Total Lesion Glycolysis Assessment Identifies a Patient Fraction With a High Cure Rate Among Esophageal Adenocarcinoma Patients Treated With Definitive Chemoradiation.

OBJECTIVE: We aimed to determine whether tumor metabolism could be prognostic of cure in L-EAC patients who receive definitive chemoradiation. SUMMARY BACKGROUND DATA: Patients with inoperable localized esophageal adenocarcinoma (L-EAC) often receive definitive chemoradiation; however, biomarkers and/or imaging variables to prognosticate cure are missing. METHODS: Two hundred sixty-six patients with L-EAC who had chemoradiation but not surgery were analyzed from the prospectively maintained EAC databases in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center (Texas, USA) between March 2002 and April 2015. Maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) from the positron emission tomography data were evaluated. RESULTS: Of 266 patients, 253 (95%) were men; the median age was 67 years (range 20-91 yrs) and 153 had poorly differentiated L-EAC. The median SUVmax was 10.3 (range 0-87) and the median TLG was 85.7 (range 0-3227). Both SUVmax and TLG were higher among those with: tumors >5 cm in length, high clinical stage, and high tumor and node categories by TNM staging (all P < 0.0001). Of 234 patients evaluable for cure, 60 (25.6%) achieved cure. In the multivariable logistic regression model, low TLG (but not low SUVmax) was associated with cure (continuous TLG value: odds ratio 0.70, 95% confidence interval (CI) 0.54-0.92). TLG was quantified into 4 quartile categorical variables; first quartile (Q1; <32), second quartile (Q2; 32.0-85.6), third quartile (Q3; 85.6-228.4), and fourth quartile (Q4; >228.4); the cure rate was only 10.3% in Q4 and 5.1% in Q3 but increased to 28.8% in Q2, and 58.6% in Q1. The cross-validation resulted in an average accuracy of prediction score of 0.81 (95% CI, 0.75-0.86). CONCLUSIONS: In this cross-validated model, 59% of patients in the 1st quartile were cured following definitive chemoradiation. Baseline TLG could be pursued as one of the tools for esophageal preservation.

Efficacy of Three-Drug Induction Chemotherapy Followed by Preoperative Chemoradiation in Patients with Localized Gastric Adenocarcinoma.

BACKGROUND: Preoperative induction chemotherapy followed by chemoradiation yields better R0 resection rates, pathologic complete response (pCR) rates and improved survival for localized gastric adenocarcinoma (GAC). We report the effect of three-drug induction chemotherapy on a large cohort of localized GAC patients. METHODS: We identified 97 patients with localized GAC who received three-drug induction chemotherapy followed by preoperative chemoradiation therapy. We assessed various endpoints (overall survival [OS], recurrence-free survival [RFS], R0 resection and pCR rate). RESULTS: The median follow-up time was 3.5 years (range; 0.4-16.7). The induction chemotherapy regimen was a fluoropyrimidine and a platinum compound (cisplatin or oxaliplatin) with a taxane (docetaxel or paclitaxel) for 95% of patients. Seventy-three (75.3%) out of 97 patients underwent planned surgery. R0 resection and pCR rae were 93.2 and 20.6%, respectively. Pathologic partial response (<50% residual carcinoma) rate was 50.7%. The median OS was 6.4 years (95% Cl 3.3-12.4) for the entire cohort and 11.1 years (95% Cl 7.1-not estimable) for patients that underwent surgery. The estimated 2- and 5-year OS rates were 72.4% (95% CI 62.1-80.3) and 54.3% (95% CI 43.2-64.1) for the entire cohort and 83.2% (95% CI 72.3--90.1) and 66% (95% CI 52.3-75.8) for patients that underwent surgery. Pathologic lesser stage (stage I/II vs. stage III/IV) (p = 0.001) and R0 resection (p = 0.02) were independently associated with longer RFS in the multivariate analysis. CONCLUSION: Our data shows that three-drug combination is feasible without providing substantial advantage compared with two-drug combination in this setting of preoperative induction chemotherapy followed by chemoradiation and surgery.

