Clinical significance of completion of radium-223 treatment and acute adverse events in patients with metastatic castration-resistant prostate cancer.

Objectives: In the treatment of castration-resistant prostate cancer (CRPC) with bone metastases, radium-223 dichloride (Ra-223) is the only bone-targeted drug that shows survival benefits. Completing six courses of Ra-223 treatment is thought to be associated with better patient survival, but this treatment has a relatively high rate of acute adverse events. Methods: This retrospective study included 85 patients from 12 institutions in Japan to investigate the clinical significance of the completion of Ra-223 treatment and acute adverse events in CRPC patients. Results: Six courses of Ra-223 treatment were completed in 65.9% of the patients. Grade 3 or higher acute adverse events were observed in 27.1% of patients. The prostate specific antigen and alkaline phosphatase declined at 26.9% and 87.9%, respectively. The overall survival rates at 12 and 24 months were 80.7% and 63.2%, respectively. Both completion of six courses of Ra-223 treatment and absence of grade 3 or higher acute adverse events were associated with longer overall survival. In univariate analysis, factors related to the history of treatment (five or more hormone therapy agents and cytotoxic chemotherapy) and hematological parameters (Prostate specific antigen (PSA) doubling time, alkaline phosphatase, hemoglobin, albumin, and serum calcium) were associated with completing six courses of Ra-223 treatment without experiencing grade 3 or higher acute adverse events. Multivariate analysis showed that a history of chemotherapy, PSA doubling time, hemoglobin, and serum calcium showed statistical significance. We built a predictive score by these four factors. Patients with lower scores showed higher rates of treatment success (p<0.001) and longer overall survival (p<0.001) with statistical significance. Conclusions: Accomplishing six courses of Ra-223 treatment without grade 3 or higher acute adverse events was a prognostic factor in patients with mCRPC treated with Ra-223. We built a predictive score of treatment success and need future external validation.

Palliative radiotherapy for gastric cancer bleeding: a multi-institutional retrospective study.

BACKGROUND: Palliative radiotherapy for gastric cancer bleeding has been reported to be a safe and effective treatment, but predictive factors for achievement of hemostasis and overall survival have not been established. METHODS: In this retrospective study, 120 courses of palliative radiotherapy for gastric cancer bleeding in 117 patients in 4 institutes in Japan were reviewed with approval of the ethical committee in each institute. The rate of achieving hemostasis was evaluated by 50% or more reduction of red blood cell transfusion before and after the start of radiotherapy, elevation of blood hemoglobin concentration in a period of 4 weeks from the start of radiotherapy or improvement of subjective or objective clinical symptoms in a period of 4 weeks from the start of radiotherapy. Predictive factors for overall survival and achieving hemostasis were investigated with the Cox hazards model. RESULTS: The median overall survival period was 3.7 months. Multivariate analysis showed that absence of metastatic disease, higher biological effective dose, higher serum albumin level, lower blood urea nitrogen level and lower neutrophil-to-lymphocyte ratio (NLR) were associated with longer overall survival. Elevation of hemoglobin concentration in a period of 4 weeks from the start of radiotherapy (mean concentration: 8.2 g/dL vs. 8.9 g/dL, p = 0.006) and decrease in the amount of red cell transfusion from a 4-week period before to a 4-week period after the start of radiotherapy (mean amount: 716 mL vs. 230 mL, p < 0.0001) were observed. The overall rate of achievement of hemostasis was 59.6%. In multivariate analysis, higher biological effective dose was associated with achievement of hemostasis. Grade 2 or higher acute adverse effects related to radiotherapy were observed in 17.5% of cases in 120 treatment courses. Six cases (5.0%) had grade 3 or 4 adverse effects including gastric penetration in 1 patient and anorexia requiring total parental nutrition in 3 patients. No grade 5 adverse effects were observed. CONCLUSIONS: Palliative radiotherapy for gastric cancer bleeding seems to be an effective and safe treatment strategy. Higher treatment dose was associated with longer overall survival and a hemostatic effect. Some hematological parameters may predict overall survival, and they would be helpful for deciding the treatment strategy.

Risk factors for severe gastrointestinal toxicity in patients receiving palliative radiotherapy for metastatic bone tumors: association with the use of molecular-targeted agents.

