Safety and feasibility of minimally invasive gastrectomy during the early introduction in the Netherlands: short-term oncological outcomes comparable to open gastrectomy

Background

Minimally invasive techniques for gastric cancer surgery have recently been introduced in the Netherlands, based on a proctoring program. The aim of this population-based cohort study was to evaluate the short-term oncological outcomes of minimally invasive gastrectomy (MIG) during its introduction in the Netherlands.

Methods

The Netherlands Cancer Registry identified all patients with gastric adenocarcinoma who underwent gastrectomy with curative intent between 2010 and 2014. Multivariable analysis was performed to compare MIG and open gastrectomy (OG) on lymph node yield (≥15), R0 resection rate, and 1-year overall survival. The pooled learning curve per center of MIG was evaluated by groups of five subsequent procedures.

Results

Between 2010 and 2014, a total of 277 (14%) patients underwent MIG and 1633 (86%) patients underwent OG. During this period, the use of MIG and neoadjuvant chemotherapy increased from 4% to 39% (p < 0.001) and from 47% to 62% (p < 0.001), respectively. The median lymph node yield increased from 12 to 20 (p < 0.001), and the R0 resection rate remained stable, from 86% to 91% (p = 0.080). MIG and OG had a comparable lymph node yield (OR, 1.01; 95% CI, 0.75–1.36), R0 resection rate (OR, 0.86; 95% CI, 0.54–1.37), and 1-year overall survival (HR, 0.99; 95% CI, 0.75–1.32). A pooled learning curve of ten procedures was demonstrated for MIG, after which the conversion rate (13%–2%; p = 0.001) and lymph node yield were at a desired level (18–21; p = 0.045).

Conclusion

With a proctoring program, the introduction of minimally invasive gastrectomy in Western countries is feasible and can be performed safely.

     

Hematological adverse effects in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors: a systematic review and meta-analysis

Background

The introduction of specific cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly improved progression-free survival in hormone receptor-positive metastatic breast cancer. CDK 4/6 inhibitors induce cell cycle arrest via liberating the tumor suppressor retinoblastoma protein from CDK4/6 inhibitory effect. Preliminary studies suggested an increase in the hematological toxicities which might affect the quality of life in such palliative setting.

Methods

We searched PubMed, ASCO, ESMO and San Antonio meeting databases for randomized phase II/III trials in metastatic breast cancer receiving CDK4/6 inhibitors with safety data provided on the incidence of hematological adverse effects.

Results

Our search identified 1012 citations that were screened for relevance. Thirty-six studies were found to be potentially eligible. After excluding the ineligible studies, six studies were deemed to be eligible for meta-analysis. The risk ratio (RR) was 11.31 [95% confidence interval (CI) 8.06–15.87; p < 0.0001] for all-grade leucopenia, 14.86 (95% CI 11.37–19.41; p < 0.0001) for all-grade neutropenia, 9.04 (95% CI 3.78–21.63; p < 0.0001) for all-grade thrombocytopenia and 3.57 (95% CI 2.65–4.81; p < 0.0001) for all-grade anemia. The RR for grade 3/4 leucopenia was 33.86 (95% CI 14.59–78.57; p < 0.0001), for grade 3/4 neutropenia was 44.00 (95% CI 24.72–78.33; p < 0.0001), for grade 3/4 thrombocytopenia was 5.70 (95% CI 2.03–16.01; p = 0.001) and for grade 3/4 anemia was 2.80 (95% CI 1.45–5.41; p = 0.002). There was no significant increase in the RR of febrile neutropenia with RR of 3.29 (95% CI 0.93–11.57; p = 0.06).

Conclusion

Our analysis provides evidence that the use of CDK 4/6 inhibitors is associated with an increased risk of all-grade and high-grade hematological adverse events, which seems to be a class-effect, but not of febrile neutropenia compared with hormonal therapy alone.

     

Prognostic factors affecting survival in metastatic soft tissue sarcoma: an analysis of 110 patients

Background

Data on treatment outcome and prognostic factors in patients with metastatic soft tissue sarcoma (STS) are limited in the literature.

Methods

A total of 119 patients with metastatic STS treated between June 2003 and December 2012 were analyzed for treatment outcome and prognostic factors.

