Kwan H. Cho

Stereotactic radiosurgery for recurrent malignant gliomas.

PURPOSE To evaluate the role of stereotactic radiosurgery in the management of recurrent malignant gliomas. PATIENTS AND METHODS We treated 35 patients with large (median treatment volume, 28 cm3) recurrent tumors that had failed to respond to conventional treatment. Twenty-six patients (74%) had glioblastomas multiforme (GBM) and nine (26%) had anaplastic astrocytomas (AA). RESULTS The mean time from diagnosis to radiosurgery was 10 months (range, 1 to 36), from radiosurgery to death, 8.0 months (range, 1 to 23). Twenty-one GBM (81%) and six AA (67%) patients have died. The actuarial survival time for all patients was 21 months from diagnosis and 8 months from radiosurgery. Twenty-two of 26 patients (85%) died of local or marginal failure, three (12%) of noncontiguous failure, and one (4%) of CSF dissemination. Age (P = .0405) was associated with improved survival on multivariate analysis, and age (P = .0110) and Karnofsky performance status (KPS) (P = .0285) on univariate analysis. Histology, treatment volume, and treatment dose were not significant variables by univariate analysis. Seven patients required surgical resection for increasing mass effect a mean of 4.0 months after radiosurgery, for an actuarial reoperation rate of 31%. Surgery did not significantly influence survival. At surgery, four patients had recurrent tumor, two had radiation necrosis, and one had both tumor and necrosis. The actuarial necrosis rate was 14% and the pathologic findings could have been predicted by the integrated logistic formula for developing symptomatic brain injury. CONCLUSION Stereotactic radiosurgery appears to prolong survival for recurrent malignant gliomas and has a lower reoperative rate for symptomatic necrosis than does brachytherapy. Patterns of failure are similar for both of these techniques.

Single dose versus fractionated stereotactic radiotherapy for recurrent high-grade gliomas

PURPOSE To evaluate the efficacy of stereotactic radiotherapy (SRT) in patients with recurrent high-grade gliomas by comparing two different treatment regimens, single dose or fractionated radiotherapy. METHODS AND MATERIALS Between April 1991 and January 1998, 71 patients with recurrent high-grade gliomas were treated with SRT. Forty-six patients (65%) were treated with single dose radiosurgery (SRS) and 25 patients (35 %) with fractionated stereotactic radiotherapy (FSRT). For the SRS group, the median radiosurgical dose of 17 Gy was delivered to the median of 50% isodose surface (IDS) encompassing the target. For the FSRT group, the median dose of 37.5 Gy in 15 fractions was delivered to the median of 85% IDS. RESULTS Actuarial median survival time was 11 months for the SRS group and 12 months for the FSRT group (p = 0.3, log-rank test). Variables predicting longer survival were younger age (p = 0.006), lower grade (p = 0.0006), higher Karnofsky Performance Scale (KPS) (p = 0.0005), and smaller tumor volume (p = 0.02). Patients in the SRS group had more favorable prognostic factors, with median age of 48 years, KPS of 70, and tumor volume of 10 ml versus median age of 53 years, KPS of 60, and tumor volume of 25 ml in the FSRT group. Late complications developed in 14 patients in the SRS group and 2 patients in the FSRT group (p<0.05). CONCLUSION Given that FSRT patients had comparable survival to SRS patients, despite having poorer pretreatment prognostic factors and a lower risk of late complications, FSRT may be a better option for patients with larger tumors or tumors in eloquent structures. Since this is a nonrandomized study, further investigation is needed to confirm this and to determine an optimal dose/fractionation scheme.

Patient selection criteria for the treatment of brain metastases with stereotactic radiosurgery

In this study we evaluate prognostic factors that predict local-regional control and survival following stereotactic radiosurgery (SRS) in patients with brain metastasis and establish guidelines for patient selection. Our evaluation is based on 73 patients with brain metastasis treated with SRS at the University of Minnesota between March 1991 and November 1995. The ability of stereotactic radiosurgery to improve local control in patients with brain metastases is confirmed in our study in which only 6 of 62 patients failed locally after SRS, with an actuarial local progression-free survival of 80% at 2 years. Variables that predicted worse prognosis were larger tumor size (p=0.05) for local progression-free survival and multiplicity of metastasis (p=0.03) and infratentiorial location of metastases (p=0.006) for regional progression-free survival. Absence of extracranial disease, KPS ≥ 70, and single intracranial metastasis were significant predictors of longer survival. Patients who fulfill all three criteria will survive longer after SRS (MS=17.7 months) and will most likely benefit from the increase local control in the brain achieved by SRS. Survival in patients who do not meet any of these criteria is very poor (MS=1.5 months), and these patients are less likely to benefit from this treatment. Careful selection of patients for SRS is warranted.

