Pre-Chemoradiotherapy FDG PET/CT cannot Identify Residual Metabolically-Active Volumes within Individual Esophageal Tumors.

OBJECTIVE: To study whether subvolumes with a high pre-chemoradiotherapy (CRT) FDG uptake could identify residual metabolically-active volumes (MAVs) post-CRT within individual esophageal tumors. Accurate identification will allow simultaneous integrated boost to these subvolumes at higher risk to improve clinical outcomes. METHODS: Twenty patients with esophageal cancer were treated with CRT plus surgery and underwent FDG PET/CT scans before and after CRT. The two scans were rigidly registered. Seven MAVs pre-CRT and four MAVs post-CRT within a tumor were defined with various SUV thresholds. The similarity and proximity between the MAVs pre-CRT and post-CRT were quantified with three metrics: fraction of post-CRT MAV included in pre-CRT MAV, volume overlap and centroid distance. RESULTS: Eight patients had no residual MAV. Six patients had local residual MAV (SUV ≥2.5 post-CRT) within or adjoining the original MAV (SUV ≥2.5 pre-CRT). On average, less than 65% of any post-CRT MAVs was included in any pre-CRT MAVs, with a low volume overlap <45%, and large centroid distance >8.6 mm. In general, subvolumes with higher FDG-uptake pre-CRT or post-CRT had lower volume overlap and larger centroid distance. Six patients had new distant MAVs that were determined to be inflammation from radiation therapy. CONCLUSIONS: Pre-CRT PET/CT cannot reliably identify the residual MAVs within individual esophageal tumors. Simultaneous integrated boost to subvolumes with high FDG uptake pre-CRT may not be feasible.

Analysis of pathological complete response rates with paclitaxel-based regimens in trimodality therapy for esophageal cancer.

The study aimed to examine whether omission of 5-fluorouracil (5-FU)-containing chemotherapy alters pathological complete response rates in patients receiving trimodality therapy for locally advanced esophageal cancer. A total of 159 patients were identified. One hundred twenty-nine patients received platinum/5-FU concurrently with radiotherapy, and 30 received taxane/platinum-containing chemoradiotherapy prior to esophagectomy. Patients were staged using the 2002 American Joint Committee on Cancer staging system. Patients were matched between chemotherapeutic groups, with no significant demographic or clinical differences other than T stage (14% T2 in the 5-FU group; no T2 in the platinum/taxane group) and radiotherapy technique (8.5% received intensity-modulated radiotherapy in the 5-FU group; 60% in the platinum/taxane group). Pathological complete response rates for 5-FU and platinum/taxane-based groups were not significantly different (45% and 30%, respectively; P = 0.1548). Five-year overall survival and progression-free survival were not statistically different between the two groups. Significant predictors of pathological complete response included N stage (56% N0 and 33% N1; P = 0.0083), histology (37% adenocarcinoma and 59% squamous cell; P = 0.0123), tumor location (39% distal and 59% proximal/mid; P = 0.048), gastroesophageal junction involvement (33% involved and 55% uninvolved; P = 0.005), and radiotherapy end-to-surgery interval (50% < 55 days and 34% ≥ 55 days; P = 0.04). Grades 3-4 hematological toxicity was higher in the 5-FU group (36%) than in the paclitaxel-containing therapy group (17%; P = 0.0484). Use of paclitaxel-containing chemoradiotherapy did not result in inferior pathological complete response, overall survival, or progression-free survival rates, and resulted in less hematological toxicity than 5-FU treatment.

SU-D-BRB-04: FDG-PET Histogram Distances: Novel Predictors of Tumor Response to Chemoradiotherapy.

