From Diagnostic-Therapeutic Pathways to Real-World Data: A Multicenter Prospective Study on Upfront Treatment for EGFR-Positive Non-Small Cell Lung Cancer (MOST Study).

INTRODUCTION: Gefitinib, erlotinib, and afatinib represent the approved first-line options for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Because pivotal trials frequently lack external validity, real-world data may help to depict the diagnostic-therapeutic pathway and treatment outcome in clinical practice. METHODS: MOST is a multicenter observational study promoted by the Veneto Oncology Network, aiming at monitoring the diagnostic-therapeutic pathway of patients with nonsquamous EGFR-mutant NSCLC. We reported treatment outcome in terms of median time to treatment failure (mTTF) and assessed the impact of each agent on the expense of the regional health system, comparing it with a prediction based on the pivotal trials. RESULTS: An EGFR mutation test was performed in 447 enrolled patients, of whom 124 had EGFR mutation and who received gefitinib (n = 69, 55%), erlotinib (n = 33, 27%), or afatinib (n = 22, 18%) as first-line treatment. Because erlotinib was administered within a clinical trial to 15 patients, final analysis was limited to 109 patients. mTTF was 15.3 months, regardless of the type of tyrosine kinase inhibitor (TKI) used. In the MOST study, the budget impact analysis showed a total expense of €3,238,602.17, whereas the cost estimation according to median progression-free survival from pivotal phase III trials was €1,813,557.88. CONCLUSION: Good regional adherence and compliance to the diagnostic-therapeutic pathway defined for patients with nonsquamous NSCLC was shown. mTTF did not significantly differ among the three targeted TKIs. Our budget impact analysis suggests the potential application of real-world data in the process of drug price negotiation. IMPLICATIONS FOR PRACTICE: The MOST study is a real-world data collection reporting a multicenter adherence and compliance to diagnostic-therapeutic pathways defined for patients with epidermal growth factor receptor-mutant non-small cell lung cancer. This represents an essential element of evidence-based medicine, providing information on patients and situations that may be challenging to assess using only data from randomized controlled trials, e.g., turn-around time of diagnostic tests, treatment compliance and persistence, guideline adherence, challenging-to-treat populations, drug safety, comparative effectiveness, and cost effectiveness. This study may be of interest to various stakeholders (patients, clinicians, and payers), providing a meaningful picture of the value of a given therapy in routine clinical practice.

Second-line systemic therapy for metastatic colorectal cancer.

BACKGROUND: The therapeutic management of people with metastatic colorectal cancer (CRC) who did not respond to first-line treatment represents a formidable challenge. OBJECTIVES: To determine the efficacy and toxicity of second-line systemic therapy in people with metastatic CRC. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 4), Ovid MEDLINE (1950 to May 2016), Ovid MEDLINE In-process & Other Non-Indexed Citations (1946 to May 2016) and Ovid Embase (1974 to May 2016). There were no language or date of publication restrictions. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the efficacy (survival, tumour response) and toxicity (incidence of severe adverse effects (SAEs)) of second-line systemic therapy (single or combined treatment with any anticancer drug, at any dose and number of cycles) in people with metastatic CRC that progressed, recurred or did not respond to first-line systemic therapy. DATA COLLECTION AND ANALYSIS: Authors performed a descriptive analysis of each included RCT in terms of primary (survival) and secondary (tumour response, toxicity) endpoints. In the light of the variety of drug regimens tested in the included trials, we could carry out meta-analysis considering classes of (rather than single) anticancer regimens; to this aim, we applied the random-effects model to pool the data. We used hazard ratios (HRs) and risk ratios (RRs) to describe the strength of the association for survival (overall (OS) and progression-free survival (PFS)) and dichotomous (overall response rate (ORR) and SAE rate) data, respectively, with 95% confidence intervals (CI). MAIN RESULTS: Thirty-four RCTs (enrolling 13,787 participants) fulfilled the eligibility criteria. Available evidence enabled us to address multiple clinical issues regarding the survival effects of second-line systemic therapy of people with metastatic CRC.1. Chemotherapy (irinotecan) was more effective than best supportive care (HR for OS: 0.58, 95% CI 0.43 to 0.80; 1 RCT; moderate-quality evidence); 2. modern chemotherapy (FOLFOX (5-fluorouracil plus leucovorin plus oxaliplatin), irinotecan) is more effective than outdated chemotherapy (5-fluorouracil) (HR for PFS: 0.59, 95% CI 0.49 to 0.73; 2 RCTs; high-quality evidence) (HR for OS: 0.69, 95% CI 0.51 to 0.94; 1 RCT; moderate-quality evidence); 3. irinotecan-based combinations were more effective than irinotecan alone (HR for PFS: 0.68, 95% CI 0.60 to 0.76; 6 RCTs; moderate-quality evidence); 4. targeted agents improved the efficacy of conventional chemotherapy both when considered together (HR for OS: 0.84, 95% CI 0.77 to 0.91; 6 RCTs; high-quality evidence) and when bevacizumab was used alone (HR for PFS: 0.67, 95% CI 0.60 to 0.75; 4 RCTs; high-quality evidence).With regard to secondary endpoints, tumour response rates generally paralleled the survival results; moreover, higher anticancer efficacy was generally associated with worse treatment-related toxicity, with the important exception of bevacizumab-containing regimens, where the addition of the targeted agent to chemotherapy did not result in a significant increase in the rate of SAE. Finally, we found that oral (instead of intravenous) fluoropyrimidines significantly reduced the incidence of adverse effects (without compromising efficacy) in people treated with oxaliplatin-based regimens.We could not draw any conclusions on other debated aspects in this field of oncology, such as ranking of treatments (not all possible comparisons have been tested and many comparisons were based on single trials enrolling a small number of participants) and quality of life (virtually no data available). AUTHORS' CONCLUSIONS: Systemic therapy offers a survival benefit to people with metastatic CRC who did not respond to first-line treatment, especially when targeted agents are combined with conventional chemotherapeutic drugs. Further research is needed to define the optimal regimen and to identify people who most benefit from each treatment.

