Conventional fractionated radiation therapy vs. radiosurgery for selected benign intracranial lesions (arteriovenous malformations,pituitary adenomas,and acoustic neuromas)

Despite growing interest in radiosurgery, the precise role of radiosurgery relative to that of conventional fractionated external-beam radiation therapy is not fully clear. A critical review of the available data suggests that radiosurgery is both a safe and effective treatment for small arteriovenous malformations, pituitary adenomas and acoustic neuromas. For arteriovenous malformations, the effectiveness of radiosurgery is clearly reduced as the size of the malformation increases. Conventional external-beam radiation therapy is also an effective treatment for pituitary adenomas and acoustic neuromas, while the results for arteriovenous malformations are less encouraging. However, most arteriovenous malformations that have been treated with fractionated radiation therapy were large and received relatively low doses of radiation. Onc can speculate that high doses (50 Gy) of fractionated radiation therapy may be effective in the treatment of small arteriovenous malformations. Differences in the apparent effectiveness of radiosurgery and conventional fractionated radiation therapy are partly due to patient selection. A single fraction of approximately 20 Gy (a dose frequently used during radiosurgery) is probably biologically equivalent to approximately 50 to 110 Gy of fractionated radiation therapy (at 2 Gy/fraction based on the linear quadratic model). In this regard, radiosurgery may be just a means of dose escalation. It remains to be shown that the possible benefit of radiosurgery could not be achieved by simply escalating the doses of fractionated radiation. Further clinical experience is needed to better define the role of radiosurgery. Randomized trials comparing conventional fractionated radiation vs. radiosurgery at approximately equal complication levels may be possible.     

The effect of embryonic and fetal exposure to x-ray, microwaves, and ultrasound: counseling the pregnant and nonpregnant patient about these risks

The term radiation evokes emotional responses both from lay persons and from professionals. Many spokespersons are unfamiliar with radiation biology or the quantitative nature of the risks. Frequently, microwave, ultrasound, and ionizing radiation risks are confused. Although it is impossible to prove no risk for any environmental hazard, it appears that exposure to microwave radiation below the maximal permissible levels present no measurable risk to the embryo. Ultrasound exposure from diagnostic ultrasonographic-imaging equipment also is quite innocuous. It is true that continued surveillance and research into potential risks of these low-level exposures should continue; however, at present ultrasound not only improves obstetric care, but also reduces the necessity of diagnostic x-ray procedures. In the field of ionizing radiation, we have a better comprehension of the biologic effects and the quantitative maximum risks than for any other environmental hazard. Although the animal and human data support the conclusion that no increases in the incidence of gross congenital malformations, IUGR, or abortion will occur with exposures less than 5 rad, that does not mean that there are definitely no risks to the embryo exposed to lower doses of radiation. Whether there exists a linear or exponential dose-response relationship or a threshold exposure for genetic, carcinogenic, cell-depleting, and life-shortening effects has not been determined. In establishing maximum permissible levels for the embryo at low exposures, refer to Tables 4, 5, 6, 8, and 9. It is obvious that the risks of 1-rad (.10Gy) or 5-rad (.05Gy) acute exposure are far below the spontaneous risks of the developing embryo because 15% of human embryos abort, 2.7% to 3.0% of human embryos have major malformations, 4% have intrauterine growth retardation, and 8% to 10% have early- or late-stage onset genetic disease. The maximal risk attributed to a 1-rad exposure, approximately 0.003%, is thousands of times smaller than the spontaneous risks of malformations, abortion, or genetic disease. Thus, the present maximal permissible occupational exposures of 0.5 rem for pregnant women (see Table 10) and 5 rem for medical exposure, are extremely conservative. Medically indicated diagnostic roentgenograms are appropriate for pregnant women, and there is no medical justification for terminating a pregnancy in women exposed to 5 rad or less because of a radiation exposure.(ABSTRACT TRUNCATED AT 400 WORDS)     

Vascular malformations of the thalamus with normal angiograms

We describe two patients with fatal vascular malformations of the thalamus whom we thought had gliomas. They had progressive neurological impairment with subacute onset as adults. Computed tomography showed lesions of increased density with slight post-contrast enhancement; cerebral angiography was normal. Without biopsy, they received radiation therapy without benefit. Two other patients with similar radiological studies have done well with conservative treatment. We believe that these lesions have a distinctive appearance on CT, that vascular malformations can be diagnosed, even with normal cerebral angiograms, and distinguished with reasonable certainty from gliomas.     