This study aimed to investigate whether the use of molecular-targeted agents could affect gastrointestinal (GI) toxicity in palliative radiotherapy (RT) for metastatic bone tumors in the abdominopelvic region. We collected data of patients who received palliative RT for bone metastases in the abdominopelvic region between 2013 and 2014 from six institutions. Data of 395 patients were collected and184 patients received molecularly targeted therapy, of whom 80 received vascular endothelial growth factor (VEGF)-targeted agents. For 556 lesions, 410 sessions of irradiation were undergone. GI toxicity of ≥G3 was observed in 3.8% of patients. The incidence rates of ≥G3 GI toxicity in patients without targeted agents use, in those using VEGF-targeted agents and in those using non-VEGF-targeted agents were 3.8, 7.5 and 1.0%, respectively. Regarding risk factors of the occurrence of ≥G3 GI toxicity, univariate analysis in all patients showed that a history of abdominopelvic surgery was a significant risk factor (P = 0.01), and the use of VEGF-targeted agents showed a trend of high incidence (P = 0.06). In patients using VEGF-targeted agents, both univariate and multivariate analysis showed that combined anticoagulant use (P = 0.03 and 0.01) and agent use between 1 week before and after RT (P = 0.046 and 0.03) were significant risk factors. In conclusion, the history of abdominopelvic surgery was associated with ≥G3 GI toxicity and the use of VEGF-targeted agents showed a trend for high incidence. When using VEGF-targeted agents, caution should be exercised in the combined use of anticoagulants and in the agent use between 1 week before and after RT.

Is Concurrent Chemotherapy With Radiotherapy for Esophageal Cancer Beneficial in Patients Aged 80 Years or Older?

BACKGROUND/AIM: To determine whether concurrent chemotherapy with radiotherapy should be performed in elderly patients with esophageal cancer. PATIENTS AND METHODS: A total of 185 patients aged 80 years or older who were treated with definitive radiotherapy alone or combined with chemoradiotherapy for esophageal cancer at seven institutions were enrolled. In order to compare survival rates of patients treated with chemoradiotherapy with those of patients treated with radiotherapy alone, propensity score matching was performed to homogenize the two populations. RESULTS: For the whole patient cohort, the 3-year overall survival (OS) rate was 52.6% and the median survival was 42.5 months. After propensity score matching, the 3-year OS rate for the chemoradiotherapy group was not significantly better than that for the group treated with radiotherapy alone (53.7% vs. 59.9%, p=0.876). CONCLUSION: Concurrent chemotherapy with radiotherapy for esophageal cancer in patients aged 80 years or older did not have significant OS benefit over radiotherapy alone.

Dose Escalation Improves Outcome in Stereotactic Body Radiotherapy for Pulmonary Oligometastases from Colorectal Cancer.

AIM: To evaluate the efficacy of stereotactic body radiotherapy (SBRT) for pulmonary metastasis from colorectal cancer. PATIENTS AND METHODS: Data for 104 lesions from 93 patients who underwent SBRT for pulmonary oligometastases from colorectal cancer at ten Institutions were retrospectively analyzed. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0. RESULTS: The median calculated biological effective dose using the linear-quadratic model with α/ß of 10 Gy (BED10) was 105.6 Gy. Adjuvant chemotherapy after SBRT was performed in 47 patients. The median observation period was 28 months. The 3- and 5-year local control rates were 65.2% and 56.2%, respectively. The 3- and 5-year overall survival rates were 55.9% and 42.7%, respectively. Only two patients had grade 3 radiation pneumonitis. In multivariate analysis for local control, primary site, age, adjuvant chemotherapy after SBRT and BED10 were selected as prognostic factors. CONCLUSION: Dose escalation and adjuvant chemotherapy might improve local control in SBRT for pulmonary oligometastases from colorectal cancer.

Clinical practice and outcome of radiotherapy for esophageal cancer between 1999 and 2003: the Japanese Radiation Oncology Study Group (JROSG) Survey.

