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In Asia, several challenges hinder the delivery of high-quality cancer treatment, especially radiation therapy (RT). Many Asian countries face large-scale shortage of RT centres and treatment machines. Additionally, there is also a significant technological gap, with many RT centres in Asia still using outdated technology. There is an urgent need to improve radiation treatment quality in Asia. The Federation of Asian Organizations for Radiation Oncology (FARO) was set up to foster regional collaboration, which we believe can help to identify and solve some of these issues collectively. This report describes the background and rationale of starting FARO, and puts forth some of the early achievements of the group, including fact-finding and educational activities. Finally, we discuss future possibilities, including strategic proposals that may benefit the RT community and our patients in Asia.

Aim: To establish a method of plan optimization in pelvic volumetric-modulated arc therapy (VMAT) for cervical cancer using the central-shielding (CS) principle. Patients and Methods: We created external beam VMAT plans for eight cases with non-bulky stage I-IIb using the CS principle based on the Japanese standard guideline. Clinical target volumes (CTVs) for whole-pelvis (WP) irradiation were created using published guidelines, and CTVs for CS irradiation were created by subtracting the uterus corpus and 4 cm-wide regions centered at the cervix and vagina from the CTVs for WP irradiation. For plan optimization of CS irradiation, a 4-cm diameter cylindrical volume centered in the cervix and vagina was created as the volume receiving a high dose in brachytherapy, and the volume overlapping with the rectum was defined as the Ant-Rectum. Dose–volume histogram (DVH) parameters of two CS VMAT plans with and without (VMAT(OPT)/VMAT(NO)) dose optimization to the Ant-Rectum were compared. Results: VMAT(OPT) plans resulted in significantly lower DVH parameters of the Ant-Rectum and rectum compared to VMAT(NO) plans. These were comparable to the DVH parameters of three-dimensional conformal radiotherapy (3DCRT) plans. Both VMAT plans resulted in significantly better coverage of planning target volumes than did the 3DCRT plans. Conclusion: In the implementation of IMRT/VMAT as the standard treatment for cervical cancer in Japan, our optimization method may be an essential step toward fully benefitting from the CS principle.

4027 Background: Although basic, translational and clinical research suggest a possibility of synergistic effect of radiation-induced immunogenic cell death with immune checkpoint inhibitors, the effectiveness of the combination therapy is not fully established. Therefore, we conducted a single-arm, phase 1/2 trial (ClinicalTrials.gov, NCT03453164) in gastric cancer (GC) patients treated with a combination of nivolumab and oligo-fractionated irradiation (22.5 Gy/5 fractions/5 days). Methods: Eligible patients (n = 40) had un-resectable advanced or recurrent GC which progressed after primary and secondary chemotherapy with more than one lesion assessable in diagnostic imaging (one lesion must be ≥2cm). PBMCs from enrolled patients underwent high-dimensional flow cytometry-based, multiplexed MHC multimer analysis using a total of 46 tumor-associated antigens (TAA) and 10 virus epitopes and next-generation sequencing-based repertoire analysis of TCR β-chain. Results: The disease control rate (DCR) for the non-irradiated target as abscopal effect as the primary endpoint was 22.5%, and the DCR for the irradiated lesion was 40.0%. The median survival time was 230 days (157-330 days, 95%CI) and probability of 1-year survival rate was 28.6%. Although most TAA-specific T cells could be tracked longitudinally pre- and post-treatment, some several novel TAA-specific CD8 T cells were detected de novo after irradiation, indicating that potential irradiation-driven antigen spreading. Moreover, irradiation was associated with phenotypical changes of TAA-specific CD8 T cells towards higher expressions of KLRG1, HLA-DR, TIGIT and CD160 and lower expression of CD27 and CD127. Furthermore, the T cell clonality evaluated by the inverted Pielou’s evenness indicated that longer survival patients had more diverse TCR beta repertoire during treatment in comparison to shorter survivors. Also, we confirmed several new sequence-reads after radiation and nivolumab treatment in the top 30 most frequent clonotypes. Conclusions: Taken together, our results suggest that irradiation may induce, through immunogenic cell death, an immune-modulating effect with potential antigen spreading and a more diverse TCR repertoire, ultimately resulting in better survival during combination therapy of radiation with nivolumab. Clinical trial information: NCT03453164.

Purpose The aim of this study was to investigate the efficacy of combination therapy with intravenously injected microglia (MI) and radiation therapy (RT) for malignant glioma in rats. Methods and Materials Transgenic rats expressing v-erbB and spontaneously developing malignant glioma were used. The rats were divided into 4 groups: control (n = 19), RT alone (n = 10), MI alone (n = 9), and combination MI and RT (MI + RT) (n = 10). Cranial x-ray irradiation (8 Gy per fraction; once per week) was performed at 50 and 51 weeks of age. Cultured rat microglial cells (5 × 106 cells/rat) were intravenously injected via the tail vein within 30 minutes after RT. Results No evidence of side effects, including thrombosis or graft-versus-host disease, was noted. Rats treated with RT alone, MI alone, MI + RT, and control survived 60.9, 56.3, 66.0, and 56.1 weeks, respectively. The survival period of MI + RT was significantly longer than that of control (P = .014), MI alone (P = .027), and RT alone (P = .049). Immunohistochemical analysis showed a significantly higher number of tumor-infiltrated MI in the RT alone (P = .041) and MI + RT groups (P = .014) compared with the control. Significantly more CD8-positive lymphocytes were observed in the MI + RT group (P = .049) compared with the control. A positive correlation was found between the number of MI and CD8-positive lymphocytes (R2 = 0.556). A positive correlation was also found between CD8-positive lymphocytes and survival periods (R2 = 0.460). Conclusions MI + RT increased infiltrated MI and CD8-positive T cells and prolonged survival in transgenic rats that spontaneously developed malignant glioma. Combined immunocellular therapy and RT may provide a novel treatment strategy for malignant glioma.