Fistula formation after postoperative radiation treatment for paranasal sinus cancer

Postoperative radiation is frequently used in the treatment paradigm for paranasal sinus tumors. The development of 3-dimensional conformal radiation treatment and intensity modulated radiotherapy (IMRT) has facilitated the delivery of high doses required for local control of these lesions while simultaneously decreasing toxicity. At Memorial Sloan-Kettering Cancer Center, a radiation dose of 70 Gy is routinely prescribed to gross tumor, and 59.4 Gy is prescribed to a clinical target volume at high risk for subclinical disease and 54 Gy is delivered to a clinical target volume at low risk for subclinical disease. Fistula formation can occur with the delivery of postoperative radiation treatment despite the use of IMRT. Prosthesis fabrication can be used in the short-term management of this unfortunate complication with an acceptable cosmetic result. Patients should be aware of this potential toxicity, which can develop in spite of appropriate management and acceptable dosimetry. Nonetheless, combined modality therapy is recommended for aggressive treatment of paranasal sinus tumors to inhibit local progression. This report describes the clinical scenario and management of the rare incidence of fistula formation after radiation for paranasal sinus malignancy.     

Conventional radiation therapy in the management of arteriovenous malformations of the central nervous system

Between 1967 and 1981, five patients were treated for vascular malformation of the central nervous system using conventional radiotherapy at Stanford University Medical Center. Two patients had arteriovenous malformations (AVM's) of the spinal cord, two patients had intracranial AVM's, and one patient had a hemangio-epithelioma of the occiput. All patients demonstrated clinical improvement after high dose radiation therapy with follow-up from 5 to 20 years. There have been no complications directly attributable to radiation therapy.     

The value of extended field radiation therapy in carcinoma of the prostate

Since 1970, a total of 342 patients have received radical radiation therapy for carcinoma of the prostate. The estimated 5 year survival of 78% and 5 year disease-free survival of 67% remains unchanged. Initially, all patients received radiation therapy to the prostate. Recently, patients with more advanced disease as well as a selected group of patients with less extensive disease received extended field radiation to the pelvis. comparison of these two groups of patients shows no advantage for extended field radiation in early stage disease. However, in more advanced disease [patients with involvement of more than one lobe or extraprostatic extension], there is evidence that extended field radiation improves the disease-free survival of these patients [63% for 5 year disease free for extended field radiation versus 35% for localized radiation]. This difference persists irrespective of method of diagnosis. While this study is non-randomized, the results were obtained during a period when there has been no other change in treatment philosophy. The results will require confirmation on a randomized trial basis.     

3D reconstruction of the encapsulating contour of arteriovenous malformations for radiosurgery using digital subtraction angiography

PURPOSE: Treatment planning for radiosurgery depends on the precise definition of radiation target volumes. For vascular pathologies such as arteriovenous malformations (AVM), the most usual technique remains standard X-ray projection imaging, most often carried out under stereotactic conditions. To further benefit from the advantages of two-dimensional digital subtraction angiography (DSA), the authors have developed a method for determining the three-dimensional shape of arteriovenous malformations from two views. METHODS AND MATERIALS: After correction of image intensifier distortion and calibration of both views, the 3D shape of the AVM was determined from two DSA projections using epipolarity geometry. The AVM-encapsulating contour was modeled by triangulation of a stack of almost parallel ellipses. The method was technically validated using artificial targets in a skull phantom. Clinical validation was carried out on 10 patients who were examined using both conventional angiography under stereotactic conditions (SX-ray) and DSA. RESULTS: There was excellent agreement between the artificial target volumes measured with SX-ray and with DSA. The correspondence between AVM volumes found for patients was not as good as with the phantom. CONCLUSIONS: The different image characteristics of the two modalities lead to some differences in AVM estimations. However, the results were sufficiently satisfactory to justify routine use of this AVM modeling technique for radiosurgery planning.     

