295 Background: The optimum combination curative approach to locally advanced adenocarcinoma of the esophagus and esophago-gastric junction (AEG) remains controversial, specifically whether multimodal therapy or perioperative chemotherapy is superior. Neo-AEGIS was designed as the first randomized clinical trial (RCT) to directly compare the multimodal CROSS regimen (carboplatin/paclitaxel, 41.4Gy radiation therapy) with a modified MAGIC (epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine)) regimen (pre-2018) and more latterly the FLOT (docetaxel, 5-FU, leucovorin, oxaliplatin) regimen. Methods: 377 patients with cT2-3N0-3M0 AEG were randomly assigned to CROSS or peri-operative chemotherapy (ECF/ECX/EOF/EOX pre-2018, FLOT option 2019/20) at 24 sites (Ireland, UK, Denmark, France, Sweden). The primary outcome was overall survival. The initial power calculation was based on CROSS superiority of 10%. This was modified after the first futility analysis (70 events) to a non-inferiority margin of 5% for peri-operative chemotherapy. Secondary end points included toxicity, pathologic measures of response, and postoperative complications as per the Esophageal Complications Consensus Group (ECCG) definitions and Clavien-Dindo severity grade. Results: Of 362 evaluable patients, 178 CROSS, 184 MAGIC/FLOT (157/27), 90% were male, median (range) age 64 (35-83), 84% were cT3, and 58% cN1. At a median (range) follow up of 34.2 (0.43-111.8) months, there were 186 deaths, 91 CROSS and 95 MAGIC/FLOT arm, with 3-year estimated survival probability of 57% (95% CI 49,64) and 55% (95% CI 47,62), respectively [(HR 1.03 (95%CI. 0.77-1.38))]. Conclusions: This RCT reveals no evidence that peri-operative chemotherapy is unacceptably inferior to multimodal therapy in the primary outcome of overall survival, notwithstanding greater proxy markers of local tumor response in the CROSS arm. Oncologic and operative outcomes were consistent with optimum modern benchmarks. These data strongly suggest non-inferiority and support equipoise in clinical decision making in modern practice. Clinical trial information: NCT01726452 . [Table: see text]

We investigate the accuracy of intensity-based deformable image registration (DIR) for tumor localization in liver stereotactic body radiotherapy (SBRT). We included 4DCT scans to capture the breathing motion of eight patients receiving SBRT for liver metastases within a retrospective clinical study. Each patient had three fiducial markers implanted. The liver and the tumor were delineated in the mid-ventilation phase, and their positions in the other phases were estimated with deformable image registration. We tested referenced and sequential registrations strategies. The fiducial markers were the gold standard to evaluate registration accuracy. The registration errors related to measured versus estimated fiducial markers showed a mean value less than 1.6 mm . The positions of some fiducial markers appeared not stable on the 4DCT throughout the respiratory phases. Markers’ center of mass tends to be a more reliable measurement. Distance errors of tumor location based on registration versus markers center of mass were less than 2 mm . There were no statistically significant differences between the reference and the sequential registration, i.e., consistency and errors were comparable to resolution errors. We demonstrated that intensity-based DIR is accurate up to resolution level for locating the tumor in the liver during breathing motion.

