Marcus E. Randall

Extracranial Stereotactic Radioablation Physical Principles

Extracranial stereotactic radioablation (ESR) involves treating well-demarcated targeted tissues (e.g. tumor with minimal margin for set-up uncertainties) with very large doses of radiation in single or a few fractions with the intent of causing profound late tissue damage within the targeted volume. In such circumstances, considerable effort must be taken to reduce non-target tissue exposure to the high dose levels in order to prevent late complications to involved organs. Consequently, the following conditions for effective delivery of the ESR techniques have to be satisfied: 1) delivery of a high dose per fraction, i.e. 10–24 Gy; 2) delivery of only a few fractions per course of treatment (e.g. 1–4); 3) shaping of the prescription isodose surface conformally to the target surface; 4) delivery of a non-uniform dose distribution within the target with the highest dose in centrally located regions of hypoxia; 5) rapid fall-off of dose from the target volume to healthy tissue in all directions. In this paper it is shown that high doses per fraction in few fractions can be delivered to a variety of locations with both efficacy and acceptable toxicity (conditions 1 and 2). Conformal shaping of the high isodose surfaces is best accomplished by employing many beams (5–10) each with carefully milled apertures precisely coincident with the target projection (condition 3). Beam intensity modulation creating parabolic beam entrance fluence profiles both concentrates the highest dose in central regions of tumor hypoxia and increases fall-off gradients outside of the target (conditions 4 and 5). It is also shown that isotropic, highly non-coplanar beam arrangements avoiding oppositional fields allow more optimal fall-off gradients to normal tissue as opposed to coplanar treatments (condition 5).

Monte Carlo simulation of the Leksell Gamma Knife®: II. Effects of heterogeneous versus homogeneous media for stereotactic radiosurgery

The absence of electronic equilibrium in the vicinity of bone-tissue or air-tissue heterogeneity in the head can misrepresent deposited dose with treatment planning algorithms that assume all treatment volume as homogeneous media. In this paper, Monte Carlo simulation (PENELOPE) and measurements with a specially designed heterogeneous phantom were applied to investigate the effect of air-tissue and bone-tissue heterogeneity on dose perturbation with the Leksell Gamma Knife. The dose fall-off near the air-tissue interface caused by secondary electron disequilibrium leads to overestimation of dose by the vendor supplied treatment planning software (GammaPlan) at up to 4 mm from an interface. The dose delivered to the target area away from an air-tissue interface may be underestimated by up to 7% by GammaPlan due to overestimation of attenuation of photon beams passing through air cavities. While the underdosing near the air-tissue interface cannot be eliminated with any plug pattern, the overdosage due to under-attenuation of the photon beams in air cavities can be eliminated by plugging the sources whose beams intersect the air cavity. Little perturbation was observed next to bone-tissue interfaces. Monte Carlo results were confirmed by measurements. This study shows that the employed Monte Carlo treatment planning is more accurate for precise dosimetry of stereotactic radiosurgery with the Leksell Gamma Knife for targets in the vicinity of air-filled cavities.

Adenocarcinoma of the Fallopian Tube: Results of a Multi-Institutional Retrospective Analysis of 72 Patients

PURPOSE/OBJECTIVEnTo determine the prognostic factors for predicting outcome of patients with adenocarcinoma of the fallopian tube and to evaluate the impact of treatment modalities in managing this uncommon disease.nnnMATERIALS AND METHODSnA retrospective analysis of the tumor registries from 6 major medical centers from January 1, 1960 up to March 31, 1995 yielded 72 patients with primary adenocarcinoma of the fallopian tube. The Dodson modification of the FIGO surgical staging as it applies to carcinoma of the fallopian tube was utilized. Endpoints for outcome included overall and disease-free survival. Univariate analysis of host, tumor, and treatment factors was performed to determine prognostic significance, and patterns of failure were reviewed.nnnRESULTSnThe median age of the study cohort was 61 years (range 30-79 years). Stage distribution was 24 (33%) Stage I; 20 (28%) Stage II; 24 (33%) Stage III; and 4 (6%) Stage IV. Adjuvant chemotherapy was administered to 54 (75%) patients, and postoperative radiotherapy was employed in 22 (31%). In the latter treatment group, 14 (64%) had whole pelvic external beam irradiation, 5 (23%) whole abdominal radiotherapy, 2 (9%) P-32 instillation, and 1 (4%) vaginal brachytherapy alone. Chemotherapy was used in 67% of Stage I and in 79% of Stages II/III/IV disease (not significant); radiotherapy was more commonly employed in Stage I than in Stages II/III/IV (46% vs. 23%, p = 0.05). The 5-, 8-, 15-year overall and disease-free survival for the study patients were 44.7%, 23.8%, 18.8% and 27.3%, 17%, 14%, respectively. Significant prognostic factors of overall survival included Stage I vs. II/III/IV (p = 0.04) and age < or = 60 years vs. > 60 years at diagnosis (p = 0.03). Only Stage I vs. II/III/IV (p = 0.05) was predictive of disease-free survival. Patterns of failure included 18% pelvic, 36% upper abdominal, and 19% distant. For all patients, upper abdominal failures were more frequently found in Stages II/III/IV (29%) than in Stage I (7%) (p = 0.03). Relapses solely outside of what would be included in standard whole abdominal radiotherapy portals occurred for only 15% of patients (6 of 40) with failures. Furthermore, patients having any recurrence, including the upper abdomen, were more likely (p = 0.001) to die (45%) than those without any type of relapse (18%).nnnCONCLUSIONnThis retrospective, multi-institutional study demonstrated the importance of FIGO stage in predicting the overall and disease-free survival of patients with carcinoma of the fallopian tube. Future investigations should consider exploring whole abdominal irradiation as adjunctive therapy, particularly in Stage II and higher.

