HDAC1,2 inhibition and doxorubicin impair Mre11-dependent DNA repair and DISC to override BCR-ABL1-driven DSB repair in Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia.

Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL) expressing BCR-ABL1 oncoprotein is a major subclass of ALL with poor prognosis. BCR-ABL1-expressing leukemic cells are highly dependent on double-strand break (DSB) repair signals for their survival. Here we report that a first-in-class HDAC1,2 selective inhibitor and doxorubicin (a hyper-CVAD chemotherapy regimen component) impair DSB repair networks in Ph+ B-cell precursor ALL cells using common as well as distinct mechanisms. The HDAC1,2 inhibitor but not doxorubicin alters nucleosomal occupancy to impact chromatin structure, as revealed by MNase-Seq. Quantitative mass spectrometry of the chromatin proteome along with functional assays showed that the HDAC1,2 inhibitor and doxorubicin either alone or in combination impair the central hub of DNA repair, the Mre11-Rad51-DNA ligase 1 axis, involved in BCR-ABL1-specific DSB repair signaling in Ph+ B-cell precursor ALL cells. HDAC1,2 inhibitor and doxorubicin interfere with DISC (DNA damage-induced transcriptional silencing in cis)) or transcriptional silencing program in cis around DSB sites via chromatin remodeler-dependent and -independent mechanisms, respectively, to further impair DSB repair. HDAC1,2 inhibitor either alone or when combined with doxorubicin decreases leukemia burden in vivo in refractory Ph+ B-cell precursor ALL patient-derived xenograft mouse models. Overall, our novel mechanistic and preclinical studies together demonstrate that HDAC1,2 selective inhibition can overcome DSB repair 'addiction' and provide an effective therapeutic option for Ph+ B-cell precursor ALL.

Local Excision vs. Radical Resection in T1-2 Rectal Carcinoma: Results of a Study From the Surveillance, Epidemiology, and End Results (SEER) Registry Data.

BACKGROUND: Local excision (LE) has been used in an attempt to preserve anal function in T1-2 rectal carcinoma. The current study compares LE to radical resection (RR), each with or without radiation therapy (RT). METHODS: Patients reported to the SEER registry of the National Cancer Institute from 1988 to 2003 who had T1-2N0M0 rectal carcinoma were identified. A retrospective analysis of survival was performed using the Kaplan-Meier method. Comparative risks of mortality were evaluated using multivariate adjusted Cox regression models. RESULTS: Of 4,320 patients, 13% underwent LE alone, 7% underwent LE plus RT, 70% underwent RR alone, and 10% underwent RR plus RT. On multivariate analysis, patients who underwent LE without RT had inferior overall survival compared to patients who underwent RR (P < .05). Patients who underwent LE with or without RT had inferior cause-specific survival compared to patients who underwent RR (P < .05). CONCLUSIONS: RR without RT was associated with superior overall survival compared to LE without RT, and RR without RT was associated with superior cause-specific survival compared to LE with or without RT. Randomized trials are necessary to determine if LE with or without RT can offer equivalent survival compared to RR in early stage rectal carcinoma.

Linac radiosurgery for skull base meningiomas.

INTRODUCTION: Skull base meningiomas present a difficult surgical challenge because of the high potential morbidity of radical surgical extirpation and their low potential for incapacitating symptomatology. The focal character of meningiomas makes stereotactic radiosurgery an attractive adjuvant treatment modality to resection. The purpose of this study was to evaluate the local control rates and complications in 56 patients with base of skull meningiomas undergoing radiosurgery. METHODS: Patients underwent radiosurgery using the dedicated stereotactic linear accelerator at the Brigham and Women's Hospital. Minimal peripheral doses of radiosurgery ranged from 12 to 18.5 Gy (mean 15 Gy). Doses were designed to conform to the frequently irregular tumor volumes using the X-Knife treatment planning system. Multiple isocenters were used when required to increase conformality of dose. For 36 patients (64%), radiosurgery was used as an adjunct to surgery; for 20 patients (36%) it was the primary treatment. RESULTS: Median followup was five years. Nineteen patients (34%) were improved clinically at follow-up; 32 (57%) were unchanged; and 5 patients (9%) developed new or worsened neurologic deficits. Serial imaging studies after radiosurgery showed a reduction in tumor volume in 23 patients (41%); 30 (54%) showed stable disease; 3 patients (5%) had tumors which increased in size (2 being outside the radiosurgery treatment site). The actuarial freedom from progression rate (defined as further tumor growth) was thus 95%, with a median imaging follow-up of 26 months (range, 6-66 months). Although further follow-up is necessary, the results of this series clearly demonstrate that these lesions are feasible for treatment by modern radiosurgical techniques. Linac radiosurgery can stabilize skull base meningiomas, with decreased or unchanged tumor volumes on radiologic follow-up in approximately 95% of patients. Radiosurgery is a low-morbidity, effective technique as adjunct and sometimes primary treatment of small to moderate-sized meningiomas of the skull base.