Results

Median age was 37 years (range 2–72 years) with a male to female ratio of 1.5:1. Most common histologic subtypes were synovial sarcoma (36 %) and leiomyosarcoma (16 %). Median tumor size was 12 cm (range 1.6–30 cm). Twenty-four (20 %) patients were treated with multimodality therapy and 80 % patients received systemic chemotherapy alone. At a median follow-up of 10 months (range 1–66 months), the 2-year EFS and OS were 10 and 19 %, respectively, with a median EFS and OS of 6 and 10 months, respectively. Univariate analysis identified albumin ≤4 g/dl (p = 0.001), histologic subtypes other than synovial sarcoma (p = 0.02), non-extremity tumors (p = 0.03) and single modality treatment (p = 0.03) as factors predicting poor EFS; however, for OS, hemoglobin ≤10 g/dl (p = 0.02), tumor size >10 cm (p = 0.01) and single modality treatment (p = 0.04) were identified as poor prognostic factors. Multivariate analysis identified only serum albumin ≤4 g/dl (p = 0.002, HR 0.47, 95 % CI 0.29–0.75) associated with poor EFS; however, for OS, hemoglobin ≤10 g/dl (p = 0.009, HR 0.49, 95 % CI 0.29–0.83), tumor size >10 cm (p = 0.003, HR 2.11, 95 % CI 1.28–3.47) and single modality treatment (p = 0.01, HR 0.47, 95 % CI 0.25–0.86) emerged as poor prognostic factors.

Conclusions

Serum albumin, tumor size, hemoglobin and treatment modality affect survival in metastatic STS.

     

Anthracycline-based triplets do not improve the efficacy of platinum-fluoropyrimidine doublets in first-line treatment of advanced gastric cancer: real-world data from the AGAMEMON National Cancer Registry

Background

Although anthracycline-based triplets are one of the most widely used schedules to treat advanced gastric cancer (AGC), the benefit of including epirubicin in these therapeutic combinations remains unknown. This study aims to evaluate both the efficacy and tolerance of triplets with epirubicin vs. doublets with platinum-fluoropyrimidine in a national AGC registry.

Methods

Patients with AGC treated with polychemotherapy without trastuzumab at 28 hospitals in Spain between 2008 and 2016 were included. The effect of anthracycline-based triplets against doublets was evaluated by propensity score matching (PSM) and Cox proportional hazards (PH) regression.

Result

A total of 1002 patients were included (doublets, n = 653; anthracycline-based triplets, n = 349). The multivariable Cox PH regression failed to detect significantly increased OS in favor of triplets with anthracyclines: HR 0.90 (95% CI, 0.78–1.05), p = 0.20035. After PSM, the sample contained 325 pairs with similar baseline characteristics. This method was also unable to reveal an increase in OS: 10.5 (95% CI, 9.7–12.3) vs. 9.9 (95% CI, 9.2–11.4) months, HR 0.91 (CI 95%, 0.76–1.083), and (log-rank test, p = 0.226). Response rates (42.1 vs. 33.1%, p = 0.12) and PFS (HR 0.95, CI 95%, 0.80–1.13, log-rank test, p = 0.873) were not significantly higher with epirubicin-based regimens. The triplets were associated with greater grade 3–4 hematological toxicity, and increased hospitalization due to toxicity by 68%. The addition of epirubicin is viable, but 23.7% discontinued treatment because of adverse effects or patient decision.

Conclusion

Anthracyclines added to platinum-fluoropyrimidine doublets did not improve the response rate or survival outcomes in patients with AGC but entailed greater toxicity.

     

Population-based assessment of racial/ethnic differences in utilization of radical cystectomy for patients diagnosed with bladder cancer

Purpose

Radical cystectomy is a surgical treatment for recurrent non-muscle-invasive and muscle-invasive bladder cancer; however, many patients may not receive this treatment.

Methods

A total of 27,578 patients diagnosed with clinical stage I–IV bladder cancer from 1 January 2007 to 31 December 2013 were identified from the Surveillance, Epidemiology, and End Results (SEER) registry database. We used multivariable regression analyses to identify factors predicting the use of radical cystectomy and pelvic lymph node dissection. Cox proportional hazards models were used to analyze survival outcomes.

Results

A total of 1,693 (6.1%) patients with bladder cancer underwent radical cystectomy. Most patients (92.4%) who underwent radical cystectomy also underwent pelvic lymph node dissection. When compared with white patients, non-Hispanic blacks were less likely to undergo a radical cystectomy [odds ratio (OR) 0.79, 95% confidence interval (CI) 0.64–0.96, p = 0.019]. Moreover, recent year of surgery 2013 versus 2007 (OR 2.32, 95% CI 1.90–2.83, p < 0.001), greater percentage of college education ≥36.3 versus <21.3% (OR 1.23, 95% CI 1.04–1.44, p = 0.013), Midwest versus West (OR 1.64, 95% CI 1.39–1.94, p < 0.001), and more advanced clinical stage III versus I (OR 29.1, 95% CI 23.9–35.3, p < 0.001) were associated with increased use of radical cystectomy. Overall survival was improved for patients who underwent radical cystectomy compared with those who did not undergo a radical cystectomy (hazard ratio 0.88, 95% CI 0.80–0.97, p = 0.008).

