Keisuke Otani

Histopathological effects of preoperative chemoradiotherapy for pancreatic cancer: An analysis for the impact of radiation and gemcitabine doses

BACKGROUND AND PURPOSE Histopathological findings of patients who underwent resection for pancreatic adenocarcinoma (PC) after preoperative chemoradiotherapy (CRT) reportedly showed beneficial effects. The purpose of our study was to evaluate the correlation between histopathological effects (HE) of preoperative CRT and treatment parameters [radiation and gemcitabine (GEM) doses]. MATERIAL AND METHODS HE of CRT were assessed on 158 primary lesions of 157 patients with PC who underwent pancreatic resection after preoperative CRT with GEM between January 2006 and December 2011. The radiation dose delivered to the primary tumor site and surrounding regional nodal areas was 50 Gy until September 2009 followed by the dose escalation of a 10 Gy boost added for delivery with the field-in-field technique to the roots of the celiac and superior mesenteric arteries. Intravenous administration of GEM (1000 /m(2)) was initiated concurrently on days 1, 8, and 15, every 4 weeks and generally repeated for 3 cycles. HE of CRT on the primary tumor were categorized based on the number of tumor cells destroyed. RESULTS The median overall survival time was 74.5 months and 3-year and 5-year survival rates were 64.3% and 54.5%, respectively. Dose-volume parameters of radiation such as D33 with a cut-off value of 51.6 Gy were correlated significantly with HE (p=.0230). Lesions having received GEM>7625 mg/m(2) before surgical resection more frequently showed positive HE (p=.0002). Multivariate logistic regression analysis demonstrated that both D33 and cumulative GEM dose were significant predictors of definite HE (p=.0110 and <.0001, respectively). CONCLUSIONS Our retrospective analysis showed that dose intensity of radiation and GEM is significantly related to HE of preoperative CRT for PC.

Steroid treatment increases the recurrence of radiation‐induced organizing pneumonia after breast‐conserving therapy

Radiation‐induced organizing pneumonia (RIOP) is an important complication of postoperative radiotherapy for breast cancer. Unfortunately, conventional corticosteroid therapy is frequently associated with relapses. The aim of this retrospective study was to evaluate the outcomes of steroid treatment in patients with RIOP. In total, 26 patients diagnosed with RIOP from among 2404 women who received radiotherapy after breast‐conserving surgery for breast cancer were included and classified into steroid (n = 7) and nonsteroid (n = 19) groups. Serum, sputum, and bronchoalveolar lavage composition; subjective symptoms (cough, fever, and dyspnea); migratory progression; and RIOP relapse were compared between the groups. Treatment type did not affect the duration of the subjective symptoms, which was 1.6 and 1.7 months for the steroid and nonsteroid groups, respectively. In contrast, RIOP relapse and new pulmonary lesions developed in five patients in the steroid group and only three patients in the nonsteroid group (P = 0.014). By assessing RIOP duration as the time to resolution of symptoms and discontinuation of therapy, the median duration of RIOP was significantly longer in the steroid (17.1 months) than that in the nonsteroid group (2.3 months, P = 0.005), primarily because of frequent relapses. After remission, persistent pulmonary dysfunction did not occur in the nonsteroid group. This single‐center retrospective study demonstrates that steroid therapy results in frequent relapses and significantly prolongs RIOP duration. Corticosteroid treatment is considered a critical factor in RIOP recurrence.

Risk factors for vertebral compression fractures in preoperative chemoradiotherapy with gemcitabine for pancreatic cancer

BACKGROUND AND PURPOSE Preoperative chemoradiotherapy (CRT) with gemcitabine (GEM) for pancreatic cancer is often accompanied by vertebral compression fractures (VCFs). This study aimed to establish the incidence of VCFs and identify the related risk factors (RFs) to elucidate how to decrease the overall incidence of VCF. MATERIAL AND METHODS We investigated 220 patients with resectable or borderline-resectable pancreatic cancers who had completed preoperative CRT between 2006 and 2011. The RFs associated with VCF were analyzed in a total of 1308 thoracolumbar vertebral bodies. RESULTS Thirty-seven VCFs occurred in 25 patients (11%); the cumulative incidence at two years was 18.9%. Univariate analysis revealed female sex, age and high daily GEM concentration during radiotherapy as RFs for VCF. The multivariate mixed effects logistic regression model demonstrated that the most responsible factor was radiation dose (p<0.001). We estimated the radiation condition resulting in a fracture incidence of ⩽5% by counting the patients number of the three RFs. For patients with three factors, the mean vertebral dose was 22.0 Gy. CONCLUSIONS The RFs for VCF after CRT were identified. The side effect of VCF might be avoided by regulating the radiation dose to neighboring vertebral bodies after considering the RFs.