Objectives: In a randomized phase II trial, twice daily (BID) thoracic radiotherapy (TRT) of 60 Gy/40 frac-tions improved survival compared with 45 Gy/30 fractions in limited stage small-cell lung cancer (LS SCLC). Notably, the higher dose did not cause more toxicity. Here we present health related quality of life (HRQoL) reported by the trial participants during the first 2 years. Materials and methods: 170 patients were randomized 1:1 to TRT of 45 Gy or 60 Gy concurrently with cisplatin/etoposide chemotherapy. The 150 patients who commenced TRT and completed a minimum of one HRQoL-questionnaire were included in the present study. Patients reported HRQoL on the European Organization for Research and Treatment of Cancer Core 30 and Lung Cancer 13 Quality of Life Questionnaires. Questionnaires were completed weeks 0, 4 (before TRT), 8 (end of TRT), 12 (response evaluation after chemoradiotherapy) and 16 (end of prophylactic cranial irradiation), then every 10 weeks year one, and every 3 months year two. Primary HRQoL endpoints were dysphagia and dyspnea. A difference in mean score of >= 10 was defined as clinically significant. Results: Maximum dysphagia was reported on week 8, with no significant difference between treatment arms (mean scores 45 Gy: 44.2, 60 Gy: 51.1). The 60 Gy arm had more dysphagia in the convalescence period, but dysphagia scores returned to baseline levels at week 16 in both arms. For dyspnea there were no significant changes, or differences between treatment arms, at any timepoint. There were no significant differences between treatment arms for any other HRQoL-scales. Conclusion: TRT of 60 Gy did not cause significantly higher maximum dysphagia, though patients on the 60 Gy arm reported more dysphagia the first 8 weeks of convalescence. The higher dose was well tolerated and is an attractive alternative to current TRT schedules in LS SCLC.

LBA3514 Background: Organ preserving treatment strategies based on chemoradiotherapy may spare rectal cancer patients of major surgery and stoma. We suggest substantially improved tumor control by increasing the radiotherapy dose, without significant increase in the rate of late effects. We designed a prospective phase II trial to test high-dose radiotherapy of low rectal cancer for organ preservation in a multicenter setting. Methods: We enrolled patients with localized T1-3 N0-1 M0 rectal cancer within 6 cm from the anal verge and in performance status 0-2. Any N1-nodes had to be at the level of the tumor and included in the primary tumor-volume. Radiotherapy consisted of 62 Gy to the tumor and 50.4 Gy to the regional lymph nodes, delivered in 28 fractions using intensity modulated radiation therapy and daily image guidance. Capecitabine 825 mg/m2 BID. Patients with clinical complete response (cCR) 6–12 weeks after end of treatment were allocated to follow-up. Surgery was offered only in case of residual cancer or later re-growth. The primary endpoint was the proportion of patients with locoregional tumor control after two years by chemoradiation alone. Secondary endpoints included long-term side effects (CTCAE grading), cCR, rate of distant metastases, and overall survival. Results: Three Danish centers enrolled 107 patients between 2015 and 2019. Baseline classifications were T1/T2/T3 and N1 in 15%/54%/31% and 29%, respectively. The median age was 71 years and 64% were male. 92 (86.0%) had cCR and were allocated to observation. Four patients drew consent or died leaving 103 observed for at least 2 years. 23 had regrowth after cCR, five of whom had organ preserving transanal endoscopic microsurgery, 15 other curative surgery, and three palliation. 63 had no locoregional regrowth. Thus 61% (63/103) of patients with 2 years of follow-up had locoregional tumor control with chemoradiation alone. The actuarial estimate of locoregional control at 2 years from start of observation was 73.8% (95%CI 63.2-81.8). Calculated from time of enrollment, metastasis-free and overall survival at 30 months was 85.4% (95%CI 76.5-91.1) and 94.8% (95%CI 87.8-97.8). In the 63 patients with complete response at 2 years, ‘Low Anterior Resection Syndrome-score’ was None=37%, Minor=28%, and Major=35%. The most severe toxicity was erectile dysfunction grade 3 (n=3), grade 2 (n=4), grade 1 (n=6), and grade 0 (n=26). Grade 2 diarrhea, constipation, fecal incontinence, rectal bleeding and decreased libido were each reported in one case, while urinary frequency grade 2 was seen in four patients. Conclusions: The vast majority of patients with low rectal cancer can be cured by modern radiotherapy 62 Gy in 28 fractions with excellent patient-reported outcomes, toxicity, tumor control, and survival. The treatment is feasible in a multicenter setting. We suggest this approach as a standard of care option. Clinical trial information: NCT02438839.