Intensity-modulated radiosurgery/radiotherapy using a micromultileaf collimator.

Intensity modulation with inverse treatment planning for 3 clinical stereotactic radiotherapy cases were directly compared against forward planning techniques using beam modification by enhanced dynamic wedge. Dose-volume histogram (DVH) analysis demonstrated that a significant reduction in dose to neighboring critical structures can-be achieved through intensity modulation patterns determined from inverse planning, while a marginal change is achieved in the target volume dose uniformity. This study also demonstrates that the intensity modulated dose patterns generated from inverse planning may differ significantly from the intuitive beam modified patterns developed in the forward planning model. These results suggest that one advantage of intensity modulated radiosurgery/radiotherapy with inverse planning is the significant reduction in dose to normal tissue and critical structures, with its coincident implications for dose escalation studies.

A novel alternative approach for prediction of radiation response of squamous cell carcinoma of head and neck.

Accurate prediction of human tumor response to radiation therapy and concomitant chemoradiation would be an important tool to assist the physician in making recommendations for tumor treatment. Most of the studies that define the molecular markers for prediction of radiation response are based on the observation of gene expression using immunostaining, Northern blot, or Western blot analysis of a single or several genes. The results vary among different studies, and some results are contradictory. However, the studies agree that the change in expression of the tumor-related gene affects the radiation response. In this study, we explored a novel approach to predict the radiation response of human tumor using Atlas human cancer 1.2 cDNA array to analyze the expression profile of 1187 tumor-related genes in radiation-resistant and radiation-sensitive tissues. Sixty tumor-related genes were selected as predictors of radiation response of squamous cell carcinoma of the head and neck. Using the expression intensity of these 60 tumor-related genes, in combination with cluster analysis, we successfully predicted the radiation identity of two tumor samples.

Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: prognostic factors and long-term outcome.

OBJECT: To assess the value of stereotactic radiosurgery (SRS) as adjunct therapy in patients suffering from glioblastoma multiforme (GBM), the authors analyzed their experience with 78 patients. METHODS: Between June 1988 and January 1995, 78 patients underwent SRS as part of their initial treatment for GBM. All patients had undergone initial surgery or biopsy confirming the diagnosis of GBM and received conventional external beam radiotherapy. Stereotactic radiosurgery was performed using a dedicated 6-MV stereotactic linear accelerator. Thirteen patients were alive at the time of analysis with a median follow-up period of 40.8 months. The median length of actuarial survival for all patients was 19.9 months. Twelve- and 24-month survival rates were 88.5% and 35.9%, respectively. Patient age and Radiation Therapy Oncology Group (RTOG) class were significant prognostic indicators according to univariate analysis (p < 0.05). Twenty-three patients aged younger than 40 years had a median survival time of 48.6 months compared with 55 older patients who had 18.2 months (p < 0.001). Patients in this series fell into RTOG Classes III (27 patients), IV (29 patients), or V (22 patients). Class III patients had a median survival time of 29.5 months following diagnosis; this was significantly longer than median survival times for Classes IV and V, which were 19.2 and 18.2 months, respectively (p = 0.001). Only patient age (< 40 years) was a significant prognostic factor according to multivariate analysis. Acute complications were unusual and limited to exacerbation of existing symptoms. There were no new neuropathies secondary to SRS. Thirty-nine patients (50%) underwent reoperation for symptomatic necrosis or recurrent tumor. The rate of reoperation at 24 months following SRS was 54.8%. CONCLUSIONS: The addition of a radiosurgery boost appears to confer a survival advantage to selected patients.

Initial clinical results of LINAC-based stereotactic radiosurgery and stereotactic radiotherapy for pituitary adenomas.

