Rodolfo Passalacqua

Pemetrexed Versus Pemetrexed and Carboplatin As Second-Line Chemotherapy in Advanced Non–Small-Cell Lung Cancer: Results of the GOIRC 02-2006 Randomized Phase II Study and Pooled Analysis With the NVALT7 Trial

PURPOSE To compare efficacy of pemetrexed versus pemetrexed plus carboplatin in pretreated patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with advanced NSCLC, in progression during or after first-line platinum-based chemotherapy, were randomly assigned to receive pemetrexed (arm A) or pemetrexed plus carboplatin (arm B). Primary end point was progression-free survival (PFS). A preplanned pooled analysis of the results of this study with those of the NVALT7 study was carried out to assess the impact of carboplatin added to pemetrexed in terms of overall survival (OS). RESULTS From July 2007 to October 2009, 239 patients (arm A, n = 120; arm B, n = 119) were enrolled. Median PFS was 3.6 months for arm A versus 3.5 months for arm B (hazard ratio [HR], 1.05; 95% CI, 0.81 to 1.36; P = .706). No statistically significant differences in response rate, OS, or toxicity were observed. A total of 479 patients were included in the pooled analysis. OS was not improved by the addition of carboplatin to pemetrexed (HR, 90; 95% CI, 0.74 to 1.10; P = .316; P heterogeneity = .495). In the subgroup analyses, the addition of carboplatin to pemetrexed in patients with squamous tumors led to a statistically significant improvement in OS from 5.4 to 9 months (adjusted HR, 0.58; 95% CI, 0.37 to 0.91; P interaction test = .039). CONCLUSION Second-line treatment of advanced NSCLC with pemetrexed plus carboplatin does not improve survival outcomes as compared with single-agent pemetrexed. The benefit observed with carboplatin addition in squamous tumors may warrant further investigation.

Prognostic Survival Associated With Left-Sided vs Right-Sided Colon Cancer: A Systematic Review and Meta-analysis.

Importance Primary tumor location is emerging as an important prognostic factor owing to distinct biological features. However, the side of origin of colon cancer (CC) still does not represent a prognostic parameter when deciding for adjuvant or palliative chemotherapy. Objective To determine the prognostic role of left vs right-sidedness of primary tumor location in patients with CC. Data Sources We searched PubMed, EMBASE, The Cochrane Library, Web of Science, LILACS, CINAHL, and SCOPUS for prospective or retrospective studies reporting data on overall survival for left-sided colon cancer (LCC) compared with right-sided colon cancer (RCC). Study Selection Studies were selected if: (1) side of CC was reported among variables entered into survival analysis, (2) survival information was available (overall survival [OS] was reported in the article as hazard ratio (HR) according to multivariate analysis, (3) articles were published in the English language. Data Extraction and Synthesis Data were pooled using HRs for OS of LCC vs RCC according to fixed or random-effects models. Subgroup analysis and multivariate random-effects model meta-regression was also implemented adjusting for stage distribution, sample size, race, year of publication, type and quality of studies, and adjuvant chemotherapy. Main Outcomes and Measures HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. In this analysis, all HRs with 95% CIs were pooled to obtain prognostic information on the location of the primary tumor (left vs right location site of CC) independent of other common clinicopathological covariates. Results An analysis was made from the 66 studies conducted. It included 1 437 846 patients with a median follow-up of 65 months. Left sided primary tumor location was associated with a significantly reduced risk of death (HR, 0.82; 95% CI, 0.79-0.84; P < .001) and this was independent of stage, race, adjuvant chemotherapy, year of study, number of participants, and quality of included studies. Conclusions and Relevance Based on these results, CC side should be acknowledged as a criterion for establishing prognosis in all stages of disease. It should be considered when deciding treatment intensity in metastatic settings, and should represent a stratification factor for future adjuvant studies.

Combination Therapy with Platinum and Etoposide of Brain Metastases from Breast Carcinoma

Twenty-two consecutive patients with brain metastases from breast carcinoma were treated with a combination of platinum (100 mg/m2 day 1) and etoposide (100 mg/m2 days 4, 6, 8) every three weeks. Five (23%) achieved a complete response (CR) while 7 (32%) obtained a partial response (PR) for an overall response rate of 55%. The 95% confidence interval for combined CR and PR was 34-76%. Five patients received brain irradiation after reaching the maximum degree of objective remission by chemotherapy. Median duration of combined CR plus PR was 40 weeks (12+; 152). Median duration of survival was 58 weeks (2; 208+). Fifty-five percent of the patients were alive at one year. Our study demonstrates that this combination treatment is highly effective in the management of brain metastases from breast carcinoma.

