Tatsuya Ohno

Overview of clinical experiences on carbon ion radiotherapy at NIRS

BACKGROUND AND PURPOSEnCarbon ion beams provide physical and biological advantages over photons. This study summarizes the experiences of carbon ion radiotherapy at the Heavy Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences.nnnMATERIALS AND METHODSnBetween June 1994 and August 2003, a total of 1601 patients with various types of malignant tumors were enrolled in phase I/II dose-escalation studies and clinical phase II studies. All but malignant glioma patients received carbon ion radiotherapy alone with a fraction number and overall treatment time being fixed for each tumor site, given to one field per day and 3 or 4 days per week. In dose-escalation studies, the total dose was escalated by 5 or 10% increments to ensure a safe patient treatment and to determine appropriate dose levels.nnnRESULTSnIn the initial dose-escalation studies, severe late complications of the recto-sigmoid colon and esophagus were observed in those patients who received high dose levels for prostate, uterine cervix and esophageal cancer. Such adverse effects, however, did shortly disappear as a result of determining safe dose levels and because of improvements in the irradiation method. Carbon ion radiotherapy has shown improvement of outcome for tumor entities: (a) locally advanced head and neck tumors, in particular those with non-squamous cell histology including adenocarcinoma, adenoid cystic carcinoma, and malignant melanoma; (b) early stage NSCLC and locally advanced NSCLC; (c) locally advanced bone and soft tissue sarcomas not suited for surgical resection; (d) locally advanced hepatocellular carcinomas; (e) locally advanced prostate carcinomas, in particular for high-risk patients; (f) chordoma and chondrosarcoma of the skull base and cervical spine, and (g) post-operative pelvic recurrence of rectal cancer. Treatment of malignant gliomas, pancreatic, uterine cervix, and esophageal cancer is being investigated within dose-escalation studies. There is a rationale for the use of short-course RT regimen due to the superior dose localization and the unique biological properties of high-LET beams. This has been proven in treatment of NSCLC and hepatoma, where the fraction number has been successfully reduced to 4-12 fractions delivered within 1-3 weeks. Even for other types of tumors including prostate cancer, bone/soft tissue sarcoma and head/neck tumors, it was equally possible to apply the therapy in much shorter treatment times as compared to conventional RT regimen.nnnCONCLUSIONnCarbon ion radiotherapy, due to its physical and biologic advantages over photons, has provided improved outcome in terms of minimized toxicity and high local control rates for locally advanced tumors and pathologically non-squamous cell type of tumors. Using carbon ion radiotherapy, hypofractionated radiotherapy with application of larger doses per fraction and a reduction of overall treatment times as compared to conventional radiotherapy was enabled.

A consensus-based guideline defining the clinical target volume for pelvic lymph nodes in external beam radiotherapy for uterine cervical cancer

OBJECTIVEnTo develop a consensus-based guideline as well as an atlas defining pelvic nodal clinical target volumes in external beam radiotherapy for uterine cervical cancer.nnnMETHODSnA working subgroup to establish the consensus-based guideline on clinical target volumes for uterine cervical cancer was formulated by the Radiation Therapy Study Group of the Japan Clinical Oncology Group in July 2008. The working subgroup consisted of seven radiation oncologists. The process resulting in the consensus included a comparison of contouring on CT images among the members, reviewing of published textbooks and the relevant literature and a distribution analysis of metastatic nodes on computed tomography/magnetic resonance imaging of actual patients.nnnRESULTSnThe working subgroup defined the pelvic nodal clinical target volumes for cervical cancer and developed an associated atlas. As a basic criterion, the lymph node clinical target volume was defined as the area encompassed by a 7 mm margin around the applicable pelvic vessels. Modifications were made in each nodal area to cover adjacent adipose tissues at risk of microscopic nodal metastases. Although the bones and muscles were excluded, the bowel was not routinely excluded in the definition. Each of the following pelvic node regions was defined: common iliac, external iliac, internal iliac, obturator and presacral. Anatomical structures bordering each lymph node region were defined for six directions; anterior, posterior, lateral, medial, cranial and caudal. Drafts of the definition and the atlas were reviewed by members of the JCOG Gynecologic Cancer Study Group (GCSG).nnnCONCLUSIONSnWe developed a consensus-based guideline defining the pelvic node clinical target volumes that included an atlas. The guideline will be continuously updated to reflect the ongoing changes in the field.

