6 Department of Pathology, University of California at San Francisco Medical Center, San

Transcription

1 The Impact of Stage, Grade, and Mucinous Histology on the Efficacy of Systemic Chemotherapy in Adenocarcinomas of the Appendix: Analysis of the National Cancer Data Base Elliot A. Asare, MD 1,2 ; Carolyn C. Compton, MD, PhD 3 ; Nader N. Hanna, MD 4 ; Lauren A. Kosinski, MD 2 ; Mary Kay Washington, MD, PhD 5 ; Sanjay Kakar, MD 6 ; Martin R. Weiser, MD 7 ; and Michael J. Overman, MD 8 BACKGROUND: Adenocarcinomas of the appendix represent a heterogeneous disease depending on the presence of mucinous histology, histologic grade, and stage. In the current study, the authors sought to explore the interplay of these factors with systemic chemotherapy in a large population data set. METHODS: Patients in the National Cancer Data Base (NCDB) who were diagnosed with mucinous, nonmucinous, and signet ring cell-type appendiceal neoplasms from 1985 through 2006 were selected. Multivariable Cox proportional hazards regression models were developed. RESULTS: A total of 11,871 patients met the inclusion criteria for the current study: 50.3% had mucinous neoplasms, 40.5% had nonmucinous neoplasms, and 9.2% had signet ring cell-type neoplasms. The 5-year overall survival (OS) stratified by grade was similar among patients with American Joint Committee on Cancer stage I to stage III disease but not for those with stage IV disease. The median OS for patients with stage IV mucinous and nonmucinous tumors was 6.4 years and 2.3 years, respectively, for those with well differentiated histology (P<.0001) and was 1.5 years and 0.8 years, respectively, for those with poorly differentiated histology (P<.0001). In multivariable modeling for stage I to III disease, adjuvant chemotherapy improved OS for both mucinous and nonmucinous histologies, with hazard ratios (HRs) of 0.78 (95% confidence interval [95% CI], [P ]) and 0.83 (95% CI, [P 5.002]), respectively. For patients with stage IV disease, systemic chemotherapy significantly improved OS for those with nonmucinous (HR, 0.72; 95% CI, [P<.0001]) but not mucinous (HR, 0.95; 95% CI, [P 5.2) histologies, although this was grade-dependent. The median OS for chemotherapy versus no chemotherapy was 6.4 years versus 6.5 years (P value not significant) for patients with mucinous, well-differentiated tumors and 1.6 years versus 1.0 years (P ) for patients with mucinous, poorly differentiated tumors. CONCLUSIONS: Adjuvant chemotherapy demonstrated a significant OS benefit regardless of histology. However, for patients with stage IV disease, the benefit of systemic chemotherapy varied by tumor histology and grade, with patients with well-differentiated, mucinous, appendiceal adenocarcinomas deriving no survival benefit from systemic chemotherapy. Cancer 2016;122: VC 2015 American Cancer Society. KEYWORDS: appendix, chemotherapy, mucinous, nonmucinous, survival. INTRODUCTION Adenocarcinomas of the appendix are histologically sorted into mucinous, nonmucinous, and signet ring cell types. 1,2 The seventh edition of the American Joint Committee on Cancer (AJCC) staging system separated appendiceal adenocarcinomas from colorectal adenocarcinomas and incorporated grade into the staging of stage IV disease. 3 The current AJCC staging system for appendiceal adenocarcinomas classifies mucinous tumors into low-grade (well-differentiated) and high-grade (moderately and poorly differentiated) adenocarcinomas. 3 This distinction is required for the classification of stage IV appendiceal adenocarcinomas as low-grade mucinous adenocarcinoma with peritoneal-only involvement are classified as stage IVA. Given the rarity of appendiceal neoplasms, the majority of the existing reports in the literature are classified as singleinstitution retrospective studies and hence have been limited by small sample size and selection bias. 4-7 Prior reports have demonstrated the prognostic impact of histological grade for appendiceal adenocarcinomas with mucinous histology. 