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Eleven patients were initially treated for localized prostate cancer with radical retropubic prostatectomy following negative pelvic lymph node dissection. Six or more months after surgery, these patients had elevated serum prostate specific antigen (PSA) levels. No patient had other clinical evidence of disease as determined by history, physical examination, bone scan, computed tomographic scan of the abdomen and pelvis, chest radiograph, complete blood cell count, and serum chemistry profile. These patients received prostate bed irradiation using 10-MV photons and a four-field technique. Doses ranged from 60.0 to 65.8 Gy in 1.8 to 2.0 Gy fractions. Levels of serum PSA were monitored and decreased initially in all treated patients. In two patients, levels of PSA increased after this initial decrease. In 7 of the 11 patients (64%), PSA levels decreased to less than or equal to 0.3 ng/mL at last measurement. Radiotherapy resulted in no severe toxicity. None of the patients had developed clinical evidence of disease at the time of this report. Isolated elevations of serum PSA after prostatectomy reflect residual disease, and radiotherapy appears to effectively decrease the PSA levels in most cases. This effect appears to be accomplished by killing locally residual or recurrent cancer in the postoperative tumor bed.

Patients diagnosed with prostate cancer may also have a prosthetic hip. When planning radiotherapy for these patients, one must consider the attenuation of the dose when the beam passes through the prosthetic hip. It is best to avoid administration of radiation to the target through the prosthesis. Example treatment plans are evaluated. The potential advantages and disadvantages of each plan are reviewed.

e22167 Background: Safe and effective delivery of viral vectors is important for gene therapy. Local application of such vectors is more efficient than systemic application. However, currently available injection systems are not optimal because placement of the injection needle and the vector application itself are generally not reproducibile. We developed a new injection system providing controlled injection of adenoviral vectors in tumors (xeno-transplants) in nude mice (NMRI nu/nu). Methods: The new MAGD consists of two fixation devices mounted on a 40x40cm plexi-glass plate, four injection units, and one pump unit with 4 infusion-pumps (Bee hive, Bioanalytical, Chesire, UK). Each injection unit is linked to a pump with commercially available plastic tube. Because the injection arms can be moved in x-,y- and z-direction, virus injection can easily performed for irregular tumor volumes. The entire injection volume is equally distributed to the 4 injection pumps allowing precise and steady injection rates between 0.1μl/min and 100μl/min. Success was confirmed with MRI-scans (Magnetom symphony, Siemens, Erlangen, Germany) 10 min after the injection. The efficacy of the MAGD was tested in 4 human squamous cell carcinoma cell lines from oro-/hypopharynx (FaDu, UD- SCC2, UD-SCC6, and UD-SCC7a). Virus transfection was performed with an adenovirus (serotype 5) expressing enhanced green fluorescent protein (eGFP). Transfection rates were quantified with flow cytometry. Successfully transfected cells expressed eGFP resulting in green fluorescence. In-vitro cell lines (concentration: 10 particles per cell, MOI 10) of FaDu, UD-SCC2, UD-SCC6 and UD-SCC7a served as controls. Results: The MAGD was easy to handle. Injection of 100μl (25μl per infusion pump) at an injection rate of 5μl/min took only 5 min. The in-vivo transfection rates achieved with the MAGD were 9±1% for FaDu, 39±2% for UD- SCC, 54±1% for UD-SCC6 and 54±9% for UD-SCC7a, respectively. The in-vitro transfection rates (controls) for these 4 cell lines were 2±1%, 23±4%, 29±4% and 3±2%, respectively. Conclusions: The new MAGD provided controlled injection of adenoviral vectors in tumors in nude mice. It proved to be effective, as it resulted in comparably high transfection rates. No significant financial relationships to disclose.

