Clinical outcomes and prognostic factors of concurrent chemoradiotherapy for anal squamous cell carcinoma in Japan.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locoregional anal squamous cell carcinoma (ASCC) in western countries. However, there have been few reports on the clinical outcomes of CCRT in Japan. This study aimed to evaluate the clinical outcomes of CCRT, prognostic factors, and the clinical impact of programmed cell death-ligand 1 (PD-L1) expression of ASCC in Japan. METHODS: Patients with locoregional ASCC were enrolled between 2007 and 2017. All patients received CCRT consisting of ≥ 45 Gy of radiation, 5-fluorouracil, and mitomycin C. Disease-free survival (DFS), overall survival (OS), and adverse events (AEs) were estimated. Expression of p16 and PD-L1 were assessed by immunohistochemical staining (IHC). RESULTS: This study included 36 patients, of whom 30 (83.3%) were female. Among the participants, 32 (88.9%) achieved complete clinical remission, while six (16.7%) experienced recurrence. The five-year DFS and five-year OS were 72.2% and 84.7%, respectively. Grades ≥ 3 serious AEs included neutropenia in 10 (27.7%) and perianal dermatitis in eight (22.2%). In a univariate analysis, male sex, lymph node metastasis, and large tumor size were significantly associated with worse outcome. In a multivariate analysis, tumor size was an independent factor associated with short DFS. Of the 30 patients whose biopsy specimens were available for IHC, 29 (96.7%) were positive for p16, and 13 (43.3%) were positive for PD-L1. However, PD-L1 expression did not show any clinical impact. CONCLUSIONS: The comparative etiology, clinical outcomes, and prognostic factors of CCRT observed in Japanese patients with locoregional ASCC were consistent with western data.

Adding Induction Chemotherapy Before Chemoradiotherapy with Total Mesorectal Excision and Selective Lateral Lymph Node Dissection for Patients with Poor-Risk, Locally Advanced, Mid-to-Low Rectal Cancer May Improve Oncologic Outcomes: A Propensity Score-Matched Analysis.

BACKGROUND: This study aimed to investigate whether the addition of induction chemotherapy before chemoradiotherapy (CRT) and total mesorectal excision (TME) with selective lateral lymph node dissection improves disease-free survival for patients with poor-risk, mid-to-low rectal cancer. METHODS: The authors' institutional prospective database was queried for consecutive patients with clinical stage II or III, primary, poor-risk, mid-to-low rectal cancer who received neoadjuvant treatment followed by TME from 2004 to 2019. The outcomes for the patients who received induction chemotherapy before neoadjuvant CRT (induction-CRT group) were compared (via log-rank tests) with those for a propensity score-matched cohort of patients who received neoadjuvant CRT without induction chemotherapy (CRT group). RESULTS: From 715 eligible patients, the study selected two matched cohorts with 130 patients each. The median follow-up duration was 5.4 years for the CRT group and 4.1 years for the induction-CRT group. The induction-CRT group had significantly higher rates of 3-year disease-free survival (83.5 % vs 71.4 %; p = 0.015), distant metastasis-free survival (84.3 % vs 75.2 %; p = 0.049), and local recurrence-free survival (98.4 % vs 94.4 %; p = 0.048) than the CRT group. The pathologically complete response rate also was higher in the induction-CRT group than in the CRT group (26.2 % vs 10.0 %; p < 0.001). Postoperative major complications (Clavien-Dindo classification ≥III) did not differ significantly between the two groups (12.3 % vs 10.8 %; p = 0.698). CONCLUSIONS: The addition of induction chemotherapy to neoadjuvant CRT appeared to improve oncologic outcomes significantly, including disease-free survival, for the patients with poor-risk, mid-to-low rectal cancer who underwent TME using selective lateral lymph node dissection.

Prediction and prevention of central nervous system relapse in patients with extranodal natural killer/T-cell lymphoma.

