Progression-Free and Overall Survival for Concurrent Nivolumab With Standard Concurrent Chemoradiotherapy in Locally Advanced Stage IIIA-B NSCLC: Results From the European Thoracic Oncology Platform NICOLAS Phase II Trial (European Thoracic Oncology Platform 6-14).

INTRODUCTION: The NICOLAS study is the first completed single-arm phase II trial in stage III NSCLC evaluating hierarchically first the safety and then the efficacy of adding nivolumab concurrently to standard definitive concurrent chemoradiotherapy. The safety end point was reported earlier; here, we present the efficacy results. METHODS: Stage IIIA-B unresectable treatment-naive patients with NSCLC received three cycles of platinum-based chemotherapy and concurrent radiotherapy (66 Gy, 33 fractions), along with nivolumab (360 mg, 3-weekly). Nivolumab was continued as monotherapy consolidation for a maximum of 1 year (480 mg, 4-weekly). The primary end point was 1-year progression-free survival (PFS), with a target improvement compared with historical data of at least 15%, from 45% to 60%. To test this efficacy hypothesis, a sample size of 74 assessable patients provided a power of 83% with a one-sided alpha of 5%. RESULTS: A total of 79 patients were enrolled with a median follow-up of 21.0 months (interquartile range: 15.8-25.8 mo) for the primary PFS analysis. A total of 35.4% of the patients had stage IIIA, and 63.3% had stage IIIB disease. The 1-year PFS was 53.7% (95% confidence interval [CI]: 42.0%-64.0%) and the median PFS was 12.7 months (95% CI: 10.1-22.8 mo). Because 37 PFS events occurred in the first year posttreatment among the first 74 assessable patients, a 1-year PFS rate of at least 45% could not be rejected (p = 0.23). At an extended follow-up (median 32.6 mo), 37 deaths have been recorded, with a median overall survival (OS) of 38.8 months (95% CI: 26.8 mo-not estimable) and a 2-year OS rate of 63.7% (95% CI: 51.9%-73.4%). The OS of patients with stage IIIA disease was found to be significantly higher than patients with stage IIIB disease, with a 2-year OS of 81% and 56%, respectively (p = 0.037). CONCLUSIONS: PFS and OS are arithmetically higher in studies involving the same population. However, on the basis of the formal hierarchical efficacy analysis, we could not reject that the 1-year PFS rate is at least 45%.

Impact of Early Prophylactic Cranial Irradiation With Hippocampal Avoidance on Neurocognitive Function in Patients With Limited Disease Small Cell Lung Cancer. A Multicenter Phase 2 Trial (SAKK 15/12).

PURPOSE: Our purpose was to evaluate neurocognitive function (NCF) and clinical outcomes after early hippocampal avoidance (HA) prophylactic cranial irradiation (PCI) in limited disease (LD) small cell lung cancer (SCLC). METHODS AND MATERIALS: In a phase 2 trial, patients with LD SCLC received HA-PCI concomitant with the second cycle of chemotherapy and thoracic radiation therapy. All patients underwent objective NCF testing at baseline, 6 weeks, and 6 and 12 months after HA-PCI. NCF tests included Hopkins Verbal Learning Test Revised, Controlled Oral Word Association, and Trail Making Tests A and B. The primary endpoint was NCF decline at 6 months after HA-PCI. We assumed ≤30% of patients with no NCF decline to be unpromising. Secondary endpoints included brain metastases-free survival (BMFS), overall survival (OS), and safety of the concomitant treatment. RESULTS: Among the 44 patients enrolled in the trial, 38 had evaluable NCF assessment at 6 months after HA-PCI. The proportion of evaluable patients showing no NCF decline at 6 and 12 months was 34.2% (90% confidence interval [CI], 21.6-48.8) and 48.5% (95% CI, 30.8-66.5), respectively. Median follow-up was 13.2 months (95% CI, 12.6-14.1). At 12 months, BMFS was 84.2% and OS was 87.7% (95% CI, 73.0-94.7). Four patients died of SCLC, 1 of respiratory failure, 1 of hemorrhage, and 1 for unknown reason. The most frequently reported grade ≥3 acute adverse events were anemia (21.4%), febrile neutropenia (19.1%), and fatigue (14.3%). CONCLUSIONS: The proportion of patients showing no NCF decline 6 and 12 months after early HA-PCI does not appear to be better than, but rather similar to, that observed in patients receiving sequential PCI without HA. Early HA-PCI in LD SCLC is feasible, with observation of promising BMFS and OS in this selected population.

