Gastric and esophageal cancers continue to be a significant health problem. The incidence of proximal gastric and distal esophageal cancers has been increasing, especially in white men. Gastric and esophageal cancers have high rates of locoregional and distant failure, resulting in poor overall survival. Therefore, patients with gastric and esophageal cancer may benefit from combined modality therapy. Adjuvant chemoradiation has been shown to improve survival in gastric and gastroesophageal cancers in a phase III trial. In esophageal cancer, most randomized trials have not shown a survival benefit for preoperative chemotherapy or chemoradiation, although these approaches are widely used. This article reviews the role of staging, surgery, and adjuvant and preoperative therapies in the management of localized gastric and esophageal cancers.
Combined Modality Therapy of Localized Gastric and Esophageal Cancers
Prajnan Das, Norio Fukami, and Jaffer A. Ajani
Navigating Nodal Metrics for Node-Positive Gastric Cancer in the United States: An NCDB-Based Study and Validation of AJCC Guidelines
Derek J. Erstad, Mariela Blum, Jeannelyn S. Estrella, Prajnan Das, Bruce D. Minsky, Jaffer A. Ajani, Paul F. Mansfield, Naruhiko Ikoma, and Brian D. Badgwell
Background: The optimal number of examined lymph nodes (ELNs) and the positive lymph node ratio (LNR) for potentially curable gastric cancer are not established. We sought to determine clinical benchmarks for these values using a large national database. Methods: Demographic, clinicopathologic, and treatment-related data from patients treated using an R0, curative-intent gastrectomy registered in the National Cancer Database during 2004 to 2016 were evaluated. Patients with node-positive (pTxN+M0) disease were considered for analysis. Results: A total of 22,018 patients met the inclusion criteria, with a median follow-up of 2.2 years. Mean age at diagnosis was 65.6 years, 66% were male, 68% were White, 33% of tumors were located near the gastroesophageal junction, and 29% of patients had undergone preoperative therapy. Most primary tumors (62%) were category pT3–4, 67% had a poor or anaplastic grade, and 19% had signet features. Clinical nodal staging was inaccurate compared with staging at final pathology. The mean [SD] number of nodes examined was 19 . On multivariable analysis, the pN category, ELNs, and LNR were independently associated with survival (all P<.0001). Using receiver operating characteristic (ROC) analysis, an optimal ELN threshold of ≥30 was established for patients with pN3b disease and was applied to the entire cohort. Node positivity and LNR had minimal change beyond 30 examined nodes. Stage-specific LNR thresholds calculated by ROC analysis were 11% for pN1, 28% for pN2, 58% for pN3a, 64% for pN3b, 30% for total combined. By using an ELN threshold of ≥30, prognostically advantageous stage-specific LNR values could be determined for 96% of evaluated patients. Conclusions: Using a large national cancer registry, we determined that an ELN threshold of ≥30 allowed for prognostically advantageous LNRs to be achieved in 96% of patients. Therefore, ≥30 examined nodes should be considered a clinical benchmark for practice in the United States.
Multimodality Approaches to Localized Gastric Cancer
Prajnan Das, Yixing Jiang, Jeffrey H. Lee, Manoop S. Bhutani, William A. Ross, Paul F. Mansfield, and Jaffer A. Ajani
Most patients with localized gastric cancer require multimodality therapy. Surgery is the primary treatment for localized gastric cancer, although controversy exists about the optimal extent of lymphadenectomy in these patients. Recent studies have evaluated the role of laparoscopic surgery and endoscopic mucosal resection in selected patients. Multimodality treatment options for these patients include post-operative chemoradiation and perioperative chemotherapy. The Intergroup 0116 trial demonstrated that patients treated with surgery and post-operative chemoradiation had significantly higher overall survival compared to patients treated with surgery alone. The MAGIC trial showed that patients treated with perioperative epirubicin, cisplatin, and 5-fluorouracil had significantly higher overall survival compared to patients treated with surgery alone. Other recent trials have evaluated the roles of preoperative chemoradiation and adjuvant chemotherapy. Multidisciplinary evaluation plays a crucial role in the management of these patients.