8,9 Corresponding author: Michael J. Overman, MD, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX 77030; Fax: (713) ; moverman@mdanderson.org 1 Cancer Programs, American College of Surgeons, Chicago, Illinois; 2 Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin; 3 Department of Pathology, Arizona State University, Phoenix, Arizona; 4 Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; 5 Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee; 6 Department of Pathology, University of California at San Francisco Medical Center, San Francisco, California; 7 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; 8 Department of Hematology and Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Previously presented as an abstract at: 12th Annual Gastrointestinal Cancer Symposium; January 15-17, 2015; San Francisco, CA. Published in J Clin Oncol. 2015;33(suppl 3):Pages. Abstract 668. Additional supporting information may be found in the online version of this article. DOI: /cncr.29744, Received: April 29, 2015; Revised: August 22, 2015; Accepted: September 2, 2015, Published online October 27, 2015 in Wiley Online Library (wileyonlinelibrary.com) Cancer January 15,

2 In a recent analysis of Surveillance, Epidemiology, and End Results (SEER) data, 2469 appendiceal adenocarcinomas were analyzed and the prognostic impact of histologic grade for mucinous tumors was found to be limited to stage IV disease. 8 In addition, a significant difference in cancer-specific survival (CSS) between patients with moderately differentiated and poorly differentiated mucinous appendiceal adenocarcinomas was noted. 8 However, this analysis was limited by sample size and the lack of any treatment-related data. In addition, to the best of our knowledge, the role of systemic chemotherapy in treating patients with adenocarcinoma of the appendix has not been assessed in any large national registry. Therefore, the purpose of the current study was to use the National Cancer Data Base (NCDB), which is a nationwide cancer database that captures approximately 70% of all newly diagnosed cancers in the United States, to: 1) assess the impact of histologic grade on overall survival (OS) for patients with mucinous and nonmucinous appendiceal neoplasms; and 2) to assess the impact of systemic chemotherapy on OS. MATERIALS AND METHODS Study Design We performed retrospective analyses of a cohort of patients diagnosed with appendiceal cancer from 1985 to The end date of follow-up was December Data Source and Study Population The source of data for this study was the NCDB. The NCDB is a nationwide cancer database sponsored by the Commission on Cancer of the American College of Surgeons and the American Cancer Society. Data capture from patients medical records is performed by trained cancer registrars. Only patients with topography code C18.1 of the third edition of the International Classification of Diseases for Oncology were eligible. The second and third edition histology codes selected were: mucinous (8470, 8480, and 8481), nonmucinous (8010, 8013, 8020, 8140, 8141, 8144, 8210, 8211, 8255, 8260, 8261, 8262, 8263, 8310, 8440, 8460, 8471, 8472, 8560, and 8574), and signet ring cell (8490). Excluded from further analysis were patients aged <18 years or > 90 years, those with unknown tumor stage, those with unknown treatment status, or those diagnosed at autopsy (Fig. 1). The variables of interest were age of the patient at the time of diagnosis, sex, grade (well-differentiated, moderately differentiated, poorly differentiated, undifferentiated/ Figure 1. Schematic representation of patient selection for final analysis. NCDB indicates National Cancer Data Base. anaplastic, and unknown), systemic chemotherapy status, type of surgical resection, stage of disease according to the seventh edition of the AJCC, and vital status. Stage was derived from the individual combinations of T, N, and M and only broad staging categories (stage I, II, III, and IV) could be derived because the seventh edition data components T4a, T4b, M1a, and M1b were not available to allow for stage subcategories. Details regarding the type of chemotherapy administered were not available. The types of surgical resection were: 1) local destruction or excision; 2) partial colectomy/segmental resection with or without resection of contiguous structures or organs; 3) subtotal colectomy with or without resection of contiguous structures or organs; 4) total colectomy/proctocolectomy with or without resection of contiguous structures or organs; 5) colectomy, not otherwise specified (NOS); and 6) surgery, NOS. No specific code for appendectomy exists in the NCDB but the partial colectomy/segmental resection code reflects and is defined as the performance of an appendetomy. 8 There are no specific codes for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the NCDB. The different types of surgical resection were regrouped as follows for the cohort with stage I to III disease: 1) partial colectomy/segmental 214 Cancer January 15, 2016