A phase II NCCTG “Window of Opportunity Front-line” study of the mTOR Inhibitor, CCI-779 (Temsirolimus) given as a single agent in patients with advanced NSCLC Molina, Julian R.1 Mandrekar, Sumithra J.1 Rowland, Kendrith2 Reuter, Nicholas F.3 Jett, James R.1 Marks, Randolph1 Schild, Steven E.4 Adjei, Alex A.5 1 Mayo Clinic, Rochester, MN, USA 2 NCCTG, Danville, USA 3 NCCTG, Sait Cloud, USA 4 Mayo Clinic Arizona, Scottsdale, AR, USA 5 Roswell Park Cancer Institute, Buffalo, NY, USA Background: Over-expression of Akt and loss of PTEN are frequent events in non-small cell lung cancer (NSCLC). The mammalian target of rapamycin (mTOR) is a protein downstream to Akt in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. CCI-779 (temsirolimus), an ester of sirolimus, is an inhibitor of mTOR with growth inhibitory activity in a variety of tumor cells. In an effort to evaluate the single agent activity of CCI-779 in previously untreated NSCLC, the NCCTG undertook a front-line “window of opportunity” study. Methods: N0323 was a two-stage single arm phase II trial which evaluated the response and toxicity rates of CCI-779 administered as a front line single agent treatment for stage IIIB (pleural effusion) or IV NSCLC. Fresh tumor biopsies were obtain to evaluate predictive markers of CCI-779 activity and target inhibition such as phospho AKT expression and loss of PTEN. Patients received 25 mg of CCI-779 administered intravenously as a 30 minute infusion on days 1, 8, 15, and 22 in4 week cycles. Based on a two-stage Fleming design with an exact significance level of 0.05 and 94% power to detect an effective treatment if the true CRR was at least 20%, this treatment would be promising if at least 4 of the first 25 evaluable patients in Stage I or at least 6 of the 50 evaluable patients at the end of Stage II have a confirmed response. Results: A total of 55 patients were accrued from February 2004 to November 2006 and results from the first 50 evaluable patients are reported here. Patient characteristics included a median age of 64 years (range: 44-85); 38% of patients were female; 84% had stage IV disease, and 89% were ECOG PS of 0 or 1. Median number of cycles administrated was 2 (range 1-18). One patient is still receiving active treatment (28 weeks). The most common grade 3/4 events were dyspnea (12%), fatigue (10%), hyperglycemia (8%), hypoxia (8%), nausea (8%), and rash/desquamation (6%). The clinical benefit rate was 38% with 4 (8%: 95% CI: 0.03-0.22) confirmed partial responses and 15 (30%: 95% CI: 0.14-0.48) stable disease for a minimum of 56 days. The 24-week progression-free survival (PFS) rate was 22% (11/50; 95% CI: 0.120.36). The median PFS and overall survival were respectively 2.3 and 6.6 months. Sixteen (32%) patients received subsequent treatment after progressing on CCI-779. Conclusions: CCI-779 (Temsirolimus) given as a single agent front line therapy in patients with NSCLC produced a clinical benefit rate of 38% (8% PR, 30% SD). While the study did not meet the predefined success criteria, single agent CCI-779 has activity similar to other signal transduction inhibitors and had good tolerability. Proper patient selection may enhance efficacy. The potential predictive markers of efficacy such as p70S-kinase phosphorylation and PTEN expression are being evaluated and these results will be presented. Poster Discussion Abstracts

Between 1974 and 1988, thirteen patients presented with large symptomatic unresectable and partially resected hemangiomas. Eleven of the 13 (85%) had pathologically confirmed cavernous hemangiomas and 2 others were diagnosed clinically. Included were 5 pediatric patients (ages 5 months to 17 years) and 8 adults (ages 19 to 59 years). Tumor sites included extremities (5), vertebral bodies (3), face (2), pituitary fossa (l), pelvic bones (l), and bladder (1). Symptoms included severe pain in 8 patients, inability to use an extremity in 5 patients, visual problems in 3 patients, weakness in 2 patients, hematuria and decreased urinary stream in 1 patient. Many patients had more than one symptom. Two of the pediatric cases were associated with life threatening cytopenias (Kasabach Merritt Syndrome).

