Development of clinical trial protocols involving advanced radiation therapy techniques: the European Organisation for Research and Treatment of Cancer Radiation Oncology Group approach.

The European Organisation for Research and Treatment of Cancer (EORTC) Master Protocol for phase III radiation therapy (RT) studies was published in 1995 to define in a consistent sequence the parameters which must be addressed when designing a phase III trial 'from the rationale to the references'. This was originally implemented to assist study investigators and writing committees, and to increase homogeneity within Radiation Oncology Group (ROG) study protocols. However, RT planning, delivery, treatment verification and quality assurance (QA) have evolved significantly over the last 15 years and clinical trial protocols must reflect these developments. The goal of this update is to describe the incorporation of these developments into the EORTC-ROG protocol template. Implementation of QA procedures for advanced RT trials is also briefly described as these essential elements must also be clearly articulated. This guide may assist both investigators participating in current ROG trials and others involved in writing an advanced RT trial protocol.

Second primary tumors in mycosis fungoides patients: experience at the Northern Israel Oncology Center (1979-2002).

PURPOSE: Mycosis fungoides (MF) patients enjoy longstanding remissions following total skin electron irradiation (TSEI) but run the risk of developing secondary malignancies. Our purpose was to report our experience with the phenomenon of secondary malignancies in MF patients. PATIENTS AND METHODS: From 1979 to 2002, 84 patients with biopsy-proven MF were referred to our department for TSEI, using the modified Christie Hospital translational technique until 1992 and the Stanford technique after 1992. Median total dose was 32 Gy (range 16-44) Christie; 30 Gy (range 15-36) Stanford. Underdosed areas were boosted with a median total dose of 10-20 Gy. RESULTS: During a median follow-up of 73 months (range 2-191) from the end of the TSEI, 12 (15%) patients developed 17 second primary tumors within the irradiated areas and 6 patients developed 7 second primary tumors, either simultaneously with the newly diagnosed MF or prior to introduction of radiation therapy. CONCLUSION: The long-term prognosis was related solely to the second primary. Due to excellent long-lasting response rates following TSEI coupled with long-term survival, and the prognosis mainly associated to the stage and histology of the second malignancy, physicians should be aware of the possibility of second primary tumors.

Chronic total occlusion due to diffuse in-stent restenosis: is brachytherapy the solution?

Percutaneous coronary intervention of chronic total occlusions (CTO) is associated with a significantly higher incidence of reocclusion and restenosis compared with non-total occlusions. Randomized and observational trials have demonstrated the effectiveness of intracoronary brachytherapy (ICBT) for the prevention of recurrent in-stent restenosis. However, limited data are available on the effectiveness of ICBT in patients with totally occluded in-stent restenosis. The authors assessed the long-term outcome of patients treated with intracoronary gamma radiation for totally occluded in-stent restenotic lesions. Percutaneous coronary intervention and subsequent catheter-based irradiation with iridium-192 was performed in 100 patients (103 vessels) with diffuse in-stent restenosis. At baseline, CTO of the target vessel at the site of the stent was present in 15 vessels (14.5%). Follow-up data were collected during follow-up visits and from telephone interviews. Repeat coronary angiography was performed in symptomatic patients with clinical restenosis. Clinical and angiographic characteristics were similar between the two groups, although there was a trend towards more unstable angina at the index procedure in CTO patients (66.7% versus 41.4%; p = 0.12) compared with patients without non-total occlusions. A higher percentage of patients (53.3%) with CTO required longer radiation sources (14 seeds, covering a length of 55 mm), compared with 23.9% of patients with non-total occlusion (p = 0.04). With a mean follow-up period of 47.5 +/- 24.0 months, major adverse cardiac events (MACE) were observed in 10 of 15 patients (66.7%) with CTO compared with 25 out of 88 patients (28.4%) without CTO (p = 0.009). According to multivariate analysis, total occlusion of the target vessel at baseline was the single independent predictor of MACE at one-year follow-up (relative risk 16.2, 95% confidence interval 4.2-62.9; p < 0.0001). This study shows that the use of gamma radiation for the prevention of recurrence of in-stent restenosis in patients with CTO does not seem to be as effective as in patients with non-total occlusions. Furthermore, CTO was an independent predictor of worse outcome at long-term follow-up in this study.