Radiotherapy for pelvic nodal recurrences after radical prostatectomy: patient selection in clinical practice.

AIM: There is no general consensus on the optimal treatment for prostate cancer (PC) patients with intrapelvic nodal oligorecurrences after radical prostatectomy. Besides androgen deprivation therapy (ADT) as standard of care, both elective nodal radiotherapy (ENRT) and stereotactic body radiotherapy (SBRT) as well as salvage lymph node dissection (sLND) are common treatment options. The aim of our study was to assess decision making and practice patterns for salvage radiotherapy (RT) in this setting. METHODS: Treatment recommendations from 14 Swiss radiation oncology centers were collected and converted into decision trees. An iterative process using the objective consensus methodology was applied to assess differences and consensus. RESULTS: PSMA PET/CT was recommended by 93% of the centers as restaging modality. For unfit patients defined by age, comorbidities or low performance status, androgen deprivation therapy (ADT) alone was recommended by more than 70%. For fit patients with unfavorable tumor characteristics such as short prostate-specific antigen (PSA) doubling time or initial high-risk disease, the majority of the centers (57-71%) recommended ENRT + ADT for 1-4 lesions. For fit patients with favorable tumor characteristics, there were low levels of consensus and a wide variety of recommendations. For 1-4 nodal lesions, focal SBRT was offered by 64% of the centers, most commonly as a 5-fraction course. CONCLUSIONS: As an alternative to ADT, ENRT or SBRT for pelvic nodal oligorecurrences of PC are commonly offered to selected patients, with large treatment variations between centers. The exact number of lymph nodes had a major impact on treatment selection.

Salvage radiotherapy for macroscopic local recurrences after radical prostatectomy : A national survey on patterns of practice.

INTRODUCTION: Although salvage radiotherapy (SRT) for PSA recurrence after radical prostatectomy provides better oncological outcomes when delivered early, in the absence of detectable disease many patients are treated for macroscopic locally recurrent tumors. Due to limited data from prospective studies, we hypothesized an important variability in the SRT management of these patients. Our aim was to investigate current practice patterns of SRT for local macroscopic recurrence after radical prostatectomy. MATERIAL AND METHODS: A total of 14 Swiss radiation oncology centers were asked to complete a survey on treatment specifications for macroscopic locally recurrent disease including information on pretherapeutic diagnostic procedures, dose prescription, radiation delivery techniques and androgen deprivation therapy (ADT). Treatment recommendations on ADT were analyzed using the objective consensus methodology. RESULTS: The majority of centers recommended pretreatment magnetic resonance imaging (MRI) of the pelvis and choline positron emission tomography (PET). The median prescribed dose to the prostate bed was 66 Gy (range 65-72 Gy) with a boost to the macroscopic lesion used by 79% of the centers with a median total dose of 72 Gy (range 70-80 Gy). Intensity-modulated rotational techniques were used by all centers and daily cone beam computed tomography (CT) was recommended by 43%. The use of concomitant ADT for any macroscopic recurrence was recommended by 43% of the centers while the remaining centers recommended it only for high-risk disease, which was not consistently defined. CONCLUSION: We observed a high variability of treatment paradigms when SRT is indicated for macroscopic local recurrences after prostatectomy. These data reflect the need for more standardized approaches and ultimately further research in this field.

Results of Dose-adapted Salvage Radiotherapy After Radical Prostatectomy Based on an Endorectal MRI Target Definition Model.

