Poor local control of ulcerative T1 glottic cancer treated with 2.25-Gy per fraction radiotherapy.

The Tokai Study Group for Therapeutic Radiology and Oncology (TOSTRO) started managing T1 glottic cancer using 2.25 Gy/fraction radiotherapy in 2011. The aim was to evaluate the local control (LC) rate and toxicity with 2.25-Gy radiotherapy in clinical practice and identify prognostic factors.The eligibility criteria were T1 glottic squamous cell carcinoma patients with age ≥20 years, treated with 2.25 Gy/fraction without chemotherapy between 2011 and 2017. LC rates were evaluated based on age, performance status, sex, T-category, tumor type (ulcerative or non-ulcerative), presence of anterior commissure invasion, tumor size, X-ray beam energy, and overall treatment time. Acute and late adverse events were evaluated using CTCAE version 4.0. A total of 202 patients were enrolled. The median follow-up period was 34.2 months. The 2- and 4-year LC rates were 93.8% and 93.1%, respectively. There was a significant difference in the LC rate between non-ulcerative type and ulcerative type (95.2% vs. 74.1% at 2 years, 94.4% vs. 74.1% at 4 years; p = 0.01). On univariate analysis, only tumor type was significantly correlated with a poor LC rate (hazard ratio 4.3; 95% confidence interval 1.2-15.4; p = 0.03). Acute grade 3 adverse events occurred in 17 patients. However, no late adverse events of grade 3 or higher have occurred to date. T1 glottic cancer treatment outcomes using hypofractionated radiotherapy with 2.25 Gy/fraction in clinical practice were comparable to previously reported results. However, ulcerative type tumor was associated with a poor LC rate.

Stem and progenitor cell microenvironment for bone regeneration and repair.

Stem cells reside in their native microenvironment, which provides dynamic physical and chemical cues essential to their survival, proliferation and function. A typical cell-based therapeutic approach requires the mesenchymal stem cells (MSC) to depart their native microenvironment, transplant to in-vivo environment, differentiate toward multiple lineages and participate in bone formation. The long-term survival, function and fate of MSC are dependent on the microenvironment in which they are transplanted. Transplantation of morselized autologous bone, which contains both stem cells and their native microenvironment, results in a good clinical outcome. However, implantation of bone graft substitutes does not provide the complete and dynamic microenvironment for MSC. Current bone graft therapeutics may need to be improved further to provide an optimal engineered MSC microenvironment.

A multicenter survey of stage T1 glottic cancer treated with radiotherapy delivered in 2.25-Gy fractions in clinical practice: An initial 5-year analysis.

The purpose of this study was to evaluate the acute and late toxicity as well as local control (LC) in T1 glottic cancer (GC) patients treated with hypofractionated radiotherapy (RT) in clinical practice. The Tokai Study Group for Therapeutic Radiology and Oncology started RT treatment with a dose of 2.25 Gy for T1 GC in 2011. Ten institutions combined data from 104 patients with T1 squamous cell carcinoma between 2011 and 2015. In total, 104 patients with T1 GC were irradiated with a standard radiation dose of 63 Gy in 28 fractions.The median follow-up duration was 18 (3.7-49.5) months. Acute grade 3 adverse events were observed in 7 patients, with 4 patients (5%) having dermatitis and 3 patients (4%) having mucositis. Late adverse events above grade 3 were not observed. Two patients developed local recurrence. The rates of acute adverse events in the present study were comparable to those in previous studies that have used 2 Gy fractions of RT.

Phase I study of concurrent vinorelbine and radiation therapy in high-risk postmastectomy breast cancer patients.