PURPOSE: To retrospectively evaluate the initial clinical results of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) for pituitary adenomas with regard to tumor and hormonal control and adverse effects of the treatment. SUBJECTS AND METHODS: Forty-eight patients with pituitary adenoma who underwent SRS or SRT between September 1989 and September 1995 were analyzed. Of these, 18 received SRS and 30 received SRT. The median tumor volumes were 1.9 cm3 for SRS and 5.7 cm3 for SRT. Eleven of the SRS and 18 of the SRT patients were hormonally active at the time of the initial diagnosis. Four of the SRS and none of the SRT patients had a history of prior radiation therapy. Both SRS and SRT were performed using a dedicated stereotactic 6-MV linear accelerator (LINAC). The dose and normalization used for the SRS varied from 1000 cGy at 85% of the isodose line to 1500 cGy at 65% of the isodose line. For SRT patients, a total dose of 4500 cGy at 90% or 95% of the isodose line was delivered in 25 fractions of 180 cGy daily doses. RESULTS: Disease control-The three year tumor control rate was 91.1% (100% for SRS and 85.3% for SRT). Normalization of the hormonal abnormality was achieved in 47% of the 48 patients (33% for SRS and 54% for SRT). The average time required for normalization was 8.5 months for SRS and 18 months for SRT. Adverse effects-The 3-year rate of freedom from central nervous system adverse effects was 89.7% (72.2% for SRS and 100% for SRT). Three patients who received SRS for a tumor in the cavernous sinus developed a ring enhancement in the temporal lobe as shown by follow-up magnetic resonance imaging. Two of these cases were irreversible and were considered to be radiation necrosis. None of the 48 patients developed new neurocognitive or visual disorders attributable to the irradiation. The incidence of endocrinological adverse effects were similar in the two groups, resulting in 3-year rates of freedom from newly initiated hormonal replacement of 78.4% (77.1% for SRS and 79.9% for SRT). CONCLUSION: Considering the relatively high incidence of morbidity observed in the SRS group, we recommend SRT as the primary method of radiation therapy for pituitary tumors. When treating a lesion in the cavernous sinus with SRS, special attention should be paid to dose distribution in the adjacent brain parenchyma. Longer follow-up is necessary before drawing any conclusions about the advantages of these techniques over conventional external beam radiation therapy.

Dual-isotope single-photon emission computerized tomography scanning in patients with glioblastoma multiforme: association with patient survival and histopathological characteristics of tumor after high-dose radiotherapy.

OBJECT: The study was conducted to determine the association between dual-isotope single-photon emission computerized tomography (SPECT) scanning and histopathological findings of tumor recurrence and survival in patients treated with high-dose radiotherapy for glioblastoma multiforme. METHODS: Studies in which SPECT with 201Tl and 99mTc-hexamethypropyleneamine oxime (HMPAO) were used were performed 1 day before reoperation in 47 patients with glioblastoma multiforme who had previously been treated by surgery and high-dose radiotherapy. Maximum uptake of 201Tl in the lesion was expressed as a ratio to that in the contralateral scalp, and uptake of 99mTc-HMPAO was expressed as a ratio to that in the cerebellar cortex. Patients were stratified into groups based on the maximum radioisotope uptake values in their tumor beds. The significance of differences in patient gender, histological characteristics of tissue at reoperation, and SPECT uptake group with respect to 1-year survival was elucidated by using the chi-square statistic. Comparisons of patient ages and time to tumor recurrence as functions of 1-year survival were made using the t-test. Survival data at 1 year were presented according to the Kaplan-Meier method, and the significance of potential differences was evaluated using the log-rank method. The effects of different variables (tumor type, time to recurrence, and SPECT grouping) on long-term survival were evaluated using Cox proportional models that controlled for age and gender. All patients in Group I (201Tl ratio < 2 and 99mTc-HMPAO ratio < 0.5) showed radiation changes in their biopsy specimens: they had an 83.3% 1-year survival rate. Group II patients (201Tl ratio < 2 and 99mTc-HMPAO ratio of > or = 0.5 or 201Tl ratio between 2 and 3.5 regardless of 99mTc-HMPAO ratio) had predominantly infiltrating tumor (66.6%); they had a 29.2% 1-year survival rate. Almost all of the patients in Group III (201Tl ratio > 3.5 and 99mTc-HMPAO ratio > or = 0.5) had solid tumor (88.2%) and they had a 6.7% 1-year survival rate. Histological data were associated with 1-year survival (p < 0.01): however, SPECT grouping was more closely associated with 1-year survival (p < 0.001) and was the only variable significantly associated with long-term survival (p < 0.005). CONCLUSIONS: Dual-isotope SPECT data correlate with histopathological findings made at reoperation and with survival in patients with malignant gliomas after surgical and high-dose radiation therapy.