Because non-anthracycline-based chemotherapy with l-asparaginase has improved survival outcomes in patients with extranodal natural killer/T-cell lymphoma (ENKTL), the incidence of central nerve system (CNS) relapse can be different when compared with that in previous reports. In this research, we sought to identify the incidence of and predictors for CNS relapse and to evaluate the necessity of CNS prophylaxis with intermediate-dose methotrexate (ID-MTX). The records of 399 patients in the training cohort and 253 patients in the validation cohort with ENKTL who received non-anthracycline-based chemotherapy were reviewed. Patients were divided into 2 groups according to whether the chemotherapy regimen included ID-MTX above 2 g/m2. A new central nervous system-prognostic index of natural killer (CNS-PINK) model was developed using 1-point powerful predictors of CNS relapse (PINK; hazard ratio [HR], 2.908; P = .030 and extranodal involvement [≥2]; HR, 4.161; P = .001) and was calculated as a sum of scores. The high-risk group of CNS-PINK was defined as 2 points. The cumulative incidence of CNS relapse was different between the CNS-PINK risk groups in the training (P < .001) and validation (P = .038) cohorts. Patients in the high-risk CNS-PINK group who were treated with SMILE or SMILE-like regimens with ID-MTX (S-ID-MTX) displayed a lower incidence rate of CNS relapse than did those who received other regimens without ID-MTX in the training cohort (P = .029). The CNS-PINK was demonstrated its strong predictability of CNS relapse in ENKTL patients. The effectiveness of S-ID-MTX in preventing CNS events in high-risk CNS-PINK patients should be verified in future studies.

Long-term outcomes and central nervous system relapse in extranodal natural killer/T-cell lymphoma.

To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4 years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60-343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78-30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.

Radiomics Approach Outperforms Diameter Criteria for Predicting Pathological Lateral Lymph Node Metastasis After Neoadjuvant (Chemo)Radiotherapy in Advanced Low Rectal Cancer.

BACKGROUND: Advanced low rectal cancer has a non-negligible risk of lateral pelvic lymph node (LPLN) metastasis (LPLNM) and lateral local recurrence (LR) after neoadjuvant (chemo)radiotherapy and total mesorectal excision. LPLN dissection (LPLND) reduces LR but increases postoperative complications and sexual/urinary dysfunction. OBJECTIVE: The aim of this study was to develop a new radiomics-based prediction model for LPLNM in patients with rectal cancer. METHODS: A total of 247 patients with rectal cancer and enlarged LPLNs treated by (chemo)radiotherapy and LPLND were enrolled in this retrospective, multicenter study. LPLN radiomic features were extracted from pretreatment portal venous-phase computed tomography images. A radiomics score of LPLN was constructed based on the least absolute shrinkage and selection operator regression in a primary cohort of 175 patients. Model performance was assessed in terms of discrimination, calibration, and decision curve analysis, and was externally validated in 72 patients. RESULTS: The radiomics score showed significantly better discrimination compared with pretreatment short-axis diameter measurements in both the primary (area under the curve [AUC] 0.91 vs. 0.83, p = 0.0015) and validation (AUC 0.90 vs. 0.80, p = 0.0298) cohorts. Decision curve analysis also indicated the superiority of the radiomics score. In a subanalysis of patients with a short-axis diameter ≥ 7 mm, the radiomics nomogram, incorporating the radiomics score and LPLN shrinkage to ≤ 4 mm, had better discrimination compared with a model incorporating only LPLN shrinkage in both cohorts. CONCLUSIONS: Radiomics-based prediction modeling provides individualized risk estimation of LPLNM in rectal cancer patients treated with (chemo)radiotherapy, and outperforms measurements of pretreatment LPLN diameter.

Phase II Trial of Neoadjuvant Chemotherapy, Chemoradiotherapy, and Laparoscopic Surgery with Selective Lateral Node Dissection for Poor-Risk Low Rectal Cancer.

PURPOSE: The aim of this study is to evaluate the safety and efficacy of induction modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus bevacizumab followed by S- 1-based chemoradiotherapy in magnetic resonance imaging (MRI)-defined poor-risk locally advanced low rectal cancer. PATIENTS AND METHODS: This was a prospective phase II trial at a single comprehensive cancer center. The primary endpoint was the pathological complete response (pCR) rate. Eligible patients had clinical stage II-III low rectal adenocarcinoma with any of the following MRI-defined poor-risk features: circumferential resection margin (CRM) ≤ 1 mm, cT4, positive lateral nodes, mesorectal N2 disease, and/or requiring abdominoperineal resection. Patients received six cycles of mFOLFOX6 with 5 mg/kg bevacizumab followed by oral S-1 (80 mg/m2/day on days 1-14 and 22-35) plus radiotherapy (50.4 Gy). Surgery was conducted through a laparoscopic approach. Lateral node dissection was selectively added when the patient had enlarged lateral nodes. RESULTS: A total of 43 patients were enrolled. Grade 3-4 adverse events occurred in nine patients during induction chemotherapy and in five patients during chemoradiotherapy. One patient declined surgery with a clinical complete response. Forty-two patients underwent surgery, and 16 had pCR [37.2%, 95% confidence interval (CI) 24.4-52.1%]. All underwent R0 resection without conversion, including combined resection of adjacent structures (n = 14) and lateral node dissection (n = 30). Clavien-Dindo grade 3-4 complications occurred in six patients (14.3%). With median follow-up of 52 months, six developed recurrences (lung n = 5, local n = 1; 3-year relapse-free survival 86.0%). CONCLUSIONS: This study achieved a high pCR rate with favorable toxicity and postoperative complications in poor-risk locally advanced low rectal cancer. Multicenter study is warranted to evaluate this regimen.

