Prostate-specific antigen doubling time following radium-223 treatment as a predictor of the clinical course in patients with metastatic castration-resistant prostate cancer.

Objectives: To identify useful biomarkers by reviewing laboratory data for a predictor of the clinical course following treatment with radium-223 dichloride (Ra-223) in patients with metastatic castration-resistant prostate cancer. Methods: Eighteen metastatic castration-resistant prostate cancer patients who were administered Ra-223 at our hospital were retrospectively enrolled in this study. Prostate-specific antigen doubling times before and after the administration of Ra-223 were evaluated as prognostic factors for metastatic castration-resistant prostate cancer patients treated with Ra-223 using the Kaplan-Meier method and Log-rank test. Results: Four patients failed to complete the planned six-time Ra-223 treatments with the exacerbation of their condition. In the 14 patients who completed the planned Ra-223 treatment, before the Ra-223 treatment, no significant differences were observed in overall survival between patients with prostate-specific antigen doubling time of 6 months or less and those with prostate-specific antigen doubling time of more than 6 months or stable (p = 0.642). Following the completion of the Ra-223 treatment, overall survival was significantly shorter in patients with prostate-specific antigen doubling time of 6 months or less than in those with prostate-specific antigen doubling time of more than 6 months or stable (p = 0.007). Conclusion: Prostate-specific antigen doubling time after the Ra-223 treatment is a useful predictor of the clinical course following treatment in metastatic castration-resistant prostate cancer patients.

Successful Response of Pembrolizumab Rechallenge after Radiotherapy for a Patient with Bladder Cancer of Nonresponse of Pembrolizumab First Challenge.

We report a patient with advanced bladder cancer in which the primary lesion and metastatic site disappeared following the pembrolizumab therapy rechallenge after radiotherapy for bladder cancer lesion of nonresponse of pembrolizumab first challenge. A 76-year-old man with advanced bladder cancer received three courses of the chemotherapy with gemcitabine and cisplatin combination; however, the chemotherapy was stopped because of adverse events. The patient started pembrolizumab therapy; however, the effect was not observed. Radiation therapy was given to the primary lesion and pelvic lymph node metastases for the purpose of local control of the lesions. Because the primary lesion was regrowth and para-aortic lymph node metastasis appeared, pembrolizumab therapy was resumed. Thereafter, the primary lesion and metastatic site disappeared.

Multidisciplinary Therapy in Men with Newly Diagnosed Oligometastatic Prostate Cancer.

PURPOSE: To assess the use of aggressive local therapy with systemic therapy for patients with oligometastatic prostate cancer. PATIENTS AND METHODS: Patients with oligometastatic prostate cancer received systemic therapy centered on androgen deprivation therapy (ADT). After six months or more of ADT, the patients received radiation therapy or surgery for the prostate, and radiation therapy for all metastatic sites. ADT was continued for 2-3 years after local therapy. RESULTS: Twelve patients who were judged to be able to undergo radiotherapy or surgical treatment of the prostate and radiation therapy for all metastatic sites and one case of pubic bone recurrence after radical prostatectomy were included. Bone metastases (n = 11) and para-aortic lymph node metastases (n = 2) were found. The number of bone metastases was one (n = 7), two (n = 3), and three (n = 1). Radiation therapy (70-74 Gy) was performed on the prostate in 11 of 12 patients. A prostatectomy was performed on one patient who was judged to be unable to receive a sufficient dose to the metastatic site when radical radiation was applied to the prostate. Radiation therapy (45-60 Gy) was performed on all metastatic sites. Prostate-specific antigen (PSA) levels increased again during treatment in three patients. There was a significant difference in PSA levels before local therapies between the three patients who developed castration-resistant prostate cancer (CRPC) during the course of treatment and the eight patients who did not progress to CRPC (p = 0.012). There was also a significant difference in PSA levels after local therapies between the three patients who developed CRPC during the course of treatment and the eight patients who did not progress to CRPC (p = 0.012). Four patients completed treatment. In one patient in whom the testosterone level recovered to the normal level the PSA level remained the level below the measurement sensitivity. CONCLUSION: Aggressive local therapy in combination with systemic therapy centered on ADT is a promising treatment option for oligometastatic prostate cancer.

Isolated adrenocorticotropic hormone deficiency and thyroiditis associated with nivolumab therapy in a patient with advanced lung adenocarcinoma: a case report and review of the literature.

