Moderate Survival Benefit Research Articles

Clinical outcome and prognostic factors for immunotherapy-based treatments in patients with platinum-refractory germ cell tumor

BackgroundGerm cell tumors (GCTs) are a heterogeneous group of cancers associated with a favorable prognosis when treated with platinum-based chemotherapy. However, patients with platinum-refractory GCTs face limited options and poorer outcomes, necessitating innovative treatment approaches. This study aims to evaluate the clinical outcomes and identify prognostic factors associated with immunotherapy-based treatments in this challenging patient population. MethodsThis retrospective analysis included individuals with platinum-refractory GCTs treated with immunotherapy between 2017 and 2023. Clinical outcomes, safety, and biomarkers were analyzed. ResultsThe study included 37 male patients with a median age of 26 years (range: 18–65). The overall response rate was 24.32 %, with a median progression-free survival (PFS) and overall survival (OS) of 4.67 months and 22.67 months, respectively. Patients with both serum levels of alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) below 100 (AFP & hCG < 100) demonstrated significantly better PFS and OS. Multivariate analysis indicated that lower serum tumor marker levels (AFP & hCG < 100) and treatment initiation at earlier lines were significantly associated with improved PFS. Notably, genomic analysis revealed that one patient with an MDM4 mutation experienced hyperprogression after the initiation of immunotherapy. Immune-related adverse events occurred in two patients: one developed grade 1 hyperthyroidism, and the other experienced grade 2 immune-related pneumonitis. ConclusionsImmunotherapy offers a promising treatment option for selected patients with platinum-refractory GCTs, demonstrating moderate response rates and potential survival benefits in a real-world scenario. Identifying specific prognostic factors may help tailor treatment strategies and enhance outcomes in this challenging patient cohort.

EPID-02. HISTORY OF ALLERGY OR ATOPY DECREASES RISK OF BRAIN METASTASIS IN LUNG CANCER AND MELANOMA

Abstract Both allergy/atopy and autoimmune disease (AD) are associated with decreased prevalence of glioma. We leveraged cancer registry data combined with Medicare claims to investigate the effect of prior atopy/AD on incidence, and overall survival, of brain metastasis (BrM) in lung cancer (LC) and melanoma. Surveillance, Epidemiology and End. RESULTS: data linked to Medicare claims were obtained, containing cases of melanoma and LC diagnosed from 2008-2017. Patients &amp;lt; 65 years of age, enrolled in Medicare Advantage, with prior/subsequent cancer diagnosis, or missing variables were excluded. History of allergy/atopy/ or AD (≥6 months prior to primary cancer diagnosis) and BrM status were identified by ICD-9/ICD-10 codes and SEER variables. Treatment pattern was determined using ICD-9/ICD-10 and HCPCS/CPT codes. Time to BrM and overall survival among individuals diagnosed with BrM were estimated via Cox proportional hazards regression adjusted for age, sex, race/ethnicity, stage at diagnosis, treatment, and Charlson comorbidity score. Of the 154,203 and 66,593 cases of LC and melanoma, 18.6% and 2.5% developed BrM at any point, respectively. Among LC with BrM, 27% and 16% had atopy and/or AD (compared to 33% and 20% in LC without BrM), while there were 26% and 16% of cases with atopy and/or AD among melanoma with BrM (compared to 33% and 18% in melanoma without BrM). History of atopy was associated with decreased hazard of BrM in melanoma and LC (HR=0.73, p-value&amp;lt; 0.001 and HR=0.90, p=0.024, respectively). Among those with a BrM, both history of atopy and AD were associated with improved survival in LC (HR=0.90, p&amp;lt; 0.001 and HR=0.95, p&amp;lt; 0.001) but not melanoma. History of AD is associated with a moderate survival benefit in LC with BrM, while history of allergy/atopy decreased incidence of BrM in LC and melanoma. Further research is necessary to identify potential causes of this association.

