Peyman Haghighat and Tanios Bekaii-Saab
Gastric and gastroesophageal adenocarcinoma (GGA) are significant worldwide health problems. With most patients presenting with advanced disease, palliative chemotherapy plays a significant role in treatment. Results from recent phase III studies of cytotoxic agents in combination therapy, such as docetaxel, oxaliplatin, irinotecan, capecitabine, and S-1, have been encouraging and provide patients with additional therapeutic options. Although these forthcoming regimens have allowed for more flexible patient-tailored therapy, survival continues to be suboptimal. Although still in its infancy, targeted biotherapy, including inhibitors of the vascular endothelial and epidermal growth factor receptors, seems to be promising and its incorporation into the next generation of clinical trials will hopefully improve outcomes and help advance future treatments. This article reviews current active chemotherapeutic regimens and explores the role of novel targeted therapies in advanced GGA.
Ludmila Katherine Martin and Tanios Bekaii-Saab
Neoadjuvant chemoradiation (CRT) is standard treatment for stage II-III rectal cancer. Fluoropyrimidine-based CRT prolongs disease-free survival over adjuvant CRT and improves local control over both adjuvant CRT and neoadjuvant radiotherapy alone, but does not prolong overall survival. New approaches to neoadjuvant therapy may improve outcome in this disease. Oxaliplatin, a standard component of chemotherapy for the treatment of both resected and metastatic colon cancer, is a potent radiosensitizer with synergistic radiosensitizing activity in combination with 5-FU in preclinical studies. Early clinical trials showed promising activity with the addition oxaliplatin to 5-FU-based CRT in stage II-III rectal cancer; however, early data from phase III trials seem to be disappointing. This article reviews the existing literature and explores the potential role of oxaliplatin as part of neoadjuvant CRT for rectal cancer.
Kristen Keon Ciombor and Tanios Bekaii-Saab
Metastatic colorectal cancer (mCRC) is a prevalent disease for which many new therapies have been developed over the past decade. Currently, standard of care chemotherapeutic regimens for mCRC include doublet cytotoxic chemotherapy with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies such as cetuximab and panitumumab with or without chemotherapy, and single-agent cytotoxic chemotherapy or targeted therapy for patients intolerant of combination regimens. Recent studies have investigated the efficacy of triplet cytotoxic chemotherapeutic regimens, bevacizumab in combination with chemotherapy beyond first-line therapy disease progression, dual anti-VEGF and anti-EGFR antibody therapy, and the more novel agents ziv-aflibercept and regorafenib for treatment of mCRC. Furthermore, molecular profiling of CRC has identified several genetic alterations for which targeted therapies are currently being developed. Optimal drug combinations and treatment sequences have yet to be defined, but an expanding armamentarium of therapies with which to treat CRC offers a promising future.
Marsha Reyngold, Joyce Niland, Anna ter Veer, Dana Milne, Tanios Bekaii-Saab, Steven J. Cohen, Lily Lai, Deborah Schrag, John M. Skibber, William Small Jr, Martin Weiser, Neal Wilkinson, and Karyn A. Goodman
Based on randomized data, neoadjuvant chemoradiotherapy has been incorporated into the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for stage II-III rectal cancer. Factors associated with nonadherence to evidence-based guidelines for neoadjuvant radiotherapy (RT) were examined at dedicated cancer centers. The prospective NCCN Oncology Outcomes Database for Colorectal Cancers was queried for patients with stage II-III rectal cancer who underwent a transabdominal surgical resection between September 2005 and June 2012. Multivariable logistic regression was used to identify factors associated with omission of RT. Among 1199 identified patients, 1119 (93%) received neoadjuvant RT, 51 (4%) did not receive RT, and 29 (2%) received adjuvant RT. Among 51 patients not receiving RT, only 19 (37%) were referred and evaluated by a radiation oncologist. On multivariable analysis, clinical factors associated with not receiving RT included a history of prior pelvic RT (adjusted odds ratio [aOR], 23.9; P=.0003), ECOG performance status of 2 or greater (aOR, 11.1; P=.01), tumor distance from the anal verge greater than 10 cm (aOR, 5.4; P=.009), age at diagnosis of 75 years or older (aOR, 4.43; P=.002), body mass index of 25 to 30 kg/m2 and less than 25 kg/m2 (aOR, 5.22 and 4.23, respectively; P=.03), and clinical stage II (aOR, 2.27; P=.02). No significant change was seen in RT use according to diagnosis year, nor was any correlation seen with distance to the nearest RT facility. Concordance with NCCN Guidelines for neoadjuvant RT is high among NCCN Member Institutions. After adjusting for clinical characteristics that increase the risk for RT toxicity, including history of pelvic RT and high comorbidity burden/low functional status, the authors found that non-obese patients of advanced age or those with more favorable clinical features were more likely to not receive RT.
