[en] Objective: To review the background, rationale and available results for recently completed randomized comparative clinical trials of the Radiation Therapy Oncology Group (RTOG), including inter group trials in which the RTOG has been the managing group or a major participant. When available, laboratory studies will be correlated with clinical results

[en] Purpose: To accurately implement a treatment plan obtained by virtual or CT simulation, conventional or physical simulation is still widely used. To evaluate the need for physical simulation, we prospectively randomized patients to undergo physical simulation or no additional simulation after virtual simulation. Methods and Materials: From July 1995 to September 1996, 75 patients underwent conformal four-field radiation therapy planning for prostate cancer with a commercial grade CT simulator. The patients were randomized to undergo either port filming immediately following physical simulation or port filming alone. The precision of implementing the devised plan was evaluated by comparing simulator radiographs and/or port films against the digitally reconstructed radiographs (DRRs) for x, y, and z displacements of the isocenter. Changes in beam aperture were also prospectively evaluated. Results: Thirty-seven patients were randomized to undergo physical simulation and first day port filming, and 38 had first day treatment verification films only without a physical simulation. Seventy-eight simulator radiographs and 195 first day treatment port films were reviewed. There was no statistically significant reduction in treatment setup error (>5 mm) if patients underwent physical simulation following virtual simulation. No patient required a resimulation, and there was no significant difference in changes of beam aperture. Conclusions: Following virtual simulation, physical simulation may not be necessary to accurately implement the conformal four-field technique. Because port filming appears to be sufficient to assure precise and reliable execution of a devised treatment plan, physical simulation may be eliminated from the process of CT based planning when virtual simulation is available

[en] Purpose: Accumulation of the p53 protein can result in G₁ arrest that may facilitate DNA repair, or alternatively, it may lead to apoptosis. Mutations that alter p53's ability to mediate these responses are expected to alter cell radiosensitivity to killing. However, the relationship between p53 status and cell radiosensitivity has proven to be complex. Several studies have suggested that p53 mutations are associated with increased radioresistance to killing, while others have shown no such correlation. These differences may be derived from the fact that different mutations of p53 exert different effects on cell radiosensitivity. Methods and Materials: To address this question, we examined a group of isogenic cell lines that express different 'hot spot' mutant forms of p53. These cells were generated from human osteosarcoma (SAOS) cells, a p53 null cell line, by transfection with vectors expressing different p53 mutants. Vectors with the following p53 mutations were utilized: 143Ala, 175His, 248Try, 273His, and 281Gly. As controls, we used the original SAOS cells and cells transfected with the vector alone. Results were compared to those obtained with a cell line expressing wild-type p53 (wt p53). Radiosensitivity to killing was determined in the exponential phase of growth by measuring loss of colony-forming ability. Induction and repair of DNA double-strand breaks (dsb) was measured in irradiated cells using pulsed-field gel electrophoresis. Apoptosis was assessed using morphologic evaluation of DAPI-stained cells after treatment either with radiation or paclitaxel. Results: Transfected SAOS-2 cell lines expressed a mutant form of p53 that could not be induced by radiation, and which was transcriptionally inactive. Among the 7 cell lines studied, we observed no difference in cellular radiosensitivity to killing (p = NS). When examining DNA repair, no difference in either the induction or repair of DNA dsb was noted in any of the cell lines studied (p = NS). Also, induction of apoptosis, either after exposure to radiation or paclitaxel, was low, and similar in all cell lines (p = NS). Non-isogenic cells expressing wt p53 were more radioresistant to killing by radiation, but showed similar kinetics of dsb rejoining. Conclusion: The results suggest that expression of different p53 mutants does not alter the yields of radiation-induced dsb, or the ability of cells to repair this type of lesion. In addition, the same p53 mutants do not affect cellular radiosensitivity to killing, or the induction of apoptosis after exposure to radiation or paclitaxel