Monte Carlo simulation of the Leksell Gamma Knife?: I. Source modelling and calculations in homogeneous media

The Monte Carlo code PENELOPE has been used to simulate photon flux from the Leksell Gamma Knife, a precision method for treating intracranial lesions. Radiation from a single 6OCo assembly traversing the collimator system was simulated, and phase space distributions at the output surface of the helmet for photons and electrons were calculated. The characteristics describing the emitted final beam were used to build a two-stage Monte Carlo simulation of irradiation of a target. A dose field inside a standard spherical polystyrene phantom, usually used for Gamma Knife dosimetry, has been computed and compared with experimental results, with calculations performed by other authors with the use of the EGS4 Monte Carlo code, and data provided by the treatment planning system Gamma Plan. Good agreement was found between these data and results of simulations in homogeneous media. Owing to this established accuracy, PENELOPE is suitable for simulating problems relevant to stereotactic radiosurgery.

Integrating Radiation Therapy in the Curative Management of Ovarian Cancer: Current Issues and Future Directions

Although important advances in surgery, chemotherapy (CT), and radiation therapy (RT) have been made, overall survival for patients with ovarian cancer (OC) has not changed significantly. Despite its long history in the treatment of OC and its proven curative role in patients with microscopic or minimal residual disease, the proper role of RT in the management of OC is not clearly established. Although the use of primary adjuvant RT (whole abdominal irradiation) has declined in the last 15 years, there has been a resurgence of interest in RT as part of a combined modality approach and as salvage therapy for patients with small-volume persistent disease after primary cytoreductive surgery and platinum-based CT. This article reviews the evidence supporting the use of RT alone or combined with chemotherapy as primary adjuvant therapy or in the salvage setting. Current issues in the radiotherapeutic management are discussed along with ideas for future clinical research directions.

Chemotherapy, early surgical reassessment, and hyperfractionated abdominal radiotherapy in stage III ovarian cancer: Results of a gynecologic oncology group study

PURPOSEnTo determine outcomes and treatment toxicities in patients with optimal (< or = 1 cm residual) Stage III ovarian carcinoma treated with three courses of cisplatin-cyclophosphamide, surgical reassessment (SRA), and hyperfractionated whole abdominal irradiation (WAI).nnnMETHODS AND MATERIALSnForty-two eligible patients entered this prospective Phase II study conducted by the Gynecologic Oncology Group (GOG). Disease characteristics were as follows: age range, 32-76 years (median 58); Stage IIIA (n = 1, 2%), IIIB (n = 2, 5%), IIIC (n = 39, 93%); histology-serous papillary (n = 21, 50%); other (n = 21, 50%); Grade 1 (n = 1, 2%); 2 (n = 14, 33%); 3 (n = 27, 54%); residual disease after initial surgery (present: n = 23, 55%; absent: n = 19, 45%). Five patients progressed while on chemotherapy, could not be effectively cytoreduced, and were not eligible for WAI. Of the remaining 37 patients, 35 received WAI. Surgical reassessment was not performed in five patients.nnnRESULTSnOf 37 patients with known SRA status after chemotherapy, 21 (57%) were grossly positive, 4 (11%) were microscopically positive, and 12 (32%) were negative. Based on measurements recorded following initial laparotomy and surgical reassessment, progression during chemotherapy was noted in 40%, stage disease in 37%, and objective response in 23%. Toxicity during hyperfractionated WAI was limited and reversible. No patient beginning WAI failed to complete or required a significant treatment break. Following WAI, six patients underwent laparotomies for abdominal symptoms; five had recurrent disease. Five additional patients were managed conservatively for small bowel obstruction (SBO) or malabsorption, of whom three subsequently developed recurrence. Twenty-two patients having pelvic boosts were significantly more likely to require management for gastrointestinal morbidity (p = 0.0021). Considering all eligible patients, median disease-free and overall survivals were 18.5 and 39 months, respectively. Considering patients completing chemotherapy and WAI, median disease-free and overall survivals were 24 and 46 months, respectively.nnnCONCLUSIONSn(a) Disease progression occurred within three cycles of cisplatin and cyclophosphamide chemotherapy in 40% of patients with optimal (< or = 1 cm residual) Stage III ovarian carcinoma. (b) Following limited chemotherapy, hyper-fractionated WAI was acutely well tolerated. (c) Late radiation-related toxicity was observed in only three patients (8.6%) in the absence of recurrent disease. Late gastrointestinal morbidity was significantly associated with the administration of a pelvic radiotherapy (RT) boost. (d) Short duration chemotherapy followed by SRA and hyperfractionated WAI without a pelvic boost is a promising management option for patients with optimal Stage III ovarian cancer. A Phase III trial will be necessary to determine how this treatment strategy compares with chemotherapy or RT alone in this patient population.

