Cristina Marenghi

Predictors of Health-related Quality of Life and Adjustment to Prostate Cancer During Active Surveillance

BACKGROUND Active surveillance (AS) is emerging as an alternative approach to limit the risk of overtreatment and impairment of quality of life (QoL) in patients with low-risk localised prostate cancer. Although most patients report high levels of QoL, some men may be distressed by the idea of living with untreated cancer. OBJECTIVE To identify factors associated with poor QoL during AS. DESIGN, SETTING, AND PARTICIPANTS Between September 2007 and March 2012, 103 patients participated in the Prostate Cancer Research International Active Surveillance (PRIAS) QoL study. Mental health (Symptom Checklist-90), demographic, clinical, and decisional data were assessed at entrance in AS. Health-related QoL (HRQoL) Functional Assessment of Cancer Therapy-Prostate version and Mini-Mental Adjustment to Cancer outcomes were assessed after 10 mo of AS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariate logistic regression models were used to identify predictors of low (<25th percentile) HRQoL, adjustment to cancer, and a global QoL index at 10 mo after enrollment. RESULTS AND LIMITATIONS The mean age of the study patients was 67 yr (standard deviation: ±7 yr). Lack of partner (odds ratio [OR]: 0.08; p=0.009) and impaired mental health (OR: 1.2, p=0.1) were associated with low HRQoL (p=0.006; area under the curve [AUC]: 0.72). The maladaptive adjustment to cancer (p=0.047; AUC: 0.60) could be predicted by recent diagnosis (OR: 3.3; p=0.072). Poor global QoL (overall p=0.02; AUC: 0.85) was predicted by impaired mental health (OR: 1.16; p=0.070) and time from diagnosis to enrollment in AS <5 mo (OR: 5.52; p=0.009). Influence of different physicians on the choice of AS (OR: 0.17; p=0.044), presence of a partner (OR: 0.22; p=0.065), and diagnostic biopsy with >18 core specimens (OR: 0.89; p=0.029) were predictors of better QoL. Limitations of this study were the small sample size and the lack of a control group. CONCLUSIONS Factors predicting poor QoL were lack of a partner, impaired mental health, recent diagnosis, influence of clinicians and lower number of core samples taken at diagnostic biopsy. Educational support from physicians and emotional/social support should be promoted in some cases to prevent poor QoL.

Participation in Clinical Trials as Viewed by the Patient: Understanding Cultural and Emotional Aspects Which Influence Choice

Background: Patients invited to take part in a clinical trial may evoke an archetype on which they may base their decision of adherence to participation, instead of on the study itself. Methods: A 17-item, multiple choice questionnaire was developed, tested and then administered to 102 Italian-speaking patients with advanced lung or breast cancers who had never been exposed to participation in a trial. Results: The questionnaire was answered by all patients. Eighty-five percent were positive about trial participation. Demographic factors did not influence patients’ willingness to participate. Trust in the investigator (76%) or in the institute (64%) and hope of receiving a new chance for cure (78%) were cited as reasons to accept participation. A minority was concerned by potential conflicts of interest (31%) or the thought of being ‘guinea pigs’ (36%), and feared that doctors were interested in advancing their own research, even though there were more efficient drugs available (28%). Fifty percent feared receiving a little-known medicine, and 76% considered that a thorough explanation of toxicity/safety of the proposed treatment helped them decide. Conclusion: Several prejudices, fears and some hopes have been captured by the questionnaire. Understanding such specifics will improve patient information leading patients to a more conscious motivation in deciding whether to participate in a clinical trial.