3 Chemotherapy in Appendiceal Adenocarcinomas/Asare et al TABLE 1. Characteristics of Study Cohort by Histologic Type Characteristic Mucinous n55971 Nonmucinous n54805 Signet ring cell n51095 Age, y Mean Range Sex Female 3219 (53.9%) 2181 (45.4%) 696 (63.6%) Male 2752 (46.1%) 2624 (54.6%) 399 (36.4%) Grade Well differentiated 1919 (32.1%) 813 (16.9%) 16 (1.46%) Moderately differentiated 1414 (23.7%) 2316 (48.2%) 67 (6.1%) Poorly differentiated 658 (11.0%) 943 (19.6%) 527 (48.1%) Undifferentiated/anaplastic 44 (0.74%) 41 (0.85%) 42 (3.8%) Unknown 1936 (32.4%) 692 (14.4%) 443 (40.5%) AJCC stage I 526 (8.8%) 1031 (21.5%) 42 (3.8%) II 1811 (30.3%) 1671 (34.8%) 197 (18.0%) III 529 (8.9%) 846 (17.6%) 169 (15.4%) IV 3105 (52%) 1257 (26.2%) 687 (62.7%) Chemotherapy No chemotherapy 2881 (48.2%) 2894 (60.2%) 395 (36.1%) Received chemotherapy 3090 (51.8%) 1911 (39.8%) 700 (63.9%) Surgery No surgical resection a 757 (12.7%) 436 (9.1) 119 (10.9%) Any type of surgical resection 5213 (87.3%) 4368 (90.9) 974 (89.1%) Abbreviation: AJCC, American Joint Committee on Cancer. a Includes local tumor destruction and local tumor excision. Figure 2. Overall survival (OS) stratified by (A) histologic type (11,871 patients), (B) grade (11,871 patients), (C) American Joint Committee on Cancer stage for mucinous histology (5971 patients), and (D) American Joint Committee on Cancer stage for nonmucinous histology (4805 patients). Cancer January 15,

4 TABLE 2. Multivariable Cox Proportional Hazards Regression Model to Predict Death for Cohort With AJCC Stage I to Stage III Disease Mucinous Nonmucinous Variable HR (95% CI) P HR (95% CI) P AJCC stage I Referent Referent II 1.55 ( ) < ( ) <.0001 III 3.68 ( ) ( ) <.0001 Grade 1 Referent Referent ( ) < ( ) ( ) < ( ) < ( ) ( ).01 Unknown 1.15 ( ) ( ).004 Sex Female Referent Referent Male 1.16 ( ) ( ) <.0001 Chemotherapy No Referent Referent Yes 0.79 ( ) ( ).004 Surgery Appendectomy a Referent Referent Right hemicolectomy a 0.79 ( ) ( ) <.0001 Colectomy a 1.0 ( ) ( ).4 Surgery, NOS 1.16 ( ) ( ).06 Age 1.03 ( ) < ( ) <.0001 Abbreviations: 95% CI, 95% confidence interval; AJCC, American Joint Committee on Cancer; HR, hazard ratio; NOS, not otherwise specified. a Includes resection of contiguous structures/organs. Colectomy refers to the complete removal of the colon. resection with or without resection of contiguous structures (appendectomy); 2) subtotal colectomy with or without resection of contiguous structures or organs (right hemicolectomy); 3) total colectomy/proctocolectomy with or without resection of contiguous structures or organs; and 5) surgery, NOS. Patients with stage IV disease were classified according to whether they received any type of surgical resection. Statistical Analysis All statistical analyses were performed using SAS statistical software (version 9.4; SAS Institute Inc, Cary, NC) and statistical significance was assumed for P values <.05. Data for continuous variables were reported as the mean- 6 standard deviation. Discrete values were reported as the number with the corresponding percentage. Hazard ratios (HRs) were reported as point estimates with 95% confidence intervals (95% CIs). OS estimates were calculated using the Kaplan-Meier method from the date of diagnosis to the date of death. Patients who were alive at the time of last follow-up were censored. Separate multivariable Cox regression models to predict death for patients with stage I to stage III mucinous and nonmucinous disease were developed using the variables of grade, sex, chemotherapy status, and type of surgical resection. Similar Cox regression models to predict death were built for patients with stage IV mucinous and nonmucinous disease using the variables of grade, sex, chemotherapy status, and whether they underwent surgical resection. Variables included in the Cox model were determined a priori based on clinical validity and previous studies. 