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ScienceDirect EJSO 41 (2015) 707e712
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Systemic chemotherapy (SC) before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/ HIPEC) in patients with peritoneal mucinous carcinomatosis of appendiceal origin (PMCA) V. Milovanov a, A. Sardi*, P. Ledakis a, N. Aydin a, C. Nieroda a, M. Sittig a, M. Nunez a, V. Gushchin a Department of Surgical Oncology, Mercy Medical Center, 227 St Paul Place, Baltimore, MD 21202-2001, USA Accepted 7 January 2015 Available online 17 January 2015
Abstract Background: The role of SC before CRS/HIPEC for patients with PMCA is unclear. This study explores the effect of SC prior to CRS/ HIPEC on overall survival (OS) in patients with PMCA. Methods: 72 patients with recently diagnosed PMCA who underwent CRS/HIPEC were identified from a prospective database. Thirty patients had SC before CRS/HIPEC (Group 1) and 42 did not (Group 2). Patients who were referred to our center after multiple lines of SC were excluded from this analysis. OS was estimated. Results: Median follow-up was 3.2 years. Groups were similar regarding lymph node positivity, postoperative SC and rate of complete cytoreduction. Twenty-four (80%) patients in Group 1 and 21 (50%) in Group 2 had high grade histology (HG) (p ¼ 0.01). OS from CRS/ HIPEC at 1, 2, and 3 years was 93, 68, 51% in Group 1 and 82, 64, 60% in Group 2, respectively (p ¼ 0.74). Among HG patients 3-year survival was 36% in the SC group vs. 35% in the group without SC (p ¼ 0.67). The 3-year OS for patients with low grade (LG) tumors was 100% in the SC group vs. 79% in the group with no prior SC (p ¼ 0.26). Among patients with signet ring cell (SRC) histology, 1, 2 and 3year survival was 94, 67 and 22% in the SC group vs. 43, 14, 14% in the group with no SC, respectively (p ¼ 0.028). There were only 6 patients with LG PMCA who received prior SC. Conclusions: Preoperative SC could improve the prognosis of patients with high-grade PMCA with SRC histology. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Cytoreductive surgery; Hyperthermic intraperitoneal chemotherapy; Systemic chemotherapy; Mucinous carcinomatosis of appendiceal origin
Introduction Treatment of appendiceal tumors with peritoneal dissemination is challenging due to pathological heterogeneity1e5 of disease and controversial treatment strategy. Histologically, the appendiceal malignancies can be classified into disseminated peritoneal adenomucinosis (DPAM) and * Corresponding author. Tel.: þ1 410 332 9294; fax: þ1 410 332 9731. E-mail addresses: [email protected] (V. Milovanov), asardi@ mdmercy.com (A. Sardi), [email protected] (P. Ledakis), [email protected] (N. Aydin), [email protected] (C. Nieroda), [email protected] (M. Sittig), [email protected] (M. Nunez), [email protected] (V. Gushchin). a Tel.: þ1 410 332 9294; fax: þ1 410 332 9731. http://dx.doi.org/10.1016/j.ejso.2015.01.005 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved.
Peritoneal mucinous carcinomatosis of appendiceal origin (PMCA), with some tumors having intermediate histological features.6 While an aggressive surgical approach consisting of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a standard of care for both DPAM and PMCA,7e10 systemic chemotherapy (SC) is used mostly for PMCA patients.11 It is common for PMCA patients to have several courses of 5-FU based SC either before or after CRS/HIPEC. The benefits of SC may be: increasing the probability of complete cytoreduction, better control of metastatic disease and improvement of the overall survival (OS).12 However, there is no strong evidence that use of current chemotherapy regimens achieves any of these objectives in
708
V. Milovanov et al. / EJSO 41 (2015) 707e712
patients with resectable PMCA undergoing CRS/HIPEC. Several studies were not able to show any benefit of SC.13,14 Other studies have been shown that SC prior to CRS/HIPEC is associated with poorer survival outcomes.7,15,16 There is also a concern that SC may debilitate patients prior to CRS and tumor could progress through ineffective chemotherapy closing the window of performing potentially complete cytoreduction.17 Based on the existing data, it is hard to make a clear decision about efficacy and appropriate timing of SC in patients with PMCA. Prospective randomized trials like the COMBATAC trial could clarify the exact role of SC in treatment of these patients.18 This study aims to explore the association of SC administered prior to CRS/HIPEC with OS in patients with PMCA treated at a medical center specializing in peritoneal surface malignancies. Methods A retrospective analysis of a prospective database of 344 underwent CRS/HIPEC between February-1998 and January 2014 identified 72 patients with PMCA. Patients who were referred to our center after failing previous treatment which could include multiple lines of SC, debulking surgery or both were excluded from our analyses. Only patients with recently diagnosed PMCA who were referred to our center within 4 months after initial diagnoses were evaluated. Patients with repeated CRS/HIPEC procedures were excluded from the study. A diagnosis of PMCA was based on the clinical and pathological findings established by Ronnett et al.6 CT scan of the chest, abdomen, and pelvis, and tumor markers (CEA, CA19-9, and CA 125) were obtained prior to surgery. Surgery was recommended for patients without evidence of extraperitoneal metastases and if complete cytoreduction (CC) was deemed feasible by the operating surgeon. The Peritoneal Cancer Index (PCI), as previously described by Jacquet et al., was used to assess the extent of peritoneal involvement.19 The histopathology from the first surgery or biopsy, was reviewed at our institution when available. Lymph node (LN) status was obtained from the pathology report. Following cytoreduction, HIPEC was performed. Details of the procedure have been previously reported.20,21 All patients received Mitomycin C as an intraperitoneal chemotherapy agent. Patients were divided into two groups, based on SC before the definitive CRS/HIPEC. Patients who had 3e8 cycles of SC before CRS/HIPEC were categorized in “Group 1” and patients without SC were in “Group 2” Clinicopathologic characteristics such as PCI score, LN status, completeness of cytoreduction, age, and tumor histopathology were compared between the groups. The indications for preoperative SC included: -First surgery within 4 months prior to definite CRS/ HIPEC.