Single dose versus fractionated stereotactic radiotherapy for meningiomas

OBJECTIVE To evaluate the safety and efficacy of stereotactic radiosurgery (SRS) compared to fractionated stereotactic radiation therapy (FSRT) for meningiomas treated over a seven year period. METHODS AND MATERIALS Of the 53 patients (15 male and 38 female) with 63 meningiomas, 35 were treated with SRS and the 18 patients with tumors adjacent to critical structures or with large tumors were treated with FSRT. The median doses for the SRS and the FSRT groups were 1400 cGy (500-4500 cGy) and 5400 cGy (4000-6000 cGy) respectively. Median target volumes for SRS and FSRT were 6.8 ml and 8.8 ml respectively. The median follow-up for the SRS and FSRT groups were 38 months (4.1-97 months) and 30.5 months (6.0-63 months) respectively. RESULTS The five-year tumor control probability (TC) for benign versus atypical meningiomas were 92.7% vs. 31% (P = .006). The three-year TC were 92.7% vs. 93.3% for SRS vs. FSRT groups respectively (P = .62). For benign meningiomas, the three-year TC were 92.9% vs. 92.3% for the SRS group (29 patients) vs. FSRT group (14 patients) respectively (P = .77). Two patients in the SRS group and one in the FSRT group developed late complications. CONCLUSION Preliminary data suggest that SRS is a safe and effective treatment for patients with benign meningiomas. Fractionated stereotactic radiation therapy with conventional fractionation appeared to be an effective and safe treatment alternative for patients not appropriate for SRS. A longer follow-up is required to determine the long-term efficacy and the toxicity of these treatment modalities.

Stereotactic Radiosurgery versus Fractionated Stereotactic Radiotherapy Boost for Patients with Glioblastoma Multiforme

The aim of this study is to evaluate the efficacy of stereotactic radiotherapy boost (SRB) in patients with glioblastoma multiforme (GBM) by comparing two different regimens, single dose or fractionated treatment. Between December 1994 and January 2000, 24 patients with GBM were treated with SRB in conjunction with external beam radiotherapy (EBRT). Fourteen patients (58%) were treated with stereotactic radiosurgery (SRS) and 10 patients (42%) with fractionated stereotactic radiotherapy (FSRT). Median interval between EBRT and SRS or FSRT was 1.4 months (range −0.4–3.9 months). Actuarial survival rates of the entire 24 patients at one and two years following SRB were 63% and 34% respectively, with median survival time of 16 months. Variables predicting survival were age, extent of surgery, re-operation and the RTOG (Radiation Therapy Oncology Group) classes based on recursive partitioning analysis (RPA). In comparison to historical controls, improved survival benefit after SRB was observed. The median survival times for the RTOG classes 4, 5, and 6 were 28.3, 10.3, and 6.0 months following EBRT+SRB, respectively. Expected values for these classes after EBRT are 11.1, 8.9, and 4.6 months, respectively. This improvement in survival was seen predominantly for the RTOG class 4. There was no difference in survival between SRS and FSRT treated groups. Late complications developed in 4 patients in the SRS group and 1 patients in the FSRT group. Our retrospective data suggest that SRB in conjunction with EBRT may improve survival in patients with GBM with median survival time of 16 months, when compared to historical controls of the RTOG data following EBRT. The addition of SRB appeared to improve the median survival most demonstrably in RTOG RPA class 4 patients. SRS and FSRT are equally effective with similar median survival, but potentially less late complications associated with FSRT. Since this is a nonrandomized study, further investigation is needed to confirm this and to determine an optimal dose/fractionation scheme.