4004 Background: The optimum combination curative approach to locally advanced adenocarcinoma of the esophagus and esophago-gastric junction (AEG) is unknown. A key question is whether neoadjuvant multimodal therapy, specifically CROSS (carboplatin/paclitaxel, 41.4Gy radiation therapy), is superior to optimum peri-operative chemotherapeutic regimens including modified MAGIC (epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine)) and more latterly FLOT (docetaxel, 5-FU, leucovorin, oxaliplatin). Neo-AEGIS was designed as the first randomised controlled trial to address this question. Methods: 377 patients with cT2-3N0-3M0 AEG were randomly assigned to CROSS or peri-operative chemotherapy (ECF/ECX/EOF/EOX pre-2018, FLOT option 2019/20) at 24 sites (Ireland, UK, Denmark, France, Sweden). The primary outcome was overall survival. The initial power calculation was based on CROSS superiority of 10%. This was modified after the first futility analysis (70 events) to a non-inferiority margin of 5%. Secondary end points included toxicity, pathologic measures of response, and postoperative complications as per the Esophageal Complications Consensus Group (ECCG) definitions and Clavien-Dindo severity grade. Results: Of 362 evaluable patients, 178 CROSS, 184 MAGIC/FLOT (157/27), 90% were male, median (range) age 64 (35-83), 84% were cT3, and 58% cN1. At a median (range) follow up of 24.5 (1-92) months, at the second futility analysis (60% of planned events), there were 143 deaths, 70 CROSS and 73 MAGIC/FLOT arm, with 3-year estimated survival probability of 56% (95% CI 47,64) and 57% (95% CI 48,65), respectively [(HR 1.02 (95%CI. 0.74-1.42))]. Based on the absence of futility evidenced in this data the DSMB recommended closure of recruitment in December 2020. Conclusions: This RCT reveals no evidence that peri-operative chemotherapy is unacceptably inferior to multimodal therapy, notwithstanding greater proxy markers of local tumour response in the CROSS arm. Oncologic and operative outcomes were consistent with optimum modern benchmarks. These data strongly suggest non-inferiority and support equipoise in decision making in modern practice. Clinical trial information: NCT01726452. [Table: see text]

Background Concurrent chemoradiotherapy is standard treatment for limited stage small-cell lung cancer (SCLC). Twice-daily thoracic radiotherapy of 45 Gy in 30 fractions is considered to be the most effective schedule. The aim of this study was to investigate whether high-dose, twice-daily thoracic radiotherapy of 60 Gy in 40 fractions improves survival. Methods This open-label, randomised, phase 2 trial was done at 22 public hospitals in Norway, Denmark, and Sweden. Patients aged 18 years and older with treatment-naive confirmed limited stage SCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 were eligible. All participants received four courses of intravenous cisplatin 75 ing/m 2 or carboplatin (area under the curve 5-6 mg/mL x min, Calvert's formula) on day 1 and intravenous etoposide 100 mg/m 2 on days 1-3 every 3 weeks. Participants were randomly assigned (1:1) in permuted blocks (sized between 4 and 10) stratifying for ECOG performance status, disease stage, and presence of pleural effusion to receive thoracic radiotherapy of 45 Gy in 30 fractions or 60 Gy in 40 fractions to the primary lung tumour and PET-CT positive lymph node metastases starting 20-28 days after the first chemotherapy course. Patients in both groups received two fractions per day, ten fractions per week. Responders were offered prophylactic cranial irradiation of 25-30 Gy. The primary endpoint, 2-year overall survival, was assessed after all patients had been followed up for a minimum of 2 years. All randomly assigned patients were included in the efficacy analyses, patients commencing thoracic radiotherapy were included in the safety analyses. Follow-up is ongoing. This trial is registered at ClinicalTrials.gov , NCT02041845. Findings Between July 8,2014, and June 6,2018,176 patients were enrolled, 170 of whom were randomly assigned to 60 Gy (n=89) or 45 Gy (n=81). Median follow-up for the primary analysis was 49 months (IQR 38-56). At 2 years, 66 (74.2% [95% CI 63-8-82.9]) patients in the 60 Gy group were alive, compared with 39 (48.1% 136-9-59.51) patients in the 45 Gy group (odds ratio 3.09 [95% CI 1.62-5-89]; p=0-0005). The most common grade 3-4 adverse events were neutropenia (72 [81%] of 89 patients in the 60 Gy group vs 62 181%1 of 77 patients in the 45 Gy group), neutropenic infections (24 [27%] vs 30 [39%1), thrombocytopenia (21 [24%] vs 19 125%1), anaemia (14 [16%] vs 15 120%D, and oesophagitis (19 [21%] vs 14 [18%]). There were 55 serious adverse events in 38 patients in the 60 Gy group and 56 serious adverse events in 44 patients in the 45 Gy group. There were three treatment-related deaths in each group (one neutropenic fever, one aortic dissection, and one pneumonitis in the 60 Gy group; one thrombocytic bleeding, one cerebral infarction, and one myocardial infarction in the 45 Gy group). Interpretation The higher radiotherapy dose of 60 Gy resulted in a substantial survival improvement compared with 45 Gy, without increased toxicity, suggesting that twice-daily thoracic radiotherapy of 60 Gy is an alternative to existing schedules. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