In Asia, several challenges hinder the delivery of high-quality cancer treatment, especially radiation therapy (RT). Many Asian countries face large-scale shortage of RT centres and treatment machines. Additionally, there is also a significant technological gap, with many RT centres in Asia still using outdated technology. There is an urgent need to improve radiation treatment quality in Asia. The Federation of Asian Organizations for Radiation Oncology (FARO) was set up to foster regional collaboration, which we believe can help to identify and solve some of these issues collectively. This report describes the background and rationale of starting FARO, and puts forth some of the early achievements of the group, including fact-finding and educational activities. Finally, we discuss future possibilities, including strategic proposals that may benefit the RT community and our patients in Asia.

This study evaluated the feasibility of applying volumetric-arc radiotherapy (VMAT) in standard curative radiotherapy for non-bulky cervical cancer using the central-shielding principle. Whole-pelvis irradiation of 20 Gy and central-shielding pelvis irradiation of 30 Gy, both in 2 Gy fractions, were created using 3D conformal radiotherapy (3DCRT) with a standard midline block or VMAT. Composite dose distributions and DVH parameters were compared first in a simple phantom model and then in 10 clinical cases of Stage I-II cervical cancer. Whole-pelvis clinical target volumes (CTVs) were created from published guidelines for primary disease and lymph node regions, and CTVs for central-shielding irradiation were created by subtracting uterus corpus and 4 cm-wide regions centered at the cervical canal and vagina. In a phantom model, VMAT provided adequate dose coverage to the PTVs without excessive doses to the rectum or bladder compared with the 3DCRT plan. In the clinical cases, VMAT plans resulted in slightly but significantly better coverage of PTVs. The DVH parameters for the rectum and bladder were equivalent or lower for VMAT plans compared with the 3DCRT plans. In the bowel, V30Gy, V40Gy, and V50Gy were significantly lower in VMAT plans compared with in the 3DCRT plans (47.6% vs 61.0%, 29.8% vs 56.2% and 6.8% vs 21.1%, respectively). Based on these results, VMAT may be used in external-beam radiotherapy for early-stage cervical cancer by adopting the principle of central-shielding pelvis irradiation. Furthermore, VMAT is likely to reduce doses to the small bowel and may reduce gastrointestinal toxicities for these patients.

Radiation-induced organizing pneumonia (OP) reportedly occurs in ~2% of patients who receive whole-breast radiotherapy (WBRT). Though there are several reported risk factors, they remain unclear and controversial. We analyzed the incidence of and risk factors for OP after WBRT at our institution. We analyzed 665 breast cancer patients (with WBRT of 679 breasts) who underwent WBRT from October 2007 to September 2012 at our institution and were followed up for more than 1 year after completion of WBRT. Factors included in the analysis were age, the side affected, central lung distance (CLD), radiation dose, concurrent endocrine therapy, and chemotherapy. The median age was 56 years (range, 23–89 years). The sides affected were left, right and bilateral in 342, 309 and 14 patients, respectively. The median CLD was 1.1 cm (range, 0–3.0 cm). Concurrent endocrine therapy was performed in 236 patients, and chemotherapy was given in 215 patients; of these, 4 received concurrent chemotherapy. OP developed in nine patients (1.4%). The median time taken to develop OP after the completion of WBRT was 4 months (range, 2–12 months). All nine patients were treated with steroids, and symptoms promptly improved, except in two patients who relapsed. Statistical analysis revealed that only CLD (≥1.5 cm) was significantly associated with the development of OP (P = 0.004). In conclusion, the incidence of OP after WBRT was 1.4%, and CLD was a significant risk factor. In these patients, OP was controlled with steroid administration.

To evaluate the efficacy and safety of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck, 35 patients were enrolled in this prospective study. The primary end-point was the 3-year local control rate, and the secondary end-points included the 3-year overall survival rate and adverse events. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up time for all patients was 39 months. Thirty-two and three patients received 64.0 Gy (relative biological effectiveness) and 57.6 Gy (relative biological effectiveness) in 16 fractions, respectively. Adenoid cystic carcinoma was dominant (60%). Four patients had local recurrence and five patients died. The 3-year local control and overall survival rates were 93% and 88%, respectively. Acute grade 2-3 radiation mucositis (65%) and dermatitis (31%) was common, which improved immediately with conservative therapy. Late mucositis of grade 2, grade 3, and grade 4 were observed in 11, one, and no patients, respectively. There were no adverse events of grade 5. Carbon-ion radiotherapy achieved excellent local control and overall survival rates for non-squamous cell carcinoma. However, the late mucosal adverse events were not rare, and meticulous treatment planning is required. Trial registration no. UMIN000007886.

Herein, we investigate the long-term clinical outcomes for cervical cancer patients treated with in-room computed tomography–based brachytherapy. Eighty patients with Stage IB1–IVA cervical cancer, who had undergone treatment with combined 3D high-dose rate brachytherapy and conformal radiotherapy between October 2008 and May 2011, were retrospectively analyzed. External beam radiotherapy (50 Gy) with central shielding after 20–40 Gy was performed for each patient. Cisplatin-based chemotherapy was administered concurrently to advanced-stage patients aged ≤75 years. Brachytherapy was delivered in four fractions of 6 Gy per week. In-room computed tomography imaging with applicator insertion was performed for treatment planning. Information from physical examinations at diagnosis, and brachytherapy and magnetic resonance imaging at diagnosis and just before the first brachytherapy session, were referred to for contouring of the high-risk clinical target volume. The median follow-up duration was 60 months. The 5-year local control, pelvic progression-free survival and overall survival rates were 94%, 90% and 86%, respectively. No significant differences in 5-year local control rates were observed between Stage I, Stage II and Stage III–IVA patients. Conversely, a significant difference in the 5-year overall survival rate was observed between Stage II and III–IVA patients (97% vs 72%; P = 0.006). One patient developed Grade 3 late bladder toxicity. No other Grade 3 or higher late toxicities were reported in the rectum or bladder. In conclusion, excellent local control rates were achieved with minimal late toxicities in the rectum or bladder, irrespective of clinical stage.

Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in FGFR3 and FGFR4 in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.

The combination treatment of radiotherapy with anti-PD-1/PD-L1 antibody has been shown to significantly improve the clinical outcome of various cancers. Recent studies showthat radiotherapy has multiple functions in modifying the tumor microenvironment, by inducing both immunostimulation and immunosuppression. The upregulation of PD-L1 expression in cancer cells interferes with the effector functions of interacting T cells. Preclinical studies demonstrate that radiotherapy induces PD-L1 upregulation by 4 pathways; (1)IFN-γ signaling,(2)EGFR pathway,(3)DNA damage signaling pathway, and(4)cGAS-STING pathway. All of these mechanisms are involved in the upregulation of PD-L1 expression in cancer cells via JAK/STAT pathway. Because the PD-1/PD-L1 interaction has been shown to be one of the major mechanisms of cancer immune escape, which leads to treatment failure, anti-PD-1/PD-L1 antibody may improve the efficacy of radiotherapy by enhancement of anti-tumor activity. In addition, PD-L1 expression is one of the biomarkers of good response to anti-PD-1/ PD-L1 antibody. Therefore, the comprehensive understanding of the mechanism underlying PD-L1 expression in response to radiotherapy is important for the establishment of optimal combination strategy. This approach could help to provide the basis for the combined therapies and promote personalized immuno-radiotherapy, although the signaling of PD-L1 upregulation induced by radiotherapy in tumors could be intricately regulated. In this article, we review previous researches which revealed the mechanisms of PD-L1 upregulation induced by radiotherapy.

Cardiac metastasis of uterine cervical cancer with antemortem diagnosis is extremely rare. Therefore, its landscape epidemiology has not been well elucidated to date. In the present study, a case of solitary cardiac metastasis of uterine cervical cancer diagnosed antemortem is reported, and a review of the currently available literature (which includes 18 cases of cardiac metastasis of uterine cervical cancer) is conducted. In January 2013, a 78-year-old woman with squamous cell carcinoma (SCC) of the uterine cervix (International Federation of Gynecology and Obstetrics stage IIIb) underwent definitive radiotherapy at Gunma University Hospital (Gunma, Japan). Follow-up examination at 5 months after completion of the treatment indicated no evidence of recurrence or metastasis. In April 2014, the patient reported epigastric discomfort and general malaise. Electrocardiogram suggested myocardial dysfunction. Transthoracic echocardiography revealed the presence of a mass occupying the right ventricle and pericardial effusion. Cine magnetic resonance imaging demonstrated a filling defect in the right ventricle, and transcatheter biopsy confirmed SCC. The patient was diagnosed with a solitary cardiac metastasis of uterine cervical cancer. Despite aggressive medical therapy, the patient succumbed to disease 31 days after admission to hospital. A review of the current literature revealed that 84% of cases of cardiac metastasis develop within 2 years of completion of the initial treatment, and that electrocardiogram and echocardiography reveal findings of myocardial dysfunction and the presence of a mass in the right ventricle, respectively. A treatment strategy for cardiac metastasis of uterine cervical cancer has not been standardized thus far, and the prognosis is very poor, as the majority of patients succumbed to disease within 1 year. In summary, the current case and the literature review conducted in the present study suggest that: i) Cardiac metastasis should be included in the differential diagnosis in cases with nonspecific complaints such as epigastric discomfort and general malaise when patients have a history of uterine cervical cancer, particularly within the previous 2 years; and ii) electrocardiogram and echocardiography are convenient and effective modalities for the diagnosis of cardiac metastasis of uterine cervical cancer.

This study aimed to elucidate the contribution of T cell-mediated antitumor immunity in the antitumor effect of local hyperthermia (LH).C57BL/6J mice were injected with the mouse lymphoma cell line, E.G7-OVA, in the right femur on day 0. LH was induced by immersing the right femur in a water bath at 42 °C for 60 min on day 7, followed by administration of anti-CD8 monoclonal antibodies (mAb) or anti-CTLA-4 mAb (days 8, 11, and 14). The effect of LH on tumor growth (TG) was assessed by measuring the duration until tumor volume reached 1000 mmTG with and without LH treatment was 9.0 ± 9.6 and 7.0 ± 1.6 days, respectively. TG was significantly slower with LH treatment (p = .01). The therapeutic effect of LH was mitigated by addition of anti-CD8 mAb (p .05 for both TG and survival) compared with the untreated (control) group. Furthermore, addition of anti-CTLA-4 mAb did not significantly affect the therapeutic effect of LH. The ELISpot assay showed that the number of spots in the LH group (276.3 ± 14.5) was significantly greater than in the control group (59.0 ± 4.5, p .001).CD8-positive T cell-mediated antitumor immunity significantly contributes to the antitumor effect of LH.

In radiotherapy for cervical cancer, because brachytherapy can provide concentrated dose to the primary tumor, midline block (central shielding) has been applied at least partially in external beam therapy to lower the dose to rectum and bladder and avoid severe complications. Although this practice has been decreased over the years globally, the central shielding technique continues to be used as standard in Japan. The use of central shielding in Japan has resulted in relatively low incidence of late complications in the rectum and bladder without compromising the disease control. Recent study of composite dose distributions of the treatment regimen using central shielding revealed its characteristics which explains the benefit of this technique. This chapter will cover the history, philosophy, analysis of composite dose distributions, issues of dose reporting, and the future prospect of this technique.