BACKGROUND: To determine the clinical results of radiotherapy (RT) for esophageal cancer in Japan. MATERIALS AND METHODS: A questionnaire-based survey was conducted for esophageal cancer treated by definitive RT between 1999 and 2003. Clinical results of definitive RT for patients were collected from 9 major institutions. Only patients with good performance status (PS 0-2) who received a total dose of 50 Gy or more were included. 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 by RT alone or chemo-radiotherapy (CRT) were included. For groups B and C, only those treated by CRT were included. RESULTS: In total, 167 patients were included in group A, 239 in group B, and 244 in group C. Approximately half of the patients in group A were treated by CRT. The median total RT dose ranged from 60 to 66 Gy. The median and range of the 5-year overall survival rates were 56% (48-83%) for group A, 29% (12-52%) for group B, and 19% (0-31%) for group C, respectively. A wide disparity in overall survival rates was noted among the institutions. A significant correlation between the number of patients treated per year and the 5-year overall survival rate was noted for groups B and C (both p < 0.05). CONCLUSION: Although the overall survival rates for stage I esophageal cancer were excellent, a significant disparity in survival rates was noted among the institutions for stage II-IVA tumors treated by CRT.

Impact of pathological tumor stage for salvage radiotherapy after radical prostatectomy in patients with prostate-specific antigen < 1.0 ng/ml.

BACKGROUND: To evaluate prognostic factors in salvage radiotherapy (RT) for patients with pre-RT prostate-specific antigen (PSA) < 1.0 ng/ml. METHODS: Between January 2000 and December 2009, 102 patients underwent salvage RT for biochemical failure after radical prostatectomy (RP). Re-failure of PSA after salvage RT was defined as a serum PSA value of 0.2 ng/ml or more above the postradiotherapy nadir followed by another higher value, a continued rise in serum PSA despite salvage RT, or initiation of systemic therapy after completion of salvage RT. Biochemical relapse-free survival (bRFS) was estimated using the Kaplan-Meier method. Multivariate analysis was performed using the Cox proportional hazards regression model. RESULTS: The median follow-up period was 44 months (range, 11-103 months). Forty-three patients experienced PSA re-failure after salvage RT. The 4-year bRFS was 50.9% (95% confidence interval [95% CI]: 39.4-62.5%). In the log-rank test, pT3-4 (p < 0.001) and preoperative PSA (p = 0.037) were selected as significant factors. In multivariate analysis, only pT3-4 was a prognostic factor (hazard ratio: 3.512 [95% CI: 1.535-8.037], p = 0.001). The 4-year bRFS rates for pT1-2 and pT3-4 were 79.2% (95% CI: 66.0-92.3%) and 31.7% (95% CI: 17.0-46.4%), respectively. CONCLUSIONS: In patients who have received salvage RT after RP with PSA < 1.0 ng/ml, pT stage and preoperative PSA were prognostic factors of bRFS. In particular, pT3-4 had a high risk for biochemical recurrence after salvage RT.

(18)F-fluorodeoxyglucose positron emission tomography immediately after chemoradiotherapy predicts prognosis in patients with locoregional postoperative recurrent esophageal cancer.

OBJECTIVES: The objectives of this study were to reveal the utility of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) within 7 days after chemoradiotherapy to predict prognosis in patients with postoperative recurrent esophageal cancer. MATERIALS AND METHODS: Patients scheduled to undergo concurrent chemoradiotherapy for postoperative locoregional recurrence of esophageal cancer were recruited. Selection criteria were: (1) locoregional recurrence, (2) no previous radiation therapy, (3) planning treatment with concurrent chemoradiotherapy, (4) FDG-PET performed <2 weeks before chemoradiotherapy, and (5) no serious diabetes. FDG-PET was performed <7 days after chemoradiotherapy. No more treatment after chemoradiotherapy was given until disease progression was diagnosed according to the Response Evaluation Criteria in Solid Tumors (RECIST). Correlations of FDG-PET findings with cause-specific survival and local control rates were investigated prospectively. RESULTS: Twenty patients were enrolled. Median observation period of patients who survived was 45.0 months. Median maximum standardized uptake value (SUV(max)) after chemoradiotherapy was 2.4, and median SUV(max) before chemoradiotherapy was 8.4. Cause-specific survival and local control rates were significantly better for patients with SUV(max) < or = 2.4 after chemoradiotherapy (log-rank test, P = 0.033 and 0.010, respectively). SUV(max) before chemoradiotherapy tended to be correlated only with cause-specific survival rate (log-rank test, P = 0.076). Change in metabolic activity of FDG was significantly correlated with local control rate (log-rank test, P = 0.042). CONCLUSIONS: FDG-PET performed even <7 days after chemoradiotherapy predicts prognosis in patients with postoperative recurrent esophageal cancer.

