Wound healing following combined radiation and cetuximab therapy in head and neck cancer patients.

OBJECTIVE: This study set out to determine if cetuximab treatment increases the risk of wound healing complications when combined with radiation therapy. METHOD: We performed a retrospective chart review of head and neck cancer patients who received salvage neck dissections between 1999 and 2007, at two academic tertiary care centres. Complications from wound healing were compared between radiation and combined therapy groups. RESULTS: A total of 35 patients received radiation (n=20) or combined radiation and cetuximab therapy (n=15) prior to neck dissection. The treatment groups were similar in regard to demographic and primary tumour-related characteristics. The time between treatment and salvage neck dissection did not differ between the radiation (3.9 months) and combination treatment (3.0 months) groups (p=0.15). Wound healing complications occurred in 13% (2/15) of the patients treated with radiation and cetuximab and there were no complications in patients who received radiation alone (p=0.20). CONCLUSION: Cetuximab did not significantly increase the risk of post-surgical wound complications, although a higher absolute number of wound complications was observed in the group treated with cetuximab and radiation therapy, compared with the group treated with radiation alone. CONFLICT OF INTEREST: This work was supported by a grant from the National Institute of Health (2T32 CA091078-06). One of the authors, JAB, is an occasional consultant and honoraria for ImClone and Bristol-Meyers Squibb.

Limited-stage small-cell lung cancer: patterns of intrathoracic recurrence and the implications for thoracic radiotherapy.

PURPOSE: This analysis was performed to determine the most appropriate volume that should be encompassed by thoracic radiation treatments (TRTs) for patients with limited-stage small-cell lung cancer (LSSCLC) who have responded to initial chemotherapy. PATIENTS AND METHODS: A retrospective review of all patients (N = 67) with LSSCLC who were not entered onto a research protocol and were treated at our institution between the years of 1982 and 1990 was performed. Fifty-nine of 67 patients had adequate information regarding the size of the tumor before the start of chemotherapy (computed tomographic [CT] scan of chest or chest x-ray), the size of the tumor before TRT, and the TRT field size based on a simulation radiography. All 59 patients were treated with cyclophosphamide-based chemotherapy, and TRT was generally delivered concomitantly with chemotherapy following two to three cycles of chemotherapy alone. RESULTS: Of 59 patients, 28 were treated with TRT field sizes that encompassed postchemotherapy tumor volumes, and 31 patients were treated with TRT field sizes that encompassed prechemotherapy tumor volumes (defined as a volume that included at least a 1.5-cm margin on the prechemotherapy tumor volume). Nineteen patients had an intrathoracic recurrence of disease as the first site of recurrent small-cell carcinoma: 10 of 31 patients treated with TRT fields that encompassed prechemotherapy tumor volumes and nine of 28 patients treated with TRT fields that encompassed postchemotherapy tumor volumes. For the 28 patients treated with TRT fields that encompassed postchemotherapy tumor volumes, the greatest distance that the prechemotherapy tumor volume (without margins) extended beyond the edge of the TRT field was 0.5 to 5.0 cm, with a median of 2.5 cm. All 19 of the intrathoracic recurrences were in-field failures, although two patients (one prechemotherapy volume and one postchemotherapy volume) did have concurrent pleural effusions. CONCLUSION: These results indicate that the use of TRT fields that encompass postchemotherapy tumor volumes does not increase the risk of marginal failures or intrathoracic failures outside the TRT field.

Phase I study of anti--epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer.

PURPOSE: To evaluate the safety, pharmacokinetics, and efficacy of a chimeric anti-epidermal growth factor receptor monoclonal antibody, cetuximab, in combination with radiation therapy (RT) in patients with advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: We treated 16 patients in five successive treatment schedules. A standard dose escalation procedure was used; three patients entered onto the study at each dose level of cetuximab received conventional RT (70 Gy, 2 Gy/d), and the final three patients received hyperfractionated RT (76.8 Gy, 1.2 Gy bid). Cetuximab was delivered as a loading dose of 100 to 500 mg/m(2), followed by weekly infusions of 100 to 250 mg/m(2) for 7 to 8 weeks. Circulating levels of cetuximab during therapy were determined using a biomolecular interaction analysis core instrument. Human antichimeric antibody response was evaluated with a double-antigen radiometric assay. The recommended phase II/III dose was defined as the optimal cetuximab dose level based on the pharmacologic parameters and adverse events. RESULTS: The most commonly reported adverse events were fever, asthenia, transaminase elevation, nausea, and skin toxicities (grade 1 to 2 in most patients). Skin toxicity outside of the RT field was not strictly dose-dependent; however, grade 2 or higher events were observed in patients treated with higher dose regimens. There was one grade 4 allergic reaction. Most acute adverse effects were associated with RT (xerostomia, mucositis, and local skin toxicity). No antibodies against cetuximab were detected. All patients achieved an objective response (13 complete and two partial remissions). CONCLUSION: Cetuximab can be safely administered with RT. The recommended dose for phase II/III studies is a loading dose of 400 to 500 mg/m(2) and a maintenance weekly dose of 250 mg/m(2).

Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma.

PURPOSE: Because small-cell lung cancer is a rapidly proliferating tumor, it was hypothesized that it may be more responsive to thoracic irradiation (TI) given twice-daily than once-daily. This hypothesis was tested in a phase III trial. PATIENTS AND METHODS: Patients with limited-stage small-cell lung cancer were entered onto a phase III trial, and all patients initially received three cycles of etoposide (130 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). Subsequently, patients who did not have progression to a distant site (other than brain) were randomized to twice-daily thoracic irradiation (TDTI) versus once-daily thoracic irradiation (ODTI) given concomitantly with two additional cycles of etoposide (100 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). The irradiation doses were TDTI, 48 Gy in 32 fractions, with a 2.5-week break after the initial 24 Gy, and ODTI, 50.4 Gy in 28 fractions. After thoracic irradiation, the patients received a sixth cycle of etoposide/cisplatin, followed by prophylactic cranial irradiation (30 Gy/15 fractions) if they had a complete response. RESULTS: Of 311 assessable patients enrolled in the trial, 262 underwent randomization to TDTI or ODTI. There were no differences between the two treatments with respect to local-only progression rates, overall progression rates, or overall survival. The patients who received TDTI had greater esophagitis (> or = grade 3) than those who received ODTI (12.3% v 5.3%; P =.05). Although patients received thoracic irradiation encompassing the postchemotherapy volumes, only seven of 90 local failures were out of the portal of irradiation. CONCLUSION: When TI is delayed until the fourth cycle of chemotherapy, TDTI does not result in improvement in local control or survival compared with ODTI.

Enhanced apoptosis with combination C225/radiation treatment serves as the impetus for clinical investigation in head and neck cancers.

PURPOSE: Epidermal growth factor receptor (EGFr) is overexpressed in a majority of head and neck squamous cell carcinomas, and this overexpression is associated with a poor prognosis. Therefore, EGFr has become the target of investigations aimed at disabling the receptor to determine whether this process leads to improved tumor kill with conventional treatment. MATERIALS AND METHODS: C225 is an anti-EGFr monoclonal antibody that inhibits receptor activity by blocking the ligand binding site. A panel of human head and neck squamous cell carcinoma cell lines was used to study the combination of C225 and radiation. RESULTS: It was determined that the combination of C225 (5 microgram/mL) delivered simultaneously with radiation (3 Gy) resulted in a greater decrement in cellular proliferation than either treatment alone. This reduction in proliferation correlated with reduced EGFr tyrosine phosphorylation and a reduction in phosphorylated signal transducer and activator of transcription-3 (STAT-3) protein (known to protect cells from apoptosis). Also, the decrement in proliferation correlated with increased apoptotic events, thereby indirectly linking C225/radiation-induced regulation of STAT-3 protein to apoptosis. CONCLUSION: This preclinical work serves as important support for the ongoing clinical investigation of C225 and radiotherapy for patients with head and neck carcinomas. The initial results of these clinical studies have been promising.

Significance of neuron-specific enolase levels before and during therapy for small cell lung cancer.

The level of serum neuron-specific enolase (NSE) has been implicated as a prognostic factor for patients with small cell lung cancer (SCLC). A prospective evaluation was undertaken to assess the prognostic significance of pretreatment NSE and treatment-induced minimum NSE values in patients with SCLC. Patients from two Phase III North Central Cancer Treatment Group trials [one for patients with extensive stage SCLC and one for patients with limited stage SCLC] were asked to enter this laboratory correlational trial. Both trials included treatment with four to six cycles of etoposide and cisplatin, and 121 patients (71 extensive stage SCLC and 50 limited stage SCLC) were entered into the present study of NSE. Pretreatment NSE values and treatment-induced minimum NSE values were independent predictors of time to progression and survival in multivariate analysis. Hazard rate modeling allowed the formulation of specific relationships of NSE to time to progression and survival. Pretreatment NSE levels inversely correlated with time to progression and survival in these patients with SCLC. Pretreatment NSE accounted for 28% of the variance in survival. Both pretreatment NSE and treatment-induced minimum NSE were independent prognostic predictors of time to progression and survival.

Unresectable or medically inoperable non-small cell lung cancer: the use of established clinical prognostic factors in making radiation-related treatment decisions.