Radiotherapy is an essential component of cancer therapy. Despite advances in cancer genomics, the mutation signatures of radioresistant tumors have not yet been fully elucidated. To address this issue, we analyzed a unique set of clinical specimens from a uterine cervical cancer that repeatedly locally recurred after multiple rounds of radiotherapy. Exon sequencing of 409 cancer-related genes in the treatment-naive tumor and the tumors that recurred after initial and secondary radiotherapy identified (i) activating mutations in PIK3CA and KRAS, and putative inactivating mutations in SMAD4, as trunk mutation signatures that persisted over the clinical course; and (ii) mutations in KMT2A, TET1, and NLRP1 as acquired mutation signatures observed only in recurrent tumors after radiotherapy. Comprehensive mining of published in vitro genomics data pertaining to radiosensitivity revealed that simultaneous mutations in KRAS and SMAD4, which have not been described previously in uterine cervical cancer, are associated with cancer cell radioresistance. The association between this mutation signature and radioresistance was validated by isogenic cell-based experiments. These results provide proof-of-principle for the analytical pipeline employed in this study, which explores clinically relevant mutation signatures for radioresistance, and demonstrate that this approach is worth pursuing with larger cohorts in the future.

This study aimed to provide accurate dose distribution profiles of radiotherapy for cervical cancer when treated with the central shielding technique by analysing the composite 3D EQD2 dose distribution of external beam radiotherapy (EBRT) plus intracavitary brachytherapy (ICBT). On a phantom, four patterns of the combinations of whole pelvis irradiation (WP) (4 fields), pelvis irradiation with central shielding technique (CS) [anterior–posterior/posterior–anterior (AP-PA fields), shielding width of 3 or 4 cm] and ICBT using Point-A prescription were created: 30 Gy/15 fractions + 20 Gy/10 fractions + 24 Gy/4 fractions [Plan (30 + 20 + 24)], 40 Gy/20 fractions + 10 Gy/5 fractions + 18 Gy/3 fractions [Plan (40 + 10 + 18)], 40 Gy/20 fractions + 10 Gy/5 fractions + 24 Gy/4 fractions [Plan (40 + 10 + 24)] and 45 Gy/25 fractions + 0 Gy + 28 Gy/4 fractions [Plan (45 + 0 + 28)]. The composite EQD2 dose distributions of the complete treatment were analysed. The Point-A dose of Plan (30 + 20 + 24), Plan (40 + 10 + 18), Plan (40 + 10 + 24) and Plan (45 + 0 + 28) were 78.0 Gy (CS 3 cm)/71.8 Gy (CS 4 cm), 72.1 Gy (CS 3 cm)/69.0 Gy (CS 4 cm), 80.1 Gy (CS 3 cm)/77.0 Gy (CS 4 cm) and 84.1 Gy, whereas it has been previously reported to be 62 Gy, 64 Gy, 72 Gy and 84 Gy, respectively. For all the treatment plans with CS, equivalent or wider coverage of 60 Gy (EQD2) was achieved in the right–left direction, while coverage in the anterior–posterior direction decreased in plans with CS. There were no irregularly ‘cold’ regions around the central target. The use of CS in radiotherapy for cervical cancer resulted in tumor coverage in the lateral direction with doses higher than the previously reported Point-A doses.

BACKGROUND This study sought to evaluate the toxicity and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced adenocarcinoma of the uterine cervix in a phase 1/2 clinical trial. METHODS The treatment consisted of whole-pelvic irradiation of 36.0 gray equivalents (GyE) in 12 fractions and local boost with dose escalation from 26.4 to 38.4 GyE in 8 fractions. The dose escalation was performed with careful observation of acute normal tissue responses. Total dose to the cervical tumor was 62.4 to 74.4 GyE in 20 fractions. RESULTS Between April 1998 and February 2010, 58 patients were treated with C-ion RT in this clinical trial. The number of patients with stage IIB, IIIB, and IVA disease were 20, 35, and 3, respectively. Median tumor size was 5.5 cm (range, 3.0-11.8 cm). Twenty-seven patients had pelvic lymph node metastases. The median follow-up period was 38 months. All patients completed the treatment schedule. Grade 2 or higher late toxicity was found in 8 patients: 5 with bladder and 2 with small intestine grade 2 toxicities, and 1 patient had grade 4 rectal complication, which was surgically salvaged. The 5-year local control rate, local control rate including salvage surgery, and overall survival rate in all cases were 54.5%, 68.2%, and 38.1%, respectively. CONCLUSIONS Dose escalation of C-ion RT for adenocarcinoma of the uterine cervix was accomplished without severe toxicities except in 1 case. Although the number of patients in this study was small, the results support continued investigation and analysis to confirm therapeutic efficacy. Cancer 2014;120:1663–1669. © 2014 American Cancer Society.

