Neuroendocrine tumor theranostics.

Theranostics is a term coined by combining the words "therapeutics" and "diagnostics," referring to single chemical entities developed to deliver therapy and diagnosis simultaneously. Neuroendocrine tumors are rare cancers that occur in various organs of the body, and they express neuroendocrine factors such as chromogranin A and somatostatin receptor. Somatostatin analogs bind to somatostatin receptor, and when combined with diagnostic radionuclides, such as gamma-emitters, are utilized for diagnosis of neuroendocrine tumor. Somatostatin receptor scintigraphy when combined with therapeutic radionuclides, such as beta-emitters, are effective in treating neuroendocrine tumor as peptide receptor radionuclide therapy. Somatostatin receptor scintigraphy and peptide receptor radionuclide therapy are some of the most frequently used and successful theranostics for neuroendocrine tumor. In Japan, radiopharmaceuticals are regulated under a complex law system, creating a significant drug lag, which is a major public concern. It took nearly 10 years to obtain the approval for somatostatin receptor scintigraphy and peptide receptor radionuclide therapy use by the Japanese government. In 2021, 111 Lu-DOTATATE (Lutathera), a drug for peptide receptor radionuclide therapy, was covered by insurance in Japan. In this review, we summarize the history of the development of neuroendocrine tumor theranostics and theranostics in general, as therapeutic treatment for cancer in the future. Furthermore, we briefly address the Japanese point of view regarding the development of new radiopharmaceuticals.

[Indications and Practice of a New Radionuclide Therapy, 177Lu-DOTATATE in Japan].

Peptide receptor radionuclide therapy(PRRT)is a pioneer drug in the rapid development of radio-theranostics, and a paradigm-shifting approach to treat neuroendocrine tumor( NET). The NETTER-1 trial for NETs of the midgut is currently the only global phase Ⅲ prospective clinical trial demonstrating the efficacy and safety of PRRT. In Japan, phase Ⅰ and Ⅰ/Ⅱ trials for lung and gastroenteropancreatic NETs were also conducted, and regulatory approval was granted in June of 2021. Although regulatory approval was obtained in Japan without specifying the primary organ or the history of treatment, there is limited evidence at this time, and guidelines recommend use after the second-line for midgut NETs and in the last phase for all other NETs. PRRT is expected to be utilized as upfront therapy, and the results of ongoing prospective clinical trials are awaited. The effect of PRRT is corelated with accumulation rate of somatostatin receptor scintigraphy(SRS). Sometime accumulation rate of SRS is not constant among multiple tumors in even one patient, then effective use of PRRT is depending on detailed exploration for result of SRS of each tumor. In order to perform this treatment in Japan, a special ward dedicated to radionuclide therapy or at least" a special measures patient room" prescribed by laws and regulations is necessary." A special measures patient room" is a general patient room with temporary isolation and taking radiation protection countermeasure, instead of the special exhaust and drainage systems of radionuclide therapy ward. On the other hand, in order to operate the rooms, it is necessary to set up and decontaminate the rooms for each treatment, which requires specialized knowledge and manpower. Since there is a growing demand for radionuclide therapies, it is important to promote the appropriate introduction of this therapy and to establish a collaborative network for this purpose.

Impact of superselective intra-arterial and systemic chemoradiotherapy for gingival carcinoma; analysis of treatment outcomes and prognostic factors.