Tumour markers and FDG PET/CT for prediction of disease relapse in patients with breast cancer.

PURPOSE: The aim of the study was to assess the role of CA 15.3, CT and positron emission tomography (PET)/CT in patients with breast cancer and suspected disease relapse after primary treatment. METHODS: We studied 111 consecutive patients (mean age 61 ± 12 years) with previous breast cancer, already treated and with clinical or biochemical suspicion of disease relapse. All patients underwent CT and (18)F-fluorodeoxyglucose (FDG) PET/CT. In all patients, the value of CA 15.3 was compared to PET/CT and CT. The final diagnosis of relapse was established by invasive and noninvasive follow-up and was compared with CA 15.3, CT and PET/CT results. Univariate and multivariate analyses were used to identify the independent predictors of disease relapse and receiver-operating characteristic (ROC) curve for the identification of optimal CA 15.3 cutoff. RESULTS: Of all patients, 40 (36%) showed an increased CA 15.3 value, CT was positive in 73 (66%), whereas at PET/CT imaging 64 (58%) showed positive findings for disease relapse. Of 40 patients with increased marker levels, 22 patients had positive CT and 30 positive PET/CT (55 vs 75%, p < 0.001). At the end of follow-up, recurrence occurred in 32 (29%) patients, 16 (50%) of whom showed high levels of CA 15.3. PET/CT predicted relapse in 26 (81%) patients, whereas CT correctly identified 23 (72%). At univariate analysis, recurrence was significantly associated with high CA 15.3 values (p < 0.05) and positive PET/CT (p < 0.005). At multivariable analysis only positive PET/CT remained an independent predictor of disease relapse (p < 0.05). ROC analysis showed an optimal cutoff point for CA 15.3 of 19.1 U/ml (AUC 0.65, p < 0.01) to individuate positive PET/CT. CONCLUSION: FDG PET/CT is more sensitive than CT and CA 15.3 in the evaluation of disease relapse. PET/CT might be considered a complementary imaging technique during follow-up in patients with breast cancer.

Synchronous and Metachronous Breast and Ovarian Cancer: Experience From Two Large Cancer Center.

PURPOSE: We aimed to evaluate the clinico-pathological characteristics and survival outcomes of patients with synchronous or metachronous breast cancer (BC) and ovarian cancer (OC). MATERIALS AND METHODS: Patients with synchronous or metachronous BC and OC were retrospectively identified at two large cancer centers. Clinico-pathological characteristics, BRCA1/2 status and follow-up data were gathered. Patients were classified according to the first cancer diagnosis in the following groups: Breast Cancer first, Ovarian Cancer first, Synchronous Breast and Ovarian Cancer. Overall survival (OS) was calculated as the time interval between each cancer diagnosis to death or last follow-up. RESULTS: Overall, 270 patients were included: n = 194 (72%) in BC first group, n = 51 (19%) in OC first, and n = 25 (9%) in synchronous. BRCA status was available for 182 (67.4%) patients and 112 (62%) harbored pathogenetic mutations. BC first group included more frequently patients with BRCA mutation, triple negative BC phenotype and more aggressive OC features. Median time between the two diagnosis was longer in BC first group vs OC first group (95 vs 68 months, p = 0.021). A total of 105 OS events occurred, mostly related to OC (70.5%). We observed no differences in terms of OS according to the first cancer diagnosis. Age >50 years and advanced OC stage were negative independent prognostic factors for OS from the first diagnosis. CONCLUSIONS: In this cohort of patients with BC and OC, survival was dominated by OC related mortality. These data may be useful to plan and carry out adequate and timely surveillance programs and preventive measures.