Potentially curable gastric adenocarcinoma treated without surgery.

BACKGROUND: Surgery is the best option for cure of localised gastric adenocarcinoma (GAC). When surgery is not possible due to comorbidities or patient choice, definitive chemoradiation is an option. We report on one of the largest cohorts of localised GAC patients who did not have surgery. METHODS: We identified 71 patients with localised GAC who received chemo/chemoradiation therapy but did not have surgery. We assessed various end-points: overall survival (OS), relapse-free survival (RFS), and clinical complete response (cCR; negative post therapy biopsy and no evidence of cancer by imaging). RESULTS: The median follow-up time was 1.8 years (range; 0.4-10.6). Most of the patients were men (64.8%), and the median age was 73 years (range; 30-96). Reason for not having surgery included comorbidities in 34 (47.9%), poor performance status 14 (19.7%), and patient refusal 23 (32.4%). Of all 71 patients, a complete restaging evaluation with endoscopy and imaging could be performed for 50, and 32 (45.1%) achieved a cCR. For the entire cohort, the median OS was 2.1 years (95% confidence interval [CI] 1.78-2.55). The estimated OS rates at 2 and 5 years were 54% and 18%, respectively. Female gender (HR 0.39, 95% CI 0.16-0.98, p = 0.045) and chemoradiation (HR 0.25, 95% CI 0.06-1.01; p = 0.05) were independently associated with longer OS in the multivariate analysis. CONCLUSION: Our data show that patients with localised GAC treated with chemotherapy and/or chemoradiation, who do not undergo surgery, have a 5-year OS rate of 18%.

Diagnostic serum vitamin D level is not a reliable prognostic factor for resectable breast cancer.

AIM: There are inconsistent results about the effects of vitamin D level on breast cancer prognosis. We aimed to investigate the effect of vitamin D levels on the prognosis of resectable breast cancer in a patient group with highly different clothing styles. PATIENTS & METHODS: A total of 186 breast cancer patients were enrolled in the study. RESULTS: Vitamin D level was sufficient, insufficient and deficient in 17.2, 52.2 and 30.6% of patients, respectively. There was a significant relationship between clothing style and serum 25 (OH) D levels. We could not establish any relation between vitamin D level and tumor characteristics or survival. CONCLUSION: Vitamin D supplementation can be more important than diagnostic serum vitamin D level on prognosis of breast cancer.

Barrett's Esophagus after Bimodality Therapy in Patients with Esophageal Adenocarcinoma.

INTRODUCTION: Barrett's esophagus (BE) may be present in patients with esophageal adenocarcinoma (EAC) after bimodality therapy (BMT). There is no specific guidance for follow-up of these patients with regard to the presence of BE or dysplasia. In this study, we assessed the outcomes of patients who, after BMT, had BE and those who did not. METHOD: Patients with EAC who had BMT were identified and analyzed retrospectively in two groups, with and without BE. We compared patient characteristics and outcome variables (local, distant, and no recurrence). RESULTS: Of 228 patients with EAC, 68 (29.8%) had BE before BMT. Ninety-eight (42.9%) had BE after BMT, and endoscopic intervention was done in 11 (11.2%). With a median follow-up of 37 months, the presence of post-BMT BE was not significantly associated with overall survival (OS) and local recurrence-free survival (LRFS). Similarly, endoscopic intervention was not significantly associated with OS and LRFS. Fifty (73.5%) patients with BE before BMT had BE after BMT (p < 0.0001). CONCLUSION: The presence of BE after BMT was not associated with increased risk of local recurrence. The local recurrence rate was not influenced by endoscopic intervention. Prospective studies are warranted to generate guidance for intervention, if necessary, for this group of EAC patients.

Customization of therapy for gastroesophageal adenocarcinoma patients.