Results of linear accelerator-based radiosurgery for intracranial meningiomas.

OBJECTIVE: We report the outcomes of patients treated with linear accelerator-based radiosurgery for intracranial meningiomas at our institution. METHODS: We reviewed 127 patients with 155 meningiomas treated with stereotactic radiosurgery (SRS) at the study institutions between October 1988 and December 1995. RESULTS: There were 86 female and 41 male patients (median age, 61.5 yr; range, 19.9-87.9 yr). The median follow-up period was 31 months (range, 1.2-79.8 mo). The median tumor volume was 4.1 cc (range, 0.16-51.2 cc), and the median marginal dose was 15 Gy (range, 9-20 Gy). The tumor locations were as follows: convexity, 31 tumors; parasagittal/falcine, 39 tumors; cranial base, 82 tumors; and ventricular/pineal, 3 tumors. There were 106 benign, 26 atypical, and 18 malignant meningiomas and 5 cases of meningiomatosis. SRS was performed on 48 lesions as the initial treatment and on 107 lesions as adjunct therapy. Freedom from progression was observed in 107 patients (84.3%) at a median time of 22.9 months (range, 1.2-79.8 mo). Twenty patients (15.7%) had disease progression (16 marginal [12.6%] and 4 local [3.1%]) at a median time of 19.6 months (range, 4.1-69.3 mo); the median time for freedom from progression for the benign, atypical, and malignant meningiomas was 20.9, 24.4, and 13.9 months, respectively. Actuarial tumor control for the patients with benign meningiomas was 100, 92.9, 89.3, 89.3, and 89.3% at 1, 2, 3, 4, and 5 years, respectively. Six patients (4.7%) had permanent complications attributable to SRS (median time, 10.3 mo; range, 4.3-18.0 mo); 13 patients died as a result of causes related to the meningiomas (median, 17.5 mo; range, 4.3-37.3 mo). The 1-, 2-, 3-, 4-, and 5-year survival probability for the entire group of patients was 90.3, 82.6, 73.6, 70.5, and 68.2%, respectively; for patients with benign meningiomas, excluding death resulting from intercurrent disease, the survival probability was 97.6, 94.8, 91.0, 91.0, and 91.0%, respectively. The 1-, 2-, 3-, and 4-year survival probability for the patients with atypical and malignant meningiomas was 91.7, 83.3, 83.3, and 83.3% and 92.3, 64.6, 43.1, and 21.5%, respectively. CONCLUSION: Even though complications from SRS are expected more frequently with large tumors near critical structures, SRS is a safe and effective means of treating selected meningiomas.

Childhood optic chiasm gliomas: radiographic response following radiotherapy and long-term clinical outcome.

PURPOSE: In children with chiasmal gliomas, radiation therapy can arrest progressive visual and neurologic impairment. We examined the radiographic response and clinical outcomes after irradiation. METHODS AND MATERIALS: Forty-two children (median age at diagnosis, 6.6 years) with chiasmal gliomas were managed as follows: 11 asymptomatic patients with neurofibromatosis-1 (NF-1) were observed only; 2 patients, less than 3 years old, underwent surgery and chemotherapy to delay irradiation; and 29 patients with progressive disease received radiation with or without prior surgery or chemotherapy. Time to radiographic response, long-term tumor control and late sequelae were reviewed for the 29 irradiated patients. RESULTS: The probability of at least 50% radiographic response at 24 months after irradiation was 18.1% and increased to 38.2% by 48 months and 45.9% by 60 months. By actuarial analysis, the median time for such radiographic response was 62 months. For the 29 irradiated patients, the 10-year freedom from progression and overall survival rates were 100% and 89%, respectively (median follow-up for surviving patients, 108 months). Stabilization or improvement in vision occurred in 81% of 26 evaluable irradiated patients. CONCLUSIONS: Notable radiographic response may be observed years after irradiation. Radiation therapy provides excellent long-term tumor control and vision preservation or improvement in the majority of patients with progressive chiasmal gliomas.

