Survival outcomes of esophageal cancer patients with recurrence after curative treatments.

BACKGROUND: Little is known about predictive factors for survival outcomes of esophageal carcinoma (EC) patients who developed recurrence after undergoing multimodal therapies. We aimed to investigate long-term outcomes and identify prognostic factors in patients with relapsed EC, focusing especially on those with oligometastasis (OM). METHODS: EC patients who developed recurrence after curative treatments (radical esophagectomy or definitive chemoradiotherapy (dCRT)) between 2010 and 2017 were reviewed. Multivariate Cox hazards models were applied to determine independent predictors of poor post-recurrence survival (PRS). RESULTS: In total, 178 patients were included. The median PRS was 12.9 months. Of the 178 patients, 98 had OM and 80 non-OM (NOM) disease. The survival outcomes of patients with OM were significantly better than those of patients with NOM (P < 0.01). Surgical treatments provided significantly better survival outcomes than CRT or chemo-/radiotherapy alone (3-year overall survival (OS); 78.1% vs. 42.5% vs. 28.9%, P < 0.01), mainly due to prolonging survival after the recurrence (3-year PRS 62.9% vs. 16.7% vs. 16.2%, P < 0.01). Multivariable analysis focusing on patients with OM revealed cStage III-IV disease (P < 0.01), high GPS at the time of recurrence (P = 0.02) and non-curative treatments (P < 0.01), to be independently associated with poor PRS. In contrast, in patients with NOM, no independent predictors for poor PRS were identified. CONCLUSIONS: The survival outcomes of patients with relapsed EC remain poor. Surgical treatments could provide survival benefits for patients with recurrent EC, especially for patients with OM.

A phase II randomized trial of metastasis-directed therapy with alpha emitter radium-223 in men with oligometastatic castration-resistant prostate cancer (MEDAL).

BACKGROUND: The significance of metastasis-directed therapy for oligometastatic prostate cancer has been widely discussed, and targeted therapy for progressive sites is a feasible option as a multidisciplinary treatment for castration-resistant prostate cancer (CRPC). When oligometastatic CRPC with only bone metastases progresses after targeted therapy, it tends to progress as multiple bone metastases. The progression of oligometastatic CRPC after targeted therapy may be due in part to the presence of micrometastatic lesions that, though undetected on imaging, were present prior to targeted therapy. Thus the systemic treatment of micrometastases in combination with targeted therapy for progressive sites is expected to enhance the therapeutic effect. Radium-223 dichloride (radium-223) is a radiopharmaceutical that selectively binds to sites of increased bone turnover and inhibits the growth of adjacent tumor cells by emitting alpha rays. Therefore, for oligometastatic CRPC with only bone metastases, radium-223 may enhance the therapeutic effect of radiotherapy for active metastases. METHODS: This phase II, randomized trial of Metastasis-Directed therapy with ALpha emitter radium-223 in men with oligometastatic CRPC (MEDAL) is designed to assess the utility of radium-223 in combination with metastasis-directed radiotherapy in patients with oligometastatic CRPC confined to bone. In this trial, patients with oligometastatic CRPC with three or fewer bone metastases on whole-body MRI with diffusion-weighted MRI (WB-DWI) will be randomized in a 1:1 ratio to receive radiotherapy for active metastases plus radium-223 or radiotherapy for active metastases alone. The prior use of androgen receptor axis-targeted therapy and prostate-specific antigen doubling time will be used as allocation factors. The primary endpoint will be radiological progression-free survival against progression of bone metastases on WB-DWI. DISCUSSION: This will be the first randomized trial to evaluate the effect of radium-223 in combination with targeted therapy in oligometastatic CRPC patients. The combination of targeted therapy for macroscopic metastases with radiopharmaceuticals targeting micrometastasis is expected to be a promising new therapeutic strategy for patients with oligometastatic CRPC confined to bone. Trial registration Japan Registry of Clinical Trials (jRCT) (jRCTs031200358); Registered on March 1, 2021, https://jrct.niph.go.jp/latest-detail/jRCTs031200358.

Screening of chronic radiation proctitis and colorectal cancer using periodic total colonoscopy after external beam radiation therapy for prostate cancer.

