[en] Purpose/Objective: To determine the characteristics of the penumbra in the region of lung tumor-lung parenchyma interfaces for various radiation beam energies and various field margins. Materials and Methods: A phantom simulating the thoracic cavity with a tumor arising in the lung parenchyma was irradiated with opposed 6, 10, and 18 MV photon beams. Beam profiles were obtained at the tumor's surface and midplane using film. The field edge was varied from 0.0-3.5 cm from the tumor edge. The effective penumbra (distance from 80% to 20% dose) and 'beam fringe' (distance from 90% to 50% dose) were measured. Clinically acceptable beam profiles were defined as those in which no point of a target volume consisting of the tumor and a one centimeter margin received less than 95% of the dose prescribed to the center of the tumor. Results: Mean effective penumbra and 'beam fringe' were found to differ in a statistically significant manner with respect to energy, but not with distance from field edge to tumor. With the field edge ≤ 1.5 cm from the tumor, no energy provided a clinically acceptable dose distribution as defined above. With the field edge 2.0 cm from the tumor, 6 and 10 MV provided clinically acceptable dose distributions, but 18 MV did not. With the field edge ≥ 2.5 cm from the tumor, all energies provided clinically acceptable dose distributions. Conclusions: For irradiation of lung carcinomas in which the target volume includes a margin of normal lung tissue, 6 and 10 MV opposed beams yield a superior dose distribution with respect to penumbra at both the tumor's surface and midplane with the field edge placed 2.0 cm from the tumor edge. To achieve an equivalent distribution with 18 MV photons, a distance of 2.5 cm from field edge to tumor is necessary, leading to an increase in the normal lung tissue included within the treated volume

[en] Purpose: To determine the characteristics of the penumbra in the region of the lung tumor-lung parenchyma interfaces for various radiation beam energies and various field margins. Methods and Materials: A phantom simulating the thoracic cavity with a tumor arising within the lung parenchyma was irradiated with opposed 6-, 10-, and 18-MV photon beams. Beam profiles were obtained at the tumor's surface and midplane using radiographic film. The field edge varied from 0.0 to 3.5 cm from the gross tumor volume. The effective penumbra (distance from 80 to 20% dose) and beam fringe (distance from 90 to 50% dose) were measured. Clinically acceptable beam profiles were defined as those in which no point of the planning target volume (gross tumor volume plus a 1-cm margin) received less than 95% of the central tumor dose. Results: Mean effective penumbra and beam fringe were found to differ in a statistically significant manner with respect to energy, but not with distance from field edge to gross tumor volume. With the field edge ≤1.5 cm from the gross tumor volume, no energy provided an acceptable dose distribution, as defined above. With the field edge 2 cm from the gross tumor volume, 6 and 10 MV provided acceptable dose distributions, but 18 MV did not. With the field edge ≥2.5 cm from the gross tumor volume, all energies provided acceptable dose distributions. Conclusion: For irradiation of lung carcinomas in which the planning target volume includes a margin of normal lung tissue, 6- and 10-MV opposed beams yield a superior dose distribution with respect to penumbra at the tumor's surface and midplane, with the field edge placed 2 cm from the gross tumor volume. To achieve an equivalent distribution with 18-MV photons, a distance of 2.5 cm from field edge to the gross tumor volume is necessary, leading to an increase in normal lung tissue irradiated

[en] Purpose: Ionizing radiation (IR) triggers several intracellular signaling cascades that have commonly been regarded as mitogenic, including the Raf-MEK-Erk kinase cascade. In addition to promoting proliferation, activated MEK and Erk may also prevent cell death induced by cytotoxic stimuli. Because Raf, MEK, and Erk are activated by IR in some tumor cell lines, this suggests that IR-induced activation of the kinase cascade may enhance the survival of irradiated cells. Methods and Materials: IR-induced activation of MEK and Erk was assessed in irradiated UM-SCC-6 cells, a human squamous carcinoma cell line. Activation of MEK and Erk was blocked with the pharmacological inhibitor of MEK activation, PD098059. Clonogenic survival was assessed in irradiated UM-SCC-6 cells that were pretreated with nothing or with the MEK inhibitor. Results: In UM-SCC-6 cells, IR doses as low as 2 Gy rapidly activated MEK and Erk. Pretreatment of the cells with the pharmacological inhibitor of MEK activation, PD098059, effectively blocked IR-induced activation of MEK and Erk. However, inhibition of the kinase cascade did not affect the clonogenic survival of irradiated cells in either early or delayed-plating experiments. Conclusion: Taken together, these results suggest that although MEK and Erk are rapidly activated by IR treatment, these protein kinases do not affect the clonogenic survival of irradiated UM-SCC6 cells