Radiation enhanced the local and distant anti-tumor efficacy in dual immune checkpoint blockade therapy in osteosarcoma

Radiation therapy has been long utilized as localized cancer treatment. Recent studies have also demonstrated that it has a distant effect by the enhanced immunity, but it rarely occurs. The purpose of this study was to investigate whether X-ray irradiation combined with anti-PD-L1 and anti-CTLA-4 antibodies (P1C4) provides a higher probability of this distant effect as well as enhanced local antitumor efficacy for osteosarcoma. LM8 mouse osteosarcoma cells were inoculated into both legs of C3H mice assigned to one of four groups, namely no treatment (No Tx), P1C4, X-ray irradiation (RAD) to the leg of one side, and combination (COMB) groups. Survival and treatment-related immune molecular changes were analyzed. Administration of P1C4 produced a tumor growth delay on day 30 in 18% of the mice. In contrast, combination therapy produced the strongest tumor growth inhibition not only at the irradiated tumor but also at unirradiated tumor in 67% of the mice. Accordingly, lung metastasis in the COMB group was strongly reduced by 98%, with a significant survival benefit. Unirradiated tumor in mice in the COMB group significantly recruited CD8 + tumor-infiltrating lymphocytes with a moderate reduction of Treg, producing a significant increase in the CD8/Treg ratio. These results suggest that radiation enhances the efficacy of P1C4 treatment against distant metastasis as well as local control in osteosarcoma. Our data suggest that radiation therapy combined with dual checkpoint blockade may be a promising therapeutic option for osteosarcoma.

Comparison of three moderate fractionated schedules employed in high-dose-rate brachytherapy monotherapy for clinically localized prostate cancer

BACKGROUND Herein, we report the outcomes of 3 schedules of high-dose-rate interstitial brachytherapy (HDR-BT) monotherapy for localized prostate cancer. PATIENTS AND METHODS A total of 347 patients were treated with 45.5 Gy/7 fractions (n = 86; 45.5 Gy arm, median follow-up time 131 months), 49 Gy/7 fractions (n = 149; 49 Gy arm, 75.9 months), and 54 Gy/9 fractions (n = 112; 54 Gy arm, 68 months). RESULTS The actuarial 5-year biochemical failure-free survival rates were 86.8%, 94.1%, and 88.5% (p = 0.2023) for the 45.5 Gy, 49 Gy, and 54 Gy arms in the high-risk group; 90.4%, 100%, and 97.4% (p = 0.0818) in the intermediate-risk group; and not available, 100%, and 100% in the low-risk group, respectively. The 5-year distant metastasis-free (and overall) survival rates were 94.4%, 98.2%, and 96.3% (100%, 92.8%, and 99.1%) for the 45.5 Gy, 49 Gy, and 54 Gy arms (p = 0.5454 and p = 0.0028), respectively. At 5 years, accumulated incidence of grade ≥2 gastrointestinal toxicity was 1.2%, 2.7%, and 3.4% for the 45.5 Gy, 49 Gy, and 54 Gy arms (p = 0.5605), respectively. For genitourinary toxicity, the 49 Gy arm showed a higher grade ≥2 toxicity of 20.5% than those observed in the 45.5 Gy (2.4%) and 54 Gy arms (10.1%). No grade 4 or 5 of either type of toxicity was detected. CONCLUSIONS The 3 schedules showed equivocal outcomes in each risk group, with different toxicity profiles. HDR-BT monotherapy with these schedules is an acceptable treatment option for localized prostate cancer.

Radiation-Induced Organizing Pneumonia: A Characteristic Disease that Requires Symptom-Oriented Management

Radiation-induced organizing pneumonia (RIOP) is an inflammatory lung disease that is occasionally observed after irradiation to the breast. It is a type of secondary organizing pneumonia that is characterized by infiltrates outside the irradiated volume that are sometimes migratory. Corticosteroids work acutely, but relapse of pneumonia is often experienced. Management of RIOP should simply be symptom-oriented, and the use of corticosteroids should be limited to severe symptoms from the perspective not only of cost-effectiveness but also of cancer treatment. Once steroid therapy is started, it takes a long time to stop it due to frequent relapses. We review RIOP from the perspective of its diagnosis, epidemiology, molecular pathogenesis, and patient management.

Dosimetric and clinical effects of interfraction and intrafraction correlation errors during marker-based real-time tumor tracking for liver SBRT

Abstract Correlation model error (CME) between the internal target and the external surrogate, and marker–tumor correlation error (MTCE) between the tumor and the implanted marker occur during marker-based real-time tumor tracking. The effects of these intrafraction and interfraction errors on the dose coverage in the clinical target volume (CTV) and on tumor control probability (TCP) for hepatocellular carcinoma (HCC) were evaluated in this study. Eight HCC patients treated with non-isocentric dose delivery by a robotic radiosurgery system were enrolled. The CMEs were extracted from the treatment log file, and the MTCEs were calculated from the preceding study. The CMEs and MTCEs were randomly added to each beam’s robot position, and the changes in the TCP and the 2%, 95% and 99% dose coverage values for the CTV (D2, D95 and D99) were simulated. The data were statistically analyzed as a function of the CTV to planning target volume (PTV) margin, the dose fraction and the marker–tumor distance. Significant differences were observed in the majority of the CTV D2, D95 and D99 values and the TCP values. However, a linear regression revealed that ∆CTV D2, D95 and D99 have a weak correlation with ∆TCP. A dose-difference metric would be unable to detect a critical error for tumor control if the coverage changes for the CTV and ∆TCP were weakly correlated. Because the simulated TCP-based parameter determination was based on the dose simulation, including predicted interfraction and intrafraction errors, we concluded that a 95th percentile TCP-based parameter determination would be a robust strategy for ensuring tumor control while reducing doses to normal structures.