OBJECTIVE: To investigate the incidence of colorectal cancer and chronic radiation proctitis after prostate radiotherapy using periodic total colonoscopy screening. METHODS: From February 2013 to January 2018, 270 patients who underwent external beam radiation therapy for prostate cancer were advised to receive periodic total colonoscopy screening annually. We evaluated the incidence and characteristics of colorectal cancer and chronic radiation proctitis. RESULTS: First, second, third, fourth and fifth total colonoscopy were performed in 256 (95%), 151 (56%), 60 (22%), 23 (8.5%) and 7 (2.6%) patients at a median of 14, 31, 42, 54 and 72 months after radiotherapy, respectively. The prevalence proportion of colorectal cancer in the first colonoscopy since radiotherapy was 3.9%. Twelve (4.4%) patients were diagnosed with colorectal cancer, including four invasive cancers, during a follow-up period. Eight of these 12 patients had not experienced rectal bleeding. The median time to diagnosis of colorectal cancer was 21 months. Chronic radiation proctitis was observed in 136 (50%) patients, including 67 (25%) patients with symptomatic bleeding. CONCLUSIONS: The high detection rate of asymptomatic radiation proctitis suggests the utility of total colonoscopy to screen for early-stage colorectal cancer prior to or following radiotherapy for prostate cancer. Considering the longevity after localized prostate cancer treatment, the awareness of chronic radiation-induced proctitis and the risk of colorectal cancer masked by bleeding is needed in treatment decision -making.

Algorithm for an automatic treatment planning system using a single-arc VMAT for prostate cancer.

Optimization process in treatment planning for intensity-modulated radiation therapy varies with the treatment planner. Therefore, a large variation in the quality of dose distribution is usually observed. To reduce variation, an automatic optimizing toolkit was developed for the Monaco treatment planning system (Elekta AB, Stockholm, Sweden) for prostate cancer using volumetric-modulated arc therapy (VMAT). This toolkit was able to create plans automatically. However, most plans needed two arcs per treatment to ensure the dose coverage for targets. For prostate cancer, providing a plan with a single arc was advisable in clinical practice because intrafraction motion management must be considered to irradiate accurately. The purpose of this work was to develop an automatic treatment planning system with a single arc per treatment for prostate cancer using VMAT. We designed the new algorithm for the automatic treatment planning system to use one arc per treatment for prostate cancer in Monaco. We constructed the system in two main steps: (1) Determine suitable cost function parameters for each case before optimization, and (2) repeat the calculation and optimization until the conditions for dose indices are fulfilled. To evaluate clinical suitability, the plan quality between manual planning and the automatic planning system was compared. Our system created the plans automatically in all patients within a few iterations. Statistical differences between the plans were not observed for the target and organ at risk. It created the plans with no human input other than the initial template setting and system initiation. This system offers improved efficiency in running the treatment planning system and human resources while ensuring high-quality outputs.

A phase II study of concurrent chemoradiotherapy with 5-fluorouracil and mitomycin-C for squamous cell carcinoma of the anal canal (the JROSG 10-2 trial).

This study assessed the efficacy of chemoradiotherapy for squamous cell carcinoma of the anal canal (SCCAC). Patients with T1-4N0-3M0 SCCAC received chemoradiotherapy with 5-fluorouracil (5-FU, 800 mg/m2/day, 96-h infusion) and mitomycin-C (MMC, 10 mg/m2 bolus). Patients treated with 3-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) were administered 36.0 Gy in 20 fractions or 49.5 Gy in 33 fractions for elective nodal irradiation and 59.4 Gy in 33 fractions for primary tumor and metastatic nodal irradiation. The sample size was considered sufficient to estimate 95% confidence intervals (CIs) for the true 2-year disease-free survival (DFS) within a width of +15% when the expected true 2-year DFS was 70%. The primary endpoint was 2-year DFS. The secondary endpoints were 2-year overall survival (OS), locoregional control (LC), colostomy-free survival (CFS) and adverse events. Thirty-one patients were enrolled between January 2014 and July 2019. The median follow-up was 33.3 months (range, 16.2-65.8 months). Among the 31 patients, 13%, 32%, 16% and 39% had stage I, II, IIIA and IIIB disease, respectively. Thirty patients were treated with IMRT. Complete response (CR) was achieved in 27 patients. The 2-year DFS, OS, LC and CFS rates were 77.4% (95% CI, 58.4-88.5%), 93.5% (95% CI, 76.6-98.3%), 83.9% (95% CI, 65.5-92.9%) and 80.6% (95% CI, 61.9-90.8%), respectively. One patient experienced grade 3 late adverse events; however, no grade ≥ 4 late adverse events occurred. Good DFS with a low rate of late adverse events was observed. Chemoradiotherapy with 5-FU and MMC was effective for SCCAC.

Survey of malignant pleural mesothelioma treatment in Japan: Patterns of practice and clinical outcomes in tomotherapy facilities.

