DNA damage induced by boron neutron capture therapy is partially repaired by DNA ligase IV.

Boron neutron capture therapy (BNCT) is a particle radiation therapy that involves the use of a thermal or epithermal neutron beam in combination with a boron ((10)B)-containing compound that specifically accumulates in tumor. (10)B captures neutrons and the resultant fission reaction produces an alpha ((4)He) particle and a recoiled lithium nucleus ((7)Li). These particles have the characteristics of high linear energy transfer (LET) radiation and therefore have marked biological effects. High-LET radiation is a potent inducer of DNA damage, specifically of DNA double-strand breaks (DSBs). The aim of the present study was to clarify the role of DNA ligase IV, a key player in the non-homologous end-joining repair pathway, in the repair of BNCT-induced DSBs. We analyzed the cellular sensitivity of the mouse embryonic fibroblast cell lines Lig4-/- p53-/- and Lig4+/+ p53-/- to irradiation using a thermal neutron beam in the presence or absence of (10)B-para-boronophenylalanine (BPA). The Lig4-/- p53-/- cell line had a higher sensitivity than the Lig4+/+ p53-/-cell line to irradiation with the beam alone or the beam in combination with BPA. In BNCT (with BPA), both cell lines exhibited a reduction of the 50 % survival dose (D 50) by a factor of 1.4 compared with gamma-ray and neutron mixed beam (without BPA). Although it was found that (10)B uptake was higher in the Lig4+/+ p53-/- than in the Lig4-/- p53-/- cell line, the latter showed higher sensitivity than the former, even when compared at an equivalent (10)B concentration. These results indicate that BNCT-induced DNA damage is partially repaired using DNA ligase IV.

Detection of γH2AX foci in mouse normal brain and brain tumor after boron neutron capture therapy.

AIM: In this study, we investigated γH2AX foci as markers of DSBs in normal brain and brain tumor tissue in mouse after BNCT. BACKGROUND: Boron neutron capture therapy (BNCT) is a particle radiation therapy in combination of thermal neutron irradiation and boron compound that specifically accumulates in the tumor. (10)B captures neutrons and produces an alpha ((4)He) particle and a recoiled lithium nucleus ((7)Li). These particles have the characteristics of extremely high linear energy transfer (LET) radiation and therefore have marked biological effects. High LET radiation causes severe DNA damage, DNA DSBs. As the high LET radiation induces complex DNA double strand breaks (DSBs), large proportions of DSBs are considered to remain unrepaired in comparison with exposure to sparsely ionizing radiation. MATERIALS AND METHODS: We analyzed the number of γH2AX foci by immunohistochemistry 30 min or 24 h after neutron irradiation. RESULTS: In both normal brain and brain tumor, γH2AX foci induced by (10)B(n,α)(7)Li reaction remained 24 h after neutron beam irradiation. In contrast, γH2AX foci produced by γ-ray irradiation at contaminated dose in BNCT disappeared 24 h after irradiation in these tissues. CONCLUSION: DSBs produced by (10)B(n,α)(7)Li reaction are supposed to be too complex to repair for cells in normal brain and brain tumor tissue within 24 h. These DSBs would be more difficult to repair than those by γ-ray. Excellent anti-tumor effect of BNCT may result from these unrepaired DSBs induced by (10)B(n,α)(7)Li reaction.

Safety and effectiveness of stereotactic body radiotherapy for a clinically diagnosed primary stage I lung cancer without pathological confirmation.

BACKGROUND: Pathological diagnosis fails in some pulmonary tumors, although they may be highly suspected to be primary lung cancer. We studied the outcome of stereotactic body radiotherapy for a clinically diagnosed primary stage I lung cancer without pathological confirmation. METHODS: The current study included 37 patients (39 lesions) treated with stereotactic body radiotherapy who were clinically diagnosed with primary stage I lung cancer between August 1998 and April 2009 at our hospital. Pulmonary tumors were highly suspected to be malignant from physical and imaging examinations. Biopsies were performed for 62 % of patients, although malignancy was not pathologically confirmed. In the other 38 % of patients, a biopsy was not feasible. Median age of the patients was 77 years. Median tumor diameter was 20 mm. A total median dose of 48 Gy was prescribed to the isocenter in four fractions. Median follow-up period was 39 months. RESULTS: The 3-year overall survival, local control, and regional-distant control were 74.2, 94.0, and 68.6 %, respectively. In patients with tumors ≤20 mm, overall survival and regional-distant control were significantly higher than in patients with tumors >20 mm (p ≤ 0.001), whereas no significant difference was observed regarding local control. No grade 3-5 adverse events possibly, probably, or definitely related to the treatment were observed. CONCLUSIONS: Stereotactic body radiotherapy is safe and effective for a clinically diagnosed primary stage I lung cancer when pathological diagnosis is difficult even with repeat biopsies, or a biopsy is not feasible for reasons of the patient's health condition or wishes.