Stereotactic radiosurgery in pediatric patients

Although stereotactic radiosurgery has been studied extensively in adults, the data demonstrating its efficacy in children is limited. Medical records were reviewed to identify the indications for and outcomes of patients treated with this modality. Linear accelerator-based radiosurgery was used to treat 11 recurrent brain tumors and one posterior fossa arteriovenous malformation over 3 years. The mean and median age of those treated was 10 and 8 years, respectively (range 1-20 years). Patients received 700 to 3,000 cGy delivered to the 50-90% isodose line in a single fraction. The mean and median follow-up was 15 and 17 months, respectively. Three of the four children with malignant disease died 6 to 9 months after treatment. One patient died of recurrence outside the treatment field. Another child died of complications related to radiation injury, and the third died of disease progression. All children with low-grade tumors remain alive without complications. Six of eight (75%) children exhibit substantial radiographic reductions in tumor size. The child with a vascular malformation has been followed for 26 months, without hemorrhage and with a radiographically proved decrease in size. Our series suggests that radiosurgery has limited usefulness in malignant disease. Therapeutic response is influenced by lesion size and/or location. Stereotactic radiosurgery appears to be effective in children with low-grade intracranial tumors or arteriovenous malformations. Further experience is required to establish the role and long term side effects of radiosurgery in pediatric patients.

LINAC-based stereotactic radiosurgery for treatment of trigeminal neuralgia

Trigeminal neuralgia (TN) is a disabling pain condition that has classically been treated using either surgical or medical techniques. Several researchers have shown that stereotactically delivered radiation can be an effective tool in the amelioration of this condition. For these studies, the Gamma Knife was used to deliver the radiation treatment. The target location was designated as the proximal nerve at the root entry zone, and doses greater than 70 Gy to the maximum point in a single fraction were found to be effective in controlling pain in 80% of the patients treated. LINAC‐based stereotactic radiosurgery has been notably absent from the treatment of TN, even though it has many similarities to Gamma Knife‐based stereotactic radiosurgery. The aim of this paper is to describe our LINAC‐based stereotactic technique for treatment of TN. We also compare treatment of TN using our technique to that using the Gamma Knife. We found that a LINAC‐based treatment of TN can be accomplished with accuracy comparable to treatments delivered using the Gamma Knife. The dose distributions are essentially equivalent for the two treatment approaches. The LINAC‐based system is easy to plan and offers the ability to reduce the involvement of sensitive structures from the treatment fields as well as the Gamma Knife system does. A disadvantage of the LINAC‐based system is the time involved for treatment. PACS number: 87.53.Tf 87.56.Da

Changes in Expression of Transferrin, Insulin-like Growth Factor 1, and Interleukin 4 Receptors after Irradiation of Cells of Primary Malignant Brain Tumor Cell Lines

Abstract Kim, K-U., Xiao, J., Ni, H-T., Cho, K. H., Spellman, S. R., Low, W. C. and Hall, W. A. Changes in Expression of Transferrin, Insulin-like Growth Factor 1, and Interleukin 4 Receptors after Irradiation of Cells of Primary Malignant Brain Tumor Cell Lines. Radiat. Res. 160, 224–231 (2003). Various immunotoxins have been developed for the treatment of cancer. The toxin is internalized by target cells through cell-surface receptors, and it is essential for these receptors to be expressed for the immunotoxin to have specific anti-tumor activity. Radiation therapy is one of the main treatment modalities for primary malignant brain tumors. The purpose of this study was to determine whether radiation influences the expression of cell-surface receptors. Cells of one human medulloblastoma (Daoy) and two glioblastoma (U373-MG and T98-G) cell lines were tested by exposing the cells to a single dose of 5 Gy γ rays. Expression of transferrin receptors, type-1 insulin-like growth factor receptors (IGF1R), and interleukin 4 receptors (IL4R) was measured by flow cytometry analysis on unirradiated cells and on cells 3 to 120 h after irradiation. In Daoy cells, the absolute expression index of transferrin receptors increased during the 24 h after irradiation with the greatest change of 26% above control at 9 h. The absolute expression index of IGF1R increased 26.5% above control at 12 h. The absolute expression index of IL4R decreased 9 h after irradiation. In U373-MG cells the absolute expression index of transferrin receptors increased during the 24 h after irradiation, and the greatest increase was 45% above control at 9 h. The absolute expression index of IGF1R increased during the 12 h after irradiation with a maximum increase of 33% above control at 6 h. The absolute expression index of IL4R decreased with time after irradiation. In T98-G cells, the absolute expression index of both transferrin receptors and IL4R decreased after irradiation. The results suggest that the expression of growth factor receptors on brain tumor cells may be influenced by radiation. The effect of ionizing radiation on receptor expression should be considered when administration of targeted toxin is combined with radiation. Similar studies with other growth factor receptors used in targeted toxin therapy are recommended.