Between 1976 and 1984, 139 patients with rectal cancer were treated with complete surgical resection and post-operative adjuvant pelvic radiation therapy with or without chemotherapy. In this group, tumor extended beyond the bowel wall or involved lymph nodes or both. Irradiation was begun between 15 and 182 days postoperatively (median delay, 42 days). The radiation was delivered with 4-, 6-, or 10-MV photons given 5 days per week at 1.8 to 2.0 Gy per fraction. Total doses ranged from 3.8 to 64.4 Gy (median, 50 Gy). The fields were AP:PA in 49 and AP:PA plus laterals in 90. Forty-four received concurrent chemotherapy: 5-fluorouracil and semustine in 37, and 5-fluorouracil alone in seven. Follow-up in survivors ranged from 2 to 10 years (median, 4.2 years). This analysis includes all failures, both initial and subsequent sites of failure. Local failure occurred in 30 (22%) of the 139 patients overall, 6 (18%) of 33 in Stage B-2, 1 of 3 in Stage B-3, 2 (10%) of 20 in Stage C-1, 20 (26%) of 76 in Stage C-2, and 1 (14%) of 7 in Stage C-3. Five-year actuarial survival was 59% overall, 82% in Stage B-2, 79% in Stages B-2 and B-3, 89% in Stage C-1, 41% in Stage C-2, and 42% in Stages C-2 and C-3. The following prognostic factors were independently associated with poorer survival and increasing distant failure: lymph node involvement, tumor extension beyond the bowel wall, and high histologic grade. Use of chemotherapy was associated with a significant improvement in survival and decrease in distant failure. No single factor was significantly associated with local failure. Adequate perineal coverage after combined abdominoperineal resection yielded significantly fewer perineal failures. Overall, serious complications developed in 7%, but none was fatal. Treatment recommendations and optimal treatment techniques are discussed.

Between 1977 and 1984, 17 patients received external beam irradiation after subtotal resection of rectal carcinoma. Ten patients had microscopic residual disease and 7 had gross residual disease. In the group with microscopic residual disease, 4 had tumor cut through with pathologically involved margins, 5 had adjacent unresected structures that were biopsy positive, and 1 had tumor spillage into the pelvis. The patients with gross residual disease were noted by the surgeon to have visible tumor after maximal debulking. Nine of 17 cases had involved pelvic lymph nodes. Radiation was administered to the pelvis with 4, 6, or 10 MV photons. Doses ranged from 40 to 60 Gy, with a median dose of 50 Gy given at 1.8 to 2.0 Gy per fraction, 5 days per week. Three patients received bacillus Calmette-Guérin (BCG), 2 received 5-fluorouracil (5-FU), and 1 received hycanthone. Thirteen of the 17 patients (76%) experienced local failure and, of these, 10 also developed distant disease. No patients developed distant metastasis in the absence of local failure. Local control was achieved in 3 of 10 patients (30%) with microscopic residual and 1 of 7 (14%) with gross residual. Four of the 17 patients (24%) have remained free of disease for greater than 5 years. External beam irradiation is capable of producing long-term survival and local control in a minority of patients with rectal cancer after subtotal resection. Investigation of more aggressive forms of therapy such as the addition of intraoperative irradiation, brachytherapy, radiation dose modifiers, and chemotherapy is warranted.

Introduction: The purpose of this study was to assess the safety and efficacy of gemcitabine and carboplatin with (arm A) or without (arm B) daily oral cediranib as first-line therapy for advanced non–small-cell lung cancer. Methods: A lead-in phase to determine the tolerability of gemcitabine 1000 mg/m 2 on days 1 and 8, and carboplatin on day 1 at area under curve 5 administered every 21 days with cediranib 45 mg once daily was followed by a 2 (A):1 (B) randomized phase II study. The primary end point was confirmed overall response rate (ORR) with 6-month progression-free survival (PFS6) rate in arm A as secondary end point. Polymorphisms in genes encoding cediranib targets and transport were correlated with treatment outcome. Results: On the basis of the safety assessment, cediranib 30 mg daily was used in the phase II portion. A total of 58 and 29 evaluable patients were accrued to arms A and B. Patients in A experienced more grade 3+ nonhematologic adverse events, 71% versus 45% ( p = 0.01). The ORR was 19% (A) versus 20% (B) ( p = 1.0). PFS6 in A was 48% (95% confidence interval: 35%–62%), thus meeting the protocol-specified threshold of at least 40%. The median overall survival was 12.0 versus 9.9 months ( p = 0.10). FGFR1 rs7012413, FGFR2 rs2912791, and VEGFR3 rs11748431 polymorphisms were significantly associated with decreased overall survival (hazard ratio 2.78–5.01, p = 0.0002–0.0095). Conclusions: The trial did not meet its primary end point of ORR but met its secondary end point of PFS6. The combination with cediranib 30 mg daily resulted in increased toxicity. Pharmacogenetic analysis revealed an association of FGFR and VEGFR variants with survival.