OBJECTIVES: To assess the outcome of patients treated with a dose-adapted salvage radiotherapy (SRT) protocol based on an endorectal magnetic resonance imaging (erMRI) failure definition model after radical prostatectomy (RP). METHODS: We report on 171 relapsing patients after RP who had undergone an erMRI before SRT. 64 Gy were prescribed to the prostatic bed with, in addition, a boost of 10 Gy to the suspected local relapse as detected on erMRI in 131 patients (76.6%). RESULTS: The 3-year biochemical relapse-free survival (bRFS), local relapse-free survival, distant metastasis-free survival, cancer-specific survival, and overall survival were 64.2±4.3%, 100%, 85.2±3.2%, 100%, and 99.1±0.9%, respectively. A PSA value >1 ng/mL before salvage (P=0.006) and an absence of biochemical progression during RT (P=0.001) were both independently correlated with bRFS on multivariate analysis. No significant difference in 3-year bRFS was observed between the boost and no-boost groups (68.4±4.6% vs. 49.7±10%, P=0.251). CONCLUSIONS: A PSA value >1 ng/mL before salvage and a biochemical progression during RT were both independently correlated with worse bRFS after SRT. By using erMRI to select patients who are most likely expected to benefit from dose-escalated SRT protocols, this dose-adapted SRT approach was associated with good biochemical control and outcome, serving as a hypothesis-generating basis for further prospective trials aimed at improving the therapeutic ratio in the salvage setting.

Outcome and Predictive Factors in Uterine Carcinosarcoma Using Postoperative Radiotherapy: A Rare Cancer Network Study.

Uterine carcinosarcomas (UCS) are rare tumors. Consensus regarding therapeutic management in non-metastatic disease is lacking. This study reports on outcome and predictive factors when using postoperative radiotherapy. We analyzed a retrospective analysis in 124 women treated between 1987-2007 in the framework of the Rare-Cancer-Network. Median follow-up was 27 months. Postoperative pelvic EBRT was administered in 105 women (85%) and 92 patients (74%) received exclusive or additional vaginal brachytherapy. Five-year overall survival (OS), disease-free survival (DFS), cancer specific survival (CSS) and locoregional control (LRC) were 51.6% (95% CI 35-73%), 53.7% (39-71%), 58.6% (38-74%) and 48% (38-67%). Multivariate analysis showed that external beam radiation therapy (EBRT) >50Gy was an independent prognostic factor for better OS (P=0.03), CSS (P=0.02) and LRC (P=0.01). Relative risks (RR) for better OS (P=0.02), DFS (P=0.04) and LRC (P=0.01) were significantly associated with younger age (≤60 years). Higher brachytherapy (BT)-dose (>9Gy) improved DFS (P=0.04) and LRC (P=0.008). We concluded that UCS has high systemic failure rate. Local relapse was reduced by a relative risk factor of over three in all stages of diseases when using higher doses for EBRT and brachytherapy. Postoperative RT was most effective in UCS stage I/II-diseases.

Pelvic Lymph Node Irradiation Including Pararectal Sentinel Nodes for Prostate Cancer Patients: Treatment Optimization Comparing Intensity Modulated X-rays, Volumetric Modulated Arc Therapy, and Intensity Modulated Proton Therapy.

We aimed to assess the dosimetric impact of advanced delivery radiotherapy techniques using either intensity modulated x-ray beams (IMXT), volumetric modulated arc therapy (VMAT), or intensity modulated proton therapy (IMPT), for high-risk prostate cancer patients with sentinel nodes in the pararectal region. Twenty high-risk prostate cancer patients were included in a prospective trial evaluating sentinel nodes on pelvic SPECT acquisition. To be eligible for the dosimetric study, patients had to present with pararectal sentinel nodes usually not included in the clinical target volume encompassing the pelvic lymph nodes. Radiotherapy-plans including the prostate, the seminal vesicles, and the pelvic lymph nodes with the pararectal sentinel nodes were optimized for 6 eligible patients. IMXT and IMPT were delivered with 7 and 3 beams respectively and VMAT with 2 arcs. Results were assessed with Dose-Volume Histograms and predictive normal tissue complication probabilities (NTCPs) models between the three competing treatment modalities aiming to deliver a total dose of 50.4 Gy in 1.8 Gy daily fractions. Target coverage was optimized with IMPT when compared to IMXT and VMAT. Coverage of the sentinel node was slightly better with IMXT (D98% 5 57.3 ± 5.1 Gy) when compared with VMAT (D98% 5 56.2 ± 4.1 Gy). The irradiation of rectal, bladder, small bowel, and femoral heads volumes was significantly reduced with IMPT when compared to IMXT and VMAT. NTCPs rates for rectal and bladder ≥ grade-3 late toxicity were better with IMPT (0.4 ± 0.0% and 0.0 ± 0.0%) compared with IMXT (4.6 ± 3.3% and 1.4 ± 1.1%), and VMAT (4.5 ± 4.0% and 1.6 ± 1.6%), respectively. Acceptable dose-volume distributions and low rectal and urinary NTCPs were estimated to geometrically complex pelvic volumes such as the ones proposed in this study using IMXT, VMAT and IMPT. IMPT succeeded, however, to propose the best physical and biological treatment plans compared to both X-ray derived plans.

