Age, Gleason Score, and PSA are important prognostic factors for survival in metastatic castration-resistant prostate cancer. Results of The Uroncor Group (Uro-Oncological Tumors) of the Spanish Society of Radiation Oncology (SEOR).

INTRODUCTION: The treatment of metastatic castration-resistant prostate cancer (mCRPC) has changed significantly in recent years. Inhibitors of androgen receptors have shown especially significant benefits in overall (OS) and progression-free survival (PFS), with a good toxicity profile. Treatment selection depends on the patient's individual clinical, radiological, and biological characteristics. OBJECTIVE: To describe treatment outcomes (efficacy, toxicity) in a cohort of patients with mCRPC in Spain. MATERIALS AND METHODS: Multicenter, retrospective study of patients with mCRPC included in a database of the Urological Tumour Working Group (URONCOR) of the Spanish Society of Radiation Oncology (SEOR). Metastatic CRPC was defined according to the prostate cancer working group 3 (PCWG3) criteria. The Kaplan-Meier technique was used to evaluate OS and the Common Terminology Criteria for Adverse Events (CTCAE, v.4.0) were used to assess toxicity. Univariate and multivariate Cox regression analyses were performed to identify the factors significantly associated with OS. RESULTS: A total of 314 patients from 17 hospitals in Spain diagnosed with mCRPC between June 2010 and September 2017 were included in this study. Mean age at diagnosis was 68 years (range 45-89). At a median follow-up of 35 months, OS at 1, 3, and 5 years were 92%, 38%, and 28%, respectively. Grades 1-2 and grade 3 toxicity rates were, respectively, 68% and 19%. No grade 4 toxicities were observed. On the multivariate analysis, the following factors were significantly associated with OS: age (hazard ratio [HR] 0.42, p = 0.010), PSA value at diagnosis of mCRPC (HR 0.55, p = 0.008), and Gleason score (HR 0.61, p = 0.009). CONCLUSIONS: Age, Gleason score, and PSA at diagnosis of mCRPC are independently associated with overall survival in patients with mCRPC. The efficacy and toxicity outcomes in this patient cohort treated in radiation oncology departments in Spain are consistent with previous reports.

Survival after biochemical failure in prostate cancer treated with radiotherapy: Spanish Registry of Prostate Cancer (RECAP) database outcomes.

INTRODUCTION: The clinical course in patients with prostate cancer (PCa) after biochemical failure (BF) has received limited attention. This study analyzes survival time from recurrence, patterns of progression, and the efficacy of salvage therapies in patients treated with radical or postoperative radiotherapy (RT). METHODS: This is a multicenter retrospective comparative study of 1135 patients diagnosed with BF and treated with either radical (882) or postoperative (253) RT. Data correspond to the RECAP database. Clinical, tumor, and therapeutic characteristics were collected. Descriptive statistics, survival estimates, and comparisons of survival rates were calculated. RESULTS: Time to BF from initial treatment (RT or surgery) was higher in irradiated patients (51 vs 37 months). At a median follow-up of 102 months (14-254), the 8-year cause-specific survival (CSS) was 80.5%, without significant differences between the radical (80.1%) and postoperative (83.4%) RT groups. The 8-year metastasis-free survival rate was 57%. 173 patients (15%) died of PCa and 29 (2.5%) of a second cancer. No salvage therapy was given in 15% of pts. Only 5.5% of pts who underwent radical RT had local salvage treatment and 71% received androgen deprivation (AD) ± chemotherapy. The worst outcomes were in patients who developed metastases after BF (302 pts; 26.5%) and in cases with a Gleason > 7. CONCLUSIONS: In PCa treated with radiotherapy, median survival after BF is relatively long. In this sample, no differences in survival rates at 8-years have been found, regardless of the time of radiotherapy administered. AD was the most common treatment after BF. Metastases and high Gleason score are adverse variables. To our knowledge, this is the first study to compare outcomes after BF among patients treated with primary RT vs. those treated with postoperative RT and to evaluate recurrence patterns, treatments administered, and causes of death. The results allow avoiding overtreatment, improving quality of life, without negatively affecting survival.

Outcomes and prognostic factors in intermediate-risk prostate cancer: multi-institutional analysis of the Spanish RECAP database.