OS06.6.A Real-World Pattern of Care Study on Glioblastoma in the Austrian Population. Final results from 2014-2020

Abstract Background The Austrian ABTR-SANO Glioblastoma Registry is the first population-based assessment of patterns of care for patients with Glioblastoma across Austrian healthcare institutions. The primary aim is to assess the real world effectiveness of administered therapies. Material and Methods Clinical data are collected via a common web-based IT platform “ABTR-SANO Net” since 2014. The database and the ongoing evaluation of clinical parameters, as well as interims analysis are provided in cooperation with a review board. First Outcome analysis, including patients from 2014-2020, was performed at the end of 2021. Results Eleven centers across Austria are involved, and the data of 1416 patients (m/f ratio: 1,35, median age: 66 years) were recently analyzed in detail. Age, extent of resection, as well as ECOG was associated with improved survival. Methylated MGMT Status also showed a moderate survival benefit. Patients with re-resection and re-radiation also exhibited improved survival, which however may be attributed to a selection bias.Second line treatment manly comprised of antiangiogenic treatment, followed by alkylated agents, re-radiation and re-surgery. Median overall survival of all patients was 344 days and clearly age dependent (best for &amp;lt;50 years, worse for&amp;gt;80 years). Conclusion This is the first population based outcome analysis of Glioblastoma in Austria. Results regarding prognostic markers and outcome are mostly comparable with international data. Robust population based data are important in order to monitor quality of health care, and to match the data with results from clinical studies.

A contemporary update on glioblastoma: molecular biology, current management, and a vision towards bio-adaptable personalized care.

Glioblastoma (GBM) is the most fatal brain tumor in adults. Current survival rates of GBM remain below 2years due to GBM's aggressive cellular migration and genetically driven treatment escape pathways. Despite our rapidly increasing understanding of GBM biology, earlier diagnoses, and refined surgical techniques, only moderate survival benefits have been achieved. Nonetheless, the pressing need for better survival rates has brought forward a multitude of newer therapeutic approaches and opened the door for potential personalization of these modalities in the near future. We reviewed the published literature discussing the current state of knowledge regarding GBM biology and therapy and summarized the information that may point toward future personalized therapeutic strategies. Several novel modalities such as oncolytic viruses, targeted immune, and molecular therapies, and tumor treating fields have been introduced. To date, there is no single treatment modality for GBM, but rather a wide spectrum of combined modalities that address intratumoral cellular and genetic variabilities. While the current state of GBM research and clinical trial landscape may hold promise, current literature lacks any fruitful progress towards personalized GBM therapy. In this review, we are discussing our recent knowledge of the GBM genetic biologic landscape and the current advances in therapy, as well as providing a blueprint for an envisioned GBM management paradigm that should be personalized and adaptable to accommodate each patient's diverse genetic variations and therapy response/escape patterns.

First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial

Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM. This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m2 intravenously] plus cisplatin [75 mg/m2 intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual. Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64-75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7-32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8-21·4] vs 14·1 months [12·4-16·2]; hazard ratio 0·74 [96·6% CI 0·60-0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1-46·5) in the nivolumab plus ipilimumab group and 27% (21·9-32·4) in the chemotherapy group. Grade 3-4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression). Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM. Bristol Myers Squibb.