How to promote, improve and test adherence to scientific evidence in clinical practice

BackgroundNegative variation in the management of patients with the same clinical condition is frequent, and affects quality of care. Recent studies indicate that single interventions are not an effective solution. We aim to demonstrate that a multifaceted strategy can favor the introduction of research into practice, and to assess its long-term effects on a set of common medical conditions exhibiting significant negative variation at our institution.MethodsThe strategy, devised and agreed upon by a multidisciplinary group, was first applied to one relevant medical condition – cerebral ischemic stroke. To test its effectiveness a quasi-experimental study was conducted, comparing an intervention group with historical controls. After validation the strategy was extended to other pathologies, and its long-term effect measured using evidence-based quality indicators. Adherence to each indicator was determined prospectively on a six-month basis for a period of at least two consecutive years. Measures are expressed as proportions with 95% confidence intervals.ResultsValidation findings demonstrated that the strategy improved compliance with scientific evidence: the percentage of patients who received a CT scan within 24 hours of hospital presentation rose from 56% to 75%, (χ2 = 7.43 p < 0.01); admissions to selected wards increased from 45% to 64%, (χ2 = 7.81 p < 0.01); the number of physical medicine visits within 24 hours of the request grew from 59% to 91% (χ2 = 14,40 p < 0.001). Over a four-year period the program was gradually applied to 14 medical conditions. Except for 3 cases, compliance with the pathway, i.e. number of eligible patients for whom data on the care process is collected, was above the minimum requirement of 75%. Indicator adherence generally exhibited a positive trend, though variability was observed both among different conditions and between different semesters for the same pathology.ConclusionAccording to our experience, incorporation of research into practice can be favored by systematically applying a shared, multifaceted strategy, involving multidisciplinary teams supported by central coordination. Institutions should device a tailor-made approach, should train personnel on implementation strategies, and create cultural acceptance of change. Just like for experimental trials, human and economic resources should be allocated within health care services to allow the achievement of this objective.

Adjuvant low-dose interleukin-2 (IL-2) plus interferon-α (IFN-α) in operable renal cell carcinoma (RCC): a phase III, randomized, multicentre trial of the Italian Oncology Group for Clinical Research (GOIRC).

There is currently no standard therapy to reduce the recurrence rate after surgery for renal cell carcinoma (RCC). The aim of this study was to assess efficacy and safety of adjuvant treatment with low doses of interleukin-2 (IL-2)+interferon-&agr; (IFN-&agr;) in operable RCC. The patients were randomized 1:1 to receive a 4-week cycle of low-dose IL-2+IFN-&agr; or observation after primary surgery for RCC. Treatment cycles were repeated every 4 months for the first 2 years and every 6 months for the subsequent 3 years. The primary endpoint was recurrence-free survival (RFS); safety; and overall survival (OS) were secondary endpoints. ClinicalTrials.gov registration number was NCT00502034. 303/310 randomized patients (156 in the immunotherapy arm and 154 in the observation group) were evaluable at the intention-to-treat analyses. The 2 arms were well balanced. At a median follow-up of 52 months (range, 12–151 mo), RFS, and OS were similar, with an estimated hazard ratio (HR) of 0.84 [95% confidence interval (CI), 0.54–1.31; P=0.44] and of 1.07 (95% CI, 0.64–1.79; P=0.79), respectively in the 2 groups. Unplanned, subgroup analysis showed a positive effect of the treatment for patients with age 60 years and younger, pN0, tumor grades 1-2, and pT3a stage. Among patients with the combined presence of ≥2 of these factors, immunotherapy had a positive effect on RFS (HR=0.44; 95% CI, 0.24–0.82; P⩽0.01), whereas patients with <2 factors in the treatment arm exhibited a significant poorer OS (HR=2.27; 95% CI, 1.03–5.03 P=0.037). Toxicity of immunotherapy was mild and limited to World Health Organization grade 1-2 in most cases. Adjuvant immunotherapy with IL-2+IFN-&agr; showed no RFS or OS improvement in RCC patients who underwent radical surgery. The results of subset analysis here presented are only hypothesis generating.