Introduction We investigated the relationships between progression-free survival (PFS), response, confirmed response, and failure-free survival (FFS) with overall survival (OS) to assess their suitability as primary endpoints in phase II trials for advanced non-small cell lung cancer. Methods Individual data of 284 patients from four phase II trials were pooled. Progression status and response were modeled as time dependent variables in a multivariable (adjusted for baseline age, gender, stage, and performance status) Cox proportional hazards model for OS, stratified by trial. Subsequently, Cox proportional hazards models were used to assess the impact of PFS, response, confirmed response, and FFS on subsequent survival, using landmark analysis at 8, 12, 16, 20, and 24 weeks. Model discrimination was evaluated using the concordance index (c-index). Results The overall median OS, PFS, and FFS were 9.6, 3.7, and 2.8 months, and the response and confirmed response rates were 21 and 15%, respectively. Both progression status and response as time dependent covariates were significantly associated with OS ( p p = 0.009). PFS and FFS at 12 weeks significantly predicted for subsequent survival with the strongest c-index and hazard ratio combination in landmark analyses (hazard ratio, c-index: PFS: 0.39, 0.67; FFS: 0.37, 0.67). The c-indices for response and confirmed response were low (0.59–0.60), indicating their inability to sufficiently discriminate subsequent patient survival outcomes. Conclusions FFS or PFS at 12 weeks is a stronger predictor of subsequent patient survival compared with tumor response and should be routinely used as endpoints in phase II trials for advanced non-small cell lung cancer.

Background It is currently not possible to get an approval of our ethics committee for a randomized trial cmparing 5x4 Gy and 10x3 Gy for MSCC that includes patients with favorable survival prognoses. Therefore, this matched-pair study following strict matching criteria was perfomed instead. Methods In this study, 142 receiving 5x4 Gy were retrospectively matched (1:1) to 142 patients receiving 10x3 Gy with respect to ten characteristics. These characteristics included age, gender, performance status, tumor type, involved vertebrae, other bone metastases, visceral metastases, interval between tumor diagnosis and MSCC, pre-RT ambulatory status, and time developing motor deficits. Results On multivariate analysis, post-RT motor function was associated with performance status (p

Background To compare definitive radiochemotherapy with weekly administration of 30–40 mg/m2 of cisplatin to 100 mg/m2 of cisplatin on days 1, 22 and 43 for outcomes and toxicity in patients with squamous cell carcinoma of the head-and-neck. Methods Seventy-five patients receiving radiochemotherapy with weekly cisplatin (30–40 mg/m2) were compared to 58 patients receiving radiochemotherapy with 100 mg/m2 cisplatin on days 1, 22 and 43. Radiochemotherapy regimen plus seven characteristics (age, gender, performance score, tumor site, T-/N-category, histologic grading) were evaluated for locoregional control (LRC), metastases-free survival (MFS) and overall survival (OS). Radiochemotherapy groups were compared for toxicity. Results On multivariate analysis, improved LRC was associated with cisplatin 100 mg/m2 (hazard ratio [HR] 1.57; p = 0.008) and female gender (HR 4.37; p = 0.003). Radiochemotherapy regimen was not significantly associated with MFS on univariate analysis (p = 0.66). On multivariate analysis, better MFS was associated with ECOG performance score 0–1 (HR 5.63; p