-High grade tumor histology. SC was administered at the discretion of the medical oncologist due to the high probability for disease progression. Clinical data were collected prospectively during followup visits and no patients have been lost to follow-up. Mean follow-up was calculated from the date of surgery until death or last follow-up visit. Overall survival (OS) was calculated from the date of CRS/HIPEC to the date of death or last encounter. Progression-free survival (PFS) was defined as no evidence of disease by physical exam, CT scan, and/or normal tumor markers and was calculated from the date of CRS/HIPEC to date of recurrence or date of last encounter. Estimates of survival were calculated using the KaplaneMeier method. Differences were calculated with a log rank test. Separate survival analyses were provided for patients with high grade (HG) and low grade (LG) tumor depending on preoperative SC. Cox proportional hazard ratio was used to compare pertinent variables. Results were considered statistically significant if p < 0.05. Progression-free survival was only estimated for patients with complete cytoreduction. Multivariable analyses of such factors as: Grade of tumor, CC 0e1, PCI > 20, LN status and preoperative SC has been provided using Cox Regression. Results Seventy-two patients with PMCA were included in the study. Mean age was 54 years (range 26e79). Median follow up was 3.2 years. The mean PCI score was 25. Eighty-eight percent of patients had complete cytoreduction (CC-0/CC-1). Rate of grade 3/4 complications was 20%. There were no 30 day peri-operative or in hospital mortality. Forty-five patients were diagnosed with high grade tumors according to the 7th AJCC classification (moderately or poorly differentiated adenocarcinoma, signet ring cell carcinoma and goblet cell carcinoid). Thirtysix patients were alive with no evidence of disease, 10 alive with disease. Twenty-five disease related deaths occurred. One patient died of other cause. The estimated median survival was 4.2 years (95% CI: 1.2e7.2). The overall 1, 2, 3, and 5 year survival rates were 87%, 68%, 58% and 48%, respectively. PFS for patients with complete cytoreduction was 74%, 49% and 46% at 1, 2 and 3 years, respectively. PFS was evaluated only in patients who were considered disease free (CC 0e1) after CRS/HIPEC. Thirty patients had SC before CRS/HIPEC (Group 1) and the remaining 42 did not (Group 2). The groups were similar in Age, lymph node positivity and postoperative SC. The two groups were different in prior surgical score9 e PSS 2 in 73% vs. 31%; p ¼ 0.001, percentage of female patients e (73% vs. 48%; p ¼ 0.029), HG histopathology rate e (80% vs. 50%; p ¼ 0.01) (Table 1). In Group 1, 25 patients received FOLFOX regimen, 3 FOLFIRI and 2 capecitabine with oxaliplatin. Eight patients received
V. Milovanov et al. / EJSO 41 (2015) 707e712 Table 1 Clinicopathological characteristics of patient population.
Mean age (years) Female Mean PCI CC 0e1 Positive LN PSS 2* Delay of CRS/HIPEC (mon.) Postoperative SC High grade histology SRC histology
Prior SC (n ¼ 30)
No prior SC (n ¼ 42)
p-value
54 73% 24 93% 43% 73% 5 82% 80% 60%
55 48% 27 83% 43% 31% 3 77% 50% 24%
0.206 0.029 0.492 0.206 0.968 0.001 0.034 0.556 0.010 0.002
PCI e Peritoneal Cancer Index; CC e completeness of cytoreduction score; LN e lymph nodes; PSS e prior surgical score; SRC e signet ring cells. p-value was considered statistically significant if less than 0.05. Statistically significant p-values were highlighted in bold.
bevacizumab as a part of their regimen. Mean number of prior SC cycles was 4.4 (range 3e8). Median time from diagnosis to CRS/HIPEC was 5 months (Group 1) and 3 months (Group 2) (p ¼ 0.034). CCR 0e1 rate was 93% vs. 83% in Group 1 and Group 2, respectively (p ¼ 0.2). In the group of patients with prior SC (Group 1) OS was 93, 68, and 51% for 1, 2 and 3 years, respectively. OS in patients without SC before the CRS/HIPEC was 82, 64, 60% for 1, 2 and 3 year respectively (p ¼ 0.74) (Fig. 1). In patients with prior SC (Group 1) PFS was 78%, 49%
Figure 1. OS of patients with PMCA treated with CRS/HIPEC depending on prior chemotherapy.
