Postoperative chemoradiotherapy in patients with locally advanced gastric cancer with poor pathologic response to neoadjuvant chemotherapy.

PURPOSE: To evaluate the effect of postoperative chemoradiotherapy (CRT) in patients with locally advanced gastric cancer (LAGC) who respond poorly to neoadjuvant chemotherapy (ChT). MATERIALS AND METHODS: The database of a tertiary medical center (2009-2020) was retrospectively reviewed for patients with LAGC in whom the initial treatment strategy consisted of perioperative ChT and surgery. Those who were subsequently referred for postoperative CRT because of a poor pathologic primary-tumor response (ypT3-4, ypN2-3, R1 resection) were selected for the study. CRT consisted of 45 Gy in 25 fractions of 1.8 Gy combined with capecitabine 825 mg/m2 twice daily on radiotherapy days or continuous infusion of 5-fluorouracil 180 mg/m2/day. RESULTS: The cohort included 26 patients of median age 61 years with LAGC (clinical stage IIA-III) after surgery with D1-D2 lymphadenectomy. R0 resection was achieved in 15 (58%). The pathological stage was III in 69% (IIA-IVA). Treatment was well tolerated. During a median follow-up time of 39 months, recurrences were documented in 14 patients (54%): 11 distant and 3 locoregional. Median progression-free survival was 23 months, and median overall survival was 65 months. Estimated 5-year survival rates were 42 and 54%, respectively. CONCLUSIONS: This small retrospective study suggests that in patients with LAGC who show a poor pathologic response to neoadjuvant ChT, a good outcome relative to reference arms in randomized trials can still be achieved with the addition of postoperative CRT. Further studies of the benefit of a tailored adaptive treatment approach to LAGC based on the response to neoadjuvant ChT are warranted.

Sarcopenia as a Predictor of Survival in Patients with Pancreatic Adenocarcinoma After Pancreatectomy.

OBJECTIVE: To determine whether sarcopenia can potentially predict worse survival after resection of pancreatic ductal adenocarcinoma. BACKGROUND: Sarcopenia is correlated with poor outcomes in hepatopancreatobiliary malignancies, but the relationship of both its qualitative and quantitative features with patient survival after pancreatectomy has not been investigated in a western population. PATIENTS AND METHODS: Preoperative cross-sectional computed tomography scans of consecutive patients who underwent pancreatectomy in 2005-2017 were evaluated for skeletal muscle index (SMI), intramuscular adipose tissue content (IMAC), and visceral-to-subcutaneous adipose tissue area ratio (VSR). Sex-specific categorical cut-offs were determined. Findings were correlated with outcome. RESULTS: The study included 111 patients, 47% of whom were female, with a median age of 67 years (range: 35-87 years), and median body mass index of 23 kg/m2 (range: 16-40 kg/m2); 77% had a Whipple procedure and 66% received adjuvant chemotherapy. Low SMI correlated with poor overall survival (OS) (P = 0.007), disease-specific survival (DSS) (P = 0.006), and recurrence-free survival (RFS) (P = 0.01). High IMAC correlated with poor OS (P = 0.04). Patients with high IMAC tended to have a shorter DSS (P = 0.09), with no correlation with RFS (P = 0.6). VSR was not associated with survival. Multivariable analysis yielded an independent association of low SMI with OS (HR = 1.7, 95%CI: 1.1-2.8, P = 0.02), DSS (HR = 1.8, 95%CI: 1.03-3.2, P = 0.04), and RFS (HR = 1.8, 95%CI: 1.1-2.8, P = 0.01), and of high IMAC with OS (HR = 1.9, 95%CI: 1.1-3.1, P = 0.01). CONCLUSION: Both qualitative and quantitative measures of skeletal muscle were independently associated with impaired survival in patients with resectable PDAC. Sarcopenia might serve as an early radiographic surrogate of aggressive tumor behavior, with potential implications for clinical decision-making and future study.