PURPOSE: To examine the accuracy of FGD-PET histogram distances as predictors of pathologic tumor response to chemo-radiotherapy (CRT) in esophageal cancer. METHODS: Twenty patients were included. A rigid registration was used to align the post-CRT PET/CT with the pre-CRT PET/CT images. The primary tumor was delineated using a region-growing algorithm with a threshold of SUV = 2.5 on the pre-CRT PET. Two histograms of SUVs within the tumor were constructed on the pre-CRT PET and registered post-CRT PET, respectively. The differences between the two histograms reflected changes in the SUV distribution and were therefore potential predictors of tumor response. The differences were quantitatively measured by histogram distances using 12 bin-to-bin and 8 cross-bin algorithms. The accuracy of histogram distances in predicting pathologic tumor response to CRT was measured using the area under ROC curve (AUC), prediction accuracy, and the Mann-Whitney tests, in comparison with traditional PET response measures and texture features. RESULTS: Cross-bin histogram distances were shown to be significant (p<0.05) predictors of pathologic tumor response. They were more accurate than bin- to-bin histogram distances (not significant). The most accurate cross-bin histogram distances were: Quadratic-Chi distance (AUC=0.89, accuracy=80%, p=0.003), Earth Mover distance (AUC=0.83,accuracy=80%, p=0.014), diffusion distance (AUC = 0.82, accuracy=85%, p=0.02) and Match distance (AUC = 0.79, accuracy=80%, p=0.03). This family of novel predictors were more accurate than traditional PET response measures using SUVmax (AUC=0.76, accuracy=75%, p=0.05), SUVpeak (AUC=0.74, accuracy=70%, p=0.08), Total Glycolytic Volume (AUC=0.76, accuracy=70%, p=0.05), as well as texture features based on the cooccurrence matrix (Inertia: AUC=0.85, accuracy=80%, p=0.01). CONCLUSIONS: The cross-bin histogram distances characterized changes in the SUV distribution within a tumor and showed high accuracy for the prediction of pathologic response to CRT in esophageal cancer. This workwas supported in part by the National Cancer Institute Grant R21 CA131979.

Trimodality treatment versus surgery alone for esophageal cancer. A stratified analysis with minimally invasive pretreatment staging.

BACKGROUND: Accurate pretreatment staging of esophageal cancer (EC) is important in the evaluation and comparison of results of different treatment modalities. Few studies using minimally invasive staging techniques for this purpose have been reported. We previously demonstrated the usefulness of the thoracoscopic/laparoscopic (Ts/Ls) technique in pretreatment staging of EC. This study was conducted to evaluate the impact of trimodality based on pretreatment Ts/Ls staging diagnosis on EC. METHODS: A retrospective study was performed on 2 groups of EC patients. Group A (44 patients) underwent pretreatment Ts/Ls staging and had trimodality treatment. Preoperative therapy consisted of concurrent chemotherapy (5-FU + cisplatinum) and radiotherapy. Group B (33 patients) underwent surgery alone. The study focused on stratified comparison of patterns of recurrence and survival in different pretreatment surgical T, N, and TNM stage categories. RESULTS: The 3-year disease free survival of Group A was 40.8% with a median survival of 32.0 months, it was 43.6% with a median survival of 23.6 months in Group B. The difference was not significant (p=0.87). There was no difference in recurrence pattern between the 2 groups. Patients with squamous cell carcinoma in Group A had no local recurrence during the follow-up period while those in Group B had a high local recurrence rate of 40% (p<0.005). When stratified by T factor, patients with locally advanced T stage (T3-4) in Group A had a lower distant recurrence rate than their counterpart patients in Group B (9.1 vs 38.5%, p=0.03), they had a better survival but the difference was not significant (3-year disease free survival: 41.7 vs 17.9%, p=0.14). There were no significant differences in recurrence pattern and survival in different N categories and TNM stages between 2 groups. Multivariate analysis showed that only pretreatment surgical N status was an independent prognostic factor for the whole group (p=0.02). CONCLUSIONS: Pretreatment Ts/Ls staging can provide accurate staging information for EC patients. Trimodality treatment was successful in local control for patients with squamous cell carcinoma. It was effective in reducing distant recurrence and might prolong survival in patients with advanced T stages. Pretreatment lymph node status was the most important prognosticator regardless of treatment modality. Pretreatment pathological staging should be included in the future clinical trials on multimodality treatments in EC patients.

Optimized intensity-modulated arc therapy for prostate cancer treatment.

We recently implemented intensity-modulated arc therapy (IMAT) at our institution. In this study, we evaluate the dosimetric merits of the application of this technique to the treatment of prostate cancer. Each IMAT treatment plan incorporated bilateral overlapping arcs. The dose from each beam segment was computed using the three-dimensional dose model of a clinical treatment planning system (Render Plan 3.5, Precision Therapy). The weights assigned to the individual arc segments were optimized using a gradient search method. For 12 patients, comparisons were made between the IMAT treatment plans and corresponding plans using fixed cone-beam intensity-modulated radiotherapy (IMRT) from a commercial inverse planning system (CORVUS, NOMOS Corp.). We found that the optimized IMAT treatments produced similar dose distributions to the IMRT deliveries. Compared with the IMRT treatments, the IMAT treatments produced slightly less target dose homogeneity with consistently greater sparing of the rectum in regions of lower dose. The trade-off between target dose conformity and rectum sparing can be adjusted in both optimization procedures. Because the total beam-on time for IMAT delivery is 1 to 2 minutes with approximately 5-6 minutes of patient setup time, the delivery efficiency of the IMAT treatment was significantly better than the multiple-beam IMRT treatment.