BACKGROUND: Postmastectomy chest wall irradiation is recommended for high-risk breast cancer patients, such as those with ≥4 positive nodes. Irradiation is performed sequentially rather than concurrently with chemotherapy. However, the 5-year locoregional recurrence-free survival was statistically better in the concurrent method in node-positive patients in a prior study. The benefit of concurrent chemoradiotherapy for postmastectomy breast cancer patients is uncertain. Vinorelbine is often used as concurrent chemoradiotherapy for non-small cell lung cancer in Japan and has antitumor activity in breast cancer as well. Thus, we planned this dose-finding study of concurrent vinorelbine and radiation therapy in high-risk postmastectomy breast cancer patients. METHODS: High-risk postmastectomy breast cancer patients were recruited. Patients received weekly vinorelbine administered concurrently with radiation therapy. The radiation dose was 50 Gy in 25 fractions over 5 weeks. Vinorelbine was administered weekly without a break, so the maximum number of vinorelbine cycles was five. A 3 + 3 dose-escalation design was used for determining maximal tolerable dose, recommended dose and safety. RESULTS: A total of 10 patients were enrolled in cohorts of 10 and 15 mg/m(2). Dose-limiting toxicity was observed in one case in 10 mg/m(2) and two cases in 15 mg/m(2). Therefore, the maximal tolerable dose was defined at 15 mg/m(2) and the recommended dose was determined at 10 mg/m(2). The main adverse events included radiation dermatitis and neutropenia. Recurrence was observed in one patient with a median follow-up of 40 months. CONCLUSIONS: Concurrent vinorelbine and radiation therapy has a manageable safety profile at 10 mg/m(2) in high-risk postmastectomy breast cancer patients.

Retrospective case series of 15 patients treated with chemoradiation using 5-FU and nedaplatin for gynecological malignancy: with regard to hemotoxicity.

We conducted a retrospective comparison of the hemotoxicity of the sequential administration of 5-Fluorouracil (5-FU) prior to Nedaplatin (NDP) (FN therapy) and that of its reverse sequence (NF therapy) for gynecological malignancy. From February 2002 to November 2004, a total of 15 gynecological malignancy patients were treated with radiation therapy combined with NDP and 5-FU. Of these 15 patients, 5 were treated with NF therapy, and 10 were treated with FN therapy. No significant differences were detected between the FN and NF groups with regard to white blood cell count (WBC), hemoglobin level (Hb), and platelet count. The results of this study do not show that the FN group has a lesser degree of hemotoxicity than the NF group.

Health-related quality of life after carbon-ion radiotherapy for prostate cancer: a 3-year prospective study.

OBJECTIVES: To assess 3-year health-related quality of life of patients treated with carbon ion radiotherapy for prostate cancer. METHODS: A total of 213 patients received carbon-ion radiotherapy at a total dose of 66 Gy equivalent in 20 fractions over 5 weeks, and neoadjuvant and adjuvant androgen deprivation therapy were administered for high-risk patients for at least 12 months. A health-related quality of life assessment was carried out at four time-points (immediately before the initiation of carbon-ion radiotherapy, immediately after, 12 and 36 months after completion of carbon-ion radiotherapy) using Functional Assessment of Cancer Therapy General and for Prostate Cancer Patients. RESULTS: The evaluable response rates among all responses were more than 94%. Overall, a significant decrease in the scores of the health-related quality of life 12 months after carbon-ion radiotherapy returned to their baseline levels at 36 months. Additionally, no significant decrease was observed in the scores at any of the assessment time-points compared with their baseline scores in the group of carbon-ion radiotherapy without androgen deprivation therapy; however, the presence of morbidity and biochemical failure significantly worsened the scores, and the decreases in the scores did not improve even at 36 months after carbon-ion radiotherapy. CONCLUSIONS: An assessment based on a subjective scoring system shows a significant decrease in health-related quality of life at 12 months after carbon-ion radiation therapy, which tends to return to baseline levels at 36 months. The presence of morbidity and biochemical failure significantly worsen health-related quality of life scores. Further controlled studies focusing on health-related quality of life assessment in patients with prostate cancer are warranted.

Multi-institutional analysis of early glottic cancer from 2000 to 2005.

