Optimizing smartphone psychotherapy for depressive symptoms in patients with cancer: Multiphase optimization strategy using a decentralized multicenter randomized clinical trial (J-SUPPORT 2001 Study).

AIM: Patients with cancer experience various forms of psychological distress, including depressive symptoms, which can impact quality of life, elevate morbidity risk, and increase medical costs. Psychotherapy and pharmacotherapy are effective for reducing depressive symptoms among patients with cancer, but most patients prefer psychotherapy. This study aimed to develop an efficient and effective smartphone psychotherapy component to address depressive symptom. METHODS: This was a decentralized, parallel-group, multicenter, open, individually randomized, fully factorial trial. Patients aged ≥20 years with cancer were randomized by the presence/absence of three cognitive-behavioral therapy (CBT) skills (behavioral activation [BA], assertiveness training [AT], and problem-solving [PS]) on a smartphone app. All participants received psychoeducation (PE). The primary outcome was change in the patient health questionnaire-9 (PHQ-9) total score between baseline and week 8. Secondary outcomes included anxiety. RESULTS: In total, 359 participants were randomized. Primary outcome data at week 8 were obtained for 355 participants (99%). The week 8 PHQ-9 total score was significantly reduced from baseline for all participants by -1.41 points (95% confidence interval [CI] -1.89, -0.92), but between-group differences in change scores were not significant (BA: -0.04, 95% CI -0.75, 0.67; AT: -0.16, 95% CI -0.87, 0.55; PS: -0.19, 95% CI -0.90, 0.52). CONCLUSION: As the presence of any of the three intervention components did not contribute to a significant additive reduction of depressive symptoms, we cannot make evidence-based recommendations regarding the use of specific smartphone psychotherapy.

The implementation status of prehabilitation during neoadjuvant chemotherapy for patients with locally advanced esophageal cancer: a questionnaire survey to the board-certified facilities in Japan.

BACKGROUND: Prehabilitation during neoadjuvant therapy has the potential to improve clinical outcomes. However, information on its global dissemination status is limited. This Japanese nationwide survey investigated the implementation status of and barriers to prehabilitation during neoadjuvant chemotherapy (NAC) for patients with locally advanced esophageal cancer in hospitals. METHODS: This multicenter nationwide survey was conducted by post. The eligible facilities were 155 Japanese hospitals that had been certified within the last 10 years as authorized institutes for board-certified esophageal surgeons by the Japan Esophageal Society. We administered an original questionnaire to investigate the current status of prehabilitation during NAC. RESULTS: The response rate was 75% (117/155 facilities). Forty-six facilities (39%) provided prehabilitation during NAC. The most frequently selected reasons for not providing or providing insufficient prehabilitation were lack of human resources, issues with the reimbursement of medical fees, difficulty in providing continuous prehabilitation during repeated inpatient and outpatient care, the lack of established standard prehabilitation programs, challenges in providing multidisciplinary prehabilitation, and difficulty in managing physical symptoms. CONCLUSION: We observed that the implementation rate of prehabilitation during NAC was low. Critical reasons were not only the lack of medical resources but also the lack of evidence-based standard prehabilitation programs during NAC and the lack of evidence for how to continuously deliver prehabilitation during NAC to patients with physical symptoms.

Novel approach of prophylactic radiation to reduce toxicities comparing 2-step40 with 56-Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck, an intergroup phase III trial (JCOG1912, NEW BRIDGE).

BACKGROUND: Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN. METHODS: This study is a multicenter, two-arm, open-label, randomized phase III trial. Patients with LA-SCCHN excluding p16 positive oropharynx cancer are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m2 are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score. DISCUSSION: If the experimental arm is non-inferior to the standard arm in terms of TTF and superior on the safety endpoints, the 2-step40 procedure is the more useful treatment than SIB56 for definitive CRT. TRIAL REGISTRATION: This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100 ( https://jrct.niph.go.jp/latest-detail/jRCTs031210100 ). Date of Registration: May 2021.