MP82-02 SURVIVAL IMPACT OF VARIANT HISTOLOGY DIAGNOSIS IN UPPER TRACT UROTHELIAL CARCINOMA

You have accessJournal of UrologyBladder Cancer: Upper Tract Transitional Cell Carcinoma II (MP82)1 Apr 2020MP82-02 SURVIVAL IMPACT OF VARIANT HISTOLOGY DIAGNOSIS IN UPPER TRACT UROTHELIAL CARCINOMA Andrew Tracey*, Melissa Assel, Nathan Wong, Lucas Noguiera, Ricardo Alvim, Dean Bajorin, and Jonathan Coleman Andrew Tracey*Andrew Tracey* More articles by this author , Melissa AsselMelissa Assel More articles by this author , Nathan WongNathan Wong More articles by this author , Lucas NoguieraLucas Noguiera More articles by this author , Ricardo AlvimRicardo Alvim More articles by this author , Dean BajorinDean Bajorin More articles by this author , and Jonathan ColemanJonathan Coleman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000974.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: While the significance of variant histology is well established in urothelial carcinoma of the bladder, less is known regarding its prognostic implications in the upper tract (UTUC). Furthermore, unlike bladder cancer, variant histology UTUC is rarely diagnosed until the time of nephroureterectomy, presenting unique management challenges. We sought to evaluate the impact of variant histology UTUC on patient survival outcomes at our institution. METHODS: After excluding patients who underwent nephroureterectomy for non-urothelial primary or metastatic tumors and benign disease, we identified 705 unique patients for analysis. All patients had surgery at Memorial Sloan Kettering Cancer Center between January 1995 and December 2018. We tested the association between variant histology and cancer-specific and overall survival using separate multivariable Cox models after adjusting for pathological stage. All analyses were performed using R version 3.6.0. RESULTS: 47 (6.7%) patients had variant histology on pathology. Variant histology tended to be found in patients treated in more recent years (p=0.003), reflective of evolving pathologic recognition. Other patient demographic and surgical characteristics were similar between variant histology and pure urothelial carcinoma groups. While patients with variant histology were more likely to receive neoadjuvant chemotherapy (38% vs 15%; p<0.001), they were also more likely to have a higher T stage on final pathology (p<0.001). The presence of variant histology was associated with significantly worse cancer-specific (HR 1.96; 95% CI 1.19, 3.24; p=0.008) and overall survival (HR 1.74; 95% CI 1.15, 2.63; p=0.008). After adjusting for pathological T stage, variant histology was not significantly associated with cancer-specific (HR 1.07; 95% CI 0.65, 1.79; p=0.8) or overall survival (HR 1.20; 95% CI 0.79, 1.84; p=0.4), indicating the strong associated influence of pathologic stage on survival in these high-risk patients. CONCLUSIONS: The inferior cancer-specific and overall survival in patients with variant histology UTUC can be explained by the higher tumor stage on nephroureterectomy. We cannot exclude the possibility that variant histology is associated with up to a moderate survival benefit or harm; larger studies could provide a more precise estimate of risk. Source of Funding: This research was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers and funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1245-e1246 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrew Tracey* More articles by this author Melissa Assel More articles by this author Nathan Wong More articles by this author Lucas Noguiera More articles by this author Ricardo Alvim More articles by this author Dean Bajorin More articles by this author Jonathan Coleman More articles by this author Expand All Advertisement PDF downloadLoading ...

Palliative Outpatient Inotrope in End Stage Heart Failure Patients is Safe with Moderate Survival Benefit: A Single Center Retrospective Study

Introduction With the advent of newer heart failure (HF) medications and devices such as implantable cardioverter-defibrillator (ICD), the survival benefits of long-term intravenous (IV) inotropes might be underestimated. 1-year mortality from outpatient IV inotropes (continuous and intermittent) have been reported between 25% to 47.6%. However, a study solely based on outpatient continuous inotropes for palliation has not been done in the past. This study hypothesizes that the survival rate of patients with end stage HF on palliative intravenous inotrope is better than previously expected (6 months) and may be a viable option for certain patients. Methods and Results We performed a single-center, retrospective chart review of HF patients who were discharged with an inotrope (milrinone or dobutamine) for palliation. Inclusion criteria included age > 18, diagnosis of HF, and patients discharged on inotropes after January 1, 2010. Exclusion criteria included patients who had received mechanical circulatory support (MCS) or patients who had received a heart transplant. Data were collected on 119 patients from the existing database of the Advocate Christ Medical Center's heart failure clinic. Primary outcome was survival on inotropes. Secondary outcomes included number of hospitalizations, number of clinic visits, infection rates and incidence of arrhythmia on inotrope. SAS software was used for statistical analysis. 87.38% of patients were discharged on Milrinone whereas 13.51% were discharged on dobutamine. Demographics, comorbidities, medications and devices are shown in table 1. The mean follow-up time was 255.36±23.93 days. 27.03% were alive on inotrope, 15.32% were alive but weaned off of inotrope, 18.92% were on hospice, 17.12% had expired, and 21.62% were lost to follow-up. Using product-limiting survival estimates, the unconditional probability of surviving beyond 6.5 months was 84%. Mean number of hospitalizations after discharge on inotrope was 1.92±0.25. Mean number of clinic visits in 3, 6 and 12 months were 2.61±0.26, 4.48±0.49, 7.92±0.95 respectively. The rate of peripherally inserted central catheter infection and arrhythmia were 8.11% and 9.91% respectively. Conclusions Palliative inotrope after diagnosis of end-stage heart failure is a safe option with moderate survival benefit in patients who opt out of or who do not meet criteria for MCS or transplant.