Mohamedtaki A. Tejani, Anna ter Veer, Dana Milne, Rebecca Ottesen, Tanios Bekaii-Saab, Al B. Benson III, Deborah Schrag, Stephen Shibata, John Skibber, Martin Weiser, Neal Wilkinson, and Steven J. Cohen
Appendiceal malignancies are rare and represent 1% of intestinal tumors in the United States. The role and efficacy of modern systemic therapy in advanced appendiceal adenocarcinoma has not been established. This study analyzed patients with recurrent or metastatic appendiceal adenocarcinoma in the database for Colorectal Cancer (CRC; 2005-2012). This database tracks longitudinal care for patients treated at 8 specialty centers across the Unites States. Study objectives were to describe and evaluate the efficacy of systemic therapy and investigate relationships with clinicopathologic features. Cox regression analysis was performed to identify predictors of progression-free survival (PFS) and overall survival (OS). Of 248 patients with advanced appendiceal carcinoma, 112 (45%) received systemic therapy for measurable disease and are the focus of this report. The most common chemotherapy regimens included FOLFOX with or without bevacizumab (n=39 and n=37, respectively), FOLFIRI (n=15), and single-agent fluoro-pyrimidine (n=10). Among 99 patients evaluable for best response, 39 experienced a response (response rate [RR], 39%) and 36 (36%) had stable disease. The median PFS was 1.2 years (95% CI, 1.0-1.8) and median OS was 2.1 years (95% CI, 1.6-2.3). Patients with non-mucinous histology or high-grade tumors and those who underwent nondebulking surgery had worse PFS and OS. Treatment of advanced appendiceal adenocarcinoma at NCCN Member Institutions commonly incorporates agents used for CRC. RR, PFS, and OS are comparable to those achieved in the treatment of metastatic CRC. Poor prognostic factors include nonmucinous histology or high-grade tumors and history of nondebulking surgery.
Sherif R. Z. Abdel-Misih, Lai Wei, Al B. Benson III, Steven Cohen, Lily Lai, John Skibber, Neal Wilkinson, Martin Weiser, Deborah Schrag, and Tanios Bekaii-Saab
Background: Nodal status has long been considered pivotal to oncologic care, staging, and management. This has resulted in the establishment of rudimentary metrics regarding adequate lymph node yield in colon and rectal cancers for accurate cancer staging. In the era of neoadjuvant treatment, the implications of lymph node yield and status on patient outcomes remains unclear. Patient and Methods: This study included 1,680 patients with locally advanced rectal cancer from the NCCN prospective oncology database stratified into 3 groups based on preoperative therapy received: no neoadjuvant therapy, neoadjuvant chemoradiation, and neoadjuvant chemotherapy. Clinicopathologic characteristics and survival were compared between the groups, with univariate and multivariate analyses undertaken. Results: The clinicopathologic characteristics demonstrated statistically significant differences and heterogeneity among the 3 groups. The neoadjuvant chemoradiation group demonstrated the statistically lowest median lymph node yield (n=15) compared with 17 and 18 for no-neoadjuvant and neoadjuvant chemotherapy, respectively (P<.0001). Neoadjuvant treatment did impact survival, with chemoradiation demonstrating increased median overall survival of 42.7 compared with 37.3 and 26.6 months for neoadjuvant chemotherapy and no-neoadjuvant therapy, respectively (P<.0001). Patients with a yield of fewer than 12 lymph nodes had improved median overall survival of 43.3 months compared with 36.6 months in patients with 12 or more lymph nodes (P=.009). Multivariate analysis demonstrated that neither node yield nor status were predictors for overall survival. Discussion: This analysis reiterates that nodal yield in rectal cancer is multifactorial, with neoadjuvant therapy being a significant factor. Node yield and status were not significant predictors of overall survival. A nodal metric may not be clinically relevant in the era of neoadjuvant therapy, and guidelines for perioperative therapy may need reconsideration.
