International Journal of Surgery 26 (2016) 64e68
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.journal-surgery.net
Original research
Retrospective analysis of survival after resection of pancreatic renal cell carcinoma metastases Felix Rückert a, *, 1, Marius Distler b, 1, David Ollmann a, Anja Lietzmann a, Emrullah Birgin a, Patrick Teoule a, Robert Grützmann c, 1, Torsten J. Wilhelm a, 1 a
Department of Surgery, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany €t Dresden, Fetscherstrasse 74, 01307 Department of General, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universita Dresden, Germany c Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Krankenhausstr. 12, 91054 Erlangen, Germany b
h i g h l i g h t s Pancreatic renal cell carcinoma metastasis is rare and the best treatment is uncertain. We analysed outcome after resection of those metastasis in two German centers. Due to selection of patients we found no risk factor. Due to lymph node metastases in some patients we advice to perform lymphadenectomy.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 September 2015 Received in revised form 25 November 2015 Accepted 4 December 2015 Available online 29 December 2015
Introduction: Previous reports showed an excellent survival for patients after resection of pancreatic metastases from renal cell cancer (pRCC) and reported several predictive factors. This study aims to give more evidence to reported risk factors by analyzing a large cohort of patients with pancreatic resection due to pRCC. Patients and methods: We retrospectively analyzed all pancreatic resections due to pRCC between January 1993 and October 2014 in two German pancreatic surgery centers. Predictive factors were analyzed using the chi square test. Results: Surgery was performed in 40 patients. Mean survival after resection was 147.9 months (SD 25.6 months). No predictive factors for survival were identified. Pathological examination showed that five out of 21 patients with examined peripancreatic lymph nodes had lymph node metastases. Conclusions: Although our analysis comprised the biggest cohort of patients with pRCC it rendered no significant predictor for survival. This might be due to the overall excellent prognosis of study patients and the relatively rare condition with a limited number of patients. Several patients had lymph node metastases. Therefore lymphadenectomy should be considered in pRCC resection if the health condition of the patient permits this. By this more aggressive approach to pRCC, a better prognosis after resection might be achieved. © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.
Keywords: Pancreatic surgery Renal cell carcinoma Metastases Resection Survival
1. Introduction Renal cell carcinoma (RCC) is a cancer with a high incidence; for example, there were an estimated 64,000 new cases in the US alone
* Corresponding author. University Hospital Mannheim Medical Faculty Mannheim, University of Heidelberg, Germany Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. E-mail address: [email protected] (F. Rückert). 1 These authors contributed equally.
in 2014 [1]. Metastases may occur a long time after resection of the primary tumor [2]. Although RCC is one of only few tumors that spreads to the pancreas, pancreatic metastases are rare. Only 4% of all pancreatic resections account for metastases of RCC (pRCC) and less than 300 cases were reported in the last 60 years [2]. Consequently, there is limited data in the literature concerning the prognosis after resection of pRCC. The European Society for Medical Oncology (ESMO) guidelines for the treatment of metastatic renal cell carcinoma state that metastasectomy may provide a possible survival benefit for a selected group of patients with lung
http://dx.doi.org/10.1016/j.ijsu.2015.12.003 1743-9191/© 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.
F. Rückert et al. / International Journal of Surgery 26 (2016) 64e68
metastases only (i.e., those a long metachronous disease-free interval and a positive response to immunotherapy/targeted therapy) [3]. Recently it was also shown that targeted therapy might be an option for metastatic RCC [4,5]. However, several retrospective and nonrandomized studies with a limited number of pRCC patients suggested that resection of metastases might also lead to a prolonged median survival [6]. After operation, three- and five-year survival rates were 78% and 72%, respectively [2]. RCC is highly resistant to chemotherapy, thus surgery seems to be a better option than chemotherapy in the opinion of the authors [7]. Data from a randomized controlled clinical trial for the treatment of metastatic renal cell carcinoma only showed a survival of up to 11 months under first line chemotherapy [8]. Therefore chemotherapy must be regarded as relatively ineffective and surgery still must be considered as an alternative. Although mortality after pancreatic surgery has recently decreased, it nonetheless has a high morbidity rate and not all patients may benefit from resection of pRCC [9,10]. Predictive factors could facilitate the decision of when to operate. Recent retrospective studies revealed different predictive factors for patient survival after resection of pRCC. These include lymph node involvement [11], multifocal metastases, synchronous metastases, symptomatic metastases [12,13], size of the metastasis [13], and recurrent metastases [2]. The aim of this study was twofold: to evaluate the prognosis after resection of pRCC, and to both analyse predictive factors and identify new predictive factors, in a large cohort of patients with pRCC.
