|Year : 2018 | Volume
| Issue : 12 | Page : 1129-1134
Survival and the prognosticators of peritoneal cytology-positive pancreatic cancer patients undergoing curative resection followed by adjuvant chemotherapy
Toru Aoyama1, Yosuke Atsumi1, Keisuke Kazama1, Masaaki Murakawa1, Manabu Shiozawa1, Satoshi Kobayashi2, Makoto Ueno2, Manabu Morimoto2, Norio Yukawa3, Takashi Oshima3, Takaki Yoshikawa3, Yasushi Rino3, Munetaka Masuda3, Soichiro Morinaga1
1 Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
2 Department of Hepatobiliary Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan
3 Department of Surgery, Yokohama City University, Yokohama, Japan
|Date of Web Publication||11-Dec-2018|
Department of Gastrointestinal Surgery, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama 241-8515
Source of Support: None, Conflict of Interest: None
Background: The factors associated with the survival and prognosis of peritoneal cytology (CY)-positive pancreatic cancer patients who undergo curative resection followed by adjuvant chemotherapy have not been established.
Patients and Methods: Both overall survival (OS) and recurrence-free survival (RFS) were examined in 23 peritoneal CY-positive pancreatic cancer patients who underwent curative resection followed by adjuvant chemotherapy between 2005 and 2015.
Results: When the length of OS was evaluated using a log-rank test, significant differences were observed in the number of metastatic lymph nodes. In addition, univariate and multivariate analyses demonstrated that the number of metastatic lymph nodes was a significant independent risk factor for OS and a marginally significant risk factor for RFS. The 3-year OS rate was 20.2% in patients with ≤8 metastatic lymph nodes, and it was 0% in those with the ≥9 metastatic lymph nodes (P = 0.017). The 3-year RFS rate was 6.3% in patients with ≤8 metastatic lymph nodes, whereas it was 0% in those with ≥9 metastatic lymph nodes (P = 0.062).
Conclusions: The number of metastatic lymph nodes is the most important prognostic factor for OS and RFS in peritoneal CY-positive pancreatic cancer patients who underwent curative resection followed by adjuvant chemotherapy. To improve the survival of these patients, it is necessary to establish optimal treatments.
Keywords: Adjuvant chemotherapy, pancreatic cancer, peritoneal cytology-positive
|How to cite this article:|
Aoyama T, Atsumi Y, Kazama K, Murakawa M, Shiozawa M, Kobayashi S, Ueno M, Morimoto M, Yukawa N, Oshima T, Yoshikawa T, Rino Y, Masuda M, Morinaga S. Survival and the prognosticators of peritoneal cytology-positive pancreatic cancer patients undergoing curative resection followed by adjuvant chemotherapy. J Can Res Ther 2018;14, Suppl S5:1129-34
|How to cite this URL:|
Aoyama T, Atsumi Y, Kazama K, Murakawa M, Shiozawa M, Kobayashi S, Ueno M, Morimoto M, Yukawa N, Oshima T, Yoshikawa T, Rino Y, Masuda M, Morinaga S. Survival and the prognosticators of peritoneal cytology-positive pancreatic cancer patients undergoing curative resection followed by adjuvant chemotherapy. J Can Res Ther [serial online] 2018 [cited 2019 Sep 17];14:1129-34. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/1129/194927
| > Introduction|| |
Pancreatic cancer is a major cause of cancer death worldwide, with a 5-year survival rate of <5%., Complete resection is essential to achieving a cure in patients with pancreatic cancer. Although the resection rate has gradually increased, the prognosis remains poor.
Peritoneal lavage cytology (CY) has been used widely in the diagnosis and staging of gastric cancer, ovarian cancer, and pancreatic cancer. Malignant cells can be identified in 7–30% of the peritoneal washing samples from pancreatic cancer patients.,,,,,,, The American Joint Committee on Cancer staging of pancreatic cancer includes positive CY findings as an indicator of Stage IV disease. The National Comprehensive Cancer Network pancreatic adenocarcinoma guidelines also state that positive CY from washing samples obtained at laparoscopy or laparotomy is an indicator of M1 disease. However, the survival and prognostic factors of peritoneal lavage CY-positive pancreatic cancer patients have not been established and remain controversial. It is, therefore, important to identify the prognostic factors for these patients to select candidates for more aggressive treatment.
In the present study, we investigated factors associated with the survival and prognosis of peritoneal lavage CY-positive pancreatic cancer patients who underwent curative resection followed by adjuvant chemotherapy.
| > Patients and Methods|| |
The patients were selected from the medical records of consecutive patients who underwent pancreatic surgery at our center from 2005 to 2015, according to the following criteria: (1) A pathologically common type of pancreatic cancer according to the International Union Against Cancer (UICC) TNM 7th edition; (2) patients who underwent curative resection followed by adjuvant chemotherapy as the initial treatment for pancreatic cancer in whom macroscopically curative resection was achieved; (3) patients who were diagnosed as peritoneal lavage CY-positive. The resected specimens were examined histopathologically and were staged according to the UICC TNM 7th edition. Patients with other pancreatic and periampullary neoplasms, such as intraductal papillary mucinous neoplasms, cystadenocarcinomas, and endocrine tumors, were excluded from the study. Patients who underwent R2 resection were also excluded from the study.