INTRODUCTION: Immune checkpoint inhibitors are a promising class of anticancer drugs. The clinical benefits afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events that affect multiple organs, and endocrine immune-related adverse events include thyroiditis and hypophysitis. Hypophysitis is less frequent and has a less severe clinical presentation in patients treated with other immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and atezolizumab, than in those treated with ipilimumab. However, studies have described isolated adrenocorticotropic hormone deficiency cases associated with nivolumab, pembrolizumab, and atezolizumab therapy, most of which occurred during the course of immune checkpoint inhibitor therapy. We report a rare case of patient with isolated adrenocorticotropic hormone deficiency that occurred after nivolumab therapy. CASE PRESENTATION: A 69-year-old Japanese woman with advanced lung adenocarcinoma developed painless thyroiditis with transient elevations of serum thyroid hormones during 3 months of cancer treatment with nivolumab and began thyroid hormone replacement therapy for subsequent primary hypothyroidism. Four months after nivolumab therapy was discontinued, she developed isolated adrenocorticotropic hormone deficiency; corticosteroid replacement therapy relieved her secondary adrenal insufficiency symptoms, such as anorexia and fatigue. Human leukocyte antigen typing revealed the presence of DRB1*04:05-DQB1*04:01-DQA1*03:03 and DRB1*09:01-DQB1*03:03-DQA1*03:02 haplotypes, which increase susceptibility to autoimmune polyendocrine syndrome associated with thyroid and pituitary disorders in the Japanese population. CONCLUSIONS: Our patient developed thyroiditis during cancer treatment with nivolumab and subsequently exhibited isolated adrenocorticotropic hormone deficiency 4 months after discontinuing the drug. Administration of nivolumab in combination with a genetic predisposition to polyglandular autoimmunity probably caused both the thyroiditis and hypophysitis, resulting in primary hypothyroidism and isolated adrenocorticotropic hormone deficiency, respectively, in our patient. The present case highlights the need for physicians to be aware that endocrine immune-related adverse events, including hypophysitis, can occur more than several months after discontinuing a drug.

Clinical commissioning of a new patient positioning system, SyncTraX FX4, for intracranial stereotactic radiotherapy.

BACKGROUND & AIMS: A new real-time tracking radiotherapy (RTRT) system, the SyncTraX FX4 (Shimadzu, Kyoto, Japan), consisting of four X-ray tubes and four ceiling-mounted flat panel detectors (FPDs) combined with a linear accelerator, was installed at Uonuma Kikan Hospital (Niigata, Japan) for the first time worldwide. In addition to RTRT, the SyncTraX FX4 system enables bony structure-based patient verification. Here we provide the first report of this system's clinical commissioning for intracranial stereotactic radiotherapy (SRT). MATERIALS & METHODS: A total of five tests were performed for the commissioning: evaluations of (1) the system's image quality; (2) the imaging and treatment coordinate coincidence; and (3) the localization accuracy of cone-beam computed tomography (CBCT) and SyncTraX FX4; (4) the measurement of air kerma; (5) an end-to-end test. RESULTS & DISCUSSION: The tests revealed the following. (1) All image quality evaluation items satisfied each acceptable criterion in all FPDs. (2) The maximum offsets among the centers were ≤0.40 mm in all combinations of the FPD and X-ray tubes (preset). (3) The isocenter localization discrepancies between CBCT and preset #3 in the SyncTraX FX4 system were 0.29 ± 0.084 mm for anterior-posterior, -0.19 ± 0.13 mm for superior-inferior, 0.076 ± 0.11 mm for left-right, -0.11 ± 0.066° for rotation, -0.14 ± 0.064° for pitch, and 0.072±0.058° for roll direction. the Pearson's product-moment correlation coefficient between the two systems was >0.98 in all directions. (4) The mean air kerma value for preset #3 was 0.11 ± 0.0002 mGy in predefined settings (80 kV, 200 mA, 50 msec). (5) For 16 combinations of gantry and couch angles, median offset value in all presets was 0.31 mm (range 0.14-0.57 mm). CONCLUSION: Our results demonstrate a competent performance of the SyncTraX FX4 system in terms of the localization accuracy for intracranial SRT.

Two-fraction high-dose-rate brachytherapy within a single day combined with external beam radiotherapy for prostate cancer: single institution experience and outcomes.