BACKGROUND: We compared outcomes and toxicities between concurrent retrograde super-selective intra-arterial chemoradiotherapy (IACRT) and concurrent systemic chemoradiotherapy (SCRT) for gingival carcinoma (GC). METHODS: We included 84 consecutive patients who were treated for non-metastatic GC ≥ stage III, from 2006 to 2018, in this retrospective analysis (IACRT group: n = 66; SCRT group: n = 18). RESULTS: The median follow-up time was 24 (range: 1-124) months. The median prescribed dose was 60 (6-70.2) Gy (IACRT: 60 Gy; SCRT: 69 Gy). There were significant differences between the two groups in terms of 3-year overall survival (OS; IACRT: 78.8, 95% confidence interval [CI]: 66.0-87.6; SCRT: 50.4, 95% CI: 27.6-73.0; P = 0.039), progression-free survival (PFS; IACRT: 75.6, 95% CI: 62.7-85.2; SCRT: 42.0, 95% CI: 17.7-70.9; P = 0.028) and local control rates (LC; IACRT: 77.2, 95% CI: 64.2-86.4; SCRT: 42.0, 95% CI: 17.7-70.9; P = 0.015). In univariate analysis, age ≥ 65 years, decreased performance status (PS) and SCRT were significantly associated with worse outcomes (P < 0.05). In multivariate analysis, age ≥ 65 years, clinical stage IV, and SCRT were significantly correlated with a poor OS rate (P < 0.05). Patients with poorer PS had a significantly worse PFS rate. Regarding acute toxicity, 22 IACRT patients had grade 4 lymphopenia, and osteoradionecrosis was the most common late toxicity in both groups. CONCLUSIONS: This is the first report to compare outcomes from IACRT and SCRT among patients with GC. ALL therapy related toxicities were manageable. IACRT is an effective and safe treatment for GC.

Outcomes of treatment for localized prostate cancer in a single institution: comparison of radical prostatectomy and radiation therapy by propensity score matching analysis.

OBJECTIVES: To compare the outcomes of radical prostatectomy (RP), intensity-modulated radiation therapy (IMRT), and low-dose-rate brachytherapy (BT) using propensity score matching analysis in patients with clinically localized prostate cancer. METHODS: A group of 2273 patients with clinically localized prostate cancer between January 2004 and December 2015 at the Yokohama City University hospital were identified. The records of 1817 of these patients, who were followed up for a minimum of 2 years, were reviewed; 462 were treated with RP, 319 with IMRT, and 1036 with BT. The patients were categorized according to the National Comprehensive Cancer Network risk classification criteria, and biochemical outcomes and overall survival rates were examined. Biochemical failure for RP was defined as prostate-specific antigen (PSA) levels > 0.2 ng/ml, and for IMRT and BT as nadir PSA level + 2 ng/ml. Propensity scores were calculated using multivariable logistic regression based on covariates, including the patient's age, preoperative PSA, Gleason score, number of positive cores, and clinical T stage. RESULTS: Median follow-up was 77 months for the RP, 54 months for IMRT, and 66 months for BT patients. After the propensity scores were adjusted, a total of 372 (186 each) and 598 (299 each) patients were categorized into RP vs IMRT and RP vs BT groups, respectively. Kaplan-Meier analysis did not show any statistically significant differences in terms of overall survival rate between these groups (RP vs IMRT: p = 0.220; RP vs BT: p = 0.429). IMRT was associated with improved biochemical failure-free survival compared to RP in all risk groups (high-risk: p < 0.001; intermediate-risk: p = 0.009; low-risk: p = 0.001), whereas significant differences were observed only in the intermediate-risk group (p = 0.003) within the RP vs BT group. CONCLUSION: The results of our propensity score analysis of mid-term localized prostate cancer treatment outcomes demonstrated no significant differences in the overall survival rate. Despite the difference in biochemical failure definition between surgery and radiotherapeutic approaches, the results of this study demonstrate improved biochemical control favoring IMRT and BT as compared to RP.

Clinical Usefulness of Somatostatin Receptor Scintigraphy in Japanese Patients with Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND/AIMS: Somatostatin receptor (SSTR) scintigraphy (SRS) is the standard imaging modality for evaluation of gastroenteropancreatic neuroendocrine tumor (GEP-NET) in Western countries. However, this modality was not approved in Japan until recently. The purpose of this study was to evaluate the clinical efficacy of SRS for detecting GEP-NET in Japanese patients. METHODS: Japanese patients with advanced GEP-NET were enrolled and evaluated by the SRS and CT. We also compared SRS and immunohistochemical expression of SSTR type 2a (SSTR2a). RESULTS: We enrolled 16 patients and the primary sites were the pancreas in 9, the stomach in 1, the small intestine in 2, the colon in 3, and unknown in 1. SRS showed positive findings in 3 (100%) of grade 1 (G1) and in 12 (92.3%) of grade 2 (G2) lesions. In the liver, SRS and CT detected lesions in 13 and 14 cases, respectively. The concordance rate of SSTR2a expression with SRS findings was 93.8% in the whole body and 92.9% in the liver. CONCLUSIONS: SRS could detect almost all of G1 and G2. SRS could be useful to detect lesions, with a high concordance rate with CT and pathological findings. We confirmed that SRS is a useful and reliable modality for Japanese patients.