Determinants of regret in elderly dialysis patients.

In Singapore, most elderly end-stage renal disease (ESRD) patients choose dialysis over palliative management. However, dialysis may not be the optimal treatment option given only moderate survival benefits and high costs and treatment burden compared to non-dialysis management. Elderly patients may therefore come to regret this decision. This study investigated: (i) extent of patients' decision regret after starting dialysis, and (ii) potentially modifiable predictors of regret: satisfaction with chronic kidney disease education, decisional conflict, and decision-making involvement. The present study was a cross-sectional study of 103 dialysis patients above 70 years of age, surveyed at Singapore General Hospital's renal medicine clinics between March and June 2017. Participants reported their levels of decision regret on the Decision Regret Scale (DRS), retrospective decisional conflict on the Decisional Conflict Scale, information satisfaction, and decision-making involvement. In total, 81% of participants reported no decision regret (DRS score < 50), 11% ambivalence (DRS = 50), and 8% regret (DRS >50). In individual DRS items, 19% felt dialysis had done them harm and 16% would not make the same decision again. In multivariable analyses, lower information satisfaction [b = -0.07 (95% CI: -0.13, -0.01)] and decisional conflict [b = 0.004 (95% CI: 0.002, 0.006)] were significantly associated with decision regret. Although the majority of elderly dialysis patients were comfortable with their decision to start dialysis, a proportion was ambivalent or regretted this choice. Regret was more likely among those who experienced decisional conflict and/or expressed poorer information satisfaction. Healthcare professionals should recognize these risk factors and take steps to minimize chances of regret among this population subset.

21 Inhibiting PARP-1 to restore temozolomide sensitivity and prevent resistance in glioblastoma

Adult Glioblastomas (GBMs) remain one of the least curable brain cancers despite the discovery and use of DNA alkylating agent Temozolomide (TMZ). TMZ provides a moderate survival benefit to sensitive patients whose O6-methylguanine-methyltransferase (MGMT) gene is silenced by promoter methylation. Unfortunately, TMZ potential is stunted because of the rapid onset of tumour recurrence and acquired resistance believed to result from the upregulation of DNA damage repair by the base excision repair (BER), mismatch repair (MMR), or homologous recombination (HR) systems. Our laboratory previously demonstrated that cell lines obtained from recurrent, TMZ-resistant GBMs could be re-sensitized to TMZ when treated with an inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1) – a protein instrumental in the recruitment of BER machinery. From this preliminary research, we postulate that PARP-1 inhibition may not only be used to overcome established resistance in GBM but may also be used to prevent its emergence altogether. To test this hypothesis, we utilized the MGMT-methylated GBM cell line U251N and developed an in vitro model of inducible TMZ resistance. We verified that prolonged treatment of U251N cells with TMZ resulted in the emergence of resistant colonies that resembled recurrent GBM clinically observed in TMZ-treated patients. However, when the parental U251N line was co-treated with TMZ and PARP-1 inhibitor ABT-888, resistant colonies failed to appear. Therefore, PARP-1 inhibition may possess the potential to maintain tumour sensitivity to TMZ as well as evade the otherwise inevitable development of resistance in GBM.

Patients' and clinicians' preferences for adjuvant chemotherapy in endometrial cancer: an ANZGOG substudy of the PORTEC-3 intergroup randomised trial.