[en] Purpose: The purpose of this retrospective study is to present the results of postoperative adjuvant radiotherapy after primary surgery for squamous cell carcinoma of the tongue base and to compare these results to those obtained with surgery alone. Methods: Between 1974 and 1993, continuous-course postoperative radiotherapy was delivered to 24 patients (Adjuvant Radiotherapy Group). Results were compared to those from a group of 55 patients treated with surgery alone (Surgery Group). Results: Characteristics of the two groups were similar, except that a larger proportion of patients in the Adjuvant Radiotherapy Group had higher pathologic TNM stages. Ipsilateral neck control (87% vs. 68%, p = 0.04), contralateral neck control (100% vs. 76%, p = 0.002), relapse-free survival (64% vs. 46%, p = 0.04), and control above the clavicles (80% vs. 48%, p 0.007) were significantly higher in the Adjuvant Radiotherapy Group compared to those in the Surgery Group (5-year figures shown). Conclusion: The use of adjuvant radiotherapy after surgical resection of tongue base squamous cell carcinoma significantly decreased the rate of local-regional recurrence and improved relapse-free survival compared with surgery alone but did not alter cause-specific or overall survival

[en] Purpose: To evaluate changes in preoperative and postoperative positions of structures used to define target volumes (i.e., pancreatic bed, porta hepatis, local-regional lymph nodes) for postoperative irradiation of pancreatic malignancies as defined by abdominal computed tomographs. Methods and Materials: Eleven consecutive patients who had Whipple resection and postoperative irradiation for pancreatic cancer were evaluated. Preoperative and postoperative computed tomographs of each patient were evaluated for the position of the portal vein bifurcation and the origin of the celiac axis and superior mesenteric artery. The length along the x (medial-lateral position) and y (anterior-posterior position) axes was determined with calipers to the closest millimeter. Length along the z axis (cephalad-caudad position) was determined with the computed tomographic sectional interval between images. Statistical significance of the change in the structure's position along the x, y, or z axis between preoperative and postoperative computed tomographs was assessed with the paired t-test. Results: Evaluation of the preoperative and postoperative positions of the portal vein, celiac axis, and superior mesenteric artery along the x, y, and z axes revealed a statistically significant change in the location of the portal vein and celiac axis postoperatively. The median change of the celiac axis in the anterior-posterior position was significant (p = 0.0047), but the mean change was only 2 mm and not considered clinically significant. The median change for the portal vein was 0.97 cm and 1.07 cm along the y and x axes, respectively, and was significant (p = 0.008 and p = 0.0001). The range in position change for the portal vein was 0.0 to 2.0 cm along the y axis and 0.4 to 1.9 along the x axis. The remaining mean changes in position along all axes for all the structures were less than 3 mm (not statistically significant). Conclusions: The mean position of the portal vein-porta hepatis after Whipple resection is approximately 1.0 cm medial and 1.0 cm posterior compared with its preoperative position. These data suggest that postoperative abdominal computed tomographs are useful in determining treatment volumes of nodal drainage basins after Whipple resection of pancreatic malignancies