Intracranial germinoma: the case for lower dose radiation therapy.

PURPOSE: To determine the optimal dose and treatment outcome of patients treated with radiation for intracranial germinoma. METHODS AND MATERIALS: Between 1975 and 1995, 40 patients with the diagnosis of intracranial germinoma were treated with radiation (RT) to the central nervous system. All patients received whole-brain (WB) RT (median dose: 32.4 Gy, range: 15-44.37 Gy) and a boost to the tumor volume (median total tumor volume dose: 52 Gy, range: 45-59.5 Gy). Thirty patients received RT to the spine (median dose: 26 Gy, range: 18.75-37.5 Gy). Four patients were treated with cisplatin-based chemotherapy and WB RT with a boost to the tumor volume (dose range: 51-54 Gy). A low-dose RT only group was defined as < or = 25.5 Gy to the WB (9 patients); < 50 Gy to the primary site (14 patients); and < 22 Gy to the spine (9 patients). Seventeen tumors were biopsy-proven germinoma, and 17 patients presented with multiple midline germinomas (MMG). Among 26 patients who had tumor markers measured, 27% had elevation of beta-human chorionic gonadotropin and by definition, no patient had an elevation of AFP. Twenty-four percent of 26 patients who had spine imaging or cerebral spinal fluid cytology had evidence of tumor seeding at diagnosis. The male to female ratio was 1.9:1. Median age at diagnosis was 14 years for male patients and 9.5 years for female patients (p = 0.02), (overall age ranges: 0.5-31 years). Median follow-up was 62 months (range: 3-226 months). Late effects of 29 patients with follow-up of > or = 20 months and adequate documentation in their medical records were analyzed. RESULTS: The 5-year actuarial rate of disease-free survival (DFS) and overall survival (OS) for biopsy-proven germinomas and presumed germinomas was 97%. No patient died of germinoma. There were no local failures regardless of the dose of RT, elevation of HCG tumor marker, or CSF dissemination at presentation. At presentation 22 patients had evidence of at least one endocrine abnormality. At follow-up there were no new patients diagnosed with an endocrine abnormality; however, 13 out of 22 patients had an increase in the number of endocrine deficiencies requiring hormone replacement. At presentation, 14 patients showed evidence of growth retardation. At follow-up there were no new cases of growth failure in the remaining patients. CONCLUSIONS: Germinomas are highly curable with RT alone. Lower doses of RT to the craniospinal axis without chemotherapy appear to produce equally effective DFS and OS as do higher doses of RT or combination chemotherapy and RT. Craniospinal RT may be indicated for patients with MMG or patients with evidence of spinal seeding. Long-term effects of growth retardation, and other endocrine deficiencies appear to be correlated with disease at presentation rather than solely with treatment.

Beam shaping for conformal fractionated stereotactic radiotherapy: a modeling study.

PURPOSE: The patient population treated with fractionated stereotactic radiotherapy (SRT) is significantly different than that treated with stereotactic radiosurgery (SRS). Generally, lesions treated with SRT are larger, less spherical, and located within critical regions of the central nervous system; hence, they offer new challenges to the treatment planner. Here a simple, cost effective, beam shaping system has been evaluated relative to both circular collimators and an ideal dynamically conforming system for effectiveness in providing conformal therapy for these lesions. METHODS AND MATERIALS: We have modeled a simple system for conformal arc therapy using four independent jaws. The jaw positions and collimator angle are changed between arcs but held fixed for the duration of each arc. Eleven previously treated SRT cases have been replanned using this system. The rectangular jaw plans were then compared to the original treatment plans which used circular collimators. The plans were evaluated with respect to tissue sparing at 100%, 80%, 50%, and 20% of the prescription dose. A plan was also done for each tumor in which the beam aperture was continuously conformed to the beams eye view projection of the tumor. This was used as an ideal standard for conformal therapy in the absence of fluence modulation. RESULTS: For tumors with a maximum extent of over 3.5 cm the rectangular jaw plans reduced the mean volume of healthy tissue involved at the prescription dose by 57% relative to the circular collimator plans. The ideal conformal plans offered no significant further improvement at the prescription dose. The relative advantage of the rectangular jaw plans decreased at lower isodoses so that at 20% of the prescription dose tissue involvement for the rectangular jaw plans was equivalent to that for the circular collimator plans. At these isodoses the ideal conformal plans gave substantially better tissue sparing. CONCLUSION: A simple and economical field shaping device has been shown to provide all of the beam shaping advantage of a hypothetical ideal dynamically conforming system at the prescription level. This system may be immediately implemented in the clinic. It offers a substantial advantage over the currently used circular collimators in the high dose region with equivalent performance in the low dose region.

