original articles
Annals of Oncology
Annals of Oncology 23: 652–658, 2012 doi:10.1093/annonc/mdr279 Published online 8 June 2011
Systemic chemotherapy and surgical cytoreduction for poorly differentiated and signet ring cell adenocarcinomas of the appendix C. H. Lieu1, L. A. Lambert2, R. A. Wolff1, C. Eng1, N. Zhang3, S. Wen3, S. Rafeeq2, M. Taggart4, K. Fournier2, R. Royal2, P. Mansfield2 & M. J. Overman1* Departments of 1Gastrointestinal Medical Oncology; 2Surgical Oncology; 3Biostatistics; 4Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA
Received 29 January 2011; revised 6 April 2011; accepted 7 April 2011
Background: Poorly differentiated and signet ring cell adenocarcinomas of the appendix represent a subset with aggressive tumor biology and poor outcomes with few studies evaluating the impact of systemic chemotherapy and cytoreductive surgery (CRS). Patients and methods: A retrospective chart review of patients with either poorly differentiated and signet ring cell appendiceal adenocarcinomas was completed from 1992 to 2010. Results: One hundred forty-two patients were identified. Seventy-eight patients with metastatic disease received chemotherapy. Radiographic response was 44%, median progression-free survival (PFS) was 6.9 months, and median overall survival (OS) was 1.7 years. In multivariate analysis, response to chemotherapy [hazard ratio (HR) 0.5; P = 0.02] predicted improved PFS, and complete CRS (HR 0.3; P = 0.004) predicted improved OS. Patients who underwent complete CRS (n = 26) had a median relapse-free survival (RFS) of 1.2 years and a median OS of 4.2 years. *Correspondence to: Dr M. J. Overman, Department of Gastrointestinal Medical Oncology, Unit 0426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. Tel: +1-713-745-4317; Fax: +1-713-5630541; E-mail:
[email protected]
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
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Annals of Oncology
original articles
In multivariate analysis for this subset, complete cytoreduction score of 0 was significantly correlated with improved RFS (HR 0.07; P = 0.01) and OS (HR 0.02; P = 0.01). Conclusions: Systemic chemotherapy appears to be a viable treatment option for patients with metastatic poorly differentiated and signet ring cell appendiceal adenocarcinomas. Complete CRS is associated with improved RFS and OS, though part of this benefit likely reflects the selection of good tumor biology. Key words: appendiceal cancers, cytoreductive surgery, poorly differentiated, retrospective review, signet ring
introduction Appendiceal tumors encompass a rare and diverse group of neoplasms that have an age-adjusted incidence of 0.12 cases per 1 million individuals per year. Appendiceal tumors represent only 1% of all colorectal cancers diagnosed each year in the United States [1]. Little is known about the risk factors or etiology of epithelial tumors of the appendix, and historically, these tumors have been grouped together with colorectal cancers. However, appendiceal tumors, for which outcomes are strongly determined by histologic subtype, tend to have a biology and natural history that are markedly different from those of adenocarcinomas of the colon and rectum [2]. The primary treatment of patients with metastatic peritoneal dissemination of mucinous epithelial appendiceal neoplasms is complete cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) [3]. Retrospective single-institution studies of complete CRS and HIPEC in patients with disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA) histological subtypes report median overall survival (OS) durations of 5–10 years [4–8]. Patients with PMCA have worse outcomes than patients with DPAM with 5-year OSs for patients who undergo complete CRS and HIPEC of 30%–35% [8, 9]. Studies also suggest worse outcomes for the subset of PMCA patients who have either signet ring cell or poorly differentiated tumor histology [9–11]. In one study of patients who were not candidates for CRS, poorly differentiated tumor histology [hazard ratio (HR) = 2.86, P = 0.03] and the presence of signet ring cells (HR = 3.99, P = 0.001) were both associated with shorter OS [11]. At present, the benefit of CRS with or without HIPEC for the subgroup of patients with either signet ring cell or poorly differentiated tumor histology is not known. The majority of metastatic appendiceal adenocarcinomas demonstrates a relatively slow-growing biology and are primarily treated with CRS and HIPEC. Consequently, the role of systemic chemotherapy for these relatively slow-growing tumors has not been well investigated. An initial report from investigators at Memorial Sloan-Kettering showed no benefit in OS for patients treated with systemic chemotherapy [12]. More recent studies have begun to evaluate the role of systemic chemotherapy in this disease process, though the exact benefit still remains unclear [11, 13]. Because appendiceal adenocarcinomas with poor differentiation or signet ring cell histology appear to have a more aggressive biology, the potential effects of systemic chemotherapy in this subtype of appendiceal adenocarcinomas may be distinct from the effects in appendiceal adenocarcinomas with well or moderately differentiated histologies. To date, no study has evaluated the natural history, clinical behavior, or treatment response in
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this histologic subgroup of appendiceal adenocarcinomas. The goal of this retrospective study was to define the subset of poorly differentiated and/or signet ring cell histologies in appendiceal adenocarcinomas and to determine the effects of systemic chemotherapy and CRS on survival in this group of patients.
