Gastric cancer molecular classification and adjuvant therapy: Is there a different benefit according to the subtype?

BACKGROUND: Gastric cancer (GC) has been defined in distinct molecular subtypes with different therapeutic implications. However, its clinical significance and prognosis regarding standard chemotherapy (CMT) remains unclear. This study aimed to analyze the impact of perioperative or adjuvant treatment among subtypes of GC. METHODS: We retrospectively evaluated all stage II/III patients with GC who underwent a curative gastrectomy. Based on immunohistochemistry and in situ hybridization techniques, GC was classified into five subtypes: Epstein-Barr virus (EBV) positive, microsatellite instability (MSI), e-cadherin aberrant, p53-aberrant, and p53-normal. RESULTS: Among the 178 CG included, 111 patients received CMT and 67 were treated with surgery alone. Survival analysis showed that p53-aberrant GC treated with CMT had better disease-free survival (DFS) compared with surgery alone (P = .001).There was no significant difference in DFS between patients who received CMT and those with surgery alone for EBV, MSI, E-cadherin, and p53-normal GC. An improvement in overall survival was observed only for E-cadherin (P = .001) and p53-aberrant (P < .001) patients who received CMT. CONCLUSIONS: CMT showed different impact on the survival of CG according to the molecular subtype. No survival benefit was observed for EBV and MSI groups who received CMT. GC with p53-aberrant had a significant benefit in survival with standard therapy.

Cisplatin versus carboplatin in combination with third-generation drugs for advanced non-small cell lung cancer.

BACKGROUND: Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death in both sexes worldwide. Approximately 50% of those diagnosed with lung cancer will have locally advanced or metastatic disease and will be treated in a palliative setting. Platinum-based combination chemotherapy has benefits in terms of survival and symptom control when compared with best supportive care. OBJECTIVES: To assess the effectiveness and safety of carboplatin-based chemotherapy when compared with cisplatin-based chemotherapy, both in combination with a third-generation drug, in people with advanced non-small cell lung cancer (NSCLC). To compare quality of life in people with advanced NSCLC receiving chemotherapy with cisplatin and carboplatin combined with a third-generation drug. SEARCH METHODS: We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; 13 January 2019), MEDLINE (via PubMed) (1966 to 13 January 2019), and Embase (via Ovid) (1974 to 13 January 2019). In addition, we handsearched the proceedings of the American Society of Clinical Oncology Meetings (January 1990 to September 2018) and reference lists from relevant resources. SELECTION CRITERIA: Randomised clinical trials (RCTs) comparing regimens with carboplatin or cisplatin combined with a third-generation drug in people with locally advanced or metastatic NSCLC. We accepted any regimen and number of cycles that included these drugs, since there is no widely accepted standard regimen. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the search results, and a third review author resolved any disagreements. The primary outcomes were overall survival and health-related quality of life. The secondary outcomes were one-year survival rate, objective response rate and toxicity. MAIN RESULTS: In this updated review, we located one additional RCT, for a total of 11 included RCTs (5088 participants, 4046 of whom were available for meta-analysis). There was no difference in overall survival (hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.82 to 1.20; 10 RCTs; 2515 participants; high-quality evidence); one-year survival rate (risk ratio (RR) 0.98, 95% CI 0.89 to 1.08; I2 = 17%; 4004 participants; all 11 RCTs; high-quality evidence); or response rate (RR 0.89, 95% CI 0.79 to 1.00; I2 = 12%; all 11 RCTs; 4020 participants; high-quality evidence). A subgroup analysis comparing carboplatin with different doses of cisplatin found an overall survival benefit in favour of carboplatin-based regimens when compared to cisplatin at lower doses (40 to 80 mg/m2) (HR 1.15, 95% CI 1.03 to 1.28; 6 RCTs; 2508 participants), although there was no overall survival benefit when carboplatin-based chemotherapy was compared to cisplatin at higher doses (80 to 100 mg/m2) (HR 0.93, 95% CI 0.83 to 1.04; I2 = 0%; 4 RCTs; 1823 participants). Carboplatin caused more thrombocytopenia (RR 2.46, 95% CI 1.49 to 4.04; I2 = 68%; 10 RCTs; 3670 participants) and was associated with more neurotoxicity (RR 1.42, 95% CI 0.91 to 2.23; I2 = 0%, 5 RCTs; 1489 participants), although we believe this last finding is probably related to a confounding factor (higher dose of paclitaxel in the carboplatin-containing treatment arm of a large study included in the analysis). There was no statistically significant difference in renal toxicity (RR 0.52, 95% CI 0.19 to 1.45; I2 = 3%; 3 RCTs; 1272 participants); alopecia (RR 1.11, 95% CI 0.73 to 1.68; I2 = 0%; 2 RCTs; 300 participants); anaemia (RR 1.37, 95% CI 0.79 to 2.38; I2 = 77%; 10 RCTs; 3857 participants); and neutropenia (RR 1.18, 95% CI 0.85 to 1.63; I2 = 94%; 10 RCTs; 3857 participants) between cisplatin-based chemotherapy and carboplatin-based chemotherapy regimens. Two RCTs performed a health-related quality of life analysis; however, as they used different methods of measurement we were unable to perform a meta-analysis. One RCT reported comparative health-related quality of life data between cisplatin and carboplatin-containing arms but found no significant differences in global indices of quality of life, including global health status or functional scales. In this Cochrane review, we found that the quality of evidence was high for overall survival, one-year survival rate and response rate but moderate quality evidence for the other outcomes measured. AUTHORS' CONCLUSIONS: Advanced NSCL patients treated with carboplatin or cisplatin doublet with third-generation chemotherapy drugs showed equivalent overall survival, one-year survival, and response rate. Regarding adverse events, carboplatin caused more thrombocytopenia, and cisplatin caused more nausea/vomiting. Therefore, in this palliative therapeutic intent, the choice of the platin compound should take into account the expected toxicity profile, patient's comorbidities and preferences.

