Evaluating the Necessity of Adaptive RT and the Role of Deformable Image Registration in Lung Cancer with Different Pathologic Classifications.

BACKGROUND: This study aimed to analyze differential radiotherapy (RT) responses according to the pathological type of lung cancer to see the possibility of applying adaptive radiotherapy (ART). METHODS: ART planning with resampled-computed tomography was conducted for a total of 30 patients (20 non-small-cell lung cancer patients and 10 small-cell lung cancer patients) using a deformable image registration technique to reveal gross tumor volume (GTV) changes according to the duration of RT. RESULTS: The small-cell lung cancer group demonstrated an average GTV reduction of 20.95% after the first week of initial treatment (p = 0.001), whereas the adenocarcinoma and squamous cell carcinoma groups showed an average volume reduction of 20.47% (p = 0.015) and 12.68% in the second week. The application of ART according to the timing of GTV reduction has been shown to affect changes in radiation dose irradiated to normal tissues. This suggests that ART applications may have to be different depending on pathological differences in lung cancer. CONCLUSION: Through these results, the present study proposes the possibility of personalized treatment options for individual patients by individualizing ART based on specific radiation responses by pathologic types of lung cancer.

Stereotactic ablative radiotherapy for pulmonary oligometastases from primary hepatocellular carcinoma: a multicenter and retrospective analysis (KROG 17-08).

OBJECTIVE: Hypofractionated radiotherapy has recently been applied to treat pulmonary metastases of hepatocellular carcinoma. However, there is no definite evidence on its safety and efficacy. We evaluate the clinical outcomes of hypofractionated radiotherapy for oligo pulmonary metastases of hepatocellular carcinoma in the multicenter and retrospective study. METHODS: From March 2011 to February 2018, 58 patients with fewer than five pulmonary metastases of hepatocellular carcinoma who underwent hypofractionated radiotherapy in nine tertiary university hospitals were analyzed retrospectively. The primary endpoint was the local control rate. The secondary endpoints were overall survival, progression-free survival, prognostic factors affecting the treatment outcomes and treatment-related side effects. RESULTS: The local tumor response rate including complete and partial response was 77.6% at 3 months after hypofractionated radiotherapy. The median survival and progression-free survival times were 20.9 and 5.3 months, respectively. The 1-year overall survival and progression-free survival rates were 65.5 and 22.4%, respectively. The good treatment response after hypofractionated radiotherapy (P = 0.001), the absence of intrahepatic tumor (P = 0.004) and Child-Pugh class A (P = 0.010) were revealed as significant prognostic factors for overall survival in the multivariate analysis. A progression-free interval of <6 months (P = 0.009) was a negative prognostic factor for overall survival in the multivariate analysis. Of 58 patients, five (8.6%) had grade 2 or higher radiation pneumonitis after hypofractionated radiotherapy. CONCLUSIONS: The favorable local control rate and acceptable toxicity indicate the clinical usefulness of hypofractionated radiotherapy for hepatocellular carcinoma patients who have less than five pulmonary metastases.

Effects of Tumor-Rib Distance and Dose-Dependent Rib Volume on Radiation-Induced Rib Fractures in Patients with Breast Cancer.

This study aimed to investigate the effects of tumor-rib distance and dose-dependent rib volume on radiation-induced rib fractures (RIRFs) in patients with breast cancer. We retrospectively included 510 women with breast cancer who underwent surgical resection with adjuvant radiotherapy. The tumor-rib distance was measured using preoperative computed tomography (CT) images. Postoperative chest wall thickness and dose-dependent rib volumes, which are absolute rib volumes receiving >20 Gy (V20), 30 Gy (V30), 40 Gy (V40), 45 Gy (V45), and 50 Gy (V50), were measured from the stimulation CT images for radiation treatment planning. We assessed the relationship of RIRF with tumor-rib distance, postoperative chest wall thickness, and dose-dependent rib volumes. Patients with high values of tumor-rib distance and postoperative chest wall thickness had significantly lower risks of RIRF than those with low values. Patients with high values of V20, V30, V40, V45, and V50 had significantly higher risks of RIRF than those with low values. In a multivariate analysis, tumor-rib distance and all five dose-dependent rib volumes, as well as osteoporosis and radiation field, were independent risk factors for RIRF. Tumor-rib distance and dose-dependent rib volume were independent risk factors for RIRF in patients with breast cancer.