6,8-10 RESULTS Clinicopathologic Characteristics Of 25,992 patients with tumors of the appendix recorded in the NCDB from 1985 to 2006, a total of 11,871 met the inclusion criteria for final analysis (Fig. 1). The distribution by histologic type was 5971 patients with mucinous (50.3%), 4805 patients with nonmucinous (40.5%), and 1095 patients with signet ring cell (9.2%) type (Table 1). The mean age at diagnosis was higher for patients with nonmucinous tumors ( years) compared with those with mucinous ( years) and signet ring cell-type ( years) tumors. The histological differentiation of well was more common in mucinous tumors whereas moderate and poor differentiation were more common in nonmucinous tumors (Table 1). Patients with signet ring cell-type histology were more likely to have stage IV disease (62.7%) compared with patients with mucinous (52%) and nonmucinous (26.2%) histologic types (Table 1). 216 Cancer January 15, 2016

5 Chemotherapy in Appendiceal Adenocarcinomas/Asare et al Figure 3. Overall survival (OS) stratified by American Joint Committee on Cancer stage, histology, and administration of chemotherapy (chemo) among (A) patients with stage II to III mucinous histology (2345 patients), (B) patients with stage II to III nonmucinous histology (2520 patients), (C) patients with well-differentiated stage IV tumors (1149 patients), (D) patients with moderately differentiated stage IV tumors (974 patients), and (E) patients with poorly differentiated stage IV tumors (786 patients). 1 indicates chemotherapy received; -, no chemotherapy received. For those patients who received systemic chemotherapy, administration occurred within 90 days from the time of diagnosis in >98% of patients. Survival The 5-year OS rates for the cohort based on the histologic type of tumor were 53.6%, 46.2%, and 24.7%, respectively, for mucinous, nonmucinous, and signet ring cell-type (Fig. 2A). Due to the small percentage of tumors with signet ring cell histology (9%), further analyses were limited to tumors with mucinous and nonmucinous histologies. When stratified by grade, the 5-year OS rates were 63.9%, 50.1%, 25.2%, 20.5%, and 46.9%, respectively, for tumors with well, Cancer January 15,

6 TABLE 3. Multivariable Cox Proportional Hazards Regression Model to Predict Death for Cohort With AJCC Stage IV Disease Mucinous Nonmucinous Variable HR (95% CI) P HR (95% CI) P Grade 1 Referent Referent ( ) < ( ) < ( ) < ( ) < ( ) < ( ).003 Unknown 1.34 ( ) < ( ).03 Sex Female Referent Referent Male 1.23 ( ) < ( ).002 Chemotherapy No Referent Referent Yes 0.95 ( ) ( ) <.0001 Surgery No resection a Referent Referent Any type of surgical resection 0.78 ( ) < ( ).0005 Age 1.02 ( ) < ( ) <.0001 Abbreviations: 95% CI, 95% confidence interval; AJCC, American Joint Committee on Cancer; HR, hazard ratio. a Includes local tumor destruction and local tumor excision. moderate, poor, undifferentiated, and unknown grades, respectively (Fig. 2B). OS rates stratified by stage of disease for mucinous and nonmucinous histologic types are shown by the Kaplan-Meier plots in Figures 2C and 2D, respectively. The 5-year OS rates for patients with mucinous stage I to III disease were 74.9%, 63.2%, and 51.1%, respectively, for well, moderate, and poor differentiation (Supporting Information Fig. 1A). Patients with stage I to III, nonmucinous disease had 5-year OS rates of 68.9%, 59.6%, and 39.8% for well, moderate, and poor differentiation (Supporting Information Fig. 1B). Among patients with stage IV disease, the 5-year OS rates were 56.7%, 31.5%, and 11.3% for patients with mucinous tumors with well, moderate, and poor differentiation, whereas the 5-year OS rates were 29.7%, 11.2%, and 6%, respectively, for patients with nonmucinous tumors with well, moderate, and poor differentiation (Supporting Information Figs. 1C and 1D). Multivariable Cox Regression Analysis for Stage I to III Disease On multivariable analysis of patients with stage I to III disease, higher AJCC stage was associated with an increased risk of death for both patients with mucinous and nonmucinous histologic