A phase II study of lapatinib for brain metastases in patients with HER2-overexpressing breast cancer following trastuzumab based systemic therapy and cranial radiotherapy: subset analysis of Japanese patients.

BACKGROUND: It is known that one third of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer (MBC) treated with trastuzumab will develop brain metastases. As the development of brain metastases is fatal, controlling its progression is clinically meaningful. However, effective therapy for MBC patients with brain metastasis after cranial radiation is limited. The international clinical study in which six Japanese patients participated indicated the antitumor activity of lapatinib against brain metastases of HER2-overexpressing breast cancer. METHODS: The efficacy, safety, and pharmacokinetics of lapatinib 750 mg given twice daily to Japanese HER2-overexpressing MBC patients with brain metastases were assessed as part of the international clinical study. RESULTS: Of six Japanese patients treated in this study, two patients had shown volumetric reduction >20 % in their central nervous system (CNS), one of whom had >50 % reduction. Three patients, including two of these patients, had shown >20 % volumetric reduction in non-CNS lesions. Frequently reported adverse events were diarrhea and rash, all of which were controllable. The AUC0-12 of lapatinib on day 28 was 1.74 times higher than that on day 1. CONCLUSION: These results suggest that lapatinib monotherapy 750 mg given twice daily can exert some efficacy and has potential as a clinically meaningful treatment option for Japanese HER2-overexpressing breast cancer patients with brain metastases after cranial radiation.

Recurrence patterns and progression-free survival after chemoradiotherapy with or without consolidation durvalumab for stage III non-small cell lung cancer.

Chemoradiotherapy followed by consolidation durvalumab (CCRT+D) improves survival in patients with stage III non-small-cell lung cancer (NSCLC). We compared recurrence patterns and survival in the CCRT+D and CCRT cohorts. We conducted a multicenter, retrospective study in Japan. Patients who received CCRT for stage III NSCLC were included in this study. Of 178 eligible patients, 136 were in the CCRT+D and 42 were in the CCRT cohorts. Locoregional recurrence (LR), LR plus distant metastases (DM), and DM were observed in 20.6%, 8.8%, 27.9% of the CCRT+D, and 26.2%, 16.7% and 33.3% of the CCRT cohorts, respectively. In-field recurrence was the most common LR pattern in both cohorts. Squamous cell carcinoma and PD-L1 expression < 1%, and female sex and EGFR mutations were significantly associated with an increased risk of LR and DM. In patients with any risk factors for LR, the incidence of LR was similar in the CCRT+D and CCRT (39.5% vs 45.5%). The 24 month progression-free survival (PFS) and overall survival (OS) were 40.3% and 69.4% in the CCRT+D and 24.7% and 61.0% in the CCRT cohorts, respectively. Poor performance status and no consolidation durvalumab were significantly associated with shorter PFS. There was a significant difference in PFS between the CCRT+D and CCRT in the propensity score-matched cohort (HR = 0.51, P = 0.005). In conclusion, consolidation durvalumab decreased both LR and DM, and significantly improved PFS. However, in-field recurrence was still a major problem, as well as DM.

First clinical pharmacokinetic dose-escalation study of sagopilone, a novel, fully synthetic epothilone, in Japanese patients with refractory solid tumors.