Early-stage endometrial cancer: is intravaginal radiation therapy alone sufficient therapy?

For half a century, adjuvant radiation therapy has been an important component in the treatment of patients with early-stage endometrial cancer believed to be at significant risk of local or regional recurrence. The widespread adoption of up-front surgical treatment and staging, including nodal assessment, has raised new questions about the need for and extent of postoperative adjuvant treatment. Furthermore, in some institutions, even in the absence of complete surgical staging, the extent of postoperative adjuvant treatment is being reassessed. These developments have increased interest in the use of intravaginal brachytherapy (IVRT) alone in selected patients whose major risk of recurrence is at the vaginal cuff. The potential advantages of this approach include lower cost and decreased acute and late toxicity. The use of IVRT alone in select patients was examined through a review of the available literature. The authors conclude that there is a subset of patients in whom adjuvant treatment with IVRT alone is adequate. A clinical approach involving patient selection criteria is proposed which suggests separate selection criteria based on whether or not complete surgical staging information is available.

A technique for inguinal node boost using photon fields defined by asymmetric collimator jaws

A technique is described for treating inguinal nodes when using radiotherapy in the control of pelvic malignancies. A posterior photon field treats the pelvis. A wider anterior photon field treats pelvis and inguinal nodes. An anterior photon boost to nodes is delivered using asymmetric collimator jaws moved across center line. Advantages of this technique include simplicity of setup and treatment (a single isocenter is retained, and no transmission block is needed), minimal dose inhomogeneity, reduced dose to femoral necks reducing the risk of femoral fracture, low risk of nodal underdose, and elimination of dosimetric difficulties inherent in electron beam boosts.

Lung cancer radiation therapy: Monte Carlo investigation of "under dose" by high energy photons

Loss of electronic equilibrium in lung tissue causes a build-up region in the tumor. Increasing the photon energy increases the depth at which electronic equilibrium is reestablished within the lung tumor. This study uses the Monte Carlo code PENELOPE for simulations of radiation treatment of tumor surrounded by lung. Six MV photons were compared to 15 MV photons using four beam arrangements in both homogeneous and heterogeneous media. The experimental results demonstrate that for every beam arrangement in heterogeneous media 15 MV photons delivered 5% to 10% lower dose to the tumor periphery than 6 MV photons. The simulations also show that in axial coplanar treatment plans, the loss of electronic equilibrium was greatest in the coronal plane. In conclusion there is a tumor sparing effect at the tumor-lung interface that is a function of beam energy. As an alternative to increasing beam energy, the addition of multiple beam angles with lower energy photons improved target coverage. If higher energy beams are required for patients with large separation, then adding multiple beam angles does offer some improved target coverage. The non-coplanar technique with the lower energy photons covered the tumor with a greatest isodose at the tumor periphery without tangential sparing in the coronal plane.

Quantitative Analysis of Three-dimensional Conformal Radiotherapy Techniques for Posterior Fossa Treatment in Children

Numerous beam directions using 3-D conformal techniques can be employed in treating tumors in the posterior fossa, each with characteristic normal tissue exposure along the entrance and exit trajectory. A representative variety of beam configurations were modeled in a modern computer planning system initially with the entire posterior fossa as the target. These beams were quantitatively scored using criteria based on integral doses for both low dose and high dose effects encompassing a variety of critical normal structures, thus identifying strengths and weaknesses of each beam. By blocking portions of a particular beam accounting for unfavorable scores, a map of “zones” within the posterior fossa ideally treated by a certain beam or beams could be constructed. No universally ideal photon beam arrangement for the entire posterior fossa target could be identified. However, using single beam analysis, the strengths and weaknesses of particular strategies could be quantified. For example, vertex beams treating the cerebellar hemispheres allow the greatest sparing of cochlea and hypothalamus but at the cost of increased low to moderate dose to the supratentorial brain. Using the constructed maps identifying “zones” appropriately treated by a given beam or beams, three-dimensional conformal treatment plans with favorable dose-volume statistics can be designed based on previously defined normal tissue tolerance considerations. It is shown how this approach can be individualized based on specific patient characteristics (e.g., age). We conclude that radiotherapy directed to the posterior fossa can be optimized based on systematic assessment of individual beam contributions to normal tissues. This technique allows fast selection of treatment beams based on known normal tissue anatomical and tolerance information. Further studies will be required regarding long term effects of various radiation doses on specific volumes of normal tissue in order to individualize beam selection. When treating children, knowledgeable consideration of these beam characteristics can help avoid late effects.