We investigated the outcomes of treatment for patients with localized prostate cancer (PCa) treated with 3D conformal radiation therapy (3D-CRT) followed by two-fraction high-dose-rate brachytherapy within a single day (2-fr.-HDR-BT/day) at a single institution. A total of 156 consecutive Asian males (median age, 67 years) were enrolled. To compare our findings with those of other studies, we analyzed our results using the D'Amico classification, assigning the patients to low- ( N =: 5; 3.2%), intermediate- ( N =: 36; 23.1%) and high-risk ( N =: 115; 73.7%) groups (Stage T3 PCa patients were classified as high-risk). One patient in the D'Amico low-risk group (20%), 13 intermediate-risk patients (36.1%) and 99 high-risk patients (86.1%) underwent androgen deprivation therapy. We administered a prescription dose of 39 Gy in 13 fractions of 3D-CRT combined with 18 Gy of HDR-BT in two 9-Gy fractions delivered within a single day. We did not distinguish between risk groups in determining the prescription dose. The median follow-up period was 38 months. Of the 156 patients, one died from primary disease and five died from other diseases. The 3-year overall survival (OS) rates were 100%, 100% and 93.7%, and the 3-year 'biochemical no evidence of disease (bNED)' rates were 100%, 100% and 96.9% for the D'Amico low-, intermediate- and high-risk groups, respectively. No patient developed ≥ Grade 3 early toxicity. The Grade 3 late genitourinary toxicity rate was 2.6%, and no ≥ Grade 3 late gastrointestinal toxicity occurred. The efficacy and safety of this study were satisfactory, and longer-term follow-up is necessary.

Clinical outcomes of radiotherapy for esophageal cancer between 2004 and 2008: the second survey of the Japanese Radiation Oncology Study Group (JROSG).

BACKGROUND: This second questionnaire-based survey was performed to determine the clinical results of definitive esophageal cancer treatment with radiotherapy (RT) or chemoradiotherapy (CRT) between 2004 and 2008. MATERIALS/METHODS: Clinical results of definitive RT for patients were collected from major Japanese institutions. Patients were classified into three groups: (A) stage I, (B) resectable stages II-III, (C) unresectable stages III-IVA. For group A, all patients treated with RT alone or CRT were included. For groups B and C, only those treated with CRT were included. RESULTS: In total, 990 patients (group A 259, group B 333, group C 398 patients) were included from 11 institutions. In group A, 199 patients (78 %) were treated with CRT, and 60 patients (23 %) received RT alone. In groups B and C, 420 patients (57 %) were treated with full-dose cisplatin/5-FU, and 181 patients (25 %) with low-dose protracted-infusion cisplatin/5-FU. The median and range of the 5-year overall survival rate were 73 % (40-94 %) for group A, 40 % (0-57 %) for group B, and 18 % (6-26 %) for group C, respectively. The 5-year overall survival rates were consistently good for five high-volume centers where more than 20 patients/year with esophageal cancer were treated definitively as compared with the remaining six medium-volume centers (5-15 patients/year). The median and range of the incidence of grade ≥3 late toxicities were 10 % and 6-22 %, respectively. CONCLUSIONS: A wide disparity in 5-year overall survival rates among the institutions was still apparent in the second survey for groups A and B.

Superiority of a soft tissue-based setup using cone-beam computed tomography over a bony structure-based setup in intensity-modulated radiotherapy for prostate cancer.

The purpose of this study was to test the superiority of a soft tissue-based setup using cone-beam computed tomography (CBCT) to a bony structure-based setup using the ExacTrac system in intensity-modulated radiotherapy (IMRT) for prostate cancer. We studied 20 patients with localized prostate cancer who received IMRT between November 2010 and February 2012. After the initial setup, the pelvic bony structure-based setup and ExacTrac system were applied. After that, CBCT and a soft tissue-based setup were used. A shift in the isocenter between the ExacTrac-based and CBCT-based setup was recorded in the anterior-posterior (AP), superior-inferior (SI), and left-right (LR) axes. The shift was considered an interfractional prostate shift. Post-treatment CBCT was also taken once a week to measure the intrafractional prostate shift, based on the coordinates of the isocenter between pre- and post-treatment CBCT. The planning target volume (PTV) margins were determined using van Herk's method. We measured the elapsed time required for soft tissue matching and the entire treatment time using CBCT. The means ± standard deviation (SD) of the inter- and intrafractional shifts were 0.9 ± 2.8 mm and -0.3 ± 1.4 mm in the AP, 0.9 ± 2.2 mm and -0.1 ± 1.2 mm in the SI, and 0.1 ± 0.7 mm and -0.1 ± 0.7 mm in the LR directions. The PTV margins in the cases of bony structure-based and soft tissue-based setups were 7.3 mm and 2.7 mm in the AP, 5.8 mm and 2.3 mm in the SI, and 1.9 mm and 1.2 mm in the LR directions. Even though the median elapsed time using CBCT was expanded in 5.9 min, the PTV margins were significantly reduced. We found the calculated PTV margins in the soft tissue-based setup using CBCT were small, and this arrangement was superior to the bony structure-based setup in prostate IMRT.