Comparison of Dose Distribution in Regional Lymph Nodes in Whole-Breast Radiotherapy vs. Whole-Breast Plus Regional Lymph Node Irradiation: An In Silico Planning Study in Participating Institutions of the Phase III Randomized Trial (KROG 1701).

The purpose of the current in silico planning study is to compare radiation doses of whole-breast irradiation (WBI) and whole-breast plus regional lymph node irradiation (WBI+RNI) administered to the regional lymph nodes (RLN) in pN1 breast cancer. Twenty-four participating institutions were asked to create plans of WBI and WBI+RNI for two dummy cases. To compare target coverage between the participants, an isodose line equal to 90% of the prescribed dose was converted to an isodose contour (contour90% iso). The relative nodal dose (RND) was obtained using the ratio of RLN dose to the target dose. The Fleiss's kappa values which represent inter-observer agreement of contour90% iso were over 0.68. For RNI, 6 institutions included axillary lymph node (ALN), supraclavicular lymph node (SCN), and internal mammary lymph node (IMN), while 18 hospitals included only ALN and SCN. The median RND between the WBI and WBI+RNI were as follows: 0.64 vs. 1.05 (ALN level I), 0.27 vs. 1.08 (ALN level II), 0.02 vs. 1.12 (ALN level III), 0.01 vs. 1.12 (SCN), and 0.54 vs. 0.82 (IMN). In all nodal regions, the RND was significantly lower in WBI than in WBI+RNI (p < 0.01). In this study, we could identify the nodal dose difference between WBI and WBI+RNI.

Dosimetric comparison of incidental axillary irradiation between three-dimensional conformal and volumetric modulated arc techniques for breast cancer.

Radiotherapy techniques for breast cancer have evolved with efforts to reduce treatment-related side effects. In the present study, we conducted dosimetric analysis of incidental axillary irradiation between volumetric modulated arc therapy (VMAT) and three-dimensional conformal radiotherapy (3D-CRT). A total of 20 patients with early stage left breast cancer who underwent breast-conserving surgery followed by postoperative radiotherapy were analyzed. For VMAT plans, dose-volume constraints were not imposed on the axilla, as with 3D-CRT. We compared the dosimetric parameters of the planning target volumes, organs at risk and axillary level I-III of the two plans. VMAT showed better target coverage and a normal organ-sparing effect compared with 3D-CRT. The incidental axillary irradiation of VMAT was lower; the mean dose and the V40Gy were significantly reduced at all axillary levels, with the exception of no difference in the maximum dose to axillary level I. In conclusion, VMAT decreased incidental axillary irradiation, even in the absence of a dose-volume constraint on the axilla, and can, therefore, decrease the risk of radiotherapy-related lymphedema. However, caution is also required because it is unclear whether this incidental axillary irradiation is beneficial for reducing recurrence on the axilla.

Relationship Between Changes in Myocardial F-18 Fluorodeoxyglucose Uptake and Radiation Dose After Adjuvant Three-Dimensional Conformal Radiotherapy in Patients with Breast Cancer.

