A pilot study on interobserver variability in organ-at-risk contours in magnetic resonance imaging-guided online adaptive radiotherapy for pancreatic cancer.

Purpose: Differences in the contours created during magnetic resonance imaging-guided online adaptive radiotherapy (MRgOART) affect dose distribution. This study evaluated the interobserver error in delineating the organs at risk (OARs) in patients with pancreatic cancer treated with MRgOART. Moreover, we explored the effectiveness of drugs that could suppress peristalsis in restraining intra-fractional motion by evaluating OAR visualization in multiple patients. Methods: This study enrolled three patients who underwent MRgOART for pancreatic cancer. The study cohort was classified into three conditions based on the MRI sequence and butylscopolamine administration (Buscopan): 1, T2 imaging without butylscopolamine administration; 2, T2 imaging with butylscopolamine administration; and 3, multi-contrast imaging with butylscopolamine administration. Four blinded observers visualized the OARs (stomach, duodenum, small intestine, and large intestine) on MR images acquired during the initial and final MRgOART sessions. The contour was delineated on a slice area of ±2 cm surrounding the planning target volume. The dice similarity coefficient (DSC) was used to evaluate the contour. Moreover, the OARs were visualized on both MR images acquired before and after the contour delineation process during MRgOART to evaluate whether peristalsis could be suppressed. The DSC was calculated for each OAR. Results: Interobserver errors in the OARs (stomach, duodenum, small intestine, large intestine) for the three conditions were 0.636, 0.418, 0.676, and 0.806; 0.725, 0.635, 0.762, and 0.821; and 0.841, 0.677, 0.762, and 0.807, respectively. The DSC was higher in all conditions with butylscopolamine administration compared with those without it, except for the stomach in condition 2, as observed in the last session of MR image. The DSCs for OARs (stomach, duodenum, small intestine, large intestine) extracted before and after contouring were 0.86, 0.78, 0.88, and 0.87; 0.97, 0.94, 0.90, and 0.94; and 0.94, 0.86, 0.89, and 0.91 for conditions 1, 2, and 3, respectively. Conclusion: Butylscopolamine effectively reduced interobserver error and intra-fractional motion during the MRgOART treatment.

A new workflow of the on-line 1.5-T MR-guided adaptive radiation therapy.

PURPOSE: The aim of this study was to develop a new workflow for 1.5-T magnetic resonance (MR)-guided on-line adaptive radiation therapy (MRgART) and assess its feasibility in achieving dose constraints. MATERIALS AND METHODS: We retrospectively evaluated the clinical data of patients who underwent on-line adaptive radiation therapy using a 1.5-T MR linear accelerator (MR-Linac). The workflow in MRgART was established by reviewing the disease site, number of fractions, and re-planning procedures. Five cases of prostate cancer were selected to evaluate the feasibility of the new workflow with respect to achieving dose constraints. RESULTS: Between December 2021 and September 2022, 50 consecutive patients underwent MRgART using a 1.5-T MR-Linac. Of these, 20 had prostate cancer, 10 had hepatocellular carcinoma, 6 had pancreatic cancer, 5 had lymph node oligo-metastasis, 3 had renal cancer, 3 had bone metastasis, 2 had liver metastasis from colon cancer, and 1 had a mediastinal tumor. Among a total of 247 fractions, 235 (95%) were adapt-to-shape (ATS)-based re-planning. The median ATS re-planning time in all 50 cases was 17 min. In the feasibility study, all dose constraint sets were met in all 5 patients by ATS re-planning. Conversely, a total of 14 dose constraints in 5 patients could not be achieved by virtual plan without using adaptive re-planning. These dose constraints included the minimum dose received by the highest irradiated volume of 1 cc in the planning target volume and the maximum dose of the rectal/bladder wall. CONCLUSION: A new workflow of 1.5-T MRgART was established and found to be feasible. Our evaluation of the dose constraint achievement demonstrated the effectiveness of the workflow.

Comparison of CT-based and MRI-based high-risk clinical target volumes in image guided-brachytherapy for cervical cancer, referencing recommendations from the Japanese Radiation Oncology Study Group (JROSG) and consensus statement guidelines from the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC ESTRO).