Intracystic epidermal growth factor level is predictive of breast-cancer risk in women with gross cystic disease of the breast

Women affected by gross cystic disease of the breast have an increased risk of breast cancer. We report here the incidence of breast cancer by cyst type and intracystic epidermal growth factor (EGF) concentration. Our retrospective study included 504 women who had at least 1 cyst aspiration between 1985 and 1993. Cyst fluids were processed for electrolyte concentration (n = 378), EGF concentration (n = 347) or both (n = 337). Age‐standardized incidence ratios (SIRs) were estimated using the population of the Genoa Cancer Registry. A multivariate Poisson regression model was used to estimate relative risks (RRs) when the study groups were compared directly. By June 1999, 19 invasive breast cancers had developed in the cohort of women. The age SIR of breast cancer calculated for the whole cohort was 3.32 (95% confidence interval 2.00–5.18). The ratio was not affected by age and was only moderately increased in women with a positive family history of breast cancer and type I cysts (i.e., those with a Na+/K+ ratio <3). However, it was significantly increased in women with high EGF concentrations. Direct comparisons confirmed that age, cyst type and family history only moderately increased the RR, whereas EGF concentration was a strong predictor of risk. Our results confirm that women affected by palpable cysts have an increased risk of developing breast cancer and suggest that the risk is higher in women with high intracystic EGF concentrations.

Lifestyle interventions to improve the quality of life of men with prostate cancer: A systematic review of randomized controlled trials

Improving quality of life is a key issue for patients with prostate cancer (PCa). Lifestyle interventions could positively impact the quality of life of patients. However, there is no clear-cut understanding of the role of diet, exercise and risky behaviour reduction in improving the quality of life of men with PCa. The aim of this review was to systematically summarize randomized controlled trials on lifestyle in PCa patients with quality of life as main outcome. 17 trials were included. Most of them referred to exercise interventions (71%) and involved men undergoing androgen deprivation therapy (47%). Exercise studies yielded the greater amount of positive results on quality of life outcomes (67%), followed by dietary interventions (50%) and combined lifestyle interventions (33%). In particular, supervised exercise programs with resistance training sessions were the ones producing greater convincing evidence for benefits on quality of life. Further studies with high methodological quality providing adequate information to develop evidence-based, personalized lifestyle interventions that can effectively ameliorate PCa-related quality of life are needed.

Chemotherapy with cisplatin and 5-fluorouracil chronomodulated infusion in locally advanced or metastatic/recurrent carcinoma of the cervix.

Aims and Background The purpose of this study was to review our experience with the combination of circadian chronomodulated 5-fluorouracil infusion in association with cisplatin in patients with locally advanced or metastatic cancer of the cervix in order to assess the activity and tolerability of the combination. Methods Twenty patients with locally advanced disease and 21 patients with metastatic or recurrent disease were treated from January 1995 to May 1999. 5-fluorouracil (600 mg/m2, days 1 to 5) was administered by a continuous circadian-shaped infusion employing an external programmable portable pump; cisplatinum (20 mg/m2) was infused days 1 through 5 iv over a 2-hr period. Response to treatment was evaluated after 3 and 6 cycles of therapy. Patients with locally advanced disease who achieved a clinical shrinkage of their tumor or were at least stable were submitted to surgery; pelvic radiotherapy was administered to patients with disease progression. Results Seven patients with locally advanced disease achieved a partial clinical response (overall response, 35%; 95% Cl, 15.4-59.2), and 12 of 20 patients were submitted to surgery. Median progression-free and overall survival were 17 months and 36 months, respectively. Objective responses were observed in 9 of 21 patients with metastatic/recurrent disease (7 partial plus 2 minor responses: overall response 43%; 95% Cl, 21.8-65.9). Median time to progression and overall survival were 5 and 17 months, respectively. Conclusions Cisplatinum plus 5-fluorouracil chronomodulated infusion showed a moderate but definite activity and was well tolerated in both groups of patients. In consideration of clinical results comparable to more toxic and expensive regimens reported in the literature, the combination appears to be a reasonable option especially for women with metastatic/recurrent cervical carcinoma and a promising treatment in combination with definitive radiotherapy in patients with locally advanced disease.

Paclitaxel by 72-hour continuous infusion followed by bolus intravenous ifosfamide or epirubicin: results of two phase I studies.

