Seung Jae Huh

Interleukin 12 Gene Therapy of Cancer by Peritumoral Injection of Transduced Autologous Fibroblasts: Outcome of a Phase I Study

A phase I dose-escalation clinical trial of peritumoral injections of interleukin 12 (IL-12)-transduced autologous fibroblasts was performed in patients with disseminated cancer for whom effective treatment does not exist. The goals of this study were to assess the safety and toxicities as well as the efficacy, and ancillarily the immunomodulatory effects, of peritumoral IL-12 gene transfer. Primary dermal fibroblasts cultured from the patients were transduced with retroviral vector carrying human IL-12 genes (p35 and p40) as well as the neomycin phosphotransferase gene (TFG-hIL-12-Neo). Patients received four injections at intervals of 7 days. Nine patients were enrolled in this dose-escalation study, with secreted IL-12 doses ranging from 300 ng/24 hr for the first three patients to 1000, 3000, and 5000 ng/24 hr for two patients in each subsequent dosage level. Although a definite statement cannot be made, there appears to be perturbation of systemic immunity. Also, the locoregional effects mediated by tumor necrosis factor alpha (TNF-alpha) and CD8+ T cells were observed with tumor regression. Treatment-related adverse events were limited to mild to moderate pain at the injection site; clinically significant toxicities were not encountered. Transient but clear reductions of tumor sizes were observed at the injected sites in four of nine cases, and at noninjected distant sites in one melanoma patient. Hemorrhagic necrosis of tumors was observed in two melanoma patients. These data indicate that gene therapy by peritumoral injection of IL-12-producing autologous fibroblasts is feasible, and promising in patients with advanced cancer.

Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients

In patients with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer, treatment with trastuzumab has been shown to markedly improve the outcome. We investigated the role of trastuzumab on brain metastasis (BM) in HER2-positive breast cancer patients. From 1999 to 2006, 251 patients were treated with palliative chemotherapy for HER2-positive metastatic breast cancer at Samsung Medical Center. The medical records of these patients were analysed to study the effects of trastuzumab on BM prevalence and outcomes. Patients were grouped according to trastuzumab therapy: pre-T (no trastuzumab therapy) vs post-T (trastuzumab therapy). The development of BM between the two treatment groups was significantly different (37.8% for post-T vs 25.0% for pre-T, P=0.028). Patients who had received trastuzumab had longer times to BM compared with patients who were not treated with trastuzumab (median 15 months for post-T group vs 10 months for pre-T group, P=0.035). Time to death (TTD) from BM was significantly longer in the post-T group than in the pre-T group (median 14.9 vs 4.0 months, P=0.0005). Extracranial disease control at the time of BM, 12 months or more of progression-free survival of extracranial disease and treatment with lapatinib were independent prognostic factors for TTD from BM.

Effects of Supervised Exercise Therapy in Patients Receiving Radiotherapy for Breast Cancer

Purpose Postoperative radiotherapy for breast cancer has a number of associated complications. This study examined whether supervised moderate-intensity exercise could mitigate the complications that occur during radiotherapy. Patients and Methods Forty women were randomized before radiotherapy after various operations for breast cancer. Seventeen patients who were assigned to the exercise group performed supervised moderate-intensity exercise therapy for 50 min 3 times per week for 5 weeks. Twenty-three patients in the control group were asked to perform self-shoulder stretching exercise. The World Health Organization Quality of Life-BREF (WHOQOL-BREF), brief fatigue inventory (BFI), range of motion (ROM) of the shoulder, and pain score were assessed before and after radiotherapy. Results There were no significant differences noted at baseline between groups. In the exercise group, there was an increase in the WHOQOL-BREF and shoulder ROM and decrease in BFI and pain score after radiotherapy. On the other hand, patients in the control group showed decrease in the WHOQOL-BREF and shoulder ROM and increase in BFI and pain score after radiotherapy. There were statistically significant differences in the changes in the WHOQOL, BFI, shoulder ROM, and pain score between the groups. Conclusion Patients receiving radiotherapy for breast cancer may benefit in physical and psychological aspects from supervised moderate-intensity exercise therapy.