PURPOSE: To retrospectively assess outcomes and to identify prognostic factors in patients diagnosed with intermediate-risk (IR) prostate cancer (PCa) treated with primary external beam radiotherapy (EBRT). MATERIALS AND METHODS: Data were obtained from the multi-institutional Spanish RECAP database, a population-based prostate cancer registry in Spain. All IR patients (NCCN criteria) who underwent primary EBRT were included. The following variables were assessed: age; prostate-specific antigen (PSA); Gleason score; clinical T stage; percentage of positive biopsy cores (PPBC); androgen deprivation therapy (ADT); and radiotherapy dose. The patients were stratified into one of three risk subcategories: (1) favourable IR (FIR; GS 6, ≤ T2b or GS 3 + 4, ≤ T1c), (2) marginal IR (MIR; GS 3 + 4, T2a-b), and (3) unfavourable IR (UIR; GS 4 + 3 or T2c). Biochemical relapse-free survival (BRFS), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) were assessed. RESULTS: A total of 1754 patients from the RECAP database were included and stratified by risk group: FIR, n = 781 (44.5%); MIR, n = 252 (14.4%); and UIR, n = 721 (41.1%). Mean age was 71 years (range 47-86). Mean PSA was 10.4 ng/ml (range 6-20). The median radiotherapy dose was 74 Gy, with mean doses of 72.5 Gy (FIR), 73.4 Gy (MIR), and 72.8 Gy (UIR). Most patients (88%) received ADT for a median of 7.1 months. By risk group (FIR, MIR, UIR), ADT rates were, respectively, 88.9, 86.5, and 86.9%. Only patients with ≥ 24 months of follow-up post-EBRT were included in the survival analysis (n = 1294). At a median follow-up of 52 months (range 24-173), respective 5- and 10-year outcomes were: OS 93.6% and 79%; BRFS 88.9% and 71.4%; DFS 96.1% and 89%; CSS 98.9% and 94.6%. Complication rates (≥ grade 3) were: acute genitourinary (GU) 2%; late GU 1%; acute gastrointestinal (GI) 2%; late GI 1%. There was no significant association between risk group and BRFS or OS. However, patients with favourable-risk disease had significantly better 5- and 10-year DFS than patients with UIR: 98.7% vs. 92.4% and 92% vs. 85.8% (p = 0.0005). CSS was significantly higher (p = 0.0057) in the FIR group at 5 (99.7% vs. 97.3%) and 10 years (96.1% vs. 93.4%). On the multivariate analyses, the following were significant predictors of survival: ADT (BRFS and DFS); dose ≥ 74 Gy (BRFS); age (OS). CONCLUSIONS: This is the first nationwide study in Spain to report long-term outcomes of patients with intermediate-risk PCa treated with EBRT. Survival outcomes were good, with a low incidence of both acute and late toxicity. Patients with unfavourable risk characteristics had significantly lower 5- and 10-year disease-free survival rates. ADT and radiotherapy dose ≥ 74 Gy were both significant predictors of treatment outcomes.

Clinical Audit of the Radiotherapy Process in Rectal Cancer: Clinical Practice Guidelines and Quality Certification Do Not Avert Variability in Clinical Practice.

BACKGROUND: The therapeutic approach to cancer is complex and multidisciplinary. Radiotherapy is among the essential treatments, whether used alone or in conjunction with other therapies. This study reports a clinical audit of the radiotherapy process to assess the process of care, evaluate adherence to agreed protocols and measure the variability to improve therapeutic quality for rectal cancer. METHODS: Multicentre retrospective cohort study in a representative sample of patients diagnosed with rectal cancer in the Institut Català d'Oncologia, a comprehensive cancer centre with three different settings. We developed a set of indicators to assess the key areas of the radiotherapy process. The clinical audit consisted of a review of a random sample of 40 clinical histories for each centre. RESULTS: The demographic profile, histology and staging of patients were similar between centres. The MRI reports did not include the distance from tumour to mesorectal fascia (rCRM) in 38.3% of the cases. 96.7% of patients received the planned dose, and 57.4% received it at the planned time. Surgery followed neoadjuvant treatment in 96.7% of the patients. Among this group, postoperative CRM was recorded in 65.5% of the cases and was negative in 93.4% of these. With regard to the 34.5% (n = 40) of cases where no CRM value was stated, there were differences between the centres. Mean follow-up was 3.4 (SD 0.6) years, and overall survival at four years was 81.7%. CONCLUSIONS: The audit revealed a suboptimal degree of adherence to clinical practice guidelines. Significant variability between centres exists from a clinical perspective but especially with regard to organization and process.