This study aimed to assess the relationship between radiation dose and changes in the irradiated myocardial F-18 fluorodeoxyglucose (FDG) uptake after radiotherapy (RT) in breast cancer patients. The data of 55 patients with left and 48 patients with right breast cancer who underwent curative surgical resection and adjuvant three-dimensional conformal RT and staging (PET1), post-adjuvant chemotherapy (PET2), post-RT (PET3), and surveillance (PET4) FDG positron emission tomography/computed tomography (PET/CT) were retrospectively reviewed. The median interval between PET1 and curative surgical resection, between the end of adjuvant chemotherapy and PET2, between the end of RT and PET3, and between the end of RT and PET4 were five days, 13 days, 132 days, and 353 days, respectively. The myocardial-to-blood pool uptake ratio was measured in all patients. For patients with left breast cancer, the 30 Gy- (30 Gy) and 47.5 Gy-irradiated myocardium-to-low-irradiated myocardium (47.5 Gy) FDG uptake ratios were additionally measured. There were no differences in the myocardial-to-blood pool uptake ratios between left and right breast cancer on all PET scans. For left breast cancer, higher 30 Gy and 47.5 Gy uptake ratios were observed on PET3 than on PET1 and PET2. Both uptake ratios decreased on PET4 compared to PET3, but, were still higher compared to PET1. On PET3 and PET4, the 47.5 Gy were higher than the 30 Gy uptake ratios, while there were no differences between them on PET1 and PET2. Although the whole myocardium FDG uptake showed no significant change, the irradiated myocardium FDG uptake significantly increased after RT and was related to radiation dose to the myocardium in breast cancer patients. These results might be an imaging evidence that supports the increased risk of heart disease after RT in patients with left breast cancer.

A phase 2 multicenter study of stereotactic body radiotherapy for hepatocellular carcinoma: Safety and efficacy.

BACKGROUND: Although several prospective studies have reported the efficacy of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC), treatment-related toxicity varies and has not been determined. Therefore, the authors evaluated the safety and efficacy of SBRT for patients with HCC in a hepatitis B virus-endemic area. METHODS: This multicenter phase 2 trial enrolled patients with unresectable HCC. Patients received SBRT with 45 to 60 Gy in 3 fractions. To evaluate gastroduodenal toxicity, esophagogastroduodenoscopy (EGD) was performed before and 2 months after SBRT. The primary endpoint was treatment-related severe toxicity at 1 year after SBRT. The secondary endpoints were the 2-year local control, progression-free survival, and overall survival rates. RESULTS: In total, 74 patients were enrolled between January 2012 and April 2015, and 65 eligible patients were analyzed. One patient experienced radiation-induced liver disease with acute grade ≥3 toxicity 1 month after SBRT. In addition, 1 patient had a grade 3 esophageal ulcer with stenosis 5 months after SBRT. The actuarial rate of treatment-related severe toxicity at 1 year was 3%. The pre-SBRT and post-SBRT EGD findings were not significantly different among the 57 evaluable patients who underwent EGD. The 2-year and 3-year local control rates were 97% and 95%, respectively. The progression-free and overall survival rates were 48% and 84% at 2 years, respectively, and 36% and 76% at 3 years, respectively. CONCLUSIONS: With a median follow-up of 41 months, this prospective multicenter study demonstrated that SBRT for patients with HCC is well tolerated and is an effective treatment modality.

Clinical significance of radiation-induced liver disease after stereotactic body radiation therapy for hepatocellular carcinoma.

BACKGROUND/AIMS: The aim of this study was to investigate parameters that predict radiation-induced liver disease (RILD) following stereotactic body radiotherapy (SBRT) in patients with hepatocellular carcinoma (HCC) and to identify the clinical significance of RILD. METHODS: We retrospectively reviewed the medical records of 117 HCC patients who were treated by SBRT from March 2011 to February 2015. RILD was defined as elevated liver transaminases more than five times the upper normal limit or a worsening of Child-Pugh (CP) score by 2 within 3 months after SBRT. All patients were assessed at 1 month and every 3 months after SBRT. RESULTS: Median follow-up was 22.5 months (range, 3 to 56) after SBRT. RILD was developed in 29 of the 117 patients (24.7%). On univariate analysis, significant predictive factors of RILD were pretreatment CP score (p < 0.001) and normal liver volume (p = 0.002). Multivariate analysis showed that CP score was a significant predictor of RILD (p < 0.001). The incidence of RILD increased above a CP score of 6 remarkably. The rate of recovery from RILD decreased significantly above a CP score of 8. Survival analysis showed that CP score was an independent prognostic factor of overall survival (p = 0.001). CONCLUSION: CP score is a significant factor to predict RILD in patients with chronic liver disease. RILD can be tolerated by patients with a CP score ≤ 7. However, careful monitoring of liver function is needed for patients with a CP score 7 after SBRT.