Film dosimetry for intensity modulated radiation therapy: Dosimetric evaluation

X-ray film has been used for the dosimetry of intensity modulated radiation therapy (IMRT). However, the over-response of the film to low-energy photons is a significant problem in photon beam dosimetry, especially in regions outside penumbra. In IMRT, the radiation field consists of multiple small fields and their outside-penumbra regions; thus, the film dosimetry, for it involves the source of over-response in its radiation field. In this study we aim to verify and possibly improve film dosimetry for IMRT. Two types of modulated beams were constructed by combining five to seven different static radiation fields using 6 MV x rays. For verifying film dosimetry, x-ray films and an ion chamber were used to measure dose profiles at various depths in a phantom. The film setups include both parallel and perpendicular arrangements against the beam incident direction. In addition, to reduce an over-response, we placed 0.01 in. (0.25 mm) thick lead filters on both sides of the film. Compared with ion-chamber measurement, measured dose profiles showed the film over-response at outside-penumbra and low-dose regions. The error increased with depths and approached 15% as a maximum for the field size of 15 cm x 15 cm at 10 cm depth. The use of filters reduced the error down to 3%. In this study we demonstrated that film dosimetry for IMRT involves sources of error due to its over-response to low-energy photons, with the error most transparent in the low-dose region. The use of filters could enhance the accuracy in film dosimetry for IMRT. In this regard, the use of an optimal filter condition is recommended.

Pelvic Bone Complications After Radiation Therapy of Uterine Cervical Cancer: Evaluation with MRI

OBJECTIVE The purpose of this study was to assess the prevalence and distribution of radiation-induced insufficiency fractures and to investigate other bony complications of the female pelvis associated with radiation therapy using MR images. MATERIALS AND METHODS Two radiologists retrospectively evaluated pelvic MR images of 510 patients (mean age, 54.7 years) who underwent pelvic irradiation for uterine cervical cancer for the presence and location of insufficiency fractures by consensus. We calculated the cumulative prevalence of pelvic insufficiency fractures on the basis of their results. In addition, we identified other associated bony complications of the female pelvis by reviewing the MR images. RESULTS Insufficiency fractures were diagnosed in 100 patients; the 5-year cumulative prevalence was 45.2%. An insufficiency fracture was diagnosed a median of 16.9 months after radiation therapy. The fracture sites were the sacrum body and alae, medial side of the iliac bone, the roof of the acetabulum, superior rami of the pubic bone, femoral heads, and L5 vertebra. Sixty-one patients (61%) developed multiple fractures, and among them, 40 (40%) had bilateral symmetric lesions of the sacral alae. Other complications associated with the radiation therapy, as determined by evaluation of the MR images, were osteolysis and avascular necrosis of the femoral head. CONCLUSION Radiation-induced pelvic insufficiency fractures are a frequent complication of radiation therapy for uterine cervical cancer. Osteolysis and avascular necrosis of the femoral head were also diagnosed using MRI after radiation therapy.

Fractionated stereotactic radiation therapy for extracranial head and neck tumors

BACKGROUND This study is to report the clinical experiences of fractionated stereotactic radiation therapy (FSRT) for extracranial head and neck tumors. METHODS AND MATERIALS Between the period of July 1995 and November 1998, 48 patients with extracranial head and neck tumors were given FSRT as a boost and sole modality. Individualized treatment planning was performed using XKnife-3 system with relocatable Gill-Thomas-Cosman frame. In 24 patients, FSRT was applied as a boost technique following the 2-dimensional conventional external radiation therapy (ERT); in 24 patients FSRT was the sole radiotherapy modality. The primary diseases in the boost group consisted of nasopharynx cancer (19), lacrimal gland adenoid cystic carcinoma (3), orbital lymphoma (1), and skull-base recurrence of maxillary sinus adenoid cystic carcinoma (1). The primary diseases in the sole modality group consisted of recurrent nasopharynx cancer (12), orbital pseudotumor (4), skull-base recurrence of maxillary sinus, submandibular gland, and hypopharynx cancers (3), orbital rhabdomyosarcoma (2), orbital lymphoma (1), orbital metastasis of neuroblastoma (1), and nasal cavity melanoma (1). The fractionation schedule was to give 5 treatments per one week and the fractional doses were 2.0-3 Gy depending on the treatment aim and the FSRT volume. The FSRT doses varied depending on the nature of the primary diseases. RESULTS The local tumor response in nasopharynx cancer patients was excellent compared to retrospective data without occurrence of unexpectedly severe complication. FSRT to other regions was well tolerated by the patients and resulted in good to excellent local tumor responses with no unacceptable side effects as expected by the authors. CONCLUSION Based on the current observations, FSRT is a very effective and safe modality in the treatment of extracranial head and neck tumors.