types (Table 2). Stage was found to be the strongest predictor of death for both mucinous (stage III: HR, 3.68; 95% CI, [P 5 003]) and nonmucinous histologies (stage III: HR, 2.76; 95% CI, [P<.0001]) (Table 2). Higher tumor grade predicted an increased risk of death for both mucinous and nonmucinous histologic types. Male sex also was found to be associated with an increased risk of death, although the association was higher for the nonmucinous histologic type (HR, 1.29; 95% CI, [P<.0001]) compared with mucinous histologic type (HR, 1.16; 95% CI, [P 5.02]) (Table 2). Among patients with localized disease, those who underwent a right hemicolectomy had a decreased risk of death compared with those who underwent an appendectomy for both mucinous and nonmucinous histological types. Among both mucinous and nonmucinous histologic types, there was an associated protective effect for patients who received systemic chemotherapy compared with those who did not receive chemotherapy (HR, 0.79; 95% CI, [P ] for mucinous; and HR, 0.84; 95% CI, [P 5.004] for nonmucinous) (Table 2). Among patients with stage II to III mucinous and nonmucinous histology, improved OS was observed for patients who received systemic chemotherapy (Figs. 3A and 3B). Multivariable Cox Regression Analysis for Stage IV Disease On multivariable analysis of patients with stage IV disease, receipt of chemotherapy was not found to be associated with improved survival in the cohort with mucinous histology (HR, 0.95; 95% CI, [P 5.3]), whereas patients with nonmucinous histology had improved survival when chemotherapy was administered (HR, 0.73; 95% CI, [P<.0001]) (Table 3). Because no code for cytoreductive surgery existed in the 218 Cancer January 15, 2016

7 Chemotherapy in Appendiceal Adenocarcinomas/Asare et al NCDB, we compared patients who did and did not undergo a surgical resection. There was a decreased risk of death among those patients who underwent surgical resection for both histologic types (mucinous: HR, 0.78; 95% CI, [P<.0001]; and nonmucinous: HR, 0.76; 95% CI, [P ]) (Table 3). Due to the heterogeneity in OS rates among patients with stage IV disease, OS stratified by histologic type, grade, and chemotherapy was assessed. There was no statistically significant difference in the median OS for patients with well-differentiated mucinous histology who received chemotherapy compared with those who did not receive chemotherapy (6.4 vs 6.5 years [P not significant]) (Fig. 3C) (Supporting Information Table 1). There was an improvement in the median OS between patients with stage IV mucinous disease who received chemotherapy compared with those who did not among those with moderately differentiated tumors (2.99 vs 1.64 years [P ]) and poorly differentiated tumors (1.57 vs 1.02 years [P ]) (Figs. 3D and 3E) (Supporting Information Table 1). DISCUSSION To the best of our knowledge, the current analysis represents the largest cohort of patients with appendiceal adenocarcinoma reported to date, and demonstrates the important interplay between mucinous histology, grade, and stage. Although grade was found to have a robust impact on survival for patients with stage IV mucinous compared with nonmucinous appendiceal adenocarcinoma, this impact was not observed among patients with stage I to III disease. Because significantly different outcomes were noted for patients with moderately and poorly differentiated mucinous appendiceal adenocarcinomas, these data support the removal of the current (seventh edition) AJCC manual s mucinous high-grade category. It is important to note that the results of the current study demonstrate a benefit to adjuvant chemotherapy for patients with localized disease, and indicate that the benefit is similar between patients with both mucinous and nonmucinous histologies. In contrast, the benefit of systemic chemotherapy for patients with stage IV disease was dependent on both histological subtype and grade because patients with well-differentiated mucinous appendiceal adenocarcinomas demonstrated no benefit from systemic chemotherapy. Similar to a prior report using the SEER database, the prognostic impact of grade was found to be similar for localized mucinous and nonmucinous histologies, but was markedly differed for stage IV mucinous and nonmucinous histologies. 