A Retrospective Evaluation of the Benefit of Referring Pediatric Cancer Patients to an External Proton Therapy Center.

BACKGROUND: Pediatric cancer patients requiring radiation therapy (RT) have been routinely assessed and referred to proton therapy (PT) at an external institution. The benefit of the delivered PT compared to the state-of-the-art intensity modulated x-ray RT (XT) at the home institution was evaluated. PROCEDURE: Twenty-four consecutive children referred for PT during 2010-2013 for craniospinal (CSI, n = 10), localized intracranial (IC, n = 7), head/neck (HN, n = 4) or parameningeal (PM, n = 3) lesions were included. The median age was 8 years (2-16 years). XT plans were generated for each patient, blinded to the PT delivered. Dosimetry, estimated growth hormone deficiency (GHD), and neurocognitive dysfunction (NCD) risks were compared for PT and XT (Wilcoxon). RESULTS: PT started (median) 5 weeks (± 1.3 weeks, 95% CI) after referral. For CSI patients, PT was clearly superior to XT plans with median dose reductions for the heart, lungs and thyroid of 17, 2.5 and 18 Gy, respectively (P = 0.005). The median estimated NCD and GHD risks were 1-3 (max 16) and 2 (max 61) percentage points, respectively, lower for PT compared to XT. The median of the mean doses to the brain, cochleae and pituitary gland was lower with PT than XT for the IC, H/N and PM patients (P < 0.039). For a single IC patient, the dose to hippocampi and optic chiasm was higher for PT compared to XT. CONCLUSIONS: PT clearly benefitted the patients studied, except for IC disease where differences between PT and XT were modest, and comparative PT and XT treatment planning is warranted prior to referral.

Diagnostic accuracy of risk of malignancy index in predicting complete tumor removal at primary debulking surgery for ovarian cancer patients.

Ovarian cancer patients in whom complete tumor removal is impossible with primary debulking surgery (PDS) may benefit from neoadjuvant chemotherapy and interval debulking surgery. However, the task of performing a pre-operative evaluation of the feasibility of PDS is difficult. We aimed to investigate whether the risk of malignancy index (RMI) was a useful marker for this evaluation. RMI and surgical outcome were investigated in 164 patients, 49 of whom had no residual tumor after PDS. The receiver operating characteristic curve showed an area under the curve of 0.72 (confidence interval: 0.64-0.80). The possibility of complete tumor removal decreased with increasing RMI and there was a tendency towards higher RMI in patients with residual tumor after PDS, but no single cut-off value of RMI produced useful clinical predictive values. In conclusion, RMI alone is not an optimal method to determine whether complete tumor removal is possible with PDS.

Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass.

OBJECTIVE: Diagnostic factors are needed to improve the currently used serum CA125 and risk of malignancy index (RMI) in differentiating ovarian cancer (OC) from other pelvic masses, thereby achieving precise and fast referral to a tertiary center and correct selection for further diagnostics. The aim was to evaluate serum Human Epididymis protein 4 (HE4) and the risk of ovarian malignancy algorithm (ROMA) for these purposes. METHODS: Serum from 1218 patients in the prospective ongoing pelvic mass study was collected prior to diagnosis. The HE4 and CA125 data were registered and evaluated separately and combined in ROMA and compared to RMI. RESULTS: 809 benign tumors, 79 borderline ovarian tumors, 252 OC (64 early and 188 late stage), 9 non-epithelial ovarian tumors and 69 non-ovarian cancers were evaluated. Differentiating between OC and benign disease the specificity was 62.2 (CA125), 63.2 (HE4), 76.5 (ROMA) and 81.5 (RMI) at a set sensitivity of 94.4 which corresponds to RMI=200. The areas under the curve (AUC) were 0.854 (CA125), 0.864 (HE4), 0,897 (ROMA) and 0.905 (RMI) for benign vs. early stage OC. For premenopausal benign vs. OC AUC were 0.925 (CA125), 0.905 (HE4), 0.909 (ROMA) and 0.945 (RMI). CONCLUSION: HE4 and ROMA helps differentiating OC from other pelvic masses, even in early stage OC. ROMA performs equally well as the ultrasound depending RMI and might be valuable as a first line biomarker for selecting high risk patients for referral to a tertiary center and further diagnostics. Further improvements of HE4 and ROMA in differentiating pelvic masses are still needed, especially regarding premenopausal women.