patients and methods patient and data collection Review of The University of Texas MD Anderson Cancer Center (UTMDACC) tumor registry between September 1992 and January 2010 was conducted. A total of 584 patients with appendiceal adenocarcinomas were identified. For inclusion in this study, each patient’s pathology was reviewed at UTMDACC and found to have either signet ring cells or poor histologic differentiation. Histological groupings for analysis were poorly differentiated adenocarcinomas with or without focal signet ring cells, signet ring cell adenocarcinomas (defined by the World Health Organization as adenocarcinomas with >50% signet ring cells), and well or moderately differentiated adenocarcinomas with focal signet ring cells. Patients’ medical records were reviewed for information regarding demographic data, tumor characteristics, treatment history, response to treatments, laboratory tumor markers [carcinoembryonic antigen, cancer antigen (CA) 125, and CA 19-9], disease progression, and survival. Complete cytoreduction was defined as patients with peritoneal metastases who had £2.5 mm of disease remaining following CRS. The complete cytoreduction cohort was further stratified into two groups: those with no visible remaining disease [complete cytoreduction score of 0 (CC-0)] and those with remaining visible disease £2.5 mm (CC-1). Available pathology specimens from patients who underwent complete CRS were rereviewed by a gastrointestinal pathologist (MT) for histological grade confirmation. Perioperative chemotherapy was defined as patients who received chemotherapy either neoadjuvantly or adjuvantly. Oligometastatic disease within the peritoneal cavity was defined as disease that involved no more than two localized sites of disease (e.g. patients with bilateral ovarian disease). Distant metastases were defined as nonperitoneal sites of disease that were discontiguous from nearby peritoneal sites. For systemic chemotherapy evaluation, patients were required to have had visible disease on radiographic imaging before chemotherapy, to have received at least one cycle of chemotherapy, and to have had a follow-up radiologic imaging evaluation. Patients excluded from this study generally had been seen in consultation and recommended to initiate systemic chemotherapy but had not met the above criteria. Response to chemotherapy was categorized according to a review of radiologic reports and the treating physician’s clinical notes. Only patients with improvement in disease as shown on radiologic imaging were considered to have a response. Patients considered to have stable disease were required to have both radiographic and clinical stability, while patients with progressive disease could have either radiographic progression or clinical decline. Because tumor markers were not documented in all patients, tumor markers were not included in the determination of response. This
doi:10.1093/annonc/mdr279 | 653
original articles retrospective analysis was approved by the MD Anderson institutional review board, and a waiver of consent was allowed.
