Chang Ok Suh

Dose-response relationship in local radiotherapy for hepatocellular carcinoma.

PURPOSE Dose escalation using three-dimensional conformal radiotherapy (3D-CRT) is based on the hypothesis that increasing the dose can enhance tumor control. This study aimed to determine whether a dose-response relationship exists in local radiotherapy for primary hepatocellular carcinoma (HCC). METHODS AND MATERIALS One hundred fifty-eight patients were enrolled in the present study between January 1992 and March 2000. The exclusion criteria included the presence of an extrahepatic metastasis, liver cirrhosis of Child class C, tumors occupying more than two-thirds of the entire liver, and a performance status on the Eastern Cooperative Oncology Group scale of more than 3. Radiotherapy was given to the field, including the tumor, with generous margin using 6- or 10-MV X-rays. The mean radiation dose was 48.2 +/- 7.9 Gy in daily 1.8-Gy fractions. The tumor response was assessed based on diagnostic radiologic examinations, including a computed tomography scan, magnetic resonance imaging, and hepatic artery angiography 4-8 weeks after the completion of treatment. Liver toxicity and gastrointestinal complications were evaluated. RESULTS An objective response was observed in 106 of 158 (67.1%) patients. Statistical analysis revealed that the total dose was the most significant factor associated with the tumor response. The response rates in patients treated with doses <40 Gy, 40-50 Gy, and >50 Gy were 29.2%, 68.6%, and 77.1%, respectively. Survivals at 1 and 2 years after radiotherapy were 41.8% and 19.9%, respectively, with a median survival time of 10 months. The rate of liver toxicity according to the doses <40 Gy, 40-50 Gy, and >50 Gy was 4.2%, 5.9%, and 8.4%, respectively, and the rate of gastrointestinal complications was 4.2%, 9.9%, and 13.2%, respectively. CONCLUSIONS The present study showed the existence of a dose-response relationship in local radiotherapy for primary HCC. Only the radiation dose was a significant factor for predicting an objective response. The results of this study showed that 3D-CRT can theoretically be used for treating primary HCC.

Angiocentric Lymphoma of the Head and Neck: Patterns of Systemic Failure After Radiation Treatment

PURPOSE To investigate the patterns of systemic failure and the clinical outcome in patients with angiocentric lymphoma of the head and neck who were treated with radiation alone, and to discuss the optimal mode of treatment for these patients. PATIENTS AND METHODS We reviewed the records of 92 patients with stage I or II angiocentric lymphoma who were treated at Yonsei Cancer Center between 1976 and 1994. All patients were treated with involved-field irradiation. Radiation doses ranged from 40 to 60 Gy (median dose, 50.4 Gy). Treatment response, patterns of treatment failure including systemic failure, and clinical outcome after radiation treatment were analyzed. RESULTS The most frequently involved site was the nasal cavity, either alone or in conjunction with other sites. In 16 patients (17.4%), angiocentric lymphoma was accompanied by cervical lymphadenopathy. Disease was classified as stage I in 62 patients (67.4%) and stage II in 30 patients (32.6%). After completion of radiation treatment, 61 patients (66.3%) achieved a complete response and 16 (17.4%) a partial response. Half of the patients (50.0%) ultimately experienced local recurrence with or without other components of failure, whereas regional failure was relatively uncommon (10.9%). Systemic failure occurred in 25.0% of patients during follow-up. Six patients had histologic findings identical to those at the time of the original disease (group I), whereas four patients exhibited morphologic features of frank lymphomas (group II). The majority of patients with systemic relapse had the predilection sites for widespread extranodal involvement, such as the skin, brain, lung, gastrointestinal tract, or testes. In addition, seven patients died from various medical illnesses or immunologic disorders, including hemophagocytic syndrome and second primary cancers (group III). After a median follow-up of 56 months, the overall survival and disease-free survival rates for all patients were 40.1% and 37.8%, respectively. All patients except one with systemic failure died within 1 year. CONCLUSION Treatment with radiation alone had suboptimal results, partly because of the occurrence of a variety of systemic failure with diverse clinicopathologic features. Given the frequent occurrence of systemic failure after radiation treatment, we believe that the multimodality treatment approach containing more effective chemotherapeutic agents should be incorporated in the treatment of angiocentric lymphoma confined to the head and neck.