At our institution we treat liver metastases with stereotactic body radiotherapy (SBRT) on the magnetic resonance linear accelerator (MR-Linac). This enables tracking on the liver, tumor, or tumor-adjacent structures and provides improved soft tissue visualization compared to cone beam computerized tomography. Hence the implementation of fiducials can be omitted. Another benefit of MR-guided treatment is the potential for daily plan adaptation, which we explore in this study. 10 consecutive patients were treated in a total of 41 fractions with non-adapted liver SBRT at the MR-Linac. Prescribed doses were 48 Gy to 75 Gy to the gross tumor volume (GTV) in 3 to 6 fractions. GTV to planning target volume (PTV) margins were 10 mm in craniocaudal direction and 5 mm in other directions for 8 patients and isotropic 5 mm for 2 patients. The original plan was calculated on the MR simulation scan (original plan). There was an automatic calculation of the original plan on the daily patient anatomy (delivered plan). Dose distributions of these clinically delivered fractions were summed by deformable registration to the MR simulation scan. In addition, we simulated an adaptive workflow retrospectively for all fractions by optimizing the original plan on the daily anatomy (optimized plan). Delivered and optimized plans were compared based on D98% for the GTV and PTV, and the plan with the best coverage was chosen as the daily adapted plan (adapted plan). Adapted doses were summed by deformable registrations to the MR-simulation scan. One patient was omitted from the results due to problems in dose summation. Plans selected in the adapted workflow resulted in a median increase in D98% of 0.1% (range -1.4% to 8.8%) and 2.7% (range -2.7% to 7.8%) of the prescription dose to GTV and PTV, respectively, compared to a non-adaptive workflow. The adaptive workflow would result in a median 3.0 cm3 decrease (range -44.8 cm3 to 24.8 cm3) in the volume of the healthy liver (liver minus GTV) receiving less than 15 Gy compared to a non-adapted workflow. Online plan adaptation appears unnecessary for most patients treated with liver SBRT, with only minor improvement of target coverage and clinically non-significant changes in healthy liver V<15Gy. The next step will be investigation of the adaptive workflow on a subgroup of liver SBRT patients, where critical structures such as duodenum or bowel are close to the PTV.Tabled 1Abstract 2754; Table; Medians and rangesDose parameters in plansDifferences between plansOriginal PlanDelivered PlanAdapted PlanOriginal - DeliveredOriginal - AdaptedAdapted - DeliveredD98%(GTV) [%]92.5 (79.2 to 94.6)86.7 (69.2 to 94.8)90.3 (72.9 to 94.9)4.9 (-.17 to 12.3)2.8 (-1.8 to 6.3)0.1 (-1.4 to 8.8)D98%(PTV) [%]69.2 (58.0 to 91.3)65.2 (51.7 to 88.0)68.5 (56.6 to 90.5)5.9 (-1.1 to 9.5)2.3 (-1.9 to 6.2)2.7 (-2.7 to 7.8)V<15Gy (Liver minus GTV) [cm3]1412.3 (998.3 to 1804.8)1409.8 (984.4 to 1819.6)1384.1 (996.5 to 1791.9)3.7 (-142.1 to 73.2)13.6 (-142.1 to 79.9)-3.0 (-44.8 to 24.8) Open table in a new tab