Protocol for a confirmatory trial of the effectiveness and safety of palliative arterial embolization for painful bone metastases.

BACKGROUND: Transcatheter arterial embolization (TAE) has long been used for hemostasis of traumatic or postoperative hemorrhage and embolization of tumors. Previous retrospective studies of TAE for painful bone metastases showed 60%-80% pain reduction with a median time to response of 1-2 days. Compared with radiotherapy and bisphosphonates, time to response appeared earlier than that of radiotherapy or bone-modifying agents. However, few prospective studies have examined TAE for this indication. Here, we describe the protocol for a confirmatory study designed to clarify the efficacy and safety profile of TAE. METHODS: This study will be a multicenter, single-arm confirmatory study (phase 2-3 design). Patients with painful bone metastases from any primary tumor are eligible for enrollment. TAE will be the main intervention. Following puncture of the femoral artery under local anesthesia and insertion of an angiographic sheath, angiography will confirm that the injected region includes tumor vasculature. Catheter position will be adjusted so that the embolization range does not include non-target tissues. Spherical embolic material will then be slowly injected into the artery to embolize it. The primary endpoint (efficacy) is the proportion of subjects with pain relief at 72 h after TAE and the secondary endpoint (safety) is the incidence of all NCI Common Terminology Criteria for Adverse Events version 5.0 Grade 4 adverse events and Grade ≥ 3 necrosis of the central nervous system. DISCUSSION: If the primary and secondary endpoints are met, TAE can be a treatment choice for painful bone metastases. Trial registry number is UMIN-CTR ID: UMIN000040794. TRIAL REGISTRATION: The study is ongoing, and patients are currently being enrolled. Enrollment started in March 2021. A total of 36 patients have participated as of Aug 2022. PROTOCOL VERSION: Ver1.4, 13/07/2022.

Potential efficacy of local therapy for progressive lesions after nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: In recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), local therapy (LT) such as surgery or radiotherapy can be treatment options for improved survival or quality of life. To date, however, few reports have addressed the efficacy of LT for sites of disease progression after immune checkpoint inhibitors, including other cancers. METHODS: We conducted a retrospective analysis of patients with R/M SCCHN originating from the oral cavity, oropharynx, hypopharynx, and larynx and treated with nivolumab. We extracted patients undergoing salvage LT or palliative radiotherapy (RT) to the selected progressive lesion at any time after initiation of nivolumab. RESULTS: Twenty-four patients received LT. Salvage LT was performed in 9 (37.5%) patients, including surgery and definitive RT in 5 and 4 patients, respectively. Palliative RT was performed in 15 (62.5%) patients. LT was provided in 10 (41.7%) patients for oligoprogressive disease. Twelve (50.0%) patients received subsequent systemic therapy immediately after LT. Classification based on patient treatment divided the population into four subgroups with different prognoses (salvage LT followed by subsequent systemic therapy [n = 3], salvage LT alone [n = 6], palliative RT followed by subsequent systemic therapy [n = 9], and palliative RT alone [n = 6]). Median OS in this order was 24.5, 9.0, 7.3, and 2.4 months (p = 0.001). All patients in the salvage LT followed by subsequent systemic therapy group continued nivolumab. CONCLUSION: In R/M SCCHN patients who have received nivolumab, salvage LT for the selected progressive lesion with continuation of nivolumab potentially provides an excellent survival prognosis.

Adjuvant treatments for locally advanced differentiated thyroid cancer: a nationwide survey in Japan.

