Is Systemic Chemotherapy Useful in Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Colorectal Peritoneal Metastases? A Propensity-Score Analysis.

PURPOSE: Multimodal treatment of colorectal (CRC) peritoneal metastases (PM) includes systemic chemotherapy (SC) and surgical cytoreduction (CRS), eventually with hyperthermic intraperitoneal chemotherapy (HIPEC), in select patients. Considering lack of clear guidelines, this study was designed to analyze the role of chemotherapy and its timing in patients treated with CRS-HIPEC. METHODS: Data from 13 Italian centers with PM expertise were collected by a collaborative group of the Italian Society of Surgical Oncology (SICO). Clinicopathological variables, SC use, and timing of administration were correlated with overall survival (OS), disease-free survival (DFS), and local (peritoneal) DFS (LDFS) after propensity-score (PS) weighting to reduce confounding factors. RESULTS: A total of 367 patients treated with CRS-HIPEC were included in the propensity-score weighting. Of the total patients, 19.9% did not receive chemotherapy within 6 months of surgery, 32.4% received chemotherapy before surgery (pregroup), 28.9% after (post), and 18.8% received both pre- and post-CRS-HIPEC treatment (peri). SC was preferentially administered to younger (p = 0.02) and node-positive (p = 0.010) patients. Preoperative SC is associated with increased rate of major complications (26.9 vs. 11.3%, p = 0.0009). After PS weighting, there were no differences in OS, DFS, or LDFS (p = 0.56, 0.50, and 0.17) between chemotherapy-treated and untreated patients. Considering SC timing, the post CRS-HIPEC group had a longer DFS and LDFS than the pre-group (median DFS 15.4 vs. 9.8 m, p = 0.003; median LDFS 26.3 vs. 15.8 m, p = 0.026). CONCLUSIONS: In patients with CRC-PM treated with CRS-HIPEC, systemic chemotherapy was not associated with overall survival benefit. The adjuvant schedule was related to prolonged disease-free intervals. Additional, randomized studies are required to clarify the role and timing of systemic chemotherapy in this patient subset.

Microsatellite and RAS/RAF Mutational Status as Prognostic Factors in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS. METHODS: Data were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS). RESULTS: The study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4-51.2 months], and the median DFS was 13.6 months (95% CI, 12.3-14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4-24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS. CONCLUSION: For patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.

A multidisciplinary approach to improve preoperative understanding and reduce anxiety: a randomised study.

BACKGROUND: Emotional factors may influence reception of information provided during informed consent leading to incomplete understanding and reduced satisfaction. OBJECTIVE: This study was designed to test the hypothesis that a multidisciplinary approach could improve understanding of the information provided by the anaesthesiologist and in turn, reduce anxiety. DESIGN: A randomised controlled clinical trial. SETTING: Veneto Oncology Institute, Italian comprehensive cancer centre. Recruitment from December 2008 to June 2010. PATIENTS: Two hundred and fifty-one women requiring anaesthesia for breast cancer surgery. INTERVENTIONS: Women undergoing surgery for primary breast cancer were randomly assigned to either the structured anaesthesiology interview group (SAI) or the integrated multidisciplinary psycho-oncological approach (IPA). In the IPA arm, patients underwent an interview with the psycho-oncologist. Subsequently, and prior to preoperative anaesthesia evaluation, the psycho-oncologist informed the anaesthesiologist of the type of communicative strategy to adopt for each individual. In the SAI arm, patients received only the anaesthesiology interview. MAIN OUTCOME MEASURES: Anxiety as assessed by State-Trait Anxiety Inventory (STAI) questionnaire. RESULTS: Two hundred and fifty-one patients were randomised and 234 analysed: 124 in the IPA arm and 110 in the SAI arm. For both groups, mean anxiety scores, according to the STAI questionnaire, were statistically lower after the anaesthesiology visit than at baseline, with a reduction of 6.5 points for the IPA arm [95% confidence interval (CI) 4.6 to 8.4, P < 0.0001] and 4.7 points for the SAI arm (95% CI 2.6 to 6.7, P < 0.0001). There were no significant differences between the two groups in the mean anxiety score before and after the interview. For highly anxious patients, the STAI score decreased significantly more in the IPA group (10.2 points, 95% CI 7.4 to 13.0) than in the SAI group (6.8 points, 95% CI 3.8 to 9.8), P = 0.024.The information provided during the anaesthesiology visit was correctly understood by more than 80% of patients and was similar in both groups. CONCLUSION: In breast cancer surgical patients with high levels of preoperative anxiety, a multidisciplinary approach with psycho-oncological intervention proved to be useful at the preoperative anaesthesiology interview.

Patient-reported outcomes after neoadjuvant chemoradiotherapy for rectal cancer: a multicenter prospective observational study.

OBJECTIVE: To prospectively describe patient-reported outcomes (PROs) after preoperative chemoradiotherapy (pCRT) for rectal cancer. BACKGROUND: Little evidence is available on PROs after pCRT for rectal cancer. PATIENTS AND METHODS: Patients with rectal cancer, candidates to receive pCRT, were enrolled in a multicenter prospective observational trial. Health-related quality of life was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and its colorectal cancer module (QLQ-CR38), and fecal incontinence and bowel function were evaluated using the fecal incontinence score questionnaire and a set of ad hoc questions. Questionnaires were filled out before CRT (t0), 2 to 3 weeks after completion of CRT (t1), and at 6 (t2) and 12 months (t3) after surgery. Primary analysis of selected scales included: global quality of life, physical functioning, social functioning, fatigue, body image, future prospective, and gender-related sexual problems. RESULTS: Of 149 eligible patients, questionnaires were completed in 100%, 95%, 88% and 77% of cases at t0, t1, t2, and t3, respectively. At t3, 78% of patients reported stool fractionation and 72% sensation of incomplete defecation. Only 14% of patients had optimal continence. Physical/social functioning, fatigue, and body image showed a decrease just after pCRT and returned to baseline levels at 1 year after treatment. Global quality of life was stable over time. Male sexual problems were greatly impaired throughout the study period (P < 0.001) with major clinically meaningful changes between baseline and 1 year after treatment. CONCLUSIONS: These findings add to the body of evidence available regarding pCRT and help clinicians to make more informed treatment decisions.