Gemcitabine (GEM) was started within 8 weeks after surgery. The patients received a weekly dose of 1000 mg/m2 for 3 weeks, which was followed by a 1-week rest. S-1 chemotherapy was started within 10 weeks after surgery., The patients received 40 mg of S-1/m2 of body surface area twice a day for 4 weeks, followed by a 2-week rest as one course (6-week schedule) or for 2 weeks followed by a 1-week rest as one course (3-week schedule). GEM or S-1 treatment was continued for 6 months.
The patients were followed up at outpatient clinics. Hematological tests and physical examinations were performed at least every 2 weeks during adjuvant chemotherapy, and at least every 3 months for 5 years after the completion of adjuvant chemotherapy. The carcinoembryonic antigen and cancer antigen 19-9 tumor marker levels were checked at least every 3 months for 5 years. The patients underwent a computed tomography examination every 3 months during the first 3 years after surgery, and then every 6 months until 5 years after surgery.
Peritoneal lavage cytology
Peritoneal lavage CY and a cytological analysis were routinely performed at the time of surgical exploration using normal saline, which was introduced into the abdominal cavity. After gentle agitation, as much fluid as possible was collected by syringe and centrifuged. Cytological smears were prepared from the centrifuged deposit and were examined by an experienced pathologist after Papanicolaou staining.
Evaluations and statistical analyses
Overall survival (OS) was defined as the period between surgery and death. Recurrence-free survival (RFS) was defined as the period between surgery and the occurrence of an event, recurrence, or death, whichever came first. The data of the patients who had not experienced an event were censored on the date of the final observation. OS and RFS were evaluated by a univariate analysis and multivariate analysis. OS and RES curves were calculated using the Kaplan–Meier method and were compared using the log-rank test. A Cox proportional hazards model was used to perform the univariate and multivariate survival analyses. An unpaired Student's t-test or the Chi-squared method was used to compare differences between the two groups. P <0.05 was considered to indicate statistical significance. The survival data were obtained from hospital records or from the city registry system. The SPSS software program (v11.0 J Win, SPSS, Chicago, IL, USA) was used for all of the statistical analyses. This study was approved by the Institutional Review Board Committee.
| > Results|| |
A total of 225 patients underwent surgical resection between 2005 and 2015. Twenty-three of these patients were eligible for inclusion in the present study. The median age was 66 years (range: 45–76 years); 15 patients were males and 8 were females. The types of surgery were as follows: Distal pancreatectomy (n = 8), pancreaticoduodenectomy (n = 13), and total pancreatic resection (n = 2). The median follow-up period was 62.7 months (range: 18.1–129.6 months).
The median OS was 17.9 months (95% confidence interval [CI], 14.9–20.9 months) in the present study. When OS, stratified by clinical factors, was compared by the log-rank test, a significant difference was observed with regard to the number of metastatic lymph nodes [Table 1]. There was a marginally significant difference in the tumor location. Nine metastatic lymph nodes were regarded as the optimal critical point of classification, based on the 1-year and 3-year survival rates. Each clinicopathological factor was categorized, as shown in [Table 2], and was analyzed to determine its prognostic significance with respect to OS. Univariate and multivariate analyses to determine the factors that were associated with OS demonstrated that the number of metastatic lymph nodes was a significant prognostic factor. The 3-year OS rate was 20.2% in patients with ≤8 metastatic lymph nodes, and it was 0% in those with ≥9 metastatic lymph nodes [Figure 1]. The median RFS in the present study was 8.6 months (95% CI, 7.2–10.1 months). Each clinicopathological factor was categorized, as shown in [Table 3], and was analyzed to determine its prognostic significance with regard to RFS. The univariate and multivariate analyses of the factors associated with RFS demonstrated that the number of metastatic lymph nodes was a marginally significant prognostic factor. The 3-year RFS rate was 6.3% in patients with ≤8 metastatic lymph nodes, and it was 0% in those with ≥9 metastatic lymph nodes [Figure 2].
|Table 1: Comparison of survival rates stratified by patient characteristics|
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|Table 2: The univariate and multivariate Cox proportional hazards analyses of the clinicopathological factors associated with overall survival|
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|Figure 1: Overall survival in the patients with ≤ 8 metastatic lymph nodes and those with ≥9 metastatic lymph nodes|
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|Table 3: The univariate and multivariate Cox proportional hazards analyses of the clinicopathological factors associated with recurrence-free survival|
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|Figure 2: Recurrence-free survival in the patients with ≤ 8 metastatic lymph nodes and those with ≥9 metastatic lymph nodes|
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| > Discussion|| |
We herein describe the first investigation of the factors associated with the survival and prognosis of peritoneal lavage CY-positive pancreatic cancer patients who underwent curative resection followed by adjuvant chemotherapy. We clarified that the number of metastatic lymph nodes was the most important prognostic factor, based on the hazards ratio and P values.