Autologous Peripheral Blood Stem Cell Transplantation and Timing of Local Radiation Therapy in Patients With Malignant Lymphoma: Results of the Japanese Radiation Oncology Study Group Questionnaire Survey.

BACKGROUND/AIM: Malignant lymphoma (ML) including Hodgkin's lymphoma and non-Hodgkin's lymphoma is often treated with local radiation therapy (RT) in combination with autologous hematopoietic stem cell transplantation (ASCT) to prevent relapse; however, the efficacy and optimal timing of this approach is unclear. In this study, a national survey conducted by the Japanese Radiation Oncology Study Group reviewed ML cases from 2011 to 2019 to determine whether RT should be added to ASCT, focusing on the use of autologous peripheral blood stem cell transplantation (auto-PBSCT), a predominant form of ASCT. PATIENTS AND METHODS: The survey encompassed 92 patients from 11 institutes, and assessed histological ML types, treatment regimens, timing of RT relative to auto-PBSCT, and associated adverse events. RESULTS: The results indicated no significant differences in adverse events, including myelosuppression, based on the timing of RT in relation to auto-PBSCT. However, anemia was more prevalent when RT was administered before auto-PBSCT, and there was a higher incidence of neutropenia recovery delay in patients receiving RT after auto-PBSCT. CONCLUSION: This study provides valuable insights into the variable practices of auto-PBSCT and local RT in ML treatment, emphasizing the need for optimized timing of these therapies to improve patient outcomes and reduce complications.

Clinical course and treatment of radiation-induced hemorrhagic gastritis: a case series study.

Radiation-induced hemorrhagic gastritis is a relatively uncommon complication of irradiation that can be severe. However, appropriate treatment guidelines have not yet been established because of the small number of known cases. At our hospital, we encountered nine cases of radiation-induced hemorrhagic gastritis between July 2005 and July 2018. All patients initially underwent argon plasma coagulation (APC) for hemostasis. The treatment was highly effective, and hemostasis was successfully achieved in eight of the cases. Hemostasis could not be achieved in one case treated with APC; therefore, surgical resection was required. This patient had risk factors, such as liver cirrhosis and a history of abdominal surgery. Our case series suggests that APC is an effective hemostatic method that should be considered as the initial treatment option for radiation-induced hemorrhagic gastritis; however, surgical resection may be considered when the patient is at high risk for rebleeding.

Dosimetric comparison between three-dimensional conformal radiotherapy followed by electron beam boost and volumetric modulated arc therapy using concomitant boost for the heart and cardiac segments in patients with left-sided breast cancer at risk for radiation-induced cardiac toxicity.

PURPOSE: We aimed to compare dosimetric parameters between three-dimensional conformal radiation therapy followed by electron beam boost (3D-CRT + EB) and volumetric modulated arc therapy using simultaneous integrated boost (SIB-VMAT) in left-sided breast cancer patients. METHODS: This study included 57 patients with left-sided breast cancer who underwent SIB-VMAT. All patients had a computed tomography-based maximum heart distance of ≥ 1 cm and were prescribed a dose of 42.56 Gy/16 fractions to the planning target volume and a concomitant-boosted target dose of 53.2 Gy or 51.2 Gy. The 3D-CRT + EB plan was retrospectively created for the purpose of comparison using tangential fields with field-in-field technique followed by electron beam irradiation. RESULTS: The doses to the clinical target volume significantly improved in the SIB-VMAT plans. All dosimetric parameters for the left anterior descending coronary artery (LAD) and LAD middle position (LAD mid) in the SIB-VMAT plans were significantly lower than those for 3D-CRT + EB plans (P < 0.01), while the doses to the heart, lung, contralateral breast and non-target tissue were decreased in the 3D-CRT + EB plans compared with those in the SIB-VMAT plans (e.g., 1.9 Gy vs. 2.9 Gy; P < 0.001 for the mean dose of heart). CONCLUSIONS: SIB-VMAT significantly improved the dose to the target while reducing the doses to the LAD and LAD mid, whereas 3D-CRT + EB significantly decreased the doses to the heart and other organs at risk in patients with left-sided breast cancer at risk for radiation-induced coronary artery disease.