[en] Purpose: There is no consensus in the literature regarding the role of lymphangiography in promoting hypothyroidism in individuals with Hodgkin's disease irradiated with a mantle field. We sought to analyze the onset and rate of developing clinical or chemical hypothyroidism as well as possible factors related to its development in patients who received irradiation to the thyroid gland during treatment of Hodgkin's disease. Methods and Materials: One hundred and forty-two patients with Hodgkin's disease were treated at the Fox Chase Cancer Center between June 1967 and October 1993. All patients were treated with curative intent with radiation therapy using a mantle field. After exclusion of patients without available thyroid function tests, < 200 days of follow-up, or no radiation to the thyroid, 104 patients were eligible for analysis. Follow-up ranged from 7-170 months (median: 43 months). Sixty-seven patients had a lymph angiogram. Seventy-three patients were treated with radiation alone and 31 with radiation plus chemotherapy. Results: The actuarial 2-, and 5-year rates of biochemical hypothyroidism for all 104 patients were 18 and 37%, respectively. Forty patients developed hypothyroidism: 9 (23%) at ≤ 1 year, 18 (45%) at ≤ 2 years, and 33 (83%) at ≤ 5 years. The actuarial 2-, and 5-year rates of biochemical hypothyroidism for patients who underwent a lymph angiogram were 23 and 42%, respectively, compared to 9 and 28%, respectively, for patients who received mantle irradiation without a lymph angiogram (p = 0.05). The effects of lymph angiogram, total thyroid dose, stage, chemotherapy, dose per fraction, energy, and age were evaluated for all patients by Cox proportional hazards regression analysis. The use of a lymph angiogram (p = 0.05) was the only variable that significantly influenced hypothyroidism. Conclusions: This paper demonstrates in a multivariate analysis accounting for other potentially important variables the significant effect of lymphangiography and subsequent radiation therapy on the development of hypothyroidism. This information must be balanced with the fact that lymph angiograms remain a useful aid in assessing lymph node involvement, staging patients, and planning treatment fields

[en] Purpose/Objective: The prognosis for patients with glioblastoma multiforme (GBM) is poor. Although cranial radiation (RT) may improve symptoms and prolong survival, cure is rare and survival is often <1 year. The addition of standard nitrosourea-based adjuvant chemotherapy improves the outlook only modestly. New, more effective treatments are needed. Topotecan, a camptothecin analogue, is a new chemotherapeutic agent which acts predominantly as a topoisomerase I inhibitor. Topotecan has demonstrated some activity against human malignant gliomas and may be a radiation sensitizer. The purpose of this study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of combined topotecan and standard cranial RT, and to determine that acute and delayed treatment-related toxicity is acceptable with this regimen. Materials and Methods: Eligibility criteria included: histologically confirmed GBM; supratentorial tumor; age ≥18 years; Karnofsky performance status ≥50; adequate bone marrow reserve and normal renal and hepatic function; preoperative and postoperative CT scan (or MRI) with and without contrast; and study-specific informed consent. Ineligibility criteria included: multifocal glioma; recurrent GBM; prior RT or chemotherapy; and concurrent or recent major medical illnesses. RT had to begin within 5 weeks of surgery, using megavoltage photon beam machines of energy ≥4 MeV in 2 Gy fractions once daily with treatment volumes based on preoperative CT/MRI. The initial 46 Gy in 23 fractions included the contrast enhancing lesion and surrounding edema plus a 2 cm margin and the final 14 Gy in 7 fractions included the contrast enhancing lesion plus a 2.5 cm margin. Topotecan was given as a 30 minute intravenous infusion daily for 5 days every 3 weeks for 3 courses. Topotecan was given before RT on RT days 1-5 (protocol days 1-5) and 16-20 (protocol days 22-26) and on protocol days 43-47. Topotecan doses were reduced or treatment delayed for toxicity. DLT was defined as ≥ grade 3 nonhematological or ≥ grade 4 hematological toxicity lasting >7 days. Topotecan was given in three dose levels, 0.5 mg/m²/day (level 1), 1.0 mg/m²/day (level 2) and 1.5 mg/m²/day (level 3, the usual MTD when used alone). Results: Level 1 (topotecan 0.5 mg/m²) opened October 1995 and closed December 1995 with 15 patients accrued. One grade 3 CNS toxicity (headache) and 1 grade 3 other toxicity (hyperglycemia) were observed, neither thought directly due to topotecan treatment. No grade 4 toxicities were seen. Level 2 (topotecan 1.0 mg/m²) opened May 1996 and closed June 1996 with 15 patients accrued. Four patients had brief grade 4 neutropenia (absolute granulocyte count <0.5 x 10⁹/L) and 1 patient had grade 3 thrombocytopenia (platelet count 25-49.9 x 10⁹/L). No DLT was observed. Level 3 (topotecan 1.5 mg/m²) opened October 1996 and closed December 25, 1996, accruing 17 patients. Acute toxicity data is limited to date in this cohort. One grade 4 neutropenia, 1 grade 3 thrombocytopenia, 1 grade 3 leukopenia, and no DLT were seen in the first three patients. No grade 3 or grade 4 late toxicities (within 90 days from start of RT) were seen in level 1 or level 2. The treatment was well tolerated with minimal nausea/vomiting or other acute side effects and no excessive RT skin reactions were seen to date. No survival data is available yet. Conclusions: Although toxicity data is limited from level 3, the combination of topotecan daily x 5 days every 3 weeks during RT for GBM was well tolerated and produced acceptable acute toxicities, primarily hematologic (brief neutropenia). Acute and late toxicity data will be updated and survival data reported and compared to historical controls adjusted for RTOG Recursive Partitioning Analysis Prognostic Group. Unless 3 or more DLTs are seen in level 3, the recommended topotecan dose for the phase II study of topotecan plus cranial RT for glioblastoma multiforme (RTOG study 95-13) will be 1.5 mg/m²/day x 5 days every 3 weeks x 3 courses