PURPOSE: The Working Group of the Gynecological Tumor Committee of the Japanese Radiation Oncology Study Group (JROSG) published recommendations for contouring high-risk clinical target volumes (HR-CTV) on CT for 3-dimentional image-guided brachytherapy for cervical cancer. The purpose of this study was to compare HR-CTV delineated on CT, referencing recommendations from JROSG, with HR-CTV delineated on MRI, referencing consensus guidelines from the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC ESTRO). MATERIAL AND METHODS: Fourteen patients were evaluated. After the insertion of the CT/MR applicator into the patient, CT and MRI were performed. HR-CTVMR was delineated on MRI for clinical examination and HR-CTVCT was delineated on CT retrospectively referencing the MRI just before brachytherapy within a week. The volume and dosimetry of HR-CTV based on a 6 Gy dose of the Manchester system were evaluated. RESULTS: The median volumes of HR-CTVMR and HR-CTVCT were 24.4 ml (range, 13.6-50.4 ml) and 29.9 ml (range, 13.2-49.2 ml), respectively. Median D90 of HR-CTVMR and HR-CTVCT were 6.7 Gy (range, 5.8-10.1 Gy) and 6.8 Gy (range, 5.1-10.4 Gy), respectively. CONCLUSION: Somewhat difference could be seen between HR-CTVMR and HR-CTVCT.

Imaging of Hypoxic Tumor: Correlation between Diffusion-weighted MR Imaging and 18F-fluoroazomycin Arabinoside Positron Emission Tomography in Head and Neck Carcinoma.

We investigated the usefulness of diffusion-weighted imaging (DWI) for detecting changes in the structure of hypoxic cells by evaluating the correlation between 18F-fluoroazomycin arabinoside (FAZA) positron emission tomography activity and DWI parameters in head and neck carcinoma. The diffusion coefficient corresponding to the slow compartment of a two-compartment model had a significant positive correlation with FAZA activity (ρ = 0.58, P = 0.016), whereas the diffusional kurtosis from diffusion kurtosis imaging had a significant negative correlation (ρ = -0.62, P = 0.008), which suggests that those DWI parameters might be useful as indicators for changes in cell structure.

Radiation Therapy for Extrapelvic Lymph Node Recurrence After Curative Treatment for Cervical Cancer.

BACKGROUND/AIM: To investigate outcomes of patients with cervical cancer who received radiation therapy for extrapelvic lymph node recurrence after initial pelvic radiotherapy. PATIENTS AND METHODS: The treatment charts of 20 patients were retrospectively reviewed, and factors influencing patient's prognosis were statistically analyzed. RESULTS: The three-year in-field tumor control rate was 55% and overall survival (OS) at 2, 3, and 5 years was 55%, 45%, and 37.5%, respectively. The rate of the three-year OS in patients with recurrence within and after 9 months was 20% and 70%, respectively (p=0.016). None of the 4 patients who were diagnosed with supraclavicular lymph node recurrence alone at more than 9 months after initial treatment experienced further recurrence. Five-year survival of the remaining 16 patients was only 21% (p=0.021). CONCLUSION: Time to recurrence significantly influenced survival in patients with cervical cancer who received radiotherapy for extra-pelvic lymph node recurrence. Supraclavicular lymph node recurrence alone had a favorable impact on patient's prognosis.

Prognostic value of PET/CT with (18)F-fluoroazomycin arabinoside for patients with head and neck squamous cell carcinomas receiving chemoradiotherapy.

OBJECTIVE: The prognostic value of positron emission tomography/computed tomography (PET/CT) with (18)F-fluoroazomycin arabinoside (FAZA) was evaluated in patients with head and neck squamous cell carcinoma (HNSCC) who underwent chemoradiotherapy (CRT). METHODS: Twenty-nine patients with head and neck cancer underwent FAZA PET/CT before treatment. Data acquisition started 2 h after FAZA administration. In 26 patients with squamous cell carcinoma, FAZA uptakes by the primary lesions (tumor-muscle ratio in primary lesion: Pr T/M) and by the lymph node metastases (tumor-muscle ratio in lymph node metastasis) were compared with various clinical parameters. For the HNSCC patients who completed CRT protocol (n = 23), those who experienced disease progression were compared with those who did not experience disease progression with respect to the clinical and PET parameters. The prognostic values of the clinical and PET parameters were then evaluated with regard to progression-free survival (PFS). RESULTS: Pr T/M positively correlated with the lesion's maximum diameter, and it was significantly higher in stage IV lesions compared with stage I-III lesions. No significant differences were observed between the patients who experienced disease progression and those who did not, with respect to the clinical parameters. The average Pr T/M tended to be higher in patients with disease progression, although the differences were not statistically significant (p = 0.086). Kaplan-Meier analysis with log-rank tests indicated that Pr T/M was an only significant predictor of PFS among PET and clinical parameters evaluated (p = 0.010). CONCLUSIONS: FAZA uptake by the primary lesion was a significant prognostic indicator in HNSCC patients undergoing CRT. Hence, FAZA PET/CT may provide useful information in the management of HNSCC patients treated with CRT. Registration number of clinical trial's registry: UMIN000003440.