Pregnancy outcome after treatment for Wilms tumor: a report from the National Wilms Tumor Study Group.

PURPOSE: This study was undertaken to determine the effect, if any, of prior treatment with radiation therapy or chemotherapy for Wilms tumor diagnosed during childhood or adolescence on live births, birthweight, and the frequency of congenital malformations. PATIENTS AND METHODS: We reviewed pregnancy outcomes among survivors of Wilms tumor treated with or without irradiation to the flank or tumor bed on National Wilms Tumor Studies 1, 2, 3, and 4 using a maternal questionnaire and review of both maternal and offspring medical records. RESULTS: We received reports regarding 427 pregnancies with duration of 20 weeks or longer, including 409 liveborn singletons for whom 309 sets of medical records were reviewed. Malposition of the fetus and early or threatened labor were more frequent among irradiated women. Both were more frequent among women who received higher radiation therapy doses. The offspring of the irradiated female patients were more likely to weigh less than 2,500 g at birth and to be of less than 36 weeks gestation, with both being more frequent after higher doses of radiation. An increased percentage of offspring of irradiated females had one or more congenital malformations. CONCLUSION: Women who receive flank radiation therapy as part of their treatment for Wilms tumor are at increased risk of fetal malposition and premature labor. The offspring of these women are at risk for low birthweight, premature (< 36 weeks gestation) birth, and the occurrence of congenital malformations. These risks must be considered in the obstetrical management of female survivors of Wilms tumor.     

Radiosurgery for Intracranial Malignancies

Radiosurgery was historically designed as a technology to be used for the treatment of functional disorders, benign tumors, and vascular malformations. In the last 5 years, malignant lesions have become an increasingly common target for the radiosurgeon. In fact, by 1994 the most common disease treated with radiosurgery in the United States was metastatic disease. Published data suggest that radiosurgery offers excellent local control for intracranial metastatic lesions regardless of location or histology with the majority of patients demonstrating an improved quality of life. Recent information from the Joint Center for Radiation Therapy suggests that radiosurgery compares favorably with interstitial brachytherapy for both recurrent as well as in newly diagnosed patients with malignant gliomas in terms of improved survival and the need of surgery and steroid support for symptomatic radiation changes. Prospective studies (Phase I through III) are ongoing to determine the ultimate role of radiosurgery in the management of patients with newly diagnosed and recurrent malignant gliomas, recurrent pediatric brain tumors disease, and patients with single or multiple intracranial metastases.     

The occurrence and management of esophageal fistulas resulting from Hodgkin's disease.

At their radiation therapy (RT) department, the authors saw a young woman with an esophageal fistula from Hodgkin's disease that was not responsive to chemotherapy; this prompted a review of the literature concerning such patients. Twenty-two patients with Hodgkin's disease and esophageal fistula were found to have been reported previously. Most patients had active disease at the fistula site, and most who were treated with RT or chemotherapy had prompt fistula closure. Fistula formation as a complication of RT for Hodgkin's disease was found to be an extremely unusual occurrence.     

Vaccinia-related kinase 1 (VRK1) confers resistance to DNA-damaging agents in human breast cancer by affecting DNA damage response