Radiotherapy of intracranial germinomas

Between 1980 and 1992, 32 patients with intracranial germinomas were treated with radiation. All patients were confirmed histopathologically prior to treatment. Of the 32 intracranial germinomas reviewed, 14 were located in the suprasellar region, 12 in the basal ganglia and thalamus, four in the pineal, and two in both the pineal and suprasellar regions. Three patients had subarachnoid seeding. Craniospinal irradiation was undertaken for 29 patients. The median dose of 54 Gy was delivered to the tumor bed, 36 Gy to the whole brain and 24 Gy to the spinal axis. Five and 10-year survival rates were 96.9 and 96.9%, respectively. Local control was achieved in all patients except one who died of persistent tumor after 2 months following radiotherapy. No intracranial recurrence or spinal metastasis were found. Tumor site did not relate to the prognosis. One patient developed severe intellectual deterioration, three patients had vertebral growth impairment. The present study confirms the excellent result with radiotherapy alone for patients with germinomas.

Patterns of failure in gastric carcinoma after D2 gastrectomy and chemoradiotherapy: a radiation oncologist's view

The risk of locoregional recurrence in resected gastric adenocarcinoma is high, but the benefit of adjuvant treatment remains controversial. In particular, after extended lymph node dissection, the role of radiotherapy is questionable. Since 1995, we started a clinical protocol of adjuvant chemoradiotherapy after D2 gastrectomy and analysed the patterns of failure for 291 patients. Adjuvant chemotherapy consisted of five cycles of fluorouracil and leucovorin, and concurrent radiotherapy was given with 4500 cGy from the second cycle of chemotherapy. With a median follow-up of 48 months, 114 patients (39%) showed any type of failure, and the local and regional failures were seen in 7% (20 out of 291) and 12% (35 out of 291), respectively. When the recurrent site was analysed with respect to the radiation field, in-field recurrence was 16% and represented 35% of all recurrences. Our results suggest that adjuvant chemoradiotherapy has a potential effect on reducing locoregional recurrence. Moreover, low locoregional recurrence rates could give a clue as to which subset of patients could be helped by radiotherapy after D2 gastrectomy. However, in order to draw a conclusion on the role of adjuvant radiotherapy, a randomised study is needed.

Evaluation of therapeutic response to concurrent chemoradiotherapy in patients with cervical cancer using diffusion-weighted MR imaging

To investigate the changes in apparent diffusion coefficients (ADCs) in cervical cancer patients receiving concurrent chemoradiotherapy (CCRT), and to assess the relationship between tumor ADCs or changes in tumor ADCs and final tumor responses to therapy.

Effect of customized small bowel displacement system in pelvic irradiation

PURPOSE Authors designed a customized small bowel displacement system (SBDS) to displace the small bowel out of the pelvic radiation fields and to minimize treatment related bowel morbidity. METHODS AND MATERIALS From August 1995 to May 1996, 55 consecutive patients who received pelvic radiation therapy with the SBDS were included in this study. The SBDS consists of a customized Styrofoam compression device that can displace the small bowel out of the radiation fields and an individualized immobilization abdominal board for easy daily setup of the patient in prone position. After opacifying the small bowel with barium, the patients were laid prone and posterior-anterior (PA) and lateral (LAT) simulation films were taken with and without the SBDS. The volume of the small bowel included in the radiation fields with and without the SBDS were compared. RESULTS Using the SBDS, the mean small bowel volume was reduced by 59% on PA and 51% on LAT films (p = 0.0001). In six patients (6 of 55, 11%), it was possible that no small bowel was included within the treatment fields. The mean upward displacement of the most caudal small bowel was 4.8 cm using the SBDS. Patients treated with the SBDS manifested a significantly lower incidence of diarrhea requiring medication (8 of 55, 15%) vs. those without the SBDS (24 of 39, 62%) (p < 0.05). CONCLUSION The SBDS is a novel method that can be used to displace the small bowel away from the treatment portal effectively and to reduce the radiation therapy morbidity. Compliance with setup is excellent.