8 The 5-year OS rate for patients with well-differentiated and moderately differentiated, mucinous, stage IV disease was 56.7% and 31.5%, respectively, which is in contrast to the 5-year OS rate of 11.3% for patients with poorly differentiated, mucinous, stage IV tumors. These data do not support the current categorization of moderately and poorly differentiated mucinous histologies into a single mucinous high-grade category, because a statistically significant near-doubling in the HR was observed between these 2 grades (1.92 vs 3.71). In contrast, there was no statistically significant difference noted between moderate and poor histological grades for nonmucinous stage IV disease. A recent SEER analysis found similar findings for stage IV disease, with HRs for moderately differentiated and poorly differentiated mucinous histologies of 1.6 and 4.9, respectively. 8 Further support for a 3-tier system for metastatic mucinous appendiceal adenocarcinomas was provided by a recent retrospective study that evaluated several histopathological features and demonstrated significant stratification of OS across a 3-tiered grading system. 9 To the best of our knowledge, this is the first data set to evaluate the role of systemic chemotherapy for the adjuvant treatment of appendiceal adenocarcinoma. Currently, the use of adjuvant chemotherapy is extrapolated from its benefit for colorectal cancer. The validity of such an extrapolation is uncertain. Although limited data exist regarding the molecular alterations of appendiceal adenocarcinomas, preliminary studies have suggested lower rates of both microsatellite instability and adenomatous polyposis coli (APC) mutations, which represent the common early genomic events driving the development of colorectal cancer In the current study, we demonstrated a statistically significant benefit from adjuvant chemotherapy that is similar for both mucinous (HR, 0.79) and nonmucinous (HR, 0.84) histologies. It is interesting to note that a much smaller percentage of patients with mucinous histology presented with stage III disease compared with nonmucinous histology (8.9% vs 17.6%). This was particularly evident for well-differentiated mucinous histology, because 4.9% of patients presented with stage III disease whereas 42.5% presented with either stage I or II disease and 52.6% presented with stage IV disease. This stage distribution supports a preferential peritoneal manner of spread for mucinous appendiceal adenocarcinomas in contrast to lymphatic spread. For welldifferentiated, mucinous appendiceal adenocarcinomas, this finding correlates with the histological primary lesion termed a low-grade appendiceal mucinous neoplasm, which is characterized by a pushing invasion with Cancer January 15,

8 subsequent fibrosis and a thinning of the appendiceal wall rather than a direct invasion through the appendiceal wall layers. 14 A major finding from the current study is the lack of a benefit for systemic chemotherapy for patients with mucinous, well-differentiated, stage IV disease. This finding is in agreement with the current consensus treatment approach of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for this subset of cancers with intraperitoneal involvement. 15 Although cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are used for higher-grade appendiceal adenocarcinomas, to the best of our knowledge the benefit of such an approach is less certain. Because 41% of patients in the current study with stage IV, mucinous, well-differentiated appendiceal adenocarcinoma received systemic chemotherapy as their first treatment, these data strongly support a change in clinical practice. Although a limited number of retrospective studies have evaluated chemotherapy for metastatic mucinous appendiceal adenocarcinomas, the interpretation of these data is inherently challenging due to the heterogeneity of behavior across histological grades and the indolent biology and generally good overall outcome for patients with well-differentiated tumors In what to our knowledge are the 2 largest retrospective reports evaluating systemic chemotherapy for appendiceal cancers, efficacy endpoints for chemotherapy were not analyzed across histological grades, and thus the impact of systemic chemotherapy for well-differentiated as opposed to poorly differentiated tumor grades could not be determined. 