PURPOSE: Sagopilone has recently been identified and preferentially used for the treatment of taxane-resistant cancer. The purpose of this dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics (PK) of sagopilone in refractory solid tumors. METHODS: A total of 17 Japanese patients received sagopilone in this Phase I study. Sagopilone was given as a 30-min intravenous infusion once every 3 weeks (one course) with an initial dose of 12.4 mg/m(2) up to 22.0 mg/m(2) for a maximum of 6 courses. RESULTS: The maximum tolerated dose (MTD) was determined to be 16.5 mg/m(2). The major dose-limiting toxicity (DLT) was peripheral sensory neuropathy. The PK data demonstrated that sagopilone did not accumulate after repeated administration. Two patients had stable disease (SD) over a period of 12 weeks. CONCLUSIONS: Our study demonstrated clinically favorable safety, tolerability, and efficacy of sagopilone, which will help define the treatment of advanced tumors in more extensive clinical trials.

Psychological distress of the bereaved seeking medical counseling at a cancer center.

OBJECTIVE: The death of a loved one is one of the most stressful events in life and is related to the physical and psychological wellbeing of the bereaved. Some bereaved individuals seek medical counseling to alleviate their distress. However, no studies have focused on the bereaved who have lost a loved one to cancer and have asked for medical help at a cancer center as a result. The aim of this study was to investigate the distress of the bereaved who sought consultation, as basic information for considering support. METHODS: We conducted a survey of people consulting outpatient services for bereaved families between April 2007 and September 2009. Data were obtained from medical records at initial consultation and qualitatively analyzed by content analysis using all statements related to their distress. RESULTS: Their statements were classified into 11 categories, which were further classified into six themes. The main categories of bereavement-related distress were as follows: (i) regret; (ii) anger; (iii) memories; (iv) loneliness; (v) anxiety; and (vi) hopelessness. 'Regret' was frequently recognized in their distress and it includes some points related to the cancer trajectory. CONCLUSIONS: Psychological distresses of the bereaved who have lost a loved one and have asked for medical counseling are revealed. Their distresses are strongly related to the cancer trajectory of a family member. Some of these distresses are related to medical misunderstanding about the course of cancer. These findings might provide basic information for considering their appropriate treatment.

Hypomanic episode during recurrent gastric cancer treatment: report of a rare case and literature review.

S-1 plus cisplatin is the standard chemotherapy for recurrent gastric cancer. While depression and delirium are frequent in cancer patients, hypomania during chemotherapy is rare. We describe a rare case of hypomania during S-1 plus cisplatin treatment for recurrent gastric cancer. A 66-year-old woman, with no previous psychiatric disorder, received S-1 plus cisplatin for recurrent gastric cancer. She showed peculiar behavior. Physical examination, urine, blood and imaging findings were normal. There was no gastric cancer progression. During psychiatric consultation, she behaved inappropriately. However, she behaved normally while performing daily activities. She manifested a persistently elevated, expansive or irritable mood, clearly different from her usual non-depressed state, meeting hypomania diagnostic criteria. Her condition did not require chemotherapy discontinuation or additional medication. During the second and subsequent S-1 plus cisplatin cycles, symptoms were stable. Cancer patients often have adjustment disorders, depression and delirium, but rarely hypomania. Our patient showed no significant changes in blood biochemistry and brain and whole body imaging. While S-1 plus cisplatin-induced hypomania cannot be excluded, hypomanic symptoms did not improve during the chemotherapy rest period, nor was there deterioration during subsequent cycles, suggesting drug-induced mania to be unlikely. Possible onset mechanisms include manic defense phenomena, common with stressful life events. There are no reports of recurrent gastric cancer patients experiencing hypomania during S-1 or S-1 plus cisplatin therapy, i.e. our patient represents a rare course. Clinicians should recognize psychosis or mood disorders during gastric cancer treatment. Further accumulation of such rare cases might elucidate pathological mechanisms underlying hypomania in cancer patients.

Detailed dosimetric evaluation of intensity-modulated radiation therapy plans created for stage C prostate cancer based on a planning protocol.