Neutrophil-to-Lymphocyte Ratio Predicts Recurrence Pattern in Patients with Resectable Colorectal Liver Metastases.

BACKGROUND: Studies have suggested that neutrophil-to-lymphocyte ratio (NLR) has value as a predictor of long-term outcomes in various cancer types. Its prognostic potential in patients with CRLM has not been thoroughly investigated. This original, retrospective study assessed the relationship between the preoperative NLR, survival outcomes, and recurrence patterns in patients after colorectal liver metastasis resection (CRLM). METHODS: The prospectively maintained database of a tertiary medical center was queried for all patients who underwent CRLM resection between 2005 and 2017. Patients were divided into two groups: NLR <3 (normal) or >3 (high). Recurrence risk was analysed using Fine and Gray correction for competing risk method and cause specific analyses. RESULTS: The cohort included 231 patients of whom 53 (23%) had a high neutrophil-to-lymphocyte ratio. At presentation, 35% had synchronous disease and 48% had a solitary metastasis; median tumor size was 2 cm. Patients with a high NLR had a significantly higher rate of simultaneous colorectal resection (P = 0.01). A high NLR was independently associated with worse OS (P = 0.02), worse DFS (P = 0.03), and higher risk of recurrence (P = 0.048), specifically recurrence with an extrahepatic pattern (P = 0.03). CONCLUSIONS: A high preoperative NLR was independently associated with poorer survival outcomes and extrahepatic recurrence pattern. The NLR appears to have prognostic importance in CRLM and may serve as a surrogate marker of aggressive systemic disease after resection. These findings warrant external validation, preferably in a prospective design.

Signet Ring Cell Features are Associated with Poor Response to Neoadjuvant Treatment and Dismal Survival in Patients with High-Grade Esophageal Adenocarcinoma.

BACKGROUND: While the prognosis of patients with locoregional esophageal adenocarcinoma (EAC) has improved in the neoadjuvant treatment (NAT) era, high-grade histology (G3) is still associated with a limited treatment response. We sought to investigate oncologic outcomes in patients after esophagectomy for G3 EAC and to identify predictors of poor survival among these patients. METHODS: Patients with EAC who underwent resection with curative intent in 2011-2018 were divided by histologic grade (G3, G1/2) and compared for overall survival (OS). Cox regression was performed to analyze the response to NAT and the predictive role of signet ring cell (SRC) features. RESULTS: The cohort included 163 patients, 94 (57.7%) with G3 histology. NAT was administered to 69 (73.4%) patients. Following resection, OS in the G3 EAC group was 30 months (95% confidence interval [CI] 23.9-36.1). On univariate analysis, G3 disease (p = 0.050) and SRC features (p = 0.019) predicted low OS. Median survival in the G3 EAC group was worse in patients with SRC histology (18 months, 95% CI 8.6-27.4) than those without (30 months, 95% CI 23.8-36.1; p = 0.041). No patients with SRC histology were alive at 5 years of follow-up. Among all patients administered NAT, 88.2% of those with SRC showed minimal or no pathologic response and only 27.8% were downstaged. CONCLUSIONS: High-grade histology was found in most patients with EAC and predicted poor survival and treatment response. SRC features in patients with G3 disease were associated with lower OS. The benefit of NAT for G3 EAC in patients with SRC histology appears limited.

Efficacy of immune-checkpoint inhibitors in metastatic gastric or gastroesophageal junction adenocarcinoma by patient subgroups: A systematic review and meta-analysis.