The median OS of the 23 patients who underwent curative resection followed by adjuvant chemotherapy was 17.9 months. This was similar to the previous studies.
For example, Yamada et al. examined peritoneal lavage samples from 523 consecutive patients with pancreatic cancer and evaluated the relationships among the CY results, the clinicopathological parameters, and survival. They reported that the median survival time of 34 patients with resected CY+ tumors who received adjuvant chemotherapy was 15.3 months, whereas that of 17 patients who only received surgery was 10.0 months. The median RFS (8.6 months) was also similar to that reported in the previous studies. Yoshioka et al. reviewed the clinical data from 254 consecutive patients who underwent macroscopically curative resection for pancreatic cancer from February 2003 to December 2010 and evaluated the correlations between the CY status and survival and the clinicopathological findings. They found that the median RFS of CY-positive and CY-negative patients was 8.1 (95% CI = 0.0–17.9) months and 13.5 (95% CI = 11.5–15.5) months, respectively. On the other hand, the OS and RFS rates reported in some previous studies were worse than in the present study. However, these previous reports only analyzed patients who were treated with surgery alone. Thus far, several investigators have conducted randomized controlled studies of adjuvant chemotherapy after pancreatic cancer resection. As a result of the European Study Group for Pancreatic Cancer trials 1 and 3 and the Charite Onkologie 001 (CONKO-001) trial, adjuvant chemotherapy with GEM has come to be accepted as the standard treatment for patients with resected pancreatic cancer who are treated with surgery alone., Uesaka et al. recently reported the findings of a randomized phase III study of GEM versus S-1 in patients with pathological Stage I, II, or III (treated with celiac axis resection) macroscopically-resected (R0 or R1 resection) pancreatic cancer (JASPAC-01). Based on the results of the JASAPC-01 trial, adjuvant chemotherapy with S-1 after curative surgery is now considered to be the standard therapy for such patients in Japan. Theoretically, adjuvant chemotherapy improves patient survival by inhibiting micrometastasis. Thus, the OS and RFS might be altered following adjuvant chemotherapy.
The present study showed that the number of the metastatic lymph nodes affected the OS and RFS rates of peritoneal CY-positive pancreatic cancer patients who underwent curative resection followed by adjuvant chemotherapy. The prognostic significance of nodal involvement has been reported in previous studies. For example, Breslin et al. evaluated 132 consecutive patients who received preoperative chemoradiation (CRT) followed by pancreaticoduodenectomy for adenocarcinoma of the pancreatic head. They reported that the survival of patients who were negative for nodal involvement (median survival: 25 months) was significantly more favorable than that of patients who were positive for nodal involvement (median survival: 19 months). Moreover, White et al. examined 67 pancreatic cancer resection specimens from patients undergoing preoperative CRT. They reported that the median survival times of patients who were negative and positive for nodal involvement were 29 and 18 months, respectively. Although the mechanism is unclear, this observation suggests that nodal involvement indicates a high possibility of the systemic spread of tumor cells that survive despite the administration of systemic adjuvant chemotherapy during the perioperative treatment period. Nodal involvement could indicate the tendency of the tumor to spread to distant sites systemically, through the blood or lymphatic pathways and be an indicator of resistance to systemic chemotherapy. Further studies should focus on this issue.
The present study is associated with several potential limitations. Thus, special attention is required when interpreting its results. First, it was a retrospective single-center study with a relatively small sample size. Our findings might have been obtained by chance. Second, peritoneal washing CY (PWC) has some limitations due to its low sensitivity. Small numbers of cancer cells cannot be detected by conventional PWC. Eguchi et al. reported that sensitivity was increased by reverse-transcription polymerase chain reaction. In addition, free cancer cells were present in the pouch of Douglas. Homma et al. performed PWC in multiple sites in addition to the pouch of Douglas and found that multiple PWC was more sensitive than PWC in a single cavity. Thus, the CY status might have led to an underestimation. However, the incidence of the CY positivity was similar to that of previous studies. Third, the optimal cutoff value is unclear. In the present study, the cutoff value was set based on the 1- and 3-year survival rates. However, the appropriate cutoff value should be determined in further validation studies. Considering these limitations, the current results should be validated in other series with a larger number of patients.
| > Conclusions|| |
The number of metastatic lymph nodes was found to be a risk factor for OS and disease recurrence in peritoneal CY-positive pancreatic cancer patients who underwent curative resection followed by adjuvant chemotherapy. To improve patient survival, it will be necessary to establish optimal treatments for these patients.