Vaccinia-related kinase 1 (VRK1) belongs to a group of sixteen kinases associated to a poorer prognosis in human breast carcinomas, particularly in estrogen receptor positive cases based on gene expression arrays. In this work we have studied the potential molecular mechanism by which the VRK1 protein can contribute to a poorer prognosis in this disease. For this aim it was first analyzed by immunohistochemistry the VRK1 protein level in normal breast and in one hundred and thirty six cases of human breast cancer. The effect of VRK1 to protect against DNA damage was determined by studying the effect of its knockdown on the formation of DNA repair foci assembled on 53BP1 in response to treatment with ionizing radiation or doxorubicin in two breast cancer cell lines. VRK1 protein was detected in normal breast and in breast carcinomas at high levels in ER and PR positive tumors. VRK1 protein level was significantly lower in ERBB2 positive cases. Next, to identify a mechanism that can link VRK1 to poorer prognosis, VRK1 was knocked-down in two breast cancer cell lines that were treated with ionizing radiation or doxorubicin, both inducing DNA damage. Loss of VRK1 resulted in reduced formation of DNA-damage repair foci complexes assembled on the 53BP1 scaffold protein, and this effect was independent of damaging agent or cell type. This observation is consistent with detection of high VRK1 protein levels in ER and PR positive breast cancers. We conclude that VRK1 can contribute to make these tumors more resistant to DNA damage-based therapies, such as ionizing radiation or doxorubicin, which is consistent with its association to a poor prognosis in ER positive breast cancer. VRK1 is potential target kinase for development of new specific inhibitors which can facilitate sensitization to other treatments in combination therapies; or alternatively be used as a new cancer drugs.     

Clinical uses of radiosurgery

Radiosurgery uses stereotactic targeting methods to precisely deliver highly focused, large doses of radiation to small intracranial tumors and arteriovenous malformations (AVMs). This article reviews the most common clinical applications of radiosurgery and the clinical results reported from a number of series using either a cobalt-60 gamma knife or linear accelerator as radiation sources. Radiosurgery is used to treat malignant tumors, such as selected cases of brain metastases and malignant gliomas (for which stereotactic radiosurgical boosts are utilized in conjunction with fractionated radiation therapy), as well as benign tumors, such as meningiomas, acoustic neuromas, and pituitary adenomas. Treatment of small AVMs is also highly effective. Although radiosurgery has the potential to produce complications, the majority of patients experience clinical improvement with less morbidity than occurs with surgical resection.     

A prospective study of whether radiation pneumonitis is influenced by low-dose irradiated lung volume in primary lung cancer with chronic pulmonary disease

The current study prospectively investigated the optimal dose-volume condition in cases of lung cancer with chronic pulmonary disease compared to those without chronic pulmonary disease. Cases of primary lung cancer treated with intended curative radiation therapy were registered in the current study. Their fraction size was limited to 2-3 Gy, so-called standard fractionation. They were prescribed a total dose of 60 Gy for non-small cell lung cancer (NSCLC; n=17) and a total dose of 54 Gy for small cell lung cancer (SCLC; n=4). Of the 21 patients enrolled in this study, 4 had chronic pulmonary disease (study arm), and the others had no chronic pulmonary disease (control arm). Seven received chemotherapy. Symptomatic radiation pneumonitis occurred in 5. Of the four patients in the study arm, two (50%) experienced symptomatic radiation pneumonitis; only 3 of the 17 patients in the control arm (17.6%) experienced symptomatic radiation pneumonitis. Furthermore, the median V(20) of patients who experienced symptomatic radiation pneumonitis in the study arm was 14%, which was higher than that of patients with no symptomatic radiation pneumonitis in the study arm, 5.8%. On the other hand, in the control arm, the median V(20) of patients with symptomatic radiation pneumonitis was 14.2%, about the same as that of patients with no symptomatic radiation pneumonitis in the control arm, 15.1%. The current study suggested that, as much as 15% of V(20), might play an important role in cases of lung cancer with chronic pulmonary disease.     