65
Table 1 Characteristics of our patient cohort. (SD ¼ standard deviation; BMI ¼ Body-MassIndex; x ¼ missing data).* Values are mean with standard deviation. Patients n ¼ 40 n (%) Age (years) Male sex BMI Time after primary tumor (months) Age at initial diagnosis (years) Classification of primary tumor T 1 2 3 4 x N 0 1 x G 1 2 3 x R 0 x Metachronous metastases (>6 months) History of other metachronous metastases
65.5 24 28.0 125.4 55.7
(SD 9.0)* (60) (SD 4.5)* (SD 77.4)* (SD 9.6)*
11 (27.5) 11 (27.5) 7 (17.5) e 11 (27.5) 21 (52.5) e 19 (47.5) 1 (2.5) 8 (20) e 31 (77.5) 3 37 39 13
(7.5) (92.5) (97.5) (32.5)
2. Patients and methods 2.1. Patients A retrospective search for patients with a diagnosis of metastases from RCC (pRCC) was performed at the Department of General, Thoracic, and Vascular Surgery of the Carl Gustav Carus University Hospital, Dresden, and the Surgical Department of the University Hospital, Mannheim. The patients were selected from the prospective pancreas databases. Between October 1993 and March 2014 we identified 40 consecutive patients that were resected for pRCC. The final pathological diagnosis confirmed metastases from RCC in all patients. The demographic characteristics of the patients are summarized in Table 1. 2.2. Data collection Patients who had undergone pancreas resection for pRCC were identified from our databases and their medical records were analyzed retrospectively. In accordance with the guidelines for human subject research, approval was obtained from the Ethics Committee at the University Hospital, Mannheim. The data were complemented with clinical notes from the patients' physicians and surgeons. The information regarding deceased patients was obtained from family members or from the respective general practitioner. Patient characteristics and parameters used for statistical analysis are listed in Supplementary information 1. The postoperative events and clinical outcomes were also recorded prospectively and analyzed retrospectively. Tumor stage designation was categorized according to the TNM system of the Union Internationale Contre le Cancer (UICC) 2007 guidelines. Literature search was performed using Pubmed (www.pubmed.com) and the keywords “pancreatic metastases” and “renal cell carcinoma”.
Postoperative pancreatic hemorrhage (PPH) was categorized according to the International Study Group on Pancreatic Surgery (ISGPS) consensus definition [14]. Delayed gastric emptying (DGE) was classified according to the suggested definition by the ISGPS [15]. Postoperative pancreatic fistula (POPF) was defined analogous to the ISGPF criteria [16]. Synchronous metastasis was defined as metastasis within 6 month of initial diagnosis. 2.4. Statistical analysis Statistical analyses were performed using the Statistical Package for the Social Sciences for Windows, version 15.0 (SPSS, Inc., Chicago, IL, USA). All clinical and pathological characteristics were stratified to build categorical or nominal variables. The thresholds used for categorization were based on previously described thresholds in the literature and/or recursive partitioning as previously described [18]. Laboratory values were defined as elevated if values were higher than the normal cut-off value. Continuous data are presented as mean with standard deviation (SD). The univariate examination of the relationship between the assessed criteria and survival was performed with a Chi-square test. For the assessment of the impact of different parameters on survival, we utilized a three-year survival rate. The estimates of patient survival were generated using the KaplaneMeier method. Factors significant (at p < 0.10) at the univariate level were entered into the multivariate model. A Cox regression analysis with stepwise backwards elimination based on likelihood ratios was employed to test for independent predictors of survival (at p < 0.05). 3. Results 3.1. Study cohort