BACKGROUND: The purpose of this study is to analyze the outcome of patients with early glottic cancer (GC) treated with radiotherapy (RT) with or without chemotherapy at 10 institutions in the Tokai District, Japan. METHODS: Ten institutions combined data from 279 patients with T1-T2 GC treated with RT with or without chemotherapy between 2000 and 2005. The overall survival rate, disease-specific survival rate, and local control rate were evaluated in 270 patients, except for incomplete cases due to issues such as discontinuation, using the method of Kaplan-Meier and compared using the log-rank test. Results were considered statistically significant at the level of p < 0.05. RESULTS: For 122 patients, the tumors were classified as T1a, while 64 patients had T1b tumors, and 84 patients had T2 tumors. In three cases of T1 tumors, the subtype was unknown. Combined chemoradiotherapy (CRT) was administered during each stage, and various chemotherapy drugs and regimens were used. The median follow-up period was 55.4 months. The 5-year LC rates for T1a, Tb, and T2 tumors in all patients were 87.9%, 82.7%, and 74.1%, respectively. The difference between T1a and T2 was statistically significant (p = 0.016). The 5-year LC rates for T1a, Tb, and T2 with CRT were 92.7%, 78.6%, and 80.7%, respectively, while the rates with radiation alone were 86.5%, 83.8%, and 64.4%, respectively. The difference between CRT and RT alone was not statistically significant in each stage. CONCLUSIONS: In this survey, CRT was performed for early GC at most institutions in clinical practice. Our data showed no statistical difference in the LC rates between CRT and RT alone in each stage. However, there was a tendency for the LCRs of the CRT group to be more favorable than those of the RT group in the T2-stage.

Relationship between hematotoxicity and serum albumin level in the treatment of head and neck cancers with concurrent chemoradiotherapy using cisplatin.

OBJECTIVE: Patients with locally advanced head and neck cancer were treated with concurrent chemoradiotherapy using three courses of cisplatin. However, many patients were unable to complete the scheduled cisplatin treatment due to adverse effects. The objective of this study was to retrospectively elucidate the source of the low completion rate of cisplatin courses. METHODS: Between November 2007 and 28 May 2010, patients with head and neck cancer were treated with curative intent according to the concurrent chemoradiotherapy protocol (66-70 Gy at 2 Gy/day with cisplatin 80 mg/m(2) on Days 1, 22 and 43). Treatment courses, hematological data and other parameters were investigated, and the treatment completion rates and reasons for treatment failure were analyzed. RESULTS: Among the 28 patients, cisplatin was administered during the period of radiotherapy a total of 3 times in 9 (32%) patients, 2 times in 15 (54%) patients and only 1 time in 4 (14%) patients. Multiple regression analysis of the development of neutropenia at 3 weeks after the first cisplatin administration revealed that the serum albumin level was a significant explanatory variable (R(2)= 0.664, ß = 0.517, P< 0.01). Pearson's product-moment correlation coefficient showed a strong correlation between the serum albumin level and the neutrophil count after 3 weeks (r = 0.605, P< 0.01). CONCLUSIONS: The treatment completion rate by this protocol was low in head and neck cancer patients even when the cisplatin dose was reduced to 80 mg/m(2). This tendency was seen in patients with a low serum albumin level.

Combined chemoradiotherapy for early glottic cancer in clinical practice in Japan: analysis of 10 institutions.

AIM: To conduct a retrospective analysis regarding treatment strategies for early glottic cancer (GC) at ten institutions. PATIENTS AND METHODS: A questionnaire-based survey was used to obtain personal and medical information on patients who started radiation therapy for T1 or T2 GC between January 2000 and December 2005. RESULTS: A total of 279 patients were registered for the survey, of whom 124 patients were classified as T1a, with 65 patients as T1b and 87 patients as T2. The rates of chemoradiotherapy for T1a, T1b and T2 were 24%, 23% and 60%, respectively. A comparison of results for academic and non-academic hospitals showed statistically different rates of combination therapy for T1a (6.9% vs. 39.3%, respectively; p<0.001) and T1b (11.4% vs. 36.6%, respectively; p<0.05) but not for T2 (70.0% vs. 54.4%, respectively; p = 0.158). CONCLUSION: In clinical practice, combined chemoradiotherapy was performed for early GC at most institutions in Tokai District, Japan.

Radiotherapy with or without chemotherapy for patients with T1-T2 glottic carcinoma: retrospective analysis.