709
and 36% for 1, 2 and 3 years, respectively. PFS in patients without SC before the CRS/HIPEC was 67%, 53% and 53% for 1, 3 and 5 years, respectively (p ¼ 0.46). Due to different number of patients with HG tumors among the groups, additional survival analyses were performed. We evaluated the effect of preoperative SC on the OS within the HG and LG groups. We also evaluated the effect of preoperative SC in the subgroup of patients with signet ring cell histology. Among the patients with HG tumors (n ¼ 24)overall survival was 91%, 60% and 36% for 1, 2 and 3 years after prior SC. OS in patients without SC (n ¼ 21) was 65%, 35% and 35% for 1, 2 and 3 years respectively (p ¼ 0.665). Among the patients with LG histology, after SC (n ¼ 6) overall survival was 100% for 1, 2 and 3 years. OS in patients without SC (n ¼ 21) was 90%, 79% and 71% for 1, 2 and 3 years respectively (p ¼ 0.259) (Fig. 2). Patients with SRC tumors, who received prior SC (n ¼ 18) had overall survival 94%, 67% and 22% at 1, 2 and 3 years, respectively. OS in patients with SRC histology who did not receive SC (n ¼ 10) was 43%, 14% and 14% at 1, 2 and 3 years respectively (p ¼ 0.028) (Fig. 3). Multivariate analysis of tumor grade of tumor, LN status, completeness of cytoreduction, PCI score >20 and preoperative chemotherapy performed. The impact of
Figure 2. OS of patients with high grade and low grade PMCA treated with CRS/HIPEC depending on prior chemotherapy.
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Figure 3. OS of patients with signet ring cell histology treated with CRS/ HIPEC depending on prior chemotherapy.
preoperative chemotherapy on the OS was not significant according to this analyses (HR 1.0; 95% CI: 0.4e2.3; p ¼ 0.925). Tumor grade, completeness of cytoreduction, PCI score >20 had an independent impact on the OS in this population (Table 2). Discussion While aggressive surgical approach consisting of cytoreductive surgery (CRS) and hyperthermic intraperitoneal Table 2 Multivariable and univariable analyses of variables impacted overall survival of PMCA patients. Hazard ratio
Multivariable analyses HG histology 4.5 CCR 0e1 3.4 PCI > 20 3.6 LN status 2.4 Prior SC 1.0 Univariable analyses HG histology 5.4 CCR 0e1 3.2 PCI > 20 2.9 LN status 3.7 Prior SC 1.1
95% Confidence interval
p
Lower
Upper
1.2 1.2 1.2 0.8 0.4
17.6 9.9 10.5 7.4 2.3
0.030 0.022 0.019 0.106 0.925
2.0 1.2 1.1 1.6 0.5
14.7 8.0 7.7 8.4 2.5
0.001 0.016 0.036 0.002 0.738
PCI e Peritoneal Cancer Index; CCR e completeness of cytoreduction score; LN e lymph nodes; HG e high grade. p-value was considered statistically significant if less than 0.05. Statistically significant p-values were highlighted in bold.
chemotherapy (HIPEC) has become a treatment of choice for PMCA, the role of preoperative SC in treatment of these patients is still controversial.7,9,10 Inconsistent data about SC in this group of patients has been reported in the medical literature.7,11,14,16,22e24 Some authors recommend SC prior CRS/HIPEC22,23 others recommend SC only in case of recurrence disease.14 There are also reports of association of SC prior CRS/HIPEC with worse OS.7 To clarify whether preoperative SC provides any survival benefit for PMCA patients this retrospective study compared OS of patients with and without SC prior to CRS/HIPEC. A significant difference in histology was observed between Group 1 and Group 2. This was consistent with the results of multi-institutional study of Chua et al., who observed poor survival outcomes in patients with SC prior to CRS/HIPEC, which were associated with aggressive tumor biology.7 Thus, SC before the CRS/HIPEC could just highlight aggressive tumor histopathology. At the same time, there is also a possibility that prior chemotherapy may lead to the auto-selection of chemoresistant clones, and eventually to the high rate of aggressive tumors in Group 1. However, we do not have enough data to prove or disprove this theory. A separate analysis focusing on histological tumor grade indicated that prior SC may not impact the overall survival in most patients with HG or LG histology (Fig. 2). Both analyses showed a non-significant statistical difference between the groups. However, small