History of the rare cancer network and past research.

Approximately, twenty years ago, the Rare Cancer Network (RCN) was formed in Lausanne, Switzerland, to support the study of rare malignancies. The RCN has grown over the years and now includes 130 investigators from twenty-four nations on six continents. The network held its first international symposium in Nice, France, on March 21-22, 2014. The proceedings of that meeting are presented in two companion papers. This manuscript reviews the history of the growth of the RCN and contains the abstracts of fourteen oral presentations made at the meeting of prior RCN studies. From 1993 to 2014, 74 RCN studies have been initiated, of which 54 were completed, 10 are in progress or under analysis, and 9 were stopped due to poor accrual. Forty-four peer reviewed publications have been written on behalf of the RCN.

First imaging results of an intraindividual comparison of (11)C-acetate and (18)F-fluorocholine PET/CT in patients with prostate cancer at early biochemical first or second relapse after prostatectomy or radiotherapy.

PURPOSE: (18)F-Fluorocholine (FCH) and (11)C-acetate (ACE) PET are widely used for detection of recurrent prostate cancer (PC). We present the first results of a comparative, prospective PET/CT study of both tracers evaluated in the same patients presenting with recurrence and low PSA to compare the diagnostic information provided by the two tracers. METHODS: The study group comprised 23 patients studied for a rising PSA level after radical prostatectomy (RP, 7 patients, PSA ≤ 3 ng/ml), curative radiotherapy (RT, 7 patients, PSA ≤ 5 ng/ml) or RP and salvage RT (9 patients, PSA ≤ 5 ng/ml). Both FCH and ACE PET/CT scans were performed in a random sequence a median of 4 days (range 0 to 11 days) apart. FCH PET/CT was started at injection (307 ± 16 MBq) with a 10-min dynamic acquisition of the prostate bed, followed by a whole-body PET scan and late (45 min) imaging of the pelvis. ACE PET/CT was performed as a double whole-body PET scan starting 5 and 22 min after injection (994 ± 72 MBq), and a late view (45 min) of the prostate bed. PET/CT scans were blindly reviewed by two independent pairs of two experienced nuclear medicine physicians, discordant subgroup results being discussed to reach a consensus for positive, negative end equivocal results. RESULTS: PET results were concordant in 88 out of 92 local, regional and distant findings (Cohen's kappa 0.929). In particular, results were concordant in all patients concerning local status, bone metastases and distant findings. Lymph-node results were concordant in 19 patients and different in 4 patients. On a per-patient basis results were concordant in 22 of 23 patients (14 positive, 5 negative and 3 equivocal). In only one patient was ACE PET/CT positive for nodal metastases while FCH PET/CT was overall negative; interestingly, the ACE-positive and FCH-negative lymph nodes became positive in a second FCH PET/CT scan performed a few months later. CONCLUSION: Overall, ACE and FCH PET/CT showed excellent concordance, on both a per-lesion and a per-patient basis, suggesting that both tracers perform equally for recurrent prostate cancer staging.

Dose-adapted salvage radiotherapy after radical prostatectomy based on an erMRI target definition model: toxicity analysis.