BACKGROUND: To assess the results for local control (LC) and survival in patients with early-stage glottic cancer (GC) who were treated by radiotherapy (RT) with or without chemotherapy. METHODS: Fifty-eight patients with T1-T2 squamous cell carcinoma of the glottis who were treated between 2001 and 2006 were analyzed retrospectively. Potential prognostic factors for LC were evaluated by univariate analysis. RESULTS: The 5-year LC rate in all patients was 84.3%. The overall 5-year LC rates for patients with T1a, Tb, and T2 GC were 85.9%, 83%, and 85%, respectively. Of the 58 patients, eight developed recurrent disease at the primary site, and one had lymph node recurrences on the neck. In the final analysis, the total laryngectomy-free survival rate was 93% at five years, and the ultimate LC rates for T1a, Tb, and T2 were 100%, 90.9%, and 95.2%, respectively. In a univariate analysis of 55 patients, there was no statistical significance between the LC rate for RT alone and that for chemoradiation. Only two patients died of laryngeal carcinoma, and one died of intercurrent disease. Fifty-five patients were living disease-free at the end of the study period. The 5-year overall survival (OS) rate for all patients was 88.1%, and the 5-year OS rates for T1a, Tb, and T2 were 91.6%, 77.8%, and 89.9%, respectively. CONCLUSIONS: The retrospective analysis showed a high rate of LC and larynx preservation in patients with T1-T2 GC by means of RT with or without chemotherapy. There was, however, no statistical difference in LC rates for the two types of therapy.

Adverse effects of androgen deprivation therapy on persistent genitourinary complications after carbon ion radiotherapy for prostate cancer.

PURPOSE: To determine the risk factors for persistent late genitourinary (GU) morbidity after carbon ion radiotherapy (C-ion RT) for prostate cancer. METHODS AND MATERIALS: Between April 2000 and November 2003, a Phase II study of 175 prostate cancer patients was performed to assess C-ion RT with a dose fractionation (66 Gray equivalent in 20 fractions) established from previous Phase I-II studies. The effects of the clinical and dosimetric parameters on the occurrence of persistent GU toxicity in 172 patients who survived for >18 months after C-ion RT were examined retrospectively. C-ion RT alone was performed for 33 low-risk patients, and 139 high-risk patients received C-ion RT combined with androgen deprivation therapy (ADT). RESULTS: Grade 1 and 2 persistent GU toxicities developed in 36 (21%) and 3 (2%) patients, respectively. The use of long-course ADT (>or=24 months) and acute GU toxicity were associated with the occurrence of persistent toxicity by multivariate analysis (p = 0.016 and p = 0.048, respectively), but short-course ADT (<24 months) had no effect on the development of toxicity (p = 0.35). The 5-year actuarial complication rate of 80 patients undergoing long-course ADT was 31.1%; the corresponding rate for the 92 patients who received no ADT or short-course ADT was 22.2%. CONCLUSION: Adverse effects with long-course ADT on persistent GU morbidity were observed in this study. Additional investigation is needed to identify suitable ADT administration according to risk groups, but long-course ADT should not be adopted for non-high-risk prostate cancer patients to reduce the GU toxicity rate with C-ion RT.

Carbon ion radiation therapy for primary renal cell carcinoma: initial clinical experience.