Molecular Biomarkers in Gastric Cancer
Elena Elimova, Roopma Wadhwa, Hironori Shiozaki, Kazuki Sudo, Jeannelyn S. Estrella, Brian D. Badgwell, Prajnan Das, Aurelio Matamoros Jr, Shumei Song, and Jaffer A. Ajani
Gastric cancer (GC) represents a serious health problem on a global scale. Despite some recent advances in the field, the prognosis in metastatic GC remains poor. Even in localized disease the adjunctive therapies improve overall survival (OS) by only approximately 10%. A better understanding of molecular biology, which would lead to improved treatment options, is needed and is the basis for this review. Many potential biomarkers of prognostic significance have been identified, including ALDH, SHH, Sox9, HER2, EGFR, VEGF, Hippo/YAP, and MET. However, inhibition of only HER2 protein has led to a modest survival benefit. A new approach to GC treatment, which is a disease influenced by inflammation, is the exploitation of the immune system to fight disease. Two interesting targets/prognostic markers that bear further investigation in GC are PD1 and PDL, particularly given their success in the treatment of other inflammation/immune-associated malignancies.
Early and Midtreatment Mortality in Palliative Radiotherapy: Emphasizing Patient Selection in High-Quality End-of-Life Care
Matthew S. Ning, Prajnan Das, David I. Rosenthal, Bouthaina S. Dabaja, Zhongxing Liao, Joe Y. Chang, Daniel R. Gomez, Ann H. Klopp, G. Brandon Gunn, Pamela K. Allen, Paige L. Nitsch, Rachel B. Natter, Tina M. Briere, Joseph M. Herman, Rebecca Wells, Albert C. Koong, and Mary Frances McAleer
Background: Palliative radiotherapy (RT) is effective, but some patients die during treatment or too soon afterward to experience benefit. This study investigates end-of-life RT patterns to inform shared decision-making and facilitate treatment consistent with palliative goals. Materials and Methods: All patients who died ≤6 months after initiating palliative RT at an academic cancer center between 2015 and 2018 were identified. Associations with time-to-death, early mortality (≤30 days), and midtreatment mortality were analyzed. Results: In total, 1,620 patients died ≤6 months from palliative RT initiation, including 574 (34%) deaths at ≤30 days and 222 (14%) midtreatment. Median survival was 43 days from RT start (95% CI, 41–45) and varied by site (P<.001), ranging from 36 (head and neck) to 53 days (dermal/soft tissue). On multivariable analysis, earlier time-to-death was associated with osseous (hazard ratio [HR], 1.33; P<.001) and head and neck (HR, 1.45; P<.001) sites, multiple RT courses ≤6 months (HR, 1.65; P<.001), and multisite treatments (HR, 1.40; P=.008), whereas stereotactic technique (HR, 0.77; P<.001) and more recent treatment year (HR, 0.82; P<.001) were associated with longer survival. No difference in time to death was noted among patients prescribed conventional RT in 1 to 10 versus >10 fractions (median, 40 vs 47 days; P=.272), although the latter entailed longer courses. The 30-day mortality group included 335 (58%) inpatients, who were 27% more likely to die midtreatment (P=.031). On multivariable analysis, midtreatment mortality among these inpatients was associated with thoracic (odds ratio [OR], 2.95; P=.002) and central nervous system (CNS; OR, 2.44; P=.002) indications, >5-fraction courses (OR, 3.27; P<.001), and performance status of 3 to 4 (OR, 1.63; P=.050). Conversely, palliative/supportive care consultation was associated with decreased midtreatment mortality (OR, 0.60; P=.045). Conclusions: Earlier referrals and hypofractionated courses (≤5–10 treatments) should be routinely considered for palliative RT indications, given the short life expectancies of patients at this stage in their disease course. Providers should exercise caution for emergent thoracic and CNS indications among inpatients with poor prognoses due to high midtreatment mortality.