Prospective comparison of surgery alone and chemoradiotherapy with selective surgery in resectable squamous cell carcinoma of the esophagus.

PURPOSE: Esophagectomy remains the mainstay treatment for esophageal cancer, although retrospective studies have suggested that chemoradiotherapy (CRT) is as effective as surgery. To determine whether CRT can substitute for surgery as the primary treatment modality, we performed a prospective direct comparison of outcomes after treatment in patients with resectable esophageal cancer who had received CRT and those who had undergone surgery. METHODS AND MATERIALS: Eligible patients had resectable T1-3N0-1M0 thoracic esophageal cancer. After the surgeon explained the treatments in detail, the patients selected either CRT (CRT group) or surgery (OP group). The CRT course consisted of two cycles of cisplatin and fluorouracil with split-course concurrent radiotherapy of 60Gy in 30 fractions. Patients with progressive disease during CRT and/or with persistent or recurrent disease after CRT underwent salvage resection. RESULTS: Of 99 eligible patients with squamous cell carcinoma registered between January 2001 and December 2005, 51 selected CRT and 48 selected surgery. Of the patients in the CRT group, 13 (25.5%) underwent esophagectomy as salvage therapy. The 3- and 5-year survival rates were 78.3% and 75.7%, respectively, in the CRT group compared with 56.9% and 50.9%, respectively, in the OP group (p = 0.0169). Patients in the OP group had significantly more metastatic recurrence than those in the CRT group. CONCLUSIONS: Treatment outcomes among patients with resectable thoracic esophageal squamous cell carcinoma were comparable or superior after CRT (with salvage therapy if needed) to outcomes after surgery alone.

Comparison of cisplatin and 5-fluorouracil chemotherapy protocols combined with concurrent radiotherapy for esophageal cancer.

PURPOSE: The optimal chemotherapeutic protocol for the treatment of esophageal cancer has not yet been established. This study was performed to identify the differences in toxicity and completion rates of various chemotherapy protocols with that goal in mind. MATERIALS AND METHODS: A total of 61 patients with esophageal cancer were enrolled in this study between June 2002 and January 2004. The total radiotherapy dose was 64 Gy. Three chemotherapy protocols were used. Arm A comprised daily low-dose cisplatin (CDDP) and 5-fluorouracil (5FU) (CF protocol) (3 mg/m(2) and 180 mg/m(2), respectively). Arm B was intermediate between arm A and C (CDDP 7 mg/m(2) and 5FU 250 mg/m(2) on days 1-5, 8-12, 29-33, and 36-40). Arm C comprised two courses of standard CF (CDDP 70 mg/m(2) on day 1 and 5FU 600 mg/m(2)/24 h on days 1-4). RESULTS: Although there were no significant differences in hematological toxicity between the protocols, leukocytopenia was slightly milder in arm A. Nausea was significantly more severe in arm C. The completion rate was higher in arm A. The 3-year survival rates were 40%, 31%, and 62%, respectively. CONCLUSION: The daily low-dose CF protocol showed a trend of mild toxicity regarding leukocytopenia. However, we could not find statistical difference between arms. It also showed a better completion rate than the other two arms.

Clinical correlations between treatment with anticoagulants/antiaggregants and late rectal toxicity after radiotherapy for prostate cancer.