Brain functional connectivity in lung cancer population: an exploratory study.

The present study aimed to explore the functional connectivity differences in Resting State Networks (RSNs) induced by cancer and chemotherapy in Lung Cancer (LC) patients using an Independent Component Analysis (ICA). Three matched groups of 15 LC patients following Chemotherapy (C+), 15 LC patients before Chemotherapy (C-) and 15 Healthy Controls (HC) were included. Analysis was performed using ICA and a multivariate pattern analysis (MVPA) to classify groups based on profiles of functional connectivity. We found significant differences in four of the RSN identified: Default Mode Network (DMN), Predominantly Left and Right Anterior Temporal Network, and Cerebellum Network. Whereas DMN showed decreased connectivity, the other RSNs exhibited increased connectivity in both LC groups compared to HC and in C+ in comparison to C-. MVPA discriminated significantly and accurately between all groups. Our study showed that disrupted functional connectivity associated with cancer and chemotherapy-induced cognitive deficits is not only related to DMN decreased connectivity abnormalities but also to an increased connectivity of other RSNs, suggesting a potential compensatory mechanism. Graphical abstract.

Adjuvant versus salvage radiotherapy in prostate cancer: multi-institutional retrospective analysis of the Spanish RECAP database.

PURPOSE: To compare adjuvant radiotherapy (ART) to salvage radiotherapy (SRT) after radical prostatectomy (RP) in a cohort of prostate cancer (PCa) patients. The primary aim was to comparatively assess 2- and 5-year biochemical relapse-free survival (BRFS). A secondary aim was to identify predictors of survival. PATIENTS AND METHODS: Data were acquired from the RECAP database, a population-based prostate cancer registry in Spain. Inclusion criteria included RP (with or without lymphadenectomy) followed by ART or SRT. A total of 702 patients were analyzed. Pre-RT PSA values (>0.5 vs. ≤0.5 ng/ml), pathological stage (T1-2 vs. T3-4), post-surgical Gleason score (≤7 vs. 8-10), margin status (positive vs. negative), hormonal treatment (yes vs. no), and RT dose (≤66 Gy vs. >66 Gy) were evaluated to assess their impact on BRFS. RESULTS: The mean patient age in the ART and SRT groups, respectively, was 64 years (range 42-82) and 64.8 years (range 42-82). Median follow-up after RT in the whole sample was 34 months (range 3-141). A total of 702 patients were included: 223 (31.8%) received ART and 479 (68.2%) SRT. BRFS rates (95% CI) in the ART and SRT groups at months 24 and 60 were, respectively: 98.1% (95.9-100.0%) vs. 91.2% (88.2-94.2%) and 84.5% (76.4-92.6%) vs. 74.0% (67.4-80.7%) (p = 0.004). No significant differences in OS were observed (p = 0.053). The following variables were significant predictors of biochemical recurrence in the SRT group: (1) positive surgical margin status (p = 0.049); (2) no hormonotherapy (p = 0.03); (3) total prostate dose ≤66 Gy (p = 0.004); and pre-RT PSA ≥0.5 ng/ml (p = 0.013). CONCLUSIONS: This is the first nationwide study in Spain to evaluate a large cohort of PCa patients treated with RP followed by postoperative RT. ART yielded better 2- and 5-year BRFS rates, although OS was equivalent. These findings are consistent with most other published studies and support ART in patients with adverse prognostic characteristics after radical prostatectomy. Prospective trials are needed to compare immediate ART to early SRT to better determine their relative benefits.

The number of risk factors is the strongest predictor of prostate cancer mortality: multi-institutional outcomes of an extreme-risk prostate cancer cohort.