Nipple- and areola-sparing mastectomy for the treatment of breast cancer.

BACKGROUND: The efficacy and safety of nipple-sparing mastectomy and areola-sparing mastectomy for the treatment of breast cancer are still questionable. It is estimated that the local recurrence rates following nipple-sparing mastectomy are very similar to breast-conserving surgery followed by radiotherapy. OBJECTIVES: To assess the efficacy and safety of nipple-sparing mastectomy and areola-sparing mastectomy for the treatment of ductal carcinoma in situ and invasive breast cancer in women. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's Specialized Register, the Cochrane Center Register of Controlled Trials (CENTRAL), MEDLINE (via PubMed), Embase (via OVID) and LILACS (via Biblioteca Virtual em Saúde [BVS]) using the search terms "nipple sparing mastectomy" and "areola-sparing mastectomy". Also, we searched the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov. All searches were conducted on 30th September 2014 and we did not apply any language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) however if there were no RCTs, we expanded our criteria to include non-randomised comparative studies (cohort and case-control studies). Studies evaluated nipple-sparing and areola-sparing mastectomy compared to modified radical mastectomy or skin-sparing mastectomy for the treatment of ductal carcinoma in situ or invasive breast cancer. DATA COLLECTION AND ANALYSIS: Two review authors (BS and RR) performed data extraction and resolved disagreements. We performed descriptive analyses and meta-analyses of the data using Review Manager software. We used Cochrane's risk of bias tool to assess studies, and adapted it for non-randomised studies, and we evaluated the quality of the evidence using GRADE criteria. MAIN RESULTS: We included 11 cohort studies, evaluating a total of 6502 participants undergoing 7018 procedures: 2529 underwent a nipple-sparing mastectomy (NSM), 818 underwent skin-sparing mastectomy (SSM) and 3671 underwent traditional mastectomy, also known as modified radical mastectomy (MRM). No participants underwent areola-sparing mastectomy. There was a high risk of confounding for all reported outcomes. For overall survival, the hazard ratio (HR) for NSM compared to SSM was 0.70 (95% CI 0.28 to 1.73; 2 studies; 781 participants) and the HR for NSM compared to MRM was 0.72 (95% CI 0.46 to 1.13; 2 studies, 1202 participants). Local recurrence was evaluated in two studies, the HR for NSM compared to MRM was 0.28 (95% CI 0.12 to 0.68; 2 studies, 1303 participants). The overall risk of complications was different in NSM when compared to other types of mastectomy in general (RR 0.10, 95% CI 0.01 to 0.82, 2 studies, P = 0.03; 1067 participants). With respect to skin necrosis, there was no evidence of a difference with NSM compared to other types of mastectomy, but the confidence interval was wide (RR 4.22, 95% CI 0.59 to 30.03, P = 0.15; 4 studies, 1948 participants). We observed no difference among the three types of mastectomy with respect to the risk of local infection (RR 0.95, 95% CI 0.44 to 2.09, P = 0.91, 2 studies; 496 participants). Meta-analysis was not possible when assessing cosmetic outcomes and quality of life, but in general the NSM studies reported a favourable aesthetic result and a gain in quality of life compared with the other types of mastectomy. The quality of evidence was considered very low for all outcomes due to the high risk of selection bias and wide confidence intervals. AUTHORS' CONCLUSIONS: The findings from these observational studies of very low-quality evidence were inconclusive for all outcomes due to the high risk of selection bias.