BACKGROUND: Intensity-modulated radiation therapy (IMRT) has been employed as a precision radiation therapy with higher conformity to the target. Although clinical outcomes have been reported for many investigations, detailed treatment planning results have not been mentioned to date. The aim of this study was to evaluate the dose specifications of our IMRT treatment plans for locally advanced prostate cancer. METHODS: Seventy-seven clinically applied IMRT plans treated between September 2003 and December 2005, in which patients were irradiated with 78 Gy in the prone position, were retrospectively analyzed. Dosimetric data output from dose volume histograms were evaluated in detail. RESULTS: The mean dose ± standard deviation, homogeneity index, and conformity index to the planning target volume (PTV) were 78.3 ± 0.7 Gy (100.4 ± 0.9%), 13.7 ± 3.0, and 0.83 ± 0.04, respectively. For the clinical target volume, the mean dose was 80.3 ± 0.7 Gy (102.9 ± 0.9%).The V40, V60, and V70 Gy of the rectal wall were 58.3 ± 2.8, 29.6 ± 2.7, and 15.2 ± 3.0%, respectively. Planning difficulties were encountered in patients whose bowels were displaced downward, as constraints imposed by the bowel position altered the dose index of the PTV. In many cases, additional bowel optimization parameters were required to satisfy constraints for organs at risk. However, major deviation could be avoided by inverse planning with computer optimization. CONCLUSION: IMRT allowed the creation of acceptable and practical treatment plans for locally advanced prostate cancer. Reports regarding detailed dosimetric evaluations are mandatory for interpreting clinical outcomes in the future.

Sister Mary Joseph's Nodule From Renal Cell Carcinoma: A Case Report.

Sister Mary Joseph's nodules (SMJNs) are umbilical skin metastases of various abdominopelvic malignancies, and they rarely originate from renal cell carcinomas. Radiotherapy is typically used to treat the nodules as a palliative intention. We report a rare case of SMJN that originated from clear cell renal cell carcinoma, which was treated with external beam radiation therapy (EBRT) and interstitial brachytherapy (ISBT). A 74-year-old male patient with a history of left renal cell carcinoma developed an umbilical nodule which was diagnosed as SMJN. The patient underwent EBRT (30 Gy in 10 fractions) and ISBT (12 Gy in two fractions), leading the nodule to complete resolution. This case report might support that radiotherapy, including ISBT, is effective for the treatment of SMJN from renal cell carcinoma.

Delayed elimination of SN-38 in cancer patients with severe renal failure.

This prospective study is designed to examine the effects of severe renal failure on the pharmacokinetics of irinotecan. The pharmacokinetics of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide (SN-38G) in three cancer patients with severe renal failure [creatinine clearance (Ccr) ≤ 20 ml/min] who were undergoing dialysis and received 100 mg/m(2) irinotecan as monotherapy were prospectively compared with those in five cancer patients with normal renal function (Ccr ≥ 60 ml/min). To ensure that the subjects had similar genetic backgrounds of UDP-glucuronosyltransferase (UGT) 1A1, patients with UGT1A1*1/*1, *1/*6, or *1/*28 were enrolled. The estimated terminal elimination rate constant of SN-38 in patients undergoing dialysis was approximately one tenth of that in patients with normal renal function (P = 0.025). Approximately 50% of SN-38 was dialyzed with a 2.1-m(2) dialysis membrane, whereas 27% was dialyzed with a 1.5-m(2) membrane. Our results showed that the elimination of SN-38 was significantly delayed in patients with severe renal failure compared with patients with normal renal function. We demonstrated that SN-38 was partly dialyzed.

Psychiatric disorders in patients who lost family members to cancer and asked for medical help: descriptive analysis of outpatient services for bereaved families at Japanese cancer center hospital.

OBJECTIVE: There have been no previous studies about consultation of the bereaved who have lost a loved one to cancer and ask for medical help. The aim of this study was to investigate their basic characteristics and their psychiatric disorders. METHODS: A retrospective study using clinical and background data obtained over 30 months (from April 2007 to September 2009) was conducted at outpatient services for bereaved families at the Department of Psycho-Oncology at Saitama Medical University International Medical Center, Japan. RESULTS: During the period of investigation, 51 patients underwent consultation. The patients were frequently female (P < 0.0001) and the spouse of the deceased. Regarding the psychiatric diagnoses, major depression was the most common (39%), followed by adjustment disorders (28%). CONCLUSIONS: This study revealed basic characteristics and psychiatric disorders of the bereaved who asked for medical help. Most of the patients were women (86.3%) and 86.3% of them received a psychiatric diagnosis. This information is important for both physicians and psychologists since the bereaved who have lost a loved one to cancer often ask for medical help in clinical settings.

Phase I/II study of FOLFIRI in Japanese patients with advanced colorectal cancer.