Synchronous Coexpression of Epidermal Growth Factor Receptor and Cyclooxygenase-2 in Carcinomas of the Uterine Cervix A Potential Predictor of Poor Survival

Purpose: To evaluate the potential of the new prognostic information gained by analyzing the coexpression of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) in cervical cancer patients. Experimental Design: Sixty-eight patients with International Federation of Gynecology and Obstetrics stage IIB squamous cell carcinoma of the uterine cervix, who underwent concurrent chemoradiotherapy between 1993 and 1996, were divided into the following four groups according to their immunoreactivities for EGFR and COX-2 in paraffin-embedded sections: (a) the EGFR-negative/COX-2-negative group (n = 11); (b) the EGFR-negative/COX-2-positive group (n = 8); (c) the EGFR-positive/COX-2-negative group (n = 27); and (d) the EGFR-positive/COX-2-positive group (n = 22). The clinical features, patterns of treatment failure, and survival data in the four groups were compared. Results: Positive immunoreactivity for EGFR and COX-2 was observed in 49 of 68 (72%) and 19 of 68 (28%), respectively. However, no strong correlation was found between the levels of EGFR and COX-2 immunopositivity (R2 = 0.05, P = 0.07). Patients in the EGFR-positive/COX-2-positive group had a higher likelihood of locoregional recurrence than those in the other three groups (P = 0.02). Of the patients in the four groups, patients positive for both oncoproteins were found to have the worst prognosis with an overall 5-year disease-free survival rate of 55% compared with 91% for the EGFR-negative/COX-2-negative patients, 88% for the EGFR-negative/COX-2-positive patients, and 69% for the EGFR-positive/COX-2-negative patients (P = 0.05, log-rank test). In addition, the synchronous coexpression of the EGFR and COX-2 oncoproteins was found to be an independent prognostic factor by univariate and multivariate analyses (relative risk = 4.0, P = 0.03). Conclusions: Given these observations, we conclude that the coexpression of EGFR and COX-2 immunoreactivity may be used as a potent molecular risk factor for predicting the poor survival of patients with the International Federation of Gynecology and Obstetrics stage IIB squamous cell carcinoma of the uterine cervix.

Local radiotherapy for unresectable hepatocellular carcinoma patients who failed with transcatheter arterial chemoembolization

PURPOSE The purpose of this study was to investigate the efficacy of local radiotherapy (RT) as a salvage treatment for unresectable hepatocellular carcinoma (HCC) patients who failed with transcatheter arterial chemoembolization (TACE). METHODS AND MATERIALS Patients with unresectable HCC who had been treated with and eventually failed with TACE were eligible. The judgment of TACE failure was based on incomplete tumor filling of lipiodol-adriamycin mixture on either angiography or computed tomography (CT) scan. From January 1993 to December 1997, 27 patients were entered into this study. They had UICC Stage III (17) or IVA (10) disease, with a mean tumor size of 7.2 +/- 2.9 cm. Local RT was done, with a mean tumor dose of 51.8 +/- 7.9 Gy, in daily 1.8-Gy fractions using a 10- or 6-MV linear accelerator. Survival was calculated from both the diagnosis and the start of RT using the Kaplan-Meier method. RESULTS An objective response was observed in 16 of 24 patients (66.7%) including 1 CR. Intrahepatic metastasis was noted outside the RT field in 10 patients (37.0%). Extrahepatic distant metastasis occurred in 4 patients. Survival rates at 1, 2, and 3 years were 85. 2%, 58.1%, and 33.2%, respectively, from the diagnosis and 55.9%, 35. 7%, and 21.4%, respectively, from the start of RT. The median survivals were 26 months from the diagnosis and 14 months from the start of RT. Acute toxicity involved alteration in liver function test (13 patients) and thrombocytopenia (2 patients). Subacute and chronic toxicity involved gastroduodenal ulcer (3 patients) and duodenitis (2 patients). There was no treatment-related death. CONCLUSION In unresectable HCC patients who failed with TACE, local RT induced a substantial tumor response of 66.7%, with a 3-year survival rate of 21.4% and a median survival time of 14 months. Toxicity was significant but manageable. Although we do not know if there is survival benefit through this treatment, local RT in these patients seems to be valuable as a salvage for TACE-failed HCC.

Local radiotherapy as a complement to incomplete transcatheter arterial chemoembolization in locally advanced hepatocellular carcinoma

Abstract: Purpose: In order to determine the effect of additional radiotherapy (RT) after an incomplete transcatheter arterial chemoembolization (TACE) in an unresectable hepatocellular carcinoma (HCC), the treatment results of patients receiving TACE plus RT were analyzed and compared with those treated with TACE alone.