Study Purposes: To determine the maximum-tolerated dose (MTD) of paclitaxel administered by 72-hour continuous infusion followed by bolus intravenous ifosfamide on days 4 and 5 or epirubicin on day 4, every 21 days. To assess the toxicity and preliminary activity in patients with advanced refractory solid tumors. Patients and Methods: Sixteen patients with progressive disease after standard chemotherapy for advanced disease were treated with the combination paclitaxel-ifosfamide and 10 patients with the combination paclitaxel-epirubicin. Results: In the first phase I study the MTDs were: paclitaxel 135 mg/m2 and ifosfamide 2.5 mg/m2/day; hematologic toxicity was the dose-limiting toxicity (DLT) during the first cycle of therapy at dose level 4. Paclitaxel administered at 135 mg/m2 and epirubicin 50 mg/m2 were the MTDs in the second phase I study; grade 4 stomatitis was the DLT of this combination. Conclusions: Paclitaxel by 72-hour continuous infusion followed by bolus ifosfamide was a manageable regimen with an acceptable hematologic toxicity in the absence of neurotoxicity. Preliminary activity of this combination was encouraging in a group of patients with ovarian cancer. The optimal way to combine paclitaxel and epirubicin and the best schedule relative to such a long paclitaxel infusion time in this combination regimen remain to be determined.

Eleven-year management of prostate cancer patients on active surveillance: what have we learned?

Purpose To evaluate the outcomes of active surveillance (AS) on patients with low-risk prostate cancer (PCa) and to identify predictors of disease reclassification. Methods In 2005, we defined an institutional AS protocol (Sorveglianza Attiva Istituto Nazionale Tumori [SAINT]), and we joined the Prostate Cancer Research International: Active Surveillance (PRIAS) study in 2007. Eligibility criteria included clinical stage ≤T2a, initial prostate-specific antigen (PSA) <10 ng/mL, and Gleason Pattern Score (GPS) ≤3 + 3 (both protocols); ≤25% positive cores with a maximum core length containing cancer ≤50% (SAINT); and ≤2 positive cores and PSA density <0.2 ng/mL/cm3 (PRIAS). Switching to active treatment was advised for a worsening of GPS, increased positive cores, or PSA doubling time <3 years. Active treatment-free survival (ATFS) was assessed using the Kaplan-Meier method. Factors associated with ATFS were evaluated with a multivariate Cox proportional hazards model. Results A total of 818 patients were included: 200 in SAINT, 530 in PRIAS, and 88 in personalized AS monitoring. Active treatment-free survival was 50% after a median follow-up of 60 months. A total of 404/818 patients (49.4%) discontinued AS: 274 for biopsy-related reclassification, 121/404 (30%) for off-protocol reasons, 9/404 (2.2%) because of anxiety. Biopsy reclassification was associated with PSA density (hazard ratio [HR] 1.8), maximum percentage of core involvement (HR 1.5), positive cores at diagnostic biopsy (HR 1.6), older age (HR 1.5), and prostate volume (HR 0.6) (all p<0.01). Patients from SAINT were significantly more likely to discontinue AS than were the patients from PRIAS (HR 1.65, p<0.0001). Conclusions Five years after diagnosis, 50% of patients with early PCa were spared from active treatment. Wide inclusion criteria are associated with lower ATFS. However, at preliminary analysis, this does not seem to affect the probability of unfavorable pathology.

What if…: decisional regret in patients who discontinued active surveillance

Purpose To investigate the presence of regret in patients about having followed an active surveillance (AS) protocol. The secondary aim was to identify variables that influence regret. Methods From February 2006 to May 2014, 204 patients discontinued the AS protocols and were invited to enter the study. Sociodemographic variables were collected at AS enrollment, together with health-related quality of life (Functional Assessment of Cancer Therapy-Prostate version [FACT-P]) and coping (Mini-Mental Adjustment to Cancer). Patients were asked to complete a Treatment Regret Scale as well as the FACT-P questionnaire. Clinical data were gathered, as well as time of stay within the AS protocol, reason for discontinuing AS, kind of post-AS treatment, and time elapsed since AS discontinuation. Questionnaires were completed by 105 patients (51.5% of those who had been invited to enter the study). Results Most of the patients had a low or null degree of regret on the Treatment Regret Scale from 0 to 100 (82/105 patients [78.1%] obtained a score <30, and about 30% of the sample had a score equal to zero). Only 5 patients (4.7%) scored 60 or more, indicating some degree of regret. None of the statistical tests between regret scores and a number of analyzed variables reached significance. Conclusions These results show that the degree of regret about following an AS protocol and after its discontinuation because of entering active treatment was very low. The regret after AS was not related to sociodemographic or clinical factors.