Conclusion

There is significant underutilization of radical cystectomy in patients across all age groups diagnosed with bladder cancer, especially among older, non-Hispanic black patients.

     

<Emphasis Type="Italic">UDP-glucuronosyltransferase 1A1*6</Emphasis> and <Emphasis Type="Italic">*28</Emphasis> polymorphisms as indicators of initial dose level of irinotecan to reduce risk of neutropenia in patients receiving FOLFIRI for colorectal cancer

Background

Irinotecan (CPT-11)-induced neutropenia is associated with UDP-glucuronosyltransferase (UGT) 1A1*6 and *28 polymorphisms. This prospective study investigated whether using these polymorphisms to adjust the initial dose of CPT-11 as part of FOLFIRI treatment in colorectal cancer patients might improve safety.

Methods

All data were collected by a physician. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia, reasons for treatment discontinuation, and time-to-treatment failure were evaluated. Multivariate analysis was used to assess the risk of neutropenia.

Results

A total of 795 patients were divided into wild-type (*1/*1) (50.1 %), heterozygous (*28/*1, *6/*1) (41.1 %), and homozygous (*28/*28, *6/*6, *28/*6) (8.which are associated with a decrease in the8 %) groups, in which the median starting dose of CPT-11 was 143.0, 143.0, and 115.0 mg/m², respectively. First-cycle grade ≥3 neutropenia occurred in 17.3, 25.4, and 28.6 % of these patients, respectively. Multivariate analysis revealed that the incidence of grade ≥3 neutropenia was significantly greater in the heterozygous and homozygous groups than in the wild-type group [odds ratio (OR) 1.67; 95 % confidence interval (CI) 1.16–2.42; p = 0.0060, and OR 2.22; 95 % CI 1.22–4.02; p = 0.0088, respectively]. Age (OR 1.77; 95 % CI 1.24–2.53; p = 0.0017), coelomic fluid (OR 1.84; 95 % CI 1.05–3.25; p = 0.0343), and non-reduction in starting dose (OR 1.53; 95 % CI 1.08–2.18; p = 0.0176) were also identified as significant risk factors.

Conclusion

The risk of neutropenia was higher in the heterozygous and homozygous groups at initiation of CPT-11 treatment. This suggests that when a reduction in dose is required in patients harboring two variant alleles, the decrease should be approximately 20 %.

     

Expression of chemokine receptor CCR7 is a negative prognostic factor for patients with gastric cancer: a meta-analysis

Background

The prognostic significance of CC chemokine receptor type 7 (CCR7) for survival of patients with gastric cancer remains controversial. To investigate the impacts of CCR7 on clinicopathological findings and survival outcome in gastric cancer, we performed a meta-analysis.

Methods

A comprehensive search in PubMed, Embase, the Cochrane Library, and the CNKI database (1966 to November 2015) was undertaken for relevant studies. The relative risk and hazard ratios with their 95 % confidence intervals were used as measures to investigate the correlation between CCR7 expression and clinicopathological findings and overall survival rate. Sensitivity analysis was conducted to assess the stability of outcomes.

Results

Fifteen eligible studies comprising 1697 participants were included in our analysis. The pooled relative risks indicated CCR7 expression was significantly associated with deeper tumor invasion [0.61, 95 % confidence interval (CI) 0.45–0.84, p = 0.003], advanced stage (0.47, 95 % CI 0.32–0.69, p < 0.001), vascular invasion (2.12, 95 % CI 1.20–3.73, p = 0.009), lymph node metastasis (2.00, 95 % CI 1.48–2.70, p < 0.001), and lymphatic invasion (1.98, 95 % CI 1.43–2.72, p < 0.001) but not with age, tumor size, and histological type. The pooling of hazard ratios showed a significant relationship between positive CCR7 expression and worse 5-year overall survival rate (0.46, 95 % CI 0.31–0.70, p < 0.001).

Conclusions

Our meta-analysis indicated high CCR7 expression is likely to be a negative clinicopathological prognostic factor for patients with gastric cancer and to predict a worse long-term survival outcome.

     

Incidence,risk and prognostic role of anti-epidermal growth factor receptor-induced skin rash in biliary cancer: a meta-analysis

Background

Anti-epidermal growth factor receptor (EGFR)-induced skin rash is a common adverse event and is considered a prognostic factor of various cancers. However, the role of rash is rarely known in biliary cancer, possibly owing to the low incidence of this frequently fatal malignancy. We thus performed a meta-analysis to investigate the incidence, risk and prognostic significance of skin rash related to anti-EGFR treatment for biliary cancer.