[en] The Radiation Therapy Oncology Group (RTOG) designed a random sampling process and observed its influence upon radiotherapy review mechanisms in cooperative group clinical trials. The method of sampling cases for review was modeled from sampling techniques commonly used in pharmaceutical quality assurance programs, and applied to the initial (on-study) review of protocol cases. 'In control' (IC) status is defined for a given facility as the ability to meet minimum compliance standards. Upon achieving IC status, activation of the sampling process was linked to the rate of continued patient accrual for each participating institution in a given protocol. The sampling design specified that ≥ 30% cases not in compliance would be detected with 80% power. A total of 458 cases was analyzed for initial review findings in four RTOG Phase III protocols. Initial review findings were compared with retrospective (final) review results. Of the 458 cases analyzed, 370 underwent initial review at on-study, while 88 did not require review as they were enrolled from institutions that had demonstrated protocol compliance. In the group that had both initial and final review, (345(370)) (93%) were found to have followed the protocol or had a minor variation. Of the exempted cases, (79(88)) (90%) were found to be per protocol or a minor variant. The sampling process proved itself to be cost-effective and resulted in a noticeable reduction in the workload, thus providing an improved approach to resource allocation for the group. Continued evaluation of the sampling mechanism is appropriate as study designs and participants vary over time, and as more data become available to study. Further investigation of individual protocol compliance is appropriate to identify problems specific to new trial investigations