Non-operative management after chemoradiotherapy plus consolidation or sandwich (induction with bevacizumab and consolidation) chemotherapy in patients with locally advanced rectal cancer: a multicentre, randomised phase II trial (NOMINATE trial).

INTRODUCTION: Total mesorectal excision (TME) and postoperative adjuvant chemotherapy following neoadjuvant chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal cancer (LARC). However, neoadjuvant CRT has no recognised impact on reducing distant recurrence, and patients suffer from a long-lasting impairment in quality of life (QOL) associated with TME. Total neoadjuvant therapy (TNT) is an alternative approach that could reduce distant metastases and increase the proportion of patients who could safely undergo non-operative management (NOM). This study is designed to compare two TNT regimens in the context of NOM for selecting a more optimal regimen for patients with LARC. METHODS AND ANALYSIS: NOMINATE trial is a prospective, multicentre, randomised phase II selection design study. Patients must have clinical stage II or III (T3-T4Nany) LARC with distal location (≤5 cm from the anal verge or for those who are candidates for abdominoperineal resection or intersphincteric resection). Patients will be randomised to either arm A consisting of CRT (50.4 Gy with capecitabine) followed by consolidation chemotherapy (six cycles of CapeOx), or arm B consisting of induction chemotherapy (three cycles of CapeOx plus bevacizumab) followed by CRT and consolidation chemotherapy (three cycles of CapeOx). In the case of clinical complete response (cCR) or near cCR, patients will progress to NOM. Response assessment involves a combination of digital rectal examination, endoscopy and MRI. The primary endpoint is the proportion of patients achieving pathological CR or cCR≥2 years, defined as the absence of local regrowth within 2 years after the start of NOM among eligible patients. Secondary endpoints include the cCR rate, near cCR rate, rate of NOM, overall survival, distant metastasis-free survival, locoregional failure-free survival, time to disease-related treatment failure, TME-free survival, permanent stoma-free survival, safety of the treatment, completion rate of the treatment and QOL. Allowing for a drop-out rate of 10%, 66 patients (33 per arm) from five institutions will be accrued. ETHICS AND DISSEMINATION: The study protocol was approved by Wakayama Medical University Certified Review Board in December 2020. Trial results will be published in peer-reviewed international journals and on the jRCT website. TRIAL REGISTRATION NUMBER: jRCTs051200121.

Clinical significance of soluble programmed cell death-1 and soluble programmed cell death-ligand 1 in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.

BACKGROUND: Inhibition of the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) axis in combination with radiotherapy may be a promising approach to treat cancer. In the present study, we aimed to evaluate serum soluble PD-1/PD-L1 levels in patients with advanced rectal cancer treated with neoadjuvant chemoradiotherapy (CRT). METHODS: Serum soluble PD-L1 and PD-1 levels were measured using an enzyme-linked immunosorbent assay before and after CRT in 117 patients with low rectal cancer. Changes in the levels of sPD-L1/PD-1 after CRT, and the correlation between sPD-L1/PD-1 level and clinicopathological characteristics or disease-free survival (DFS) were evaluated. RESULTS: sPD-L1 levels significantly increased after CRT (p < 0.0001), whereas sPD-1 levels did not change significantly (p = 0.1050). High sPD-L1 before CRT was significantly associated with younger age (p = 0.044), and after CRT, with lymphovascular invasion (p = 0.021). High sPD-1 before and after CRT was significantly associated with a longer distance of the tumor from the anal verge (both p < 0.001). There was no correlation between sPD-L1 level and local PD-L1 expression on stromal immune cells. High sPD-L1 level after CRT tended to be associated with worse DFS (p = 0.0752). The multivariate analysis could not demonstrate an independent association for sPD-L1 levels after CRT with DFS. CONCLUSIONS: Significant increase of sPD-L1 levels after CRT suggests that anti-PD-L1 therapy might be a potential treatment strategy in combination with CRT in advanced rectal cancer.

Altered-fractionation radiotherapy improves local control in early-stage glottic carcinoma: A systematic review and meta-analysis of 1762 patients.