Methods

Eligible studies were enrolled after a systematic search of electronic databases. A fixed-effects or random-effects model was utilized according to the heterogeneity.

Results

Fourteen clinical trials published between 2006 and 2017 comprising 1,106 patients with advanced biliary cancer were included. The overall incidence of all-grade and high-grade (grade ≥3) rash was 78.2% [95% confidence interval (CI) 70.4–84.3] and 11.3% (7.6–16.5), respectively. Anti-EGFR treatment correlates with a significantly increased risk of all-grade [risk ratio (RR) 7.37, 95% CI 5.11–10.64, p < 0.0001] and high-grade (RR 6.94, 95% CI 1.89–25.45, p = 0.0035) rash compared with control medication. Higher grades of skin rash correlate with a higher objective response rate (RR 3.50, 95% CI 1.47–8.33, p = 0.0048), and a longer overall [hazard ratio (HR) 0.47, 95% CI 0.31–0.71, p = 0.0003) and progression-free survival (HR 0.51, 95% CI 0.36–0.72, p = 0.0001) compared with lower grades or no rash in patients who received anti-EGFR treatment.

Conclusions

Anti-EGFR treatment correlates with an increased risk of skin rash in advanced biliary cancer. Stratifying patients by the severity of rash may have major implications for survival benefit regarding anti-EGFR treatment for biliary cancer.

     

Evaluation of Long-Term Outcomes of Microsatellite Instability Status in an Asian Cohort of Sporadic Colorectal Cancers

Purpose

Microsatellite instability in colorectal cancer (CRC) and its long-term outcomes remains poorly studied in Asians. We investigate the prognostic significance of microsatellite instability in an Asian population and assess its clinical impact in patients who undergo adjuvant chemotherapy.

Methods

Six hundred fifty-four consecutive CRC patients who underwent surgical resection between January 2010 and December 2012 were recruited. Survival was estimated using the Kaplan-Meier approach. Univariate Cox proportional hazard models were used to estimate the hazard ratios for variables associated with survival. A subgroup analyses was performed for stage III patients who underwent chemotherapy to evaluate the prognostic significance of microsatellite instability in this group.

Results

Five hundred ninety-one (90.4%) patients were microsatellite stable (MSS) while 63 (9.6%) were microsatellite instable (MSI). Three years recurrence-free survival (RFS) and disease-specific survival (DSS) were 83.7 versus 73.7% (p = 0.295) and 87.1 versus 91.2% (p = 0.307) in MSS and MSI tumors, respectively. Among stage III patients who received adjuvant therapy, MSI status was found to be an adverse prognostic factor for RFS (HR 2.74 (95% CI 1.43–5.26), p = 0.002). This remained significant on multivariate analysis (HR 2.38 (95% CI 1.15–4.93), p = 0.018). Adjuvant chemotherapy was associated with survival benefit for patients with MSS tumors (HR 0.35, 95% CI 0.17–0.69, p = 0.002) but not MSI tumors (HR 0.67, 95% CI 0.08–8.15, p = 0.750).

Conclusions

MSI status is not a prognostic indicator in the general CRC population but appears to be an adverse prognostic indicator for RFS in stage III CRC patients who received adjuvant chemotherapy.

     

High rate of occult cancer found in prophylactic mastectomy specimens despite thorough presurgical assessment with MRI and ultrasound: findings from the Hereditary Breast and Ovarian Cancer Registration 2016 in Japan

Objective

To investigate ovarian function and therapeutic efficacy among estrogen receptor (ER)-positive, premenopausal breast cancer patients treated with gonadotropin-releasing hormone agonist (GnRHa) and chemotherapy simultaneously or sequentially.

Method

This study was a phase 3, open-label, parallel, randomized controlled trial (NCT01712893). Two hundred sixteen premenopausal patients (under 45 years) diagnosed with invasive ER-positive breast cancer were enrolled from July 2009 to May 2013 and randomized at a 1:1 ratio to receive (neo)adjuvant chemotherapy combined with sequential or simultaneous GnRHa treatment. All patients were advised to receive GnRHa for at least 2 years. The primary outcome was the incidence of early menopause, defined as amenorrhea lasting longer than 12 months after the last chemotherapy or GnRHa dose, with postmenopausal or unknown follicle-stimulating hormone and estradiol levels. The menstrual resumption period and survivals were the secondary endpoints.