Quality assurance for a multicenter Phase II study of stereotactic ablative radiotherapy for hepatocellular carcinoma ≤5 cm: a planning dummy run.

OBJECTIVE: The Korean Radiation Oncology Group (12-02) investigated the outcome of stereotactic ablative radiotherapy for hepatocellular carcinoma ≤5 cm using 60 Gy in three fractions. To evaluate dosimetric differences and compliance in a multicenter trial, a planning dummy run procedure was performed. METHODS: All six participating institutions were provided the contours of two dummy run cases. Plans were performed following the study protocol to cover the planning target volume with a minimum of 90% of the prescription dose and to satisfy the constraints for organs at risk. We assessed the institutional variations in plans using dose-volume histograms. RESULTS: Different planning techniques were applied: static intensity-modulated radiotherapy in two institutions, CyberKnife in two institutions and RapidArc in two institutions. The conformity index of all 12 plans was ≤1.2. In terms of the planning target volume coverage, all participants followed our study protocol. For the second dummy run case, located in Segment 8 near the heart, the minimum dose of the planning target volume (D99%: dose covering 99% of the planning target volume) was variable because there was no mention of constraints of D99% of the planning target volume in the study protocol. As an important organ at risk, the normal liver volumes receiving <17 Gy in all 12 plans were >700 ml. CONCLUSIONS: Dosimetric parameters showed acceptable compliance with the study protocol. However, we found the possibility of underdose to the planning target volume if the hepatocellular carcinoma lesion was located near organs at risk such as the heart. Based on this dummy run, we will conduct individual case reviews to minimize the effects of study protocol deviation.

The role of 18F-fluorodeoxyglucose uptake of bone marrow on PET/CT in predicting clinical outcomes in non-small cell lung cancer patients treated with chemoradiotherapy.

OBJECTIVES: This study aimed to assess the relationship between bone marrow (BM) FDG uptake on PET/CT and serum inflammatory markers and to evaluate the prognostic value of BM FDG uptake for predicting clinical outcomes in non-small cell lung cancer (NSCLC) patients. METHODS: One hundred and six NSCLC patients who underwent FDG PET/CT for staging work-up and received chemoradiotherapy were enrolled. Mean BM FDG uptake (BM SUV) and BM-to-liver uptake ratio (BLR) were measured, along with volumetric parameters of PET/CT. The relationship of BM SUV and BLR with hematologic parameters and serum inflammatory markers was evaluated. Prognostic values of BM SUV and BLR for predicting progression-free survival (PFS) and overall survival (OS) were assessed. RESULTS: BM SUV and BLR were significantly correlated with white blood cell count and C-reactive protein level. On univariate analysis, BLR was a significant prognostic factor for both PFS and OS. On multivariate analysis, TNM stage and BLR were independent prognostic factors for PFS, and only TNM stage was an independent prognostic factor for OS. CONCLUSIONS: In NSCLC patients, FDG uptake of BM reflects the systemic inflammatory response and can be used as a biomarker to identify patients with poor prognosis. KEY POINTS: • Bone marrow FDG uptake is correlated with serum inflammatory markers. • Bone marrow FDG uptake is an independent prognostic factor for progression-free survival. • Bone marrow FDG uptake can provide information on predicting lung cancer progression.

Practical patterns for stereotactic body radiotherapy to hepatocellular carcinoma in Korea: a survey of the Korean Stereotactic Radiosurgery Group.