Radiation dose response for supratentorial low-grade glioma--institutional experience and literature review.

PURPOSE To examine radiation dose response for low-grade glioma (LGG) based on our institutional experience and to review the literature on this topic. METHODS AND MATERIALS Sixty-seven patients with supratentorial low-grade nonpilocytic astrocytomas (n=36) or oligodendrogliomas (n=31) were treated with postoperative radiation therapy (RT). Twenty-seven patients (group A) received 5520 cGy; 24 patients (group B) received 5940 cGy; and 16 patients (group C) received 6375 cGy. The corresponding median follow-up was 60, 35 and 91 months, respectively. RESULTS The disease-specific survival (DSS) at 5 and 10 years were 90.2% and 56.2%, 67.6% and 47.3%, and 62.5% and 50% for groups A, B and C, respectively (P=0.40). Only a greater extent of surgical resection and absence of contrast enhancement predicted DSS on multivariate analyses. Patients receiving higher doses of RT had higher complication rates. CONCLUSION Our data confirmed the lack of radiation dose response for supratentorial LGG as demonstrated in the previous randomized trials. The radiation dose should not exceed 5520 cGy because dose escalation did not result in an improvement of DSS and it also increased the complication rates. Future research should focus on the eradication of radioresistant clones either by the improvement of surgical resection or the use of cytotoxic agents that can target on the radioresistant tumor cells.

Immunotoxin therapy for primary malignant brain tumors

Abstract The prognosis of malignant brain tumors is poor in spite of aggressive treatment. Immunotoxin therapy is a novel approach for the treatment of tumors. Targeted fusion toxins, chimeric protein consisting of the cytotoxic domain of the natural toxin and carrier ligands such as a growth factor or an antibody, have been introduced in the treatment of malignant central nervous system (CNS) tumors, with promising results. The toxin is internalized into the cytosol of the target cell via cell-surface receptors and it is essential for these receptors on the tumor cell to be highly expressed in order for the immunotoxin to have specific anti-tumor activity. Studies on expression of cell-surface receptor for immunotoxin targeting was performed on transferring (TR), insulin-like growth factor-1 (IGF-1R), and interleukin-4 (IL-4R) receptors of human glioblastoma (U373-MG and T98-G) and medulloblastoma (Daoy) cell lines, and the effect of irradiation on expressibility of these receptors was studied. Recombinant diphtheria toxin–murine interleukin-4 conjugate (DT 390 –mIL4) was developed and its cytotoxic efficacy against murine glioblastoma (SMA-560) and neuroblastoma (Neuro-2a and NB41-A3) cell lines was examined, and the combined effect with irradiation was tested. Receptors were expressed in all cases except IGF-1R on T98-G. After irradiation, TR expression was increased for Daoy, IGF-1R expression was increased on Daoy and U373-MG, and IL-4R expression was decreased on Daoy and U373-MG. DT 390 –mIL4 exhibited dose-dependent, specific cytotoxic effects on all cell lines tested with IC 50 (concentration of DT 390 –mIL4 that inhibit 50% of protein synthesis) value of 0.56×10 −9 M in SMA-560, 1.28×10 −9 M in Neuro-2a and 0.95×10 −10 M in NB41-A3. Cytotoxicity was additive when DT 390 –mIL4 at 10 −9 M was administered with irradiation. Targeted fusion toxins are characterized by great potency and high specificity with minimal damage to normal neuronal tissue, and interleukin-4 receptor is one of the proper targets for fusion toxin. The cytotoxicity of the immunotoxin is additive when it is administrated with irradiation. Targeted toxin therapy is a promising adjuvant treatment modality for the malignant brain tumors.