Prospective, Multicenter, Randomized Trial of a New Organizational Modality for Providing Information and Support to Cancer Patients

PURPOSE No structured modality for providing information and support to patients in oncology wards has been validated in clinical trials. METHODS This is a pragmatic, two-arm, cluster randomized trial, with the oncology ward as random assignment unit. Centers were allocated to implement a Point of Information and Support (PIS) or to a control group. The PIS included a library for cancer patients and a specifically trained oncology nurse. End points, measured at patient level, were psychological distress and satisfaction with received information. Both intent-to-treat and per-protocol analyses considering clustering were performed. RESULTS Thirty-eight Italian cancer centers were randomly assigned, and 6 months after PIS creation, 3,286 unselected, consecutive cancer patients were surveyed (1,654 in the experimental group and 1,632 in the control group). Three thousand one hundred ninety-seven (97%) questionnaires were collected and deemed valid. Fifty-two percent of centers (11 of 21 centers) in the experimental arm did not implement the PIS in accordance with the protocol. Overall, 34% of patients showed moderate to severe psychological distress, and only 9% declared dissatisfaction. Intent-to-treat analysis did not yield significant differences. Although the per-protocol analysis did show a reduction in psychological distress (28.9% for functioning PIS v 33.3% for no PIS) and dissatisfaction (6.4% for functioning PIS v 9.3% for no PIS), differences did not reach significance. CONCLUSION This is the first cluster randomized trial aiming to demonstrate that a structured modality of providing information reduces psychological distress. We did not find this, but we believe results should be interpreted cautiously, particularly because of the low compliance with PIS implementation. Context analysis preceding such interventions is essential.

Cross-cultural adaptation and patients' judgments of a Question Prompt List for Italian-speaking cancer patients

BackgroundQuestion Prompt Lists (QPLs) have proven very effective in encouraging cancer patients to ask questions, allowing them to take up a more active role during visits with the oncologist. As no such tool has yet been validated for Italian-speaking users, we carried out the cross-cultural adaptation and evaluation of an existing Australian Question Prompt List.MethodsCross-cultural adaptation was performed in accordance with the five steps described by Guillemin and Beaton. Forward and back translations of the original tool were carried out, and the products discussed by an Expert Committee who agreed on a prefinal version of the Italian QPL, which was submitted to 30 volunteer patients for evaluation. They rated each questions adequacy of content, clarity of wording, usefulness, and generated anxiety, on a 3-point Likert scale. Based on the analysis of patient ratings, the final version of the Italian QPL was produced.ResultsFew discrepancies between the two back translations and the original version of the instrument were noted, indicating that the Italian translation (synthesis of the 2 forward translations) was substantially accurate. Most volunteer patients felt that the questionnaire was adequate, easy to understand and useful. Only a few minor criticisms were expressed. Certain questions on diagnosis and prognosis generated the highest level of anxiety. Patient comments and ratings on clarity highlighted the need to clarify common health care terms which are not widely used by the public (i.e. guideline, multidisciplinary team and clinical trial)ConclusionsThis cross-cultural adaptation has produced an Italian Question Prompt List that is now available for multi-center international studies and can be safely used with Italian-speaking cancer patients.

Epirubicin versus CMF as adjuvant therapy for stage I and II breast cancer: a prospective randomised study