Result

The median follow-up time was 56.9 months (IQR 49.5–72.4 months). One hundred and eight patients were enrolled in each group. Among them, 92 and 78 patients had complete primary endpoint data in the sequential and simultaneous groups, respectively. The rates of early menopause were 22.8% (21/92) in the sequential group and 23.1% (18/78) in the simultaneous group [simultaneous vs. sequential: OR 1.01 (95% CI 0.50–2.08); p = 0.969; age-adjusted OR 1.13; (95% CI 0.54–2.37); p = 0.737]. The median menstruation resumption period was 12.0 (95% CI 9.3–14.7) months and 10.3 (95% CI 8.2–12.4) months for the sequential and simultaneous groups, respectively [HR 0.83 (95% CI 0.59–1.16); p = 0.274; age-adjusted HR 0.90 (95%CI 0.64–1.27); p = 0.567]. No significant differences were evident for disease-free survival (p = 0.290) or overall survival (p = 0.514) between the two groups.

Conclusion

For ER-positive premenopausal patients, the sequential use of GnRHa and chemotherapy showed ovarian preservation and survival outcomes that were no worse than simultaneous use. The application of GnRHa can probably be delayed until menstruation resumption after chemotherapy.

     

Effects of metformin on survival outcomes of lung cancer patients with type 2 diabetes mellitus: a meta-analysis

Background

Anti-cancer effect of metformin on different kinds of lung cancer has been studied frequently. However, the association between metformin and the prognosis of lung cancer in type 2 diabetes patients is still controversial.

Methods

An electronic search was conducted using PubMed/Medicine, EMBASE and Cochrane library databases. Statistical analyses were carried out using either random-effects or fixed-effects models according to the heterogeneity examined by I ² statistics.

Results

Six studies involving 2350 patients were included in the current meta-analysis. In all, the pooled HR of overall survival (OS) was 0.90 (95 % CI 0.84–0.96; P = 0.003). Sub-group analysis showed that when stratified by region the HR of OS was 0.52 (95 % CI 0.31–0.87; P = 0.012) and 0.86 (95 % CI 0.67–1.11, P = 0.361) for Asian and Western countries. When stratified by study design, the HR of OS was 0.78 (95 % CI 0.52–1.15, P = 0.206) and 0.82 (95 % CI 0.59–1.16, P = 0.264) for cohort and medical data-based studies. When stratified by lung cancer subtype, HR of OS was 0.52 (95 % CI 0.31–0.87; P = 0.012), 1.06 (95 % CI 0.51–2.19; P = 0.878) and 0.82 (95 % CI 0.59–1.16; P = 0.264) for SCLS, NSCLC and non-divided subtypes, respectively.

Conclusion

Metformin use may associate with a good prognosis in lung cancer patients with type 2 diabetes but the effect was modest. However, it could achieve benefits in a selective sub-group of lung cancer patients especially in SCLC patients from Asian. Further studies are warranted to confirm this efficacy.

     

Tumor infiltrating lymphocytes in acral lentiginous melanoma: a study of a large cohort of cases from Latin America

Purpose

Acral lentiginous melanoma (ALM) is a poor prognosis subtype and is the most prevalent in non-Caucasian populations. The presence of tumor infiltrating lymphocytes (TILs) has been associated with poor prognosis in melanoma. A large cohort of ALM cases was studied to determine status of TIL and its association with outcome.

Methods

All patients with cutaneous melanoma presenting from 2005 to 2012 at Instituto Nacional de Enfermedades Neoplasicas in Peru were retrospectively identified. Clinicopathological information was obtained from the medical charts. A prospective evaluation of TIL was performed. Analysis of association between ALM and clinicopathological features including TIL as well as survival analysis compared the outcome of ALM to whole group and extremity NALM was performed.

Results

537 ALM from a total of 824 cutaneous melanoma cases were studied. Older age (p = 0.022), higher Breslow (p = 0.008) and ulceration (p < 0.001) were found to be more frequent in ALM. Acral had worse overall survival (OS) compared with the whole group (p = 0.04). Clinical stage (CS) I–II patients had a median OS of 5.3 (95% CI 4.3–6.2) for ALM and 9.2 (95% CI 5.0–7.0) for extremity NALM (p = 0.016). Grade 0 (absence of TIL), I, II and III were found in 7.5, 34.5, 32.1, and 25.9%, respectively. Lower TIL grade was associated with larger tumor size (p = 0.003), higher Breslow (p = 0.001), higher Clark level (p = 0.007), higher CS (p = 0.002), extremity location (p = 0.048), histological subtype ALM (p = 0.024) and better OS (p = 0.001).

Conclusions

ALM is highly prevalent in Peru and carries poor outcome. Lower TIL levels were associated with poor outcome and ALM.

     

Combination of anthracyclines and anti-CD47 therapy inhibit invasive breast cancer growth while preventing cardiac toxicity by regulation of autophagy

Background

The 21-gene recurrence score (RS) predicts outcome and benefit from adjuvant chemotherapy benefit in breast cancer patients treated with adjuvant endocrine therapy. In the NSABP B-28 study, we evaluated the 21-gene RS for its prognostic impact and its ability to predict benefit from paclitaxel (P) in node-positive, estrogen receptor-positive (ER+) breast cancer patients treated with adjuvant chemotherapy plus tamoxifen.