Permanent low-activity iodine-125 implants for cerebral metastases.

Beginning in 1987, selected patients with metastatic brain tumors were treated with permanent implants of low-activity radioactive iodine-125(125I) seeds. These patients underwent craniotomy, gross total resection of the metastatic lesion, and placement of the seeds. In general, criteria for treatment included the presence of a recurrent tumor with a volume too large to permit radiosurgery, and a Karnofsky Performance Score of 70 or higher. Thirteen patients underwent 14 implant procedures; all received external whole-brain radiotherapy. Implant dose ranged from 43 Gy to 132 Gy, with a mean of 83 Gy. Survival after implantation ranged from 2 weeks to almost 9 years, with a median of 9 months. Clinical and radiographic local control was obtained in 9 patients. Two patients died of acute, postoperative complications within a month of implantation, so no information regarding tumor control is available for them. Late complications included a bone flap infection in one patient and a CSF leak in another; both were treated without further sequelae. These results demonstrate that permanent 125I implants can results in good survival and quality of life, and occasionally can yield long-term survival. Potentially, it is a cost-effective treatment in that a separate procedure for stereotactic implantation or radiosurgery is not needed, as is the case with the use of temporary high-activity seeds. The permanent implantation itself adds less than 10 minutes to the craniotomy, and the risk of symptomatic radiation necrosis is low. We recommend consideration of this procedure in patients harboring large, recurrent metastatic tumors that require further surgery.

Stereotactic radiosurgery and radiotherapy: new developments and new directions.

Stereotactic irradiation is a precise method for the delivery of focused radiation beams to small intracranial targets. Treatment can be administered in single or multiple fractions (radiosurgery or stereotactic radiotherapy, respectively). The technology has evolved rapidly because of advances in both hardware and software design. Clinical indications are unfolding through the prospective trial mechanism.

Fractionated stereotactic radiotherapy for the treatment of acoustic neuromas: preliminary results.

PURPOSE: To evaluate the efficacy and toxicity of fractionated, stereotactic radiotherapy (SRT) for acoustic neuromas. METHODS AND MATERIALS: Twelve patients with acoustic neuroma were treated with SRT between June 1992 and October 1994. Follow-up ranged from 16-44 months. Patient age ranged from 27-70 (median: 45). Eight patients were treated with primary SRT and four patients were treated after primary surgical intervention for recurrent [3] or persistent [1] disease. Tumor volumes were 1.2-18.4 cm3 (median: 10.1 cm3). Collimator sizes ranged from 30-50 mm (median: 37.5). Tumors received 1.8 Gy/day normalized to the 95% isodose line. Patients received a minimum prescribed dose of 54 Gy in 27-30 fractions over a 6-week period. RESULTS: After a median follow-up of 26.5 months, local control was obtained in 12 out of 12 lesions. Tumor regression was noted in three patients, and tumor stabilization was found in the remaining nine patients. No patient developed a new cranial nerve deficit. One patients developed worsening of preexisting Vth cranial neuropathy and another experienced a decrease in hearing. However, all nine patients with useful hearing prior to SRT maintained useful hearing at last follow-up. CONCLUSIONS: Stereotactic radiotherapy provided excellent local control without new cranial nerve deficits. These results must be viewed as tentative in nature because of the small number of patients and the short median follow-up period.

Radiosurgery for hemangioblastoma: results of a multiinstitutional experience.