Total skin electron irradiation in mycosis fungoides: comparison between a modified Christie Hospital translational technique and the Stanford technique.

Seventy-one patients with mycosis fungoides (MF) were treated by Total skin electron irradiation (TSEI) using either a modified Christie Hospital translational technique (44 pts) or a six dual-field Stanford technique (27 pts). There was no statistical difference in response rate, disease-free survival and overall survival between the two irradiation techniques. However, the Stanford technique was significantly less toxic than the modified Christie Hospital technique.

A simple oral cone attachment for the Varian linear accelerator.

Lesions in the oral cavity are often treated with two opposed lateral fields. These include a significant amount of normal healthy tissue whose radiation tolerance is dose-limiting. The tumor dose can be boosted to tumorcidal levels by brachytherapy or by small electron fields directed straight on the lesion. We have developed a simple attachment to the standard electron applicator of the Varian Clinac 1800 that allows irradiation of small electron fields through acrylic tubes-the oral cones. These tubes have been evaluated in terms of depth dose and field profiles for 6, 9, 12, 16, and 20 MeV electrons using film for relative dosimetry. At these small field sizes there are significant changes in output factors, in the depth dose as well as in the effective size of the field, and a thorough dosimetric evaluation is imperative prior to treatment. The attachment can be manufactured locally at low cost. For reasons of patient safety the assembly is collapsible. In clinical practice the cone is directed directly on the tumor. For deep-seated lesions we use a penlight and a mirror for positioning.

Dose perturbation due to the presence of a prostatic urethral stent in patients receiving pelvic radiotherapy: an in vitro study.

Temporary metallic intraprostatic stent is a new alternative treatment for patients with urinary obstructive syndrome caused by prostate cancer. Definitive radiotherapy is a treatment of choice for localized prostate cancer. This study evaluates in vitro the effect of a urethral intraprostatic metallic stent on the dose absorbed by the surrounding tissue. The study was designed to mimic the conditions under which the prostatic stent is placed in the body during pelvic irradiation. A urethral stent composed of a 50% nickel-50% titanium alloy (Uracoil-InStent) was imbedded in material mimicking normal tissue (bolus) at a simulated body depth of 10 cm. The distribution of the absorbed dose of irradiation was determined by film dosimetry using Kodak X-Omat V film. Irradiation was done in a single field at the isocenter of a 6 MV linear accelerator with a field size of 7 x 7 cm. The degree of film blackening was in direct proportion to the absorbed dose. The measurements showed an increase in dose of up to 20% immediately before the stent and a decrease of up to 18% immediately after the stent. These changes occurred within a range of 1-3 mm from both sides of the stent. In practice, irradiation in prostate cancer is given by two pairs of opposed co-axial fields; a total of four fields (Box Technique). The dose perturbations are partly cancelled in a pair of opposed beams resulting in a net variation of +/- 4%; therefore, the presence of the intraprostatic stent should not influence radiotherapy planning for prostate cancer.

Clinical characteristics of non-Hodgkin's lymphoma as a second primary tumor: a population-based survey.

Data from 29,845 patients with lymphomas, 981 of whom had lymphoma as a second primary tumor, registered in the Surveillance Epidemiology and End Results (SEER) program in the U.S.A. between 1973 and 1986 were analyzed. The characteristics of the 274 patients with lymphoma as a second tumor who had received chemotherapy and/or radiotherapy for their primary tumor (SEP PT) were compared with 675 patients with second primary lymphomas who had no prior treatment (SEP NT) and with patients with single lymphomas (SIP). Patients with SEP PT disease had a significantly higher percentage of intermediate and high-grade tumors (80%) compared to those with SEP NT or SIP tumors (73% and 72%, respectively). The survival of all patients with SIP tumors did not differ from those with SEP tumors, but the median survival of those with SEP PT disease was shorter than for SEP NT disease. This was most probably due to the high percentage of intermediate and high-grade lymphomas in the SEP PT group. This was statistically significant in the group treated by combined chemotherapy and radiotherapy but not in those treated by a single modality alone. These findings relating to a worse prognosis in patients with SEP PT lymphoma are in line with our previous observations of a poor survival in patients with other multiple primary tumors.

The relation between wedge factors in air and water.

