Aerobic Exercise Improves Radiation Therapy Efficacy in Non-Small Cell Lung Cancer: Preclinical Study Using a Xenograft Mouse Model.

The "oxygen effect" improves radiation efficacy; thus, tumor cell oxygen concentration is a crucial factor for improving lung cancer treatment. In the current study, we aimed to identify aerobic exercise-induced changes in oxygen concentrations in non-small cell lung cancer (NSCLC) cells. To this end, an NSCLC xenograft mouse model was established using human A549 cells. Animals were subsequently subjected to aerobic exercise and radiation three times per week for 2 weeks. Aerobic exercise was performed at a speed of 8.0 m/m for 30 min, and the tumor was irradiated with 2 Gy of 6 MV X-rays (total radiation dose 12 Gy). Combined aerobic exercise and radiation reduced NSCLC cell growth. In addition, the positive effect of aerobic exercise on radiation efficacy through oxygenation of tumor cells was confirmed based on hypoxia-inducible factor-1 and carbonic anhydrase IX expression. Finally, whole-transcriptome analysis revealed the key factors that induce oxygenation in NSCLC cells when aerobic exercise was combined with radiation. Taken together, these results indicate that aerobic exercise improves the effectiveness of radiation in the treatment of NSCLC. This preclinical study provides a basis for the clinical application of aerobic exercise to patients with NSCLC undergoing radiation therapy.

Salvage hypofractionated accelerated versus standard radiotherapy for the treatment of biochemical recurrence after radical prostatectomy (SHARE): the protocol of a prospective, randomized, open-label, superiority, multi-institutional trial.

BACKGROUND: While several phase III trials have investigated the role of hypofractionated radiotherapy in the definitive treatment of localized prostate cancer, prospective data reporting the outcomes of hypofractionated radiotherapy in the postoperative treatment setting are sparse. Therefore, this study is designed to assess the efficacy and treatment-related toxicity of hypofractionated salvage radiotherapy for the treatment of biochemical recurrence in men who underwent radical prostatectomy. The primary objective of this trial is to investigate whether hypofractionated radiotherapy improves biochemical control compared with conventionally fractionated radiotherapy. In addition, treatment-related toxicity, quality of life, and survival will be evaluated as secondary endpoints. METHODS: In this prospective, randomized, multi-institutional trial (the SHARE study), patients with intermediate- or high-risk prostate cancer will be randomized to receive either hypofractionated radiotherapy (65 Gy in 2.5-Gy fractions) or conventionally fractionated radiotherapy (66 Gy in 2-Gy fractions). Prostate bed irradiation or elective pelvic nodal irradiation including the prostate bed will be performed using intensity-modulated radiotherapy and daily image guidance. Treatment efficacy will be assessed using the serum tumor marker prostate-specific antigen, and toxicity will be evaluated through both physician- and patient-reported outcomes. Quality of life will also be investigated. DISCUSSION: This study is designed to demonstrate whether hypofractionated radiotherapy is beneficial in terms of biochemical control and toxicity compared with standard salvage radiotherapy. If hypofractionated radiotherapy is shown to be superior to conventionally fractionated radiotherapy, it will mean that improved biochemical control can be achieved, accompanied by greater patient convenience and more efficient use of medical resources. TRIAL REGISTRATION: ClinicalTrials.gov NCT03920033. Registered on 18 April 2019.

18F-FDG PET/CT Parameters for Predicting Prognosis in Esophageal Cancer Patients Treated With Concurrent Chemoradiotherapy.