To compare the incidence and degree of hematological toxicity between innovator and generic cisplatin formulations, decreases in white blood cell (WBC) count (leukopenia) and platelet counts (thrombocytopenia) were retrospectively examined, using the Common Toxicity Criteria for Adverse Events ver. 4.0, in patients with uterine cervical cancer treated with concurrent chemoradiotherapy using innovator (innovator group, n = 22) or generic (generic group, n = 22) cisplatin formulations. There were no significant differences in patient characteristics except in the technique of external irradiation; larger numbers of patients in the innovator and generic groups were irradiated using the parallel-opposed two-field technique and the four-field box technique, respectively (P = 0.00012), which is in line with the historical progress of external beam radiation therapy. The numbers of patients showing Grade 1, 2, 3 and 4 leukopenia were 1 (4.5%), 14 (64%), 7 (32%) and 0 (0.0%) in the innovator group, and 1 (4.5%), 6 (27%), 13 (59%) and 2 (9.0%) in the generic group, respectively. The number of patients showing Grade 3–4 leukopenia was significantly greater in the generic group than in the innovator group (P = 0.034). There was no significant relationship between the incidence of Grade 3–4 leukopenia and the technique of external irradiation. There were no significant differences in the incidence and degree of thrombocytopenia between the two groups. These results indicate the possibility that the generic cisplatin formulation may have a different toxicity profile compared to the innovator formulation in terms of the incidence of leukopenia.

Purpose: To assess the feasibility of applying trans-applicator intracavitary ultrasonography to image-guided brachytherapy for cervical cancer. Material and methods : For this experiment, a phantom was created and included a polyethylene tube, intended to simulate a tandem applicator, which was inserted into chicken meat and embedded in agar, along with magnetic reso­nance imaging (MRI)-compatible ovoid applicators. Three-dimensional images of the phantom were obtained using computed tomography (CT), MRI (T2-weighted), and intracavitary ultrasonography sectional images acquired at 1 mm slice intervals. Intracavitary ultrasonography images were acquired from within the simulated tandem applicator using a radial transducer. Magnetic resonance imaging and intracavitary ultrasonography images were manually registered onto CT images. The chicken meat was contoured as the target volume independently on the CT, MRI, and intracavitary ultrasonography images, and the Dice similarity coefficient was used to compare the target volumes. The dose distributions of a sample brachytherapy plan were also evaluated. Results : Computed tomography, MRI, and intracavitary ultrasonography all visualized the three-dimensional phantom volumes. Intracavitary ultrasonography images depicted the meat with high echoic signals and a border clearly distinguishable from the surrounding agar. The Dice similarity coefficient values for the target volumes on CT vs. MRI, CT vs. intracavitary ultrasonography, and MRI vs. intracavitary ultrasonography were 0.966, 0.965, and 0.971, respectively, indicating similar contouring with the three modalities. Among the modalities, the differences in D 50 , D 90 , D 98 , and D 100 values were 1.8%, 2.9%, 3.7%, and 2.9%, respectively. Conclusions : Three-dimensional reconstructed trans-applicator intracavitary ultrasonographic images clearly depicted meat tissue within the phantom, and could thus be used for brachytherapy planning. This study proves the concept of trans-applicator intracavitary ultrasonography for intracavitary brachytherapy. Further research such as development of intracavitary ultrasonography system, 3D reconstruction method, ultrasonography-compatible applicators, and ultrasonography-based target concept is warranted to assess the potential clinical application.

Purpose To analyze the dose–volume histogram of the central shielding technique for cervical cancer radiotherapy by computing the composite three-dimensional EQD2 dose distributions of external-beam radiotherapy plus intracavitary brachytherapy. Methods and Materials On a phantom, three patterns of high-risk clinical target volume (HR-CTV) with right–left diameters of 3, 4, and 5 cm were created using clinical data. Four patterns of combinations of whole-pelvis irradiation plus “pelvis irradiation using the central shielding technique” (CS) (shielding width, 3 or 4 cm) were created: 20 Gy/10 fractions + 30 Gy/15 fractions, 30 Gy/15 fractions + 20 Gy/10 fractions, 40 Gy/20 fractions + 10 Gy/5 fractions, and 50 Gy/25 fractions + 0 Gy. The intracavitary brachytherapy plan was set as 24 Gy/4 fractions prescribed to the Point A. The HR-CTV D90/D98 and modeled bladder/rectum D2cc were computed using the composite EQD2 dose distributions of all the treatment combinations. Results If appropriate combinations of the treatment plans were selected on the basis of the CS doses and the HR-CTV sizes, the D90/D98 of HR-CTV 3 cm, HR-CTV 4 cm, and HR-CTV 5 cm were 89.7 Gy/80.6 Gy, 77.3 Gy/72.0 Gy, and 73.0 Gy/69.2 Gy in the case of CS width 3 cm, respectively; and 86.2 Gy/76.0 Gy, 73.3 Gy/67.6 Gy, and 70.9 Gy/67.1 Gy in the case of CS width 4 cm, respectively. The contributions of CS to the HR-CTV D90/bladder D2cc/rectum D2cc values were 24–56%/28–32%/9% of the CS plan doses for shielding width of 3 cm and were 13–35%/11–16%/5–6% for shielding width of 4 cm. Conclusion The dose contributions of CS were variable but not negligible when analyzing the total doses delivered to the HR-CTV.

Purpose To compare the efficacy and the incidence of complications of high-dose-rate (HDR) and low-dose-rate (LDR) intraluminal brachytherapy (IBT) boost after external beam radiation therapy in patients with superficial esophageal cancer. Methods and Materials Fifty-four consecutive patients with Stage I thoracic esophageal squamous cell carcinoma who were treated with definitive radiotherapy using IBT between 1991 and 2007 were studied retrospectively. LDR-IBT and HDR-IBT were performed for 19 and 35 patients, respectively. After external beam radiation therapy of 56–60 Gy with a conventional fractionation, LDR-IBT (5 Gy × 2) or HDR-IBT (3 Gy × 3) was given within 2 weeks. The median follow-up was 47 months (7–151 months). Results Overall, the 5-year overall survival, cause-specific survival (CSS), and locoregional control (LRC) rates were 61%, 86%, and 79%, respectively. The 5-year overall survival, CCS, and LRC rates did not differ significantly between the LDR-IBT and HDR-IBT groups (68% vs. 58% (p = 0.50), 83% vs. 85% (p = 0.63), and 84% vs. 75% (p = 0.42), respectively). Salvage treatment was given in 8 locally recurrent patients, and 6 patients were rescued. The Grade ≥2 late morbidities of esophagus and heart/lung were observed in 5 patients (4 in the LDR-IBT group and 1 in the HDR-IBT group) and 2 patients (one from each group), respectively. Conclusions In view of the safety profile and effectiveness, our results encourage the continued adoption of HDR-IBT as radiation boost in medically inoperable or elderly superficial esophageal cancer patients undergoing definitive radiotherapy.