The role of adjuvant external-beam radiotherapy (EBRT) for locally advanced differentiated thyroid cancer (DTC) is controversial because of the lack of prospective data. To prepare for a clinical trial, this study investigated the current clinical practice of adjuvant treatments for locally advanced DTC. A survey on treatment selection criteria for hypothetical locally advanced DTC was administered to representative thyroid surgeons of facilities participating in the Japan Clinical Oncology Group Radiation Therapy Study Group. Of the 43 invited facilities, surgeons from 39 (91%) completed the survey. For R1 resection or suspected residual disease, 26 (67%) facilities administered high-dose (100-200 mCi) radioactive iodine (RAI), but none performed EBRT. For R2 resection or unresectable primary disease, 26 (67%) facilities administered high-dose RAI and 7 (18%) performed adjuvant treatments, including EBRT. For complete resection with nodal extra-capsular extension, 13 (34%) facilities administered high-dose RAI and 1 (3%) performed EBRT. For unresectable mediastinal lymph node metastasis, 31 (79%) facilities administered high-dose RAI and 5 (13%) performed adjuvant treatments, including EBRT. Adjuvant EBRT was not routinely performed mainly because of the lack of evidence for efficacy (74%). Approximately 15% of the facilities routinely considered adjuvant EBRT for DTC with R2 resection or unresectable primary or lymph node metastasis disease. Future clinical trials will need to optimize EBRT for these patients.

Research policy in supportive care and palliative care for cancer dyspnea.

BACKGROUND: Dyspnea is a common and distressing symptom in patients with cancer. To improve its management, multicenter confirmatory studies are necessary. Research policy would be useful in conducting these studies. Here, we propose a new research policy for the management of dyspnea in patients with cancer. METHODS: The first draft was developed by a policy working group of 11 specialists in the field of supportive care or palliative care for dyspnea. Then, a provisional draft was developed after review by a research support group (the Japanese Supportive, Palliative and Psychosocial Care Study Group) and five Japanese scientific societies (Japanese Association of Supportive Care in Cancer, Japanese Society of Medical Oncology, Japanese Society of Palliative Medicine, Japanese Association of Rehabilitation Medicine and Japanese Society of Clinical Oncology), and receipt of public comments. RESULTS: The policy includes the following components of research policy on dyspnea: (i) definition of dyspnea, (ii) scale for assessment of dyspnea, (iii) reason for dyspnea or factors associated with dyspnea and (iv) treatment effectiveness outcomes/adverse events. The final policy (Ver1.0) was completed on 1 March 2021. CONCLUSIONS: This policy could help researchers plan and conduct studies on the management of cancer dyspnea.

Difference of compliance rates for the recommendations in Japanese Guideline on Febrile Neutropenia according to respondents' attributes: the second report on a questionnaire survey among hematology-oncology physicians and surgeons.

PURPOSE: The Japanese Society of Medical Oncology (JSMO) published a guideline (GL) on febrile neutropenia (FN) in 2017. This study aims to identify promoting factors and disincentives for complying with GL recommendations according to attributes of doctors providing chemotherapy. METHODS: A questionnaire survey was conducted with SurveyMonkey™ for physician members of the Japanese Association of Supportive Care in Cancer and relevant academic organizations. Each question had four options (always do, do in more than half of patients, do in less than half, do not at all) and a free description form. Responses were analyzed according to the respondents' attributes. RESULT: Seven hundred eighty-eight out of retrieved 801 responses were available for analysis. Multivariable analysis demonstrated that the percentage of GL users was higher among women and Japanese Society of Clinical Oncology members. The overall compliance rate was higher among women, JSMO members, and board-certified medical oncologists. Internists emphasized the significance of collecting blood cultures at FN onset, and surgeons stressed the importance of G-CSF prophylaxis. Hematologists were less likely to adhere to recommendations on risk assessment of FN by the Multinational Association of Supportive Care in Cancer score and administration of gammaglobulin products. However, those are acceptable due to the characteristics of their practice. Eight recommendations had no difference in compliance rates between users and non-users, some of whose statements were ambiguous and discretionary. CONCLUSION: Women were more likely to use and adhere to GL. The recommendations should be developed considering the characteristics of specialty and subspecialty and avoiding ambiguity and discretionary statements.

Establishment of a research policy for supportive and palliative care in Japan.