BACKGROUND: Efficacy of immune checkpoint inhibitors (ICIs) in metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma is inconsistent. Whether the efficacy of ICIs is comparable across different subgroups remains unknown. METHODS: We identified randomized controlled trials (RCTs) that compared standard treatment for metastatic gastric/GEJ adenocarcinoma to ICIs. Hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival (OS) were extracted and pooled in a meta-analysis. Prespecified subgroups were included as follows: age at randomization (65 years), gender (female vs male), ethnicity (Asians vs non-Asians), performance-status (0 vs 1), tumor location (gastric vs GEJ), and histological subtype (diffuse vs others). OS in patients with programmed death ligand (PD-L1) positive and with microsatellite instability-high (MSI-H) were also extracted and pooled in a meta-analysis. RESULTS: Five RCTs comprising 2,264 patients were analyzed. Compared to standard therapy, ICIs did not improve OS (HR = 0.86, 95% CI 0.71-1.03, P = .10) and the effect of ICIs on OS was similar in all subgroups. Nonsignificantly greater effect sizes were seen in older patients (HR = 0.85 vs 0.88, P = .81), male (HR = 0.82 vs 0.99, P = .16), Asians (HR = 0.86 vs 0.96, P = .55), performance-status 0 (HR = 0.84 vs 0.88, P = .81), GEJ tumors (HR = 0.78 vs 0.90, P = .37), and nondiffuse subtype (HR = 0.71 vs 0.79, P = .62). ICIs were associated with significantly improved OS in patients with MSI-H (HR = 0.33, P = .001), but not in PD-L1 positive disease (HR = 0.86, P = .06). CONCLUSIONS: Compared to standard treatment, ICIs in metastatic gastric/GEJ adenocarcinoma did not improve OS. None of the evaluated subgroups has shown increased magnitude of effect to ICIs, aside of the small group with MSI-H tumors.

Early PET-CT in patients with pathological stage III colon cancer may improve their outcome: Results from a large retrospective study.

BACKGROUND: Current staging of pathological stage III colon cancer (CC) is suboptimal; many patients recur despite unremarkable preoperative staging. We previously reported that early postoperative PET-CT can alter the stage and management of up to 15% of patients with high-risk stage III CC. This study aimed to determine the role of the test in the general stage III CC population. METHODS: A retrospective study of all consecutive patients with stage III CC who underwent early postoperative PET-CT between 2005 and 2017. RESULTS: A total of 342 patients, 166 (48.5%) males, median age 66 years (range, 29-90), were included. Pathological stage was IIIA, IIIB, and IIIC in 18 (5.3%), 257 (75.1%), and 67 (19.6%) patients, respectively. Median number of positive lymph nodes was 2 (range, 0-32). PET-CT results modified the management of 46 patients (13.4%): 37 (10.8%) with overt metastatic disease and 9 (2.6%) with a second primary. The 5-year disease-free survival for true stage III patients was 81%. The median overall survival for the entire cohort and for true stage III patients was not reached and was 57.2 months for true stage IV. Of the 37 patients found to be metastatic, 14 (37.8%) underwent curative treatments and 9/14 (64.3%) remain disease-free, with a median follow-up of 83.8 months. Predictive factors for upstaging following PET-CT were identified. CONCLUSION: Early postoperative PET-CT changed the staging and treatment of 13.4% of stage III CC patients and has the potential for early detection of curable metastatic disease. Outcome results are encouraging. Prospective validation is ongoing.

Brain metastasis in gastroesophageal adenocarcinoma and HER2 status.

The increased survival of patients with gastroesophageal adenocarcinoma (GAD) following improvements in treatment has been accompanied by a rising incidence of secondary brain metastasis. HER2 amplification/overexpression, which has been associated with an increased risk of brain metastasis in breast cancer, is found in about 20% of patients with GAD. The aim of this study was to evaluate the effect of HER2 status on brain metastasis in GAD. The database of a tertiary cancer center was searched for patients with GAD diagnosed in 2011-2015, and data were collected on clinical characteristics, brain metastasis, HER2 status, and outcome. We identified 404 patients with a confirmed diagnosis of GAD. HER2 results were available for 298: 69 (23.2%) positive and 227 negative. Brain metastasis developed in 15 patients with GAD (3.7%); HER2 results, available in 13, were positive in 6, negative in 6, and equivocal in 1. The brain metastasis rate was significantly higher in HER2-positive than HER2-negative patients with GAD (6/69, 8.7% vs. 6/227, 2.6%; RR = 3.3, 95% CI 1.1-9.9, p = 0.034). Median overall survival from diagnosis of brain metastasis was 2.3 months, with no significant difference by HER2 status. HER2 positive GAD patients may be at increased risk to develop BM. Clinicians should maintain a lower threshold for performing brain imaging in patients with HER2-positive GAD given their increased risk of brain metastasis. The role of anti-HER2 agents in the development and treatment of brain metastasis in GAD warrants further study.