Watchful waiting without surgery for rectal cancer is an option after complete response to chemoradiation. There is a need for optimising patient selection and radiotherapy to cure more patients with this modality. The aim of the study was to test high-dose radiotherapy of low rectal cancer for organ preservation in a multi-centre setting. The early endpoint of clinical complete response (cCR) at 12 weeks is reported here. This prospective trial enrolled patients with rectal cancer 0-6 cm from the anal verge, T1-3 N0-1 M0, performance status 0-2, and adequate organ function. Radiotherapy consisted of 62 and 50.4 Gy to the tumour and regional lymph nodes, respectively, in 28 fractions using intensity-modulated radiation therapy and daily image guidance. Capecitabine 825mg/m2 BID was administered on treatment days. Patients with cCR 6-12 weeks from end of treatment judged by MRI, endoscopy, and digital rectal exam were referred to observation without surgery. The patients continue follow-up for recurrence, adverse events, and patient reported outcomes irrespective of treatment. Three Danish centres enrolled 108 patients from 9/2015 to 12/2019; with 15%/54%/31% T1/T2/T3 tumours; median tumour distance from anal verge 4.5 cm; 29% with N1 disease; 36% female; median age 71 years. 107 patients started treatment, the majority receiving full dose of radiotherapy (n=104) and of chemotherapy (n=80). The most frequent grade 3-4 toxicities were diarrhoea (7%), constipation (2%), and nausea, vomiting, pain, and skin reaction (all 1%). One patient died from other causes and one left the study before evaluation. 12 weeks after end of treatment, 13 patients had residual tumour and were referred for surgery; two had distant metastasis leaving 90 of 108 patients (83.3%) with cCR and allocation to follow-up without surgery. The unprecedented high cCR rate of 83.3% in this multicentre phase II trial demonstrates that rectal cancer patients can be offered curative chemoradiation. Long-term outcomes, including tumour control, organ function, and quality of life, are still needed to evaluate the full potential of high-dose 62 Gy radiotherapy as a new standard treatment.

OBJECTIVES:To evaluate intrafractional fiducial marker position variations during stereotactic body radiotherapy (SBRT) in patients treated for liver metastases in visually guided, voluntary deep inspiration breath-hold (DIBH).METHODS:10 patients with implanted fiducial markers were studied. Respiratory coaching with visual guidance was used to ensure comfortable voluntary breath-holds for SBRT imaging and delivery. Three DIBH CTs were acquired for treatment planning. Pre- and post-treatment CBCTs were acquired for each of the three treatment fractions. Per-fraction marker position was evaluated on planar 2D kV images acquired during treatment fractions for 4 of the 10 patients.RESULTS:The median difference in marker position was 0.3 cm (range, 0.0-0.9 cm) between the three DIBH CTs and 0.3 cm (range, 0.1 to 1.4 cm) between pre- and post-treatment CBCTs. The maximum intrafractional variation in marker position in craniocaudal (CC) direction on planar kV images was 0.7 to 1.3 cm and up to 1.0 cm during a single DIBH.CONCLUSION:Difference in marker position of up to 1.0 cm was observed during a single DIBH despite use of narrow external gating window and visual feedback. Stability examination on pre-treatment DIBH CTs was not sufficient to guarantee per-fraction stability. Evaluation of differences in marker position on pre- and post-treatment CBCT did not always reveal the full magnitude of the intrafractional variation.ADVANCES IN KNOWLEDGE:To increase treatment accuracy, it is necessary to apply real-time monitoring of the tumour or a reliable internal surrogate when delivering liver SBRT in voluntary DIBH.

Purpose or ObjectivePatients with localised esophageal and gastroesophageal junction (GEJ) cancer are offered definite chemoradiotherapy if considered non-resectable or medically inoperable.Despite treatment with curative intent a median survival of less than 20 months and a 5-year survival of 15-25% were found in clinical trials.Survival is affected by several factors, including lack of locoregional control with failures located in the treated target volumes.