[en] BACKGROUND: The routinely recommended target volume for off-cord lung oblique fields in the treatment of postoperative bronchogenic carcinoma includes the entire mediastinum, as defined by coverage of the contralateral mainstrem bronchus and subcarinal space. However, this may be difficult to accomplish with the suggested field angles of 20 - 40 degrees recommended in the recently completed Intergroup Trial (RTOG 91-05). This project was undertaken to define the oblique angle necessary to encompass the entire mediastinum as determined by computerized tomography (CT) simulator verification. METHODS: Axial CT simulation images of 25 patients with thoracic malignancies were used in this study. Sites of disease included bronchogenic carcinoma (n=23) and other (n=2). Five patients received prior resection as part of their management. The contralateral mainstem bronchus (CMB), subcarinal space (SS), and the spinal cord (SC) were each contoured as separate volumes. The length of the CMB was defined as extending from the carina to the bifurcation of the lobar bronchi. The SS was defined as a rectangular space (in coronal plane) with the carina at the apex, the mainstem bronchi superiorly, and a horizontal line 5 cm below the carina as the base of the triangle. The smallest angle (SA) to encompass the CMB and SS, and to exclude the spinal cord was determined for each patient. The contoured volumes did not have additional margin added. The position of the carina was scored as 'midline' if located in the mid-sagittal plane, or 'off-midline' if deviated to either side from midline. Midline deviation (MD) was determined at the level of the carina in order to evaluate possible anatomic distortion relating to the tumor or prior surgery, and its effect on the SA was assessed. RESULTS: The median SA measured was 45 degrees (range: 28-65 degrees) for the entire group, and in 64% of those evaluated, this oblique angle was significantly greater than 40 degrees recommended in RTOG guidelines (p=0.017). In patients without MD (n=19), the median SA was 45 degrees (range: 28-60), and in patients with MD (n=6), it was determined to be 44 degrees (range: 27-65), with no statistical difference noted between the two groups (p=NS). Although MD was present in two patients previously resected (n=5), the above relationship remained unchanged. CONCLUSION: Based on CT simulation verification, off-cord oblique field angles of 20-40 degrees do not adequately cover the entire mediastinum in most patients. To adequately encompass the entire mediastinum as defined in the Intergroup Trial (RTOG 91-05) with off-cord oblique fields, treatment angles greater than 40 degrees are necessary. Whether the potential increase in lung volume exposed to radiation from these larger angles results in a poorer therapeutic ratio requires further investigation

[en] Purpose: Radiation management of intracranial tumors may require a noncoplanar vertex field that often irradiates the entire length of the body. In view of radiation related risks to the normal tissues dose estimation to the extracranial organs such as the thyroid gland, spinal cord, heart, and genitalia is performed for a vertex field. Methods and Materials: A vertex field used clinically was reproduced on an anthropomorphic Rando phantom to measure radiation dose to various organs in the primary beam. Three photon beams (4, 6, and 10 MV), and two high energy electron beams (16 and 20 MeV) were used. Dosimetry was performed with an ion chamber sandwiched between phantom slices at the appropriate positions. All doses were normalized to the target dose at a depth of 5 cm. The effect of the head position was studied by rotating the gantry angle up to ±20 deg. to mimic the extension and flexion of the head. Theoretical calculation was performed using an exponential best fit to the depth dose table to estimate the dose to various points and compare with the measured dose. Results: The measured normalized dose to the cervical cord, thyroid, heart, and female and male gonads are 60, 36, 16, 2.5, and 1.6%, respectively, for a 6 MV photon beam. The dose from 4 MV and 10 MV are slightly lower and higher, respectively. Doses from electron beams are about a factor of 4-10 lower than those of the photon beams. The measured gonadal dose from the primary beam is <5% of the target dose for all energies used in the study. The actual value, however, is dependent on the body structure, length, and the posture of the patient. A ±5 deg. head flexion had little effect on the dose to the various parts of the body. The head rotations greater than ±10 deg. produced relatively lower doses by a factor of 10^-2 to the organs at distances greater than 40 cm from the prescription point. The radiation doses to the different critical organs estimated from the fitted curves are lower than the measured doses up to 35%. Conclusions: When a vertex field is used for the treatment of the brain tumors, the entire axial length of the body is irradiated which adds to the integral dose. Unlike the scattered and leakage radiation, the primary dose to extracranial critical organs is greater for higher energies. For a 10 MV beam the ovary and testis at a distance of 80 cm and 90 cm may receive a dose of 4.2 and 3%, respectively, of the target dose. The gonadal dose could be quite significant if the entire treatment is delivered using a vertex field. For pediatric and smaller patients, dose to the critical organs at known distances could be estimated from the empirical equation obtained from the measured data. While the risk-benefit ratio is often evaluated and acceptable for treating malignant tumors, the long-term complications need thorough assessment in younger and curable patients. In view of radiation carcinogenesis and genetic burden, dose reduction to critical organs should be considered using a 3D planning system to arrange beams in other nonaxial planes and by considering electron beams for the vertex field