Esophageal Cancer in Israel has Unique Clinico-Pathological Features: A Retrospective Study.

Introduction: Data regarding esophageal cancer (EC) in Israel are limited. The aim of this study was hence to characterize this entity in the Israeli population and to compare it to the literature. Patients/Methods: This is a retrospective study of all consecutive EC patients treated at our institution between 1997-2013. Data were retrieved from patients' medical files. Results: Two hundred patients were included. The median age at diagnosis was 70.5 years; 63.5% were males; 63% were Ashkenazi Jews, 29% were Sephardic Jews, and 0.5% were Arabs. Squamous cell carcinoma (SCC) was predominant: 52% versus 45.5% with adenocarcinoma (ADC). SCC was common even in the distal esophagus (45%). The overall 5-year survival rate was 25.5%. A temporal trend (2006-2013 vs 1997-2005) shows a decline in the proportion of SCC (47% vs 63%, p=0.061) and a rise in ADC (50% vs 33%, p=0.041), with a parallel decrease in patients' age (median: 68.5 vs 73 years, p=0.014). In the later period, patients received more treatment for localized and metastatic disease, with a trend for improved median survival (20.1 vs 14.9 months, p=0.658). Ashkenazi Jews were diagnosed at an older age than Sephardic Jews (median: 73 vs. 65 years, p=0.001), had a higher rate of family history of GI cancer (34% vs. 17%, p=0.026) and a higher rate of cardiovascular co-morbidity (41% vs. 24%, p=0.041). Conclusion: EC in Israel represents an intermediate entity between the Western and the endemic subtypes, showing some unique features. These included delayed reversal of the SCC/ADC ratio, commonness of SCC in the distal esophagus, prevalence of other malignancies and predominance of Ashkenazi ethnicity. The reason for these findings is unclear and its further evaluation is warranted.

[FERTILITY PRESERVATION IN YOUNG CANCER PATIENTS - CAN WE OPTIMIZE THE PATH?]

INTRODUCTION: Advances in cancer therapy have improved the long-term survival of cancer patients. Concerns about fertility represent a major issue for young cancer patients. The emergent discipline of oncofertility, an intersection between oncology and fertility, is a new concept that describes an integrated network of clinical resources that focus on fertility preservation from both clinical and research perspectives. Patients and methods: In this article we describe our designated multidisciplinary program for fertility preservation in pediatric and young adult populations. The program is also designed to serve as a prospective platform for the evaluation of reproductive outcomes in this patient cohort. RESULTS: We have observed considerably higher referral rates following launching the program and earlier referral of chemonaïve patients that concedes maximal fertility preservation. Two hundred and thirty five patients were referred to the program over a period of 3 years. CONCLUSIONS: Our program demonstrates that multidisciplinary programs that encompass relevant specialists, skilled laboratory resources and a facilitated path that drives the process in the shortest time, maximizes the yield.

The impact of oxaliplatin on the gonads: from bedside to the bench.