Effect of BRCA germline mutations on breast cancer prognosis: A systematic review and meta-analysis.

BACKGROUND: The contribution of BRCA germline mutational status to breast cancer patients' prognosis is unclear. We aimed to systematically review and perform meta-analysis of the available evidence of effects of BRCA germline mutations on multiple survival outcomes of breast cancer patients as a whole and in specific subgroups of interest, including those with triple negative breast cancer, those with Ashkenazi Jewish ancestry, and patients with stage I-III disease. METHODS: Sixty studies met all inclusion criteria and were considered for this meta-analysis. These studies involved 105,220 breast cancer patients, whose 3588 (3.4%) were BRCA mutations carriers. The associations between BRCA genes mutational status and overall survival (OS), breast cancer-specific survival (BCSS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) were evaluated using random-effect models. RESULTS: BRCA1 mutation carriers have worse OS than BRCA-negative/sporadic cases (hazard ratio, HR 1.30, 95% CI: 1.11-1.52) and worse BCSS than sporadic/BRCA-negative cases among patients with stage I-III breast cancer (HR 1.45, 95% CI: 1.01-2.07). BRCA2 mutation carriers have worse BCSS than sporadic/BRCA-negative cases (HR 1.29, 95% CI: 1.03-1.62), although they have similar OS. Among triple negative breast cancer, BRCA1/2 mutations carriers had better OS than BRCA-negative counterpart (HR 0.49, 95% CI: 0.26-0.92). Among Ashkenazi Jewish women, BRCA1/2 mutations carriers presented higher risk of death from breast cancer (HR 1.44, 95% CI: 1.05-1.97) and of distant metastases (HR 1.82, 95% CI: 1.05-3.16) than sporadic/BRCA-negative patients. CONCLUSION: Our results support the evaluation of BRCA mutational status in patients with high risk of harboring BRCA germline mutations to better define the prognosis of breast cancer in these patients.

Intraperitoneal Chemotherapy in Patients Pretreated for Ovarian Cancer Matched with Patients Treated with Parenteral Chemotherapy.

BACKGROUND: Our aim was to analyze the impact of intraperitoneal chemotherapy (IPC), administered with direct peritoneal puncture, on the survival of patients with pretreated ovarian cancer in a real-life setting. PATIENTS AND METHODS: This was a retrospective study comparing patients with advanced ovarian cancer treated with IPC (N=33) and patients treated with standard intravenous (i.v.) chemotherapy matching cases for known prognostic factors (age, platinum sensitivity, histological subgroup and grade). Data were then analyzed for survival with nested Cox multivariate regression. RESULTS: The case matching resulted in two homogeneous cohorts by age, platinum sensitivity, resistance to therapy and histology. When analyzed by hazard ratio (HR), the number of previous treatments and IPC vs. i.v. therapy were significant (HR=1.97 for i.v. and HR=1.90 for each incremental previous treatment line, multivariate p<0.001). When analyzing the patients with fewer than three previous treatment lines, IPC conferred a survival advantage of about 2.2 months (IPC=10.0 vs. i.v.=7.8 months, p=0.011). However, the survival advantage in heavily pre-treated patients (with three or more previous treatments) was not significant. One case, pre-treated with more lines of chemotherapy, with renal failure after intraperitoneal cisplatin was followed by death. None of the patients had bowel sub-occlusions and we recorded a lower incidence of local toxicity, such as cellulite, with IPC (two out of 33 cases). Two patients thereafter refused IPC due to abdominal pain. CONCLUSION: Our findings confirm that IPC is an effective approach compared to systemic chemotherapy for advanced ovarian cancer, even in pre-treated patients, including platinum-resistant cases. The survival benefit appears to be confined to non-heavily treated patients. Overall, direct intraperitoneal drug injection (without permanent devices) appears to be feasible, safe and possibly advantageous.

Heterogeneity in hormone-receptor status and survival outcomes among women with synchronous and metachronous bilateral breast cancers.