BACKGROUND AND AIMS: This study evaluated the prognostic value of 18F-fluorodeoxyglucose positron emission tomography with integrated computed tomography (18F-FDG PET/CT) performed before and after concurrent chemoradiotherapy (CCRT) in esophageal cancer. METHODS: We analyzed the prognosis of 50 non-metastatic squamous cell esophageal cancer (T1-4N0-2) patients who underwent CCRT with curative intent at Inje University Busan Paik Hospital and Haeundae Paik Hospital from 2009 to 2019. Median total radiation dose was 54 Gy (range 34-66 Gy). Our aim was to investigate the relationship between PET/CT values and prognosis. The primary end point was progression-free survival (PFS). RESULTS: The median follow-up period was 9.9 months (range 1.7-85.7). Median baseline maximum standard uptake value (SUVmax) was 14.2 (range 3.2-27.7). After treatment, 29 patients (58%) showed disease progression. The 3-year PFS and overall survival (OS) were 24.2% and 54.5%, respectively. PFS was significantly lower (P = 0.015) when SUVmax of initial PET/CT exceeded 10 (n = 22). However, OS did not reach a significant difference based on maximum SUV (P = 0.282). Small metabolic tumor volume (≤14.1) was related with good PFS (P = 0.002) and OS (P = 0.001). Small total lesion of glycolysis (≤107.3) also had a significant good prognostic effect on PFS (P = 0.009) and OS (P = 0.025). In a subgroup analysis of 18 patients with follow-up PET/CT, the patients with SUV max ≤3.5 in follow-up PET/CT showed longer PFS (P = 0.028) than those with a maximum SUV >3.5. CONCLUSION: Maximum SUV of PET/CT is useful in predicting prognosis of esophageal cancer patients treated with CCRT. Efforts to find more effective treatments for patients at high risk of progression are still warranted.

The value of prophylactic cranial irradiation in limited-stage small cell lung cancer: should it always be recommended?

PURPOSE: Prophylactic cranial irradiation (PCI) is a standard treatment for limited-stage small cell lung cancer (LS-SCLC) showing a response to initial treatment, but many patients do not receive PCI due to comorbidities or refusal. This study aims to define the patient group for whom PCI can be omitted with minimal risk. MATERIALS AND METHODS: Patients with LS-SCLC who underwent radiotherapy with curative aim at our institution between January 2004 and December 2015 were retrospectively reviewed. Patients who did not receive PCI were evaluated for brain metastasis-free survival (BMFS), progression-free survival (PFS), overall survival (OS), and prognostic factors for survival, and treatment outcomes were compared with a patient cohort who received PCI. RESULTS: A total of 350 patients achieved a response following thoracic radiotherapy, and 190 of these patients did not receive PCI. Stage I-II and a complete response (CR) to initial therapy were good prognostic factors for BMFS and OS on univariate analysis. Patients with both stage I-II and a CR who declined PCI showed comparable 2-year BMFS to those who received PCI (92% vs. 89%). In patients who achieved CR, PCI did not significantly improve OS or PFS. CONCLUSION: There should be less concern about omitting PCI in patients with comorbidities if they have stage I-II or a CR, with brain metastasis control being comparable to those patients who receive PCI.

The pretreatment erythrocyte sedimentation rate predicts survival outcomes after surgery and adjuvant radiotherapy for extremity soft tissue sarcoma.

BACKGROUND: Systemic inflammation plays a critical role in cancer progression and oncologic outcomes in cancer patients. We investigated whether preoperative inflammatory biomarkers, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and neutrophil to lymphocyte ratio (NLR), could be surrogate biomarkers for predicting overall survival (OS) in soft tissue sarcoma (STS) patients treated with surgery and postoperative radiotherapy. METHODS: A series of 99 patients who presented with localized extremity STS were retrospectively reviewed. The preoperative CRP levels, ESR, and NLR were evaluated for associations with OS, disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS). Cutoff values for CRP, ESR, and NLR were derived from receiver-operating characteristic curve analysis. RESULTS: Elevated CRP (> 0.14 mg/dL), ESR (> 15 mm/h), and NLR (> 1.95) levels were seen in 33, 44, and 45 patients, respectively. Of these three inflammatory biomarkers, elevated CRP and ESR were associated with a poorer OS (CRP: P = 0.050; ESR: P = 0.001), DFS (CRP: P = 0.023; ESR: P = 0.003), and DMFS (CRP: P = 0.015; ESR: P = 0.001). By multivariate analysis, an elevated ESR was found to be an independent prognostic factor for OS (HR 3.580, P = 0.025) and DMFS (HR 3.850, P = 0.036) after adjustment for other established prognostic factors. CONCLUSIONS: The preoperative ESR level is a simple and useful surrogate biomarker for predicting survival outcomes in STS patients and might improve the identification of high-risk patients of tumor relapse in clinical practice.