STUDY HYPOTHESIS: What is the impact of oxaliplatin on gonadal function? STUDY FINDING: Our results in both the clinical and pre-clinical settings indicate that oxaliplatin exerts moderate transient gonadal toxicity. WHAT IS KNOWN ALREADY: Recent studies have indicated a significant increase in survivorship of colorectal cancer patients of reproductive age, who may then face fertility concerns. The impact of oxaliplatin on gonadal function is yet to be discovered. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Eleven female (<43 years) and eight male (<45 years) patients recently diagnosed with colorectal cancer, who were candidates for oxaliplatin-based protocol, were enrolled into the study. FSH, estradiol, anti-Müllerian hormone (AMH) and menstrual pattern were measured in female patients, whereas FSH, inhibin-B, testosterone, and steroid-hormone binding globulin were measured in male patients. Hormones were measured at baseline and 6 months post-treatment (last chemotherapy administration) in men and women. In the animal model, pubertal mice were injected with oxaliplatin and sacrificed 1 week, 1 month and 3 months later. Ovarian reserve was estimated by serum AMH measurements. Testicular function was evaluated by serum inhibin-B and sperm evaluation. Gonadal apoptosis (TUNEL), proliferation (Ki-67), repair (PCNA), ovarian reserve (AMH) and testicular reserve (DAZL) were measured by immunohistochemistry. MAIN RESULTS AND THE ROLE OF CHANCE: In all women, AMH decreased post-treatment, but remained above the detection limit in 9/11 patients (P < 0.05). FSH was elevated, but did not exceed the premenopausal range in 9/11 patients. All patients remain menstruating or resumed menstruation post-treatment. In female mice oxaliplatin induced transient apoptosis at 1-month post-treatment. In men Inhibin-B was slightly reduced post-treatment. In male mice oxaliplatin did not affect spermatozoa concentration, but was associated with transient, moderate reductions of spermatocytes-spermatogonia numbers and spermatozoa motility. LIMITATIONS, REASONS FOR CAUTION: Future prospective large-scale studies are warranted in order to affirm these outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Due to high survival rates of colorectal cancer patients of reproductive age that were diagnosed at early stages of the disease, the issue of treatment-induced gonadotoxicity gains significance. Since at the individual level there might be a risk of infertility, a detailed discussion and referral to fertility preservation prior to initiation of treatment is recommended. Nevertheless, oxaliplatin-based protocols appear to be less gonadotoxic than other chemotherapeutic protocols. LARGE SCALE DATA: None. STUDY FUNDING AND COMPETING INTERESTS: This study was supported by the Israeli Science Foundation (ISF) grant 13-1816 (I.B.-A.). There is no conflict of interest.

Addition of taxane to induction therapy in head and neck malignancies: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Head and neck cancer, mostly squamous cell carcinoma, ranks sixth among the most common cancers. Despite progress in treatment in recent years, survival remains poor. Since induction chemotherapy has been associated with survival benefit, it is a reasonable treatment option. The standard protocol up to recently has been cisplatin and 5-flourouracil. The addition of taxanes to the standard induction protocol has shown superiority in terms of the overall response rate. Nevertheless, not all trials demonstrated survival benefit. We aimed to evaluate the effect of taxane added to the standard protocol of induction therapy. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials that compared the addition of taxane to the standard induction protocol of cisplatin and 5-flourouracil for patients with head and neck malignancy. We searched The Cochrane library, PubMed, LILACS, conference proceedings, and references of published trials. Two reviewers independently assessed the quality of the trials and extracted data. Hazard ratios (HRs) for time-to-event were determined and pooled. RESULTS: A total of 4 trials comprising 1,441 patients were included in this meta-analysis. All patients were available for the meta-analysis of overall survival. Patients treated with the addition of taxane had statistically significant overall survival [HR = 0.82, 95% confidence interval (CI) 0.71-0.94] and progression-free survival (HR = 0.82, 95% CI 0.72-0.93). No effect was observed in larynx preservation rate (relative risk = 0.88, 95% CI 0.64-1.19). The rate of hematological adverse events was higher in the taxane group than in the control group. CONCLUSIONS: These results suggest that induction therapy with the addition of taxane is superior to induction therapy with cisplatin and 5-flourouracil in terms of overall survival and progression-free survival. The higher rate of neutropenia and neutropenic fever should be taken into consideration when making treatment decisions.