Radiation recall dermatitis induced by methotrexate in a patient with Hodgkin's disease

Radiation recall dermatitis refers to an inflammatory skin reaction at a previously irradiated field subsequent to chemotherapy administration. A number of antineoplastic agents have been reported to cause this phenomenon. We observed radiation recall dermatitis in a patient with stage IV nodular sclerosing Hodgkin's disease after methotrexate therapy for acute graft-versus-host disease (GVHD) prophylaxis. The patient had previously undergone matched related bone marrow transplantation with busulfan and cyclophosphamide as a preparative regimen. Subsequently, she received cyclosporine and methotrexate for acute GVHD prophylaxis. Two areas of skin previously irradiated to 3,000 cGy developed radiation recall dermatitis after two doses of methotrexate given 2 days apart and exacerbated by the third and fourth doses. This reaction occurred 34 days after the last dose of radiation therapy (RT). We believe this is the first case of radiation recall dermatitis after methotrexate therapy. Given the increased use of methotrexate in several neoadjuvant and adjuvant protocols in association with RT, its potential to produce radiation recall reactions should be considered.     

Radiotherapy during pregnancy: fact and fiction

Radiotherapy during pregnancy might cause harm to the developing fetus. Generally, pregnant women with malignant diseases are advised to delay radiotherapy until after delivery. However, this advice is not based on knowledge of the risks of radiation to the unborn child. In general, the expected radiation effects, such as mental retardation and organ malformations probably only arise above a threshold dose of 0.1-0.2 Gy. This threshold dose is not generally reached with curative radiotherapy during pregnancy, provided that tumours are located sufficiently far from the fetus and that precautions have been taken to protect the unborn child against leakage radiation and collimator scatter of the teletherapy machine; such precautions also reduce the risk of radiation-induced childhood cancer and leukaemia in the unborn child.     

Radiation therapy versus combination chemotherapy in the treatment of early-stage Hodgkin's disease: seven-year results of a prospective randomized trial

The study population included 136 patients with stage IA, IB, IIA, IIB, or IIIA1 Hodgkin's disease. The median follow-up is 7.5 years. Among the 30 patients with peripheral IA disease, all patients achieved a complete response (CR) with radiation therapy, and no patient has relapsed. Patients of other stages were randomized to receive radiation therapy or mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). Among the 51 patients randomized to receive radiation therapy, 49 (96%) achieved complete remission, 17 (35%) have relapsed, and 10 (20%) have died. Fifty-two of the 54 (96%) assessable patients randomized to receive MOPP obtained CRs, seven (13%) have relapsed, and four (7%) have died. The projected 10-year disease-free survival of patients randomized to receive radiation therapy is 60%; for those randomized to receive MOPP, it is 86% (P2 = .009 in favor of MOPP). The projected 10-year overall survival for patients randomized to radiation therapy is 76%, and for MOPP-treated patients it is 92% (P2 = .051 in favor of MOPP). When the randomized patients with massive mediastinal disease or stage IIIA1 disease were excluded from the analysis, the disease-free (67% for radiation v 82% for MOPP) and overall survival (85% for radiation v 90% for MOPP) were not significantly different between the two arms. Subset analysis showed significant superiority of MOPP in the treatment of the following patient groups: stage IIIA1 or massive mediastinal disease, no B symptoms, initial erythrocyte sedimentation rate greater than 20 mm, four or more sites of disease, and younger than age 40 years. Preliminary analysis of this ongoing study shows that MOPP chemotherapy is at least as effective as radiation therapy in the treatment of the specific groups of early-stage Hodgkin's disease patients randomized. The final assessment of these two diverse treatment options will depend largely on the long-term survival and the incidence of early- and late-treatment complications for which patients are continuing to be observed.     

Gamma Knife Radiosurgery

The concept of radiosurgery and its requirements are presented. Dedicated radiosurgical tools include the modified linear accelerators working with a single rotating beam and the Gamma Knife with multiple stationary radiation sources. The 201 gamma beams from the cobalt 60 sources of the Gamma Knife intersect within 0.3 mm and it is possible to align the selected target point with the focal point within a mechanical accuracy of 0.5 mm. The technical specifications of the Gamma Knife make it possible to safely produce sharply circumscribed lesions in a single session with superior accuracy and precision. Gamma Knife surgery is a four-step neurosurgical procedure including application of a stereotactic frame to the patient's head, stereotactic image acquisition, treatment planning, and the radiation. The system allows stereotactic acquisition of images from computed tomography, magnetic resonance tomography, cerebral angiography, and positron-emission tomography. Applications for Gamma Knife surgery include the treatment of cerebral vascular malformations, well-delineated benign and malignant tumors of the head, the treatment of certain pain conditions such as trigeminal neuralgia, as well as the treatment of some movement and psychiatric disorders. The results of treating arteriovenous malformations, acoustic neurinomas, and cerebral metastases are particularly outstanding.     