BACKGROUND: To assess treatment tolerance by patients treated with a dose-adapted salvage radiotherapy (SRT) protocol based on an multiparametric endorectal magnetic resonance imaging (erMRI) failure definition model after radical prostatectomy (RP). MATERIAL AND METHODS: A total of 171 prostate cancer patients recurring after RP undergoing erMRI before SRT were analyzed. A median dose of 64 Gy was delivered to the prostatic bed (PB) with, in addition, a boost of 10 Gy to the suspected relapse as visualized on erMRI in 131 patients (76.6%). Genitourinary (GU) and gastrointestinal (GI) toxicities were scored using the RTOG scale. RESULTS: Grade ≥ 3 GU and GI acute toxicity were observed in three and zero patients, respectively. The four-year grade ≥ 2 and ≥ 3 late GU and GI toxicity-free survival rates (109 patients with at least two years of follow-up) were 83.9 ± 4.7% and 87.1 ± 4.2%, and 92.1 ± 3.6% and 97.5 ± 1.7%, respectively. Boost (p = 0.048) and grade ≥ 2 acute GU toxicity (p = 0.008) were independently correlated with grade ≥ 2 late GU toxicity on multivariate analysis. CONCLUSIONS: A dose-adapted, erMRI-based SRT approach treating the PB with a boost to the suspected local recurrence may potentially improve the therapeutic ratio by selecting patients that are most likely expected to benefit from SRT doses above 70 Gy as well as by reducing the size of the highest-dose target volume. Further prospective trials are needed to investigate the use of erMRI in SRT as well as the role of dose-adapted protocols and the best fractionation schedule.

Impact of 18F-FDG PET/CT on target volume delineation in recurrent or residual gynaecologic carcinoma.

BACKGROUND: To evaluate the impact of 18F-FDG PET/CT on target volume delineation in gynaecological cancer. METHODS: F-FDG PET/CT based RT treatment planning was performed in 10 patients with locally recurrent (n = 5) or post-surgical residual gynaecological cancer (n = 5). The gross tumor volume (GTV) was defined by 4 experienced radiation oncologists first using contrast enhanced CT (GTVCT) and secondly using the fused 18F-FDG PET/CT datasets (GTVPET/CT). In addition, the GTV was delineated using the signal-to-background (SBR) ratio-based adaptive thresholding technique (GTVSBR). Overlap analysis were conducted to assess geographic mismatches between the GTVs delineated using the different techniques. Inter- and intra-observer variability were also assessed. RESULTS: The mean GTVCT (43.65 cm3) was larger than the mean GTVPET/CT (33.06 cm3), p = 0.02. In 6 patients, GTVPET/CT added substantial tumor extension outside the GTVCT even though 90.4% of the GTVPET/CT was included in the GTVCT and 30.2% of the GTVCT was found outside the GTVPET/CT. The inter- and intra-observer variability was not significantly reduced with the inclusion of 18F-FDG PET imaging (p = 0.23 and p = 0.18, respectively). The GTVSBR was smaller than GTVCT p ≤ 0.005 and GTVPET/CT p ≤ 0.005. CONCLUSIONS: The use of 18F-FDG PET/CT images for target volume delineation of recurrent or post-surgical residual gynaecological cancer alters the GTV in the majority of patients compared to standard CT-definition. The use of SBR-based auto-delineation showed significantly smaller GTVs. The use of PET/CT based target volume delineation may improve the accuracy of RT treatment planning in gynaecologic cancer.

Target volume definition in high-risk prostate cancer patients using sentinel node SPECT/CT and 18 F-choline PET/CT.

BACKGROUND: To assess the influence of sentinel lymph nodes (SNs) SPECT/CT and 18 F-choline (18 F-FCH) PET/CT in radiotherapy (RT) treatment planning for prostate cancer patients with a high-risk for lymph node (LN) involvement. METHODS: Twenty high-risk prostate cancer patients underwent a pelvic SPECT acquisition following a transrectal ultrasound guided injection of 99mTc-Nanocoll into the prostate. In all patients but one an 18 F-FCH PET/CT for RT treatment planning was performed. SPECT studies were coregistered with the respective abdominal CTs. Pelvic SNs localized on SPECT/CT and LN metastases detected by 18 F-FCH PET/CT were compared to standard pelvic clinical target volumes (CTV). RESULTS: A total of 104 pelvic SNs were identified on SPECT/CT (mean 5.2 SNs/patient; range 1-10). Twenty-seven SNs were located outside the standard pelvic CTV, 17 in the proximal common iliac and retroperitoneal regions above S1, 9 in the pararectal fat and 1 in the inguinal region. SPECT/CT succeeded to optimize the definition of the CTV and treatment plans in 6/20 patients due to the presence of pararectal SNs located outside the standard treatment volume. 18 F-FCH PET/CT identified abnormal tracer uptake in the iliac LN region in 2/19 patients. These abnormal LNs were negative on SPECT/CT suggesting a potential blockade of lymphatic drainage by metastatic LNs with a high tumour burden. CONCLUSIONS: Multimodality imaging which combines SPECT/CT prostate lymphoscintigraphy and 18 F-FCH PET/CT identified SNs outside standard pelvic CTVs or highly suspicious pelvic LNs in 40% of high-risk prostate cancer patients, highlighting the potential impact of this approach in RT treatment planning.