statistical analysis Progression-free survival (PFS), relapse-free survival (RFS), and OS were analyzed using the Kaplan–Meier method of product-limit estimation. For the overall study population, OS was calculated from the date of diagnosis to death. For the chemotherapy subgroup, PFS and OS were calculated from the date of initial chemotherapy for metastatic disease, and for the CRS subgroup, RFS and OS were calculated from the date of CRS. The logrank test was used to calculate the survival difference for categorical variables. The chi-square test and Fisher’s exact test were used to assess the relationship between categorical variables. All P values were two-sided and P values 3.68 >2.46 >6.97 7.52–17.06
0.421 0.892 0.927 0.222 0.229 0.002
0.98 0.74 0.62 0.98 0.62 0.49
0.95–1.02 0.21–2.63 0.15–2.56 0.43–2.23 0.28–1.35 0.27–0.89
0.30 0.64 0.51 0.97 0.23 0.02
1.5 1.73 2.55 0.75 2.75 2.22
0.89–4.05 1.49–2.22 >0.515 >0.6 >1.73 1.73–3.86
0.725 0.991 0.951 0.045 0.009 0.069
0.99 2.81 1.53 1.10 0.26 0.68
0.97–1.02 0.75–10.56 0.36–6.45 0.48–2.53 0.10–0.66 0.36–1.29
0.73 0.13 0.57 0.84 0.004 0.24
PFS, progression-free survival; OS, overall survival; CI, confidence interval; HR, hazard ratio; NR, not reached; CRS, cytoreductive surgery.
Patients with either signet ring cell adenocarcinoma or poorly differentiated adenocarcinoma had similarly poor OS. Patients whose appendiceal adenocarcinoma had only a subset of signet ring cells had an improved OS, but this subgroup was small, representing only 6% of our patients. Prior studies have noted a worse outcome for patients with either poor differentiation or signet ring cells; however, no previous study has directly compared outcomes associated with these two histologic features [9–11]. Despite the poor outcome for this subset of appendiceal adenocarcinomas, the development of extraperitoneal disease still remains rare, occurring in only 10% of patients. However, those patients who did develop distant extraperitoneal metastases appeared to have a worse OS. Our findings are similar to those of a prior small retrospective study of 30 patients that compared well-differentiated appendiceal adenocarcinomas with moderate or poorly differentiated appendiceal adenocarcinomas [15]. In that study, a higher rate
656 | Lieu et al.
of extraperitoneal metastases (0% versus 43%) and worse mean OS (26 versus 13 months, P < 0.01) was seen in patients with a moderate or poorly differentiated histology. Interestingly, no molecular differences in microsatellite instability, p53 overexpression, or K-ras mutations were seen between these two histological groups [15]. The role of systemic chemotherapy has not been delineated in appendiceal epithelial neoplasms and has generally been utilized in patients who are not candidates for surgical cytoreduction. A phase II study evaluating the use of concurrent mitomycin C and capecitabine in 40 patients with advanced unresectable DPAM or PMCA suggested a role for systemic chemotherapy [13]. In that study, 6 patients (15%) demonstrated radiographic reductions in disease, and 18 patients (46%) demonstrated disease stabilization. However, only 32% of patients in that study had PMCA histology, and efficacy end points were not stratified by histologic subtype. A
Volume 23 | No. 3 | March 2012
original articles
Annals of Oncology
recent retrospective review of patients with PMCA who were not candidates for CRS reported a radiographic reduction or symptom improvement in 13 (24%) of 52 patients and a median PFS of 7.6 months [11]. In that study, poorly differentiated histology was present in only 15 patients (28%). In our study, semiquantitative radiographic response was seen in 44% of patients. The median PFS was 6.9 months, and chemotherapy response correlated with an improved PFS in the multivariate analysis. Interestingly, patients who received second-line chemotherapy appeared to have less benefit from systemic chemotherapy, with a response rate of 13% and a median PFS of 2.8 months. These results appear comparable to the results demonstrated with oxaliplatin- or irinotecanbased regimens used in colorectal cancer [16]. The differential
impact of systemic therapy between the first- and second-line therapy suggests that, for this subset of appendiceal adenocarcinomas, systemic chemotherapy is affecting the natural behavior of this cancer. In our study, complete CRS was associated with a significant increase in OS (4.2 versus 1.7 years, P < 0.001). In a prior study from Glehen et al. [10], patients with appendiceal epithelial neoplasms who underwent a CC-0 or CC-1 resection had a 5-year OS of 80%. However, in the histologic subset of patients with poorly differentiated or signet ring cell histology in that study, the 5-year OS was only 20%. In our study, only 21% of our patients achieved a CC0 or CC-1 resection. Complete CRS was significantly
Table 4. Uni- and multivariate analysis of RFS and OS data for the cytoreductive surgery cohort Univariate Multivariate Years 95% CI P value HR 95% CI RFS Age (