Background:To determine the minimum survival benefits that patients, and their clinicians, judged sufficient to make adjuvant chemotherapy (ACT) worthwhile, in addition to pelvic radiotherapy, for women with high risk and advanced stage endometrial cancer.Methods:Eighty-three participants in the PORTEC-3 trial completed a time trade-off questionnaire before and after adjuvant therapy; 44 of their clinicians completed it once only. The questionnaire used four hypothetical scenarios including baseline survival times without ACT of 5 and 8 years, and baseline survival rates at 5 years without ACT of 50 and 65%.Results:Over 50% of patients judged an extra 1 year of survival time or an extra 5% in survival rate sufficient to make ACT worthwhile. Over 50% of clinicians judged an extra 1 year of survival time, or an extra 10% in survival rate, sufficient to make ACT worthwhile. Compared with patients, clinicians required similar survival time benefits (medians both 1 year, P=0.4), but larger survival rate benefits (medians 8.5% vs 5%, P=0.03), and clinicians' preferences varied less (IQR 0.5–1.5 years vs 0.4–2 years, P=0.0007; 5–10% vs 1–13%, P=0.004). Patients' preferences changed over time for the survival rate scenarios depending on whether they had ACT or not (change in median benefit - 3 months vs 2.5 months respectively, P=0.028). There were no strong predictors of patients' or clinicians' preferences.Conclusions:Patients and clinicians judged moderate survival benefits sufficient to make ACT worthwhile after pelvic radiotherapy for endometrial cancer. These benefits are larger than those judged sufficient by patients with breast or colon cancers, but similar to those judged sufficient by patients with lung or ovarian cancers.

Abstract 1315: Nanoparticles targeting RAF/ERK-driven cell-autonomous resistance to sorafenib for effective treatment of hepatocellular carcinoma

Abstract Sorafenib is the only systemic therapy approved for advanced hepatocellular carcinoma (HCC). Sorafenib's efficacy has been attributed in part to inhibition of cancer cell proliferation due to B- and CRAF targeting in HCC cells. However, cell autonomous mechanisms promote evasion from sorafenib treatment, leading to moderate survival benefit. Herein, we demonstrated that the effects of sorafenib on HCC cell viability were initially independent of RAF kinase inhibition and were mediated in part by p38MAPK inhibition. Moreover, sorafenib treatment led to RAF heterodimerization (BRAF/CRAF) and subsequent ERK activation and thus converted HCC cell dependence for survival signaling to the RAF/ERK pathway. Inhibition of ERK pathway by the MEK inhibitor AZD6244 significantly enhanced the therapeutic efficacy of sorafenib efficacy on HCC in vitro and in vivo. Furthermore, we developed HCC-targeted nanoparticles (NPs) to efficiently co-deliver both sorafenib and AZD6244 into HCC, downregulate RAF/ERK pathway, suppress angiogenesis and enhance anti-cancer effect in the orthotopic HCC model. In conclusion, sorafenib treatment leads to rapid MAPK activation due to BRAF heterodimerization as a cell-autonomous mechanism of treatment resistance. Co-delivery of sorafenib and MEK inhibitor AZD6244 using HCC targeted NPs downregulates the compensatory activated RAF/ERK pathway and overcomes resistance to sorafenib in HCC. Citation Format: Yunching Chen, Ya-Chi Liu, Ts-Ting Lin, Rakesh Ramjiawan, Dan Duda. Nanoparticles targeting RAF/ERK-driven cell-autonomous resistance to sorafenib for effective treatment of hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1315.

Defining the possible therapeutic benefit of lymphadenectomy among patients undergoing hepatic resection for intrahepatic cholangiocarcinoma.