We compared a relatively short regimen of monochemotherapy with epirubicin versus polychemotherapy with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) as adjuvant treatment for stage I and II breast cancer patients. 348 patients with oestrogen receptor negative (ER-) node negative and ER- or ER+ node-positive with <10 nodes were accrued. CMF was given intravenously (i.v.) on days 1 and 8, every 4 weeks, for six courses; epirubicin was given weekly for 4 months. Postmenopausal patients received tamoxifen for 3 years. The primary endpoints were overall survival (OS), relapse-free survival (RFS) and event-free survival (EFS). Outcome evaluation was performed both in eligible patients and in all randomised patients according to the intention-to-treat principle. 8 randomised patients were considered ineligible. At a median follow-up of 8 years, there was no difference in OS (Hazard Ratio (HR)=1.11, 95% Confidence Interval (CI): 0.77-1.61, P=0.58), EFS (HR=1.14, 95% CI: 0.78-1.64, P=0.48), and RFS (HR=1.14, 95% CI: 0.8-1.64, P=0.48) between the two arms for all of the patients. At 8 years, the RFS percentages (+/-Standard Error (S.E.)) were 65.4% (+/-4%) in the CMF arm and 62.7% (+/-4%) in the epirubicin arm; for EFS these were 64.2% (+/-4%) for CMF and 60.8% (+/-4%) for epirubicin, respectively. A significant difference in RFS (P=0.015) was observed in patients with 4-9 positive nodes in favour of the CMF arm. Toxicity in the two arms was superimposable except for more frequent grade 3 alopecia in the epirubicin-treated patients (P=0.001). Overall, at a median follow-up of 8 years, there were no differences between the two arms in terms of OS, EFS and RFS.

The value of bone marrow biopsy in breast cancer at time of diagnosis: A prospective study

Bone marrow biopsies (BMB) were performed in 173 consecutive unselected breast cancer patients at the time of diagnosis to define the value of this diagnostic tool in the initial staging of mammary carcinoma. In a group of 160 patients with a negative standard staging work‐up, BMB was positive in two (1%). Both of them had negative x‐ray but bone scan was positive in one and doubtful in the other. Bone marrow biopsy was positive in 31% of 13 additional patients with metastatic disease and in 44% of the nine among them with radiologically involved skeleton. These results exclude that BMB is able to discover micrometastatic foci of neoplastic disease. Its positivity appears strictly correlated with that of bone x‐ray and scan. Based on the results of this prospective study, BMB is not required when both bone survey and scan are negative, but could be useful in clarifying diagnostic doubts of skeletal involvement.

FOLFOXIRI Plus Bevacizumab as Conversion Therapy for Patients With Initially Unresectable Metastatic Colorectal Cancer: A Systematic Review and Pooled Analysis

Importance The combination of fluorouracil, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-Bev) is an established and effective first-line chemotherapy regimen for metastatic colorectal cancer. However, resection rates of metastases and overall survival with this schedule have never been systematically evaluated in published studies including, but not limited to, the TRIBE (TRIplet plus BEvacizumab) trial. Objective To assess the clinical efficacy of FOLFOXIRI-Bev, including outcomes and rates of surgical conversions. Data Sources A systematic review was conducted in October 2016 in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, Google Scholar, CINAHL, Ovid, and EMBASE using the terms FOLFOXIRI and bevacizumab and (colorectal cancer). Study Selection Clinical trials, retrospective case series, and prospective case series that used FOLFOXIRI-Bev for the treatment of initially unresectable metastatic colorectal cancer in humans were included. Individual case reports and retrospective case series with fewer than 10 patients were excluded. Data Extraction and Synthesis Data were extracted independently by 2 reviewers on a predesigned, standardized form. Ultimately, data were aggregated to obtain the pooled effect size of efficacy, according to the random-effects model and weighted for the number of patients included in each trial. Main Outcomes and Measures Median overall survival and progression-free survival, overall response rates, and rates of R0 surgical conversions and overall surgical conversions. Results Eleven FOLFOXIRI-Bev studies published between 2010 and 2016 met the inclusion criteria and were pooled for analysis. The studies included 889 patients, with 877 patients clinically evaluable for overall response rates. The objective response rate to FOLFOXIRI-Bev was 69% (95% CI, 65%-72%; I2 = 25%). The rate of overall surgical conversions was 39.1% (95% CI, 26.9%-52.8%), and the rate of R0 surgical conversions was 28.1% (95% CI, 18.1%-40.8%). Median pooled overall survival was 30.2 months (95% CI, 26.5-33.7 months) in 6 trials with data available, and progression-free survival was 12.4 months (95% CI, 10.0-14.3 months) in 9 trials with data available. In meta-regression analysis, variables significantly associated with conversion surgery were disease limited to the liver and a higher median number of cycles (close to 12). Conclusions and Relevance For patients with surgically unresectable metastatic colorectal cancer, FOLFOXIRI-Bev is associated with a significant overall response rate. Such an effective regimen leads to a probability of surgical conversion of distant metastases approaching 40%, with more than one-fourth of patients having an R0 resection.