Radiosensitivity Enhancement by Celecoxib, a Cyclooxygenase (COX)-2 Selective Inhibitor, via COX-2–Dependent Cell Cycle Regulation on Human Cancer Cells Expressing Differential COX-2 Levels

To characterize the radiation-enhancing effects on human cancer cells and underlying mechanisms of celecoxib, a cyclooxygenase (COX)-2 selective inhibitor, and to ascertain whether its effects are COX-2 dependent. Clonogenic cytotoxicity assays and radiation survival assays after treatment with celecoxib +/- radiation were done on four human cancer cell lines that expressed differential COX-2 levels. Stably COX-2 knocked down or overexpressed cell lines were developed, and clonogenic assays, apoptosis assays, or cell cycle change measurements were conducted after treatment with celecoxib +/- radiation. Prostaglandin E(2) (PGE2) was applied to medium after treatment with celecoxib +/- radiation to determine whether the radiation-enhancing effect associated with celecoxib results from reduced generation of prostaglandin. Celecoxibs radiation-enhancing effect was observed in COX-2-expressing A549 and NCI-H460 cells but was not observed in the COX-2 nonexpressing MCF-7 and HCT-116 cells. Celecoxibs radiation-enhancing effects in A549 cells were shown to disappear after the administration of COX-2 knocked down. In contrast, the HCT-116 cells were radiosensitized by celecoxib after being transfected with COX-2 expression vector. The addition of PGE2 after treatment with celecoxib +/- radiation had no significant effects on celecoxibs radiation-enhancing effects in A549 and COX-2 transfected HCT-116 cells. Radiation-induced G2-M arrest was enhanced and sustained in the COX-2-overexpressing cells compared with that seen in COX-2 low-expressing cells. Celecoxib or NS-398 effected no changes or attenuated radiation-induced G(2)-M arrest in the COX-2-overexpressing cells but further enhanced the radiation-induced G(2)-M arrest in the COX-2 low-expressing cells. Celecoxibs radiation-enhancing effects seem to occur in a COX-2 expression-dependent manner in the cancer cells. This effect does not seem to be the result of reduced PGE2 generation. Celecoxib may exert an inhibitory effect on enhanced radiation-induced G2-M arrest in the COX-2-overexpressing cells, which may allow the arrested cells to enter mitosis and die after radiation, but may also further enhance radiation-induced G2-M arrest in the COX-2 low-expressing cells, by virtue of another mechanism.

Clinical relevance of three subtypes of primary sinonasal lymphoma characterized by immunophenotypic analysis

The purpose of this study was to investigate the clinical relevance of subtypes categorized by immunophenotypic analysis in primary sinonasal lymphomas.

Combination of external beam irradiation and high-dose-rate intraluminal brachytherapy for inoperable carcinoma of the extrahepatic bile ducts

PURPOSE To assess the feasibility and therapeutic benefits of a combination of external beam radiotherapy (EBRT) and high-dose-rate intraluminal brachytherapy (ILBT) for treating patients with inoperable carcinoma of the extrahepatic bile ducts. METHODS AND MATERIALS Of 31 patients who received RT at the Yonsei Cancer Center, Yonsei University College of Medicine in Seoul, Korea between 1986 and 1995, 17 patients underwent EBRT alone (Group 1) and 14 patients were treated with EBRT in combination with high-dose-rate ILBT (Group 2). After external drainage, EBRT was delivered with a total dose ranging from 36 to 55 Gy (median 50.4) in both groups. High-dose-rate ILBT for the patients in Group 2 was performed using a high-intensity (192)Ir source (Gamma-med remote afterloading system) within the expandable intrabiliary prosthesis (Gianturco stent), inserted transhepatically at the site of the obstruction. The radiation dose of the high-dose-rate ILBT was prescribed at 1.5 cm from the center of the source with a single daily dose of 5 Gy to a total of 15 Gy given in three fractions. The response rate, patterns of treatment failure, treatment morbidity, and survival data in the two groups were compared. RESULTS Although locoregional recurrence was the most common pattern of failure in both groups, no statistically significant difference was found in the recurrence rates between those who did and did not receive ILBT (53% for Group 1 vs. 36% for Group 2; p > 0.05). However, a prolongation of the median time to tumor recurrence was observed in the Group 2 patients (5 months for Group 1 vs. 9 months for Group 2; p = 0.06). When the EBRT dose delivered was >50 Gy, most patients experienced various degrees of GI symptoms, but the frequency of radiation-induced complications in the two groups was similar. No enhancement in treatment morbidity was attributed to the addition of high-dose-rate ILBT to EBRT. With a median follow-up of 12 months, the overall actuarial 2-year survival rate for Group 2 patients was significantly better than that for Group 1 patients (0% for Group 1 vs. 21% for Group 2; p = 0.015). CONCLUSION Given these observations, we believe that the combined use of EBRT and high-dose-rate ILBT is a beneficial, relatively safe, and effective method of improving the treatment outcome in selected patients with inoperable carcinoma of the extrahepatic bile ducts.