Pretreatment surgical lymph node staging predicts results of trimodality therapy in esophageal cancer.

OBJECTIVE: Prediction of responders to induction therapy in esophageal cancer (EC) patients is important. In this study, we evaluated the role of thoracoscopic/laparoscopic (Ts/Ls) staging in prediction of treatment response and survival in EC patients with trimodality treatment. METHODS: Retrospective study of EC patients who had undergone Ts/Ls staging and received trimodality treatment at the University of Maryland Medical Center and the Baltimore Veterans Administration Hospitals from July, 1991 to December, 1999. Preoperative therapy consisted of concurrent chemotherapy (5-FU + cisplatinum) and radiotherapy. RESULTS: Forty-four EC patients who underwent pretreatment Ts/Ls staging during the study period were able to complete concurrent chemoradiotherapy followed by surgical resection. There were 36 men and 8 women aged 40 to 77 (median age 62). Twenty-seven (61.4%) patients were found to have lymph node metastasis by surgical staging. Fourteen patients (31.8%) had a pathologic complete response. Patients with positive lymph nodes had a lower response rate than those with negative lymph nodes (14.8% vs. 58.8%, P=0.006). Other clinicopathologic features including gender, weight loss, clinical TNM stage, surgical T stage, and histology did not correlate with treatment response. Univariate analysis showed that weight loss and treatment response were important prognostic factors for disease-free survival (P=0.01 and P=0.02, respectively). Histology, surgical N stage and surgical TNM stage appeared to be associated with prognosis (P=0.067-0.097). Multivariate analysis revealed that only surgical N status and weight loss were significant prognostic factors (P=0.05, and P=0.006, respectively). CONCLUSIONS: Surgical Ts/Ls staging provides accurate evaluation of tumor spread in EC patients. Pretreatment N status was the single most important predictor of response to induction treatment as well as a reliable prognosticator of survival.

Protective role of Bcl2 in metabolic oxidative stress-induced cell death.

Previous studies have shown that overexpression of Bcl2 protects cells from glucose deprivation-induced cell death in multidrug-resistant human breast carcinoma, MCF-7/ADR cells. In this study, we further investigated the protective role of Bcl2 in glucose deprivation-induced cytotoxicity. Although Bcl2 did not prevent a 3.2-fold increase in the level of hydroperoxide during glucose deprivation, it led to a compartmentalization of hydroperoxide molecules in the mitochondria. It also inhibited glucose deprivation-induced cytochrome c release from the mitochondria. It is possible that overexpression of Bcl2 prevents glucose deprivation-induced ceramide generation, probably by preventing the leakage of hydroperoxide from the mitochondria. We also observed that glucose deprivation induced a sixfold increase in oxidized glutathione content, as well as in thiol precursor content. Overexpression of Bcl2 suppressed an increase in oxidized glutathione content and thiol precursor content. Our results indicate that Bcl2 protects cells from metabolic oxidative stress-induced damage by inhibiting the leakage of hydroperoxide from the mitochondria and subsequently preventing ceramide generation. Preventing ceramide generation inhibits the signal transduction pathway and results in the suppression of cytochrome c release from the mitochondria.

Predictors of response and survival after concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck.