sample size, especially in patients with low grade PMCA, does not allow us to make any definitive conclusions based on this number. It is important to note, that when we evaluated OS in the subgroup of patients with SRC histology, we observed an improvement with preoperative systemic chemotherapy (Fig. 3). This result is consistent with several case reports in which radiologic response or stable disease was achieved with systemic chemotherapy (FOLFOX) for similar histology.25,26 We observed that most of the patients who received preoperative chemotherapy (Group 1) had more extensive surgical history (PSS 2) prior to definitive CRS/HIPEC. Often, the surgeries were performed at clinics without experience in appendiceal malignancies, resulting in frequent incomplete cytoreduction. One of the goals of preoperative chemotherapy is to increase the chances of complete cytoreduction. In this study, there was no significant difference between the groups in terms of complete cytoreduction rate. These results are consistent with those of Turner’s et al. data who reported 65 vs. 72% rate of complete cytoreduction among PMCA patients treated with CRS/HIPEC with or without preoperative SC (FOLFOX and Bevacizumab), respectively.16 Also, in Turner’s study, longer operative time has been reported among the patients who had SC prior to CRS/HIPEC (438 vs. 325 min; p ¼ 0.016). Although it has been shown by Alakus et al. that PMCA reveals genetic alterations distinct from colorectal cancer,
V. Milovanov et al. / EJSO 41 (2015) 707e712
we use identical chemotherapy regimens in the systemic management of these different malignancies.27 The most commonly used chemotherapy for appendiceal cancer includes fluorouracil (5-FU) based combination regimens containing oxaliplatin (FOLFOX) or irinotecan with or without bevacizumab. The reported response rate of these regimens in PMCA was 29%, 44% and 58% in the studies of Bijelic et al., Lieu et al. and Turner et al., respectively.16,22e24 Bijelic et al. observes an association between the response rate (RR) and OS. Lieu et al., correlated RR with an improved PFS. All three studies were unable to show improvement in OS among PMCA patients who received SC prior to CRS/HIPEC comparing to the patient without SC. The current systemic chemotherapy regimens for colorectal cancer may be suboptimal in the management of advanced appendiceal malignances. This applies to the choice of agents as well as the schedule, dosing and the manner of administration. Further preclinical research in addition to clinical trials are urgently needed to optimize the systemic management of abdominal appendiceal malignance. Although we observed a statistically significant improved OS in the subgroup of patients with preoperative SC of SRC histology with (Fig. 3), no such benefit was demonstrated in the overall groups of HG or LG histology (Fig. 2). The results could be explained by the small sample size as well the retrospective nature of the analyses. We conclude, that currently used preoperative SC could improve OS in PMCA patients with SRC histology. Further prospective studies are needed to determine the role of SC in PMCA patients. Conflict of interest All authors disclose no financial and personal relationships with other people or organisations that could inappropriately influence or bias this work.
References 1. Andreasson H, Wanders A, Sun XF, et al. Histopathological classification of pseudomyxoma peritonei and the prognostic importance of PINCH protein. Anticancer Res 2012;32:1443–8. 2. Carr NJ, Finch J, Ilesley IC, et al. Pathology and prognosis in pseudomyxoma peritonei: a review of 274 cases. J Clin Pathol 2012;65: 919–23. 3. Kabbani W, Houlihan PS, Luthra R, et al. Mucinous and nonmucinous appendiceal adenocarcinomas: different clinicopathological features but similar genetic alterations. Mod Pathol 2002;15:599–605. 4. Nitecki SS, Wolff BG, Schlinkert R, Sarr MG. The natural history of surgically treated primary adenocarcinoma of the appendix. Ann Surg 1994;219:51–7. 5. Shetty S, Natarajan B, Thomas P, et al. Proposed classification of pseudomyxoma peritonei: influence of signet ring cells on survival. Am Surg 2013;79:1171–6.