PURPOSE: Renal cell carcinoma (RCC) is known as a radioresistant tumor, and there are few reports on radiotherapy for primary RCC. We evaluated the efficacy of carbon ion radiotherapy (CIRT) for patients with RCC. METHODS AND MATERIALS: Data for patients with RCC who received CIRT were analyzed. A median total dose of 72 GyE (gray equivalents) in 16 fractions was administered without any additional treatment. Clinical stage was determined based on TNM classification by the International Union Against Cancer (UICC). Local recurrence was defined as definite tumor regrowth after treatment. RESULTS: Data for 10 patients were included in the analyses, including 7 patients with Stage I and 3 patients with Stage IV (T4NxM0 or TxN2M0) disease. The median maximum diameter of the tumor was 43 mm (24-120 mm). The median follow-up for surviving patients was 57.5 months (9-111 months). The 5-year local control rate, progression-free survival rate, cause-specific survival rate, and overall survival rates were 100%, 100%, 100%, and 74%, respectively. Interestingly, treated tumors showed very slow shrinkage, and the tumor in 1 case has been shrinking for 9 years. One patient with muscular invasion (T4 tumor) developed Grade 4 skin toxicity, but no other toxicity greater than Grade 2 was observed. CONCLUSIONS: This is one of the few reports on curative radiotherapy for primary RCC. The response of the tumor to treatment was uncommon. However despite inclusion of T4 and massive tumors, favorable local controllability has been shown. The results indicate the possibility of radical CIRT, as well as surgery, for RCC.

Carbon ion radiotherapy for stage I non-small cell lung cancer using a regimen of four fractions during 1 week.

BACKGROUND: A phase I/II study was first conducted for the treatment of stage I non-small cell lung cancer (NSCLC) from 1994 to 1999 to determine the optimal dose. On the basis on the results, a phase II study using a regimen of four fractions during 1 week was performed. The purpose of the present study was to determine the local control and 5-year survival rates. METHODS: From December 2000 to November 2003, 79 patients with 80 primary lesions were treated. Using a fixed dose of 52.8 GyE for stage IA NSCLC and 60.0 GyE for stage IB NSCLC in four fractions during 1 week, the primary tumors were irradiated with carbon beams alone. The average age of the patients was 74.8 years. Sixty-two (78.5%) of these patients were medically inoperable. Local control and survival were determined using the Kaplan-Meier method. The data were statistically processed using the log-rank test. RESULTS: All patients were observed for a minimum of 3 years or until death, with a median follow-up time of 38.6 months, ranging from 2.5 to 72.2 months. The local control rate for all patients was 90% (T1: 98%, T2: 80%). The patients' 5-year lung cancer-specific survival rate was 68% (IA: 87%, IB: 42%). The overall survival was 45% (IA: 62%, IB: 25%). Half of the deaths were attributable to intercurrent diseases. No toxic reactions in the lung greater than grade 3 were detected. CONCLUSION: Carbon ion beam radiotherapy with a regimen of four fractions during 1 week has been proven as a valid alternative to surgery for stage I NSCLC and to offer particular benefits, especially for elderly and inoperable patients.

Carbon-ion radiotherapy for locally advanced or unfavorably located choroidal melanoma: a Phase I/II dose-escalation study.

PURPOSE: To evaluate the applicability of carbon ion beams for the treatment of choroidal melanoma with regard to normal tissue morbidity and local tumor control. METHODS AND MATERIALS: Between January 2001 and February 2006, 59 patients with locally advanced or unfavorably located choroidal melanoma were enrolled in a Phase I/II clinical trial of carbon-ion radiotherapy at the National Institute of Radiologic Sciences. The primary endpoint of this study was normal tissue morbidity, and secondary endpoints were local tumor control and patient survival. Of the 59 subjects enrolled, 57 were followed >6 months and analyzed. RESULTS: Twenty-three patients (40%) developed neovascular glaucoma, and three underwent enucleation for eye pain due to elevated intraocular pressure. Incidence of neovascular glaucoma was dependent on tumor size and site. Five patients had died at analysis, three of distant metastasis and two of concurrent disease. All but one patient, who developed marginal recurrence, were controlled locally. Six patients developed distant metastasis, five in the liver and one in the lung. Three-year overall survival, disease-free survival, and local control rates were 88.2%, 84.8%, and 97.4%, respectively. No apparent dose-response relationship was observed in either tumor control or normal tissue morbidity at the dose range applied. CONCLUSION: Carbon-ion radiotherapy can be applied to choroidal melanoma with an acceptable morbidity and sufficient antitumor effect, even with tumors of unfavorable size or site.

Risk factors for neovascular glaucoma after carbon ion radiotherapy of choroidal melanoma using dose-volume histogram analysis.