AIM: To assess variables related to grade 2 or higher late rectal toxicity (LRT) in prostate cancer treated with external radiotherapy. PATIENTS AND METHODS: A retrospective analysis was carried out of 232 patients with T1-T3 prostate cancer treated with 3-dimensional conformal radiotherapy (3DCRT) (106 patients) or intensity modulated radiotherapy (IMRT) (126 patients) between June 2000 and May 2007. One hundred and seventy-seven patients received androgen deprivation therapy (ADT); fifty patients used anticoagulants/antiaggregants for vascular disease. RESULTS: The median follow-up was 31 months (range, 6-79). At 5 years, the cumulative incidence of grade 2 or 3 LRT was 5.6% . On multivariate analysis, medication with anticoagulants/antiaggregants was correlated with grade 2 or 3 LRT (p=0.027), whereas age, National Comprehensive Cancer Network risk group classification, use of ADT, radiotherapy technique (3DCRT vs. IMRT) and total irradiated dose were not. CONCLUSION: Treatment with anticoagulants/antiaggregants appears to be a factor in grade 2 or 3 LRT.

Temporal change in brain natriuretic Peptide after radiotherapy for thoracic esophageal cancer.

PURPOSE: To investigate the relationships of plasma levels of brain natriuretic peptide (BNP) with abnormal (18)F-fluorodeoxyglucose (FDG) accumulation in the myocardium corresponding to irradiated fields and temporal changes in BNP, which is used as an index of heart remodeling, after radiotherapy for the mediastinum. MATERIALS AND METHODS: Brain natriuretic peptide concentrations were measured before and after radiotherapy for thoracic esophageal cancer, and the change in BNP concentration after radiotherapy was investigated. Moreover, FDG accumulation in the myocardium was investigated in patients who had undergone FDG positron emission tomography less than 14 days before or after measurement of BNP concentration, and the Mann-Whitney U test was used to detect significant difference between BNP concentrations in patients with and without abnormal FDG accumulation corresponding to the irradiated field. RESULTS: There was significant difference between the levels of BNP in patients without abnormal FDG accumulation in the irradiated myocardium and in patients with abnormal FDG accumulation (p < 0.001). The levels of BNP in the 9-24 months after radiotherapy group and in the >24 months after radiotherapy group were significantly higher than the levels in the before radiotherapy group, immediately after radiotherapy group, 1-2 months after radiotherapy group, and control group. CONCLUSIONS: The level of BNP was significantly increased more than 9 months after the start of radiotherapy and was significantly higher in patients who had high FDG accumulation corresponding to the irradiated field. The results of this study indicate that BNP concentration might be an early indicator of radiation-induced myocardial damage.

The utility of 18F-fluorodeoxyglucose positron emission tomography for early diagnosis of radiation-induced myocardial damage.

PURPOSE: We evaluated the clinical significance of focal increased uptake in the basal myocardium on F-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with esophageal cancer after radiotherapy. METHODS AND MATERIALS: Between August 2004 and July 2005, a total of 64 patients who had been irradiated for thoracic esophageal cancer underwent FDG-PET at least three months after the completion of chemoradiotherapy. Some patients showed increased FDG uptake in the basal portion of the myocardium. To clarify the clinical significance of these findings, further examinations of hearts were performed. The dose distribution in the myocardium with high FDG uptake was also analyzed retrospectively. RESULTS: Thirteen (20.3%) of the 64 patients showed high FDG uptake in the basal myocardium corresponding to the irradiated fields compared with FDG uptake in the myocardium outside the irradiated fields. Eight of the 13 patients consented to undergo examinations of the heart. Five of those eight patients showed low 123I-BMIPP uptake and four showed low 201TlCl uptake in the myocardium corresponding with high FDG uptake regions. In two patients, delayed enhancement was found in some parts of the area with high FDG uptake on Gd-DTPA magnetic resonance imaging (MRI), and the delay-enhanced lesion showed hypokinesia on cine-MRI in one patient. CONCLUSIONS: FDG-PET often shows focal increased uptake in the basal myocardium after radiotherapy for esophageal cancer. This finding indicates the possibility of radiation-induced cardiac damage, and cardiac function and symptoms of such patients should be followed carefully.

Salvage radiation therapy for residual superficial esophageal cancer after endoscopic mucosal resection.