Methods

The B-28 trial compared doxorubicin/cyclophosphamide (AC) with AC followed by P in 3060 patients. Tamoxifen for 5 years was also given to patients > 50 years and those < 50 years with ER+ and/or progesterone receptor-positive (PR+) tumors. The present study includes 1065 ER-positive, tamoxifen-treated patients with RS assessment. Median follow-up time was 11.2 years.

Results

In univariate analyses, RS was a significant predictor of outcome. In multivariate analyses, RS remained a significant independent predictor of outcome beyond clinico-pathologic factors, age, and type of surgery (p < 0.001). In the study population (n = 1065), the disease-free survival (DFS) hazard ratio (HR) with adding P to AC was 0.87 (95% CI 0.72–1.05; p = 0.14). RS was not a significant predictor of P benefit: for DFS, HRs for adding P to AC in RS low, intermediate, and high subgroups were 1.01 (95% CI 0.69–1.47; p = 0.99), 0.84 (95% CI 0.62–1.14; p = 0.26), and 0.81 (95% CI 0.60–1.10; p = 0.21), respectively (interaction p = 0.64). Similar findings were observed for the other study endpoints.

Conclusions

RS maintains significant prognostic impact in ER-positive, node-positive patients treated with adjuvant chemotherapy plus tamoxifen. However, RS did not significantly predict benefit from adding paclitaxel to AC chemotherapy. (Trial Registration: PDQ: NSABP-B-28).

     

Availability of prior mammograms affects incomplete report rates in mobile screening mammography

Purpose

To identify modifiable factors predictive of long-term adherence to adjuvant endocrine therapy (AET).

Methods

As part of a 2-year cohort study in primary care (n = 116), we investigated whether initial treatment expectations predict adherence at 24 months after controlling for demographic, medical, and psychosocial variables. Treatment expectations were measured as necessity–concern beliefs, expected side-effect severity, and expected coping with side effects. Their stability over time and differences of trajectories between the adherent and nonadherent group were examined.

Results

Nonadherence at 24 months was 14.7% (n = 17). Side-effect severity at 3 months [OR 0.25, 95% CI (0.08, 0.81), p = 0.02] and necessity–concern beliefs [OR 2.03, 95% CI (1.11, 3.72), p = 0.02] were the sole predictors of adherence. Necessity–concern beliefs remained stable over 2 years, whereas expected side-effect severity (p = 0.01, η _p ²  = 0.07) and expected coping with side effects became less optimistic over time (p < 0.001, η _p ²  = 0.19), the latter particularly among nonadherers (p < 0.01, η _p ²  = 0.10).

Conclusions

Patients’ initial necessity–concern beliefs about the AET and early severity of side effects affect long-term adherence. Expecting poor management of side effects may also facilitate nonadherence. We suggest that discussing benefits, addressing concerns of AET, and providing side-effect coping strategies could constitute a feasible and promising option to improve adherence in clinical practice.

     

Factors predicting efficacy and adverse effects of enzalutamide in Japanese patients with castration-resistant prostate cancer: results of retrospective multi-institutional study

Background

We aimed to evaluate the factors predicting efficacy and adverse effects of enzalutamide in patients with castration-resistant prostate cancer.

Methods

We retrospectively evaluated data on 345 patients who had received enzalutamide for castration-resistant prostate cancer in 20 hospitals (Kyoto University Hospital and other satellite hospitals). Cox proportional hazards regression analysis was performed to identify factors predicting prostate-specific antigen (PSA) progression after enzalutamide treatment and logistic regression analysis for those associated with development of adverse effects.

Results

PSA titers decreased by >50 % in 197 patients (57 %). The median PSA progression free survival was 163 days. Gleason score >8 (HR 2.078, 95 % CI 1.37–3.153, P = 0.00058), performance status ≥1 (HR 2.292, 95 % CI 1.463–3.592, P = 0.000296), presence of bone metastasis (HR 1.774, 95 % CI 1.019–3.090, P = 0.0429), visceral metastasis (HR 2.127, 95 % CI 1.215–3.722, P = 0.00823), previous steroid treatment (HR 1.780, 95 % CI 1.207–2.626, P = 0.00361) and docetaxel treatment (HR 1.602, 95 % CI 1.051–2.442, P = 0.0284) significantly predicted the efficacy of enzalutamide. Adverse effects, including fatigue or appetite loss, occurred in 169 patients (49 %), 48 (18 %) of whom stopped enzalutamide. Age >75 years (HR 1.980, 95 % CI 1.270–3.09, P = 0.00246) and lower enzalutamide dose (HR 0.437, 95 % CI 0.255–1.270, P = 0.00249) were significantly associated with development of adverse effects.