Purpose: To determine the predictive risk factors for Grade 2 or worse rectal bleeding after high-dose-rate brachytherapy (HDR-BT) combined with hypofractionated external-beam radiotherapy (EBRT) for prostate cancer using dose-volume histogram analysis. Methods and Materials: The records of 216 patients treated with HDR-BT combined with EBRT were analyzed. The treatment protocols for HDR-BT were 5 Gy Multiplication-Sign five times in 3 days or 7 Gy Multiplication-Sign three, 10.5 Gy Multiplication-Sign two, or 9 Gy Multiplication-Sign two in 2 days. The EBRT doses ranged from 45 to 51 Gy with a fractional dose of 3 Gy. Results: In 20 patients Grade 2 or worse rectal bleeding developed, and the cumulative incidence rate was 9% at 5 years. By converting the HDR-BT and EBRT radiation doses into biologic effective doses (BED), the BED{sub 3} at rectal volumes of 5% and 10% in the patients who experienced bleeding were significantly higher than those in the remaining 196 patients. Univariate analysis showed that a higher rectal BED{sub 3-5%} and the use of fewer needles in brachytherapy were correlated with the incidence of bleeding, but BED{sub 3-5%} was found to be the only significant factor on multivariate analysis. Conclusions: The radiation dose delivered to small rectalmore » lesions as 5% is important for predicting Grade 2 or worse rectal bleeding after HDR-BT combined with EBRT for prostate cancer.« less

BACKGROUND: The authors previously demonstrated that fibroblast growth factor 2 (FGF2) expression levels in tumor cells (FGF2-T) may be an indicator of the efficacy of radiotherapy in patients with cervical cancer (CC). In the current study, this finding was extended in newly enrolled patients and was investigated further in stromal FGF2 (FGF2-S) expression. METHODS: Sixty-nine patients with CC were recruited as a validation set for the immunohistochemical detection of FGF2-T from biopsy samples that were taken before (pretreatment) or 1 week after the initiation of radiotherapy (midtreatment). The authors also investigated the expression of FGF2 in tumor FGF2-S and investigated vascular endothelial growth factor (VEGF), and cluster of differentiation 31 (CD31) (also called platelet endothelial cell adhesion molecule) in these patients and in an additional 35 patients from a previous study. RESULTS: FGF2 expression was detected in tumor cells from all patients and in stromal cells from 87% of patients. FGF2-T was significantly higher in midtreatment samples (P = .0002), and a high ratio of midtreatment/pretreatment FGF2-T was related significantly to a better prognosis (P = .025). Increased VEGF expression after the initiation of radiotherapy was related significantly to positive FGF2-S in pretreatment samples (P = .035); however, it was not related to prognosis or microvessel density detected by CD31 expression. CONCLUSIONS: Radiation causes a response in tumor cells and adjacent normal cells and changes the extracellular matrix environment. In this study, the authors confirmed their previous findings and demonstrated that changes in FGF2-T expression may be used as a marker to monitor the effectiveness of radiotherapy in patients with CC. These findings should improve patient selection for molecular targeted therapies, such as cytokine inhibitors, after standard-of-care treatment. Cancer 2010. © 2010 American Cancer Society.

Purpose: To clarity how carbon-ion radiotherapy on primary tumors affects the characteristics of subsequently-arising metastatic tumor cells. Methods and Materials: Mouse squamous cell carcinomas, NR-S1, in synergic C3H/HeMsNrs mice were irradiated with a single dose of 5-50 Gy of carbon-ions (C-ion) (290 MeV/nucleon, 6 cm spread-out Bragg peak) or gamma-rays (GAMMA-rays) (137Cs source) as a reference beam. The volume of the primary tumors and the number of metastatic nodules in lung were studied, and histological analysis and microarray analysis of laser-microdissected tumor cells were also performed. Results: Including 5 Gy of C-ion and 8 Gy of GAMMA-rays, which did not inhibit the primary tumor growth, all doses used in this study inhibited lung metastasis significantly. Pathological findings showed no difference among the metastatic tumor nodules in the non-irradiated, carbon-ion-irradiated, and GAMMA- ray-irradiated groups. Clustering analysis of expression profiles among metastatic tumors and primary tumors revealed a single cluster consisting of metastatic tumors different from their original primary tumors, indicating that the expression profiles of the metastatic tumor cells were not affected by the local application of C-ion radiotherapy or GAMMA-ray radiotherapy. Conclusion: We found no difference in the incidence and histology, and only small differences in expression profile, of distant metastasis between local C-ion and GAMMA-ray radiotherapy. The application of local radiotherapy per se or the type of radiotherapy applied did not influence the transcriptional changes caused by metastasis in tumor cells.