Chemotherapy for advanced non-small cell lung cancer in the elderly population.

BACKGROUND: Approximately 50% of patients with newly diagnosed non-small cell lung cancer (NSCLC) are over 70 years of age at diagnosis. Despite this fact, these patients are underrepresented in randomized controlled trials (RCTs). As a consequence, the most appropriate regimens for these patients are controversial, and the role of single-agent or combination therapy is unclear. In this setting, a critical systematic review of RCTs in this group of patients is warranted. OBJECTIVES: To assess the effectiveness and safety of different cytotoxic chemotherapy regimens for previously untreated elderly patients with advanced (stage IIIB and IV) NSCLC. To also assess the impact of cytotoxic chemotherapy on quality of life. SEARCH METHODS: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (1966 to 31 October 2014), EMBASE (1974 to 31 October 2014), and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 31 October 2014). In addition, we handsearched the proceedings of major conferences, reference lists from relevant resources, and the ClinicalTrial.gov database. SELECTION CRITERIA: We included only RCTs that compared non-platinum single-agent therapy versus non-platinum combination therapy, or non-platinum therapy versus platinum combination therapy in patients over 70 years of age with advanced NSCLC. We allowed inclusion of RCTs specifically designed for the elderly population and those designed for elderly subgroup analyses. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results, and a third review author resolved disagreements. We analyzed the following endpoints: overall survival (OS), one-year survival rate (1yOS), progression-free survival (PFS), objective response rate (ORR), major adverse events, and quality of life (QoL). MAIN RESULTS: We included 51 trials in the review: non-platinum single-agent therapy versus non-platinum combination therapy (seven trials) and non-platinum combination therapy versus platinum combination therapy (44 trials). Non-platinum single-agent versus non-platinum combination therapy Low-quality evidence suggests that these treatments have similar effects on overall survival (hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.72 to 1.17; participants = 1062; five RCTs), 1yOS (risk ratio (RR) 0.88, 95% CI 0.73 to 1.07; participants = 992; four RCTs), and PFS (HR 0.94, 95% CI 0.83 to 1.07; participants = 942; four RCTs). Non-platinum combination therapy may better improve ORR compared with non-platinum single-agent therapy (RR 1.79, 95% CI 1.41 to 2.26; participants = 1014; five RCTs; low-quality evidence).Differences in effects on major adverse events between treatment groups were as follows: anemia: RR 1.10, 95% 0.53 to 2.31; participants = 983; four RCTs; very low-quality evidence; neutropenia: RR 1.26, 95% CI 0.96 to 1.65; participants = 983; four RCTs; low-quality evidence; and thrombocytopenia: RR 1.45, 95% CI 0.73 to 2.89; participants = 914; three RCTs; very low-quality evidence. Only two RCTs assessed quality of life; however, we were unable to perform a meta-analysis because of the paucity of available data. Non-platinum therapy versus platinum combination therapy Platinum combination therapy probably improves OS (HR 0.76, 95% CI 0.69 to 0.85; participants = 1705; 13 RCTs; moderate-quality evidence), 1yOS (RR 0.89, 95% CI 0.82 to 0.96; participants = 813; 13 RCTs; moderate-quality evidence), and ORR (RR 1.57, 95% CI 1.32 to 1.85; participants = 1432; 11 RCTs; moderate-quality evidence) compared with non-platinum therapies. Platinum combination therapy may also improve PFS, although our confidence in this finding is limited because the quality of evidence was low (HR 0.76, 95% CI 0.61 to 0.93; participants = 1273; nine RCTs).Effects on major adverse events between treatment groups were as follows: anemia: RR 2.53, 95% CI 1.70 to 3.76; participants = 1437; 11 RCTs; low-quality evidence; thrombocytopenia: RR 3.59, 95% CI 2.22 to 5.82; participants = 1260; nine RCTs; low-quality evidence; fatigue: RR 1.56, 95% CI 1.02 to 2.38; participants = 1150; seven RCTs; emesis: RR 3.64, 95% CI 1.82 to 7.29; participants = 1193; eight RCTs; and peripheral neuropathy: RR 7.02, 95% CI 2.42 to 20.41; participants = 776; five RCTs; low-quality evidence. Only five RCTs assessed QoL; however, we were unable to perform a meta-analysis because of the paucity of available data. AUTHORS' CONCLUSIONS: In people over the age of 70 with advanced NSCLC who do not have significant co-morbidities, increased survival with platinum combination therapy needs to be balanced against higher risk of major adverse events when compared with non-platinum therapy. For people who are not suitable candidates for platinum treatment, we have found low-quality evidence suggesting that non-platinum combination and single-agent therapy regimens have similar effects on survival. We are uncertain as to the comparability of their adverse event profiles. Additional evidence on quality of life gathered from additional studies is needed to help inform decision making.