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6. Ronnett BM, Zahn CM, Kurman RJ, et al. 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; 19:1390–408. 7. 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: 2449–56. 8. Elias D, Blot F, El OA, et al. Curative treatment of peritoneal carcinomatosis arising from colorectal cancer by complete resection and intraperitoneal chemotherapy. Cancer 2001;92:71–6. 9. Sugarbaker PH, Chang D. Results of treatment of 385 patients with peritoneal surface spread of appendiceal malignancy. Ann Surg Oncol 1999;6:727–31. 10. Sugarbaker PH. New standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome? Lancet Oncol 2006; 7:69–76. 11. Blackham AU, Swett K, Eng C, et al. Perioperative systemic chemotherapy for appendiceal mucinous carcinoma peritonei treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Surg Oncol 2014;109:740–5. 12. Shapiro JF, Chase JL, Wolff RA, et al. Modern systemic chemotherapy in surgically unresectable neoplasms of appendiceal origin: a singleinstitution experience. Cancer 2010;116:316–22. 13. Gough DB, Donohue JH, Schutt AJ, et al. Pseudomyxoma peritonei. Long-term patient survival with an aggressive regional approach. Ann Surg 1994;219:112–9. 14. Smith JW, Kemeny N, Caldwell C, et al. Pseudomyxoma peritonei of appendiceal origin. The Memorial Sloan-Kettering Cancer Center experience. Cancer 1992;70:396–401. 15. Baratti D, Kusamura S, Nonaka D, et al. Pseudomyxoma peritonei: clinical pathological and biological prognostic factors in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Ann Surg Oncol 2008;15:526–34. 16. Turner KM, Hanna NN, Zhu Y, et al. Assessment of neoadjuvant chemotherapy on operative parameters and outcome in patients with peritoneal dissemination from high-grade appendiceal cancer. Ann Surg Oncol 2013;20:1068–73. 17. Bertuzzo VR, Coccolini F, Pinna AD. Peritoneal seeding from appendiceal carcinoma: a case report and review of the literature. World J Gastrointest Surg 2010;2:265–9. 18. Glockzin G, Rochon J, Arnold D, et al. A prospective multicenter phase II study evaluating multimodality treatment of patients with peritoneal carcinomatosis arising from appendiceal and colorectal cancer: the COMBATAC trial. BMC Cancer 2013;13:67. 19. Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer Treat Res 1996;82:359–74. 20. El HH, Gushchin V, Francis J, et al. The role of cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) in patients with high-grade appendiceal carcinoma and extensive peritoneal carcinomatosis. Ann Surg Oncol 2012;19:110–4. 21. Halabi HE, Gushchin V, Francis J, et al. Prognostic significance of lymph node metastases in patients with high-grade appendiceal cancer. Ann Surg Oncol 2012;19:122–5. 22. Bijelic L, Kumar AS, Stuart OA, Sugarbaker PH. Systemic chemotherapy prior to cytoreductive surgery and HIPEC for carcinomatosis from appendix Cancer: impact on perioperative outcomes and short-term survival. Gastroenterol Res Pract 2012; 2012:163284. 23. 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: 652–8.
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24. Tejani MA, Ter VA, 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; 12:1123–30. 25. Ko YH, Jung CK, Oh SN, et al. Primary signet ring cell carcinoma of the appendix: a rare case report and our 18-year experience. World J Gastroenterol 2008;14:5763–8.
26. Powell ED, Macdonald DB, Elkeilani AM, Asmis TR. A case of appendiceal adenocarcinoma with clinical benefit from FOLFOX and bevacizumab. Case Rep Oncol 2009;2:111–5. 27. Alakus H, Babicky M, Ghosh P, et al. Genome-wide mutational landscape of mucinous carcinomatosis peritonei of appendiceal origin. Genome Med 2014;6:43.
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Systemic chemotherapy (SC) before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/ HIPEC) in patients with peritoneal mucinous carcinomatosis of appendiceal origin (PMCA) V. Milovanov a, A. Sardi*, P. Ledakis a, N. Aydin a, C. Nieroda a, M. Sittig a, M. Nunez a, V. Gushchin a Department of Surgical Oncology, Mercy Medical Center, 227 St Paul Place, Baltimore, MD 21202-2001, USA Accepted 7 January 2015 Available online 17 January 2015
Abstract Background: The role of SC before CRS/HIPEC for patients with PMCA is unclear. This study explores the effect of SC prior to CRS/ HIPEC on overall survival (OS) in patients with PMCA. Methods: 72 patients with recently diagnosed PMCA who underwent CRS/HIPEC were identified from a prospective database. Thirty patients had SC before CRS/HIPEC (Group 1) and 42 did not (Group 2). Patients who were referred to our center after multiple lines of SC were excluded from this analysis. OS was estimated. Results: Median follow-up was 3.2 years. Groups were similar regarding lymph node positivity, postoperative SC and rate of complete cytoreduction. Twenty-four (80%) patients in Group 1 and 21 (50%) in Group 2 had high grade histology (HG) (p ¼ 0.01). OS from CRS/ HIPEC at 1, 2, and 3 years was 93, 68, 51% in Group 1 and 82, 64, 60% in Group 2, respectively (p ¼ 0.74). Among HG patients 3-year survival was 36% in the SC group vs. 35% in the group without SC (p ¼ 0.67). The 3-year OS for patients with low grade (LG) tumors was 100% in the SC group vs. 79% in the group with no prior SC (p ¼ 0.26). Among patients with signet ring cell (SRC) histology, 1, 2 and 3year survival was 94, 67 and 22% in the SC group vs. 43, 14, 14% in the group with no SC, respectively (p ¼ 0.028). There were only 6 patients with LG PMCA who received prior SC. Conclusions: Preoperative SC could improve the prognosis of patients with high-grade PMCA with SRC histology. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Cytoreductive surgery; Hyperthermic intraperitoneal chemotherapy; Systemic chemotherapy; Mucinous carcinomatosis of appendiceal origin
Introduction Treatment of appendiceal tumors with peritoneal dissemination is challenging due to pathological heterogeneity1e5 of disease and controversial treatment strategy. Histologically, the appendiceal malignancies can be classified into disseminated peritoneal adenomucinosis (DPAM) and * Corresponding author. Tel.: þ1 410 332 9294; fax: þ1 410 332 9731. E-mail addresses: [email protected] (V. Milovanov), asardi@ mdmercy.com (A. Sardi), [email protected] (P. Ledakis), [email protected] (N. Aydin), [email protected] (C. Nieroda), [email protected] (M. Sittig), [email protected] (M. Nunez), [email protected] (V. Gushchin). a Tel.: þ1 410 332 9294; fax: þ1 410 332 9731. http://dx.doi.org/10.1016/j.ejso.2015.01.005 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved.