Key Clinical MessageSurvival of stage 4 ganglioneuroblastoma (GNB) patients is poor; no reports exist of patients surviving up to 5 years (1, 2). We report the clinical and therapeutic course of a patient with stage 4 GNB surviving beyond expectations due to a multimodal treatment approach incorporating new technologies in cancer diagnostic and treatment.

INTRODUCTION:Oncological treatment of lung cancer has been available in Greenland since 2004. We evaluated patient characteristics and survival rates for the first six years of local lung cancer treatment.METHODS:From September 2004 to August 2010, a total of 173 patients with lung cancer were referred to treatment at Queen Ingrid's Hospital. On 1 February 2014, treatment results, survival, and prognostic variables were analysed.RESULTS:The mean age at diagnosis was 63 years. Non-small cell lung cancer (NSCLC) was diagnosed in 145 patients (84%); 56% had squamous cell carcinoma, 34% had adenocarcinoma, 2% had large cell carcinoma and 8% had NSCLC not otherwise specified (NOS). In all, 28 (16%) had small cell lung cancer. A total of 142 patients (82%) received treatment; 20 underwent surgery (ten stage Ib, one stage IIa, five stage IIb, four stage IIIa); palliative chemotherapy was given to 122 of the 142 treated patients (86%). Of these, 36 patients (30%) received second-line chemotherapy.The median survival of patients undergoing primary lobectomy/pneumonectomy, palliative chemotherapy, and no treatment was 76.3 months, 11.8 months, and 2.0 months, respectively (p < 0.0001).CONCLUSION:Evaluation of the first six years of lung cancer treatment in Greenland revealed a disease incidence and survival comparable to those found in the Nordic countries. To further decrease mortality from lung cancer, health-care resources should continue to be allocated to the prevention and treatment of lung cancer in Greenland.FUNDING:not relevant.TRIAL REGISTRATION:not relevant.

e17609 Background: In Greenland, the incidence of lung cancer (LC) is now as high as in the other Nordic countries; 59.8/100,000 for men and 43.9/100.000 for women. In 2004, oncological treatment of LC following Danish guidelines became available to LC patients in Greenland. We performed a retrospective evaluation of treatment results and overall survival (OS) after the first six years of LC treatment in Greenland. Methods: From September 2004 to August 2010, 173 patients with LC were referred to treatment at Queen Ingrid’s Hospital in Nuuk. OS was calculated as the interval from the date of diagnosis to the date of death or to February 1, 2014; follow-up was > 30 months. Survival analysis was done with the method of Kaplan and Meier and the log-rank test. P < 0.05 was the level of significance. Results: The mean age at diagnosis was 63 years (range 26 – 87 years). Histological diagnoses and stages are shown in Table 1. Of the 173 patients, 142 (82%) received treatment; 20 patients underwent surgery (10 stage Ib, 1 stage IIa, 5 stage IIb, 4 stage IIIa); 11 patients had a lobectomy and 9 patients had a pneumonectomy (9 patients had postoperative chemotherapy). Palliative chemotherapy (PC) was given to 122 of the 142 treated patients (86%); 36 patients (30%) had second line chemotherapy. The median survival of patients undergoing primary surgery, PC, and no treatment was 76.3 months, 11.8 months, and 2.0 months, respectively (P<0.0001). Conclusions: Evaluation of the first six years of LC treatment in Greenland showed that treatment according to Danish guidelines is feasible and long-term survivors were seen. To further decrease mortality from LC, health care resources should continue to be allocated to the prevention and treatment of LC in Greenland. Histologic diagnoses and stages in 173 patients with lung cancer. Diagnosis/stages Number of patients Small cell lung cancer (SCLC) 28 (16%) Limited disease 4 Extensive disease 24 Non-small cell lung cancer (NSCLC) 145 (84%) Squamous cell carcinoma 81 (56%) Stage Ib 10 Stage IIa 1 Stage IIb 7 Stage IIIa 13 Stage IIIb 27 Stage IV 23 Adenocarcinoma 49 (34%) Stage Ib 2 Stage IIb 1 Stage IIIa 8 Stage IIIb 19 Stage IV 19 Large cell carcinoma 3 (2%) (1 stage IIIa, 1 stage IIIb,1 stage IV) Not otherwise specified 12(8%) (2 stage IIIa, 3 stage IIIb, 7 stage IV)