Reliability and validity of the Functional Assessment of Chronic Illness Therapy–Spiritual (FACIT–Sp) for Japanese patients with cancer

The reliability and validity of the Japanese version of the Functional Assessment of Chronic Illness Therapy–Spiritual (FACIT–Sp) scale were assessed. This scale was developed in the United States to assess quality of life (QOL) in relation to spirituality. Two surveys were conducted on each of 306 cancer patients. In addition to the FACIT–Sp, the Hospital Anxiety and Depression Scale (HADS) was administered. Cronbach’s alpha reliability coefficient, an evaluation of internal consistency, for the FACIT–Sp subscales ranged from 0.81 to 0.91. There were no significant differences between the patients evaluated using the FACIT–Sp subscale and the HADS subscale with regard to degree of religious feelings. The correlation coefficients between the FACIT–Sp and the HADS depression and anxiety scales indicated a moderate correlation. These findings suggest that the Japanese version of the FACIT–Sp scale is satisfactory in terms of reliability and validity and is a useful tool in the study of spirituality among Japanese cancer patients.

Psychological distress and quality of life in cervical cancer survivors after radiotherapy: do treatment modalities, disease stage, and self-esteem influence outcomes?

The present study evaluated whether differences in the type of radiotherapy, disease stage, and self-esteem influence psychological distress and quality of life (QOL) among cervical cancer survivors. Sixty survivors, after radiotherapy, chemoradiotherapy, or postoperative radiotherapy for cervical cancer, participated in the study. The participants were asked to complete questionnaires during follow-up visits. The questionnaires included the Japanese version of the Hospital Anxiety and Depression Scale, the Functional Assessment of Cancer Therapy-General, and the Rosenberg Self-esteem Scale. The results indicated that psychological distress and QOL in cervical cancer survivors were not significantly different among treatment modalities and disease stage. Psychological distress and QOL differed significantly in accordance with the survivors self-esteem. Survivors in the high self-esteem group had lower levels of anxiety and depression and higher QOL scores (emotional and social/family aspects of QOL and total QOL) than those in the low self-esteem group. Psychosocial support with consideration of a patients self-esteem is necessary throughout and beyond radiotherapy for cervical cancer.

Serum CYFRA 21-1 in cervical cancer patients treated with radiation therapy.

Background: A fragment of cytokeratin 19, referred to as CYFRA 21-1, is abundant in the serum of many patients with malignant tumors and is recognized as one of the established tumor markers, especially for non-small-cell lung cancer. In this study, the clinical usefulness of CYFRA 21-1 was investigated in cervical cancer patients treated with radiation therapy with reference to squamous-cell-carcinoma-related antigen (SCC-Ag), a common tumor marker of cervical squamous cell carcinoma. Materials and methods: The serum levels of CYFRA 21-1 and SCC-Ag of 50 patients with squamous cell carcinoma of the uterine cervix were measured before and after radiation therapy. Results: CYFRA 21-1 was positive in 52% of the patients. The incidence increased with the stage of the cancer, and post-treatment increases were a sign of disease progression. During radiation, serum levels of CYFRA 21-1 decreased significantly and reflected the radiation effect well. In addition, CYFRA 21-1 was negative in all patients without distant metastasis at the end of radiation therapy. Compared with SCC-Ag, patients were less often positive for CYFRA 21-1, but there was a statistically positive correlation between the two markers (correlation matrix = 0.69). Conclusions: CYFRA 21-1 can be used in monitoring the outcome of patients with squamous cell carcinoma of the uterine cervix. It may be particularly useful for patients without SCC-Ag.

Application of Carbon-Ion Beams or Gamma-Rays on Primary Tumors Does Not Change the Expression Profiles of Metastatic Tumors in an In Vivo Murine Model

PURPOSEnTo clarify how carbon-ion radiotherapy (C-ion) on primary tumors affects the characteristics of subsequently arising metastatic tumor cells.nnnMETHODS AND MATERIALSnMouse squamous cell carcinomas, NR-S1, in synergic C3H/HeMsNrs mice were irradiated with a single dose of 5-50 Gy of C-ion (290 MeV per nucleon, 6-cm spread-out Bragg peak) or gamma-rays ((137)Cs source) as a reference beam. The volume of the primary tumors and the number of metastatic nodules in lung were studied, and histologic analysis and microarray analysis of laser-microdissected tumor cells were also performed.nnnRESULTSnIncluding 5 Gy of C-ion and 8 Gy of gamma-rays, which did not inhibit the primary tumor growth, all doses used in this study inhibited lung metastasis significantly. Pathologic findings showed no difference among the metastatic tumor nodules in the nonirradiated, C-ion-irradiated, and gamma-ray-irradiated groups. Clustering analysis of expression profiles among metastatic tumors and primary tumors revealed a single cluster consisting of metastatic tumors different from their original primary tumors, indicating that the expression profiles of the metastatic tumor cells were not affected by the local application of C-ion or gamma-ray radiotherapy.nnnCONCLUSIONnWe found no difference in the incidence and histology, and only small differences in expression profile, of distant metastasis between local C-ion and gamma-ray radiotherapy. The application of local radiotherapy per se or the type of radiotherapy applied did not influence the transcriptional changes caused by metastasis in tumor cells.