We conducted a nationwide survey of tomotherapy for malignant pleural mesothelioma (MPM) in Japan. Fifty-six facilities were surveyed and data on 31 patients treated curatively between 2008 and 2017 were collected from 14 facilities. Twenty patients received hemithorax irradiation after extrapleural pneumonectomy (EPP) (first group). Five patients received irradiation without EPP (second group), while six received salvage radiotherapy for local recurrence (salvage group). Among the seven patients not undergoing EPP, five (four in the second group and one in the salvage group) were treated with lung sparing pleural irradiation (LSPI) and two with irradiation to visible tumors. Two-year overall survival (OS) rates in the first and second groups were 33% and 60%, respectively (median, 13 vs 30 months, P = 0.82). In the first and second groups, 2-year local control (LC) rates were 53 and 67%, respectively (P = 0.54) and 2-year progression-free survival (PFS) rates were 16% and 60%, respectively (P = 0.07). Distant metastases occurred in 15 patients in the first group and three in the second group. In the salvage group, the median OS was 18 months. Recurrence was observed in the irradiated volume in four patients. The contralateral lung dose was higher in LSPI than in hemithorax irradiation plans (mean, 11.0 ± 2.2 vs 6.1 ± 3.1 Gy, P = 0.002). Grade 3 or 5 lung toxicity was observed in two patients receiving EPP and hemithorax irradiation, but not in those undergoing LSPI. In conclusion, outcomes of EPP and hemithorax irradiation were not satisfactory, whereas LSPI appeared promising and encouraging.

Therapeutic effect of linac-based stereotactic radiotherapy with a micro-multileaf collimator for the treatment of patients with brain metastases from lung cancer.

OBJECTIVE: To assess the efficacy of hypofractionated linac-based stereotactic radiotherapy with a micro-multileaf collimator (mMLC) in lung cancer patients with brain metastases. METHODS: Seventy-eight lesions of brain metastases in 49 lung cancer patients treated by stereotactic radiotherapy between September 2003 and December 2006 were analyzed. In the treatment planning, the planning target volume (PTV) was defined as an enhanced lesion plus 3 mm margin. A total dose of 39-42 Gy in three fractions was delivered to the isocenters of the PTV. RESULTS: The median survival time after stereotactic radiotherapy was 17.4 months. The 1- and 2-year survival rates were 61% and 32%, respectively. The presence of extracranial tumors, the pre-treatment performance status, and the Radiation Therapy Oncology Group recursive partitioning analysis class were significant prognostic factors. The 1- and 2-year local recurrence rates were 14% and 17%, respectively, with no serious acute toxic effect. Injuries involving brain necrosis were observed in six patients. New brain metastases or meningeal carcinomatosis was seen in more than half of the patients following treatment with stereotactic radiotherapy. CONCLUSIONS: Hypofactionated stereotactic radiotherapy with mMLC is considered to be an effective and safe modality for the treatment of brain metastases in lung cancer patients.

Whole-bladder Radiation Therapy for Lymph Node-negative Bladder Cancer With Muscle Invasion in Elderly Patients.

BACKGROUND: The Japanese bladder cancer treatment guidelines recommend concurrent chemoradiotherapy, including wide pelvic irradiation. Many elderly patients, however, cannot tolerate standard treatment because of low performance status. Therefore, to reduce complications, elderly patients sometimes receive radiation therapy without elective nodal irradiation or chemotherapy. PATIENTS AND METHODS: Outcomes were retrospectively analyzed in 19 elderly patients with N0 muscle-invasive bladder cancer treated with whole-bladder irradiation without chemotherapy. RESULTS: The 3- and 5-year overall survival rates were 30.7% and 12.2%, respectively. No patient experienced severe late complications (grade 3 or higher). Recurrence was observed in 11 patients (57.9%). The initial location of recurrence was within the bladder. CONCLUSION: Whole-bladder irradiation alone did not increase lymph node metastases or severe complications in elderly patients. Whole-bladder radiation therapy without chemotherapy or wide pelvic irradiation may be a promising treatment method for patients who are not candidates for standardized treatment.

Nationwide survey of radiation therapy in Japan for lung cancer complicated with interstitial lung disease.

