Shinroku Morita

Efficacy and Safety of Carbon Ion Radiotherapy in Bone and Soft Tissue Sarcomas

PURPOSE To evaluate the tolerance for and effectiveness of carbon ion radiotherapy in patients with unresectable bone and soft tissue sarcomas. PATIENTS AND METHODS We conducted a phase I/II dose escalation study of carbon ion radiotherapy. Fifty-seven patients with 64 sites of bone and soft tissue sarcomas not suited for resection received carbon ion radiotherapy. Tumors involved the spine or paraspinous soft tissues in 19 patients, pelvis in 32 patients, and extremities in six patients. The total dose ranged from 52.8 to 73.6 gray equivalent (GyE) and was administered in 16 fixed fractions over 4 weeks (3.3 to 4.6 GyE/fraction). The median tumor size was 559 cm(3) (range, 20 to 2,290 cm(3)). The minimum follow-up was 18 months. RESULTS Seven of 17 patients treated with the highest total dose of 73.6 GyE experienced Radiation Therapy Oncology Group grade 3 acute skin reactions. Dose escalation was then halted at this level. No other severe acute reactions (grade > 3) were observed in this series. The overall local control rates were 88% and 73% at 1 year and 3 years of follow-up, respectively. The median survival time was 31 months (range, 2 to 60 months), and the 1- and 3-year overall survival rates were 82% and 46%, respectively. CONCLUSION Carbon ion radiotherapy seems to be a safe and effective modality in the management of bone and soft tissue sarcomas not eligible for surgical resection, providing good local control and offering a survival advantage without unacceptable morbidity.

Carbon ion radiotherapy for stage I non-small cell lung cancer.

BACKGROUND AND PURPOSE Heavy ion radiotherapy is a promising modality because of its excellent dose localization and high biological effect on tumors. Using carbon beams, a dose escalation study was conducted for the treatment of stage I non-small cell lung cancer (NSCLC) to determine the optimal dose. MATERIALS AND METHODS The first stage phase I/II trial using 18 fractions over 6 weeks for 47 patients and the second one using nine fractions over 3 weeks for 34 patients were conducted by the dose escalation method from 59.4 to 95.4 Gray equivalents (GyE) in incremental steps of 10% and from 68.4 to 79.2 GyE in 5% increments, respectively. The local control and survival rates were obtained using the Kaplan-Meier method. RESULTS Radiation pneumonitis at grade III occurred in three of 81 patients, but they fully recovered. This was not a dose-limiting factor. The local control rates in the first and second trials were 64% and 84%, respectively. The total recurrence rate in both trials was 23.2%. The infield local recurrence in the first trial was significantly dependent on carbon dose. The doses greater than 86.4 GyE at 18 fractions and 72 GyE at nine fractions achieved a local control of 90% and 95%, respectively. The 5 year overall and cause-specific survivals in 81 patients were 42% and 60%, respectively. CONCLUSIONS With our dose escalation study, the optimum safety and efficacy dose of carbon beams was determined. Carbon beam therapy attained almost the same results as surgery for stage I NSCLC although this was a I/II study.

High-dose-rate remote afterloading intracavitary radiation therapy for cancer of the uterine cervix. A 20-year experience

Retrospective analysis was performed on 1022 patients with squamous cell carcinoma of the uterine cervix who were treated with high‐dose‐rate remote afterloading intracavitary irradiation at the National Institute of Radiological Sciences, Angawa, Chiba‐shi, Japan, from 1968 to 1982 in comparison with low‐dose‐rate intracavitary radiation therapy. The patient population consisted of 147 patients with Stage I disease, 256 patients with Stage II disease, 515 patients with Stage III disease, and 104 patients with Stage IV disease. Absolute 5‐year survival rates for Stages Ib, IIa, IIb, IIIb, IVa, and IVb disease were 88.1%, 76.9%, 67.0%, 52.2%, 24.1%, and 13.3%, respectively. The rates of severe complication of Grades 3 and 4 were 4.1% for the rectosigmoid colon, 1.2% for the bladder, and 1.1% for the small intestine. In the case of Stage I to II disease, the optimal dose from intracavitary sources was suggested to be 2900 cGy ± 200 cGy at point A, with 4 to 5 fractions of 600 to 700 cGy delivered over 4 to 5 weeks. These results suggested that high‐dose‐rate intracavitary radiation therapy provided clinical results comparable to those of a low‐dose‐rate technique.