Performance Status Restriction in Phase III Cancer Clinical Trials
Joseph Abi Jaoude, Ramez Kouzy, Walker Mainwaring, Timothy A. Lin, Austin B. Miller, Amit Jethanandani, Andres F. Espinoza, Dario Pasalic, Vivek Verma, Noam A. VanderWalde, Benjamin D. Smith, Grace L. Smith, C. David Fuller, Prajnan Das, Bruce D. Minsky, Claus Rödel, Emmanouil Fokas, Reshma Jagsi, Charles R. Thomas Jr, Ishwaria M. Subbiah, Cullen M. Taniguchi, and Ethan B. Ludmir
Background: Patients with good performance status (PS) tend to be favored in randomized clinical trials (RCTs), possibly limiting the generalizability of trial findings. We aimed to characterize trial-related factors associated with the use of PS eligibility criteria and analyze patient accrual breakdown by PS. Methods: Adult, therapeutic, multiarm phase III cancer-specific RCTs were identified through ClinicalTrials.gov. PS data were extracted from articles. Trials with a PS restriction ECOG score ≤1 were identified. Factors associated with PS restriction were determined, and the use of PS restrictions was analyzed over time. Results: In total, 600 trials were included and 238,213 patients had PS data. Of those trials, 527 studies (87.8%) specified a PS restriction cutoff, with 237 (39.5%) having a strict inclusion criterion (ECOG PS ≤1). Enrollment criteria restrictions based on PS (ECOG PS ≤1) were more common among industry-supported trials (P<.001) and lung cancer trials (P<.001). Nearly half of trials that led to FDA approval included strict PS restrictions. Most patients enrolled across all trials had an ECOG PS of 0 to 1 (96.3%). Even among trials that allowed patients with ECOG PS ≥2, only 8.1% of those enrolled had a poor PS. Trials of lung, breast, gastrointestinal, and genitourinary cancers all included <5% of patients with poor PS. Finally, only 4.7% of patients enrolled in trials that led to subsequent FDA approval had poor PS. Conclusions: Use of PS restrictions in oncologic RCTs is pervasive, and exceedingly few patients with poor PS are enrolled. The selective accrual of healthier patients has the potential to severely limit and bias trial results. Future trials should consider a wider cancer population with close toxicity monitoring to ensure the generalizability of results while maintaining patient safety.
Jaffer A. Ajani, James S. Barthel, Tanios Bekaii-Saab, David J. Bentrem, Thomas A. D'Amico, Prajnan Das, Crystal Denlinger, Charles S. Fuchs, Hans Gerdes, James A. Hayman, Lisa Hazard, Wayne L. Hofstetter, David H. Ilson, Rajesh N. Keswani, Lawrence R. Kleinberg, Michael Korn, Kenneth Meredith, Mary F. Mulcahy, Mark B. Orringer, Raymond U. Osarogiagbon, James A. Posey, Aaron R. Sasson, Walter J. Scott, Stephen Shibata, Vivian E. M. Strong, Mary Kay Washington, Christopher Willett, Douglas E. Wood, Cameron D. Wright, and Gary Yang
Gastric Cancer, Version 2.2013
Jaffer A. Ajani, David J. Bentrem, Stephen Besh, Thomas A. D’Amico, Prajnan Das, Crystal Denlinger, Marwan G. Fakih, Charles S. Fuchs, Hans Gerdes, Robert E. Glasgow, James A. Hayman, Wayne L. Hofstetter, David H. Ilson, Rajesh N. Keswani, Lawrence R. Kleinberg, W. Michael Korn, A. Craig Lockhart, Kenneth Meredith, Mary F. Mulcahy, Mark B. Orringer, James A. Posey, Aaron R. Sasson, Walter J. Scott, Vivian E. Strong, Thomas K. Varghese Jr, Graham Warren, Mary Kay Washington, Christopher Willett, Cameron D. Wright, Nicole R. McMillian, and Hema Sundar
The NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer provide evidence- and consensus-based recommendations for a multidisciplinary approach for the management of patients with gastric cancer. For patients with resectable locoregional cancer, the guidelines recommend gastrectomy with a D1+ or a modified D2 lymph node dissection (performed by experienced surgeons in high-volume centers). Postoperative chemoradiation is the preferred option after complete gastric resection for patients with T3-T4 tumors and node-positive T1-T2 tumors. Postoperative chemotherapy is included as an option after a modified D2 lymph node dissection for this group of patients. Trastuzumab with chemotherapy is recommended as first-line therapy for patients with HER2-positive advanced or metastatic cancer, confirmed by immunohistochemistry and, if needed, by fluorescence in situ hybridization for IHC 2+.