Risk of malignancy index used as a diagnostic tool in a tertiary centre for patients with a pelvic mass.

OBJECTIVE: Risk of malignancy index (RMI), based on a serum cancer antigen 125 level, ultrasound findings and menopausal status, is used to discriminate ovarian cancer from benign pelvic mass. In Denmark, patients with pelvic mass and RMI ≥200 are referred to tertiary gynecologic oncology centers according to the national guidelines for ovarian cancer treatment. The guidelines include recalculation of RMI at the tertiary center and, if indicated, positron emission tomography/computed tomography and fast-track surgery by specialists in cancer surgery. The aim of this study was to validate the use of RMI ≥200 as a tool for preoperative identification of ovarian cancer at a tertiary center. DESIGN: Prospective observational study. SETTING: A tertiary center in Copenhagen, Denmark. POPULATION: One thousand one hundred and fifty-nine women with pelvic mass. METHODS: The RMI was calculated after ultrasound examination and blood sampling for serum cancer antigen 125 analysis within two weeks before surgery. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values were calculated to evaluate the ability of RMI to distinguish between ovarian cancer and benign pelvic mass. RESULTS: There were 778 women diagnosed with benign pelvic mass, while 251 had ovarian cancer and 74 had borderline ovarian tumor. Fifty-six women were diagnosed with other forms of cancer. Sensitivity and specificity for ovarian cancer vs. benign pelvic mass for RMI ≥200 were 92 and 82%, respectively. Corresponding positive and negative predictive values were 62 and 97%. CONCLUSIONS: Risk of malignancy index ≥200 is a reliable tool for identifying patients with ovarian cancer pelvic masses at a tertiary centre to select patients for further preoperative examinations.

A novel proteomic biomarker panel as a diagnostic tool for patients with 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.

Standardized FDG uptake as a prognostic variable and as a predictor of incomplete cytoreduction in primary advanced ovarian cancer.

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.

Influence of 2-(18F) fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography on recurrent ovarian cancer diagnosis and on selection of patients for secondary cytoreductive surgery.

The objective of this prospective study was to compare the sensitivities and the specificities of combined 2-(F) fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (PET/CT), abdominal/transvaginal ultrasound (US), and CT for diagnosing recurrent ovarian cancer (OC) and to evaluate the influence of PET/CT on referral of patients with solitary recurrence to secondary cytoreductive surgery. From April 2005 to November 2007, 60 patients were consecutively included to PET/CT 68 times. The inclusion criteria were remission of 3 months or longer and recurrent OC suspected from physical examination, US, or increasing cancer antigen 125 (CA125) level (>50 U/mL or >15% above baseline level). Recurrent OC was diagnosed 58 times in 52 patients. The sensitivities of US, CT, and PET/CT for diagnosing recurrence were 66% (P = 0.003), 81% (P = 0.0001), and 97% (P < 0.0001), respectively. The specificity of US, CT, and PET/CT for diagnosing recurrence was 90%. Positron emission tomography/CT diagnosed recurrence in 19 (66%) of 29 patients without recurrence according to US and in 10 (50%) of 20 patients without recurrence after CT. Multiple recurrent tumors were found using PET/CT in 27 (69%) of 39 patients with solitary tumors on US and in 8 (42%) of 19 patients with solitary tumors on CT. We conclude that the diagnostic value of PET/CT for detecting recurrent OC was higher than those of US and CT and that PET/CT more accurately identified patients with solitary recurrence. However, prospective clinical trials are needed to specify the characteristics of patients most likely to undergo complete secondary surgery and to further clarify the role of PET/CT in selecting patients for secondary surgery.

A proteomics panel for predicting optimal primary cytoreduction in stage III/IV ovarian cancer.