OBJECTIVES: To perform a systematic review of 1762 patients to comprehensively assess the benefit of altered-fractionation radiotherapy (ART) in early stage glottic carcinoma (ESGC). MATERIALS AND METHODS: Studies were identified in PubMed and EMBASE. Inclusion criteria were: (1) diagnosis of squamous cell ESGC (Tis, T1, T2); (2) ART versus conventionally-fractionationated radiotherapy (CRT); and (3) provision of number of local recurrence events and total numbers per fractionation arm. The random-effects model was fitted to estimate the pooled hazard ratio (HR). Subgroup sensitivity analyses were performed based on ART strategy (hypo- versus hyperfractionation), treatment-day reductions, machine type, tumor stage, and anterior commissure involvement. RESULTS: Eleven studies met inclusion criteria: 4 randomized controlled trials (RCTs) and 7 two-arm retrospective studies. ART was associated with 38% fewer (HR 0.62; 95% CI: 0.46-0.82, p = 0.0009) and 60% fewer (HR 0.40; 95% CI: 0.24-0.66, p = 0.0003) local failure events in pooled analyses of the RCTs and retrospective studies, respectively. Both hyperfractionation (HR 0.65; 95% CI: 0.43-0.97, p = 0.03) and hypofractionation (HR 0.55; 95% CI: 0.33-0.91, p = 0.02) strategies were superior to CRT. The benefit persisted for all treatment- and tumor-related parameters, including anterior commissure involvement, with the exception of a pooled analysis of studies with predominantly T2 (<50% T1) cases (HR 0.60, 95% CI: 0.30-1.20, p = 0.15). CONCLUSION: Both hypofractionation and hyperfractionation improve local control in ESGC, including T1 tumors and for anterior commissure involvement. However, this benefit may not persist for T2 tumors, for which alternative strategies should be considered.

Circulating Cytokine Levels in Patients with Prostate Cancer: Effects of Neoadjuvant Hormonal Therapy and External-beam Radiotherapy.

AIM: The aim of the study was to better characterize the temporal induction of inflammatory cytokines in the serum of patients with prostate cancer (PCa) treated with radiotherapy and to ascertain the influence of hormonal therapy upon those expressions. PATIENTS AND METHODS: Between May 2007 and December 2009, 30 patients with localized PCa were treated with 3-dimensional conformal external-beam radiotherapy. Fifteen patients had received neoadjuvant hormonal therapy using a leuteinizing hormone-releasing hormone (LH-RH) analog for six months prior to radiotherapy. The cytokine levels were collectively measured using a multiplex assay system. RESULTS: Seventeen cytokines were at detectable levels throughout the blood sampling times before and during radiotherapy. Hormonal therapy for six months significantly decreased the serum levels of fibroblast growth factor-2 (FGF2) and vascular endothelial growth factor (VEGF). The levels of epidermal growth factor (EGF), granulocyte-colony stimulating factor (G-CSF), and interferon-gamma (IFNγ) significantly increased during radiotherapy. Most cytokine levels, except for eotaxin, G-CSF, growth-related oncogene (GRO), transforming growth factor-beta (TGFß)-1 and TGFß2, significantly increased during radiotherapy compared to the levels observed before radiotherapy. CONCLUSION: The present study revealed the influence of hormonal, and of radiation therapy on the proinflammatory cytokine levels in the sera of patients with PCa. In addition, neoadjuvant hormonal therapy amplified the radiation-induced alteration of serum cytokines. Further studies to characterize the mechanism underlying a radiation- or hormone-induced inflammatory state are, therefore, necessary.

Prognosis of primary central nervous system lymphoma treated with radiotherapy alone.

PURPOSE: Standard treatment for patients with primary central nervous system (CNS) lymphoma involves combining high-dose methotrexate-based chemotherapy and radiation. However, chemotherapy is sometimes contraindicated, and radiotherapy alone becomes the only option. We retrospectively investigated the clinical outcomes of primary CNS lymphoma patients treated with radiotherapy alone. MATERIALS AND METHODS: Between 1983 and 2006, 35 patients (median age 69 years, range 37-89 years) with primary CNS lymphoma were treated with radiotherapy alone. Of these, 74 % had an Eastern Cooperative Oncology Group performance status (PS) of 2-4. Most patients (91 %) received whole-brain irradiation with or without irradiation boost to the tumor site (median dose 50 Gy, range 22-50 Gy); remaining patients received partial brain irradiation. RESULTS: Median follow-up time was 20 (range 1-152) months, median survival time was 20 months, and the 1- and 2-year overall survival rates were 65 and 32 %, respectively. Median survival in patients aged <70 and ≥ 70 years was 26 and 10 months, respectively (p = 0.01). CONCLUSION: Median survival with radiotherapy alone was 20 months. Patients aged <70 years have a better prognosis than those ≥ 70 years.