Long-term Outcomes of Early-stage Non-stomach Gastrointestinal Mucosa-associated Lymphoid Tissue Lymphoma Treated With Radiation Therapy.

BACKGROUND/AIM: Non-stomach gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphoma is rare, and there are only a few reports regarding radiation therapy (RT) for non-stomach gastrointestinal MALT lymphoma. There has been no established cure and no reports on RT use with long-term follow-up. Herein, we report a retrospective long-term investigation of early-stage non-stomach gastrointestinal MALT lymphoma. Our aim was to evaluate whether RT is a valid treatment option for this disease. PATIENTS AND METHODS: We retrospectively analyzed 6 patients who were diagnosed with early-stage non-stomach gastrointestinal MALT lymphoma and received RT. The median age was 66 years (range=38-89 years). The primary tumor originated from the duodenum in 2 patients and from the rectum in 4 patients. The RT dose was 30-34 Gy in 15-20 fractions to the involved site or field, depending on the case. RESULTS: The median follow-up time was 89.5 months (range=6-170). All patients had complete remission within 3 months after RT. The 5-year overall survival and progression-free survival rates were 83.3% and 100%, respectively. During the observation period, no patient had a confirmed recurrence. One patient died of causes unrelated to cancer or treatment. There were no late toxicities by RT. CONCLUSION: Our results show good long-term local control and no late toxicities requiring treatment. Moderate-dose RT was appropriate and well tolerated for early-stage non-stomach gastrointestinal MALT lymphoma.

Factors Contributing to Tumor Shrinkage after Peptide Receptor Radionuclide Therapy in Patients with Unresectable Neuroendocrine Tumors.

Peptide receptor activation therapy (PRRT) is a promising treatment option for metastatic neuroendocrine tumors (NETs). However, predicting tumor shrinkage before treatment is challenging. We analyzed the shrinkage rate of each metastatic tumor lesion to identify predictive factors related to shrinkage. Patients with metastatic NET who underwent PRRT were included in this retrospective study. For each patient, between one to five metastatic lesions were selected in descending order of size, and the change in the maximum tumor diameter after treatment was defined as the shrinkage rate per lesion (L-SR). We analyzed the relationship between pretreatment clinicopathological factors and L-SR. The median L-SR of all 75 lesions in 20 patients was 20% (95% CI: 4.8−26.1%). While previous treatment with cytotoxic agents (34.4%, p < 0.05) and primary tumor of the pancreas (27.8%, p < 0.05) were significantly favorable factors, a primary tumor of the rectum was significantly more resistant to shrinkage (−20.5%, p < 0.001). Therefore, lesion-based analysis of PRRT for NETs showed that pancreatic NET and previous treatment with cytotoxic agents were favorable factors for tumor shrinkage; however, rectal NET was a factor associated with resistance to shrinkage.

Safety and response after peptide receptor radionuclide therapy with 177 Lu-DOTATATE for neuroendocrine tumors in phase 1/2 prospective Japanese trial.