The effectiveness of endoscopic submucosal dissection followed by chemoradiotherapy for superficial esophageal cancer.

BACKGROUND: To evaluate the risks and benefits of endoscopic submucosal dissection (ESD) in addition to chemoradiotherapy (CRT) for the treatment of superficial esophageal squamous cell carcinoma (SESCC). METHODS AND MATERIALS: We retrospectively reviewed the treatment outcomes of 47 patients with SESCC treated between October 2000 and December 2011. Sixteen patients with invasion into the submucosal layer (T1b) or the muscularis mucosa (m3) with positive vascular invasion were treated with CRT after ESD (ESD-CRT group). The lymph node area was irradiated to a total dose of 40-44 Gy and a boost radiation was administered if PET-positive lymph nodes or positive margins were observed. The remaining 31 patients received definitive CRT only (dCRT group). RESULTS: The radiation field was significantly larger in the ESD-CRT group; the "long T" was used in 11 patients (35.4%) in the dCRT group and 15 (93.7%) in the ESD-CRT group (p = 0.0001). The total radiation dose was smaller in the ESD-CRT group; 40 Gy was used in 10 patients (62.5%) in the ESD-CRT group and all but one patient in the dCRT group received ≥60 Gy (p = 0.00001). The 3-year overall survival rates in the dCRT and ESD-CRT groups were 63.2% and 90.0% respectively (p = 0.118). Recurrence developed in nine patients (29.0%) in the dCRT group and one (6.3%) in the ESD-CRT group. Local recurrence was observed in six patients (19%) in the dCRT group and none in the ESD-CRT-group (p = 0.029). Pericardial effusion (≥Grade 3) occurred in three patients (9.7%) in the dCRT group and none in the ESD-CRT group. CONCLUSIONS: ESD followed by CRT is an effective and safe approach for SESCC at m3 or T1b. This combination of ESD and CRT improves the local control rate, and it could decrease the number of cardiac toxicities due to a radiation-dose reduction relative to CRT alone.

Salvage endoscopic submucosal dissection in patients with local failure after chemoradiotherapy for esophageal squamous cell carcinoma.

OBJECTIVE: For locoregional failure after chemoradiotherapy (CRT) in patients with esophageal squamous cell carcinoma (ESCC), salvage esophagectomy and endoscopic mucosal resection have disadvantages, such as a high morbidity rate and a high local recurrence rate, respectively. The aim of this study was to clarify the efficacy of salvage endoscopic submucosal dissection (ESD) for locoregional failure of CRT. METHODS: A total of 19 lesions in 19 patients were treated with salvage ESD; 15 lesions were local recurrences at the primary site and 4 lesions were residual. All lesions were intramucosal or submucosal tumors without metastases. A case-control study was retrospectively evaluated to clarify whether the clinical outcomes of salvage ESD were equivalent to those of control primary ESD. RESULTS: No significant differences were observed between salvage ESD and primary ESD in short-term outcomes, including procedure time. For salvage ESD, the complete en bloc resection rate was 94.7% (18 of 19), and no severe complications were observed. At a median follow up of 54.6 (range: 5-98) months after salvage ESD, the local recurrence rate was 0%. However, three patients (15.8%) died due to lymph node and distant metastases and six patients (31.5%) died from other diseases, including radiation pneumonitis, pyothorax or respiratory failure with no recurrence of ESCC. The 3-year overall survival rate for all 19 patients was 74%. CONCLUSIONS: ESD represents an acceptable treatment option for recurrent or residual ESCC because of its improvement in local control, when local failure after CRT is limited to the submucosal layer without metastases.

Elevation of serum carcinoembryonic antigen level in a patient with hypothyroidism after radiation therapy for cervical esophageal cancer.

We report the case of a 51-year-old woman who showed elevation of serum carcinoembryonic antigen (CEA) level 14 months after chemoradiation therapy for her cervical esophageal cancer. Close examination demonstrated that the patient was suffering from hypothyroidism probably due to the chemoradiation therapy. The serum CEA level decreased after starting supplementary treatment with oral levothyroxine. The exact mechanism underlying the elevated level of CEA observed in a patient with hypothyroidism is unclear. However, we should be aware of the possibility of transient elevation of CEA affected by thyroid function in patients after radiation therapy for head and neck cancer.