PURPOSE: To determine the risk factors for neovascular glaucoma (NVG) after carbon ion radiotherapy (C-ion RT) of choroidal melanoma. METHODS AND MATERIALS: A total of 55 patients with choroidal melanoma were treated between 2001 and 2005 with C-ion RT based on computed tomography treatment planning. All patients had a tumor of large size or one located close to the optic disk. Univariate and multivariate analyses were performed to identify the risk factors of NVG for the following parameters; gender, age, dose-volumes of the iris-ciliary body and the wall of eyeball, and irradiation of the optic disk (ODI). RESULTS: Neovascular glaucoma occurred in 23 patients and the 3-year cumulative NVG rate was 42.6 +/- 6.8% (standard error), but enucleation from NVG was performed in only three eyes. Multivariate analysis revealed that the significant risk factors for NVG were V50IC (volume irradiated > or =50 GyE to iris-ciliary body) (p = 0.002) and ODI (p = 0.036). The 3-year NVG rate for patients with V50IC > or =0.127 mL and those with V50IC <0.127 mL were 71.4 +/- 8.5% and 11.5 +/- 6.3%, respectively. The corresponding rate for the patients with and without ODI were 62.9 +/- 10.4% and 28.4 +/- 8.0%, respectively. CONCLUSION: Dose-volume histogram analysis with computed tomography indicated that V50IC and ODI were independent risk factors for NVG. An irradiation system that can reduce the dose to both the anterior segment and the optic disk might be worth adopting to investigate whether or not incidence of NVG can be decreased with it.

Risk factors of late rectal bleeding after carbon ion therapy for prostate cancer.

PURPOSE: The aim of this study was to determine the risk factors for late gastrointestinal (GI) morbidity after hypofractionated carbon ion radiotherapy (C-ion RT) for prostate cancer. METHODS AND MATERIALS: Between April 2000 and November 2003, a Phase II clinical trial of C-ion RT with a total dose of 66 GyE in 20 fractions was performed on 175 patients with prostate cancer, and the correlations of clinical and dosimetric parameters with the incidence of late GI toxicity in 172 patients who survived for more than 18 months were investigated. RESULTS: Although no Grade 3-4 late morbidities of the rectum were observed, Grade 1 and 2 morbidities developed in 23 (13%) and 4 (2%) patients, respectively. Dose-volume histogram analysis revealed that the percentage of rectal volume receiving 50% of the prescribed dose (V50) was significantly higher in patients with rectal toxicity than without toxicity (13.2 +/- 5.6% with toxicity; 11.4 +/- 4.0% without toxicity, p = 0.046). Multivariate analysis demonstrated that the use of anticoagulation therapy (p = 0.010) and rectal V50 (p = 0.012) were significant risk factors for the occurrence of Grade 1-2 late GI toxicity. CONCLUSIONS: Although C-ion RT with hypofractionation yielded favorable results regarding late GI complication, dosimetric parameter was a very important factor in the occurrence of rectal bleeding after C-ion RT as well as photon beam RT. Our results provide useful information for physicians applying charged particle RT in the treatment of prostate cancer.

[Chemoradiation using 5-fluorouracil (5-FU) and nedaplatin (NDP) for gynecological malignancy--the relation between hemotoxicity and sequence of 5-FU and NDP].

We compared sequence-dependent schedules of 5-fluorouracil (5-FU) and nedaplatin (NDP) for hemotoxicity in genecological malignancy (GM). The safety of schedules using 5-FU before/after NDP combined radiotherapy in 8 patients with GM was evaluated. They received either 5-FU 700 mg/m2 i.v. continuous infusion on days (D) 1-4 + NDP 100 mg/m2 i.v. bolus on D1 (group A: 5 pts), or NDP on D4, 5-FU on D1-4 (group B: pts). In group A, 4 patients received a reduced dose of NDP because of less than 60 ml/min of creatinine clearance. In group A, WBC (2 pts), hemoglobin (3 pts), and platelet (1 pts) were grade 3 or higher. In group B, grade 3 or higher in hemotoxicity was not seen. A higher percentage of hemotoxicity was seen in group A compared with group B.