BACKGROUND: While several small groups in Japan have attempted to conduct prospective studies in the field of supportive and palliative care, development of exploratory research into multicentre confirmatory studies has been difficult. The main reason for this is the difference in clinical research methodology in supportive and palliative care compared with medical oncology in terms of the style of multidisciplinary approaches, study design and endpoints. Here, we establish a new research policy for cancer supportive and palliative care in Japan. METHODS: The first draft was developed by a policy working group within the Japanese Supportive, Palliative and Psychosocial Care Study Group. A provisional draft was subsequently developed after review by nine Japanese scientific societies (Japanese Association of Supportive Care in Cancer, Japanese Society of Medical Oncology, Japanese Society of Clinical Oncology, Japanese Society of Palliative Medicine, Japanese Society of Cancer Nursing, Japanese Society of Pharmaceutical Oncology (JASPO), Japan Cancer Association (JCA), Japanese Society of Therapeutic Radiation Oncology and Japanese Cancer Association) and receipt of public comments. The final research policy in the area of supportive and palliative care in Japan (Ver1.0) was completed in December 2018 and underwent its first revision (Ver1.1) in February, 2020. RESULTS: The policy includes the following components of clinical research: (i) objective of the research policy in the areas of supportive and palliative care; (ii) definitions of supportive care and palliative care; (iii) characteristics of supportive and palliative care research; (iv) target population for research; (v) research design; (vi) endpoints and assessment measures; (vii) handling of the deaths of subjects and (viii) operational structure and quality management. CONCLUSIONS: We hope that studies conducted according to this policy will play important roles in the future development of the supportive and palliative field.

The current status of inpatient cancer rehabilitation provided by designated cancer hospitals in Japan.

OBJECTIVE: This survey was conducted to clarify the current status of inpatient cancer rehabilitation provided by designated cancer hospitals in Japan. METHODS: A survey questionnaire was sent to 427 designated cancer hospitals in Japan. Information was sought regarding whether inpatient cancer rehabilitation was provided by the center, and if so, whether respondents regarded such provision as satisfactory. RESULTS: Responses were obtained from 235/427 surveyed institutions (55.0%). Cancer rehabilitation was provided in inpatient settings by 97.4%. Two-thirds of respondents (67.7%) regarded inpatient cancer rehabilitation provision as still inadequate. The primary reasons claimed for this inadequacy were a lack of human resources, a lack of rehabilitation professionals with the requisite knowledge/skills and patients who would benefit from cancer rehabilitation present but not prescribed. The total number of rehabilitation staff was identified as associated factor of inadequate inpatient cancer rehabilitation in multivariate analysis (odds ratio = 0.979, 95% confidence interval = 0.96-1.00, P = 0.009). CONCLUSIONS: In order to provide adequate cancer rehabilitation, a sufficient supply of rehabilitation staff, education and recognition of the need for cancer rehabilitation within oncology units are necessary.

A questionnaire survey on evaluation for penetration and compliance of the Japanese Guideline on Febrile Neutropenia among hematology-oncology physicians and surgeons.

PURPOSE: The Japanese Society of Medical Oncology published a guideline (GL) on febrile neutropenia (FN) in 2017. The study's purpose is to reveal how widely GL penetrated among physicians and surgeons providing chemotherapy. METHODS: A questionnaire survey was conducted with SurveyMonkey™ for members of the Japanese Association of Supportive Care in Cancer and relevant academic organizations. Each question had four options (always do, do in more than half of patients, do in less than half, do not at all) and a free description form. Responses were analyzed with statistical text-analytics. RESULT: A total of 800 responses were retrieved. Major respondents were experts with more than 10-year experience, physicians 54%, and surgeons 46%. Eighty-seven percent of respondents knew and used GL. Forty-eight percent assessed FN with Multinational Association of Supportive Care in Cancer (MASCC) score "always" or "more than half." Eighty-one percent chose beta-lactam monotherapy as primary treatment in high-risk patients. Seventy-seven percent did oral antibacterial therapy in low-risk patients ambulatorily. Seventy-eight percent administered primary prophylactic G-CSF (ppG-CSF) in FN frequency ≥ 20% regimen. Fifty-nine percent did ppG-CSF for high-risk patients in FN frequency 10-20% regimen. Ninety-seven percent did not use ppG-CSF in FN frequency < 10% regimen. The medians of complete and complete plus partial compliance rates were 46.4% (range 7.0-92.8) and 77.8% (range 35.4-98.7). The complete compliance rates were less than 30% in seven recommendations, including the MASCC score assessment. CONCLUSION: GL is estimated to be widely utilized, but some recommendations were not followed, presumably due to a mismatch with actual clinical practices in Japan.

Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Olanzapine 10 mg added to standard antiemetic therapy including aprepitant, palonosetron, and dexamethasone has been recommended for the prevention of chemotherapy-induced nausea and vomiting. Guidelines suggest that a dose reduction to 5 mg should be considered to prevent sedation. In several phase 2 studies, olanzapine 5 mg has shown equivalent activity to olanzapine 10 mg and a favourable safety profile in relation to somnolence. We evaluated the efficacy of olanzapine 5 mg combined with standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting caused by cisplatin-based chemotherapy. METHODS: This was a randomised, double-blind, placebo-controlled, phase 3 study to evaluate the efficacy of olanzapine 5 mg with triplet-combination antiemetic therapy done in 26 hospitals in Japan. Key inclusion criteria were patients with a malignant tumour (excluding those with a haemopoietic malignancy) who were scheduled to be treated with cisplatin (≥50 mg/m2) for the first time, age between 20 and 75 years, and with Eastern Cooperative Oncology Group performance status of 0-2. Eligible patients were randomly assigned (1:1) to receive either oral olanzapine 5 mg or placebo once daily on days 1-4 combined with aprepitant, palonosetron, and dexamethasone (dosage based on the standard antiemetic therapy against highly emetogenic chemotherapy). Patients were randomly assigned to interventions by use of a web entry system and the minimisation method with a random component, with sex, dose of cisplatin, and age as factors of allocation adjustment. Patients, medical staff, investigators, and individuals handling data were all masked to treatment assignment. The primary endpoint was the proportion of patients who achieved a complete response, defined as absence of vomiting and no use of rescue medications in the delayed phase (24-120 h). All randomly assigned patients who satisfied eligibility criteria received a dose of cisplatin 50 mg/m2 or more, and at least one study treatment, were included in efficacy analysis. All patients who received any treatment in this study were assessed for safety. This study is registered at UMIN Clinical Trials Registry, number UMIN000024676. FINDINGS: Between Feb 9, 2017, and July 13, 2018, 710 patients were enrolled; 356 were randomly assigned to receive olanzapine and 354 were assigned to receive placebo. All eligible patients were observed 120 h after cisplatin initiation. One patient in the olanzapine group and three in the placebo group did not receive treatment and were excluded from all analyses. One patient in the olanzapine group discontinued treatment on day 1 and was excluded from the efficacy analysis. In the delayed phase, the proportion of patients who achieved a complete response was 280 (79% [95% CI 75-83] of 354 patients in the olanzapine group and 231 (66% [61-71] of 351 patients in the placebo group (p<0·0001). One patient had grade 3 constipation and one patient had grade 3 somnolence related to treatment in the olanzapine group. INTERPRETATION: Olanzapine 5 mg combined with aprepitant, palonosetron, and dexamethasone could be a new standard antiemetic therapy for patients undergoing cisplatin-based chemotherapy. FUNDING: Japan Agency for Medical Research and Development.

Comparison of salvage surgery for recurrent or residual head and neck squamous cell carcinoma.