OBJECTIVE: This phase I/II study determined the recommended dose of FOLFIRI (irinotecan, infusional 5-fluorouracil and leucovorin) for Japanese patients with advanced colorectal cancer, and evaluated safety at the recommended dose in patients without the UDP-glucuronosyltransferase 1A1*28 allele which caused reduced enzyme expression. METHODS: The phase I part assessed the maximum tolerated dose of FOLFIRI to determine the recommended doses of irinotecan and infusional 5-fluorouracil. The doses were escalated from 150 to 180 mg/m(2) (irinotecan) and 2000 to 2400 mg/m(2) (5-fluorouracil). UDP-glucuronosyltransferase 1A1*6 and *28, and pharmacokinetics of irinotecan were observationally examined. In the phase II part, patients without the UDP-glucuronosyltransferase 1A1*28 allele received FOLFIRI at the recommended dose to evaluate safety. RESULTS: Among 15 patients in the phase I part, dose-limiting toxicity (diarrhea) occurred in one patient who received 150 mg/m(2) irinotecan and 2400 mg/m(2) infusional 5-fluorouracil. The respective recommended doses were 180 and 2400 mg/m(2) for irinotecan and infusional 5-fluorouracil, without reaching the maximum tolerated dose. Twenty-five patients received FOLFIRI at the recommended doses. Grade 3 or 4 neutropenia occurred in 44%, and Grade 3 diarrhea in 4%. CONCLUSIONS: This phase I/II study demonstrates that the recommended doses of irinotecan and infusional 5-fluorouracil in FOLFIRI for Japanese patients with advanced colorectal cancer who do not possess the UDP-glucuronosyltransferase 1A1*28 allele are 180 and 2400 mg/m(2), respectively. Toxicities occurring at the recommended doses are manageable in these patients.

Drug-induced akathisia as a cause of distress in spouse caregivers of cancer patients.

OBJECTIVE: Family caregivers of cancer patients suffer from physical, psychological, and social distress and therefore are often referred to as second order patients. Akathisia is a common side effect of antipsychotics and antidepressants that causes great discomfort and even agitation and is often described by patients administered these drugs as the most distressing side effect of their treatment. Several studies of akathisia as a cause of distress in cancer patients have been reported. However, akathisia has not been reported as a cause of distress in family caregivers of cancer patients. METHOD/CASE REPORT: A 74-year-old spouse caregiver who was under treatment for major depressive disorder was not able to visit the hospital where her husband, a terminally ill cancer patient, was being treated. Initially, the spouse caregiver thought that she could not visit the hospital because of the symptoms of her depression and her grief about losing her husband. However, careful clinical examination revealed that she was suffering from akathisia in addition to her grief. RESULTS: Discontinuation of her sulpiride treatment resulted in the disappearance of her akathisia symptoms, and therefore she became able to visit the hospital and care for her terminally ill husband. SIGNIFICANCE OF RESULTS: Drug induced akathisia is a cause of distress in spouse caregivers taking certain drugs. It is important for clinicians to realize that family caregivers might suffer from not only socioeconomic, physical, and psychological problems but also side effects of medication.

Comparison of thoracic and abdominal deep inspiration breath holds in whole-breast irradiation for patients with left-sided breast cancer.

BACKGROUND: The deep inspiration breath hold (DIBH) technique is effective for heart dose reduction in patients with left-sided breast cancer. In deep breathing, some women breathe in thoracic respiration; and others, in abdominal respiration. This study evaluated differences in dose reduction in organs at risk (OAR) and reproducibilities of the target and OAR between thoracic DIBH (T-DIBH) and abdominal DIBH (A-DIBH). METHODS: Fourteen patients with left-sided breast cancer who had planned to receive whole-breast irradiation were included. Computed tomography (CT) was performed in free breathing (FB), T-DIBH, and A-DIBH, and the dosimetric indexes of the target and OAR for three treatment plans were compared. In T-DIBH and A-DIBH, two series CTs were taken in each breathing method and the displacements of the target and heart were calculated. RESULTS: The averaged mean heart doses (MHDs) were 1.5 Gy and 1.6 Gy in T-DIBH and A-DIBH, respectively, significantly lower than 2.7 Gy in FB (p < 0.001 for both breathing methods). Between T-DIBH and A-DIBH, no significant difference in MHD was found (p = 0.95); however, the percentage increase in lung volume positively moderately correlated with the reduction in MHD (R = 0.68). The three-dimensional target displacements were 2.3 mm in T-DIBH and 2.0 mm in A-DIBH (p = 0.64). The three-dimensional heart displacements were 1.7 mm in T-DIBH and 1.8 mm in A-DIBH (p = 0.85). CONCLUSION: The present study demonstrates that the MHD and reproducibility did not differ between T-DIBH and A-DIBH. However, the superior breathing method for increasing lung volume should be determined for each patient.