BACKGROUND: The present prospective phase 1/2 study aimed to elucidate the efficacy and safety of 177 Lu-DOTATATE (four cycles of 7.4 GBq) in Japanese patients with unresectable, progressive neuroendocrine tumors (NETs). METHODS: From April 2018 to October 2020, 15 patients with advanced NETs (five midgut, eight pancreatic, and two lung NETs) were enrolled. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were evaluated. Pharmacokinetics and dosimetry were also evaluated in three midgut patients. RESULTS: The mean absorbed doses of 177 Lu-DOTATATE to the kidneys (20.7 Gy/29.6 GBq) and the bone marrow (0.631 Gy/29.6 GBq) were within the radiation tolerance doses. The ORR of the whole population was 53% (90% CI, 30%-76%). ORRs of the midgut and non-midgut NETs were 60% (90% CI, 19%-92%) and 50% (90% CI, 22%-78%), respectively. There was no difference in the maximum reduction rate of the sum of the target lesion diameters between patients with midgut and non-midgut NET. The median PFS was not reached; the PFS rate at 52 weeks was 80% (90% CI, 56.1%-91.7%). AEs of Grade 3 or higher were lymphopenia (47%) and leukopenia (7%). CONCLUSION: 177 Lu-DOTATATE demonstrated remarkable tumor shrinkage and tolerability in Japanese patients with advanced NETs.

Retrospective study of peptide receptor radionuclide therapy for Japanese patients with advanced neuroendocrine tumors.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is an innovative treatment for advanced somatostatin-positive neuroendocrine tumors (NETs). PRRT cannot be performed in Japan because there is no approval or insurance cover so far. METHODS: We relied on foreign institutions to perform PRRT for Japanese patients with NETs. We retrospectively evaluated the safety and efficacy of PRRT. The inclusion criteria were pathologically confirmed well-differentiated NET and visible tumor uptake on pre-therapeutic somatostatin receptor scintigraphy. 177 Lu-DOTA-TOC was used as the standard treatment, and patients received three infusions every 8 weeks. Until the end of 2017, combination treatment with 90 Y and 177 Lu-DOTA-TOC was performed using the same protocol. RESULTS: Thirty-five patients were evaluated, and the primary lesions were pancreas, rectum, small intestine, stomach, and other locations. The partial response rate was 42.9%. Progression-free survival (PFS) was 12.8 months and overall survival was 42.8 months. There was no significant difference in PFS between front-line and late-line PRRT (11.0 months vs 28.0 months; P = .383). Severe adverse events included lymphocytopenia (20.0%) and thrombocytopenia (5.7%). Myelodysplastic syndrome occurred in one case. CONCLUSION: PRRT was effective and safe for Japanese patients with advanced NETs. PRRT was equally effective as front-line and late-line treatment.

Safety and efficacy of peptide receptor radionuclide therapy with 177Lu-DOTA0-Tyr3-octreotate in combination with amino acid solution infusion in Japanese patients with somatostatin receptor-positive, progressive neuroendocrine tumors.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA0-Tyr3-octreotate (177Lu-DOTATATE) is one of the most reliable treatments for unresectable, progressive neuroendocrine tumors (NETs) with somatostatin receptor expression. We have, for the first time, reported the results of the tolerability, safety, pharmacokinetics, dosimetry, and efficacy of this treatment for Japanese patients with NET. METHODS: Patients with unresectable, somatostatin receptor scintigraphy (SRS)-positive NETs were enrolled in this phase I clinical trial. They were treated with 29.6 GBq of 177Lu-DOTATATE (four doses of 7.4 GBq) combined with amino acid solution infusion plus octreotide long-acting release (LAR) 30 mg. The primary objective of this study was to evaluate the tolerability, safety, pharmacokinetics, and dosimetry of a single administration of this treatment in patients with SRS-positive NETs. RESULTS: Six Japanese patients (three men and three women; mean age 61.5 years; range 50-70 years) with SRS-positive unresectable NETs were recruited. 177Lu-DOTATATE was eliminated from the blood in a two-phase manner. Cumulative urinary excretion of radioactivity was 60.1% (range 49.0%-69.8%) within the initial 6 h. The cumulative renal absorbed dose for 29.6 GBq of 177Lu-DOTATATE was 16.8 Gy (range 12.0-21.2 Gy), and the biological effective dose was 17.0 Gy (range 12.2-21.5 Gy). Administration of 177Lu-DOTATATE was well tolerated, with no dose-limiting toxicities. Grade 3 lymphopenia occurred in two (33.3%) cases, but there were no other severe toxicities. Four patients achieved partial response (objective response rate, 66.7%), one patient had stable disease, and one patient had progressive disease. CONCLUSION: PRRT with 177Lu-DOTATATE was well-tolerated and showed good outcomes in Japanese patients with unresectable NETs. Peptide receptor radionuclide therapy, 177Lu-DOTA0-Tyr3-octreotate .