PURPOSE: To report treatment outcomes in a cohort of extreme-risk prostate cancer patients and identify a subgroup of patients with worse prognosis. MATERIALS AND METHODS: Extreme-risk prostate cancer patients were defined as patients with at least one extreme-risk factor: stage cT3b-cT4, Gleason score 9-10 or PSA > 50 ng/ml; or patients with 2 or more high-risk factors: stage cT2c-cT3a, Gleason 8 and PSA > 20 ng/ml. Overall survival (OS), cause-specific survival (CSS), clinical-free survival (CFS), and biochemical non-evidence of disease (bNED) survival are the four outcomes of interest in a population of 1341 patients. RESULTS: With a median follow-up of 71.5 months, 5- and 10-year bNED survival, CFS, CSS and OS for the entire cohort were 77.1 % and 57.0, 89.2 and 78.9 %, 97.4 and 93.6 %, and 92.0 and 71.3 %, respectively. On multivariate analysis, PSA and clinical stage were associated with bNED survival. PSA and Gleason score predicted for CFS, whereas only Gleason score predicted for OS. When a simplified model was performed using the "number of risk factors" variable, this model provided the best distinction between patients with ≥2 extreme-risk factors and patients with 2 high-risk factors, showing a hazard ratio (HR) of 1.737 (p = 0.0003) for bNED survival, HR 1.743 (p = 0.0448) for OS and an HR of 3.963 (p = 0.0039) for the CSS endpoint. CONCLUSIONS: Patients presenting at diagnosis with two extreme-risk criteria have almost fourfold higher risk for prostate cancer mortality. Such patients should be considered for more aggressive multimodal treatments.

Pharmacokinetics of the peritoneal-plasma barrier after systemic mitomycin C administration.

The peritoneal plasma barrier (PPB) is a pharmacologic entity of importance for treatment planning in patients with malignant tumors confined to the abdominal cavity. We have examined the pharmacokinetics of the PPB by sampling abdominal fluid following intravenous mitomycin C (MMC) administration. The study included 15 cycles of treatment in seven patients with peritoneal carcinomatosis from colorectal cancer. Five patients were studied twice and one patient was studied three times for a total of 15 cycles. Patients were treated with intraperitoneal 5-fluorouracil (5-FU) at 20 mg/m2 in 11 of fluid. Between 250 and 500 ml of ascites remained after the 23 hour intraperitoneal dwell. On day 3, MMC (12 mg/m2) was administered intravenously as a 2-hour continuous infusion in 200 ml of dextrose solution. The concentration of MMC was determined in plasma, peritoneal fluid, and urine by high performance liquid chromatolography (HPLC) at frequent intervals for 8 hours. The area under the curve (AUC) for plasma as related to peritoneal fluid was three times greater for plasma in one cycle, two times greater for plasma in three cycles, 1.5 times greater for plasma in five cycles, and the same in six cycles. AUC ratios showed a correlation with the extent of peritoneal stripping at the prior surgical procedure 6 weeks to 14 weeks previously. We conclude that malignant ascites may be less exposed to chemotherapy than systemic tumor nodules when the intravenous route of drug administration is used. This inadequacy is even more pronounced in patients who have had extensive abdominal surgery.

Prognostic implications of chemoresistance-sensitivity assays for colorectal and appendiceal cancer.

A major problem with pharmacologic treatments for cancer is the unpredictable nature of the clinical response. Therefore, many patients are treated but few benefit from chemotherapy. Selection of patients for drug treatment would greatly benefit both responders and nonresponders. Mitomycin C (MMC) and 5-fluorouracil (5-FU) are important drugs widely used in the treatment of patients with gastrointestinal malignancies. In a prospective study, an in vitro chemoresistance-sensitivity assay (CR-SA) was performed for 95 patients at the time of surgery for peritoneal carcinomatosis from colorectal and appendiceal cancer. Following cytoreductive surgery, all of these patients had minimal-to-moderate residual disease. All patients were treated with the same chemotherapy regimen regardless of the results of the in vitro assay in the postoperative period. Clinical status of patients was correlated to the assay predictions, and the results were statistically evaluated. When resistance was correlated with outcome, there was no statistical difference. In addition, the mean percentage of growth inhibition was not increased when responders and nonresponders were compared. Finally, more patients who had > or = 95% in vitro growth inhibition of cancer did not survive than did those with < or = 95% growth inhibition. The in vitro test did not predict sensitivity or resistance to cancer when regional chemotherapy was administered in a clinical setting of peritoneal carcinomatosis.

Peritoneal carcinomatosis from gastrointestinal malignancy: natural history and new prospects for management.