High-Dose-Rate Brachytherapy Monotherapy versus Image-Guided Intensity-Modulated Radiotherapy with Helical Tomotherapy for Patients with Localized Prostate Cancer

The aim of this paper is to compare outcomes between high-dose-rate interstitial brachytherapy (HDR-BT) monotherapy and image-guided intensity-modulated radiotherapy (IG-IMRT) for localized prostate cancer. We examined 353 HDR-BT and 270 IG-IMRT patients. To reduce background selection bias, we used the method of inverse probability treatment weighting (IPTW) with propensity scores. The actuarial five-year biochemical failure-free survival rates were 92.9% and 96.7% (p = 0.1847; p = 0.077 in IPTW) for HDR-BT and IG-IMRT, respectively; they were 100% and 95.8% (p = 0.286) for the low-risk group, 95.6% and 92% (p = 0.42) for the intermediate-risk group, 90.4% and 84.9% (p = 0.1059; p = 0.04 in IPTW) for the high-risk group, and 87.1% and 89.2% (p = 0.3816) for the very-high-risk group. In the assessment of accumulated incidences of grade ≥ 2 toxicity (Common Terminology Criteria for Adverse Events version 4.0) at five years, HDR-BT monotherapy showed higher genitourinary toxicity (11.9%) than IG-IMRT (3.3%) (p < 0.0001). The gastrointestinal toxicity was equivalent for HDR-BT (2.3%) and IG-IMRT (5.5%) (p = 0.063). No Grade 4 or 5 toxicity was detected in either modality. HDR-BT showed higher genitourinary toxicity than IG-IMRT. HDR-BT and IG-IMRT showed equivalent outcomes in low-, intermediate-, and very-high-risk groups. For high-risk patients, HDR-BT showed potential to improve prostate-specific antigen (PSA) control rate compared to IG-IMRT.

Long-term Outcomes of Radiotherapy Regimen of 72 Gy in 30 Fractions for Prostate Cancer

Background/Aim: The long-term efficacy and safety of moderately hypofractionated intensity-modulated radiation therapy (MH-IMRT) in prostate cancer remains uncertain. This study aimed to evaluate MH-IMRT regimen of 72 Gy in 30 fractions in patients with prostate cancer. Patients and Methods: The outcomes of 412 consecutive prostate cancer patients, who received MH-IMRT between May 2007 and December 2012, were retrospectively reviewed. The median patient age was 70.9 (range=50-84) years. Late gastrointestinal (GI) and genitourinary (GU) toxicity rates were evaluated according to the CTCAE ver. 3.0. The overall survival, biochemical relapse-free survival rate (bRFS), late GI toxicity, and GU toxicity rates were analyzed with the Kaplan–Meier method. Results: The median follow-up was 71.5 (range, 1.4-124.8) months. The 5-year bRFS rate was 93.2%. The 5-year grade ≥2 late GI and GU toxicity rates were 3.3% and 4.5%, respectively. Conclusion: MH-IMRT regimen of 72 Gy in 30 fractions was effective and safe for prostate cancer patients.

Cell-cycle-controlled radiation therapy was effective for treating a murine malignant melanoma cell line in vitro and in vivo

Radiotherapy is a commonly used regimen for treating various types of intractable cancers, although the effects depend on the cell cycle of the targeted cancer cell lines, and for irradiation purposes it is therefore critical to establish a protocol for controlling the cell cycle. Here, we showed that a common murine melanoma cell line B16BL6 was more vulnerable to irradiation during the early S phase, and that synchronisation of the cell cycle greatly increased the therapeutic effects of radiotherapy. Cell-sorting experiments, according to cell-cycle phase, using B16BL6 cells demonstrated that cells in the early S phase were the most susceptible to radiotherapy. Gemcitabine, a clinically utilised anti-cancer drug, induced cell-cycle arrest during the early S phase in B16BL6 cells, and thus a synergistic therapeutic effect was observed when irradiation was administered at the right time. Human pancreatic cancer cell line PANC-1 exhibited similar properties to B16BL6 in terms of its radiosensitivity during the S/G2/M phase and also demonstrated a synergistic effect of cell cycle synchronisation. These results show the importance of cell-cycle control in the application of irradiation and suggest a suitable time interval between chemotherapy and radiotherapy, as well as providing useful information for treating intractable cancer.