Esophageal and Esophagogastric Junction Cancers, Version 1.2015
Jaffer A. Ajani, Thomas A. D’Amico, Khaldoun Almhanna, David J. Bentrem, Stephen Besh, Joseph Chao, Prajnan Das, Crystal Denlinger, Paul Fanta, Charles S. Fuchs, Hans Gerdes, Robert E. Glasgow, James A. Hayman, Steven Hochwald, Wayne L. Hofstetter, David H. Ilson, Dawn Jaroszewski, Kory Jasperson, Rajesh N. Keswani, Lawrence R. Kleinberg, W. Michael Korn, Stephen Leong, A. Craig Lockhart, Mary F. Mulcahy, Mark B. Orringer, James A. Posey, George A. Poultsides, Aaron R. Sasson, Walter J. Scott, Vivian E. Strong, Thomas K. Varghese Jr, Mary Kay Washington, Christopher G. Willett, Cameron D. Wright, Debra Zelman, Nicole McMillian, and Hema Sundar
Esophageal cancer is the sixth most common cause of cancer deaths worldwide. Adenocarcinoma is more common in North America and Western European countries, originating mostly in the lower third of the esophagus, which often involves the esophagogastric junction (EGJ). Recent randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival in patients with resectable cancer. Targeted therapies with trastuzumab and ramucirumab have produced encouraging results in the treatment of advanced or metastatic EGJ adenocarcinomas. Multidisciplinary team management is essential for patients with esophageal and EGJ cancers. This portion of the NCCN Guidelines for Esophageal and EGJ Cancers discusses management of locally advanced adenocarcinoma of the esophagus and EGJ.
Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology
Jaffer A. Ajani, Thomas A. D'Amico, Khaldoun Almhanna, David J. Bentrem, Joseph Chao, Prajnan Das, Crystal S. Denlinger, Paul Fanta, Farhood Farjah, Charles S. Fuchs, Hans Gerdes, Michael Gibson, Robert E. Glasgow, James A. Hayman, Steven Hochwald, Wayne L. Hofstetter, David H. Ilson, Dawn Jaroszewski, Kimberly L. Johung, Rajesh N. Keswani, Lawrence R. Kleinberg, W. Michael Korn, Stephen Leong, Catherine Linn, A. Craig Lockhart, Quan P. Ly, Mary F. Mulcahy, Mark B. Orringer, Kyle A. Perry, George A. Poultsides, Walter J. Scott, Vivian E. Strong, Mary Kay Washington, Benny Weksler, Christopher G. Willett, Cameron D. Wright, Debra Zelman, Nicole McMillian, and Hema Sundar
Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of death from cancer in the world. Several advances have been made in the staging procedures, imaging techniques, and treatment approaches. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer provide an evidence- and consensus-based treatment approach for the management of patients with gastric cancer. This manuscript discusses the recommendations outlined in the NCCN Guidelines for staging, assessment of HER2 overexpression, systemic therapy for locally advanced or metastatic disease, and best supportive care for the prevention and management of symptoms due to advanced disease.