60 (Gray equivalent) GyE/10 fr in 20 patients, 52.8 GyE/4 fr in 16, 66 GyE/10 fr in 16, 80 GyE/20 fr in 14, and other in four patients, respectively. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, Version 4.0. Results: The median follow-up period for living patients was 51 months (range, 24–103). For all 70 patients, the 4-year overall survival, local control, and progression-free survival rates were 58% (T2a, 53%; T2b, 67%), 75% (T2a, 70%; T2b, 84%), and 46% (T2a, 43%; T2b, 52%), respectively, with no significant differences between the two groups. The 4-year regional recurrence rate was 17%. Grade 3 pulmonary toxicity was observed in only two patients. Conclusion: Particle therapy is well tolerated and effective for T2a/bN0M0 NSCLC. To further improve treatment outcome, adjuvant chemotherapy seems a reasonable option, whenever possible.

Radiotherapy for metastatic brain tumors

Radiation therapy has been the most important treatment for patients with brain metastases. With the development of stereotactic irradiation, conventional radiotherapy is being employed less often. However, whole-brain radiation therapy (WBRT) is still the mainstay of treatment for multiple brain metastases. This article reviews the results of conventional radiotherapy for brain metastases, and discusses optimal treatment, including fractionation schedules and combination with stereotactic irradiation, and the effects on neurocognitive functions. The authors conclude that WBRT with 30 Gy in ten fractions is no longer optimal for every patient with multiple brain metastases. WBRT employing appropriate fractionation schedules with or without stereotactic boost should be considered, depending on the patient’s condition, disease status, and expected period of life.

Compatibility of the repairable-conditionally repairable, multi-target and linear-quadratic models in converting hypofractionated radiation doses to single doses

We investigated the applicability of the repairable-conditionally repairable (RCR) model and the multi-target (MT) model to dose conversion in high-dose-per-fraction radiotherapy in comparison with the linear-quadratic (LQ) model. Cell survival data of V79 and EMT6 single cells receiving single doses of 2–12 Gy or 2 or 3 fractions of 4 or 5 Gy each, and that of V79 spheroids receiving single doses of 5–26 Gy or 2–5 fractions of 5–12 Gy, were analyzed. Single and fractionated doses to actually reduce cell survival to the same level were determined by a colony assay. Single doses used in the experiments and surviving fractions at the doses were substituted into equations of the RCR, MT and LQ models in the calculation software Mathematica, and each parameter coefficient was computed. Thereafter, using the coefficients and the three models, equivalent single doses for the hypofractionated doses were calculated. They were then compared with actually-determined equivalent single doses for the hypofractionated doses. The equivalent single doses calculated using the RCR, MT and LQ models tended to be lower than the actually determined equivalent single doses. The LQ model seemed to fit relatively well at doses of 5 Gy or less. At 6 Gy or higher doses, the RCR and MT models seemed to be more reliable than the LQ model. In hypofractionated stereotactic radiotherapy, the LQ model should not be used, and conversion models incorporating the concept of the RCR or MT models, such as the generalized linear-quadratic models, appear to be more suitable.