Peritoneal mucinous carcinomatosis of appendiceal origin (PMCA), with some tumors having intermediate histological features.6 While an aggressive surgical approach consisting of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a standard of care for both DPAM and PMCA,7e10 systemic chemotherapy (SC) is used mostly for PMCA patients.11 It is common for PMCA patients to have several courses of 5-FU based SC either before or after CRS/HIPEC. The benefits of SC may be: increasing the probability of complete cytoreduction, better control of metastatic disease and improvement of the overall survival (OS).12 However, there is no strong evidence that use of current chemotherapy regimens achieves any of these objectives in
708
V. Milovanov et al. / EJSO 41 (2015) 707e712
patients with resectable PMCA undergoing CRS/HIPEC. Several studies were not able to show any benefit of SC.13,14 Other studies have been shown that SC prior to CRS/HIPEC is associated with poorer survival outcomes.7,15,16 There is also a concern that SC may debilitate patients prior to CRS and tumor could progress through ineffective chemotherapy closing the window of performing potentially complete cytoreduction.17 Based on the existing data, it is hard to make a clear decision about efficacy and appropriate timing of SC in patients with PMCA. Prospective randomized trials like the COMBATAC trial could clarify the exact role of SC in treatment of these patients.18 This study aims to explore the association of SC administered prior to CRS/HIPEC with OS in patients with PMCA treated at a medical center specializing in peritoneal surface malignancies. Methods A retrospective analysis of a prospective database of 344 underwent CRS/HIPEC between February-1998 and January 2014 identified 72 patients with PMCA. Patients who were referred to our center after failing previous treatment which could include multiple lines of SC, debulking surgery or both were excluded from our analyses. Only patients with recently diagnosed PMCA who were referred to our center within 4 months after initial diagnoses were evaluated. Patients with repeated CRS/HIPEC procedures were excluded from the study. A diagnosis of PMCA was based on the clinical and pathological findings established by Ronnett et al.6 CT scan of the chest, abdomen, and pelvis, and tumor markers (CEA, CA19-9, and CA 125) were obtained prior to surgery. Surgery was recommended for patients without evidence of extraperitoneal metastases and if complete cytoreduction (CC) was deemed feasible by the operating surgeon. The Peritoneal Cancer Index (PCI), as previously described by Jacquet et al., was used to assess the extent of peritoneal involvement.19 The histopathology from the first surgery or biopsy, was reviewed at our institution when available. Lymph node (LN) status was obtained from the pathology report. Following cytoreduction, HIPEC was performed. Details of the procedure have been previously reported.20,21 All patients received Mitomycin C as an intraperitoneal chemotherapy agent. Patients were divided into two groups, based on SC before the definitive CRS/HIPEC. Patients who had 3e8 cycles of SC before CRS/HIPEC were categorized in “Group 1” and patients without SC were in “Group 2” Clinicopathologic characteristics such as PCI score, LN status, completeness of cytoreduction, age, and tumor histopathology were compared between the groups. The indications for preoperative SC included: -First surgery within 4 months prior to definite CRS/ HIPEC.
-High grade tumor histology. SC was administered at the discretion of the medical oncologist due to the high probability for disease progression. Clinical data were collected prospectively during followup visits and no patients have been lost to follow-up. Mean follow-up was calculated from the date of surgery until death or last follow-up visit. Overall survival (OS) was calculated from the date of CRS/HIPEC to the date of death or last encounter. Progression-free survival (PFS) was defined as no evidence of disease by physical exam, CT scan, and/or normal tumor markers and was calculated from the date of CRS/HIPEC to date of recurrence or date of last encounter. Estimates of survival were calculated using the KaplaneMeier method. Differences were calculated with a log rank test. Separate survival analyses were provided for patients with high grade (HG) and low grade (LG) tumor depending on preoperative SC. Cox proportional hazard ratio was used to compare pertinent variables. Results were considered statistically significant if p < 0.05. Progression-free survival was only estimated for patients with complete cytoreduction. Multivariable analyses of such factors as: Grade of tumor, CC 0e1, PCI > 20, LN status and preoperative SC has been provided using Cox Regression. Results Seventy-two patients with PMCA were included in the study. Mean age was 54 years (range 26e79). Median follow up was 3.2 years. The mean PCI score was 25. Eighty-eight percent of patients had complete cytoreduction (CC-0/CC-1). Rate of grade 3/4 complications was 20%. There were no 30 day peri-operative or in hospital mortality. Forty-five patients were diagnosed with high grade tumors according to the 7th AJCC classification (moderately or poorly differentiated adenocarcinoma, signet ring cell carcinoma and goblet cell carcinoid). Thirtysix patients were alive with no evidence of disease, 10 alive with disease. Twenty-five disease related deaths occurred. One patient died of other cause. The estimated median survival was 4.2 years (95% CI: 1.2e7.2). The overall 1, 2, 3, and 5 year survival rates were 87%, 68%, 58% and 48%, respectively. PFS for patients with complete cytoreduction was 74%, 49% and 46% at 1, 2 and 3 years, respectively. PFS was evaluated only in patients who were considered disease free (CC 0e1) after CRS/HIPEC. Thirty patients had SC before CRS/HIPEC (Group 1) and the remaining 42 did not (Group 2). The groups were similar in Age, lymph node positivity and postoperative SC. The two groups were different in prior surgical score9 e PSS 2 in 73% vs. 31%; p ¼ 0.001, percentage of female patients e (73% vs. 48%; p ¼ 0.029), HG histopathology rate e (80% vs. 50%; p ¼ 0.01) (Table 1). In Group 1, 25 patients received FOLFOX regimen, 3 FOLFIRI and 2 capecitabine with oxaliplatin. Eight patients received