Many physicians consider the prognosis exceptionally poor for patients with localized non-small cell lung cancer who are not eligible for surgery, either because of the extent of their disease or because a coexisting medical condition precludes surgery. Thus, these patients frequently are not offered aggressive curative therapy. However, the disease of many of these patients is potentially curable and should be considered for curative treatment. Although pathologic data from surgical specimens are useful in predicting prognosis, many prognostic factors have also been identified for medically inoperable and locally advanced, unresectable disease. Several of these prognostic factors can and should be used clinically to estimate the risk of lymph node involvement within the clinically uninvolved mediastinum, thereby aiding in the design of radiation therapy fields, and to estimate prognosis, thereby helping to determine which patients should be offered aggressive therapy with curative intent.

Postoperative irradiation in non-small cell lung cancer.

A growing body of evidence suggests that postoperative irradiation for non-small cell lung cancer may cause life-threatening toxicity and, when the risk of local-regional recurrence is low, the toxicity of irradiation may outweight the benefit. However, many of these studies used outdated, even crude techniques. Although these techniques may be responsible for a significant amount of the toxicity reported in these studies, essentially no randomized or high-quality retrospective study has shown a survival benefit for postoperative irradiation for patients with N0 or N1 disease. The situation for N2 tumors is more positive. Taken as a whole, the available data suggest that, as a worst-case scenario, the net effect of adjuvant irradiation is neutral (with neither a net survival decrement nor a net advantage). As a best-case scenario, postoperative irradiation may improve the chance for long-term survival in patients with N2 tumors.

Point: the potential importance of elective nodal irradiation in the treatment of non-small cell lung cancer.

Patients who receive radiation therapy for non-small cell lung cancer (NSCLC) will require accurate targeting of the grossly involved primary and nodal disease. However, the treatment of grossly uninvolved elective nodal sites that may harbor microscopic occult disease is controversial. In simple terms, physicians are guided by 1 of 2 paradigms when they decide about the use of elective nodal irradiation in NSCLC. First, one may consider that high doses of radiation therapy for the primary and grossly involved lymph nodes represents the most important aspect of treatment and that elective irradiation of potential occult micrometastasis is not necessary because it may limit the doses that can be given to the gross disease. Additionally, this line of thought often includes the belief that most or all patients with occult micrometastasis are not curable. Alternatively, one may consider that the evidence for a dose response, for grossly involved NSCLC, beyond 60 Gy is very limited and that the omission of elective nodal irradiation obviates the chance for cure in many patients. These small deposits of tumor in regional nodes are common, are amenable to low doses of radiation (50 Gy), and treatment of these lesions does result in cures. This review focuses on this latter paradigm and the available evidence to support it.

Protection of doxorubicin cytotoxicity by cycloheximide.

The effect of cycloheximide (an inhibitor of cellular protein synthesis) on doxorubicin-induced cytotoxicity in V79 (rodent fibroblasts) cells was investigated. Cycloheximide is a potent protector of doxorubicin-induced cytotoxicity at concentrations paralleling those required for protein synthesis inhibition. The greatest protective effect was achieved at 10 microM cycloheximide; this concentration correlated with 95% inhibition of protein synthesis. A 15 minute cycloheximide (10 microM) exposure resulted in maximal protein synthesis inhibition; however, 4-6 hr of pretreatment with cycloheximide (10 microM) was required to maximally protect cells from doxorubicin. These results suggest that a time-dependent depletion of a protein is required for cycloheximide's protective effect. Cycloheximide treatments were found to decrease intracellular accumulation of doxorubicin by 35-50% but this decrease accounts for only a small fraction of the total protective effect. When corrections were made for differences in doxorubicin accumulation, cycloheximide had no effect on the formation of DNA-protein crosslinks (DNA-topoisomerase II complexes revealed as single strand DNA breaks in alkaline elution studies). These studies suggest that cycloheximide confers protection from doxorubicin cytotoxicity by a step which occurs following the stabilization of DNA-topoisomerase II complexes.

Interaction of buthionine sulfoximine and the stabilization of DNA-topoisomerase II complexes by doxorubicin.

Although it has been shown previously that the depletion of cellular thiols increases doxorubicin cytotoxicity, the mechanism of sensitization is not clear. To study this question, the effect of D,L-buthionine-S,R-sulfoximine (BSO) on doxorubicin cytotoxicity and the stabilization of DNA-topoisomerase II complexes (cleavable complexes) was investigated in V79 cells. Incubations with BSO (10 mM) were for 5 hr beginning 4 hr prior to doxorubicin exposure since a 4 hr incubation with 10 mM BSO is known to decrease glutathione levels below 5% of control V79 cells. These BSO pre-treatment increased doxorubicin cytotoxicity. At doxorubicin concentrations of 5 micrograms/ml, BSO resulted in an 8-10 fold decrease in surviving cells, compared to cells exposed to doxorubicin alone. It was determined that BSO pre-treatments did not affect the accumulation of doxorubicin into the cell, the rate of cleavable complex stabilization by doxorubicin, or the rate of dissociation of stabilized cleavable complexes. These data suggest that BSO-induced doxorubicin sensitization occurs at a step following the stabilization of cleavable complexes or by an independent mechanism.