17,18 One prospective phase 2 study has been conducted in patients with mucinous appendiceal adenocarcinoma. 19 In this study of 40 patients with unresectable pseudomyxoma peritonei of appendiceal origin, semiquantitative reductions in mucinous deposition were noted in 6 patients (15%). 19 The 1-year and 2-year OS rates were 84% and 61%, respectively. In contrast, a retrospective study evaluating poorly differentiated or signet ring cell appendiceal adenocarcinomas demonstrated a response rate of 44%, a median progression-free survival of 6.9 months, and a median OS of 1.7 years. 20 The differential benefit of chemotherapy across tumor grade and histological subtypes is a reflection of the inherent differences in the biology across these various subsets of appendiceal adenocarcinomas. Although CSS rates were not available in the NCDB, the pattern of OS observed in the current study cohort mirrors the trend reported for CSS in studies using SEER data. The 5-year OS rates for patients with mucinous (53.6%) and signet ring cell (24.7%) histology reported herein are comparable to studies using SEER data, in which the 5-year CSS rates were 56% for mucinous and 22% for signet ring cell histologic subtypes. 8,10 The SEER studies reported a 5-year CSS rate of 54% for patients with nonmucinous histology whereas the 5-year OS rate from the current NCDB study was 46%. Similar to previously published literature, stage IV disease, female sex, and welldifferentiated grade were more common among the cohort of patients with mucinous adenocarcinoma compared with those with nonmucinous adenocarcinoma. 8 The current study has some important limitations. First, we excluded patients with missing data from the final analysis, which could potentially introduce bias. Second, the NCDB does not collect data regarding the use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, or the type and method of administration of chemotherapy. Because treatment for appendiceal cancer is based on that for colorectal cancer, the systemic chemotherapy used is reflective of a fluoropyrimidinebased chemotherapy. For the years 2003 through 2006, the NCDB recorded the elapsed time from diagnosis to chemotherapy administration and during this time frame, <3% of all patients with stage IV mucinous appendiceal adenocarcinomas received chemotherapy on the same day as a surgical procedure. This finding strongly supports that the recording of chemotherapy in the NCDB reflects the use of systemic chemotherapy. Third, the surgical coding for an appendectomy is imperfect because a partial colectomy/segmental resection code reflects an appendectomy or cecectomy procedure. Fourth, the NCDB does not allow for the determination of disease-specific mortality. This limitation prevents direct comparison of survival estimates with those in other studies in which only CSS mortality was reported. Fifth, the high rate of unknown tumor grade within mucinous histology reflects a further limitation of the current study. This finding likely reflects the presence of multiple classification systems for lowcellularity, mucinous appendiceal neoplasms, such as mucinous carcinoma peritonei of low grade or high grade by Bradley et al or peritoneal mucinous carcinomatosis or disseminated adenomucinosis by Ronnett et al. 21,22 Our missing grade rate of 32% for mucinous histology is similar to the rate noted using the SEER database, in which a rate of 35% was noted. 8 Despite these limitations, to our knowledge the current study is the largest cohort of patients with appendiceal adenocarcinoma published to date. The current large, retrospective cohort study affirms the importance of histologic grade in predicting survival outcomes for patients with appendiceal adenocarcinoma. The evidence from this study does not support the current 220 Cancer January 15, 2016