Objective: To elucidate the in vivo biological effects induced by carbon-ion irradiation using comprehensive expression analysis. \nMaterials and Methods: We examined gene expression changes after carbon-ion (C-ion) irradiation (290 MeV/m, SOBP 6 cm middle, 50 kev/MUm) with a single dose of 30 Gy in four mouse tumors (NR-S1, SCCVII, NFSa, and #8520) transplanted into the hind legs of C3H/HeNrs mice, using 44K single-color oligo-microarrays at 6 hours (h), 1 day, and 3 days after irradiation. Gamma rays of 30 Gy and 50 Gy were used as a reference beam. Identification of C-ion-responsive genes was based on a false discovery rate of < 5% using the Wilcoxon test (P < 0.001) and the Benjamini-Hochberg correction. \nResults: In all tumors, the level of expression of several tens of genes, including Ccl3, Ccng1, Cd80, Cdkn1a, Cxcl2, IL7r, Lrdd, Mgmt, Mmp8, and Polk, was significantly altered 6 h and day 1 following C-ion irradiation. At day 3, several hundred genes, many of which are also classified as stress-response or cell-communication genes, including Tnfrsf5, Ikbke, and Icam1, were upregulated following C-ion irradiation. The expression level of the majority of these genes was similar following GAMMA-ray treatment, although the change was not as extensive and intertumor variance was apparent. Several genes, including Ikbke, Serpina3n, and Saa3, responded differentially following C-ion irradiation than after GAMMA-ray irradiation. Pathological investigation and immunohistochemical analysis of Cdkn1a revealed cell cycle arrest with mitotic catastrophe in tumors irradiated by C-ions. \nConclusions: This study revealed significant C-ion induced upregulation of stress-responsive and cell-communication genes common to different tumor types. These findings provide evidence for the efficacy of this modality for the treatment of local tumors.

Objective: To investigate the protein expression change of FGF2 in cervical cancers during chemoradiotherapy, as indicated in our previous study using microarray analysis. In addition, we sought to examine the predictive value of such changes in expression for disease failure after chemoradiotherapy. Patients and Methods: Biopsy specimens were obtained from 35 patients with cervical cancers before (pretreatment) and 1 week after initiation (midtreatment) of chemoradiotherapy (CRT) (9 Gy and 40 mg/m2 of cisplatin). Immunohistochemical studies (IHS) were performed to detect FGF2, laminin, and CD44 expression using an automated streptavidin-biotin immunoperoxidase staining system. Positive area proportion (%) of FGF2 and CD44 were analyzed using an image analysis system, and laminin staining pattern was scored by continuity of the basement membrane immunopositivity. Patients were defined as good (n =18) or poor responders (n =10) based on their two-year disease-free survival. Results: Protein expression of FGF2 in midtreatment samples (mid) was significantly higher than in pretreatment samples (pre). Discontinuity of laminin staining pattern in mid was significantly higher than in pre. Protein expression of CD44 was not significantly different between mid and pre. The ratio change (mid versus pre) of FGF2 expression in poor responders was significantly lower than that in good responders (P < 0.05). The number of cases with discontinuity of laminin staining pattern at pre was significantly increased in the poor responders (P < 0.05). Ratio changes of FGF2 or CD44 expression in mid correlated with laminin staining pattern in pre. Conclusions: Using biopsy specimens from pretreatment and midtreatment cervical cancers, we revealed significant changes in FGF2 protein expression during fractionated radiotherapy with cisplatin. We also found that FGF2 ratio change and laminin discontinuity staining pattern at pretreatment were significantly associated with prognosis. These molecular features might help us to identify patients at high risk of disease failure after CRT.

Background The prognostic value of rectal invasion is still unclear in stage IVA cervical cancer. The objective of this study is to evaluate patient outcome and prognostic factors in stage IVA cervical cancer treated with radiation therapy. Methods A retrospective review of the medical records of patients treated with definitive photon radiation therapy for pathologically proven stage IVA cervical cancer between 1980 and 2010 was performed. Eligible patients for the present study were diagnosed with clinical stage IVA cervical cancer by cystoscopy or/and proctoscopy, and they received definitive radiation therapy consisting of a combination of external beam radiotherapy and high-dose-rate brachytherapy. All patients underwent CT scans of the abdomen and pelvis. Results Among the 67 stage IVA patients studied, 53 patients were stage IVA on the basis of bladder invasion, 7 according to rectal mucosal invasion, and 7 because of both bladder and rectal mucosal invasion. Median follow-up of all patients and surviving patients was 19 months (range, 2–235 months) and 114 months (range, 14–223 months), respectively. The 5-year local control (LC), disease-free survival (DFS), and overall survival (OS) rate were 55, 17, and 24 %, respectively. Rectal invasion had significant impact on DFS, but bladder invasion had the opposite effect (p = 0.00006 and 0.005, respectively). There were significant differences of LC, DFS and OS rates between patients with and without rectal invasion (p = 0.006, 0.00006 and 0.05, respectively). Conclusions Patients with stage IVA cervical cancer had poor prognosis, with 5-year survival of only 24 %. Furthermore, in stage IVA, rectal invasion might be a worse prognostic factor than bladder invasion.

We investigated the first site of distant failure after carbon ion radiotherapy (C-ion RT) for locally advanced cervical cancer in three clinical trials. A total of 91 cases were enrolled in the three trials (Protocol 9702, 9704 and 9902). Histologically, 36 cases had squamous cell carcinoma (SqCC) and 55 cases had adenocarcinoma (AC), including 13 with adenosquamous cell carcinoma. The number of cases with Stage IIB, IIIB and IVA disease was 21, 59 and 11, respectively. Of the 91 cases, 42 had positive pelvic lymph nodes (PLNs). The median tumor size was 6.0 cm (range, 3.0–12.0 cm). The median follow-up duration for all cases was 40 months (range, 7–181 months). A total of 40 cases developed distant failure as the first site of failure: 13 of 36 (36.1%) SqCC cases had distant failure, with 9 of them with para-aortic lymph node (PALN) failure; 27 of 55 (44.0%) AC cases had distant failure, and 23 of them had distant failure excluding PALN metastasis. Distant failure rates of SqCC cases who had positive and negative PLNs before C-ion RT were 61.1% and 11.1%, respectively (P = 0.0045). Those of AC cases were 54.2% and 45.2%, respectively (P = 0.507). In conclusion, there were high rates of distant failure after C-ion RT in AC cases regardless of PLN status, and there were high rates of distant failure after C-ion RT, especially PALN failure, in SqCC cases with positive PLNs.