Postoperative radiotherapy for mucoepidermoid carcinoma of the major salivary glands: long-term results of a single-institution experience.

PURPOSE: This study aimed to evaluate the long-term survival outcomes and prognostic factors that affect the clinical outcomes of patients who underwent surgery and postoperative radiotherapy for major salivary gland mucoepidermoid carcinoma (MEC). MATERIALS AND METHODS: We retrospectively reviewed the clinical data of 44 patients who underwent surgery followed by radiotherapy for primary MEC of the major salivary glands between 1991 and 2014. The median follow-up period was 9.8 years (range, 0.8 to 23.8 years). RESULTS: The overall outcomes at 5 and 10 years were 81.5% and 78.0% for overall survival (OS), 86.2% and 83.4% for disease- free survival, 90.6% and 87.6% for locoregional recurrence-free survival, and both 90.5% for distant metastasis-free survival (DMFS). Histologic grade was the only independent predictor of OS (low vs. intermediate vs. high; hazard ratio = 3.699; p = 0.041) in multivariate analysis. A poorer survival was observed among patients with high-grade tumors compared with those with non-high- grade tumors (5-year OS, 37.5% vs. 91.7%, p < 0.001; 5-year DMFS, 46.9% vs. 100%, p < 0.001). CONCLUSION: Surgery and postoperative radiotherapy resulted in excellent survival outcomes for patients with major salivary gland MEC. However, high-grade tumors contributed to poor DMFS and OS. Additional aggressive strategies for improving survival outcomes should be developed for high-grade MEC.

Chemoradiotherapy versus surgery followed by postoperative radiotherapy in tonsil cancer: Korean Radiation Oncology Group (KROG) study.

BACKGROUND: Treatment of tonsil cancer, a subset of oropahryngeal cancer, varies between surgery and radiotherapy. Well-designed studies in tonsil cancer have been rare and it is still controversial which treatment is optimal. This study aimed to assess the outcome and failure patterns in tonsil cancer patients treated with either approaches. METHODS: We retrospectively reviewed medical records of 586 patients with tonsil cancer, treated between 1998 and 2010 at 16 hospitals in Korea. Two hundred and one patients received radiotherapy and chemotherapy (CRT), while 385 patients received surgery followed by radiotherapy and/or chemotherapy (SRT). Compared with the SRT group, patients receiving CRT were older, with more advanced T stage and received higher radiotherapy dose given by intensity modulation techniques. Overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and clinicopathologic factors were analyzed. RESULTS: At follow-up, the 5-year OS, DFS, LRRFS and DMFS rates in the CRT group were 82, 78, 89, and 94%, respectively, and in the SRT group were 81, 73, 87, and 89%, respectively. Old age, current smoking, poor performance status, advanced T stage, nodal involvement, and induction chemotherapy were associated with poor OS. Induction chemotherapy had a negative prognostic impact on OS in both treatment groups (p = 0.001 and p = 0.033 in the CRT and SRT groups, respectively). CONCLUSIONS: In our multicenter, retrospective study of tonsil cancer patients, the combined use of radiotherapy and chemotherapy resulted in comparable oncologic outcome to surgery followed by postoperative radiotherapy, despite higher-risk patients having been treated with the definitive radiotherapy. Induction chemotherapy approaches combined with either surgery or definitive radiotherapy were associated with unfavorable outcomes.

Definitive extended-field intensity-modulated radiotherapy with chemotherapy for cervical cancer with para-aortic nodal metastasis.