BACKGROUND: The objective of this study was to determine prognostic factors for response and survival on three consecutive institutional trials utilizing concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck (SCCHN). METHODS: Since 1985, patients with locally advanced SCCHN at the University of Maryland have been managed with concurrent chemotherapy and radiation therapy (RT). Three consecutive pilot studies have been performed evaluating the utility of weekly chemotherapy with standard fractionated RT. Chemotherapy consisted of carboplatin either alone (28 patients) or in combination with bleomycin (23 patients) or paclitaxel (60 patients). In all three studies, RT was given to 70.2 gray (Gy) at 1.8 Gy/fraction/day to the primary site. All patients had locally advanced SCCHN and were believed to be poor surgical candidates. Sixty-seven percent of patients had T4 disease, and 21% had T3 disease. Seventy-five percent of patients had N2-N3 disease. One hundred eleven patients were examinable for toxicity, response, and survival analysis. Factors including age, race, gender, primary site location, histologic grade, T classification, N classification, and treatment regimen were evaluated to identify predictors of these endpoints. RESULTS: The median follow-up for patients treated on study 1 (carboplatin and RT) and study 2 (carboplatin and bleomycin [C + B]/RT) was 98 months, and it was 30 months for study 3 (carboplatin and paclitaxel [C + P]/RT). The complete response rates were 54%, 52%, and 70% respectively (P = 0.01). Multivariate analysis identified length of treatment break (< 1 week vs. > 1 week) as the only predictor of complete response to therapy. The local control for the entire group was 50%. The local control for C + P/RT was 63%, versus 32% and 36% for C/RT and C + B/RT respectively (P = 0.004). The 2-, 3-, and 5-year disease free and overall survivals for the entire population were 41%, 41%, and 35% and 42%, 36%, and 33%, respectively. The 3-year overall survival rates by treatment regimen were 18% (C/RT), 35% (C + B/RT), and 47% (C + P/RT; P = 0.01). On univariate analysis, age younger than 50 years (P = 0.01), treatment with C + P/RT (P = 0.005), and treatment break of 5 days or fewer (P < 0.05) were also predictive of improved overall survival. On multivariate analysis, only complete response (P < 0.0001) and treatment with C + P/RT (P = 0.02) remained statistically significant. CONCLUSIONS: Chemoradiation provides patients with locally advanced SCCHN the opportunity for long term survival. Among the three chemoradiation regimens studied, C + P/RT was associated with the best complete response and survival rates. Complete response to therapy was the single most important predictor of overall survival. These three consecutive concurrent chemotherapy and radiation trials achieved a 5-year survival of greater than 30% for the entire population. These results support the use of this nonoperative approach for this group of patients with a historically poor prognosis.

Accurate lymph node assessment prior to trimodality therapy for esophageal carcinoma.

PURPOSE: The diagnosis of esophageal carcinoma has historically been associated with a poor prognosis. Recently, investigators have reported improved outcomes for this patient population with the use of trimodality therapy. These results have fueled the debate regarding which patients may benefit from this aggressive treatment course. This retrospective analysis was conducted in order to evaluate the importance of regional lymph node involvement, determined by surgical staging before the initiation of therapy. PATIENTS AND MATERIALS: Between July 1991 and June 1999, 45 patients underwent surgical staging with thoracoscopy and/or laparoscopy followed by induction chemoradiation and surgical resection. All patients underwent consultation in our thoracic multidisciplinary clinic. Thoracoscopy included nodal sampling from American Thoracic Society levels 5, 6, 8, and 9 within the mediastinum. Laparoscopy included inspection of the liver and nodal sampling from the lesser curvature and the celiac axis. Preoperative chemoradiation consisted of two cycles of 5-fluorouracil (1000 mg/M2) and cisplatin (100 mg/M2) weeks 1 and 4 with 50.4 Gy. Radiotherapy was delivered at 1.8 Gy/fraction with 39.6 Gy being delivered to the large-field and 10.8 Gy to a small-field boost. The routine surgical procedure was an Ivor-Lewis esophagectomy performed 4 to 6 weeks after completion of induction therapy. RESULTS: The median follow up was 24 months for all patients. The median overall survival was 23 months, with 1-, 2-, and 3-year survivals of 64%, 42%, and 34%, respectively. Thirty patients had pathological evidence of lymph node disease before therapy. The pathological complete response rate for the entire group was 51%. Node-positive patients had a path complete response rate of 14%, as compared with 59% for those who were NO. The median survival for these two groups was 15 months versus 35 months. Patients whose nodes were cleared by chemoradiation had a 3-year survival of 40%, whereas all patients with persistent nodal disease were dead by 2 years. Twenty-one patients have experienced recurrence of their disease. Thirteen patients had evidence of distant metastasis only, three local only, and five with both. CONCLUSION: Trimodality therapy offers patients with esophageal cancer an opportunity for long-term survival. Our experience has shown that minimally invasive pretreatment surgical staging provides useful information that can predict complete response and can help in the selection of appropriate patients for aggressive therapy.

Dosimetry of source stepping for intravascular brachytherapy.