To examine whether discordance in the hormone-receptor status predicts clinical outcomes in patients with bilateral synchronous (SBC) or metachronous breast cancer (MBC), we analyzed data from the Surveillance, Epidemiology, and End Results program (1998-2011) using Cox models. After excluding 10,231 patients with missing data on hormone receptors in at least one tumor, 4403 SBC and 7159 MBC were included in the study. Among SBC cases, patients with estrogen receptor (ER)-discordant tumors had higher mortality risk (multivariable-adjusted hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.60-2.40) than patients with ER concordant-positive tumors, whereas patients with ER concordant-negative tumors had the highest risk (HR = 2.49, 95% CI 2.03-3.07). Among MBC cases, patients with a positive-to-negative change in ER status (HR = 1.32, 95% CI: 1.08-1.62) or ER concordant-negative tumors (HR = 1.48, 95% CI: 1.19-1.85) had worse survival than patients with ER concordant-positive tumors. In conclusion, discordance in the hormone-receptor status was an independent predictor of survival outcomes.

Trabectedin plus pegylated liposomal doxorubicin: retrospective analysis in heavily pretreated platinum-sensitive ovarian cancer.

PURPOSE: This retrospective analysis evaluated treatment with trabectedin plus pegylated liposomal doxorubicin (PLD) in 34 heavily pretreated patients (median number of previous lines, 3; range, 2-10) with platinum-sensitive relapsed ovarian cancer (ROC) at a single center in Italy. METHODS: Trabectedin/PLD treatment consisted of trabectedin administered every 3 weeks as a 3-hour intravenous (i.v.) infusion at a dose of 1.1 mg/m2, immediately after PLD 30 mg/m2 i.v. infusion. Study objectives were the evaluation of the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Three complete responses and 8 partial responses were observed, with an ORR of 32.4% (95% CI, 17.4-50.5%). Median PFS was 6.1 months (95% CI, 4.4-8.9 months). Median OS was 16.3 months (95% CI, 6.8-23.5). Most responses (9 of 11) were found in patients with partially platinum-sensitive disease (ORR 40.9% in this subset; median PFS 6.8 months and median OS 20.8 months). Grade 3 treatment-related adverse events consisted of nausea/vomiting (n = 5; 14.7%), mucositis (n = 2; 5.9%), alanine aminotransferase increase, anemia and neutropenia (n = 1 each; 2.9%). CONCLUSIONS: The overall findings appear consistent with those previously observed in a randomized controlled clinical trial, and support the use of trabectedin/PLD in heavily pretreated patients with platinum-sensitive ROC, especially those with partially platinum-sensitive disease.

Could the serial determination of Ca15.3 serum improve the diagnostic accuracy of PET/CT?: results from small population with previous breast cancer.

OBJECTIVES: A single value of tumor marker elevation is not used for the diagnosis of breast cancer (BC) relapse, whereas the serial measurements which confirm a persistent Ca15.3 increase can represent an early signal of tumor relapse, even if described in asymptomatic patients without any other clinical or instrumental signs of cancer. The aim of this study was to assess the relationship between serial measures of Ca15.3 and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) findings in patients with already treated BC during follow-up. METHODS: We retrospectively selected 60 patients (mean age 62 ± 11 years) with previous history of BC, already treated with surgery and other treatments. Three serial measures of Ca15.3 were collected within 1 year before PET/CT examination, respectively, at 12-9 months (297 ± 30 days), 9-3 months (154 ± 51 days) and 3-0 months (46 ± 28 days). Clinical outcome or imaging follow-up data were used to define disease relapse. The increase in tumor marker value was compared with PET/CT results and disease relapse. Coefficient of variation (CV) and ROC curves were used. Disease-free survival (DFS) curves were computed by Kaplan-Meier method. RESULTS: PET/CT was negative in 36 (60%) and positive in 24 (40%) patients. The median time between initial treatment and PET/CT was 3 years. CV of the Ca15.3 serial determinations was significantly higher in patients with positive than negative PET/CT (39 vs. 24%, p < 0.05). Disease relapse was found in 25 (42%) patients, of these 21 (88%) had positive PET/CT. ROC analyses showed that an increase of Ca15.3 between the 2nd and 3rd measures have better individuated positive PET/CT and disease relapse (AUC 0.65 and 0.64, respectively; p < 0.05). DFS was higher in patients with negative than positive PET/CT (65 vs. 15%, p < 0.05). CONCLUSIONS: Serial increase of Ca15.3 could be considered optimal to address FDG PET/CT examination during BC patients follow-up. PET/CT performed just on time might allow, earlier and with higher diagnostic accuracy, the detection of disease relapse in BC patients.