PURPOSE: Between June 1988 and June 1994. 38 hemangioblastomas were treated with stereotactic radiosurgery (SR) at three SR centers to evaluate the efficacy and potential toxicity of this therapeutic modality as an adjuvant or alternative treatment to surgical resection. METHODS AND MATERIALS: SR was performed using either a 201-cobalt source unit or a dedicated SR linear accelerator. Of the 18 primary tumors treated, 16 had no prior history of surgical resection and were treated definitively with SR and two primary lesions were subtotally resected and subsequently treated with SR. Twenty lesions were treated with SR after prior surgical failure (17 tumors) or failure after prior surgery and conventional radiotherapy (three tumors). Eight patients were treated with SR for multifocal disease (total, 24 known tumors). SR tumor volumes measured 0.05 to 12 cc (median: 0.97 cc). Minimum tumor doses ranged from 12 to 20 Gy (median: 15.5 Gy). RESULTS: Median follow-up from the time of SR was 24.5 months (range: 6-77 months). The 2-year actuarial over-all survival was 88 +/- 15% (95% confidence interval). Two-year actuarial freedom from progression was 86 +/- 12% (95% confidence interval). The median tumor volume of the lesions that failed to be controlled by SR was 7.85 cc (range: 3.20-10.53 cc) compared to 0.67 cc (range: 0.05-12 cc) for controlled lesions (p - 0.0023). The lesions that failed to be controlled by SR received a median minimum tumor dose of 14 Gy (range: 13-17 Gy) compared to 16 Gy (range: 12-20 Gy) for controlled lesions (p = 0.0239). Seventy-eight percent of the surviving patients remained neurologically stable or clinically improved. There were no significant permanent complications directly attributable to SR. CONCLUSIONS: This report documents the largest experience in the literature of the use of SR in the treatment of hemangioblastoma. We conclude that SR: (a) controls the majority of primary and recurrent hemangioblastomas; (b) offers the ability to treat multiple lesions in a single treatment session, which is particularly important for patients with Von Hippel-Lindau Syndrome; and that (c) better control rates are associated with higher doses and smaller tumor volumes.

Advances in radiation therapy for brain tumors.

Despite important advances in surgery and chemotherapy, much of the recent progress that has been achieved in the treatment of brain tumors has resulted from developments in radiation therapy. This article reviews some of the recent advances in radiotherapeutic strategies being used in the treatment of brain tumors in adults. The overall management of each specific tumor type is discussed.

High-grade astrocytomas.

Despite intense research, progress in the treatment of patients with HGA has remained slow. New therapeutic strategies are emerging, however, based on technologic advances in surgery and radiotherapy, improved understanding of the molecular, cellular, and immunobiology of astrocytomas, and advances in gene therapy, It is likely that these new strategies will result in significant progress in the treatment of HGA in the next decade.

Radiation pneumonitis following combined modality therapy for lung cancer: analysis of prognostic factors.

PURPOSE: To identify factors associated with radiation pneumonitis (RP) resulting from combined modality therapy (CMT) for lung cancer. MATERIALS AND METHODS: Series published before 1994 that used CMT for the treatment of lung cancer and explicitly reported the incidence of RP are the basis for this analysis. Factors evaluated included the radiation dose per fraction (Fx), total radiation dose, fractionation scheme (split v continuous), type of chemotherapy and intended dose-intensity, overall treatment time, histology (small-cell lung cancer [SCLC] v non-small-cell lung cancer [NSCLC]), and treatment schedule (concurrent v induction, sequential, or alternating CMT). RESULTS: Twenty-four series, including 27 treatment groups and 1,911 assessable patients, met our criteria for inclusion in this analysis. The median total dose of radiation used in the trials analyzed was 50 Gy (range, 25 to 63 Gy). The median daily Fx used was 2.0 Gy (range, 1.5 to 4.0 Gy). Nineteen series included 22 treatment groups and 1,745 patients treated with single daily fractions. Among these patients, 136 received a daily Fx greater than 2.67 Gy. Five series used twice-daily radiotherapy and included 166 patients (Fx, 1.5 to 1.7 Gy). The incidence of RP was 7.8%. In a multivariate analysis, only daily Fx, number of daily fractions, and total dose were associated with the risk of RP (P < .0001, P < .018, and P < .003, respectively). CONCLUSION: In this analysis, the use of Fx greater than 2.67 Gy was the most significant factor associated with an increased risk of RP. High total dose also appears to be associated with an increased risk, but twice-daily irradiation seems to reduce the risk expected if the same total daily dose is given as a single fraction. High-Fx radiotherapy should be avoided in patients who receive CMT with curative intent.