Conclusions

Enzalutamide treatment is effective in patients with castration-resistant prostate cancer with low Gleason scores, good performance status, without bone or visceral metastasis and no prior steroid or docetaxel treatment. Lower doses of enzalutamide decrease the incidence of adverse effects, especially in older patients.

     

The relationship between polymorphisms of genes regulating DNA repair or cell division and the toxicity of platinum and vinorelbine chemotherapy in advanced NSCLC patients

Introduction

Platinum-based chemotherapy and 3rd generation drugs is still the main treatment option for advanced non-small cell lung cancer (NSCLC) patients without activating EGFR mutations or ALK rearrangements. However, the side effects associated with cytostatics are well known. Changes in the genes (e.g. single nucleotide polymorphisms, SNPs) encoding proteins regulating DNA repair or cell division could potentially influence on both the susceptibility of cancer cells to chemotherapy, and the occurrence of toxicities.

Materials and methods

In presented study, the relationship between the fourteen SNPs in nine DNA repair and cell division regulating genes: ERCC1, XPD, XPA, XPC, XRCC1, XPG, RRM1, BRCA1, STMN1 and the toxicity of first-line chemotherapy in NSCLC patients were investigated. SNPs were determined by SNaPshot PCR^® in DNA isolated from peripheral blood of 55 NSCLC patients treated with platinum compound and vinorelbine. The toxicity of therapy was evaluated according to the Common Toxicity Criteria (CTC) Version 4.03.

Results

The odds ratio (OR) of severe haematological toxicity was significantly lower in carriers of the T allele of XRCC1 gene (1196A > G, OR = 0.22, 95 % CI: 0.06–0.82, p  = 0.018) and higher in the carriers of the T allele (2704C > A) of XPC gene (OR: 7.50, 95 % CI: 0.89–63.17, p = 0.036) compared to the remaining patients. Risk of severe hepatotoxicity was significantly lower in carriers of the C allele of STMN1 (?2166T > C, OR = 0.09, 95 % CI: 0.01–1.12, p = 0.025) than in patients with T allele of this gene. In carriers of G allele (2251A > C, OR: 0.24, 95 % CI: 0.07–0.81, p = 0.017) and T (934G > A, OR: 0.26, 95 % CI: 0.07–0.90, p = 0.029) of XPD gene, risk of severe nephrotoxicity was significantly lower than in other patients.

Conclusions

Selected SNPs of genes encoding DNA repair enzymes and cell division regulation proteins could be useful biomarkers for prediction of platinum and vinorelbine-based chemotherapy toxicity in patients with advanced NSCLC.

     

The influence of familial factors on the choice of the place of death for terminally ill breast cancer patients: a retrospective single-center study

Background

The social or familial factors influencing the location chosen for end-of-life (EOL) care for terminally ill breast cancer patients are unknown.

Methods

We retrospectively analyzed 195 patients with recurrent or progressive breast cancer who received anticancer treatment at the National Cancer Center Hospital between January 2008 and May 2012. Detailed data concerning the patients’ demographic, familial, and clinical characteristics were collected, and multivariate and Cox logistic regression analyses were performed to evaluate the impact of these characteristics on the place of EOL care and on survival, respectively.

Results

Sixty-eight patients (34.9 %) died in a hospital, 26 patients (13.3 %) at home, and 101 patients (51.8 %) in hospice. Most of the patients having caregivers received EOL care at palliative care facilities (hospice or home) [odds ratio (OR) 2.57; 95 % confidence interval (CI) 1–6.6; p = 0.05]. In contrast, patients with factors suggesting a clinically severe status (performance status ≥2, use of opioids, delirium, and ascites) more often received EOL care in a hospital. Among patients who received EOL care at hospice or home, patients with minor children received EOL care at home (OR 0.08; 95 % CI 0.02–0.38; p = 0.001). Patients with brain metastases chose hospice (OR 12.37; 95 % CI 2.25–68.13; p = 0.004). Furthermore, having a caregiver was associated with prolonged survival (hazard ratio 0.62; 95 % CI 0.39–0.97; p = 0.035).

Conclusion

Familial factors such as having children and caregivers significantly influenced the place of EOL care for terminally ill breast cancer patients.

     

Clinical significance of TP53 (R72P) and MDM2 (T309G) polymorphisms in breast cancer patients

Introduction

TP53 gene is the most frequently altered tumor suppressor gene in breast cancer. It has been observed that MDM2 plays a central role in regulating the TP53 pathway. This study aimed to investigate the role of TP53 Arg72Pro and MDM2 T309G polymorphisms in breast cancer patients.