Outcome and prognostic factors in endometrial stromal tumors: a Rare Cancer Network study.

PURPOSE: To provide further understanding regarding outcome and prognostic factors of endometrial stromal tumors (EST). METHODS AND MATERIALS: A retrospective analysis was performed on the records of 59 women diagnosed with EST and treated with curative intent between 1983 and 2007 in the framework of the Rare Cancer Network. RESULTS: Endometrial stromal sarcomas (ESS) were found in 44% and undifferentiated ESS (UES) in 49% of the cases. In 7% the grading was unclear. Of the total number of patients, 33 had Stage I, 4 Stage II, 20 Stage III, and 1 presented with Stage IVB disease. Adjuvant chemotherapy was administered to 12 patients, all with UES. External-beam radiotherapy (RT) was administered postoperatively to 48 women. The median follow-up was 41.4 months. The 5-year overall survival (OS) rate was 96.2% and 64.8% for ESS and UES, respectively, with a corresponding 5-year disease-free survival (DFS) rate of 49.4% and 43.4%, respectively. On multivariate analysis, adjuvant RT was an independent prognostic factor for OS (p = 0.007) and DFS (p = 0.013). Locoregional control, DFS, and OS were significantly associated with age (≤60 vs. >60 years), grade (ESS vs. UES), and International Federation of Gynecology and Obstetrics stage (I-II vs. III-IV). Positive lymph node staging had an impact on OS (p < 0.001). CONCLUSION: The prognosis of ESS differed from that of UES. Endometrial stromal sarcomas had an excellent 5-year OS, whereas the OS in UES was rather low. However, half of ESS patients had a relapse. For this reason, adjuvant treatment such as RT should be considered even in low-grade tumors. Multicenter randomized studies are still warranted to establish clear guidelines.

Management of adenoid cystic carcinoma of the breast: a Rare Cancer Network study.

BACKGROUND: Mammary adenoid cystic carcinoma (ACC) is a rare breast cancer. The aim of this retrospective study was to assess prognostic factors and patterns of failure, as well as the role of radiation therapy (RT), in ACC. METHODS: Between January 1980 and December 2007, 61 women with breast ACC were treated at participating centers of the Rare Cancer Network. Surgery consisted of lumpectomy in 41 patients and mastectomy in 20 patients. There were 51(84%) stage pN0 and 10 stage cN0 (16%) patients. Postoperative RT was administered to 40 patients (35 after lumpectomy, 5 after mastectomy). RESULTS: With a median follow-up of 79 months (range, 6-285), 5-year overall and disease-free survival rates were 94% (95% confidence interval [CI], 88%-100%) and 82% (95% CI, 71%-93%), respectively. The 5-year locoregional control (LRC) rate was 95% (95% CI, 89%-100%). Axillary lymph node dissection or sentinel node biopsy was performed in 84% of cases. All patients had stage pN0 disease. In univariate analysis, survival was not influenced by the type of surgery or the use of postoperative RT. The 5-year LRC rate was 100% in the mastectomy group versus 93% (95% CI, 83%-100%) in the breast-conserving surgery group, respectively (p = 0.16). For the breast-conserving surgery group, the use of RT significantly correlated with LRC (p = 0.03); the 5-year LRC rates were 95% (95% CI, 86%-100%) for the RT group versus 83% (95% CI, 54%-100%) for the group receiving no RT. No local failures occurred in patients with positive margins, all of whom received postoperative RT. CONCLUSION: Breast-conserving surgery is the treatment of choice for patients with ACC breast cancer. Axillary lymph node dissection or sentinel node biopsy might not be recommended. Postoperative RT should be proposed in the case of breast-conserving surgery.