OBJECTIVE: Concomitant chemoradiation therapy is a standard treatment for head and neck cancer. Thus, salvage surgery has become a necessary treatment. The aim of the study was to evaluate the results of salvage surgery by each site of the head and neck, especially the oropharynx, hypopharynx and larynx. METHODS: This was a retrospective, single-institute study. The primary endpoint was overall survival. Secondary endpoints were disease-free survival, the locoregional control rate after salvage surgery, the indication rate for salvage surgery, the reasons for contraindications to salvage surgery, the post-operative complication rate and the predictors of survival. RESULTS: Three-year overall survival after salvage surgery was 58.8% in the salvage surgery group and 8.59% in the other treatment group (P < 0.0001). Regarding overall survival and disease-free survival after salvage surgery, there was no difference among sites. Regarding locoregional control rate among sites, there was no significant difference. The oropharyngeal cancer group had the lowest rate of salvage primary resection. Surgical margin and local and regional recurrence or residual disease were predictors on univariate and multivariate analyses. CONCLUSIONS: Salvage surgery is effective for recurrent or residual cases after concomitant chemoradiation therapy. For oropharyngeal cancer, local control is important, and for oropharyngeal cancer and hypopharyngeal cancer, distant metastasis is important.

Therapeutic results of proton beam therapy with concurrent chemotherapy for cT1 esophageal cancer and salvage endoscopic therapy for local recurrence.

BACKGROUND: Proton beam therapy (PBT) with concurrent chemotherapy is promising for esophageal squamous cell carcinoma (ESCC). The aim of study was to evaluate the outcome of concurrent chemo-proton therapy (CCPT), i.e., PBT with concurrent chemotherapy for cT1 ESCC and the salvage endoscopic therapy for local recurrence. METHODS: Patients with clinical T1 ESCC who underwent CCPT (60 GyE) between April 2013 and April 2017 at the National Cancer Center Hospital East were investigated. The efficacy of CCPT at the primary site was evaluated via endoscopy; primary complete response (CR) was defined as disappearance of the tumor lesion/ulcer and absence of cancer cells on biopsy. Endoscopic evaluation was performed with the same protocol of conventional chemoradiotherapy. Local recurrence after CCPT was treated with endoscopic resection for cT1a and with esophagectomy or photodynamic therapy for cT1b+. RESULTS: Of the 44 patients (median age, 70 years) that underwent CCPT, 43 patients (98%) achieved primary CR. Among the 44 patients, the 3-year overall survival rate was 95.2%. Five patients (11%) developed local recurrence without regional lymph node or distant metastasis and received endoscopic resection or photodynamic therapy. All five patients were alive with no recurrence after a median 23 months. CONCLUSIONS: The results suggest that CCPT is an effective treatment for cT1 ESCC and careful endoscopic follow-up allows preferable local control with salvage endoscopic treatment.

A review of head and neck cancer staging system in the TNM classification of malignant tumors (eighth edition).

A number of major modifications were made to the classification of head and neck carcinomas in the eighth edition of the American Joint Committee on Cancer, Cancer Staging Manual and Union for International Cancer Control TNM classification of Malignant Tumors. These modifications were aimed at improving the prognosis prediction accuracy of the system. In this article, we review the new edition of the TNM classification system. Among the several changes in the new system, a separate algorithm for p16-positive oropharyngeal carcinoma was included, as were new chapters on 'Head and Neck Skin Carcinoma' and 'Unknown Primary Carcinoma-Cervical Nodes.' Changes to Tumor (T) classification were made by introducing the depth of invasion of oral carcinoma, whereas changes to Node (N) classification were made by adding extra-nodal extension. It is believed that these changes will help improve the accuracy of the system in the prediction of prognosis. However, it is necessary to verify their validity through further clinical research.

The post hoc analysis comparing the severity grades of chemoradiotherapy-induced oral mucositis scored between the central and local assessors in a multicenter, randomized controlled trial of rebamipide for head and neck cancer.