Background This multicenter study aimed to create and validate a scoring system for survival of patients with metastatic spinal cord compression (MSCC) from non-small cell lung cancer (NSCLC). Methods The entire cohort of 356 patients was divided in a test group (N = 178) and a validation group (N = 178). In the test group, nine pre-treatment factors including age, gender, Eastern Cooperative Oncology Group performance status (ECOG-PS), number of involved vertebrae, pre-radiotherapy ambulatory status, other bone metastases, visceral metastases, interval from cancer diagnosis to radiotherapy of MSCC, and the time developing motor were retrospectively analyzed. Results On multivariate analysis, survival was significantly associated with ECOG-PS, pre-radiotherapy ambulatory status, visceral metastases, and the time developing motor deficits. These factors were included in the scoring system; the score for each factor was determined by dividing the 6-month survival rate (in %) by 10. The risk score represented the sum of the scores for each factor. According to the risk scores, which ranged from 6 to 19 points, three prognostic groups were designed. The 6-month survival rates were 6% for 6–10 points, 29% for 11–15 points, and 78% for 16–19 points (p Conclusions Since the survival rates of the validation group were similar to those of the test group, this score can be considered reproducible. The scoring system can help when selecting the individual treatment for patients with MSCC from NSCLC. A prospective confirmatory study is warranted.

Background It is unclear whether patients with few cerebral metastases benefit from whole-brain irradiation added to radiosurgery. Since primary tumors disseminating to the brain show different behavior, this question should be answered separately for each tumor type. This study compared both treatments in patients with 1-3 cerebral metastases from lung cancer. Methods Ninety-eight patients receiving radiosurgery alone were retrospectively compared to 50 patients receiving radiosurgery plus whole-brain irradiation for local control, distant cerebral control and overall survival. Ten other characteristics were additionally considered including radiosurgery dose, age, gender, Eastern Cooperative Oncology Group (ECOG) performance score, histology, number of cerebral metastases, maximum diameter of all cerebral metastases, site of cerebral metastases, extra-cerebral metastases, and interval from lung cancer diagnosis to irradiation. Results The treatment approach had no significant impact on local control (p = 0.61). On multivariate analysis of local control, ECOG performance score was significant (risk ratio [RR]: 2.10; p

Background An important issue in palliative radiation oncology is the whether whole-brain radiotherapy should be added to radiosurgery when treating a limited number of brain metastases. To optimize personalized treatment of cancer patients with brain metastases, the value of whole-brain radiotherapy should be described separately for each tumor entity. This study investigated the role of whole-brain radiotherapy added to radiosurgery in breast cancer patients. Methods Fifty-eight patients with 1–3 brain metastases from breast cancer were included in this retrospective study. Of these patients, 30 were treated with radiosurgery alone and 28 with radiosurgery plus whole-brain radiotherapy. Both groups were compared for local control of the irradiated metastases, freedom from new brain metastases and survival. Furthermore, eight additional factors were analyzed including dose of radiosurgery, age at radiotherapy, Eastern Cooperative Oncology Group (ECOG) performance score, number of brain metastases, maximum diameter of all brain metastases, site of brain metastases, extra-cranial metastases and the time from breast cancer diagnosis to radiotherapy. Results The treatment regimen had no significant impact on local control in the univariate analysis (p = 0.59). Age ≤59 years showed a trend towards improved local control on univariate (p = 0.066) and multivariate analysis (p = 0.07). On univariate analysis, radiosurgery plus whole-brain radiotherapy (p = 0.040) and ECOG 0–1 (p = 0.012) showed positive associations with freedom from new brain metastases. Both treatment regimen (p = 0.039) and performance status (p = 0.028) maintained significance on multivariate analysis. ECOG 0–1 was positively correlated with survival on univariate analysis (p

Over the past 20 years, several proton beam treatment programs have been implemented throughout the United States. Increasingly, the number of new programs under development is growing. Proton beam therapy has the potential for improving tumor control and survival through dose escalation. It also has potential for reducing harm to normal organs through dose reduction. However, proton beam therapy is more costly than conventional x-ray therapy. This increased cost may be offset by improved function, improved quality of life, and reduced costs related to treating the late effects of therapy. Clinical research opportunities are abundant to determine which patients will gain the most benefit from proton beam therapy. We review the clinical case for proton beam therapy. Summary sentence Proton beam therapy is a technically advanced and promising form of radiation therapy.