Increased cancer risk as a genetic effect of ionizing radiation

The well known genetic effects of ionizing radiation include severe developmental disorders in the progeny of irradiated parents resulting in embryonic death, stillbirth and early postnatal mortality, congenital abnormalities, malformations and fertility disturbances in live-born organisms. These effects are considered to be due to gross mutations (genomic, chromosomal and those of essential genes). Physiological inferiority and an increased cancer risk in phenotypically normal offspring of irradiated parents appear to be two further types of genetic effect of radiation. The genetic background of these effects is suggested to be induced recessive polygene mutations and regulatory DNA alterations, which may lead to instability of the hereditary apparatus of cells, activation of protooncogenes and other inducible processes. A comparison of somatic and genetic effects of radiation shows certain similarities, not only in phenomenology, but probably also in pathogenetic mechanisms.     

Feasibility of external beam radiation for prevention of restenosis following balloon angioplasty

PURPOSE: Brachytherapy has been shown to inhibit neointima formation after vascular balloon injury. This study was done to test the feasibility of low dose external radiation for prevention of restenosis in a non-stented balloon injury model. MATERIALS AND METHODS: Twelve red Duroc swine underwent balloon overdilation injury of both iliac arteries. Twelve Gy was delivered to one side using a Theratron T-1000 Cobalt unit with the other side used as the control. Twelve weeks post injury arteriograms were performed. The animals were then sacrificed and iliac arteries explanted. Histomorphometric analysis of arterial cross sections was performed. Results: Neointima formation was observed in all arteries. Unilateral thrombosis was noted in two animals. The mean neointimal thickness in the radiated and control arteries was 0.63 +/- 0.17 mm and 0.72 +/- 0.31 mm, respectively. The differences in minimal luminal diameter and the neointimal thickness between the two groups were not statistically significant. Complications included superficial hair loss in the radiation port in 4 animals, and 2 deaths prior to the completion date (1 of hemorrhagic enteritis possibly related to the radiation, and 1 of iliac rupture). CONCLUSION: External radiation at this low dose is not effective in preventing vascular restenosis following balloon injury in this animal model.     

Enhanced in vitro radiosensitivity of skin fibroblasts in two patients developing brain necrosis following AVM radiosurgery: a new risk factor with potential for a predictive assay

PURPOSE: Radiosurgery is an effective treatment for arteriovenous malformations (AVM) with a low risk of developing brain necrosis. Models have been developed to predict the risk of complications. We postulated that genetic differences in radiosensitivity may also be a risk factor. METHODS AND MATERIALS: Fibroblast cultures were established from skin biopsies in two AVM patients developing radiation necrosis. The results of clonogenic survival assays were compared to a parallel study with two groups of cancer patients treated with radiation: 1) patients without late side effects; 2) patients experiencing severe late sequelae. RESULTS: The survival fraction at 2 Gy (SF2) of the 2 AVM patients was 0.17 (0.14-0.19) and 0.18 (0.14-0.22). The SF2's of the cancer patients ranged between 0.25-0.38 (mean = 0.31) for the control group, and between 0. 10-0.20 (mean = 0.17) for the hypersensitive group. The SF2's of the AVM patients who developed brain necrosis were comparable to that of the hypersensitive group (p = 0.85) but significantly lower than the control group (p = 0.05). CONCLUSION: The two patients who developed radiation necrosis demonstrate increased fibroblast radiosensitivity. The SF2 of skin fibroblasts may potentially be used as a predictive assay to detect patients at risk for brain necrosis.