PURPOSE: Both beta and gamma sources of fixed length are currently used in the catheter-based intravascular brachytherapy (IVBT). Source stepping is often used to treat a lesion longer than the effective treatment length of the source. A major challenge for the stepping procedure is to attain a perfect dosimetric match (uniform dose) at the source junction. This work presents a quantitative and systematic dosimetric analysis for source stepping during an IVBT procedure. MATERIALS AND METHODS: The three most commonly used beta and gamma sources (192Ir by BEST, 90Sr by NOVOSTE and 32P by Guidant) were studied using the EGSnrc Monte Carlo code. Dose distributions were calculated for a perfect end-to-end match and for a range of end-to-end gaps and overlaps between consecutive steps. RESULTS: It is found that a perfect end-to-end match during source stepping yields uniform dose distribution in the region of source junction. The doses in the case of a mismatch (in the presence of an end-to-end gap or overlap) were found to be significantly different from those with the perfect end-to-end match. The dose deviation depends on the size of the gap or overlap, radial distance and type of source. The dose deviation decreases with radial distance for a given gap/overlap. For example, for a gap/overlap of 2 mm, dose decreases/increases of 30%, 55% and 60% were found at the radial distance of 2 mm from source for 192Ir, 90Sr and 32P, respectively. These dose deviations are reduced by approximately 10% when the radial distance increases from 2 to 3 mm. The dose deviations for gaps or overlaps in the range of 0-5 mm are presented. CONCLUSIONS: During an IVBT procedure involving source stepping, a perfect end-to-end match is always desired. Significant underdosing or overdosing can occur in the case of a source mismatch. A considerable caution should be exercised to ensure that sources are properly matched.

The use of concurrent chemotherapy with high-dose radiation before surgical resection in patients presenting with apical sulcus tumors.

PURPOSE: Patients presenting with apical sulcus tumors have historically been treated with preoperative radiotherapy followed by surgical resection. Since 1991, we have delivered an induction regimen consisting of combination chemotherapy and high-dose radiation in an attempt to improve tumor responses and increase survival for this patient population. PATIENTS AND MATERIALS: This retrospective analysis consisted of 23 (13 men and 10 women) consecutive patients who completed trimodality therapy. The median age was 53 years. Histologies included adenocarcinoma (nine patients), squamous cell (five patients), large cell (three patients), and undifferentiated non-small cell lung carcinoma (six patients). Pretreatment stages were T3NO (14 patients), T3N2 (two patients), T3N3 (one patient), T4NO (five patients), and T4N2 (one patient). Preoperative therapy consisted of daily radiotherapy (median dose, 59.4 Gy) delivered at 1.8 Gy/day and concurrent combination chemotherapy consisting of either two cycles of cisplatin and etoposide or weekly carboplatin and paclitaxel. Surgical resection typically included lobectomy with chest wall resection. RESULTS: All 23 patients were available for analysis of response and survival. The median follow-up was 53 months. The median number of days between completion of induction therapy and surgery was 56 days. Postoperative complications included prolonged atelectasis (two patients), pulmonary embolism (one patient), subarachnoid-pleural fistula (one patient), and deep vein thrombosis in the subclavian vein (one patient). The pathological complete response rate to induction therapy was 46% for the entire group. An additional 38% had evidence of tumor regression at the time of surgery. The 5-year disease-free and overall survivals were 36% and 49%, respectively. The median overall survival was 33 months. The median overall survival for those who achieved a pathological complete response has not been reached. Analysis of factors including age, sex, histology, differentiation, stage of disease, and radiation dose failed to identify any predictors of response or survival. CONCLUSION Concurrent chemotherapy and high-dose radiation can be safely delivered before surgery in patients presentingwith apical sulcus tumors. Our results compare favorably to other institutional series and support the further investigation of this approach in prospective trials.

Radiation therapy for esophageal cancer.

Radiation therapy continues to play a major role in the management of patients with esophageal carcinoma. This role continues to evolve based on the success of combined modality treatment regimens. During the past decade, the concurrent application of chemotherapy and radiation has gained acceptance as a standard of practice that offers patients an improved opportunity for long-term survival, whereas the ultimate benefit of trimodality therapy remains an unanswered question. The start of the twenty-first century brings the challenge of decreasing the toxicities associated with therapy and the need to improve therapeutic options. The recent advances in technology have positioned radiation oncology to achieve both of these goals.

The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck.