18F-fluorocholine PET-guided target volume delineation techniques for partial prostate re-irradiation in local recurrent prostate cancer.

BACKGROUND AND PURPOSE: We evaluate the contribution of (18)F-choline PET/CT in the delineation of gross tumour volume (GTV) in local recurrent prostate cancer after initial irradiation using various PET image segmentation techniques. MATERIALS AND METHODS: Seventeen patients with local-only recurrent prostate cancer (median=5.7 years) after initial irradiation were included in the study. Rebiopsies were performed in 10 patients that confirmed the local recurrence. Following injection of 300 MBq of (18)F-fluorocholine, dynamic PET frames (3 min each) were reconstructed from the list-mode acquisition. Five PET image segmentation techniques were used to delineate the (18)F-choline-based GTVs. These included manual delineation of contours (GTV(man)) by two teams consisting of a radiation oncologist and a nuclear medicine physician each, a fixed threshold of 40% and 50% of the maximum signal intensity (GTV(40%) and GTV(50%)), signal-to-background ratio-based adaptive thresholding (GTV(SBR)), and a region growing (GTV(RG)) algorithm. Geographic mismatches between the GTVs were also assessed using overlap analysis. RESULTS: Inter-observer variability for manual delineation of GTVs was high but not statistically significant (p=0.459). In addition, the volumes and shapes of GTVs delineated using semi-automated techniques were significantly higher than those of GTVs defined manually. CONCLUSIONS: Semi-automated segmentation techniques for (18)F-choline PET-guided GTV delineation resulted in substantially higher GTVs compared to manual delineation and might replace the latter for determination of recurrent prostate cancer for partial prostate re-irradiation. The selection of the most appropriate segmentation algorithm still needs to be determined.

Recurrence pattern after [(18)F]fluoroethyltyrosine-positron emission tomography-guided radiotherapy for high-grade glioma: a prospective study.

PURPOSE: To assess the failure pattern observed after (18)F fluoroethyltyrosine (FET) planning after chemo- and radiotherapy (RT) for high-grade glioma. METHODS: All patients underwent prospectively RT planning using morphological gross tumour volumes (GTVs) and biological tumour volumes (BTVs). The post-treatment recurrence tumour volumes (RTVs) of 10 patients were transferred on their CT planning. First, failure patterns were defined in terms of percentage of RTV located outside the GTV and BTV. Second, the location of the RTV with respect to the delivered dose distribution was assessed using the RTV's DVHs. Recurrences with >95% of their volume within 95% isodose line were considered as central recurrences. Finally, the relationship between survival and GTV/BTV mismatches was assessed. RESULTS: The median percentages of RTV outside the GTV and BTV were 41.8% (range, 10.5-92.4) and 62.8% (range, 34.2-81.1), respectively. The majority of recurrences (90%) were centrally located. Using a composite target volume planning formalism, the degree of GTV and BTV mismatch did not correlate with survivorship. CONCLUSIONS: The observed failure pattern after FET-PET planning and chemo-RT is primarily central. The target mismatch-survival data suggest that using FET-PET planning may counteract the possibility of BTV-related progression, which may have a detrimental effect on survival.

Molecular PET/CT imaging-guided radiation therapy treatment planning.