2.3. Definitions Perioperative mortality was defined as in-hospital mortality.
Analysis of the pancreatic databases showed that 2% of all operations at the two centers were performed for pRCC. A total of 40
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F. Rückert et al. / International Journal of Surgery 26 (2016) 64e68
cases were identified. 24 (60%) of our patients were male. The patients' mean age at diagnosis of the primary tumor was 55.7 (SD 9.6) years. Data on the initial tumor stage included a high percentage of missing data (Table 1). The mean age of our patients at operation was 65.5 (SD 9.0) years. Mean time between resection of the primary tumor and the diagnosis of the metastases was 125.4 months (SD 77.4). Consequently, 39 (97.5%) of the metastases were metachronous. In 24 (60%) of the patients, the metastases were found during routine surveillance imaging, and 13 patients had symptomatic metastases (32.5%). Of these 13 patients, nine had obstructive jaundice, two had gastrointestinal bleedings, one had hyperglycaemia, and one had abdominal pain. 3.2. Tumor characteristics 13 (32.5%) patients had other metastases at the time of pRCC diagnosis. Singular metastases within the pancreas were seen in 18 (45.0%) of patients, eight patients (20.0%) had two metastases, and 12 had multifocal metastases (30%). Two patients had no data on the number of metastases. 14 (35.0%) of the metastases were larger than 2.0 cm. Parapancreatic lymph nodes from 22 patients were pathologically examined, and of these five had metastases within the lymph nodes (22.7%). Five patients total (12.5%) had an R1 resectional status (Table 1).
preserving pancreaticoduodenectomy (PPPD) and died from multi-organ dysfunction. A 61-year old patient had leakage of the duodenojejunostomy after PPPD and died due to peritonitis in a septic shock. A 64-year old male died after distal resection due to myocardial infarction (Table 2) (Fig. 1). 3.4. Univariate and multivariate analysis Of the remaining 37 patients, four (10.8%) died during the follow-up period due to tumor progression. Of these four patients, two patients died within five years (5.4%). Mean survival after pancreatic resection was 147.9 months (SD 25.6 months) (Fig. 2). We analysed the influence of body mass index (BMI), sex, time point of metastasis (i.e., synchronous/metachronous), symptomatic metastases, resectional status, history of previous renal cell carcinoma metastases in other locations, presence of multifocal metastases within the pancreas, tumor size larger than 2.0 cm, and positive lymph nodes as predictors for survival. However, none of these factors were significant. 4. Discussion Metastases to the pancreas are rare. Only 2% of all pancreatic
3.3. Short term results Most resections were pancreatic head resections (n ¼ 15; 37.5%) followed by distal pancreatectomies (n ¼ 12; 30.0%) and pancreatectomies (n ¼ 9; 22.5%). Segmental resection was only performed in three (7.5%) patients and a broad papillary resection in one patient (2.5%) (Table 2). The mean duration of operation was 325.4 min (SD 135.9). POPF Grade A occurred in four patients (10.0%), Grade B in five patients (12.5%) and Grade C in three patients (7.5%). DGE was infrequently seen. PPH Grade A occurred in one patient (2.5%), Grade B in six patients (15.0%). The mean Intensive Care Unit (ICU) stay was 2.3 days (SD 5.1). Three patients died postoperatively (7.5%). An 83-year old patient had septic shock and myocardial infarction after pylorusTable 2 Data on the intra- and postoperative course. (SD ¼ standard deviation; POPF ¼ postoperative pancreatic fistula; DGE ¼ delayed gastric emptying; PPH ¼ postpancreatectomy hemorrhage; ICU ¼ intensive care unit).* Values are mean with standard deviation. Patients n ¼ 40 n (%) Performed procedure Pancreatic head resection Total pancreatectomy Distal pancreatectomy Segmental resection Papillary resection Duration of operation (min) Blood loss (ml) POPF A B C DGE A B C PPH A B C Stay on ICU (days) Mortality
15 9 12 3 1 325.4 501.3
(37.5) (22.5) (30.0) (7.5) (2.5) (SD 135.9)* (SD 898.8)*
4 (10.0) 5 (12.5) 3 (7.5) e 3 (7.5) 1 (2.5) 1 (2.5) 6 (15.0) e 2.3 (SD 5.1)* 3 (7.5)
Fig. 1. Surgical sample with a pancreatic renal cell metastasis (from R. Grützmann).