Health-related quality of life, faecal continence and bowel function in rectal cancer patients after chemoradiotherapy followed by radical surgery.

PURPOSE: To evaluate health-related quality of life (HRQOL), faecal continence and bowel function of patients with rectal cancer who underwent preoperative chemoradiotherapy (pCRT) in a cross-sectional setting. METHODS: Out of 185 consecutive patients who underwent pCRT for rectal cancer from 1994 to 2004 at a single institution, 101 were eligible for the study. Causes of exclusion were: death (n = 38), not radical surgery or recurrence (n = 21), presence of stoma at the time of the survey (n = 15), lost to follow-up (n = 6) and miscellaneous (n = 4). Eligible patients were asked to complete: the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, the disease specific colorectal module (EORTC QLQ-CR38) and faecal incontinence and bowel function questionnaires. HRQOL outcomes were compared with reference data from the general population, and the association among clinical variables and HRQOL was also investigated with linear regression analyses. RESULTS: Questionnaires were completed by 80% of eligible patients. Compared to population-based norms, patients showed clinically meaningful worse outcomes in terms of constipation and diarrhoea. Stool fractionation (p < 0.01) and use of enema/laxative (p < 0.01) were negatively associated with global health status/QOL. Urgency negatively affected physical (p < 0.01), role (p < 0.01) and social functioning (p < 0.01). Sensation of incomplete evacuation negatively affected social functioning (p < 0.01). CONCLUSIONS: Although HRQOL profile of these patients is broadly similar to that of healthy subjects, there are still important limitations in terms of key symptoms. The use of validated questionnaires is crucial to provide standardised information on relevant health status areas.

Tolerability of intensified intravenous interferon alfa-2b versus the ECOG 1684 schedule as adjuvant therapy for stage III melanoma: a randomized phase III Italian Melanoma Inter-group trial (IMI - Mel.A.) [ISRCTN75125874].

BACKGROUND: High-dose interferon alfa-2b (IFNalfa-2b), according to the ECOG 1684 schedule, is the only approved adjuvant treatment for stage III melanoma patients by the FDA and EMEA. However, the risk/benefit profile has been questioned limiting its world-wide use. In the late nineties, the Italian Melanoma Inter-group started a spontaneous randomized clinical trial (RCT) to verify if a more intense, but shorter than the ECOG 1684 regimen, could improve survival without increasing the toxicity profile. The safety analysis in the first 169 patients who completed the treatment is here described. METHODS: Stage III melanoma patients were randomized to receive IFNalfa-2b 20 MU/m2/d intravenously (IV) 5 days/week x 4 weeks, repeated for three times on weeks 9 to 12, 17 to 20, 25 to 28 (Dose-Dense/Dose-Intense, DD/DI, arm), or IFNalfa-2b 20 MU/m2/d IV 5 days/week x 4 weeks followed by 10 MU/m2 subcutaneously (SC) three times per week x 48 weeks (High Dose Interferon, HDI, arm). Toxicity was recorded and graded, according to the WHO criteria, as the worst grade that occurred during each cycle. RESULTS: The most common toxicities in both arms were flu-like and gastrointestinal symptoms, leukopenia, liver and neuro-psychiatric morbidities; with regard to severe toxicity, only leukopenia was statistically more frequent in DD/DI arm than in HDI arm (24% vs 9%) (p = 0.0074), yet, this did not cause an increase in the infection risk. Discontinuation of treatment, due to toxicity, was observed in 13 and 17% of the patients in the DD/DI and HDI arm, respectively. The median actual dose intensity delivered in the DD/DI arm (36.4 MU/m2/week) was statistically higher than that delivered in the HDI arm (30.7 MU/m2/week) (p = 0.003). CONCLUSION: Four cycles of intravenous high-dose IFNalfa-2b can be safely delivered with an increase in the median dose intensity. Efficacy results from this trial are eagerly awaited.

Hippocampal prosaposin changes during stress: a glucocorticoid-independent event.

Several studies indicate that stress can produce remarkable effects on neurotrophic factors. In this regard, hippocampus is the most interesting structure of the brain because of its broad involvement in behavioral and neuroendocrine phenomena. In the present study, we investigated the effect of stress on hippocampal prosaposin, which is known to act as a neurotrophic and neuroprotective factor. Rats subjected to restraint stress (120 min) had a significant and transient reduction of hippocampal, but not hypothalamic, prosaposin full-length protein. Indeed, when this stressful stimulus was applied daily for 3 days, no differences were detected in comparison with naive rats. To investigate the role of glucocorticoids in the stress-induced decrease in hippocampal prosaposin, adrenalectomized and corticosterone-treated rats were studied. The results indicate that adrenalectomized rats behave as intact animals. This finding indicates that the absence of endogenous corticosterone does not prevent a decrease in hippocampal prosaposin. When an increase of corticosterone was achieved through exogenous administration, hippocampal prosaposin concentrations were unchanged in comparison with vehicle-injected (sesame oil) rats. These results led to the conclusion that stress, not via an increase of glucocorticoid hormone, transiently reduces hippocampal prosaposin levels. This phenomenon is followed by rapid recovery of the neurotrophin level, even when the stress stimulus persists.