The purpose of this study was to clarify the opinions of radiation oncologists in Japan regarding treatment for lung cancer complicated with interstitial lung disease (ILD) by a questionnaire survey, and the risk of acute exacerbation (AE) after radiotherapy. Questionnaires were sent to all of the facilities in which radiation therapy is performed for lung cancer in Japan by using the mailing list of the Japanese Society for Radiation Oncology (JASTRO). The questionnaire survey was conducted to clarify who judges the existence of ILD, the indications for radiation therapy in cases of ILD-combined lung cancer, and the ratio of ILD-combined lung cancer in lung cancer patients treated with radiation therapy. Patients with ILD-combined lung cancer who received radiotherapy during the period from April 2014 to March 2015 were retrospectively analysed. Any cases of AE without any other obvious cause were included. ILD confirmation was performed by central radiologists using computed tomography images. A total of 47 facilities responded to the questionnaire. Radiation therapy was an option in cases of ILD-combined lung cancer in 39 (83%) of the facilities. The indication for radiation therapy was based on image findings in 35 (90%) of the 39 facilities in which radiation therapy was acceptable or was a choice in some cases of ILD. The final indication was based on the opinion of the pulmonologist in 29 (74%) of those 39 facilities. In fiscal year 2014, a total of 2128 patients in 38 facilities received chest irradiation. Seventy-eight (3.7%) of those 2128 patients had ILD-combined lung cancer. Sixty-seven patients were included in patient analysis. AE occurred in 5 patients (7.5%), and one of those 5 patients (20.0%) died from radiation-induced AE. The median period from radiotherapy to AE was 4 months (range, 2-7 months). The following four independent risk factors for AE were identified in univariate analysis: non-advanced age (<75 years), increased C-reactive protein level (≥0.3 mg/dl), adjuvant chemotherapy and ≥ Grade 2 radiation pneumonitis. Radiotherapy was an option for lung cancer even in cases with ILD in 83% (39/47) of the facilities in Japan. Seventy-eight (3.7%) of 2128 patients who received radiation therapy for lung cancer had ILD. Radiotherapy for ILD-combined lung cancer may induce AE at a substantial rate and AE can be life-threatening. Minimizing the risk of radiation pneumonitis might enable the risk of AE to be reduced.

Association Between Laryngopharyngeal Reflux and Radiation-induced Mucositis in Head and Neck Cancer.

BACKGROUND/AIM: We investigated whether laryngopharyngeal reflux (LPR) is a risk factor for radiation-induced mucositis. PATIENTS AND METHODS: This was a retrospective cohort study using our departmental database. The study included patients with stage I or II laryngeal and hypopharyngeal cancers treated with radiation therapy alone between April 2009 and March 2014. Based on endoscopic findings, baseline laryngeal signs were evaluated using the reflux finding score (RFS), and the severity of mucositis was assessed during and after radiation therapy. RESULTS: Fifty-eight patients were enrolled. Thirty-one patients were categorized as high RFS (LPR-likely), while 27 patients were categorized as low RFS (LPR-unlikely). Grade 3 mucositis occurred more frequently in the high RFS group (p<0.042). Furthermore, grade 3 mucositis developed earlier in the high RFS group (p<0.001). CONCLUSION: High RFS (i.e., increased likelihood of LPR) appears to be a potential risk factor for developing severe radiation-induced mucositis.

Successful treatment of radiation-induced mucositis with proton pump inhibitor administration: A report of two laryngeal cancer cases.

Presently, the relationship between laryngopharyngeal reflux (LPR) and radiation-induced mucositis has not been fully explored. In the present study, we report 2 cases of laryngeal cancer in which radiation-induced mucositis ameliorated after proton pump inhibitor (PPI) administration. Case 1 was diagnosed with T1aN0M0 right glottis carcinoma and was treated with radiation therapy. Grade 3 mucositis occurred after administration of 46Gy irradiation. PPI was administered and mucositis ameliorated quickly without cessation of radiation therapy. Case 2 was diagnosed with T2N0M0 supraglottic cancer and was treated with concurrent chemoradiation therapy. Grade 3 mucositis occurred after administration of 44Gy irradiation. PPI was administered and mucositis ameliorated quickly without cessation of chemoradiation therapy. In both cases, a remarkable therapeutic effect of PPI was observed in the perilaryngeal areas including the epiglottic vallecula, arytenoid, and postcricoid area. In both cases, LPR involvement was suspected before the onset of radiation therapy. The two cases presented here, indicated a causal relationship between LPR and radiation-induced mucositis. In cases of severe mucositis in the perilaryngeal area in patients with LPR prior to radiation therapy, PPI administration may be an effective therapeutic option.

Chemoradiation therapy with docetaxel in elderly patients with stage II/III esophageal cancer: A phase 2 trial.