Outcome of Radiation Therapy for Locally Advanced Vulvar Carcinoma: Analysis of Inguinal Lymph Node.

BACKGROUND/AIM: The aim of this study was to define the outcome of radiation therapy for vulvar carcinoma, and to investigate the effectiveness of therapeutic and prophylactic inguinal lymph node (ILN) irradiation. Because reports about the treatment of ILN were limited. PATIENTS AND METHODS: Thirty consecutive vulvar carcinoma patients were treated using external beam radiation therapy (EBRT) for definitive disease (n=25) or postoperatively (n=5). Twenty-four (80%) had squamous cell carcinoma (SCC). Tumor stages (2002 UICC) ranged from 0 to IVB, with no distant metastases. RESULTS: The median total prescribed dose for primary tumor was 64.8 Gy. The 2-year overall survival rate was 25.3%. The outcome was significantly better in patients with ILNs<30 mm (p=0.005) and patients receiving prescribed doses >60 Gy (p=0.002). CONCLUSIONS: ILN diameters ≤30 mm and prescribed doses over 60 Gy were associated with ILN control in patients with vulvar carcinoma.

Intensity-modulated radiation therapy using TomoDirect for postoperative radiation of left-sided breast cancer including lymph node area: comparison with TomoHelical and three-dimensional conformal radiation therapy.

Intensity-modulated radiation therapy (IMRT) delivers an excellent dose distribution compared with conventional three-dimensional conformal radiation therapy (3D-CRT) for postoperative radiation including the lymph nodes in breast cancer patients. The TomoTherapy system, developed exclusively for IMRT, has two treatment modes: TomoDirect (TD) with a fixed gantry angle for beam delivery, and TomoHelical (TH) with rotational beam delivery. We compared the characteristics of TD with TH and 3D-CRT plans in the breast cancer patients. Ten consecutive women with left breast cancer received postoperative radiation therapy using TD including the chest wall/residual breast tissue and level II-III axial and supraclavicular lymph node area. Fifty percent of the planning target volume (PTV) was covered with at least 50 Gy in 25 fractions. TD, TH and 3D-CRT plans were created for each patient, with the same dosimetric constraints. TD and TH showed better dose distribution to the PTV than 3D-CRT. TD and 3D-CRT markedly suppressed low-dose spread to the lung compared with TH. Total lung V5 and V10 were significantly lower, while V20 was significantly higher in the TD and 3D-CRT plans. The mean total lung, heart and contralateral breast doses were significantly lower using TD compared with the other plans. Compared with 3D-CRT and TH, TD can provide better target dose distribution with optimal normal-organ sparing for postoperative radiation therapy including the chest wall/residual breast tissue and lymph node area in breast cancer patients. TD is thus a useful treatment modality in these patients.

Outcome of postoperative radiation therapy for cholangiocarcinoma and analysis of dose-volume histogram of remnant liver.