The Radiation-Induced Cell-Death Signaling Pathway is Activated by Concurrent Use of Cisplatin in Sequential Biopsy Specimens from Patients with Cervical Cancer

Objective: To identify changes in gene expression related to the concurrent use of platinum compounds with radiotherapy, in the treatment of cervical cancer. Patients and Methods: Biopsy specimens were obtained from 39 patients with squamous cell carcinoma of the uterine cervix, before and during fractionated radiotherapy. Twenty patients were treated with radiotherapy (RT) alone, while 19 received the same radiotherapy plus concomitant chemotherapy with cisplatin (CRT). Changes in gene expression induced by treatment were investigated using single-color oligo-microarrays consisting of 44K human sequences. Paraffin-embedded samples were used to examine apoptosis and the expression of protein by treatment-responsive genes. Changes in mRNA expression were assessed for these genes by real-time reverse transcriptase-polymerase chain reaction. Aberrant genomic change (detected using microarray-based comparative genomic hybridization), human papillomavirus infection, and p53 status were also evaluated. Results: The expression of CDKN1A, BAX, TNFSF8, and RRM2B was consistently upregulated by CRT (9 Gy with a single administration of cisplatin). Similar expression changes were induced by RT (9 Gy) alone, although the variability between tumors was greater. Apoptotic cells were significantly increased in both groups. CRT significantly increased the numbers of cases with diffusely distributed CDKN1A-positive cells. Genetic losses at 2q33-ter and gains of 3q26-ter were detected in the samples with high frequency; 60% were positive for human papillomavirus DNA; and 3 tumors had deletions/mutations of the p53 gene. There was no difference in the incidence of these genomic changes between the groups, and no association was found with the changes in expression of CDKN1A, BAX, TNFSF8, or RRM2B. Conclusions: Using biopsy samples from pretreatment and midtreatment cervical tumors, we identified therapy-induced genes related to the cell death signaling pathway. CRT produced a homogenous pattern of changes in expression of known radiation-responsive genes.

Spiritual needs in cancer patients and spiritual care based on logotherapy

BackgroundThe suitability of Frankl’s logotherapy for the spiritual care (psychotherapy) of cancer patients in Japan is suggested. Using Functional Assessment of Chronic Illness Therapy–Spiritual (FACIT-Sp, Japanese version), the Purpose in Life test (PIL test, Japanese version), and WHO-Subjective Inventory (WHO-SUBI, Japanese version), we attempted to elucidate the complicated structure of spirituality in cancer patients in order to identify possible approaches to their spiritual care and means of evaluating such care.MaterialsTwo hundred and ninety-eight cancer patients participated in the study. All three tests were taken at the same time, and the results were evaluated by principal component analysis.ResultsIt was demonstrated that all the subscales employed in the present study could be represented by a two-dimensional structure (two principal components), and that the FACIT-Sp and PIL tests have similar contents.DiscussionFACIT-Sp (Japanese version) is very similar in conception to the PIL test, which was prepared in accordance with logotherapy. The results suggest that this test can serve as an adequate evaluation scale for measuring the effectiveness of spiritual care based on Frankl’s logotherapy.

Relationship between p21/waf-1/cip-1 and apoptosis in cervical cancer during radiation therapy

PURPOSEnP21/WAF-1/CIP-1 was not considered to be involved in the regulation of apoptosis, an important indicator of radiosensitivity. However, it has been reported recently that apoptosis was suppressed when p21 expressed. The purpose of this study was to clarify the relationship between p21 and apoptosis and to evaluate the role of p21 in cervical cancer during radiation therapy (RT).nnnMETHODS AND MATERIALSnTwenty-one patients with cervical cancer were treated by RT. Tissue samples were obtained from cervical tumors of all patients before RT, and 6 hours after the fifth dose of 1.8 Gy (5th Dose). Samples were subjected to nick end labeling for apoptosis and immunohistochemical staining for p21 and p53 antigen expression.nnnRESULTSnThe mean apoptotic index, p21 labeling index and p53 labeling index were 0.27%, 9.24% and 6.60%, respectively, before RT and increased significantly to 1.20%, 17.5% and 13.9%, respectively, after 5th Dose. The apoptotic index at 5th Dose was inversely correlated with the p21 labeling index (r = -0.50, p = 0.025). Furthermore, a positive correlation was observed between the p21 and p53 labeling indices both before RT and at 5th Dose (r = 0.52, p = 0. 02; r = 0.63, p < 0.01, respectively).nnnCONCLUSIONnOur results demonstrate that apoptosis and expression of p21 and p53 were induced in cervical cancer during RT. p21 expression was dependent on p53 expression and moreover, it is suggested-that p21 might be a potential suppressor of radiation-induced apoptosis in cervical cancer during RT.

Clinical usefulness of CYFRA 21-1 for esophageal squamous cell carcinoma in radiation therapy

Aim:u2002 The aim of this study was to examine the clinical usefulness of cytokeratin 19 fragments (CYFRA 21‐1) compared with squamous cell carcinoma (SCC) antigen in patients with esophageal cancer treated with radiation therapy.