F. Rückert et al. / International Journal of Surgery 26 (2016) 64e68
Fig. 2. Survival of patients after resection of pRCC. The numbers indicate “patients at risk”.
resections at the two centers in our study were performed for pRCC. This is in accordance to previous publications that report a range of pancreatic resections due to pRCC from 1% to 3% [13,17,18]. During the last ten years, several retrospective studies have been published that show that radical surgery for pRCC appears to be justified. However, improvements in survival must be examined in relation to the perioperative morbidity and mortality [9,10]. The aim of the present study was to analyze the postoperative course and longterm results after resection of pRCC, and to evaluate possible predictive factors for survival in a large cohort of patients with pRCC. Our database search yielded 40 patients with pRCC. To our knowledge this is one of the largest cohorts of patients with pRCC [2,17]. After resection of pRCC, three patients (7.5%) had POPF grade C and PPH grade B was seen in six patients (15.0%). Three patients died postoperatively (7.5%). Mortality was therefore slightly higher as expected. These results might be due to the fact that these patients had received previous operations. Additionally, most pancreata with metastases have very soft tissue, which leads to a higher rate of pancreatic fistulas and other complications [19]. Of note, prognosis after resection of pRCC was very good. The patients
67
in our cohort had a mean survival of 147.9 months. Several prior studies that focused on surgical resection of the pancreas for pRCC found that five-year overall survival rates range from 75% to 88% [12,17,20e25]. We cannot present three- and five-year survival rates because not all of our patients have completed the five year observation period (Fig. 2). Nearly 50% of the patients of our cohort underwent operations within the last five years. A possible reason for this high percentage might be a rising awareness of the surgical therapeutic possibilities for pRCC. This rising awareness is mirrored by an increase in the number of publications on this subject. A literature search with the keywords “pancreatic metastases” and “renal cell carcinoma” showed that the number of publications nearly doubled within the last five years (Fig. 3). However, the mean survival of 147.9 months suggests that resection might be beneficial for the patients. Previous publications demonstrated that non-surgical therapy for recurrent renal cell carcinoma has a five-year survival rate of 11e47% [23,26]. Chemotherapy, immunotherapy, and radiotherapy therefore appear to be less effective for primary RCC and metastatic disease. However, this lower survival rate could be due to selection bias as most of the patients in these studies may have more advanced disease than that patients that were resected. At the very least, surgery should be considered as a therapeutic possibility for pRCC [27]. It is also possible that an even better prognosis could be achieved through a combined surgical and medical approach. Unfortunately, the low incidence of pRCC will be an impediment for such studies. Due to the excellent survival and the relatively small number of patients in our cohort, we could not validate prognostic markers. Selection bias was a further obstacle to our statistical analysis. We considered the results of previous studies when indicating resection of pRCC, and our cohort thus show low variation in many of the tested parameters. One example is the long disease-free interval from the time of nephrectomy to the diagnosis of metastatic disease (i.e., 125.4 months). Only one patient had synchronous metastasis which is a known negative predictor. This long interval might be a major factor in the good prognosis after resection of pRCC. Such late recurrence after nephrectomy is only seen in 10% of patients after more than 10 years after surgery [17]. Some authors suggest that this long period between primary tumor and metastases might indicate a slow growth that favors local surgical resection [28], whereas synchronous metastasis might be an expression of a widespread and aggressive disease [27]. Yet most of published surgical studies on pRCC only observe late metastases;
Fig. 3. The table shows the number of patients that were operated in our two centers between 1994 and 2013 (grey bars, scale on left y-axis). The line indicates the number of references found in pubmed.com on pRCC in the same time frame (black line, scale on the right y-axis).