Initial experience of radiotherapy plus cetuximab for Japanese head and neck cancer patients.

In Japan, cetuximab with concurrent bioradiotherapy (BRT) for squamous cell carcinoma of head and neck (SCCHN) was approved in December 2012. We herein report our initial experience of BRT, with special emphasis on acute toxicities of this combination therapy. Thirty-one non-metastatic SCCHN patients who underwent BRT using cetuximab between July 2013 and June 2014 were retrospectively evaluated. All patients received cetuximab with a loading dose of 400 mg/m(2) one week before the start of radiotherapy, followed by 250 mg/m(2) per week during radiotherapy. The median cycle of cetuximab was seven cycles and the median dose of radiotherapy was 70 Gy. Twenty-five patients (80.6%) accomplished planned radiotherapy and six cycles or more cetuximab administration. Six patients (19.4%) discontinued cetuximab. Grade 3 dermatitis, mucositis and infusion reaction occurred in 19.4%, 48.3% and 3.2%, respectively. One patient experienced Grade 3 gastrointestinal bleeding caused by diverticular hemorrhage during BRT. Grade 3 drug-induced pneumonitis occurred in two patients. The response rate was 74%, including 55% with a complete response. BRT using cetuximab for Japanese patients with SCCHN was feasible as an alternative for cisplatin-based concurrent chemoradiation, although longer follow-up is necessary to evaluate late toxicities.

Synthesis and evaluation of tamoxifen derivatives with a long alkyl side chain as selective estrogen receptor down-regulators.

Estrogen receptors (ERs) play a major role in the growth of human breast cancer cells. An antagonist that acts as not only an inhibitor of ligand binding but also an inducer of the down-regulation of ER would be useful for the treatment for ER-positive breast cancer. We previously reported the design and synthesis of a selective estrogen receptor down-regulator (SERD), (E/Z)-4-(1-{4-[2-(dodecylamino)ethoxy]phenyl}-2-phenylbut-1-en-1-yl)phenol (C12), which is a tamoxifen derivative having a long alkyl chain on the amine moiety. This compound induced degradation of ERα via a proteasome-dependent pathway and showed an antagonistic effect in MCF-7 cells. With the aim of increasing the potency of SERDs, we designed and synthesized various tamoxifen derivatives that have various lengths and terminal groups of the long alkyl side chain. During the course of our investigation, C10F having a 10-fluorodecyl group on the amine moiety of 4-OHT was shown to be the most potent compound among the tamoxifen derivatives. Moreover, computational docking analysis suggested that the long alkyl chain interacted with the hydrophobic region on the surface of the ER, which is a binding site of helix 12 and coactivator. These results provide useful information to develop promising candidates as SERDs.

Delayed renal dysfunction after total body irradiation in pediatric malignancies.

The purpose of this study was to retrospectively evaluate the incidence of delayed renal dysfunction after total body irradiation (TBI) in long-term survivors of TBI/hematopoietic stem cell transplantation (HSCT). Between 1989 and 2006, 24 pediatric patients underwent TBI as part of the conditioning regimen for HSCT at Chiba University Hospital. Nine patients who survived for more than 5 years were enrolled in this study. No patient had any evidence of renal dysfunction prior to the transplant according to their baseline creatinine levels. The median age at the time of diagnosis was 6 years old (range: 1-17 years old). The follow-up period ranged from 79-170 months (median: 140 months). Renal dysfunction was assessed using the estimated glomerular filtration rate (eGFR). The TBI dose ranged from 8-12 Gy delivered in 3-6 fractions over 2-3 d. The patients were treated with linear accelerators in the supine position, and the radiation was delivered to isocentric right-left and left-right fields via the extended distance technique. The kidneys and the liver were not shielded except in one patient with a left adrenal neuroblastoma. No patient required hemodialysis. The eGFR of four patients (44.4%) progressively decreased. The remaining patients did not demonstrate any eGFR deterioration. Only one patient developed hypertension. By evaluating the changes in eGFR, renal dysfunction among long-term survivors of TBI/HSCT could be detected. Our results suggested that the TBI schedule of 12 Gy in 6 fractions over three consecutive days affects renal function.

Is the outcome of a salvage surgery for T4 thoracic esophageal squamous cell carcinoma really poor?