Carbon beam therapy overcomes the radiation resistance of uterine cervical cancer originating from hypoxia.

Purpose: High linear energy transfer (LET) particles are believed to decrease tumor radiation resistance originating from hypoxia. However, no proof of this effect has been provided by clinical trials and related clinical research. Hence, we investigated the radiation biological aspects of high LET carbon beam therapy on cervical cancer. Experimental Design: This study involved 49 patients with stage IIIb bulky and stage IVa cervical cancer treated with high LET carbon beams between October 1995 and June 2000. Oxygen partial pressure (pO2) was measured by using a needle-type polarographic oxygen electrode. Results: The 4-year disease-free survival rates of patients with pO2 ≤ 20 mm Hg (hypoxic tumor) and pO2 > 20 mm Hg (oxygenated tumor) before treatment were 37% and 21%, respectively. The local control rates of hypoxic and oxygenated tumors before treatment were 58% and 54%, respectively. The disease-free survival rates of hypoxic and oxygenated tumors assessed by oxygen status at the 5th day of irradiation were 33% and 32%, respectively. The local control rates of hypoxic and oxygenated tumors at the 5th day were 60% and 58%, respectively. There was no significant prognostic difference between hypoxic and oxygenated tumors. Conclusion: The similar disease-free survival and local control rates between hypoxic and oxygenated tumors before and during treatment indicated that the role of the tumor oxygenation status was not so important in local control in carbon beam therapy. These results indicated that high LET carbon beam irradiation might reduce the radiation-resistant nature stemming from tumor hypoxia.

Correlation of cervical carcinoma c-erb B-2 oncogene with cell proliferation parameters in patients treated with radiation therapy for cervical carcinoma

Although c‐erb B‐2 oncoprotein expression (CerbB‐OPE) is believed to be associated with tumor cell proliferation and prognosis, the correlation between CerbB‐OPE and cell proliferation parameters has not been fully analyzed.

Dose-volume histogram analysis of high dose rate intracavitary brachytherapy for uterine cervix cancer.

PURPOSE We retrospectively analyzed the relationship between dose distribution and local control using a dose-volume histogram (DVH) in patients with cancer of the uterine cervix treated by definitive radiotherapy including intracavitary brachytherapy. METHODS AND MATERIALS Twenty-five patients with squamous cell carcinoma of the uterine cervix who underwent definitive radiotherapy between August 1987 and April 1994 were selected for the present study. They included 15 patients with local control and 10 patients with local recurrence. In principle, these patients were treated with 50 Gy of external beam pelvic radiotherapy and a point A dose of 24 Gy, in four fractions, of intracavitary brachytherapy. The DVHs of tumor volumes were calculated by superimposing three-dimensional (3D) dose distributions on computed tomography (CT) images taken before brachytherapy. RESULTS Differential DVHs revealed a tendency for the portion of the total tumor volume to which the delivered dose was low to be larger in patients with local recurrence. The tumor volumes and the absolute dose volumes of which the absorbed dose was less than 24 Gy [DV (< 24 Gy)] were significantly larger in patients with local recurrence than those in local control patients (p = 0.02 and 0.03, respectively). The percent DV (<24 Gy) was not significantly different in the two groups. In patients with larger tumor volume, the absolute DV (<24 Gy) was also larger and a strong linear correlation was noted between them. CONCLUSIONS The analysis of dose distribution of brachytherapy using DVH was useful to evaluate the quality of dose distribution quantitatively. The absolute dose volume was considered more important than the percent dose volume for evaluation of the clinical outcome. Our study suggested that unfavorable dose distribution for the tumor volume in brachytherapy was one of the reasons of poor local control in patients with large tumor volume.