9 Chemotherapy in Appendiceal Adenocarcinomas/Asare et al AJCC staging system for appendiceal adenocarcinomas, in which mucinous moderately differentiated and poorly differentiated tumors are classified as high grade and thus consideration should be given to classifying mucinous appendiceal adenocarcinomas into 3-tiers: well, moderately, and poorly differentiated. Patients with appendiceal adenocarcinoma with stage IV, mucinous, welldifferentiated histology do not benefit from systemic chemotherapy and cytoreductive surgery should be considered as the frontline treatment among these individuals. FUNDING SUPPORT No specific funding was disclosed. CONFLICT OF INTEREST DISCLOSURES Elliot A. Asare is supported by the American College of Surgeons Clinical Scholars in Residence Program. REFERENCES 1. McCusker ME, Cote TR, Clegg LX, Sobin LH. Primary malignant neoplasms of the appendix: a population-based study from the Surveillance, Epidemiology and End Results program, Cancer. 2002;94: Smeenk RM, van Velthuysen ML, Verwaal VJ, Zoetmulder FA. Appendiceal neoplasms and pseudomyxoma peritonei: a population based study. Eur J Surg Oncol. 2008;34: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; Connor SJ, Hanna GB, Frizelle FA. Appendiceal tumors: retrospective clinicopathologic analysis of appendiceal tumors from 7,970 appendectomies. Dis Colon Rectum. 1998;41: Benedix F, Reimer A, Gastinger I, Mroczkowski P, Lippert H, Kube R. Primary appendiceal carcinoma epidemiology, surgery and survival: results of a German multi-center study. Eur J Surg Oncol. 2010;36: Cortina R, McCormick J, Kolm P, Perry RR. Management and prognosis of adenocarcinoma of the appendix. Dis Colon Rectum. 1995;38: Ito H, Osteen RT, Bleday R, Zinner MJ, Ashley SW, Whang EE. Appendiceal adenocarcinoma: long-term outcomes after surgical therapy. Dis Colon Rectum. 2004;47: Overman MJ, Fournier K, Hu CY, et al. Improving the AJCC/ TNM staging for adenocarcinomas of the appendix: the prognostic impact of histological grade. Ann Surg. 2013;257: Davison JM, Choudry HA, Pingpank JF, et al. Clinicopathologic and molecular analysis of disseminated appendiceal mucinous neoplasms: identification of factors predicting survival and proposed criteria for a three-tiered assessment of tumor grade. Mod Pathol. 2014; 27: Turaga KK, Pappas SG, Gamblin T. Importance of histologic subtype in the staging of appendiceal tumors. Ann Surg Oncol. 2012;19: Liu X, Mody K, de Abreu FB, et al. Molecular profiling of appendiceal epithelial tumors using massively parallel sequencing to identify somatic mutations. Clin Chem. 2014;60: Alakus H, Babicky ML, Ghosh P, et al. Genome-wide mutational landscape of mucinous carcinomatosis peritonei of appendiceal origin. Genome Med. 2014;6: Taggart MW, Galbincea J, Mansfield PF, et al. High-level microsatellite instability in appendiceal carcinomas. Am J Surg Pathol. 2013; 37: Misdraji J, Yantiss RK, Graeme-Cook FM, Balis UJ, Young RH. Appendiceal mucinous neoplasms: a clinicopathologic analysis of 107 cases. Am J Surg Pathol. 2003;27: Chua TC, Moran BJ, Sugarbaker PH, et al. Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol. 2012;30: Pietrantonio F, Maggi C, Fanetti G, et al. FOLFOX-4 chemotherapy for patients with unresectable or relapsed peritoneal pseudomyxoma. Oncologist. 2014;19: Tejani MA, Ter Veer A, Milne D, et al. Systemic therapy for advanced appendiceal adenocarcinoma: an analysis from the NCCN Oncology Outcomes Database for colorectal cancer. J Natl Compr Canc Netw. 2014;12: Shapiro JF, Chase JL, Wolff RA, et al. Modern systemic chemotherapy in surgically unresectable neoplasms of appendiceal origin: a single-institution experience. Cancer. 2010;116: Farquharson AL, Pranesh N, Witham G, et al. A phase II study evaluating the use of concurrent mitomycin C and capecitabine in patients with advanced unresectable pseudomyxoma peritonei. Br J Cancer. 2008;99: Lieu CH, Lambert LA, Wolff RA, et al. Systemic chemotherapy and surgical cytoreduction for poorly differentiated and signet ring cell adenocarcinomas of the appendix. Ann Oncol. 2012;23: Bradley RF, Stewart JH 4th, Russell GB, Levine EA, Geisinger KR. Pseudomyxoma peritonei of appendiceal origin: a clinicopathologic analysis of 101 patients uniformly treated at a single institution, with literature review. Am J Surg Pathol. 2006;30: Ronnett BM, Zahn CM, Kurman RJ, Kass ME, Sugarbaker PH, Shmookler BM. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to pseudomyxoma peritonei. Am J Surg Pathol. 1995;19: Cancer January 15,