The aim of this study was to analyze dose-volume histogram (DVH) of the remnant liver for postoperative cholangiocarcinoma (CCA) patients, to find toxicity rates, and to confirm efficacy of postoperative radiation therapy (RT).Thirty-two postoperative CCA patients received partial liver resection and postoperative RT with curative intent. The "liver reduction rate" was calculated by contouring liver volume at computed tomography (CT) just before the surgery and at CT for planning the RT. To evaluate late toxicity, the radiation-induced hepatic toxicity (RIHT) was determined by the common terminology criteria for adverse events toxicity grade of bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, and albumin, and was defined from 3 months after RT until liver metastasis was revealed. The radiation-induced liver disease (RILD) was also evaluated.Tumor stages were distributed as follows: I: 1, II: 8, IIIA: 1, IIIB: 6, IIIC: 14, IVA: 2. Median prescribed total dose was 50 Gy. Median follow-up time was 27 months. Two-year overall survival (OS): 72.4%, disease-free survival: 47.7%, local control: 65.3%, and the median survival time was 40 months. The median "liver reduction rate" was 21%. The OS had statistically significant difference in nodal status (P = .032) and "liver reduction rate" >30% (P = .016). In the association between the ≥grade 2 RIHT and DVH, there were significantly differences in V30 and V40 (P = .041, P = .034), respectively. The grade ≥2 RIHT rates differ also significantly by sex (P = .008). Two patients (6.2%) were suspected of RILD.We suggest that RT for remnant liver should be considered the liver V30, V40 to prevent radiation-induced liver dysfunction.

Acute and late toxicities in localized prostate cancer patients treated with low-dose 125I brachytherapy (110 Gy) in combination with external beam radiation therapy versus brachytherapy alone (160 Gy).

PURPOSE: The aim of this analysis was to compare acute and late toxicities between low-dose-rate brachytherapy (LDR-BT) (110 Gy) in combination with 45 Gy in 25 fractions external beam radiation therapy (EBRT) and LDR-BT (160 Gy) alone for localized prostate cancer. MATERIAL AND METHODS: One hundred five consecutive patients with localized prostate cancer treated from May 2014 to May 2017 were included in this retrospective analysis. Sixty patients received combination therapy and 45 patients received BT monotherapy. The LDR-BT procedure was performed using 125I seeds. RESULTS: The median follow-up time was 28 months in both groups. Three-year effect rates were overall survival: 100% in both groups. The biochemical failure rate was 2.3% in the combination group and 0% in the monotherapy group (p = 0.373). No patients died during the study period. In both groups, almost all the patients experienced acute urethritis. There was a significant difference between the combination therapy group (8.3%) and BT monotherapy group (11.1%) in late genitourinary (GU) toxicities ≥ grade 2 (p = 0.035). Only 2 patients (3.3%) in the combination therapy group developed late ≥ grade 2 rectal hemorrhage. There were no significant differences between two groups in hematuria ≥ grade 2 (p = 0.068) or rectal hemorrhage ≥ grade 2 (p = 0.206). CONCLUSIONS: To our knowledge, this is the first report to compare the GU and gastrointestinal toxicities between the combination therapy and BT monotherapy (160 Gy) for localized prostate cancer. Unexpectedly, there were more late GU toxicities (except for hematuria) in the BT monotherapy group.

Radiation Therapy for Patients with Bone Metastasis from Uterine Cervical Cancer: Its Role and Optimal Radiation Regimen for Palliative Care.

AIM: To determine the role of radiation therapy for patients with bone metastasis from uterine cervical cancer and identify an optimal radiation regimen. PATIENTS AND METHODS: A total of 20 patients with bone metastases from uterine cervical cancer received radiation therapy to the pelvis. The median total dose of 60.2 Gy in the 2 Gy per fraction-equivalent dose (EQD2) was delivered to cervical tumors of all patients. Thirteen patients underwent chemotherapy during and/or following radiation therapy. RESULTS: In 18 of 20 patients, the primary tumors disappeared or were markedly reduced after radiation therapy. In all but one of 17 patients with pelvic pain and bleeding, these symptoms disappeared or were remarkably relieved. However, three patients had primary tumor progression at 7, 9, and 15 months after irradiation with total doses of 56.8, 58.4, and 68.3 Gy in EQD2, respectively. Two of these patients had relapses of bleeding and pain. The primary progression-free rate considering all patients was 69% at 1 year and 34% at 2 years. The corresponding overall survival rates were 34% at 1 year, and 8% at 2 years, with an estimated median survival time of 7 months. The number of metastatic bone sites (p=0.027) and administration of chemotherapy (p<0.001) were significant prognostic factors for survival. CONCLUSION: Radiation therapy is effective for relief of pelvic symptoms in patients with bone metastasis from uterine cervical cancer. For patients who are expected to survive for more than 1 year, almost curative-dose irradiation to primary tumors is recommended.