The aim of the study was to investigate the therapeutic role of lymphadenectomy (LND) in patients with intrahepatic cholangiocarcinoma. 826 patients who underwent liver resection were identified using the SEER database from 1988 to 2011. Two groups of patients were defined: 201 (24%) undergoing potentially therapeutic LND (group A, >3 lymph nodes (LN) removed), and 625 (76%) not receiving therapeutic LND (group B, ≤3 LNs removed). A propensity score analysis was performed to create a matched cohort of 402 patients (201 in either group). The survival benefit of therapeutic LND was also estimated using multivariate parametric analysis comparing two simulated cohorts of 826 patients. 1-, 3-, and 5-year survival rates were 71%, 37%, and 27% for group A patients, and 73%, 37%, and 27% for matched group B patients (P = 0.656). When simulation analysis was performed, a moderate survival benefit of LND of 5.46 months was calculated (95%CI, 4.64-6.29). Considerable differences in LND survival benefit predictions were found according to patient's sex (males, 9.90 vs. females 1.16 months), age (≤60 years, 15 vs. >60 years, -1.34 months), and tumor size (>50 mm, 9.20 vs. ≤50 mm, -0.28). LND therapeutic benefit among a subset of patients. Future work is required to investigate the role of routine LND among these patients. J. Surg. Oncol. 2016;113:685-691. © 2016 Wiley Periodicals, Inc.

Metformin Is Associated With Slightly Reduced Risk of Colorectal Cancer and Moderate Survival Benefits in Diabetes Mellitus: A Meta-Analysis.

To systematically assess the effect of metformin on colorectal cancer (CRC) risk and mortality in type 2 diabetes mellitus (T2DM) patients.We conducted a systematic search of PubMed, Web of Science, and the Cochrane Library databases for relevant articles before August 2015. Two investigators identified and extracted data independently. We adopted adjusted estimates to calculate summary estimates with 95% confidence interval (CI) using either a fixed-effects or a random-effects model. Subgroup and sensitivity analyses were conducted to evaluate the robustness of the pooled results. The risk of publication bias was assessed by examining funnel plot asymmetry as well as Begg test and Egger test.Fifteen studies on CRC incidence and 6 studies on CRC survival were finally included in our meta-analysis. The pooled odds ratio (OR) of observational studies illustrated that a slight 10% reduction of CRC incidence was associated with metformin use (OR = 0.90, 95% CI: 0.85–0.96). Furthermore, the pooled hazard ratio (HR) revealed an improved survival outcome for metformin users in CRC patients compared to nonusers (HR = 0.68, 95% CI: 0.58–081). There was no publication bias across studies.Our meta-analysis demonstrated that metformin therapy could slightly reduce CRC incidence and moderately improve the survival outcomes in patients with T2DM. More prospective studies are warranted to certify this protective association.

Management of neoplastic meningitis.

Leptomeningeal dissemination of tumor cells, also referred to as neoplastic meningitis, is most frequently seen in patients with late-stage cancer and mostly associated with a poor prognosis. Basically, neoplastic meningitis may affect all patients with a malignant tumor but is most common in patients affected by lung cancer, breast carcinoma, melanoma or hematologic neoplasms such as lymphoma and leukemia. Controlled clinical trials are largely lacking which results in various non-standardized treatment regimens. The presence of solid tumor manifestations in the CNS as well as the extracranial tumor load defines the most appropriate treatment approach. Radiation therapy, systemic chemotherapy and intrathecal treatment must be considered. For each patient, the individual situation needs to be carefully evaluated to determine the potential benefit as well as putative side effects associated with any therapy. A moderate survival benefit and particularly relief from pain and neurological deficits are the main treatment goals. Here, we summarize the management of patients with neoplastic meningitis and review the available treatment options.

Patients’ and doctors’ preferences for adjuvant chemotherapy in resected non-small-cell lung cancer: What makes it worthwhile?

BackgroundAdjuvant chemotherapy (ACT) in non-small-cell lung cancer (NSCLC) improves overall survival, but the benefits must be weighed against its harms. We sought to determine the survival benefits that patients and their doctors judged sufficient to make ACT in NSCLC worthwhile. Methods122 patients completed a self-administered questionnaire at baseline and 6months (before & after ACT, if they had it); 82 doctors completed the questionnaire once only. The time trade-off method was used to determine the minimum survival benefits judged sufficient in four hypothetical scenarios. Baseline survival times were 3years & 5years and baseline survival rates (at 5years) were 50% & 65%. ResultsAt baseline, the median benefits judged sufficient by patients were an extra 9months (Interquartile range (IQR) 1–12months) beyond 3years & 5years and an extra 5% (IQR 0.1–10%) beyond 50% & 65%. At 6months (n=91), patients’ preferences had the same median benefit (9months & 5%) but varied more (IQRs 0–18months & 0–15%) than at baseline. Factors associated with judging smaller benefits sufficient were deciding to have ACT (P=0.01, 0.02) and better well-being (P=0.01, 0.006) during ACT. Doctors’ preferences, compared with patients’ preferences, had similar median benefits (9months & 5%) but varied less (IQR 6–12months versus 1–12months, P<0.001; 5%–10% versus 0.1–10%, P<0.001). ConclusionMost patients and doctors judged moderate survival benefits sufficient to make ACT in NSCLC worthwhile, but the preferences of doctors varied less than those of patients. Doctors should endeavour to elicit patients’ preferences during discussions about ACT in NSCLC.