Peritoneal carcinomatosis represents regional spread of gastrointestinal, gynecological and other malignancies with or without evidence of systemic metastases. The authors reviewed the natural history and the different types of peritoneal carcinomatosis. A new treatment approach that combines cytoreductive surgery and intraperitoneal chemotherapy is described. The principles of this surgery and the pharmacology principles of intraperitoneal drug administration are explained. The major attraction of intraperitoneal therapy is that following intracavitary drug administration, the peritoneal cavity is exposed to higher concentrations than the rest of the body. A total of 100 patients with peritoneal carcinomatosis followed from one to ten years were treated by this approach. Patients were divided into four prognostic groups according to the histologic findings, extent of diseases, distant metastases and the completeness of cytoreductive surgery. This new cytoreductive approach is particularly effective for patients with low-grade malignancies confined to the abdominal cavity and who had a complete cytoreductive surgery.

Morbidity and mortality of cytoreductive surgery and intraperitoneal chemotherapy.

BACKGROUND: Peritoneal carcinomatosis has been regarded as a uniformly lethal clinical entity. Recently, dose-intensive treatments combining cytoreductive surgery and intraperitoneal chemotherapy have resulted in long-term survival in selected patients. METHODS: This article reports the morbidity and mortality associated with this new treatment strategy in 45 consecutive treatments of 43 patients with peritoneal carcinomatosis treated during an 18-month interval. RESULTS: The duration of median postoperative ileus was 21 days, and increased age of the patient and extent of cytoreduction caused an increased incidence of ileus. Twenty-one complications occurred in 17 patients (37.7%). Complications related to enteric function included fistula (n = 4), bile leak (n = 1), pancreatitis (n = 1), and anastomotic disruption (n = 1). There were two early and two late episodes of postoperative bleeding requiring reoperation. Six patients had pneumonia and one had deep vein thrombosis. There were no deaths. Six of the seven complications related to enteric function occurred in patients who had undergone induction intraperitoneal chemotherapy before cytoreductive surgery plus early postoperative intraperitoneal chemotherapy. CONCLUSIONS: As a result of these findings, induction intraperitoneal chemotherapy is only recommended for patients with low-volume intraabdominal cancer. In most patients surgical removal of peritoneal carcinomatosis before intraperitoneal chemotherapy is recommended. Because of the significant morbidity related to treatment of peritoneal carcinomatosis, careful patient selection and favorable long-term results of treatment are required.

Preoperative radiological evaluation of the liver by computerized tomographic portography in patients with hepatic tumors.

The main objective of preoperative imaging studies is to define as accurately as possible the number, size, location, and relationship of tumor masses in the liver to pertinent portal and hepatic venous vasculature. Computerized tomographic portography images hepatic veins and segmental portal vein branches and identifies the anatomical location of tumor nodules with excellent sensitivity and a low false-positive rate. The intraoperative correlation of computerized tomographic portography on 30 patients in the last 20 months at this institution shows a sensitivity of 88 per cent with a low rate of false-positivity. The ability to detect metastatic lesions in the liver by computerized tomographic portography diminishes when the lesions are noted to be less than 1 cm. The authors conclude that the preoperative interpretation of the computerized tomographic portogram provides valuable information not previously available to the surgeon operating on the liver.

Post-transfusional vs. sporadic non-A, non-B chronic hepatitis. A clinico-pathological and evolutive study.

The clinical, morphological and evolutive features of 60 patients with chronic hepatitis, presumably caused by non-A, non-B virus infection, have been retrospectively analyzed. In all the cases the disease began as an acute episode of viral hepatitis that was followed by persistently abnormal liver function tests. No patient had evidence of current or past hepatitis B virus infection and other known causes of chronic liver disease were excluded. Thirty patients had received blood transfusions in the recent past, five were drug addicts and the source of the infection was not identified in the remaining 25, in whom the disease was considered to be sporadic. Clinical or biochemical differences between patients with post-transfusional and sporadic non-A, non-B chronic hepatitis were not observed, but liver histology showed a higher proportion of patients with chronic persistent hepatitis in the sporadic (72%) than in the transfusional group (53%). On follow-up, sustained normalization of liver function tests was observed in 46% of the cases with sporadic hepatitis but only in 13% of the cases with post-transfusion hepatitis. These observations suggest that non-A, non-B chronic hepatitis is more severe in patients with transfusion-related infection than in sporadic cases.