V. Milovanov et al. / EJSO 41 (2015) 707e712 Table 1 Clinicopathological characteristics of patient population.
Mean age (years) Female Mean PCI CC 0e1 Positive LN PSS 2* Delay of CRS/HIPEC (mon.) Postoperative SC High grade histology SRC histology
Prior SC (n ¼ 30)
No prior SC (n ¼ 42)
p-value
54 73% 24 93% 43% 73% 5 82% 80% 60%
55 48% 27 83% 43% 31% 3 77% 50% 24%
0.206 0.029 0.492 0.206 0.968 0.001 0.034 0.556 0.010 0.002
PCI e Peritoneal Cancer Index; CC e completeness of cytoreduction score; LN e lymph nodes; PSS e prior surgical score; SRC e signet ring cells. p-value was considered statistically significant if less than 0.05. Statistically significant p-values were highlighted in bold.
bevacizumab as a part of their regimen. Mean number of prior SC cycles was 4.4 (range 3e8). Median time from diagnosis to CRS/HIPEC was 5 months (Group 1) and 3 months (Group 2) (p ¼ 0.034). CCR 0e1 rate was 93% vs. 83% in Group 1 and Group 2, respectively (p ¼ 0.2). In the group of patients with prior SC (Group 1) OS was 93, 68, and 51% for 1, 2 and 3 years, respectively. OS in patients without SC before the CRS/HIPEC was 82, 64, 60% for 1, 2 and 3 year respectively (p ¼ 0.74) (Fig. 1). In patients with prior SC (Group 1) PFS was 78%, 49%
Figure 1. OS of patients with PMCA treated with CRS/HIPEC depending on prior chemotherapy.
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and 36% for 1, 2 and 3 years, respectively. PFS in patients without SC before the CRS/HIPEC was 67%, 53% and 53% for 1, 3 and 5 years, respectively (p ¼ 0.46). Due to different number of patients with HG tumors among the groups, additional survival analyses were performed. We evaluated the effect of preoperative SC on the OS within the HG and LG groups. We also evaluated the effect of preoperative SC in the subgroup of patients with signet ring cell histology. Among the patients with HG tumors (n ¼ 24)overall survival was 91%, 60% and 36% for 1, 2 and 3 years after prior SC. OS in patients without SC (n ¼ 21) was 65%, 35% and 35% for 1, 2 and 3 years respectively (p ¼ 0.665). Among the patients with LG histology, after SC (n ¼ 6) overall survival was 100% for 1, 2 and 3 years. OS in patients without SC (n ¼ 21) was 90%, 79% and 71% for 1, 2 and 3 years respectively (p ¼ 0.259) (Fig. 2). Patients with SRC tumors, who received prior SC (n ¼ 18) had overall survival 94%, 67% and 22% at 1, 2 and 3 years, respectively. OS in patients with SRC histology who did not receive SC (n ¼ 10) was 43%, 14% and 14% at 1, 2 and 3 years respectively (p ¼ 0.028) (Fig. 3). Multivariate analysis of tumor grade of tumor, LN status, completeness of cytoreduction, PCI score >20 and preoperative chemotherapy performed. The impact of
Figure 2. OS of patients with high grade and low grade PMCA treated with CRS/HIPEC depending on prior chemotherapy.