Clinical and dosimetric predictors of late rectal bleeding of prostate cancer after TomoTherapy intensity modulated radiation therapy.

INTRODUCTION: Rectal bleeding after radiotherapy impacts the quality of life of long-term surviving prostate cancer patients. We sought to identify factors associated with late rectal bleeding following intensity modulated radiation therapy (IMRT) using TomoTherapy for prostate cancer. METHODS: We retrospectively analysed 82 patients with localised prostate cancer treated with TomoTherapy. Most patients (95.1%) received neoadjuvant and concurrent hormone therapy. Forty-two patients (51.2%) graded as high risk using D'Amico's classification underwent radiotherapy involving the pelvic nodal area. Late bleeding complications were quantified using the Common Terminology Criteria for Adverse Events v4.0. Multiple clinical and dosimetric factors were considered with reference to rectal bleeding. RESULTS: The median follow-up period was 538 (range, 128-904) days. Grades 1, 2 and 3 rectal bleeding were observed in 14 (17.1%), four (4.9%) and one (1.2%) patient respectively. In multivariate analysis, the following factors were significantly associated with Grade ≥1 late rectal bleeding: volume, mean dose (P = 0.012) and rectal V30 (P = 0.025), V40 (P = 0.011), V50 (P = 0.017) and V60 (P = 0.036). When exclusively considering Grade 2-3 rectal bleeding, significant associations were observed with the use of anticoagulants or antiaggregates (P = 0.007), rectal V30 (P = 0.021) and V40 (P = 0.041) in univariate analysis. CONCLUSIONS: Our results suggested that the intermediate rectal dose-volume (V30-V60) was a significant predictor for mild to severe late rectal bleeding (Grade ≥1). Rectal dose-volumes >V70, which represented the volume of the highest doses, were not predictive in this study.

Radiation therapy for stage IVA uterine cervical cancer: treatment outcomes including prognostic factors and risk of vesicovaginal and rectovaginal fistulas.

PURPOSE: To evaluate the safety and efficacy of radiation therapy for stage IVA uterine cervical cancer and to identify an optimal radiation regimen. RESULTS: Seventeen of the 28 patients developed recurrence after radiation therapy (local recurrence in 10 and distant metastasis in 12). The local control and distant metastasis-free rates at 3 years in all patients were 61% and 49%, respectively. Fourteen patients died after radiation therapy, and all but 2 died of tumor progression. The disease-free, cause-specific, and overall survival rates at 3 years in all patients were 32%, 49%, and 45%, respectively, and the estimated median survival time was 32 months. Tumor size (P = 0.007) and involvement in the lower third of vagina (P = 0.006) were significant prognostic factors for local control. Older age (P = 0.018) and performance status (P = 0.020) were significant prognostic factors for distant metastasis. The presence of hydronephrosis was the sole significant prognostic factor for survival (P = 0.026). Only 2 patients developed grade 3 late toxicities (vesicovaginal fistula and radiation proctitis, respectively). MATERIALS AND METHODS: Twenty-eight patients with stage IVA uterine cervical cancer received radiation therapy. All patients initially received external pelvic irradiation at a median dose of 50.4 Gy in 28 fractions. Twenty patients also received high-dose-rate intracavitary brachytherapy at a median dose of 22 Gy in 4 fractions. These fraction sizes were lower than conventional sizes. The total median dose for all 28 patients was 68.7 Gy. CONCLUSIONS: Radiation therapy is safe and effective for treatment of stage IVA uterine cervical cancer. The reduced radiation dose per fraction may contribute to the prevention of vesicovaginal fistula formation.

Pharmacokinetics of single dose radium-223 dichloride (BAY 88-8223) in Japanese patients with castration-resistant prostate cancer and bone metastases.