Gastroesophageal adenocarcinomas (GEACs) remain a global health problem. These are most often diagnosed at advanced stage and the estimated 5-year relative survival rate is about 5%. Although cure is not possible for patients with advanced GEAC, systemic therapy (chemotherapy or biochemotherapy) can palliate symptoms, improve survival and provide a better quality of life. One of the most promising options for some patients with advanced stage GEAC is immunotherapy, which can result in durable responses. Numerous phase III trials evaluating targeted therapies in different lines are ongoing and it is hoped that better biomarkers will emerge to identify patients who can benefit from targeted agents and immunotherapy in the future. Surgery remains as the corner stone for localized GEAC and adjunctive therapies can increase the survival rates by about 10%. The high toxicity and low completion rates of adjuvant therapy led to the strategies of preoperative treatment. With the results of ongoing pre-operative therapy trials we will be able to determine the optimal adjunctive approach for resectable GEAC.

Current therapeutic landscape for advanced gastroesophageal cancers.

Treatment of advanced gastroesophageal cancers remains challenging for clinicians, patients, and caregivers alike. Despite considerable research, the therapeutic armamentarium is restricted and hardly personalized. In the first-line setting, trastuzumab with a fluoropyrimidine and platinum agent is the standard-of-care in patients with HER2-positive tumor. For the others, a platinum-based doublet (preferably with oxaliplatin) is recommended. Three-drug cytotoxic regimens should be reserved for exceptional cases where patients have good performance status. Triple combinations produce higher toxicity and provide marginal advantage. In the second line setting, the combination of paclitaxel and ramucirumab is preferred over all others. Currently, nothing is approved in the 3rd or later line. Nivolumab has resulted in an improved benefit in an Asian trial. Early trials of TAS-102, STAT3 inhibitors, anti-claudin 18.2 and other immune checkpoint inhibitors (alone or in combination) are ongoing. However, development of reproducible biomarkers for patient enrichment is critical for future progress.

Personalized therapy based on image for esophageal or gastroesophageal junction adenocarcinoma.

Preoperative therapy is the gold standard for esophageal or gastroesophageal junction adenocarcinoma. Positron emission tomography (PET) is not only essential for tumor staging, but changes in glucose consumption correspond with response to therapy and correlated with prognosis. Therefore, with further refinement, PET parameter can serve as a tool for personalized therapy. For instance, the Municon trials suggested the possibility of PET-response guided therapy for esophageal adenocarcinoma (EAC) patients, however there are limitations. New PET parameters such as total lesion glycolysis (TLG) or magnetic resonance imaging (MRI) may provide better response prediction. Furthermore, PET parameters combined with genomic profiling might enhance better treatment selection, prediction, and prognostication. Here, we summarized the current state of understanding and future possibilities.

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial.

BACKGROUND: A randomised phase 2 trial of trimodality with or without induction chemotherapy (IC) in oesophageal cancer (EC) patients showed no advantage in overall survival (OS) or pathologic complete response rate. To identify subsets that might benefit from IC, a secondary analysis was done. METHODS: The trial had accrued 126 patients (NCT 00525915). Recursive partitioning and proportional hazards regression with interactions were performed. RESULTS: The median follow-up of surviving patients was 6.7 years and the median OS duration was 3.8 years (95% confidence interval (CI), 2.6-5.8 years). OS was associated with tumour length (P=0.03), cT (P=0.02), cN (P=0.04), clinical stage (P=0.01), and tumour grade (P<0.001). The effect of IC differed according to tumour grade. Among patients with well or moderately differentiated (WMD) ECs (n=59), the 5-year survival rate was 74% with IC and 50% without IC, P=0.001. IC had no effect on OS of patients with poorly differentiated (PD) ECs (31% and 28%, respectively; interaction, P=0.04; IC, P=0.03). In the multivariate reduced model, WMD with IC was an independent prognosticator for better OS (HR=0.41, 95% CI, 0.25-0.67; P=<0.001). The following four EC phenotypes emerged for OS: (1) very high risk (PD, cN2/N3), (2) high risk (PD, cN0/N1, stage cIII), (3) moderate risk (PD, cN0/N1, stage cI/II or WMD without IC), and (4) low risk (WMD with IC). The 5-year survival rates were 11%, 27%, 48%, and 74%, respectively (P<0.001). CONCLUSIONS: Our data show that IC significantly prolonged OS of WMD EC patients who undergo trimodality; prospective evaluation is needed.