OBJECTIVE: To investigate practical patterns for stereotactic body radiotherapy to hepatocellular carcinoma in Korea. METHODS: In June 2013, the Korean Stereotactic Radiosurgery Group of the Korean Society for Radiation Oncology conducted a national patterns-of-care survey about stereotactic body radiotherapy to the liver lesion in hepatocellular carcinoma, consisting of 19 questions and 2 clinical scenarios. RESULTS: All 208 radiation oncologists (100%), who are regular members of Korean Society for Radiation Oncology, responded to this survey. Among these, 95 radiation oncologists were specialists for hepatology; 64 physicians did not use stereotactic body radiotherapy for hepatocellular carcinoma, and 31 physicians used stereotactic body radiotherapy. Most physicians (52%) performed stereotactic body radiotherapy to hepatocellular carcinoma in ≤5 cases per year. Physicians applied stereotactic body radiotherapy according to tumour size and baseline Child-Pugh class. All physicians agreed the use of stereotactic body radiotherapy to 2.8-cm hepatocellular carcinoma with Child-Pugh class of A, while 23 physicians (74%) selected stereotactic body radiotherapy for Child-Pugh class of B. Nineteen physicians (61%) selected stereotactic body radiotherapy to 5-cm hepatocellular carcinoma with Child-Pugh class of A, and only 14 physicians (45%) selected stereotactic body radiotherapy for Child-Pugh class of B. On the other hand, the preferred dose scheme was same as 60 Gy in three fractions. CONCLUSIONS: Among radiation oncologists in Korea, there was diversity in the practice for stereotactic body radiotherapy to the liver lesion in hepatocellular carcinoma. Additional prospective studies are necessary to standardize the practice and establish Korea-specific practice guidelines for hepatocellular carcinoma stereotactic body radiotherapy.

A Survey of Stereotactic Body Radiotherapy in Korea.

PURPOSE: The purpose of this study is to investigate the current status of stereotactic body radiotherapy (SBRT) in Korea. A nationwide survey was conducted by the Korean Stereotactic Radiosurgery Group of the Korean Society for Radiation Oncology (KROG 13-13). MATERIALS AND METHODS: SBRT was defined as radiotherapy with delivery of a high dose of radiation to an extracranial lesion in ≤ 4 fractions. A 16-questionnaire survey was sent by e-mail to the chief of radiation oncology at 85 institutions in June 2013. RESULTS: All institutions (100%) responded to this survey. Of these, 38 institutions (45%) have used SBRT and 47 institutions (55%) have not used SBRT. Regarding the treatment site, the lung (92%) and liver (76%) were the two most common sites. The most common schedules were 60 Gy/4 fractions for non-small cell lung cancer, 48 Gy/4 fractions for lung metastases, 60 Gy/3 fractions for hepatocellular carcinoma, and 45 Gy/3 fractions or 40 Gy/4 fractions for liver metastases. Four-dimensional computed tomography (CT) was the most common method for planning CT (74%). During planning CT, the most common method of immobilization was the use of an alpha cradle/vacuum-lock (42%). CONCLUSION: Based on this survey, conduct of further prospective studies will be needed in order to determine the appropriate prescribed doses and to standardize the practice of SBRT.

Upregulation of stromal cell-derived factor 1α expression is associated with the resistance to neoadjuvant chemoradiotherapy of locally advanced rectal cancer: angiogenic markers of neoadjuvant chemoradiation.

The ability to achieve pathologic downstaging after neoadjuvant chemoradiotherapy (NCRT) is correlated with improved survival in locally advanced rectal cancer (LARC). However, there is no effective predictive markers. In this study, the expression of angiogenic markers was evaluated in pre-treatment biopsies and corresponding post-treatment resection specimens, and were correlated to histopathological tumour characteristics and response. Fifty-five patients with stage II/III rectal cancer treated with 5-fluorouracil (5-FU)-based NCRT were studied. All patients were administered NCRT followed by surgical resection. Immunohistochemical staining for angiogenic markers [hypoxia-inducible factor 1α (HIF­1α), vascular endothelial growth factor (VEGF), stromal cell­derived factor 1α (SDF-1α) and placental growth factor (PlGF)] was performed on specimens obtained before NCRT and after surgery. Expression of VEGF, PlGF and HIF-1α protein was downregulated after NCRT in the rectal cancer tissues (P<0.001, P=0.001 and P=0.044, respectively). However, SDF-1α was upregulated after NCRT (P<0.001). Moreover, upregulated expression of SDF-1α (P=0.016) and positive PlGF staining (P=0.001) after NCRT were significantly associated with resistance to NCRT. On multivariate analysis, positive PlGF staining after NCRT was found to be independently associated with resistance to NCRT (P=0.013). Our data suggest that SDF-1α and PlGF should be evaluated as new targets for NCRT in LARC.