Incidence and Risk Factors of Symptomatic Radiation Pneumonitis in Non-Small-Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy and Consolidation Durvalumab.

INTRODUCTION: Data on the risk factors for symptomatic radiation pneumonitis (RP) in non-small-cell lung cancer (NSCLC) patients treated with concurrent chemoradiotherapy (CCRT) and consolidation durvalumab are limited; we aimed to investigate these risk factors. MATERIALS AND METHODS: This multicenter retrospective study, conducted at 15 institutions in Japan, included patients who were ≥20 years of age; who started definitive CCRT for NSCLC between July 1, 2018, and July 31, 2019; and who then received durvalumab. The primary endpoint was grade 2 or worse (grade 2+) RP. RESULTS: In the 146 patients analyzed, the median follow-up period was 16 months. A majority of the patients had stage III disease (86%), received radiation doses of 60 to 66 Gy equivalent in 2-Gy fractions (93%) and carboplatin and paclitaxel/nab-paclitaxel (77%), and underwent elective nodal irradiation (71%) and 3-dimensional conformal radiotherapy (75%). RP grade 2 was observed in 44 patients (30%); grade 3, in four patients (3%); grade 4, in one patient (1%); and grade 5, in one patient (1%). In the multivariable analysis, lung V20 was a significant risk factor, whereas age, sex, smoking history, irradiation technique, and chemotherapy regimen were not. The 12-month grade 2+ RP incidence was 34.4% (95% confidence interval [CI], 26.7%-42.1%); the values were 50.0% (95% CI, 34.7%-63.5%) and 27.1% (95% CI, 18.8%-36.2%) in those with lung V20 ≥ 26% and < 26%, respectively (P = .007). CONCLUSION: The incidence of grade 2+ RP was relatively high in this multicenter real-world study, and its risk increased remarkably at elevated lung V20. Our findings can aid in RP risk prediction and the safe radiotherapy treatment planning.

Impact of multileaf collimator width on intraprostatic dose painting plans for dominant intraprostatic lesion of prostate cancer.

The aim of this study was to investigate the impact of multileaf collimator width (MLC-W) on intraprostatic dose painting plans for prostate cancer.Prostate cancer maps based on the histopathological findings were superimposed onto simulation CT images. Clinical target volume (CTV) 1 was defined as the prostate and the base of the seminal vesicles, and CTV2 was defined as the dominant intraprostatic lesions. Planning target volume (PTV) 1 and PTV2 were delineated by adding 5 mm margins to CTV1 and CTV2, respectively. For each case, two dose painting plans were created to deliver 74 Gy to PTV1 and 84 Gy to PTV2 with dynamic multileaf collimator technique using two different MLCs: m3 (MLC-W: 3mm) and Millennium (5 mm). Plans were evaluated by comparing the conformation number (CN), a quantity that defines the degree of conformality.The CNs for plans using the m3 and Millennium were 0.68 and 0.67 for PTV1 and 0.59 and 0.58 for PTV2, respectively. The CNs tended to be higher for a thinner leaf width (p < 0.05).Dosimetric advantages associated with smaller leaves were observed. However, differences between 3 mm and 5 mm leaf width were relatively small, which suggested that 5 mm leaf width would be acceptable in dose painting plans for prostate cancer.

Diagnosis and treatment of akathisia in a cancer patient who cannot stand up or sit down, because of poor performance status: factors that make the diagnosis of akathisia difficult, and diagnosis clues.