[en] Background: Previous studies of patients with surgically resected non-small cell lung cancer and chest wall invasion have shown conflicting results with respect to prognosis. Whether high-risk subsets of the T3 N0 M0 population exist with respect to patterns of failure and overall survival has been difficult to ascertain, owing to small numbers of patients in most series. Methods and Materials: A retrospective review was performed to determine patterns of failure and overall survival for patients with completely resected T3 N0 M0 non-small cell lung cancer. From 1979 to 1993, 92 evaluable patients underwent complete resection for T3 N0 M0 non-small cell lung cancer. The following potential prognostic factors were recorded from the history: tumor size, location, grade, histology, patient age, use of adjuvant radiation therapy (18 of 92 patients), and type of surgical procedure (chest wall or extrapleural resection). Results: The actuarial 2- and 4-year overall survival rates for the entire cohort were 48% and 35%, respectively. The actuarial local control at 4 years was 94%. Neither the type of surgical procedure performed nor the addition of thoracic radiation therapy impacted local control or overall survival. Conclusion: Patients with completely resected T3 N0 M0 non-small cell lung cancer have similar local control and overall survival irrespective of primary location, type of surgery performed, or use of adjuvant radiation therapy. Additionally, the tumor recurrence rate and overall survival found in this study support the placement of this group of patients in Stage IIB of the 1997 AJCC lung staging classification

[en] Purpose: Patients with pathologically staged American Joint Committee on Cancer stage I (T1 N0 or T2 N0) non-small cell lung cancer have a favorable prognosis after complete surgical resection compared with patients with more advanced stages. Benefits of adjuvant therapy in this setting are unproved. However, there may be subgroups of patients with stage I disease at high enough risk for local recurrence to prompt consideration of adjuvant or neoadjuvant radiation therapy. Likewise, there may be subgroups of patients at high enough risk for distant metastasis to justify the evaluation of chemotherapy. Methods and Materials: From 1987 through 1990, 370 patients undergoing gross total resection of non-small cell lung cancer had stage I disease and received no chemotherapy or radiation therapy as part of their primary treatment. These patients were the subject of a retrospective review to separate patients into high-, intermediate-, and low-risk groups with respect to freedom from local recurrence (FFLR), freedom from distant metastasis (FFDM), and overall survival by using a regression tree analysis. Results: The 5-year rates of FFLR, FFDM, and survival were 85%, 83%, and 66%, respectively. Regression analyses revealed that the factors independently predicting for a poorer FFLR rate included fewer than 15 lymph nodes dissected and pathologically evaluated (p = 0.002) and the presence of a T2 tumor (p = 0.04). Factors independently predicting for a poorer FFDM rate included a maximal dimension greater than 5 cm (p = 0.02) and non squamous histology (p = 0.03). Factors independently predicting for a poorer survival rate included fewer than 15 lymph nodes dissected and pathologically evaluated (p = 0.001) and a maximal dimension greater than 3 cm (p = 0.003). Regression tree analyses were used to separate patients into risk groups. Conclusion: Incorporating the aforementioned factors into regression tree analyses, three risk groups were identified with respect to FFLR. Two each were identified for FFDM and for survival. For each of these three end-points, the differences in outcomes for each risk group were found to be both statistically and clinically significant. These risk groups may be useful in the future design of phase III trials evaluating the use of adjuvant chemotherapy and radiation therapy in the stage I setting

[en] Purpose: In the treatment of thoracic malignancies with radiotherapy, the critical dose-limiting structure is the spinal cord. Oblique fields typically are designed to exclude the spinal cord, and by convention, the field edge that shields the spinal cord is placed at the anterior border of the vertebral pedicles. Thus, the purpose of our study was to estimate the distance between the field edge and spinal cord in oblique fields that were designed by using the vertebral pedicle as a radiographic landmark. Methods and Materials: The spinal cord of a cadaver was wrapped in wire, and oblique fields were simulated at 15 deg. intervals. The distance from the spinal cord to a field edge placed at the anterior border of the pedicle was measured. In the second investigation, a three-dimensional treatment planning system was used to simulate hypothetical fields using actual patient data from computed tomography (n = 10), and measurements identical to those in the anatomical model were made (n = 1,100). Results: The results of the anatomical and computed tomographic models were in close agreement (mean difference, 0.6 mm). The computed tomographic model predicted a mean field edge to spinal cord distance of 8.7 mm (95% confidence interval, 5.6-11.8 mm) for (30 deg. (150 deg.)) oblique fields and 8.0 mm (95% confidence interval, 4.7-11.7 mm) for (45 deg. (135 deg.)) oblique fields. This distance was greatest at levels T-1, T-2, and T-11 (8 to 20% greater). Conclusions: The mean distance from a field edge placed at the anterior border of a vertebral pedicle to the spinal cord for commonly used oblique angles constitutes a sufficient margin to account for expected differences in daily positional variations and mechanical uncertainties