A systematic review of patient preference elicitation methods in the treatment of colorectal cancer.

This systematic review aimed to assess the use of patient preference in colorectal cancer treatment. Eliciting patient preference is important for shared decision-making in colorectal cancer treatment. The introduction of newer treatments, which balance quality of life and overall survival, makes this an important future focus. A systematic search strategy of MEDLINE, Embase, PsycINFO, CINAHL and the Cochrane Database for Systematic Reviews was undertaken to obtain relevant articles. Information regarding the type of patients included, preference instruments, study settings, outcomes and limitations was extracted. The eight articles comprising this review each described an empirical study using a validated instrument to define patient preference for an aspect of colorectal cancer treatment. The evidence suggests that patients are prepared to trade significant reductions in life expectancy to avoid certain complications of colorectal surgery, particularly stoma formation. In the adjuvant setting, patients are prepared to risk significant treatment side effects to gain small potential increases in life expectancy and chance of survival. Where neoadjuvant or adjuvant treatment risks worsening function, however, patients generally forgo any potential increase in survival to improve bowel function and therefore quality of life. The only predictors of preference were tertiary education and previous cancer treatment. Most patients judge a moderate survival benefit to be sufficient to make adjuvant therapy for colorectal cancer worthwhile, but they are willing to trade a potential reduction in life expectancy and survival to avoid certain unwanted surgical sequelae.

Feasibility, acceptability and preferences for intraperitoneal chemotherapy with paclitaxel and cisplatin after optimal debulking surgery for ovarian and related cancers: an ANZGOG study

ObjectiveIntraperitoneal (IP) chemotherapy in women with optimally debulked stage III ovarian cancer has been reported to prolong overall survival, but has not been widely adopted due to concerns about its toxicity, inconvenience and acceptability to patients. The purposes of this study were to determine the regimen's feasibility, adverse events, catheter-related complications, progression-free survival, health-related quality of life (HRQL), and patients' preferences for IP versus intravenous (IV) chemotherapy.MethodsWe conducted a single arm, multi-center study of IP chemotherapy with IV paclitaxel 135 mg/m2 (D1) over 3 hours, IP cisplatin 75 mg/m2 (D2), and IP paclitaxel 60 mg/m2 (D8) for 6 cycles in women with optimally debulked stage III ovarian or related cancers.ResultsThirty-eight eligible patients were recruited from 12 sites between July 2007 and December 2009. Seventy-one percent (n=27) completed at least 4 cycles and 63% (n=24) completed all 6 cycles. Grade 3 or 4 adverse events included nausea (n=2), vomiting (n=2), abdominal pain (n=2), and diarrhea (n=1), but not febrile neutropenia, neurotoxicity, or nephropathy. There were no treatment-related deaths. Catheter-related complications were the most frequent cause of early discontinuation of treatment (16 patients, 21%). Apart from neurotoxicity HRQL which worsened over time, HRQL was stable or improved with time. Most patients (≥50%) judged moderate benefits (e.g., an extra 6 months survival time or a 5% improvement in survival rates) necessary to make IP chemotherapy worthwhile.ConclusionIP chemotherapy was feasible, tolerable, and most participants considered moderate survival benefits sufficient to warrant the adverse effects and inconvenience.