Cisplatin versus carboplatin in combination with third-generation drugs for advanced non-small cell lung cancer.

BACKGROUND: An estimated 220,000 new cases of non-small cell lung cancer (NSCLC) and 160,000 deaths are expected to occur in the US in 2013, representing about 28% of cancer-related mortality. Approximately 75% of these people will have locally advanced or metastatic disease and will be treated in a palliative setting. Platinum-based combination chemotherapy has benefits in terms of survival and symptom control when compared with best supportive care. OBJECTIVES: To assess the efficacy and safety of carboplatin-based chemotherapy when compared with cisplatin-based chemotherapy, both in combination with a third-generation drug, in people with advanced NSCLC. To compare quality of life in people with advanced NSCLC receiving chemotherapy with cisplatin and carboplatin combined with a third-generation drug. SEARCH METHODS: We searched the following electronic databases: MEDLINE (via PubMed) (1966 to 6 March 2013), EMBASE (via Ovid) (1974 to 6 March 2013), Cochrane Central Register of Controlled Trials (CENTRAL; Issue 2, 2013), and LILACS (1982 to 6 March 2013). In addition, we handsearched the proceedings of the American Society of Clinical Oncology Meetings (January 1990 to March 2013), reference lists from relevant resources and the Clinical Trial.gov database. SELECTION CRITERIA: Randomised clinical trials comparing regimens with carboplatin or cisplatin combined with a third-generation drug in people with locally advanced or metastatic NSCLC. We accepted any regimen and number of cycles that included these drugs, since there is no widely accepted standard regimen. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results and a third review author resolved any disagreements. We analysed the following endpoints: overall survival, one-year survival, quality of life, toxicity and response rate. MAIN RESULTS: We included 10 trials with 5017 people, 3973 of whom were available for meta-analysis. There was no difference between carboplatin-based and cisplatin-based chemotherapy in overall survival (hazard ratio (HR) 1.00; 95% confidence interval (CI) 0.51 to 1.97, I(2) = 0%) and one-year survival rate (risk ratio (RR) 0.98; 95% CI 0.88 to 1.09, I(2) = 24%). Cisplatin had higher response rates when we performed an overall analysis (RR 0.88; 95% CI 0.79 to 0.99, I(2) = 3%), but trials using paclitaxel or gemcitabine plus a platin in both arms had equivalent response rates (paclitaxel: RR 0.89; 95% CI 0.74 to 1.07, I(2) = 0%; gemcitabine: RR 0.92; 95% CI 0.73 to 1.16, I(2) = 34%). Cisplatin caused more nausea or vomiting, or both (RR 0.46; 95% CI 0.32 to 0.67, I(2) = 53%) and carboplatin caused more thrombocytopenia (RR 2.00; 95% CI 1.37 to 2.91, I(2) = 21%) and neurotoxicity (RR 1.55; 95% CI 1.06 to 2.27, I(2) = 0%). There was no difference in the incidence of grade III/IV anaemia (RR 1.06; 95% CI 0.79 to 1.43, I(2) = 20%), neutropenia (RR 0.96; 95% CI 0.85 to 1.08, I(2) = 49%), alopecia (RR 1.11; 95% CI 0.73 to 1.68, I(2) = 0%) or renal toxicity (RR 0.52; 95% CI 0.19 to 1.45, I(2) = 3%). Two trials performed a quality of life analysis; however, they used different methods of measurement so we could not perform a meta-analysis. AUTHORS' CONCLUSIONS: The initial treatment of people with advanced NSCLC is palliative, and carboplatin can be a treatment option. It has a similar effect on survival but a different toxicity profile when compared with cisplatin. Therefore, the choice of the platin compound should take into account the expected toxicity profile and the person's comorbidities. In addition, when used with either paclitaxel or gemcitabine, the drugs had an equivalent response rate.

Low-energy amplitude-modulated electromagnetic field exposure: Feasibility study in patients with hepatocellular carcinoma.

BACKGROUND: Patients with advanced hepatocellular carcinoma (HCC) and poor liver function lack effective systemic therapies. Low-energy electromagnetic fields (EMFs) can influence cell biological processes via non-thermal effects and may represent a new treatment option. METHODS: This single-site feasibility trial enrolled patients with advanced HCC, Child-Pugh A and B, Eastern Cooperative Oncology Group 0-2. Patients underwent 90-min amplitude-modulated EMF exposure procedures every 2-4 weeks, using the AutEMdev (Autem Therapeutics). Patients could also receive standard care. The primary endpoints were safety and the identification of hemodynamic variability patterns. Exploratory endpoints included health-related quality of life (HRQoL), overall survival (OS). and objective response rate (ORR) using RECIST v1.1. RESULTS: Sixty-six patients with advanced HCC received 539 AutEMdev procedures (median follow-up, 30 months). No serious adverse events occurred during procedures. Self-limiting grade 1 somnolence occurred in 78.7% of patients. Hemodynamic variability during EMF exposure was associated with specific amplitude-modulation frequencies. HRQoL was maintained or improved among patients remaining on treatment. Median OS was 11.3 months (95% confidence interval [CI]: 6.0, 16.6) overall (16.0 months [95% CI: 4.4, 27.6] and 12.0 months [6.4, 17.6] for combination therapy and monotherapy, respectively). ORR was 24.3% (32% and 17% for combination therapy and monotherapy, respectively). CONCLUSION: AutEMdev EMF exposure has an excellent safety profile in patients with advanced HCC. Hemodynamic alterations at personalized frequencies may represent a surrogate of anti-tumor efficacy. NCT01686412.