OBJECTIVE: Akathisia is a common adverse effect of antipsychotics and, less commonly, antidepressants. Akathisia can cause great discomfort and is often described by the patient as a most distressing sensation; however, the condition is often underdiagnosed or misdiagnosed. In oncological settings, neuroleptics and antidepressants that induce akathisia are also administered. However, reports of akathisia in oncology settings are few and a case of akathisia in a bedridden patient has not been reported as far as we know. CASE REPORT: A 72-year-old man with esophageal cancer who could not sit down or stand up was administered 5 mg/day haloperidol to relieve agitation as a symptom of major depressive disorder. Three days after the administration of haloperidol, the agitation had become worse. Careful observation revealed that the patient sometimes showed slight rubbing movement of the lower extremities and slight twisting movements of the body, which were not observed before the administration of haloperidol. The patient moved his body and lower extremities to relieve restlessness, which had developed after the administration of haloperidol. Although symptoms were atypical, akathisia was suspected and discontinuation of haloperidol resolved the symptoms. RESULTS AND SIGNIFICANCE OF RESULTS: In patients with poor performance status, clues leading to the correct diagnosis of akathisia might be absent, which would not be the case in patients who were able to walk, stand up, or sit down. Careful observations of patients before and after the administration of drugs that may cause akathisia may be required to ensure correct diagnosis.

CYP2A6 and the plasma level of 5-chloro-2, 4-dihydroxypyridine are determinants of the pharmacokinetic variability of tegafur and 5-fluorouracil, respectively, in Japanese patients with cancer given S-1.

S-1 is an oral anticancer agent composed of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate. CDHP is added to prevent degradation of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase. CYP2A6 is involved in the biotransformation of FT to 5-FU. Thus, we prospectively analyzed the effects of the CYP2A6 genotype, plasma level of CDHP, and patient characteristics on the pharmacokinetic (PK) variability of FT and 5-FU. Fifty-four Japanese patients with metastatic or recurrent cancers who received S-1 were enrolled. The CYP2A6 polymorphisms (*4A, *7, and *9) with deficient or reduced activity were analyzed. All subjects were classified into three groups according to their CYP2A6 genotype: wild type (*1/*1), one-variant allele (*1/any), or two-variant alleles (combination other than *1). The PK of FT, 5-FU, and CDHP were measured on day 1 of treatment. Multivariate regression analysis revealed that oral clearance of FT was associated with the CYP2A6 genotype (analysis of variance [ANOVA], P = 0.000838). The oral clearance of FT seen in patients with the two-variant alleles was significantly lower than those in wild type and the one-variant allele (95% confidence intervals 0.75-2.41 and 0.41-1.82, respectively; Tukey-Kramer test). The area under the time-concentration curve (AUC) of 5-FU was significantly correlated with the AUC of CDHP (ANOVA, P = 0.00126). The AUC of 5-FU and CDHP were inversely correlated with creatinine clearance (ANOVA, P = 0.0164 and P = 0.000762, respectively). Although the CYP2A6 variants are the cause of the PK variability of FT, the AUC of CDHP affected by renal function is the key determinant of the variability in the PK of 5-FU.

Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for high-risk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208.

A randomized controlled trial was conducted to evaluate the efficacy of high-dose chemotherapy (HDC) as consolidation of the treatment of high-risk postoperative breast cancer. Patients under 56 years of age with stage I to IIIB breast cancer involving 10 or more axillary lymph nodes were eligible. The primary endpoint was relapse-free survival (RFS). Between May 1993 and March 1999, 97 patients were enrolled, and two patients became ineligible. The median age of the 97 patients was 46 years (range 27-55 years), and 72 (74%) were premenopausal. The median number of involved axillary nodes was 16 (range 10-49). All patients had undergone a radical mastectomy. Major characteristics were well balanced between the treatment arms. Forty-eight patients in the standard-dose (STD) arm received six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen. Forty-nine patients were assigned to undergo HDC with cyclophosphamide and thiotepa after six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen; however, 15 of these patients (31%) did not undergo HDC. HDC was well tolerated without any treatment-related mortality. At a median follow-up of 63 months, the 5-year RFS of 47 eligible patients in the STD arm and 48 eligible patients in the HDC arm was 37% and 52% on an intent-to-treat basis, respectively (P = 0.17). Five-year overall survival of all randomized patients was 62% for the STD arm and 63% for the HDC arm (P = 0.78). Although the prespecified values of the two arms were not so accurate as to allow detection of the observed difference, no advantage of HDC was observed in terms of RFS or overall survival.