BACKGROUND: In the treatment of head and neck cancer, severity of chemoradiotherapy-induced oral mucositis has been recognized as one of the key factors affecting the outcomes of the anticancer therapies. Therefore, the development of treatments mitigating oral mucositis would be of clinical significance, although the adequate assessment procedure for efficacy evaluation remains to be established. We conducted this post hoc study to assess the effect of objective evaluation of the severity grade on the outcomes of the clinical trial. METHODS: In the original trial with rebamipide liquids (0, 2, and 4%) for chemoradiotherapy-induced oral mucositis, the investigators in local sites and independent central review separately determined the severity grades in accordance with Common Terminology Criteria of Adverse Events version 3.0 based on the Assessment Sheet scored by the investigators. The discordance in severity grades between the investigators and central review was analyzed on cross table. RESULTS: The analysis revealed the discordance rate over the trial was 34%. While the incidences of severe oral mucositis in the placebo, rebamipide 2%, and 4% groups evaluated by the central review were 39%, 29%, and 25%, respectively, the respective values in the investigator's evaluation were 32%, 39%, and 44%. CONCLUSION: In the clinical trial for the treatment of oral mucositis, it was strongly suggested that objective evaluation with a consistent scale would be required.

Induction TPF chemotherapy followed by CRT with fractionated administration of cisplatin in patients with unresectable locally advanced head and neck cancer.

BACKGROUND: In treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN), the use of docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by high-dose cisplatin chemoradiotherapy (CRT) carries concerns over toxicity. We evaluated the feasibility of TPF as induction chemotherapy (IC) to Japanese patients and the tolerability of CRT with fractionated administration of cisplatin after IC. METHODS: Patients with unresectable stage III, IV SCCHN received IC followed by CRT. IC consisted of three 3-week cycles of docetaxel 70-75 mg/m2 on day 1, cisplatin 70-75 mg/m2 on day 1, and 5-fluorouracil 750 mg/m2 on days 1-5. Patients subsequently received IMRT concomitant with fractionated administration of cisplatin (20 mg/m2) on days 1-4, repeated every 3 weeks. The primary endpoint was completion of the three cycles of IC. RESULTS: Forty-eight patients were enrolled. The IC treatment completion rate was 85%. Grade 3-4 toxicities of TPF were neutropenia (79%) and febrile neutropenia (15%). Thirty-eight patients (79%) achieved a response after IC. Forty patients subsequently underwent CRT. Thirty-three patients (83%) completed the planned cycles of fractionated administration of cisplatin, but seven (18%) did not. Grade 3-4 toxicities during CRT were neutropenia (23%), mucositis (53%), and dysphagia (33%). With a median follow-up of 36.1 months, 3-year overall survival was 65%. CONCLUSION: TPF IC is feasible and CRT with fractionated administration of cisplatin after IC is tolerable. IC followed by CRT appears to be a useful and safe sequential treatment. (Trial registration no. UMIN000024686).

Frequency and predictors of detecting early locoregional recurrence/disease progression of oral squamous cell carcinoma with high-risk factors on imaging tests before postoperative adjuvant radiotherapy.

BACKGROUND: To clarify the frequency and predictors of detecting early locoregional recurrence/disease progression (LR/DP) during the interval between surgery and postoperative adjuvant radiotherapy with/without chemotherapy in patients with oral squamous cell carcinoma. METHODS: Data on 65 patients who had undergone the initial radical surgery for previously untreated oral squamous cell carcinoma which were scheduled to receive adjuvant radiotherapy with/without chemotherapy were reviewed. RESULTS: Of the 65 patients, 63 (97%) were margin-positive/close and/or extracapsular extension-positive (hereinafter, high-risk factors). Eighteen (28%) patients had abnormal findings suggestive of LR/DP on postoperative imaging. Fifteen (23%) patients were diagnosed with LR/DP and treatment policy was changed. Univariate and multivariate analyses revealed higher frequencies of abnormal findings suggestive of LR/DP (univariate/multivariate analysis, p = 0.020/0.036), diagnosing of LR/DP, and changing the treatment policy (univariate/multivariate analysis, p = 0.042/0.046), among the patients who underwent postoperative diagnostic imaging tests or radiotherapy-planning contrast-enhanced (CE) CT without diagnostic imaging tests as compared with those who underwent radiotherapy-planning non-CECT without such tests. CONCLUSION: The frequency of detecting of early LR/DP before postoperative adjuvant treatment in oral squamous cell carcinoma patients with high-risk factors was high. Furthermore, postoperative diagnostic imaging tests and radiotherapy-planning CECT may be useful to detect early LR/DP in oral squamous cell carcinoma patients before postoperative adjuvant therapy.