Liquid biopsies in gastrointestinal malignancies: when is the big day?

INTRODUCTION: Tumor tissue sample is currently the gold standard for diagnosing gastrointestinal cancers, but also for genomic/immune component analyses that can help in the selection of therapy. However, this approach of studying a 'representative' sample of the tumor does not address inherent heterogeneity. Liquid biopsies, mainly represented by circulating tumor cells, circulating tumor DNA, tumor exosomes, and microRNAs, have the potential to assess various biomarkers for early detection of cancer, carrying out genomic/immune profiling for not only selection of appropriate therapy but also to monitor effect of therapy. Areas covered: This review summarizes the current evidence in the literature on liquid biopsies in gastrointestinal cancers concerning diagnosis, prognosis, and response to therapy. The following terms were used in PubMed: 'esophageal', 'gastric', 'colorectal', 'cancer', 'circulating tumor cells', 'circulating tumor DNA', microRNA', 'diagnosis', 'prognosis', 'response', 'resistance'. Expert commentary: Data increasingly supports the potential of liquid biopsies for early detection, selection of therapy, and monitoring response to therapy. One major question is whether assaying various components of the blood would accommodate considerable context-dependent heterogeneity of gastrointestinal tumors. There are many potential strategies to exploit liquid biopsy use. To put them in to perspective, well-designed and meticulous prospective studies will be needed to prove their usefulness.

Risk of peritoneal metastases in patients who had negative peritoneal staging and received therapy for localized gastric adenocarcinoma.

BACKGROUND: Positive peritoneal cytology (+PCyt) or gross carcinomatosis (GPC) carries a poor prognosis. Laparoscopic staging to detect +PCyt/GPC is recommended for all ≥T1b gastric adenocarcinoma (GAC). The natural history of patients with GAC who have baseline -PCyt and then undergo multimodality therapy is not well documented, particularly for the risk of subsequent GPC. METHODS: We identified 238 GAC patients with baseline -PCyt who were followed for the development of peritoneal carcinomatosis (PC). Standard statistical methods were employed. RESULTS: Of 238 patients, 192 had attempted surgery after preoperative therapy. Of these, 13 patients (6.8%) had GPC and one had liver metastases, thus surgery was aborted. We followed 164 patients who had an R0 resection. The median follow-up duration was 3.4 (range, 0.6-18) years. The rate of PC was 13.4%, (22/164 patients) and the median time to PC was 15.6 months. Female gender was associated with PC on multivariate analysis. The 5-year OS rate for patients without subsequent PC was 75%. Conclusion Even with baseline -Cyt, ∼25% of patients develop PC following multimodality therapy. Patients who do not develop PC have an excellent OS rate. Further research is warranted to detect PC at baseline by the use of biomarkers.

Early Metabolic Change after Induction Chemotherapy Predicts Histologic Response and Prognosis in Patients with Esophageal Cancer: Secondary Analysis of a Randomized Trial.

BACKGROUND: Early metabolic response after preoperative induction chemotherapy (IC) appears to predict histologic response and prognosis in esophageal cancer (EC), but the usefulness of this approach needs further development. OBJECTIVE: We evaluated metabolic response after one cycle of IC using positron emission tomography (PET) to correlate PET response and outcomes. PATIENTS AND METHODS: We retrospectively analyzed PET data from a randomized phase 2 trial (NCT00525915) of chemoradiation and surgery with or without IC for the treatment of EC. PET was performed at baseline, after one cycle of IC, and 5-7 weeks after chemoradiation. The relationship between PET response (≥35% reduction in standardized uptake value [SUV]) after IC and treatment response was analyzed. RESULTS: In 63 patients who received IC, the mean initial SUVmax prior to treatment was 11.9 ± 8.04 and mean SUVmax after one cycle of IC was 6.47 ± 4.45. The mean SUV reduction after IC was 39.3%. Eleven of 37 PET responders achieved a pathologic complete response (pCR), but only two of 22 PET non-responders did (univariate logistic regression; odds ratio: 4.25, 95% confidence interval: 0.83-21.77; p = 0.08). PET responders to IC had significantly longer overall survival (OS) than PET nonresponders (log-rank p = 0.009). PET response after chemoradiation was not correlated with OS (log-rank p = 0.15). CONCLUSION: Early PET response after IC is prognostic, but subsequent PET changes (for example, after chemoradiation) are not prognostic. Early PET response might have the potential of predicting pCR.