The role of positron emission tomography (PET) during the past decade has evolved rapidly from that of a pure research tool to a methodology of enormous clinical potential. (18)F-fluorodeoxyglucose (FDG)-PET is currently the most widely used probe in the diagnosis, staging, assessment of tumor response to treatment, and radiation therapy planning because metabolic changes generally precede the more conventionally measured parameter of change in tumor size. Data accumulated rapidly during the last decade, thus validating the efficacy of FDG imaging and many other tracers in a wide variety of malignant tumors with sensitivities and specificities often in the high 90 percentile range. As a result, PET/computed tomography (CT) had a significant impact on the management of patients because it obviated the need for further evaluation, guided further diagnostic procedures, and assisted in planning therapy for a considerable number of patients. On the other hand, the progress in radiation therapy technology has been enormous during the last two decades, now offering the possibility to plan highly conformal radiation dose distributions through the use of sophisticated beam targeting techniques such as intensity-modulated radiation therapy (IMRT) using tomotherapy, volumetric modulated arc therapy, and many other promising technologies for sculpted three-dimensional (3D) dose distribution. The foundation of molecular imaging-guided radiation therapy lies in the use of advanced imaging technology for improved definition of tumor target volumes, thus relating the absorbed dose information to image-based patient representations. This review documents technological advancements in the field concentrating on the conceptual role of molecular PET/CT imaging in radiation therapy treatment planning and related image processing issues with special emphasis on segmentation of medical images for the purpose of defining target volumes. There is still much more work to be done and many of the techniques reviewed are themselves not yet widely implemented in clinical settings.

Is there a place for low-dose chest and prophylactic brain irradiation in limited-disease small cell lung cancer.

The aim of the study is to evaluate the outcome of low-dose bifractionated up-front radiotherapy (RT) followed by chemotherapy (CHT) in limited-disease small cell lung cancer (LD-SCLC). From December 1999 to February 2002, 20 LD-SCLC consecutive patients were treated by initial involved-field thoracic irradiation of 2 Gy twice daily to a total dose of 20 Gy, and concomitant prophylactic cranial irradiation (PCI) of 1.8 Gy twice daily to a total dose of 18 Gy followed 3 days later by 4-6 cycles of CHT with cisplatin and etoposide. Median follow-up was 66 months (52-77). There were no Grade 3-4 esophagitis or pneumonitis. Response rate was 90%, 45% of the patients showing a complete and 45% a partial response. Median time to first event was 13 months. Forty percent showed local infield recurrence, while 55% presented distant metastasis, 4 of them in the brain. Median survival time was 28 months. The Kaplan-Meier 1-, 3-, and 5-years survival rates were 95%, 35%, and 21%, respectively. Salvage RT was applied for local recurrence in 7 patients and for distant metastasis in 7 patients. The rate of brain recurrence with up-front low-dose PCI is favorable and should be further evaluated. Although the response and survival rates are promising, the high number of local recurrences indicates that the irradiation dose is insufficient for patients whose disease can be encompassed within a radical radiation portal.

Assessment of various strategies for 18F-FET PET-guided delineation of target volumes in high-grade glioma patients.

PURPOSE: The purpose of the study is to assess the contribution of (18)F-fluoro-ethyl-tyrosine ((18)F-FET) positron emission tomography (PET) in the delineation of gross tumor volume (GTV) in patients with high-grade gliomas compared with magnetic resonance imaging (MRI) alone. MATERIALS AND METHODS: The study population consisted of 18 patients with high-grade gliomas. Seven image segmentation techniques were used to delineate (18)F-FET PET GTVs, and the results were compared to the manual MRI-derived GTV (GTV(MRI)). PET image segmentation techniques included manual delineation of contours (GTV(man)), a 2.5 standardized uptake value (SUV) cutoff (GTV(2.5)), a fixed threshold of 40% and 50% of the maximum signal intensity (GTV(40%) and GTV(50%)), signal-to-background ratio (SBR)-based adaptive thresholding (GTV(SBR)), gradient find (GTV(GF)), and region growing (GTV(RG)). Overlap analysis was also conducted to assess geographic mismatch between the GTVs delineated using the different techniques. RESULTS: Contours defined using GTV(2.5) failed to provide successful delineation technically in three patients (18% of cases) as SUV(max) < 2.5 and clinically in 14 patients (78% of cases). Overall, the majority of GTVs defined on PET-based techniques were usually smaller than GTV(MRI) (67% of cases). Yet, PET detected frequently tumors that are not visible on MRI and added substantially tumor extension outside the GTV(MRI) in six patients (33% of cases). CONCLUSIONS: The selection of the most appropriate (18)F-FET PET-based segmentation algorithm is crucial, since it impacts both the volume and shape of the resulting GTV. The 2.5 SUV isocontour and GF segmentation techniques performed poorly and should not be used for GTV delineation. With adequate setting, the SBR-based PET technique may add considerably to conventional MRI-guided GTV delineation.