OBJECTIVE: This open-label, non-randomized, phase I study examined the pharmacokinetics (PK) and radiation dosimetry of a single dose of radium-223 in Japanese patients with castration-resistant prostate cancer (CRPC) and bone metastases. METHODS: Six male Japanese patients (mean age 72.5 years, range 65-79 years) with histologically or cytologically confirmed stage IV adenocarcinoma of the prostate were recruited. A single IV dose of radium-223 was delivered intravenously (IV) via slow bolus over a 2-5 min period: Cohort 1 received 50 kBq/kg and Cohort 2 received 100 kBq/kg. RESULTS: Following IV injection, radium-223 was rapidly eliminated from the blood in a multi-phasic manner. The fraction of the injected activity of radium-223 retained in the whole body 24 h following injection was 85 %. Biodistribution results showed initial bone uptake was 52 % (range 41-57 %). The maximum activity of radium-223 in the bone was observed within 2 h of dosing. Activity of radium-223 passed through the small intestine within 24 h. No activity was detected in other organs. The major radiation dose from radium-223 was found in osteogenic cells; calculated absorbed doses in osteogenic cells and in the red marrow were 0.76 Gy/MBq and 0.09 Gy/MBq, respectively. CONCLUSIONS: In Japanese patients with CRPC and bone metastases, radium-223 (IV) achieved maximum activity in the bone rapidly and passed through the intestine within 24 h, without signs of activity in other organs. The PK profile and absorbed radiation dose in organs and tissues in Japanese patients were similar to data from non-Japanese patients. Trial registration identification: NCT01565746.

Definitive chemo-radiotherapy for squamous cell carcinoma of the pharynx: impact of baseline low hemoglobin level (<12 g/dL) and post-radiation therapy F-18 FDG-PET/CT.

OBJECTIVE: To identify reliable predictors of overall survival (OS), locoregional control (LC), and metastasis-free survival (MFS) after definitive concurrent chemo-radiotherapy (CCRT) for squamous cell carcinoma (SCC) of the pharynx (nasopharynx, oropharynx and hypopharynx), we examined 16 potential prognostic factors, including pre-treatment hemoglobin level and pre- and post-treatment [(18)F]fluorodeoxyglucose positron emission tomography CT (F-18 FDG-PET/CT) maximum standardized up-take values (SUVmax) of primary sites and lymph node (LN) regions. METHODS: We retrospectively reviewed records of 70 patients treated with definitive CCRT for pharyngeal cancer in our institution during July 2006-April 2012, with particular regard to 16 prognostic factors: age, sex, T stage, N stage, retropharyngeal LN (RPLN) involvement, existence of multiple primary cancer, treatment interruptions, overall treatment time, chemotherapy type, pre-treatment hemoglobin level, pre-treatment body mass index, enteral feeding period, and pre- and post-treatment F-18 FDG-PET/CT SUVmax of primary site and LN region. All patients in our cohort underwent pre- and post-treatment F-18 FDG-PET/CT. RESULTS: Multivariate analysis associated improved OS with pre-treatment hemoglobin level (≥12 g/dL; hazard ratio [HR] 3.902; 95 % confidence interval [CI] 1.244-12.236; P = 0.020) and post-treatment SUVmax (primary site) (SUVmax <5.00; HR 4.237; 95 % CI 1.072-16.747; P = 0.039). Improved LC was associated with pre-treatment hemoglobin level (≥12 g/dL; HR 2.983; 95 % CI 1.123-7.920; P = 0.028), and post treatment SUVmax (primary site) (SUVmax <5.00; HR 5.233; 95 % CI 1.582-17.309; P = 0.007). No variable was found to be significant for improved MFS. CONCLUSIONS: Significant predictors for outcome in pharyngeal SCC treated with definitive CCRT were pre-treatment baseline hemoglobin level and post-treatment F-18 FDG-PET/CT SUVmax for primary site. Patients who have hemoglobin level lower than 12 g/dL may tend to have dismal prognosis. Additional treatment should be considered in those who have higher SUVmax at primary site in post-treatment F-18 FDG-PET/CT finding.