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Figure 3. OS of patients with signet ring cell histology treated with CRS/ HIPEC depending on prior chemotherapy.
preoperative chemotherapy on the OS was not significant according to this analyses (HR 1.0; 95% CI: 0.4e2.3; p ¼ 0.925). Tumor grade, completeness of cytoreduction, PCI score >20 had an independent impact on the OS in this population (Table 2). Discussion While aggressive surgical approach consisting of cytoreductive surgery (CRS) and hyperthermic intraperitoneal Table 2 Multivariable and univariable analyses of variables impacted overall survival of PMCA patients. Hazard ratio
Multivariable analyses HG histology 4.5 CCR 0e1 3.4 PCI > 20 3.6 LN status 2.4 Prior SC 1.0 Univariable analyses HG histology 5.4 CCR 0e1 3.2 PCI > 20 2.9 LN status 3.7 Prior SC 1.1
95% Confidence interval
p
Lower
Upper
1.2 1.2 1.2 0.8 0.4
17.6 9.9 10.5 7.4 2.3
0.030 0.022 0.019 0.106 0.925
2.0 1.2 1.1 1.6 0.5
14.7 8.0 7.7 8.4 2.5
0.001 0.016 0.036 0.002 0.738
PCI e Peritoneal Cancer Index; CCR e completeness of cytoreduction score; LN e lymph nodes; HG e high grade. p-value was considered statistically significant if less than 0.05. Statistically significant p-values were highlighted in bold.
chemotherapy (HIPEC) has become a treatment of choice for PMCA, the role of preoperative SC in treatment of these patients is still controversial.7,9,10 Inconsistent data about SC in this group of patients has been reported in the medical literature.7,11,14,16,22e24 Some authors recommend SC prior CRS/HIPEC22,23 others recommend SC only in case of recurrence disease.14 There are also reports of association of SC prior CRS/HIPEC with worse OS.7 To clarify whether preoperative SC provides any survival benefit for PMCA patients this retrospective study compared OS of patients with and without SC prior to CRS/HIPEC. A significant difference in histology was observed between Group 1 and Group 2. This was consistent with the results of multi-institutional study of Chua et al., who observed poor survival outcomes in patients with SC prior to CRS/HIPEC, which were associated with aggressive tumor biology.7 Thus, SC before the CRS/HIPEC could just highlight aggressive tumor histopathology. At the same time, there is also a possibility that prior chemotherapy may lead to the auto-selection of chemoresistant clones, and eventually to the high rate of aggressive tumors in Group 1. However, we do not have enough data to prove or disprove this theory. A separate analysis focusing on histological tumor grade indicated that prior SC may not impact the overall survival in most patients with HG or LG histology (Fig. 2). Both analyses showed a non-significant statistical difference between the groups. However, small sample size, especially in patients with low grade PMCA, does not allow us to make any definitive conclusions based on this number. It is important to note, that when we evaluated OS in the subgroup of patients with SRC histology, we observed an improvement with preoperative systemic chemotherapy (Fig. 3). This result is consistent with several case reports in which radiologic response or stable disease was achieved with systemic chemotherapy (FOLFOX) for similar histology.25,26 We observed that most of the patients who received preoperative chemotherapy (Group 1) had more extensive surgical history (PSS 2) prior to definitive CRS/HIPEC. Often, the surgeries were performed at clinics without experience in appendiceal malignancies, resulting in frequent incomplete cytoreduction. One of the goals of preoperative chemotherapy is to increase the chances of complete cytoreduction. In this study, there was no significant difference between the groups in terms of complete cytoreduction rate. These results are consistent with those of Turner’s et al. data who reported 65 vs. 72% rate of complete cytoreduction among PMCA patients treated with CRS/HIPEC with or without preoperative SC (FOLFOX and Bevacizumab), respectively.16 Also, in Turner’s study, longer operative time has been reported among the patients who had SC prior to CRS/HIPEC (438 vs. 325 min; p ¼ 0.016). Although it has been shown by Alakus et al. that PMCA reveals genetic alterations distinct from colorectal cancer,
V. Milovanov et al. / EJSO 41 (2015) 707e712
we use identical chemotherapy regimens in the systemic management of these different malignancies.27 The most commonly used chemotherapy for appendiceal cancer includes fluorouracil (5-FU) based combination regimens containing oxaliplatin (FOLFOX) or irinotecan with or without bevacizumab. The reported response rate of these regimens in PMCA was 29%, 44% and 58% in the studies of Bijelic et al., Lieu et al. and Turner et al., respectively.16,22e24 Bijelic et al. observes an association between the response rate (RR) and OS. Lieu et al., correlated RR with an improved PFS. All three studies were unable to show improvement in OS among PMCA patients who received SC prior to CRS/HIPEC comparing to the patient without SC. The current systemic chemotherapy regimens for colorectal cancer may be suboptimal in the management of advanced appendiceal malignances. This applies to the choice of agents as well as the schedule, dosing and the manner of administration. Further preclinical research in addition to clinical trials are urgently needed to optimize the systemic management of abdominal appendiceal malignance. Although we observed a statistically significant improved OS in the subgroup of patients with preoperative SC of SRC histology with (Fig. 3), no such benefit was demonstrated in the overall groups of HG or LG histology (Fig. 2). The results could be explained by the small sample size as well the retrospective nature of the analyses. We conclude, that currently used preoperative SC could improve OS in PMCA patients with SRC histology. Further prospective studies are needed to determine the role of SC in PMCA patients. Conflict of interest All authors disclose no financial and personal relationships with other people or organisations that could inappropriately influence or bias this work.
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