Proton Therapy in Japan

There are two facilities for clinical trials with protons in Japan: the National Institute of Radiological Sciences (NIRS), Chiba, and the Particle Radiation Medical Science Center (PARMS), University of Tsukuba. At the National Institute of Radiological Sciences, patient treatment with the 70 MeV proton beam began in November 1979, and 29 patients were treated through December 1984. Of 11 patients who received protons only, 9 have had local control of the tumor. Two of the 9 patients, suffering from recurrent tumor after radical photon beam irradiation, developed complications after proton treatment. In the patients treated with photons or neutrons followed by proton boost, tumors were controlled in 12 of 18 patients (66.6%), and no complications were observed in this series. Malignant melanoma could not be controlled with the proton beam. A spot-beam-scanning system for protons has been effectively used in the clinical trials to minimize the dose to the normal tissues and to concentrate the dose in the target volume. At the Particle Radiation Medical Science Center, University of Tsukuba, treatment with a vertical 250 MeV proton beam was begun in April 1983, and 22 patients were treated through February 1984. Local control of the tumor was observed in 14 of 22 patients (63.6%), whereas there was no local control in the treatment of glioblastoma multiforme. There have been no severe complications in patients treated at PARMS. The results suggest that local control of tumors will be better with proton beams than with photon beams, whereas additional modalities are required to manage radioresistant tumors.

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.

Progesterone receptor is a favorable prognostic factor of radiation therapy for adenocarcinoma of the uterine cervix

PURPOSE The prognostic significance of the expression of estrogen receptors (ER) and progesterone receptors (PgR) in adenocarcinoma of the uterine cervix has been controversial. Hence, the relationship between the expression of the hormone receptors and clinical outcome was evaluated for patients with adenocarcinoma treated with radiation therapy alone. MATERIALS AND METHODS This study involved 66 patients with cervical adenocarcinoma consisting of 44 adenocarcinomas and 22 adeno-squamous cell carcinomas. They received radiation therapy at the National Institute of Radiological Sciences Hospital between 1962 and 1993. The mean age of the patients was 62. 0 +/- 12.0 years (range, 36-82 years). The numbers of patients with Stage I, II, III, and IV diseases were 7, 17, 27, and 15, respectively. Their ER and PgR statuses were investigated immunohistochemically using biopsy specimens excised from the cervical tumors before radiation therapy. RESULTS ER staining was positive in 12 patients (19%). ER status did not correlate with the 5-year cause-specific, local-control, and disease-free survivals. PgR staining was positive in 12 patients (19%). The disease-free survival rate of PgR-positive patients was significantly higher than that of PgR-negative patients (p = 0.044). Although PgR status did not reach statistical significance in relation to the 5-year cause-specific survival and local-control survival, the better survival was due to less local recurrence rather than to less distant metastasis. CONCLUSION The present study suggested that PgR status was associated with prognosis after radiation therapy for adenocarcinoma of the uterine cervix.

Radiation therapy alone for adenocarcinoma of the uterine cervix

PURPOSE Radiation therapy alone for adenocarcinoma of the cervix is currently evaluated by the accumulation of long-term results because of the low incidence of this disease. MATERIALS AND METHODS Fifty-eight patients with adenocarcinoma of the cervix treated with radiation therapy alone between 1961 and 1988 were studied. The radiation therapy consisted of a combination of intracavitary and external pelvis irradiation. Intracavitary treatment was performed with low dose rate and/or high dose rate sources. RESULTS The 5-year survival rates for Stages I, II, III, and IV were 85.7%, 66.7%, 32.3%, and 9.1%, respectively, and the 10-year survival rates were 85.7%, 60.0%, 27.6%, and 9.1%, respectively. The local control rate with high dose rate treatment was 45.5%, significantly lower than 85.7% and 72.7% with low and mixed dose rate treatments, respectively. Five-year survival and local control rates by tumor volume were 68.6% and 80.0% for small tumors, 63.6% and 66.0% for medium tumors, and 14.4% and 18.2% for large tumors, respectively. The survival rate and local control rate for large tumors were significantly lower than those for small and medium tumors. Multiple regression analysis indicated that stage and tumor volume were independent variables for survival and local control, respectively. Isoeffective dose expressed by time dose fractionation (TDF) was not associated with local control. Radiation complications developed in 10 patients (17.2%), most of which were of moderate degree. CONCLUSION Radiation therapy alone for adenocarcinoma of the cervix was regarded to be an effective treatment, comparable to combination therapy of surgery and radiation therapy.