Objective: To evaluate the role of 2-deoxy-2-(F-18) fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) for selecting patients with extensive ovarian cancer (OC) for neoadjuvant chemotherapy by evaluating predictors of overall survival in patients with stage IIIC/IV OC.Materials and Methods: From September 1, 2004, to November 20, 2011, 514 consecutive patients with a pelvic tumor underwent preoperative PET/CT; 179 patients had stage IIIC/IV OC. Patients' characteristics were collected from 153 patients with stage IIIC/IV OC who underwent primary surgery. In 152 patients with stage IIIC/IV OC, clinical predictors and PET/CT predictors of survival were evaluated.Results: Median age was 64 years (range, 38-88 years); 87% (113) of the 153 patients had a performance status of less than 2; 55% (84) of the 153 patients had PET/CT stage III, and 45% (69) of the 153 patients had PET/CT stage IV. Using univariate analysis, incomplete debulking (P = 0.0001), pleural exudates (P = 0.001), postmenopausal state (P = 0.01), WHO performance status greater than 2 (P = 0.01), PET/CT stage IV (P = 0.01), and large bowel mesentery implants (P = 0.02) were statistically significant prognostic variables. Using multivariate Cox regression analysis, incomplete debulking was the only statistically significant independent prognostic variable (P = 0.0001). Median overall survival was significantly longer in the 53 patients with no residual tumor than in the 99 patients with residual tumor (33.3 vs 25.5 months; P = 0.0001)Conclusion: Suggested PET/CT criteria for referral of patients with advanced OC to neoadjuvant chemotherapy are PET/CT stage IV, pleural exudates, and PET-positive large bowel mesentery implants. Evaluation of selection criteria for neoadjuvant chemotherapy should be promoted in prospective clinical trials, with survival as the primary end point.

PURPOSE:To determine if the level of apolipoprotein A1, hepcidin, transferrin, inter-α trypsin IV internal fragment, transthyretin (TT), connective-tissue activating protein 3 (CTAP3), serum amyloid A1, β-2 microglobulin (B2M) might have impact on overall and progression-free survival for ovarian cancer (OC) patients.EXPERIMENTAL DESIGN:Serum from 150 OC patients was tested using SELDI-TOF-MS.RESULTS:A proteomic prognostic index (xb-pro) was constructed using the regression coefficients based on inter-α trypsin IV internal fragment, B2M and TT. A multivariable Cox survival analysis including the xb-pro index showed that xb-pro (p<0.0001, HR=2.50, 95% CI: 1.65-3.79), residual tumor after primary surgery (p=0.0005), age (p=0.01) and chemotherapy (p=0.0002) are of independent prognostic value for overall survival. International Federation of Gynecology and Obstetrics stage, performance status, histological type of tumor and serum CA125 were found of no independent value. A proteomic index (xb-pfs) based on B2M and CTAP3 was found to predict progression-free survival (xb-pfs: p=0.008, HR=1.77, 95% CI: 1.17-2.70 together with type of surgery, age and chemotherapy.CONCLUSIONS AND CLINICAL RELEVANCE:We found an index with three proteomic biomarkers (xb-pro) to be of independent prognostic value for overall survival and an index with two proteomic biomarkers (xb-pfs) with evidence of independent prognostic value for progression-free survival.