Material and method

The TP53 (Arg72Pro) and MDM2 (T309G) polymorphisms were studied in a hospital-based case control study by AS-PCR in 100 breast cancer patients and 100 healthy control subjects.

Results

It was observed that TP53 Arg72Pro polymorphism was significantly associated with breast cancer (χ ² = 9.92, p = 0.007). A significantly increased breast cancer risk was associated with the Proline allele [odds ratio 1.84 (95 % CI: 1.22–2.77), risk ratio 1.34 (95 % CI: 1.11–1.63), p value 0.003], HER2/neu status (p = 0.01) and distant metastasis (p = 0.05). On the other hand, we have found a significant correlation between MDM2 (T309G) polymorphism with HER2/neu status (χ ² = 11.14, p = 0.003) and distant metastasis (p value = 0.04).

Conclusion

Our finding suggests that TP53 (Arg72Pro) polymorphism may play a significant role as risk factor for breast cancer in north Indian breast cancer patients. While MDM2 (T309G) polymorphism may not be directly associated with the risk of breast cancer occurrence in the same population, but it may play role in disease progression by triggering TP53.

     

Adiposity,post-diagnosis weight change,and risk of cardiovascular events among early-stage breast cancer survivors

Purpose

We hypothesized different Overall Survival (OS) in metastatic breast cancer (MBC) after relapse vs de novo presentation.

Methods

We identified women in British Columbia with MBC diagnosed between 01/2001 and 12/2009. OS from MBC was calculated for relapsed vs de novo cohorts in 3 subgroups, based on hormone receptors (HR) and HER2 status. Age at MBC, disease-free interval (DFI), de novo vs relapsed, year of MBC diagnosis, and systemic treatment were entered into univariable and multivariable analyses.

Results

We identified 3645 pts with known HR of which 2796 had known HER2. Median follow-up was 91 months. Median OS was longer for de novo vs relapsed MBC: HR+/HER2- 34 versus 23 months (mos) (p < 0.0001), HR?/HER2- (TN) 11 versus 8 mos (p = 0.02), HER2+ 29 versus 15 mos (p < 0.0001). For TN disease, no variable independently discriminated a group with increased risk of death. For both the HR +/HER2- and the HER2 + groups, relapsed vs de novo status (HzR 1.4 [95% CI 1.2–1.5; p < 0.0001], and HzR 1.6 [95% CI 1.4–1.9; p < 0.0001], respectively) and age >50 (HzR 1.2 [95% CI 1.1–1.4; p = 0.001] and HzR 1.3 [95% CI 1.1–1.5; p = 0.01], respectively) were associated with increased risk of death on multivariable analysis.

Conclusion

These data provide information that may guide discussions about prognosis between physicians and patients with MBC. In addition, it highlights the importance of stratifying for initial stage at diagnosis in future MBC therapeutic trials.

     

Robotic gastrectomy for elderly gastric cancer patients: comparisons with robotic gastrectomy in younger patients and laparoscopic gastrectomy in the elderly

Background

Robotic surgery for gastric cancer has been adopted to overcome technical difficulties in performing laparoscopic gastrectomy. This study aimed to investigate the feasibility and safety of robotic gastrectomy in elderly gastric cancer patients.

Methods

Patients who underwent laparoscopic or robotic gastrectomy from 2003 to 2010 in a single high-volume center were included in this study. We retrospectively compared preoperative characteristics, perioperative factors, and oncological parameters among an elderly (≥70 years old) robotic gastrectomy group (n = 49), a younger (<70 years old) robotic gastrectomy group (n = 321), and an elderly laparoscopic gastrectomy group (n = 132).

Results

The elderly robotic group presented with more comorbidities than the younger robotic group. Except for number of retrieved lymph nodes (36.5 vs. 41.5; P = 0.007), short-term operative outcomes including complications and pathological parameters were comparable between the two robotic groups. The elderly robotic group showed comparable disease-specific survival to the younger robotic group although overall survival was worse. Compared to their laparoscopic counterparts, the elderly robotic group showed longer mean operation time (227 vs. 174 min). Nevertheless, the incidence and severity of postoperative complications was not different between the two elderly groups. Overall and disease-specific survival were also comparable between the elderly groups. In multivariate analysis, age and surgical approach were not risk factors for overall and major complications.

Conclusions

The outcomes of robotic gastrectomy in the elderly did not differ from those in younger robotic gastrectomy patients and were comparable to those in elderly patients who underwent laparoscopic gastrectomy. Thus, robotic gastrectomy could be a safe and feasible approach in elderly patients.