Efficient approach for determining four-dimensional computed tomography-based internal target volume in stereotactic radiotherapy of lung cancer.

PURPOSE: This study aimed to investigate efficient approaches for determining internal target volume (ITV) from four-dimensional computed tomography (4D CT) images used in stereotactic body radiotherapy (SBRT) for patients with early-stage non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: 4D CT images were analyzed for 15 patients who received SBRT for stage I NSCLC. Three different ITVs were determined as follows: combining clinical target volume (CTV) from all 10 respiratory phases (ITV10Phases); combining CTV from four respiratory phases, including two extreme phases (0% and 50%) plus two intermediate phases (20% and 70%) (ITV4Phases); and combining CTV from two extreme phases (ITV2Phases). The matching index (MI) of ITV4Phases and ITV2Phases was defined as the ratio of ITV4Phases and ITV2Phases, respectively, to the ITV10Phases. The tumor motion index (TMI) was defined as the ratio of ITV10Phases to CTVmean, which was the mean of 10 CTVs delineated on 10 respiratory phases. RESULTS: The ITVs were significantly different in the order of ITV10Phases, ITV4Phases, and ITV2Phases (all p < 0.05). The MI of ITV4Phases was significantly higher than that of ITV2Phases (p < 0.001). The MI of ITV4Phases was inversely related to TMI (r = -0.569, p = 0.034). In a subgroup with low TMI (n = 7), ITV4Phases was not statistically different from ITV10Phases (p = 0.192) and its MI was significantly higher than that of ITV2Phases (p = 0.016). CONCLUSION: The ITV4Phases may be an efficient approach alternative to optimal ITV10Phases in SBRT for early-stage NSCLC with less tumor motion.

Effect of jaw size in megavoltage CT on image quality and dose.

PURPOSE: Recently, the jaw size for the TomoTherapy Hi-Art II(®) (TomoTherapy Inc., Madison, WI) was reduced from 4 mm (J4) to 1 mm (J1) to improve the longitudinal (IEC-Y) resolution in megavoltage computed tomography (MVCT) images. This study evaluated the effect of jaw size on the image quality and dose, as well as the dose delivered to the lens of the eye, which is a highly radiosensitive tissue. METHODS: MVCT image quality (image noise, uniformity, contrast linearity, high-contrast resolution, and full width at half-maximum) and multiple scan average dose (MSAD) were measured at different jaw sizes. A head phantom and photoluminescence glass dosimeters (PLDs) were used to measure the exposed lens dose (cGy). Different MVCT scan modes (pitch = 1, 2, and 3) and scan lengths (108 mm, 156 mm, and 204 mm) were applied in the MSAD and PLDs measurements. RESULTS: The change in jaw size from J4 to J1 produced no change or only a slight improvement in image noise, uniformity, contrast linearity, and high-contrast resolution. However, the full-width at half-maximum reduced from approximately 7.2 at J4 to 4.5 mm at J1, which represents an enhancement in the longitudinal resolution. The MSAD at the center point changed from approximately 0.69-2.32 cGy (peripheral: 0.83-2.49 cGy) at J4 to 0.85-2.81 cGy (peripheral: 1.05-2.86 cGy) at J1. The measured lens dose increased from 0.92-3.36 cGy at J4 to 1.06-3.91 cGy at J1. CONCLUSIONS: The change in jaw size improved longitudinal resolution. The MVCT imaging dose of approximately 3.86 cGy, 1.92 cGy, and 1.22 cGy was delivered at a pitch of 1, 2, and 3, respectively, per fraction in the head and neck treatment plans. Therefore, allowance for an approximately 15% increase in lens dose over that with J4 should be provided with J1.