Post-trimodality expression levels of metadherin (MTDH) as a prognostic biomarker for esophageal adenocarcinoma patients.

Resectable esophageal adenocarcinoma (EAC) patients often receive chemoradiation followed by surgery. However, most patients experience recurrences. Overexpression of MTDH, an oncoprotein with multiple functions, has been found to be associated with poor prognosis in breast cancer, glioblastoma, melanoma and various gastrointestinal malignancies, but not in EAC. We sought to establish its role in resistant EAC (post-treatment residual EAC). MTDH was assessed by immunohistochemistry in resected EAC, and results were correlated with clinical outcomes. MTDH expression was detectable in 72.5% (50/69) of patients, while expression levels were high (positive) in 50.7% (35/69). Of 69 patients analyzed, 25 had no relapse and 44 patients had a relapse (8 with local-regional and 36 with distant). The median follow-up duration was 3 years (0.4-11.6). The median overall survival was not associated with MTDH status (2.79 years for MTDH-negative and 3.60 years for MTDH-positive patients, p = 0.121). In addition, MTDH was not associated with either the type of relapse (local or distant), baseline clinical stage, tumor grade, presence of signet ring cells, surgical (yp) stage, percentage of residual EAC or presence of lymphovascular invasion. Our data reveal that MTDH is not a prognostic biomarker in resistant EAC after trimodality therapy.

101 Long-Term Survivors Who Had Metastatic Gastroesophageal Cancer and Received Local Consolidative Therapy.

BACKGROUND: Through a multidisciplinary decision-making process, we developed a strategy of systemic therapy followed by local consolidative therapy (chemoradiation with/without surgery) in selected patients with metastatic gastroesophageal carcinoma (mGEAC). Only after a consensus during multidisciplinary discussions, local therapy was initiated. METHODS: We identified 101 patients with mGEAC who had local consolidation. We evaluated the association between various clinical variables (location of the primary, location of metastases, duration of initial chemotherapy, histologic grade, and radiation dose) and overall survival (OS). RESULTS: Of 101 patients, 71 had a proximal primary (esophageal, Siewert type I or II), and 30 patients had a distal primary (Siewert type III or distal). The median OS was 25.7 months (95% confidence interval [CI] 22.3-32.8). The OS rates at 2 and 5 years were 53.8% (95% CI 44.7-64.8) and 20.7% (95% CI 13.4-31.9), respectively. OS was highly associated with the location of the primary (median of 22.8 months for Siewert I/II vs. 41.5 months for Siewert III or distal, p = 0.03). The duration of initial chemotherapy was highly associated with OS (median of 21.8 months for <3 months vs. 32.5 months for ≥3 months, p = 0.004). CONCLUSION: Some mGEAC patients with a favorable clinical course can achieve a ∼20% 5-year survival rate with an approach that uses initial chemotherapy followed by multidisciplinary discussion to proceed with consolidation with local therapy. Patients with distal GEAC and those who receive initial chemotherapy for ≥3 months are the maximum beneficiaries.

Recent advances in preoperative management of esophageal adenocarcinoma.

Esophageal cancer is an aggressive malignancy with increasing incidence, and the prognosis of patients treated by surgery alone remains dismal. Preoperative treatment can modestly prolong overall survival. Preoperative chemotherapy or chemoradiation is the standard of care for resectable esophageal cancer (greater than clinical stage I and less than clinical stage IV). One of the challenges is to predict complete response in the surgical specimen from preoperative therapy and to avoid surgery in some patients but also predict ineffectiveness of preoperative therapy if the tumor is resistant and avoid such therapies altogether. In-depth understanding of the molecular biology could lead to personalized therapy, and in the future, clinical trials designed according to molecular features are expected. Here, we summarize preoperative treatment for esophageal adenocarcinoma and their potential.