INTRODUCTION:In patients with advanced ovarian cancer undergoing preoperative PET/CT, we investigated the prognostic value of SUV in the primary tumor and we evaluated the value of SUV for predicting incomplete primary cytoreduction (macroscopic residual tumor). MATERIAL AND METHODS:From September 2004 to August 2007, 201 consecutive patients with a pelvic tumor and a Risk of Malignancy Index (RMI) > 150 based on serum CA-125, ultrasound examinations and menopausal state, underwent PET/CT within two weeks prior to standard surgery/debulking of a pelvic tumor. At two-year follow-up (August 15, 2009) the association between SUV and overall survival/cytoreductive result were analyzed in 60 ovarian cancer patients (58 stage III and two stage IV). RESULTS:At inclusion median age was 62 years (range 35-85 years); 97% (58/60) had a performance status ≤2; 42% (25/60) underwent complete debulking (no macroscopic residual tumor); median SUV(max) was 13.5 (range 2.5-39.0). Median follow-up was 30.2 months. At follow-up 57% (34/60) were alive and 43% (26/60) had died from ovarian cancer. SUV(max) in patients alive was not statistically different from SUV(max) in dead patients (p=0.69), and SUV(max) was not correlated with the amount of residual tumor after surgery (p=0.19). Using univariate Cox regression analysis, residual tumor was a significant prognostic variable (p=0.001); SUV(max) was not a statistically significant prognostic variable (p=0.86). DISCUSSION:FDG uptake (SUV(max)) in the primary tumor of patients with advanced ovarian cancer was not a prognostic variable and the FDG uptake did not predict complete cytoreduction after primary surgery. Future prospective clinical trials will need to clarify if other PET tracers can serve as prognostic variables in ovarian cancer.

Background. Previous reports have shown that the proteomic markers apolipoprotein A1, hepcidin, transferrin, inter-alpha trypsin IV internal fragment, transthyretin, connective-tissue activating protein 3 and beta-2 microglobulin may discriminate between a benign pelvic mass and ovarian cancer (OC). The aim was to determine if these serum proteomic biomarkers alone as well as in combination with age and serum CA125, could be helpful in triage of women with a pelvic mass.Methods. We included prospectively 144 patients diagnosed with (OC), 40 with a borderline tumor and 469 with a benign tumor. Surface-enhanced laser desorption/ionization time of flight-mass spectrometry was used for analyses. The Danish Index (DK-Index) based on the proteomic data, age and CA125 was developed using logistic regression models.Results. Multivariate logistic regression analysis demonstrated that the selected proteomic markers, CA125 and age were independent predictors of OC and the combination of these is proposed as the DK-index. A sensitivity (SN) of 99% had a specificity (SP) of 57% for DK-index and 49% for CA125. At a SN of 95%, the SP increased to 81% for DK-index compared to 68% for CA125 alone. For stage I+II the SP was 58% for DK-index and 49% for CA125. For stage III+IV the corresponding values were 94% and 86% respectively.Conclusions. The DK-index warrants further evaluation in independent cohorts. (C) 2011 Elsevier Inc. All rights reserved.

PURPOSE:The purposes of this study were to confirm previously found candidate epithelial ovarian cancer biomarkers in urine and to compare a paired serum biomarker panel and a urine biomarker panel from the same study cohort with regard to the receiver operating characteristic curve (ROC) area under the ROC curve (AUC) values.EXPERIMENTAL DESIGN:Four significant urine biomarkers were confirmed among 130 pelvic mass patients in the present study. The four biomarkers form a potential urine biomarker panel. From the same study cohort, the potential urine biomarker panel was compared to a serum biomarker panel, consisting of seven proteins/peptides, OvaRI.RESULTS:Multivariate analysis of the urine panel demonstrated a significant differentiation (p<0.0001) between epithelial ovarian cancer patients and patients with benign ovarian pelvic masses. The ROC AUC of the urine panel was 0.84 and the ROC AUC of OvaRI was 0.83. Combining the urine panel with OvaRI demonstrated a significant contribution from both, for urine peaks, OR=2.12 and for OvaRI, OR=1.39; the ROC AUC of this model was 0.88.CONCLUSIONS AND CLINICAL RELEVANCE:We demonstrated that both urine and serum can be used individually or in combination to potentially aid in ovarian cancer diagnostics. Urine proteomic profiling could provide biomarkers for the non-invasive test required in clinical practice.