PURPOSE: Unresectable squamous cell carcinomas of the head and neck (SCCHN) continue to pose a significant therapeutic challenge. This report defines the toxicities, efficacy, and prognostic factors associated with the combination of carboplatin (CBDCA), paclitaxel, and once-daily radiation for patients with locally advanced disease. Additionally, the pharmacokinetics of paclitaxel were investigated. METHODS AND MATERIALS: From 1993-1998, 62 patients with Stage III-IV SCCHN were treated with 70.2 Gy of RT at 1.8 Gy/fraction/day to the primary site. Weekly chemotherapy was given during RT consisting of paclitaxel (45 mg/m(2)/wk) and CBDCA (100 mg/m(2)/wk). All patients presented with locally advanced disease; 77% had T4 disease and 21% had T3 disease. Fifty-eight percent had N2b-N3 disease. RESULTS: Sixty patients were evaluable for response and survival with a median follow-up of 30 months (range 7-70). Ninety-eight percent of patients completed prescribed therapy. One patient died after refusing medical management for pseudomembranous colitis and is scored as a Grade 5 toxicity. Two patients suffered Grade 4 leukopenia. Median number of break days was two. A clinical complete response (CR) at the primary site was obtained in 82%, with a total (primary site and neck) CR rate of 75%. The median survival for the entire cohort is 33 months. Response to therapy and status of the neck at presentation were the only prognostic factors found to influence survival. The median survival for patients who attained a CR is 49 months versus 9 months in those who did not attain a CR (p < 0.0001). The 2- and 3-year overall survival for complete responders are 79% and 61%. Plasma paclitaxel concentrations in the range shown to be radiosensitizing were achieved. CONCLUSIONS: Weekly carboplatin and paclitaxel given concurrently with definitive once-daily external beam radiation therapy is well tolerated with over 90% of patients completing prescribed therapy. An ultimate CR rate of greater than 70% was obtained, which translated directly into improved survival. With 48% 3-year overall survival for the entire group, this regimen is an excellent option for this group of patients with a historically poor prognosis.

Beta versus gamma for catheter-based intravascular brachytherapy: dosimetric perspectives in the presence of metallic stents and calcified plaques.

PURPOSE: Both beta and gamma emitters are currently used in the catheter-based intravascular brachytherapy. The dosimetric effects due to the presence of metallic stents and calcified plaques have not been fully addressed. This work compares these effects for two most commonly used beta and gamma sources ( (90)Sr and (192)Ir). MATERIALS AND METHODS: An EGS4 Monte Carlo package was used to calculate dose in water for a (90)Sr (supplied by NOVOSTE) and an (192)Ir (Supplied by BEST) source, with or without the presence of a calcified plaque or a metallic stent. Plaques of different shape (shell and disk), size and density, and two types of stainless-steel stents (ring or mesh stent) were studied. The ring stent consists of identical rings stacked along the long axis of the sources. The gap between two rings is 0.3 mm. The mesh stents are made of identical square (0.1 x 0.1 or 0.2 x 0.2 mm(2)) holes separated from each other by stainless-steel wire. The cross section of wire for both ring and mesh stents is 0.1 x 0.1 mm(2). A dose perturbation factor (DPF), defined as the ratio of the doses with and without the presence of a plaque or a stent, was introduced to quantify the effects. A carefully chosen set of EGS4 transport parameters for the small geometry in question was used in the calculation. RESULTS: The radial and axial dose distributions calculated in water were found to agree with the published measurements to within 3%. The dose perturbations due to the presence of calcified plaques or metallic stents were found far more significant for the (90)Sr source than those for the (192)Ir source. Up to 30% dose reduction behind a plaque were observed for the (90)Sr source, while the dose reduction for the (192)Ir source was found to be negligible. The dose enhancement inside a plaque was as high as 10% for the beta source or 6% for the gamma source. In the presence of a stent, the DPF was in the range of 1.15-0.75 for the beta source, while it was almost equal to 1.0 for the gamma source. CONCLUSION: The dose perturbation due to the presence of a calcified plaque or a metallic stent is significant for the beta source. The dose reduction in the region beyond a plaque or a stent could be more than 20%. For the gamma source, the dose effect behind a plaque or a stent is practically negligible. These dosimetric differences between the beta and gamma sources in the presence of a calcified plaque or metallic stent should be considered in the dose prescription of intravascular brachytherapy.

Comparison of three treatment options for single brain metastasis from lung cancer.

Whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and the combination of both treatment methods were used for the management of single brain metastasis from lung cancer. The purpose of this study is to compare these three different treatment options in terms of local response, survival, and quality of life. From June 1995 to July 1998, 70 lung cancer patients with new diagnosed single brain metastasis were treated with either WBRT alone (n = 29), or SRS alone (n = 23), or the combination of both methods (n = 18). Multiple endpoints, including survival, freedom from local progression (FFLP), freedom from new brain metastasis (FFNBM), local control, Karnofsky performance status (KPS), and causes of death, were measured from the date of treatment completion and compared using univariate and multivariate analyses. For patients treated with WBRT-alone, SRS-alone, and SRS+WBRT, the median survivals were 5.7, 9.3, and 10.6 months, the median FFLP were 4.0, 6.9, and 8.6 months, the median FFNBM were 4.1, 6.7, and 8.6 months, and the local response rates were 55.6, 87.0, and 88.9%, respectively. Four of the 29 patients treated with WBRT-alone continued with progression of disease. The post treatment KPS showed improvement in 41.4, 82.6, and 88.9% of patients treated with WBRT-alone, SRS-alone, and SRS+WBRT, respectively. The progression of new and/or recurred metastatic brain tumor as the cause of death accounted for 51.7%, 50. 0%, and 28.3% of the patients treated with WBRT-alone, SRS-alone, and SRS+WBRT, respectively. Univariate analyses showed that the significant differences among the three treatment arms were observed based on all of the above mentioned endpoints. However, the comparison between SRS-alone and SRS+WBRT groups indicated that adding WBRT only improves FFNBM (P = 0.0392). Cox regression analyses revealed no significant difference in both of the KPS (P = 0.1082) and causes of death (P = 0.081) among the three arms. Both SRS alone and SRS+WBRT seem better in prolonging life and improving quality of life than WBRT alone for patients with single brain metastasis from lung cancer. But the combined therapy did not show significant advantage over SRS alone in improving survival, enhancing local control, and quality of life except for a more favorable FFNBM. Further investigation via a randomized trial is needed to access the value of adding WBRT to SRS in the management of this group of patients. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 37-45 (2000).

Safe pulmonary resection after chemotherapy and high-dose thoracic radiation.

BACKGROUND: Pulmonary resection after high-dose thoracic irradiation is reported to be associated with a high morbidity and mortality, and has been considered to be prohibitive. METHODS: We report safe pulmonary resection in 19 consecutive patients receiving neoadjuvant therapy that included greater than 59 Gy thoracic radiation. The mean thoracic radiation dose was 61.8 Gy (range 59.5-66.5) and mean age was 52 years (range 36-72 years). Cell type was adenocarcinoma (6), squamous (7), and other non-small cell lung cancer (NSCLC) (6). Sixteen of 19 patients received concurrent chemotherapy. Median time from end of treatment to surgical resection was 89 days (range 22-258 days). Surgical resection included 13 lobectomies and six pneumonectomies (four right, two left). RESULTS: A complete pathologic response was seen in 8 of 19 (42%) patients. Three patients required intraoperative transfusion of blood. Mean intensive care unit stay was 2.0 days (range 1-8 days), and mean length of stay (LOS) was 8.0 days (range 3-18 days). There were four postoperative complications; one bronchopulmonary fistula, one subarachnoid-pleural fistula, and 2 patients with prolonged atelectasis. There was no incidence of acute respiratory distress syndrome (ARDS) or operative mortality. CONCLUSIONS: Pulmonary resection, including pneumonectomy, after chemotherapy and high-dose thoracic radiation may be performed safely with a low rate of intraoperative and postoperative complications.

P53 gene protein overexpression predicts results of trimodality therapy in esophageal cancer patients.

BACKGROUND: P53 protein overexpression in esophageal cancer and its correlation with response and survival after chemoradiation was retrospectively investigated. METHODS: Pretreatment and resection specimens were stained by automatic p53 immunohistochemical staining technique. RESULTS: P53 was expressed in 84.0% of esophagoscopy (EGD) biopsies; 71.4% of patients with metastasis of thoracoscopy/laparoscopy lymph nodes (TS/LS LN) identified by hematoxylin/eosin (H/E) were p53 (+); 14.2% of patients with negative TS/LS LN by H/E were p53 (+). Eleven out of 18 patients with p53 (+) in pretreatment EGD remained p53 (+) after chemoradiation; 38.8% of these patients had a pathological complete response (pCR). The median survival of this group was 15 months. Of 4 patients with p53 (-) pretreatment EGD, all of those were still p53 (-) after chemoradiation; 75% of these patients had pCR. The median survival was 30 months. In patients with p53 (+) TS/LS LN, 23% had a pCR after chemoradiation with a median survival of 16 months. In patients with p53 (-) TS/LS LN, 50.0% had a pCR with a median survival of 31.5 months. CONCLUSIONS: P53 protein overexpression in pretreatment EGD and TS/LS LN may predict response to chemoradiation and survival in esophageal cancer patients.