The objective of this prospective study was to evaluate CA-125 and a 7-marker panel as predictors of incomplete primary cytoreduction in patients with stage III/IV ovarian cancer (OC). From September 2004 to January 2008, serum from 201 patients referred to surgery for a pelvic tumor was analyzed for CA-125. In addition, serum was analyzed for 7 biomarkers using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. These biomarkers were combined into a single-valued ovarian-cancer-risk index (OvaRI). CA-125 and OvaRI were evaluated as predictors of cytoreduction in 75 stage III/IV patients using receiver operating characteristic curves. Complete primary cytoreduction (no macroscopic residual disease) was achieved in 31% (23/75) of the patients. The area under the receiver operating characteristic curve was 0.66 for CA-125 and 0.75 for OvaRI. The sensitivity and specificity of CA-125 for predicting incomplete cytoreduction were 71% (37/52) and 57% (13/23), respectively (P = 0.04). The sensitivity and specificity of OvaRI for predicting incomplete cytoreduction were 73% (38/52) and 70% (16/23), respectively (P = 0.001). In conclusion, CA-125 and an index of 7 biomarkers were found to be predictors of cytoreduction. However, future studies of biomarkers are anticipated to promote early diagnosis and provide prognostic information to guide treatment of OC patients. In addition, new biomarkers might also play a role in predicting outcome from primary surgery in OC patients.

Prognostic value of plasma soluble urokinase plasminogen activator receptor (suPAR) in Danish patients with recurrent epithelial ovarian cancer (REOC).

The level of the soluble urokinase plasminogen activator receptor (suPAR) is elevated in tumour tissue from several types of cancer. This is the first study aiming to predict the prognosis for survival by the use of a pre-chemotherapeutic plasma suPAR value in 71 patients with recurrent epithelial ovarian cancer (REOC). For determination of suPAR, pre-chemotherapeutic blood samples from the patients with REOC were processed into plasma (EDTA) within one working day from venipuncture. The plasma suPAR level is not correlated with performance status (p=0.41), FIGO stage (p=0.09), treatment-free interval (TFI) of 12 months (p=0.26), site of recurrence (peritoneum, p=0.50 or pelvis, p=0.44), age (p=0.43), or serum CA125 (p=0.09). Univariate as well as multivariate analyses cannot demonstrate that high pre-chemotherapeutic levels of plasma suPAR (p=0.22, p=0.80) are associated with shorter survival of REOC patients. Multivariate analysis showed that only TFI of 12 months (p=0.001) and performance score status of 2 (p=0.02) were independent prognostic factors. Our study indicates that pre-chemotherapeutic measurement of plasma suPAR level in REOC patients may not be useful to identify a subgroup of patients with poor prognosis.

Health-related Quality of Life in Patients with Metastatic Spinal Cord Compression.

OBJECTIVE: Improvements in cancer treatment have resulted in an increased number of patients with metastatic spinal cord compression (MSCC). Because patients with MSCC often have a limited expected survival time, maintenance of a high functional level and quality of life are important. However, there is limited information about health-related quality of life (HRQoL) in patients with MSCC. The aim of this study was to examine the feasibility of routine assessment of HRQoL based on the Euroqol-5 dimensions (EQ-5D) questionnaire in a cohort of patients consecutively admitted for evaluation of acute symptoms of MSCC. METHODS: From 1 January to 31 December 2011, 544 patients diagnosed with acute symptoms of MSCC were consecutively enrolled in a cohort study. All patients were evaluated through a centralized referral system at one treatment facility. Data were prospectively registered, the variables age, sex, primary oncologic diagnosis, Tokuhashi Revised score, EQ-5D score and treatment modality being recorded on admission. The study patients were treated conservatively with radiotherapy alone or with surgery and subsequent radiotherapy. The EQ-5D questionnaire was administered on admission (baseline) and 6, 12, 26 and 52 weeks after admission. Response rates, completion rates and HRQoL scores were analyzed by relevant subgroups. Response rates were based on all questionnaires returned regardless of whether or not they had been completed, whereas completion rates were based on fully completed questionnaires (i.e., containing responses to all five questions. RESULTS: The mean age was 65 years (range, 20-95 years); 57% of the patients were men. The overall response rate to the Euroqol-5 dimensions (EQ-5D) questionnaires was 84% and the overall completion rate 72%. At baseline, mean EQ-5D scores were significantly lower for patients treated with surgery and subsequent radiotherapy 0.28 (95% CI, 0.19-0.36) than for those treated with radiotherapy alone 0.42 (95% CI, 0.38-0.46). At the one-year follow-up, the mean EQ-5D scores had improved to 0.71 (95% CI, 0.64-0.77) for patients treated with surgery and subsequent radiotherapy and 0.63 (95% CI, 0.56-0.70) for patients treated with radiotherapy alone. CONCLUSIONS: Measurement of HRQoL in patients consecutively admitted for evaluation of acute symptoms of MSCC is feasible and detects significant changes over time between treatment modalities and different strata of expected survival.