Topical steroid versus placebo for the prevention of radiation dermatitis in head and neck cancer patients receiving chemoradiotherapy: the study protocol of J-SUPPORT 1602 (TOPICS study), a randomized double-blinded phase 3 trial.

BACKGROUND: To date, the clinical benefit of topical steroid use has only been demonstrated for radiation dermatitis induced by 50-60 Gy irradiation in breast cancer. However, these agents are also often used clinically for the control of radiation dermatitis induced by high-dose (>60Gy) irradiation with chemotherapy in head and neck cancer. Despite this, the prophylactic efficacy of topical steroids for radiation dermatitis induced by high-dose irradiation is still unclear. The aim of this study is to clarify the benefit of topical steroids in basic nursing care for radiation dermatitis induced by chemoradiotherapy in patients with head and neck cancer. METHODS: The study is being conducted as a multicenter 2-arm randomized double-blinded placebo-controlled Phase 3 trial in Japan. The study was started in May 2017, with participant enrollment between May 2017 and April 2019. Patients scheduled to receive definitive or postoperative chemoradiotherapy for head and neck cancer are eligible for enrollment. All patients will receive chemoradiotherapy, consisting of single agent CDDP and 70-Gy irradiation. Bilateral neck irradiation is mandatory. Supportive care for radiation dermatitis will consist of basic nursing care with topical steroid or placebo. When radiation dermatitis grade 1 is seen or total radiation dose reaches 30 Gy, minimally required intervention will be started as a first step. If radiation dermatitis worsens to grade 2, the irradiated area will be covered with a moderately absorbent surgical pad and steroid or placebo topical cream. The primary endpoint is a comparison of the proportion of patients with ≥ grade 2 radiation dermatitis by NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Ethical approval has been obtained from all participating sites. The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences. DISCUSSION: Evidence supporting the benefit of adding topical steroids in general nursing care for radiation dermatitis induced by high-dose irradiation with chemotherapy is insufficient. This trial aims to clarify the clinical benefit of topical steroid for radiation dermatitis induced by high-dose irradiation with chemotherapy. The trial is ongoing and is currently recruiting. TRIAL REGISTRATION NUMBER: UMIN000027161 . Protocol version 3.0, 18 April 2017.

Study protocol for J-SUPPORT 1604 (J-FORCE): a randomized, double blind, placebo-controlled Phase III study evaluating olanzapine (5 mg) plus standard triple antiemetic therapy for prevention of chemotherapy induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy.

The Guidelines of the Japan Society of Clinical Oncology recommend standard triple antiemetic therapy with aprepitant, a 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone for patients receiving highly emetogenic chemotherapy. Recently, a Phase III study demonstrated the significance of adding of olanzapine (10 mg) to standard triple antiemetic therapy. Olanzapine is associated with somnolence, and we have previously conducted a randomized Phase II study to evaluate the efficacy and safety of 10 mg and 5 mg olanzapine. Lower dose of olanzapine reduced the incidence of somnolence. Therefore, we conducted a randomized, double blind, placebo-controlled, Phase III study to evaluate the efficacy of olanzapine (5 mg) combined with standard triple antiemetic therapy for cisplatin-based highly emetogenic chemotherapy. This study initiated in Feb 2017. A total of 690 patients are planned to be enrolled over a period of 2 years. This study has been registered at the UMIN Clinical Trials Registry as UMIN000024676.