BACKGROUND: Among patients with T4 thoracic esophageal squamous cell carcinoma (TESCC), it is unclear whether the outcomes of late responders who undergo high-dose chemoradiotherapy (CRT) followed by salvage esophagectomy differs from those of early responders who undergo low-dose CRT followed by esophagectomy. METHODS: A total of 153 patients with T4 TESCC were treated with CRT. The first evaluation was performed after 40 Gy of CRT for downstaging. Of these, 28 patients could be downstaged, and underwent subsequent surgery (early responders). For the remaining patients, additional CRT was administered, and patients were re-evaluated after treatment and underwent salvage surgery. In total, 40 patients (early + late responders) were analyzed. RESULTS: The primary tumors exhibited a grade 3 response in six (21.4 %) of the early responders and two (16.7 %) of the late responders (p = 1.000). The rate of residual tumor in the primary tumor was 80 % (32/40 patients). The proportions of resected lymph nodes and positive metastatic nodes were similar between early and late responders (p = 0.406 and p = 0.859, respectively). The 5-year overall survival rates among the early and late responders were 25.9 and 36.5 %, respectively, and the median survival times were 24.8 and 24.3 months (p = 0.925), respectively. The 5-year cause-specific survival rates in the early and late responder groups were 61.5 and 72.9 % (p = 0.425), respectively. CONCLUSION: The outcomes of both early and late responders to CRT were similar, and salvage surgery for T4 TESCC outweighs the risks in patients with T4 TESCC.

The incidence and significance of retropharyngeal lymph node metastases in hypopharyngeal cancer.

OBJECTIVE: To evaluate the incidence and clinical significance of retropharyngeal lymph node metastasis in hypopharyngeal cancer. METHODS: Pretreatment computed tomography and/or magnetic resonance images of 152 patients treated between 1998 and 2009 were retrospectively reviewed. The prognostic significance of retropharyngeal lymph node metastasis for 116 patients who received definitive treatment was also analyzed. RESULTS: Twelve patients (8%) were radiologically positive for retropharyngeal lymph node metastasis. Tumors originating from the posterior wall showed significantly higher incidence of retropharyngeal lymph node than those originating from other sites (23.8 vs. 5.3%, P = 0.01). The majority of patients with retropharyngeal lymph node involvement experienced distant metastasis. The overall survival rate of patients with retropharyngeal lymph node metastasis was worse than in those lacking retropharyngeal lymph node involvement (0 vs. 68.8% at 2 years, P < 0.01), and so was the cause-specific survival rate (0 vs. 74% at 2 years, P < 0.01). CONCLUSIONS: Patients with hypopharyngeal cancer, especially those with posterior wall tumors, are at high risk for retropharyngeal lymph node involvement. Patients with retropharyngeal lymph node metastasis developed distant metastasis frequently, and showed dismal outcomes.

Radiation pneumonitis following twice-daily radiotherapy with concurrent carboplatin and paclitaxel in patients with stage III non-small-cell lung cancer.

OBJECTIVE: To examine the effects of dose-volume factors on the development of radiation pneumonitis in patients with non-small-cell lung cancer who received twice-daily radiotherapy concurrently with carboplatin and paclitaxel chemotherapy. METHODS: Radiotherapy consisted of twice-daily fractionation of 1.2 Gy, to a total dose of 60 Gy. Weekly carboplatin and paclitaxel were used as a concurrent chemotherapy. Effects of radiotherapy parameters on the development of radiation pneumonitis were retrospectively analyzed. RESULTS: Fourteen of 37 patients developed Grade 2 or worse (> or = G2) radiation pneumonitis. Grade 2 or worse radiation pneumonitis occurred in all 5 patients with V5 >40%, all 4 patients with V10 >35%, all 4 patients with V13 >32%, 9 of 14 patients with V20 >24% and 8 of 11 patients with V30 >22%, whereas 9 of 32 patients with V5 <40%, 10 of 33 patients with V10 <35%, 10 of 33 patients with V13 <32%, 5 of 23 patients with V20 <24% and 6 of 26 patients with V30 <22%, with respective P values of 0.0045, 0.015, 0.015, 0.015 and 0.008. Eight of 11 patients with a mean lung dose of >14 Gy developed > or = G2 radiation pneumonitis in contrast to 6 of 26 patients with a mean lung dose of <14 Gy (P = 0.008). CONCLUSIONS: Several cut-off values in the V(dose) and the mean lung dose differentiating probabilities of developing > or = G2 radiation pneumonitis were identified in this combination therapy.