PURPOSE: The most effective treatments in elderly patients with esophageal cancer remain a subject of debate. This multicenter phase 2 study was designed to evaluate the efficacy and toxicity of chemoradiation therapy (CRT) with docetaxel (DTX) in elderly patients with stage II/III (non-T4) esophageal cancer. METHODS AND MATERIALS: Patients ≥70 years of age with clinical stage II/III esophageal cancer received DTX at a weekly dose of 10 mg/m2 during 6 consecutive weeks and concurrent radiation therapy (60 Gy in 30 fractions). The primary endpoint was the 2-year survival rate, and the required number of enrolled patients was 37. RESULTS: Between July 2008 and January 2011, 16 patients were enrolled. The study was prematurely closed because of slow accrual. Characteristics of the patients were as follows: median age, 77 years (range, 73-81); performance status 0/1, 4/12; and clinical stage IIA/IIB/III, 3/4/9. Of the 16 patients, 14 (87.5%) completed the CRT. The 2-year survival rate was 62.5% (90% confidence interval [CI], 42.5-82.5). The median survival time was 27.7 months (95% CI, 23.3-32.2 months) and the median progression-free survival was 15.2 months (95% CI, 5.4-25.0 months). Seven patients achieved complete response, resulting in a complete response rate of 43.8% (95% CI, 19.8-70.1). Grade 3 or higher acute toxicities included esophagitis (31.3%), anorexia (12.5%), leukopenia (6.3%), neutropenia (6.3%), thrombocytopenia (6.3%), mucositis (6.3%), and infection (6.3%). Grade 3 or higher late toxicities included esophagitis (12.5%), pleural effusion (12.5%), pneumonitis (6.3%), and pericardial effusion (6.3%). CONCLUSIONS: CRT with DTX might be a treatment option for elderly patients with stage II/III esophageal cancer, particularly for patients who are medically unfit for surgery or cisplatin-containing therapy. However, further improvements of this therapy are required to decrease the incidence of esophagitis.

Comparison of the radiosensitivities of neurons and glial cells derived from the same rat brain.

Non-proliferating cells, such as mature neurons, are generally believed to be more resistant to X-rays than proliferating cells, such as glial and vascular endothelial cells. Therefore, the late adverse effects of radiotherapy on the brain have been attributed to the radiation-induced damage of glial and vascular endothelial cells. However, little is known about the radiosensitivities of neurons and glial cells due to difficulties in culturing these cells, particularly neurons, independently. In the present study, primary dissociated neurons and glial cultures were prepared separately from the hippocampi and cerebrum, respectively, which had been obtained from the same fetal rat on embryonic day 18. X-irradiations of 50 Gy were performed on the cultured neurons and glial cells at 7 and 21 days in vitro (DIV). The cells were fixed at 24 h after irradiation. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was then performed to measure the apoptotic indices (AIs). The AIs of non-irradiated and irradiated neurons at 7 DIV were 23.7±6.7 and 64.9±4.8%, and those at 21 DIV were 52.1±17.4 and 44.6±12.5%, respectively. The AIs of non-irradiated and irradiated glial cells at 7 DIV were 5.8±1.5 and 78.4±3.3% and those at 21 DIV were 9.6±2.6 and 86.3±4.9%, respectively. Glial cells and neurons were radiosensitive at 7 DIV. However, while glial cells were radiosensitive at 21 DIV, neurons were not.

Concurrent chemoradiotherapy followed by consolidation chemotherapy with bi-weekly docetaxel and carboplatin for stage III unresectable, non-small-cell lung cancer: clinical application of a protocol used in a previous phase II study.

PURPOSE: To assess the clinical applicability of a protocol evaluated in a previously reported phase II study of concurrent chemoradiotherapy followed by consolidation chemotherapy with bi-weekly docetaxel and carboplatin in patients with stage III, unresectable, non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Between January 2000 and March 2006, 116 previously untreated patients with histologically proven, stage III NSCLC were treated with concurrent chemoradiotherapy. Radiation therapy was administered in 2-Gy daily fractions to a total dose of 60 Gy in combination with docetaxel, 30 mg/m(2), and carboplatin at an area under the curve value of 3 every 2 weeks during and after radiation therapy. RESULTS: The median survival time for the entire group was 25.5 months. The actuarial 2-year and 5-year overall survival rates were 53% and 31%, respectively. The 3-year cause-specific survival rate was 60% in patients with stage IIIA disease, whereas it was 35% in patients with stage IIIB disease (p = 0.007). The actuarial 2-year and 5-year local control rates were 62% and 55%, respectively. Acute hematologic toxicities of Grade ≥3 severity were observed in 20.7% of patients, while radiation pneumonitis and esophagitis of Grade ≥3 severity were observed in 2.6% and 1.7% of patients, respectively. CONCLUSIONS: The feasibility of the protocol used in the previous phase II study was reconfirmed in this series, and excellent treatment results were achieved.