Yoshihiro Takegawa

Therapy for oral squamous cell carcinoma by tegafur and streptococcal agent OK-432 in combination with radiotherapy: Association of the therapeutic effect with differentiation and apoptosis in the cancer cells

Twenty patients with oral squamous cell carcinoma having mainly stage II or III lesions without distant metastasis, were treated with tegafur and streptococcal agent, OK-432, in combination with radiotherapy. As a consequence, 16 cases among the treated 20 cases showed complete remission by this therapy alone. Especially, we have found that the squamous cell carcinoma arising in non-keratinizing oral epithelium rather than in keratinizing oral epithelium has better response to this therapy. Among the 16 cases with complete remission (CR) by the current therapy, 10 cases were histopathologically diagnosed as well-differentiated squamous cell carcinoma and six cases as moderately differentiated squamous cell carcinoma. When we examined immunohistochemically the expres-sion of various antigens such as proliferating cell nuclear antigen (PCNA), p53 and LeY or the presence of DNA fragmentation by nick-end labelling in the biopsy materials taken at the first visit to our clinic from 20 patients treated with the current therapy, the CR group showed a significantly increased LeY expres-sion level ( p< 0.05) and DNA fragmentation rate ( p< 0.05) as compared with the partial response (PR, n= 3) + no change (NC, n= 1) group. On the other hand, the CR group with respect to PCNA expression level was significantly decreased as compared with the PR + NC group ( p< 0.05). From these findings, it can be considered that the therapy for oral squamous cell carcinoma by UFT and OK-432 in combination with radiotherapy is very effective, which may be associated with differentiation or apoptosis in oral squamous carcinoma cells. In addition, we present the clinical findings and results of immunohistochemical staining for the biopsy materials obtained from four CR cases treated with the current therapeutic method.

Phase II randomized clinical trial of LC9018 concurrently used with radiation in the treatment of carcinoma of the uterine cervix. Its effect on tumor reduction and histology

The clinical efficacy of LC9018, a biological response modifier prepared from heat‐killed Lactobacillus casei YIT9018, used in combination with radiation was studied in a randomized controlled trial on 61 patients with carcinoma of the uterine cervix of Stage IIB or III. The combination therapy with LC9018 demonstrated a significant effect on tumor reduction, compared with radiation therapy alone, at the cumulative doses of 15‐Gy and 30‐Gy external irradiation (P < 0.05). Histologic study confirmed that LC9018 also enhanced the therapeutic effect of the irradiation. Moreover, LC9018 seemed to be useful in protecting the patients from leukopenia during radiotherapy. This study suggests that LC9018, when used in combination with radiotherapy, will be an effective adjuvant immunotherapeutic agent. More studies in a large series of patients will, however, be needed to establish its long‐term efficacy, safety, and effects on both prognosis and enhancing radiotherapy.

Chemoradiation Therapy for Cervical Cancer : Toxicity of Concurrent Weekly Cisplatin

PurposeTo retrospectively evaluate the toxicity of concurrent weekly cisplatin and radiation therapy (RT) for locally advanced cervical cancer.Materials and MethodsBetween April 2001 and December 2004, 21 consecutive previously untreated patients with locally advanced cervical cancer were treated with concurrent chemoradiation therapy (CCRT) at the Tokushima University Hospital. Clinical stages were II: 5, III: 15, IVA: 1. External beam radiation therapy (EBRT) was delivered with 10 MV X-rays, 2 Gy fraction per day; total dose to the whole pelvis was 50 Gy. Iridium-192 high-doserate (HDR) intracavitary radiation therapy was performed with 10–30 Gy (median, 24 Gy) targeted at point A. Concurrent chemotherapy consisted of cisplatin, administered weekly at a dose of 40 mg/m2 for patients who were younger than 65 years and 30 mg/m2 for those 65 years or over. A maximum single dose of cisplatin, up to 70 mg/body, was administered in 5 cycles during EBRT.ResultsA total of 86 cycles of cisplatin were administered to the 21 patients, with a median of 4 cycles (range, 2–5). Severe hematological toxicity occurred in 18 patients (86%), including grade 3 in 17 patients (81%) and grade 4 in one patient (4.8%). Moderate or severe gastrointestinal toxicity occurred in 11 patients (52%), including grade 2 in 10 patients (48%) and grade 3 in one patient (4.8%). The grades of hematological toxicity were significantly greater in the 40 mg/m2 group than in the 30 mg/m2 group. All of the patients who were administered 40 mg/m2 of cisplatin developed grade 3 or greater hematological toxicity, including one patient with grade 4 toxicity. In the 30 mg/m2 group, 3 of 10 patients developed less than grade 3 toxicity, and all patients completed radiation therapy without interruption.ConclusionThe incidence of severe acute hematological toxicity was significantly higher in this study than in previously reported randomized controlled trials (RCTs), especially in the group of 40 mg/m2 cisplatin. A dose of 30 mg/m2 of cisplatin was considered to be feasible in weekly cisplatin and radiation therapy.