AIM: To evaluate the efficacy and toxicity of definitive extended-field intensity-modulated radiotherapy (EF-IMRT) with chemotherapy in cervical cancer with para-aortic lymph node (PAN) metastasis. PATIENTS AND METHODS: The present retrospective cohort study involved 45 consecutive patients. EF-IMRT consisted of 46 Gy to pelvic and para-aortic regions, 14 Gy-boost to gross nodes, and 30 Gy in six fractions of intracavitary brachytherapy. Platinum-based chemotherapy occurred simultaneously. RESULTS: Two-year overall and disease-free survival rates (median follow-up=30 months) were 85.4% and 61.7%, respectively. In 78%, 89%, and 89%, the primary cervical mass, pelvic metastasis, and PAN metastasis exhibited a complete response, respectively. Ten, four, and other four patients exhibited locoregional (including post-treatment residual disease), distant, and combined failure, respectively. The most common severe acute toxicity was hematological (n=36). One and two patients had severe late gastrointestinal and other toxicities, respectively. CONCLUSION: EF-IMRT (to 60 Gy) plus chemotherapy resulted in good locoregional control, survival rates, and acceptable toxicity.

Two-week schedule of hypofractionated radiotherapy as a local salvage treatment for small hepatocellular carcinoma.

BACKGROUND AND AIM: In cases of small hepatocellular carcinoma (HCC) where established curative treatment cannot be applied, stereotactic body radiotherapy (SBRT) has been used as a non-invasive alternative treatment modality. However, short-course SBRT may not be safe if the tumor is located around a critical normal organ. Therefore, we applied hypofractionated radiotherapy for these tumors and evaluated outcomes of this treatment. METHODS: Between December 2008 and August 2011, 26 patients (28 lesions) with HCC were treated with hypofractionated radiotherapy. Inclusion criteria were HCC not suitable for surgery or other local ablative therapy, a tumor size < 6 cm, adequate hepatic function, an HCC located within 2 cm of a critical organ, and no evidence of vascular invasion. A dose of 4-5 Gy per fraction was given, with a total dose of 40-50 Gy over 2 weeks. RESULTS: The overall response rate was 67.9%, with seven complete responses (25.0%) and 12 partial responses (42.9%) at 3 months after radiotherapy. The overall survival rates at 1 and 2 years were 88.5% and 67.2%, respectively. The local control rate at 2 years was 87.6%. The Intrahepatic recurrence-free and distant failure-free survival rates at 2 years were 36.5% and 68.2%, respectively. Grade ≥ 3 hepatic toxicity was observed in one patient. CONCLUSIONS: Two-week schedule of hypofractionated radiotherapy for small HCC was feasible with good local control and safety. This fractionation schedule can be used as an alternative treatment option for HCC located close to a critical normal organ if short-course SBRT is not feasible.

Can concurrent chemoradiotherapy replace surgery and postoperative radiation for locally advanced stage III/IV tonsillar squamous cell carcinoma?

AIM: To compare surgery and postoperative radiotherapy (PORT) with the non-surgical combination of chemotherapy and radiation therapy (CCRT) for locally advanced squamous cell carcinoma (SCC) of the tonsil by measuring treatment outcomes and treatment-related complications. PATIENTS AND METHODS: The records of 114 patients with non-metastatic stage III/IV tonsillar SCC treated between July, 1998 and December, 2010 were reviewed retrospectively. Among the 114 patients, 65 received PORT and 49 received CCRT. In the PORT group, treatment included wide surgical resection of the tumor with neck dissection and administration of PORT to the primary tumor bed with a median dose of 60 Gy. In the CCRT group, a median dose of 70 Gy was delivered to the gross tumor, and 46 patients received concurrent chemotherapy with i.v. cisplatin. The median follow-up time was 58 months in the PORT group and 44 months in the CCRT group. RESULTS: There was no significant difference between PORT and CCRT in terms of 5-year locoregional recurrence-free survival (88.4% vs. 91.4%, p=0.68), distant metastasis-free survival (88.9% vs. 92.3%, p=0.60), disease-free survival (79.5% vs. 84.2%, p=0.63) or overall survival (78.9% vs. 88.9%, p=0.45). More CCRT patients than PORT patients experienced grade 3 (or higher) hematological toxicities and grade 2 pharyngitis during treatment. Chronic toxicity, manifested as swallowing difficulty, dry mouth and trismus, was similar between the two treatment groups. CONCLUSION: CCRT provides similar levels of local and distant control in patients with locally advanced tonsillar SCC as PORT, yet fails to show any superiority in preserving functions such as swallowing, saliva production, and mastication.