A pilot trial of paclitaxel, carboplatin, and concurrent radiotherapy for unresectable squamous cell carcinoma of the head and neck.

Combined chemoradiotherapy is superior to radiotherapy alone for stage III and IV squamous cell carcinoma of the head and neck, and concurrent use of both offers the advantage of synergistic interactions. Our prior trial demonstrated the ease and convenience of administering carboplatin during radiotherapy. Since paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has activity in squamous cell carcinoma of the head and neck and can act synergistically with both radiotherapy and platinum drugs, we initially added paclitaxel at 45 mg/m2/wk to carboplatin given at 100 mg/m2 during radiotherapy given at conventional fractions. The initial dose of paclitaxel was subsequently reduced to 40 mg/m2/wk. Thirteen of 18 patients entered so far have sufficient follow-up data; 12 are assessable for toxicity and 11 are assessable for response. One died early of progressive disease, two achieved a complete response, six achieved a partial response, and two had stable disease. Toxicities have so far been manageable for the 76 weekly doses administered. Chemotherapy dose reduction was needed in 10 patients. For the planned 100 doses of chemotherapy, 53 (53%) were administered as planned, 23 (23%) were reduced, and 24 (24%) were withheld due to neutropenia or mucositis. There were no toxic deaths, and no patient stopped therapy for toxicity. Paclitaxel/carboplatin can be administered during radiotherapy for squamous cell carcinoma of the head and neck with acceptable toxicities, and further accrual is needed to evaluate the effect of this combination.

Divergent changes of flow through individual blood vessels upon localized heating.

The changes of microregional perfusion in a hamster cheek pouch membrane were investigated. The vessel network of the membrane was visualized by preparing a transparent chamber, which was heated with circulating water at 42 degree C. Blood perfusion was monitored by using a laser Doppler flowmeter (LDF), which was used either in a conventional way by positioning the probe stationary or in a novel way by constantly moving the probe over the surface of the chamber (scanning). When a segment of tissue was subjected to the LDF scanning, the profile of scanned LDF values was well correlated with the distribution of vessels. Therefore, this scanning technique was useful in localizing the probe in tissues with respect to vessels. Since the scanning can be repeated every other minute, this technique also offered continuous monitoring of tissue blood flow at multiple sites. Upon heating, different vessels individually responded to the first and second heatings followed by coolings, suggesting a heterogeneous heat response in the connective tissue of the hamster cheek pouch membrane. This scanning technique proved very useful in collecting information for the study of the heterogeneous nature of blood flow in normal and tumour tissues.

Radiotherapy for Merkel cell carcinoma of the skin of the head and neck.

BACKGROUND: Merkel cell carcinoma is a relatively rare neuroendocrine carcinoma of the skin. It arises in the head and neck region in approximately 50% of cases. Its aggressive behavior predisposes patients to local-regional recurrence and distant metastases after surgical excision alone. In this article, we describe our experience with Merkel cell carcinoma of the head and neck. METHODS: Of 18 patients with Merkel cell carcinoma treated in the Department of Radiation Oncology at the University of Florida, 12 patients who had primary tumors in the head and neck region are reported. Eight patients were treated at initial diagnosis (group A), and four were treated at the time of local-regional recurrence (group B). RESULTS: Local-regional control was achieved in seven of eight patients in group A and all four patients in group B. One patient in group A and all patients in group B developed distant metastases and eventually died of their disease. Bone exposure developed in one patient, requiring surgical debridement and hyperbaric oxygen treatment. CONCLUSION: Patients with Merkel cell carcinoma of the head and neck should be treated aggressively. Our data suggest that local-regional recurrence is a harbinger of distant metastases. We recommend that these patients receive treatment to both the primary site and draining lymphatics at initial presentation. The role of chemotherapy remains unclear.