Financial support and sponsorship
This work was supported, in part, by the Uehara Memorial Foundation and the Takeda Science Foundation.
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2011;61:133-4.
Nakao A, Fujii T, Sugimoto H, Kanazumi N, Nomoto S, Kodera Y, et al
. Oncological problems in pancreatic cancer surgery. World J Gastroenterol 2006;12:4466-72.
Meduri F, Diana F, Merenda R, Caldironi MW, Zuin A, Losacco L, et al
. Implication of laparoscopy and peritoneal cytology in the staging of early pancreatic cancer. Zentralbl Pathol 1994;140:243-6.
Fernández-del Castillo C, Rattner DW, Warshaw AL. Further experience with laparoscopy and peritoneal cytology in the staging of pancreatic cancer. Br J Surg 1995;82:1127-9.
Leach SD, Rose JA, Lowy AM, Lee JE, Charnsangavej C, Abbruzzese JL, et al
. Significance of peritoneal cytology in patients with potentially resectable adenocarcinoma of the pancreatic head. Surgery 1995;118:472-8.
Merchant NB, Conlon KC, Saigo P, Dougherty E, Brennan MF. Positive peritoneal cytology predicts unresectability of pancreatic adenocarcinoma. J Am Coll Surg 1999;188:421-6.
Jimenez RE, Warshaw AL, Fernandez-Del Castillo C. Laparoscopy and peritoneal cytology in the staging of pancreatic cancer. J Hepatobiliary Pancreat Surg 2000;7:15-20.
Nakao A, Oshima K, Takeda S, Kaneko T, Kanazumi N, Inoue S, et al
. Peritoneal washings cytology combined with immunocytochemical staining in pancreatic cancer. Hepatogastroenterology 1999;46:2974-7.
Yachida S, Fukushima N, Sakamoto M, Matsuno Y, Kosuge T, Hirohashi S. Implications of peritoneal washing cytology in patients with potentially resectable pancreatic cancer. Br J Surg 2002;89:573-8.
Meszoely IM, Lee JS, Watson JC, Meyers M, Wang H, Hoffman JP. Peritoneal cytology in patients with potentially resectable adenocarcinoma of the pancreas. Am Surg 2004;70:208-13.
Edge SB, Compton CC. The American Joint Committee on Cancer: The 7th
edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17:1471-4.
Sobin LH, Gospodarowicz MK, Wittekind CH, editors. TNM Classification of Malignant Tumors. New York: Wiley-Blackwell; 2009.
Burris HA 3rd
, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al
. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 1997;15:2403-13.
Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, et al
. Adjuvant chemotherapy with fluorouracil plus folinic acid vs. gemcitabine following pancreatic cancer resection: A randomized controlled trial. JAMA 2010;304:1073-81.
Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, et al
. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: A phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet 2016;388:248-57.
Yamada S, Fujii T, Kanda M, Sugimoto H, Nomoto S, Takeda S, et al
. Value of peritoneal cytology in potentially resectable pancreatic cancer. Br J Surg 2013;100:1791-6.
Yoshioka R, Saiura A, Koga R, Arita J, Takemura N, Ono Y, et al
. The implications of positive peritoneal lavage cytology in potentially resectable pancreatic cancer. World J Surg 2012;36:2187-91.
Breslin TM, Hess KR, Harbison DB, Jean ME, Cleary KR, Dackiw AP, et al
. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: Treatment variables and survival duration. Ann Surg Oncol 2001;8:123-32.
White RR, Xie HB, Gottfried MR, Czito BG, Hurwitz HI, Morse MA, et al
. Significance of histological response to preoperative chemoradiotherapy for pancreatic cancer. Ann Surg Oncol 2005;12:214-21.
Takahashi H, Ohigashi H, Ishikawa O, Gotoh K, Yamada T, Nagata S, et al
. Perineural invasion and lymph node involvement as indicators of surgical outcome and pattern of recurrence in the setting of preoperative gemcitabine-based chemoradiation therapy for resectable pancreatic cancer. Ann Surg 2012;255:95-102.
Eguchi H, Ohigashi H, Takahashi H, Yano M, Motoori M, Miyashiro I, et al
. Presence of minute cancer cell dissemination in peritoneal lavage fluid detected by reverse transcription PCR is an independent prognostic factor in patients with resectable pancreatic cancer. Surgery 2009;146:888-95.
Homma Y, Ushida S, Yamada M, Kobayashi H, Suzuki K. Positive peritoneal washing cytology in multiple cavities can predict poor prognosis of advanced gastric cancer patients. Ann Surg Oncol 2010;17:455-60.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]