Purpose: To evaluate the incidence of Grade 2 or worse rectal bleeding after high-dose-rate (HDR) brachytherapy combined with hypofractionated external-beam radiotherapy (EBRT), with special emphasis on the relationship between the incidence of rectal bleeding and the rectal dose from HDR brachytherapy. Methods and Materials: The records of 100 patients who were treated by HDR brachytherapy combined with EBRT for ≥12 months were analyzed. The fractionation schema for HDR brachytherapy was prospectively changed, and the total radiation dose for EBRT was fixed at 51 Gy. The distribution of the fractionation schema used in the patients was as follows: 5 Gy × 5 in 13 patients; 7 Gy × 3 in 19 patients; and 9 Gy × 2 in 68 patients. Results: Ten patients (10%) developed Grade 2 or worse rectal bleeding. Regarding the correlation with dosimetric factors, no significant differences were found in the average percentage of the entire rectal volume receiving 30%, 50%, 80%, and 90% of the prescribed radiation dose from EBRT between those with bleeding and those without. The average percentage of the entire rectal volume receiving 10%, 30%, 50%, 80%, and 90% of the prescribed radiation dose from HDR brachytherapy in those who developed rectal bleeding was 77.9%, 28.6%, 9.0%, 1.5%, and 0.3%, respectively, and was 69.2%, 22.2%, 6.6%, 0.9%, and 0.4%, respectively, in those without bleeding. The differences in the percentages of the entire rectal volume receiving 10%, 30%, and 50% between those with and without bleeding were statistically significant. Conclusions: The rectal dose from HDR brachytherapy for patients with prostate cancer may have a significant impact on the incidence of Grade 2 or worse rectal bleeding.

Background The purpose of the study was to evaluate the feasibility of deformable image registration (DIR) in assessing cumulative dose distributions of the combination of external beam radiotherapy (EBRT) and fractionated intracavitary brachytherapy (ICBT) for cervical cancer. Materials and methods Three-dimensional image data sets of five consecutive patients were used. The treatment plan consisted of whole pelvic EBRT (total dose: 45 Gy in 25 fractions) combined with computed tomography (CT)-based high-dose rate ICBT (≥24 Gy in 4 fractions to the high risk clinical target volume (HR-CTV)). Organs at risk and HR-CTV were contoured on each CT images and dose-volume parameters were acquired. Pre-imaging preparations were performed prior to each ICBT to minimize the uncertainty of the organ position. Physical doses of each treatment were converted to biologically equivalent doses in 2 Gy daily fractions by the linear quadratic model. Three-dimensional dose distributions of each treatment were accumulated on CT images of the first ICBT using DIR with commercially available image registration software (MIM Maestro®). To compare with DIR, 3D dose distributions were fused by rigid registration based on bony structure matching. To evaluate the accuracy of DIR, the Dice similarity coefficient (DSC) was measured between deformed contours and initial contours. Results The cumulative dose distributions were successfully illustrated on the CT images using DIR. Mean DSCs of the HR-CTV, rectum, and bladder were 0.46, 0.62 and 0.69, respectively, with rigid registration; and 0.78, 0.76, and 0.87, respectively, with DIR (p

The human malaria parasite Plasmodium falciparum is responsible for the death of more than a million people every year. To stimulate basic research on the disease, and to promote the development of effective drugs and vaccines against the parasite, the complete genome of P. falciparum clone 3D7 has been sequenced, using a chromosome-by-chromosome shotgun strategy. Here we report the nucleotide sequence of the third largest of the parasite's 14 chromosomes, chromosome 12, which comprises about 10% of the 23-megabase genome. As the most (A + T)-rich (80.6%) genome sequenced to date, the P. falciparum genome presented severe problems during the assembly of primary sequence reads. We discuss the methodology that yielded a finished and fully contiguous sequence for chromosome 12. The biological implications of the sequence data are more thoroughly discussed in an accompanying Article (ref. 3).

This study sought to evaluate the toxicity and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced adenocarcinoma of the uterine cervix in a phase 1/2 clinical trial.The treatment consisted of whole-pelvic irradiation of 36.0 gray equivalents (GyE) in 12 fractions and local boost with dose escalation from 26.4 to 38.4 GyE in 8 fractions. The dose escalation was performed with careful observation of acute normal tissue responses. Total dose to the cervical tumor was 62.4 to 74.4 GyE in 20 fractions.Between April 1998 and February 2010, 58 patients were treated with C-ion RT in this clinical trial. The number of patients with stage IIB, IIIB, and IVA disease were 20, 35, and 3, respectively. Median tumor size was 5.5 cm (range, 3.0-11.8 cm). Twenty-seven patients had pelvic lymph node metastases. The median follow-up period was 38 months. All patients completed the treatment schedule. Grade 2 or higher late toxicity was found in 8 patients: 5 with bladder and 2 with small intestine grade 2 toxicities, and 1 patient had grade 4 rectal complication, which was surgically salvaged. The 5-year local control rate, local control rate including salvage surgery, and overall survival rate in all cases were 54.5%, 68.2%, and 38.1%, respectively.Dose escalation of C-ion RT for adenocarcinoma of the uterine cervix was accomplished without severe toxicities except in 1 case. Although the number of patients in this study was small, the results support continued investigation and analysis to confirm therapeutic efficacy.