The wedge factor (WF) for an x-ray beam is defined as the ratio of doses with and without the wedge at a point on the central axis, in water. It is a function of depth d, field size s, and collimator setting c. It is demonstrated that WF can be calculated as WF(d,s,c) = WFairAw(d)Hw(c)/A0(d)H0(c), where WFair is a constant factor, namely, the ratio of the incident fluences measured "in air" with and without the wedge for reference conditions, e.g., at isocenter for a 10x10 cm2 collimator setting. Aw(d) and A0(d) are attenuation factors, and Hw(c) and H0(c) head-scatter factors, with and without the wedge and normalized to reference conditions. This expression is based on the approximation that the scatter factor is the same with and without the wedge. The field size, which affects the scatter factor, is therefore not an important variable for the wedge factor using this approach. The above relation has been evaluated at 6 and 25 MV for various depths (d < or = 25 cm) and field sizes (s < or = 25 cm) for built-in wedges (wedge angle approximately 60 degrees). The agreement was better than +/- 1.5%. This formulation of the wedge factor is easily implemented in calculations of dose and monitor settings.

A survey of methods to calculate monitor settings.

PURPOSE: The results of a survey of how radiation oncology institutions calculate the monitor setting (or time) to deliver the prescribed dose in a photon-beam treatment are presented. METHODS AND MATERIALS: The participants in the mail survey were 94 institutions in the Pediatric Oncology Group. They were asked to calculate for a hypothetical clinical case requiring the use of photon beams with corner blocks. A questionnaire was also distributed to gather supplemental information. RESULTS: Of the 94 institutions whose responses were analyzed, 77% selected an isocentric setup while the others used a "fixed-SSD" approach. The proportions were reversed for the choice of the reference geometry and the majority of the participants set one monitor unit equal to 1 cGy at depth of electron equilibrium with isocenter placed at the surface. The tissue-maximum ratio was the most popular quantity for description of beam characteristics, but several other choices were common. Different names were sometimes used for the same concept. CONCLUSION: The variation among institutions made the review time-consuming, but no serious systematic errors were detected. Some standardization of nomenclature and techniques may be desirable.

The pattern of diagnosis of a second primary tumor in the breast.

One hundred and sixty-seven patients with metachronous bilateral breast cancer were diagnosed at the Northern Israel Oncology Center during the years 1950-1989. The group at high risk to develop a second breast tumor included Jewish women born in Europe whose first tumor was diagnosed when the patient was under the age of 55. The mean time interval between tumors was 88 months. Seventy percent of the patients were diagnosed within nine years of the diagnosis of the first tumor. The characteristics of the 27% of patients with single breast cancers who did not comply with follow-up recommendations were compared to those who did comply. Patients who were under follow-up had smaller tumor and less lymph node involvement. Nevertheless, their survival rate did not differ from those who did not keep their follow-up appointments. This was ascribed to the fact that follow-up procedures for many years used mainly clinical examination and this was not enough to decrease mortality. The diagnosis of non-palpable breast cancer by routine yearly mammography has proved to reduce mortality in patients over the age of 50 with single breast cancers. Therefore, yearly mammography of the contralateral breast in patients with single breast tumors must be done in order to increase the cure rate of contralateral breast cancer. Less patient delay in diagnosis was found before the diagnosis of the second tumor than in patients with a single tumor.

A comparison of the clinical characteristics of second primary and single primary sarcoma: a population based study.

The clinical characteristics of 240 patients with sarcoma as a second metachronous primary neoplasm (SPN) were compared with those of 8,815 patients with sarcoma as a single tumor. The data were obtained from patients registered during the period 1973-1986 in the Surveillance, Epidemiology and End Results (SEER) Program in the United States. Seventy-four of the 240 SPN patients had postirradiation sarcoma (PIS) while the other 153 patients developed the sarcoma as a second tumor in an area which was not exposed to prior radiotherapy (non-PIS). The stage of disease at diagnosis was more advanced in patients with PIS than in those with single sarcomas but the difference did not reach statistical significance. Overall, in comparable clinical stage localized and regional disease there was no statistically significant difference in survival between PIS and non-PIS sarcoma patients after adjusting for age. The survival of patients with localized or regionally advanced sarcoma as a second tumor was significantly worse than of those with single sarcomas with the same stage. There was no difference in survival between first or second sarcomas with metastatic disease.