Al B. Benson III, Tanios Bekaii-Saab, Emily Chan, Yi-Jen Chen, Michael A. Choti, Harry S. Cooper, Paul F. Engstrom, Peter C. Enzinger, Marwan G. Fakih, Charles S. Fuchs, Jean L. Grem, Steven Hunt, Lucille A. Leong, Edward Lin, Michael G. Martin, Kilian Salerno May, Mary F. Mulcahy, Kate Murphy, Eric Rohren, David P. Ryan, Leonard Saltz, Sunil Sharma, David Shibata, John M. Skibber, William Small Jr, Constantinos T. Sofocleous, Alan P. Venook, Christopher G. Willett, Deborah A. Freedman-Cass, and Kristina M. Gregory
These NCCN Clinical Practice Guidelines in Oncology provide recommendations for the management of rectal cancer, beginning with the clinical presentation of the patient to the primary care physician or gastroenterologist through diagnosis, pathologic staging, neoadjuvant treatment, surgical management, adjuvant treatment, surveillance, management of recurrent and metastatic disease, and survivorship. This discussion focuses on localized disease. The NCCN Rectal Cancer Panel believes that a multidisciplinary approach, including representation from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology, is necessary for treating patients with rectal cancer.
Featured Updates to the NCCN Guidelines
Al B. Benson III, J. Pablo Arnoletti, Tanios Bekaii-Saab, Emily Chan, Yi-Jen Chen, Michael A. Choti, Harry S. Cooper, Raza A. Dilawari, Paul F. Engstrom, Peter C. Enzinger, Marwan G. Fakih, James W. Fleshman Jr., Charles S. Fuchs, Jean L. Grem, Lucille A. Leong, Edward Lin, Kilian Salerno May, Mary F. Mulcahy, Kate Murphy, Eric Rohren, David P. Ryan, Leonard Saltz, Sunil Sharma, David Shibata, John M. Skibber, William Small Jr., Constantinos T. Sofocleous, Alan P. Venook, Christopher Willett, and Deborah A. Freedman-Cass
The workup and management of squamous cell anal carcinoma, which represents the most common histologic form of the disease, are addressed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Anal Carcinoma. These NCCN Guidelines Insights provide a summary of major discussion points of the 2012 NCCN Anal Carcinoma Panel meeting. In summary, the panel made 4 significant changes to the 2012 NCCN Guidelines for Anal Carcinoma: 1) local radiation therapy was added as an option for the treatment of patients with metastatic disease; 2) multifield technique is now preferred over anteroposterior-posteroanterior (AP-PA) technique for radiation delivery and the AP-PA technique is no longer recommended as the standard of care; 3) PET/CT should now be considered for radiation therapy planning; and 4) a section on risk reduction was added to the discussion section. In addition, the panel discussed the use of PET/CT for the workup of anal canal cancer and decided to maintain the recommendation that it can be considered in this setting. They also discussed the use of PET/CT for the workup of anal margin cancer and for the assessment of treatment response. They reaffirmed their recommendation that PET/CT is not appropriate in these settings.
Al B. Benson III, Alan P. Venook, Tanios Bekaii-Saab, Emily Chan, Yi-Jen Chen, Harry S. Cooper, Paul F. Engstrom, Peter C. Enzinger, Moon J. Fenton, Charles S. Fuchs, Jean L. Grem, Steven Hunt, Ahmed Kamel, Lucille A. Leong, Edward Lin, Wells Messersmith, Mary F. Mulcahy, James D. Murphy, Steven Nurkin, Eric Rohren, David P. Ryan, Leonard Saltz, Sunil Sharma, David Shibata, John M. Skibber, Constantinos T. Sofocleous, Elena M. Stoffel, Eden Stotsky-Himelfarb, Christopher G. Willett, Kristina M. Gregory, and Deborah A. Freedman-Cass
The NCCN Guidelines for Colon Cancer address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease,and survivorship. This portion of the guidelines focuses on the use of systemic therapy in metastatic disease. The management of metastatic colorectal cancer involves a continuum of care in which patients are exposed sequentially to a variety of active agents, either in combinations or as single agents. Choice of therapy is based on the goals of treatment, the type and timing of prior therapy, the different efficacy and toxicity profiles of the drugs, the mutational status of the tumor, and patient preference.