Interferon activity and its characterization in the sera of patients with head and neck cancer

The interferon (IFN) assay of the sera from the 40 patients with head and neck cancer was performed by the plaque‐reduction assay with vesicular stomatitis virus in FL cells derived from human amniotic membrane. The patients mainly had Stage III or IV lesion without distant metastasis, and previously had not received any cancer therapy. All of the patients were histologically diagnosed as squamous cell carcinoma. When the serum IFN activity was characterized by acid treatment, significant increases of IFN‐α/β/γ (n = 24, P < 0.05) and acid‐labile IFN (n = 24, P < 0.001), and significant decrease of acid‐stable IFN (n = 24, P < 0.001) in the cancer patients of 50‐to‐79‐year age group were found, as compared with those in the normal controls of the same age group (n = 20). When IFN titers including various immunologic parameters of the patients and normal controls were simultaneously assayed prior to the beginning of the cancer therapy, the titers of IFN‐α/β/γ, acid‐stable IFN, and acid‐labile IFN were significantly correlated with some immunologic parameters such as natural killer (NK) activity, the absolute number of Tγ lymphocytes, the percentages of β‐ and γ‐globulin, and the amounts of IgA, IgG, IgM, and β2 microglobulin. To define further the nature of this IFN, both sera of the patients and normal donors of 50‐to‐79‐year age group were characterized by a neutralization assay with an antiserum to HuIFN‐α and HUIFN‐β. The IFN activity left when the testing sera were neutralized with these antisera was expressed as γ‐like IFN. The titers of γ‐like IFN in the sera of patients (n = 24, P < 0.0001) showed a highly significant increase as compared with the normal controls (n = 20). When the correlation between prognosis of the disease and titers of serum IFN were investigated by measuring γ‐like IFN and acid‐stable IFN in the sera of patients, all of nine patients with good prognosis after the cancer treatment showed significant decreased levels of γ‐like IFN (P < 0.01) and acid‐stable IFN (P < 0.05) as compared with those on the time before cancer therapy. On the other hand, titers of γ‐like IFN in the sera of six patients with recurrent disease showed a significant increase as compared with those on the IFN measurement before cancer therapy (P < 0.05). These findings led us to suggest that the serum IFN levels, especially γ‐like IFN activity, may be associated with a function of some loops of the immune system in the patients with head and neck cancer.

Effective bladder preservation strategy with low-dose radiation therapy and concurrent intrarrterial chemotherapy for muscle-invasive bladder cancer

PurposeThe aim of this study was to evaluate retrospectively the toxicity and response, bladder preservation, and survival of patients with muscle-invasive bladder cancer treated with multimodality therapy consisting of low-dose radiation therapy (RT) and concurrent intraarterial chemotherapy (IACT).Methods and materialsBetween November 1999 and July 2005, a total of 27 consecutive, previously untreated patients with muscle-invasive bladder cancer underwent transurethral bladder tumor resection followed by concurrent low-dose RT and IACT. Patients who achieved a complete response (CR) were followed up closely without further therapy, and patients who did not achieve a CR underwent further treatment.ResultsComplete response was achieved in 22 of 27 patients (81%). Of these 22 patients, 7 developed recurrences, and 3 died of their disease. In five patients who did not achieve CR, one died from bone metastases. The 3-year overall survival rate was 81%, with a median follow-up time of 27 months; and 22 of 27 patients (81%) with a preserved bladder were tumor-free at the last follow-up. Three patients (11%) developed grade 3 acute hematological toxicity.ConclusionMultimodality therapy consisting of low-dose RT and concurrent IACT for muscle-invasive bladder cancer can achieve survival rates similar to those in patients treated with radical cystectomy, with successful bladder preservation and minimal adverse effects.

Radiation Complications Following Breast Conserving Therapy.

BackgroundBreast conserving therapy is being established as a standard therapeutic procedure for early breast cancer in Japan. However, the indications of radiotherapy and a standardized therapeutic procedure have not been established yet. In this study, complications following radiotherapy were evaluated in patients who had previously undergone breast conserving therapy at Tokushima University Hospital.MethodsFrom October 1989 to March 1996, 60 women with stage I or II breast cancer underwent radiation therapy after breast conserving surgery, and all patients were followed-up for a median of 27 months. Radiation morbidity scoring of the breast and adjacent organs was performed using the toxity criteria of the Radiation Therapy Oncology Group (RTOG) and European Organization for Research and Treatment of Cancer (EORTC).ResultsOnly 1 patient developed local recurrence, and no distant metastasis or death was observed. The cause of recurrence in 1 case was considered to be due to extended intraductal component. Although transient dermal reaction was induced by irradiation of the breast, no side effects that may cause cosmetic problems were found. No serious radiation complications were found in the lungs, ribs, heart or other adjacent organs.ConclusionsThe adverse reactions caused by irradiation does not reduce the merit of combined use of radiation therapy in breast conserving therapy, and therefore, are not the hesitation factor in application of radiotherapy.