Advanced gastric adenocarcinoma: optimizing therapy options.

INTRODUCTION: Gastric adenocarcinoma (GAC) is the fifth most common cancer and third leading cause of cancer related mortality worldwide. When localized, cure is achievable with surgery and adjunctive therapies in some patients, however, once advanced, GAC is not a curable condition. Only two targeted agents (trastuzumab and ramucirumab) have been approved and apatinib was approved only in China. Because of the heterogeneous nature of GAC, it is not possible to assess a standard therapeutic approach. Areas covered: In this review, we aimed to describe the optimal systemic therapy regimens for advanced GAC. A literature search was performed to identify all phase II-III studies about advanced GAC from PubMed, clinicaltrials.gov, American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) websites. Expert commentary: A combination of a platinum compound and a fluoropyrimidine is ideal as first line therapy. Trastuzumab should be added if the tumor is HER2 positive. In the second line setting, paclitaxel/ramucirumab is preferred over ramucirumab alone. Recently, two similar molecular classifications for GAC have been proposed. A better understanding of molecular and immune biology of GAC could identify new therapeutic targets.

Translating genomic profiling to gastrointestinal cancer treatment.

Next-generation sequencing enables faster, cheaper and more accurate whole-genome sequencing, allowing genome profiling and discovery of molecular features. As molecular targeted drugs are developed, treatment can be tailored according to molecular subtype. Gastric and colorectal cancers have each been divided into four subtypes according to molecular features. Profiling of the esophageal cancer genome is underway and its classification is anticipated. To date, identification of HER2 expression in gastric adenocarcinoma and KRAS, NRAS and BRAF mutations in colon cancer have proved essential for treatment decisions. However, to overcome therapy resistance and improve prognosis, further individualized therapy is required. Here, we summarize the treatment options for gastrointestinal cancer according to genomic profiling and discuss future directions.

Global chemotherapy development for gastric cancer.

To combat the dismal mortality rates from metastatic gastric adenocarcinoma (GAC), new drugs and treatment strategies are needed. Today, metastatic GAC is predominantly treated by empiric chemotherapy. Combination of two cytotoxic agents has become commonplace in North America, Europe, and Asia. Human epidermal growth factor 2 (HER2) overexpression (protein or gene copy numbers) has resulted in the addition of trastuzumab in the first-line chemotherapy combination in patients whose tumor is HER2 positive. The addition of trastuzumab in this select population has provided a modest survival advantage. In this review we trace the global development of systemic therapy in patients with metastatic GAC and ponder what lies in the future.

Proteomics approach to identify biomarkers for upper gastrointestinal cancer.

INTRODUCTION: The prognosis for patients with upper gastrointestinal cancers remains dismal despite the development of multimodality therapies that incorporate surgery, chemotherapy, and radiotherapy. Early diagnosis and personalized treatment should lead to better prognosis. Given the advances in proteomic technologies over the past decades, proteomics promises to be the most effective technique to identify novel diagnostics and therapeutic targets. Areas covered: For this review, keywords were searched in combination with 'proteomics' and 'gastric cancer' or 'esophageal cancer' in PubMed. Studies that evaluated proteomics associated with upper gastrointestinal cancer were identified through reading, with several studies quoted at second hand. We summarize the proteomics involved in upper gastrointestinal cancer and discuss potential biomarkers and therapeutic targets. Expert commentary: In particular, the development of mass spectrometry has enabled detection of multiple proteins and peptides in more biological samples over a shorter time period and at lower cost than was previously possible. In addition, more sophisticated protein databases have allowed a wider variety of proteins in samples to be quantified. Novel biomarkers that have been identified by new proteomic technologies should be applied in a clinical setting.