PURPOSE: To analyze the outcomes of radiation therapy for patients with residual superficial esophageal cancer (rSEC) after endoscopic mucosal resection (EMR). METHODS AND MATERIALS: From May 1996 to October 2002, a total of 30 rSEC patients without lymph node metastasis received radiation therapy at Tohoku University Hospital and associated hospitals. The time interval from EMR to start of radiation therapy ranged from 9 to 73 days (median interval, 40 days). Radiation doses ranged from 60 Gy to 70 Gy (mean dose, 66 Gy). Chemotherapy was used in 9 of 30 patients (30%). RESULTS: The 2-year, 3-year, and 5-year overall survival rates and cause-specific survival rates were 91%, 82%, and 51%, respectively, and 95%, 85%, and 73%, respectively. The 2-year, 3-year, and 5-year local control rates for mucosal cancer were 91%, 91%, and 91%, respectively, and those for submucosal cancer were 89%, 89%, and 47%, respectively. These differences in survival rates for patients with two types of cancer were not statistically significant. Local recurrence and lymph node recurrence were more frequent in patients with submucosal cancer than in patients with mucosal cancer (p = 0.38 and p = 0.08, respectively). Esophageal stenosis that required balloon dilatation developed in 3 of the 30 patients, and radiation pneumonitis that required steroid therapy developed in 1 patient. CONCLUSIONS: Radiation therapy is useful for preventing local recurrence after incomplete EMR.

[Effect of steroid on antiemetic for side effect of anticancer chemotherapy].

The side effect of anticancer agents such as nausea and vomiting frequently interrupt chemotherapy. To reduce these side effects, 5-hydroxytryptamine (5-HT3) receptor antagonist or metoclopramide is administered combined with steroid. In this study, we examined the effect of 5-HT3 receptor antagonist on the frequency of nausea and vomiting in a male cancer patient treated with/without steroid. This patient in his sixties had esophageal cancer (stage IV). He was administered nedaplatin 100 mg/day for 1 day and then 5-fluorouracil (5-FU) 750 mg/day for 5 days combined with radiotherapy (60 Gy) as one cycle of this chemotherapy. In the first cycle, 5-HT3 receptor antagonist was administered, and in the second, the antagonist was administered after treatment with steroid. The blood levels of total bilirubin, GOT, GPT, BUN, Cre, Na, K and Cl were stable normally during both cycles of the chemotherapy, indicating that the hepatopathy and nephropathy which cause nausea and vomiting did not occur in these periods. The frequency and period of the nausea and vomiting were one-third decreased, respectively, by the combination of 5-HT3 receptor antagonist and steroid.

Long-term outcome of breast-conserving therapy for breast cancer.

PURPOSE: We present a retrospective analysis of long-term therapeutic results for patients treated in our institution to evaluate the efficacy of breast-conserving therapy (BCT). PATIENTS AND METHODS: The study population was 99 patients (102 breasts) with stage 0, I, and II breast cancer who underwent breast conservation therapy between April 1990 and November 1997. The entire breast was irradiated to a median dose of 50 Gy (range, 50-60 Gy) in 25-30 fractions. An additional 10 Gy in five fractions with 6-12 MeV electrons was given to 23 breasts (23%) with positive surgical margins. RESULTS: The 5-/10-year overall survival, cause-specific survival, relapse-free rate, local recurrence, and regional recurrence rates were 94.6/93.3%, 95.7/94.5%, 88.2/77.5%, 4.2/8.5%, and 2.0/6.3%, respectively. In both uni- and multivariate analyses, age < 40 years was a significant prognostic factor for local recurrence. No severe morbidity was observed. CONCLUSION: The long-term clinical outcome of BCT for early breast carcinoma patients in our department was favorable. Patient age <40 was the most important factor associated with an increased risk of local recurrence in the ipsilateral breast.

[Performance evaluation of dual-head coincidence gamma camera for positron imaging].

AIM AND METHODS: We assessed the performance evaluation of a dual-head coincidence gamma camera (Millennium VG, General Electric, Milwaukee, USA) as a positron emission tomography (PET) scanner based on the measurement indicator for performance evaluation of PET device. RESULTS: The axial spatial resolution was 4.98 mm FWHM at the center of the field of view. The true high count-rate characteristic curve was relatively straight within the range 0-0.2 microCi/ml. The relative recovery coefficient was 0.1 with a diameter of 10 mm and 0.39 with a diameter of 20 mm. CONCLUSION: In this study, we had to make a some change in the protocols described in the measurement indicator for performance evaluation of PET devices.