Low-dose external beam radiotherapy as a postoperative treatment for patients with diffuse pigmented villonodular synovitis of the knee: 4 recurrences in 23 patients followed for mean 9 years.

BACKGROUND AND PURPOSE: Pigmented villonodular synovitis (PVNS) is a rare proliferative disorder involving synovial membranes, and patients with PVNS have a variable prognosis. We retrospectively analyzed clinical outcomes after synovectomy plus low-dose external beam radiotherapy for diffuse PVNS of the knee. METHODS: We reviewed the medical records of 23 patients who underwent postoperative radiotherapy between 1998 and 2007. 19 patients had primary disease and 4 had recurrent disease with an average of 2.5 prior surgeries. After synovectomy (17 arthroscopic surgeries; 6 open), all 23 patients received 4-MV or 6-MV external beam radiotherapy with a median dose of 20 (12-34) Gy in 10 fractions. RESULTS: At a median follow-up of 9 (0.8-12) years, 4 patients had recurrent disease, with a median disease-free interval of 5 years. Of these 4 patients, 3 received salvage synovectomy and regained local control. Univariate analysis showed that age, sex, history of trauma, and total dose of radiation were not predictive of local control. 22 patients reported excellent or good joint function, and 1 who refused salvage synovectomy had poor joint function. None of the patients experienced grade 3 or higher radiation-related toxicity or radiation-induced secondary malignancies. INTERPRETATION: Postoperative external beam radiotherapy is an effective and acceptable modality to prevent local recurrence and preserve joint function in patients with diffuse PVNS of the knee. Low-dose (20 Gy) radiotherapy appears to be as effective as moderate-dose treatment (around 35 Gy).

Inter- and intra-observer variability in contouring of the prostate gland on planning computed tomography and cone beam computed tomography.

PURPOSE: To investigate inter-/intra-observer variability in defining the prostate by use of planning computed tomography (PCT) and cone beam CT (CBCT) with magnetic resonance image (MRI) as guidance prior to the introduction of an adaptive radiotherapy for prostate cancer. MATERIAL AND METHODS: We reviewed PCT and firstly acquired CBCT datasets of each ten patients with prostate cancer. Three physicians independently delineated the prostate based on PCT and CBCT with MRI as guidance, allowing determination of inter-physician variability. Two physicians repeated prostate contouring three times in total to investigate intra-physician variability. We compared delineated prostate volumes in terms of the generalized conformity index (CI(gen)), maximum variation ratio (MVR), and center of mass (COM). RESULTS: There were no significant inter-/intra-observer differences in the estimation of prostate volume on both PCT and CBCT. For both inter- and intra-observer variability in contouring the prostate gland, there were no significant differences in MVR between PCT and CBCT. The CI(gen) for inter-observer variability was 0.74 by PCT and 0.69 by CBCT. The CI(gen) for intra-observer variability on PCT and CBCT was 0.84 and 0.81 for observer 2 and 0.76 and 0.73 for observer 3. COM analyses showed that the greatest inter-/intra-observer variability was in the measurement of the prostate apex and base. With respect to CI(gen) and COM analysis for the inter-observer variability, more precise delineation of the prostate was possible on PCT than CBCT. More precise contouring in terms of both CI(gen) and COM was demonstrated by observer 2 than observer 3. CONCLUSIONS: Despite some ambiguity in apex and base level, there was a good consistency in delineating the gland on CBCT plus MRI-guided modification both among/within observer(s), without any significant difference from the consistency in defining the prostate on PCT. This study provides a framework for future studies of CBCT imaging of the prostate.