[en] Purpose: This Phase I study combines tegafur and uracil (UFT) with leucovorin and conventional radiation for the treatment of pancreatic cancer. The design seeks to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of this regimen as well as to define a future Phase II dose level. Methods: Patients with locally advanced and unresectable pancreatic cancer were treated with 45 Gy of radiation therapy. The initial UFT dose was 150 mg/m²/day given with leucovorin 90 mg/day, both divided into 3 daily doses for 35 days concurrent with radiation. UFT doses were escalated at increments of 50 mg/m²/day. Dose-limiting toxicity (DLT) was defined as Grade 3 or greater nausea, vomiting or diarrhea despite medical intervention; or Grade 3 or greater neutropenia/thrombocytopenia; or Grade 3 or greater hepatic toxicity; or inability of the patient to take 75% or more of the planned UFT/leucovorin; or radiotherapy interruption of greater than 1 week. The MTD for UFT/leucovorin was exceeded by one dose level when a certain dose caused DLT in 2 or more patients of 6. Results: Five evaluable patients had Stage I resectable disease but had pathologic adenopathy. Seven had Stage II unresectable disease. Compliance with therapy was excellent. At a daily dose of 300 mg/m² of UFT, we noticed minimal diarrhea and hematologic toxicity with mild-moderate nausea, anorexia, and fatigue. Three patients had Grade 4 toxicity: 1 had neutropenia on Day 38, 1 had diarrhea on Day 55, and 1 had vomiting on Day 15. Conclusion: Oral UFT/leucovorin and radiation therapy offers patients a viable treatment option for pancreatic cancer. The major known toxicity of diarrhea was tolerable. The MTD was not reached in this study. Our current plan is to expand this into a Phase I/II trial beginning at a UFT dose of 300 mg/m² and correlate this with clinical pharmacologic parameters. The potential benefit of long bioavailability and oral delivery of UFT compares favorably with continuous infusion regimens without the added morbidity of a catheter and pump

[en] Purpose: When mediastinal lymph nodes are clinically uninvolved in the setting of inoperable non-small cell lung cancer, whether conventional radiation techniques or three-dimensional dose-escalation techniques are used, the benefit of elective nodal irradiation is unclear. Inclusion of the clinically negative mediastinum in the radiation portals increases the risk of lung toxicity and limits the ability to escalate dose. This analysis represents an attempt to use clinical characteristics to estimate the risk of subclinical nodal involvement, which may help determine which patients are most likely to benefit from elective nodal irradiation. Methods: From 1987 to 1990, 346 patients undergoing complete resection of non-small cell lung cancer underwent a preoperative computed tomographic scan revealing no clinical evidence of N2/N3 involvement. Multivariate regression and regression tree analyses attempted to define which patients were at highest risk for subclinical mediastinal involvement (N2) and which patients were at highest risk for subclinical N1 and/or N2 involvement (N1/N2). Immunohistochemical data suggest that the conventional histopathologic techniques used during this study somewhat underestimate the true degree of lymph node involvement; therefore, a third end point was also evaluated: N1 involvement and/or N2 involvement and/or local-regional recurrence (N1/N2/LRR). Results: Regression analyses revealed that the following factors were independently associated with a high risk of more advanced disease: positive preoperative bronchoscopy (N2, p = 0.02; N1/N2, p < 0.0001; N1/N2/LRR, p < 0.001) and tumor grade 3/4 (N1/N2/LRR, p < 0.01). A regression tree analysis was then used to separate patients into risk groups with respect to N1/N2/LRR. Conclusion: In inoperable non-small cell lung cancer, the patients for whom mediastinal radiation therapy may most likely be indicated are those with a positive preoperative bronchoscopy, especially with large (> 3 cm) primary tumors