Italian cultural adaptation of the Memorial Anxiety for Prostate Cancer scale for the population of men on active surveillance

Purpose: The Memorial Anxiety Scale for Prostate Cancer (MAX-PC) is a self-report questionnaire that was developed in English to assess prostate cancer (PCa)-related anxiety. The aim of this study was to perform a cultural adaptation for the tool to be used in a population of Italian men on active surveillance (AS). Methods: A total of 222 patients with localized PCa who were recruited for the Prostate Cancer Research International: Active Surveillance (PRIAS) protocol completed the MAX-PC. Psychometric analysis was performed to assess reliability indexes. A Spearman rank correlation was used to test the association between MAX-PC scales and other questionnaires and was used for longitudinal analysis. Results: Cronbach coefficients and item to total correlation demonstrated good internal consistency. Some items related to the repetition of the PSA test showed a large floor effect and thus were poorly effective in measuring anxiety for PSA testing in patients on AS. Confirmatory factor analysis partly failed to reproduce the structure of the original version. A modified version of MAX-PC, excluding the items with a large floor effect, was thus considered for AS patients. Factor analysis on this version demonstrated considerable consistency with the presence of 3 subscales: anxiety related to PCa, anxiety related to PSA testing, and anxiety related to the fear of tumor progression. Longitudinal analysis showed an acceptable validity over time. The MAX-PC was correlated with the anxious preoccupation subscale of the Mini-Mental Adjustment to Cancer scale. Conclusions: A slightly modified version of the MAX-PC was developed for use in Italian men on AS. This instrument appears to be a valid and reliable tool that measures anxiety in men with PCa who are enrolled in AS programs.

Centralized revision of diagnostic pathologic slides for prostate cancer patients on active surveillance: Is it just time- and resource-consuming?

132 Background: Active Surveillance (AS) is offered to prostate cancer (PCa) patients (pts) with very low risk disease, with well defined diagnostic biopsy details. For this reason, in order to standardize diagnostic inclusion criteria, we requested pathologic review before AS enrollment. We here report on second opinion of PCa needle biopsies to determine how often the expert opinion of a uro-pathologist resulted in a different diagnosis, in the group of pts who were proposed for AS. METHODS AS institutional protocol (SAINT) started in Mar 05. Entry criteria: initial PSA≤10ng/ml, Tstage≤T2a, GPS≤3+3, positive biopsy cores≤20%, max core length containing cancer≤50%. In Nov 07 PRIAS started. PRIAS vs SAINT differs on: max 2 positive cores and PSA density<0.2ng/ml/cc. A second opinion on biopsy was requested in 248 cases (Oct 05 - Jul 10), due to outside diagnosis. We analyzed differences between outside diagnosis and institutional expert opinion. We considered two classes of differences: minor differences (which did not prevent AS enrollment) and significant changes (which resulted in a change in prognosis and closed the possibility of AS enrollment). RESULTS 40/248 (16.1%) cases had minor differences (18 SAINT and 22 PRIAS). In SAINT pts, 12/18 (66.7%) biopsies were increased in the max core length containing cancer (but still≤50%) and 6/18 (33.3%) had a change in the number of positive cores (but still≤20% of total cores). In PRIAS pts 10/22 (45.5%) changes were related to upsizing (from 1 to 2 positive cores) and 5/12 to downsizing (from 2 to 1 positive core). 7/22 changes were related to differences in core length containing cancer (from below to above 50%). Significant differences were observed in 30/248 (12.1%). 20/30 were related to upgrading, 10/30 pts had an upsizing: 1 SAINT pt exceeded 20% of positive cores, 5 SAINT pts exceeded 50% of max tumor length of positive cores, while 4 PRIAS pts increased from 2 to 3 or 4 positive cores. CONCLUSIONS Central pathology review reduces population heterogeneity in the specific setting of AS programs, significant reclassification of risk category involved 12% of pts. Current clinical consequences of central review cannot be determined.