Toxicity and efficacy of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma (Review)

The prognosis of advanced hepatocellular carcinoma (HCC) remains poor, particularly for patients with portal vein tumor thrombosis. Chemotherapy is one of the most significant treatment options for patients with advanced HCC not indicated for hepatic resection, percutaneous ablation and transcatheter arterial chemoembolization. Systemic chemotherapy does not play a central role in the treatment of HCC due to the issue of low sensitivity for chemotherapeutic agents and the difficulties in administering a sufficient dose due to chronic liver dysfunction. Therefore, patients with advanced HCC are usually treated with hepatic arterial infusion chemotherapy (HAIC), which is increasingly used as an approach to advanced HCC in Japan. HAIC provides moderate therapeutic efficacy and survival benefit with substantially tolerable toxicity profiles in patients with advanced HCC.

Cardiomyocytes from phorbol myristate acetate-activated mesenchymal stem cells restore electromechanical function in infarcted rat hearts

Despite the safety and feasibility of mesenchymal stem cell (MSC) therapy, an optimal cell type has not yet emerged in terms of electromechanical integration in infarcted myocardium. We found that poor to moderate survival benefits of MSC-implanted rats were caused by incomplete electromechanical integration induced by tissue heterogeneity between myocytes and engrafted MSCs in the infarcted myocardium. Here, we report the development of cardiogenic cells from rat MSCs activated by phorbol myristate acetate, a PKC activator, that exhibited high expressions of cardiac-specific markers and Ca(2+) homeostasis-related proteins and showed adrenergic receptor signaling by norepinephrine. Histological analysis showed high connexin 43 coupling, few inflammatory cells, and low fibrotic markers in myocardium implanted with these phorbol myristate acetate-activated MSCs. Infarct hearts implanted with these cells exhibited restoration of conduction velocity through decreased tissue heterogeneity and improved myocardial contractility. These findings have major implications for the development of better cell types for electromechanical integration of cell-based treatment for infarcted myocardium.

Lung cancer clinicians’ preferences for adjuvant chemotherapy in non-small-cell lung cancer: What makes it worthwhile?

Aims We sought (i) lung cancer clinicians’ judgements about the smallest survival benefits that would make the harms of adjuvant chemotherapy for non-small-cell lung cancer (NSCLC) worthwhile, (ii) factors associated with their judgements, and (iii) comparisons with breast cancer and colon cancer clinicians surveyed similarly in 2002–2003. Methods Delegates at the Australian Lung Cancer Conference 2008 were invited to complete a validated, self-administered questionnaire that used the time trade-off method to determine the minimum survival benefits judged sufficient to make adjuvant chemotherapy worthwhile. The baseline survival times were 3 and 5 years, and the baseline 5-year survival rates were 50% and 65%. Chemotherapy was 4 cycles of cisplatin and vinorelbine. Results Characteristics of the 156 respondents were: median age 41 years (range 23–62), female 55%, married 83%, with dependent children 62%, respiratory physician 28%, nurse 24%, medical oncologist 14%, radiation oncologist 12%, trial nurse/coordinator 12%, thoracic surgeon 4%. Moderate survival benefits were judged sufficient to make chemotherapy worthwhile. The median benefit judged sufficient was an extra 9 months beyond a baseline survival time of 3 or 5 years. The median benefit judged sufficient was an extra 5% for a baseline survival rate of 65%, versus an extra 10% for a baseline survival rate of 50% (p < 0.001). Smaller benefits were judged sufficient by clinicians who were married (p = 0.02) or had dependants (p = 0.04). Lung cancer clinicians judged smaller benefits sufficient than breast cancer ( n = 89) and colon cancer ( n = 72) clinicians in similar prior studies (median required benefit of 9 months versus 12 months, p < 0.001). Conclusion Most lung cancer clinicians attending a national lung cancer conference judged moderate improvements in survival sufficient to make adjuvant chemotherapy worthwhile. Smaller benefits were judged sufficient by lung cancer clinicians in 2008 than by breast cancer and colon cancer clinicians 5–6 years earlier. Clinicians should be aware of their own preferences, and explore their patients’ preferences, when discussing adjuvant chemotherapy.