Impact of beam energy and field margin on penumbra at lung tumor-lung parenchyma interfaces.

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 < or = 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 > or = 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.

A phase I study of combined UFT plus leucovorin and radiotherapy for pancreatic cancer.

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/m(2)/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/m(2)/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/m(2) 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/m(2) 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.

Patients with stage I non-small cell lung carcinoma at postoperative risk for local recurrence, distant metastasis, and death: implications related to the design of clinical trials.

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 nonsquamous 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.

Patterns of failure and overall survival in patients with completely resected T3 N0 M0 non-small cell lung cancer.

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.

Ionizing radiation-induced MEK and Erk activation does not enhance survival of irradiated human squamous carcinoma cells.

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.

The interaction of epidermal growth factor and radiation in human head and neck squamous cell carcinoma cell lines with vastly different radiosensitivities.

PURPOSE: This study was performed to characterize the interaction of epidermal growth factor and radiation in two human head and neck squamous cell cancer cell lines of vastly different radiosensitivities (UM-SCC-6 Radiosensitive; UM-SCC-1 radioresistant). METHODS AND MATERIALS: The two human head and neck squamous cell cancers (UM-SCC-1 and UM-SCC-6) were grown in medium and following the appropriate treatments, cell survival was assessed by a standard colony formation assay. Growth inhibition was assessed by monitoring cell counts following treatment and flow cytometry was used to assess cell cycle distributions. RESULTS AND CONCLUSION: It was determined that exposure to epidermal growth factor (10 ng/ml) for 24 h prior to radiation resulted in radiosensitization in both cell lines, however, the magnitude of radiosensitization was greater in the radiosensitive UM-SCC-6 cells compared to the radioresistant UM-SCC-1 cells. Treatment of the UM-SCC-6 cells with epidermal growth factor (EGF) (10 ng/ml) for 24 h resulted in a growth delay, however, cell growth returned to normal approximately 24 h following removal of EGF. Similar treatment of the UM-SCC-1 cells resulted in no growth inhibition. The 24 h pre-radiation exposures to EGF (10 ng/ml) did not affect the radiation-induced growth delay in either cell line. Additionally, the 24 h exposures to EGF (10 ng/ml) did not affect the radiation-induced growth delay in either cell line. Additionally, the 24 h exposures to EGF (10 ng/ml) did not cause the cells to enter a more radiosensitive cell cycle phase. Further work will be necessary to determine whether events associated with the EGF-induced growth delay in the UM-SCC-6 cells are associated with the enhanced EGF-induced radiosensitization in these cells compared to UM-SCC-1 cells.

Adjuvant radiotherapy for squamous cell carcinoma of the tongue base: improved local-regional disease control compared with surgery alone.

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.

Postoperative localization of porta hepatis and abdominal vasculature in pancreatic malignancies: implications for postoperative radiotherapy planning.

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.

Treatment of stage IE primary lymphoma of bone.

PURPOSE: A retrospective analysis was performed to assess the efficacy of various treatments of Stage IE primary non-Hodgkins lymphoma of bone. METHODS AND MATERIALS: Sixty-three patients with Stage IE primary non-Hodgkins lymphoma of bone (single osseous focus) were seen at our institution between the years 1970 and 1989. Information was obtained regarding each patients' presentation and clinical course. The histology was reviewed in all patients. Modern immunohistochemical stains were performed on each case with available paraffin-embedded tissue. RESULTS: The histologic classification of the tumors was as follows: 43 diffuse large cell, 13 diffuse mixed cell, 3 small noncleaved, and 4 unclassified. The most common presenting symptom was pain (97%) and the following bony sites were involved: 36 long bone, 9 flat bone, 13 spine, and 5 pelvis. Of the 63 cases, 50 were treated with radiation alone, 10 with chemotherapy and radiation, 2 with chemotherapy alone, and 1 with surgery alone. Univariate analysis revealed a suggestion of an improved 5-year disease-free survival for patients treated with chemotherapy and radiation vs. radiation alone (90% vs. 57% respectively, p = .08). Multivariate analysis (controlling for extent of initial evaluation, extent of pathological evaluation and other potential prognostic factors) showed that neither treatment resulted in superior outcome with respect to disease-free survival, disease specific survival, or overall survival, however, doses of radiation greater than 4000 cGy resulted in improved overall survival compared to lower doses (p = 0.01). CONCLUSION: This study supports the use of primary RT (> 4000 cGy) for Stage IE PLB, however, the addition of chemotherapy to the radiotherapeutic management may decrease the initial relapse rate of some patients. Future studies should address this question.