[en] Purpose: Conformal radiotherapy of prostate carcinoma relies on contouring of individual CT slices for target and normal tissue localization. This process can be very time consuming. In the present report, we describe a method to more efficiently localize pelvic anatomy directly from digital reconstructed radiographs (DRRs). Materials and Methods: Ten patients with prostate carcinoma underwent CT simulation (the spiral mode at 3 mm separation) for conformal four-field 'box' radiotherapy. The bulbous urethra and bladder were opacified with iodinated contrast media. On lateral and anteroposterior DRRs, the volume of interest (VOI) was restricted to 1.0-1.5 cm tissue thickness to optimize digital radiograph reconstruction of the prostate and seminal vesicles. By removing unessential voxel elements, this method provided direct visualization of those structures. For comparison, the targets of each patient were also obtained by contouring CT axial slices. Results: The method was successfully performed if the target structures were readily visualized and geometrically corresponded to those generated by contouring axial images. The targets in 9 of 10 patients were reliable representations of the CT-contoured volumes. One patient had 18 mm variation due to the lack of bladder opacification. Using VOIs to generate thin tissue DRRs, the time required for target and normal tissue localization was on the average less than 5 min. Conclusion: In CT simulation of the four-field irradiation technique for prostate carcinoma, thin-tissue DRRs allowed for efficient and accurate target localization without requiring individual axial image contouring. This method may facilitate positioning of the beam isocenter and provide reliable conformal radiotherapy

[en] Purpose: Lymphangiography has been a routine part of Hodgkin's disease staging over the past 3 decades and has an accepted role in assessing pelvic and paraaortic lymph node involvement, adequately staging patients as well as planning radiation fields. There is no consensus in the literature regarding the role of lymphangiography in promoting hypothyroidism in individuals with Hodgkin's disease irradiated with a mantle field. We sought to analyze the onset and rate of hypothyroidism in patients who received irradiation to the thyroid gland during treatment of Hodgkin's disease, as well as possible factors related to its development. Materials and Methods: One hundred and forty-two patients with Hodgkin's disease were treated between June 1967 and October 1993. All patients were treated with curative intent with radiation therapy utilizing a mantle field. Following exclusion of patients without available thyroid function tests, < 200 days of follow-up, or no radiation to the thyroid 104 patients were eligible for analysis. Follow-up ranged from 7-170 months (median 43 months). Sixty-seven patients had a lymphangiogram. 73 patients were treated with radiation alone and 31 patients with radiation therapy plus chemotherapy. All patients were treated with continuous course, once daily external beam radiotherapy using megavoltage equipment. The median external beam dose to the mantle field was 39.6 Gy while the median dose to the thyroid was 41.5 Gy. Multivariate analysis was used to determine factors affecting hypothyroidism. Results: The actuarial 2-, and 5-year rates of biochemical hypothyroidism for all 104 patients were 18% and 37%, respectively. 40 patients developed hypothyroidism: 9 (23%) at ≤ 1 year, 18 (45%) at ≤ 2 years and 33 (83%) at ≤ 5 years. 35 patients developed chemical hypothyroidism and 5 patients developed both clinical and chemical hypothyroidism. The actuarial 2-, and 5-year rates of biochemical hypothyroidism for patients who underwent a lymphangiogram were 23% and 42%, respectively compared to 9% and 28%, respectively for patients who received mantle irradiation without a lymphangiogram (P = 0.05). Thirty-one of 67 patients (46%) who underwent lymphangiography developed biochemical hypothyroidism compared to 9 of 37 patients (24%) who did not undergo lymphangiography (P = 0.03). The median time to hypothyroidism was 25 months for patients who had a lymphangiogram compared to 40 months for patients who did not have a lymphangiogram. The effects of lymphangiogram, total thyroid dose, stage, chemotherapy, dose per fraction, energy, and age were evaluated for all patients by Cox proportional hazards regression analysis. The use of a lymphangiogram (P = 0.05) was the only variable that significantly influenced hypothyroidism. Conclusion: This is the first paper to demonstrate in a time-adjusted multivariate analysis accounting for other potentially important variables the significant effect of lymphangiography and subsequent radiation therapy on the development of hypothyroidism. This information must be balanced with the fact that lymphangiograms remain a useful aid in assessing lymph node involvement, staging patients, and planning treatment fields