Adenoid cystic carcinoma of the maxillary antrum

PURPOSE To investigate characteristic clinical features and outcome for patients with adenoid cystic carcinoma (ACC) of the maxillary antrum. PATIENTS AND METHODS Twenty-two patients with ACC of the maxillary antrum were initially treated with surgery alone (3 patients), radiation alone (9 patients), or a combination of surgery and radiation (10 patients). Salvage treatment for initial failure was individualized. Patterns of failure, survival, and prognostic factors were retrospectively analyzed. RESULTS The most frequent site of failure was local recurrence at the primary site (72.7%). All patients treated with either surgery alone or radiation alone experienced one or more local recurrences, whereas patients who received planned combined surgery and radiation had a much lower local recurrence rate (40%). Neck node failure (4.6%) was an uncommon event, whereas distant metastases were clinically documented in seven patients (32%). Most of the treatment failures appeared within 5 years, but treatment failures after 5 years were not uncommon. The overall survival and disease-free survival rates at 10 years were 37.6% and 13.6%, respectively. Clinicopathological factors, such as location of primary tumor, tumor stage, and histological grade were of no value in predicting a favorable survival. The significant prognostic factors influencing 10-year survival were the pathological finding of perineural invasion and the initial mode of treatment. CONCLUSION ACC of the maxillary antrum represented a unique natural history characterized by a more aggressive tumor behavior and an unfavorable prognosis. Combined surgery and radiotherapy is recommended for optimal local control and survival.

ADAPTIVE RESPONSE TO IONIZING RADIATION INDUCED BY LOW DOSES OF GAMMA RAYS IN HUMAN CELL LINES

PURPOSE The aim of this study was to investigate whether the adaptive response could be induced in human lymphoblastoid cell lines and human tumor cell lines. The time necessary for the expression of the adaptive response was also investigated. MATERIALS AND METHODS Three lymphoblastoid cell lines from ataxia telangiectasia (AT) homozygote (GM 1526), AT heterozygote (GM 3382), and normal individual (3402p) and two hepatoma cell lines, Hep G2 and Hep 3B, were used in this study. Experiments were carried out by delivering 0.01 Gy followed by 0.5 Gy of gamma radiation to the exponentially growing cells. The time necessary for the expression of the adaptive response was determined by varying the time interval between the two doses from 1 to 72 h. In some experiments, 3-aminobenzamide, a potent inhibitor of poly (ADP-ribose) polymerase, was added immediately after the 0.5 Gy exposure. The cultures were fixed 30 min (for the G2 chromatid) and 6 h (for the S chromatid) after the 0.5 Gy exposure. Metaphase chromosome assay was carried out to score chromatid breaks as an end point. RESULTS A prior exposure to 0.01 Gy of gamma rays significantly reduced the number of chromatid breaks induced by subsequent higher doses (0.5 Gy) in all the tested cell lines. The magnitude of the adaptive response was similar among the cell lines despite their different radiosensitivities. In the G2 chromatids, the adaptive response was observed both at short-time intervals, as early as 1 h, and at long-time intervals. In the S chromatids, however, the adaptive response was shown only at long-time intervals. When 3-aminobenzamide was added after the 0.5 Gy, the adaptive responses were abolished in all the experimental groups. CONCLUSION The adaptive response was observed in human lymphoblastoid cell lines and hepatoma cell lines. The magnitude of the adaptive response did not seem to be related to the radiosensitivity of the cells. The elimination of the adaptive response with 3-aminobenzamide is consistent with the proposal that this adaptive response is the result of the induction of a certain chromosomal repair mechanisms.