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F. Rückert et al. / International Journal of Surgery 26 (2016) 64e68
synchronous metastases are far less frequent and only account for 15%e27% of identified cases so there might be statistical bias [27]. Due to the nature of resection, only a few studies report on involvement of regional lymph nodes. 21 of the patients in our cohort received analysis of parapancreatic lymph node samples, and five of these were positive for tumor cells. We consider this an important finding of the present study. Several previous reports found no involvement of lymph node and suggested omission of lymphadenectomy (LAD) [29,30]. One study even reported the feasibility of segmental resection without LAD [25]. With respect to our five study patients with positive lymph nodes, we recommend a lymphadenectomy be performed in each case. In conclusion, our results suggest that resection is beneficial due to the excellent prognosis and acceptable morbidity rates that we observed. However, the high mortality rate should be considered in the perioperative managment. We could not find significant predictors for survival after pRCC, but the literature suggests that metachronous metastases are an important factor. Five of our 40 patients had lymph nodes that were tested positive for tumor cells. Therefore, a regional lymphadenectomy might be beneficial for the patients. However, further studies seem to be necessary to draw general conclusions. Ethical approval Ethical commission II (2015-820R-MA). Funding There was no funding for the present article. Author contribution FR: Study design, statistics, writing MD: Study design, data collection DO: Data collection AL: Data collection EB: Data analysis PT: Data collection RG: Study design TW: Study design, writing Conflicts of interest There is no conflict of interest. Guarantor Guarantor is Felix Rückert. Acknowledgment This study partly contains data of the theses of David Ollmann. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.ijsu.2015.12.003. References [1] R. Siegel, J. Ma, Z. Zou, A. Jemal, Cancer statistics, 2014, CA Cancer J. Clin. 64 (2015) 9e29. [2] F. Sellner, N. Tykalsky, M. De Santis, J. Pont, M. Klimpfinger, Solitary and multiple isolated metastases of clear cell renal carcinoma to the pancreas: an
indication for pancreatic surgery, Ann. Surg. Oncol. 13 (2006) 75e85. [3] B. Escudier, C. Porta, M. Schmidinger, F. Algaba, J.J. Patard, et al., Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up, Ann. Oncol. 25 (Suppl. 3) (2014) iii49eiii56. [4] J. Mattei, R.D. da Silva, D. Sehrt, W.R. Molina, F.J. Kim, Targeted therapy in metastatic renal carcinoma, Cancer Lett. 343 (2013) 156e160. [5] B. Ljungberg, K. Bensalah, S. Canfield, S. Dabestani, F. Hofmann, et al., EAU guidelines on renal cell carcinoma: 2014 update, Eur. Urol. 67 (2015) 913e924. [6] J.A. Karam, B.I. Rini, L. Varella, J.A. Garcia, R. Dreicer, et al., Metastasectomy after targeted therapy in patients with advanced renal cell carcinoma, J. Urol. 185 (2011) 439e444. [7] R. Ballarin, M. Spaggiari, N. Cautero, N. De Ruvo, R. Montalti, et al., Pancreatic metastases from renal cell carcinoma: the state of the art, World J. Gastroenterol. 17 (2011) 4747e4756. [8] G. Hudes, M. Carducci, P. Tomczak, J. Dutcher, R. Figlin, et al., Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma, N. Engl. J. Med. 356 (2007) 2271e2281. [9] M. Distler, F. Ruckert, M. Hunger, S. Kersting, C. Pilarsky, et al., Evaluation of survival in patients after pancreatic head resection for ductal adenocarcinoma, BMC Surg. 13 12. [10] F. Ruckert, S. Kersting, D. Fiedler, M. Distler, F. Dobrowolski, et al., Chronic pancreatitis: early results of pancreatoduodenectomy and analysis of risk factors, Pancreas 40 (2011) 925e930. [11] C.H. Law, A.C. Wei, S.S. Hanna, M. Al-Zahrani, B.R. Taylor, et al., Pancreatic resection for metastatic renal cell carcinoma: presentation, treatment, and outcome, Ann. Surg. Oncol. 10 (2003) 922e926. [12] T.A. Sohn, C.J. Yeo, J.L. Cameron, A. Nakeeb, K.D. Lillemoe, Renal cell carcinoma metastatic to the pancreas: results of surgical management, J. Gastrointest. Surg. 5 (2001) 346e351. [13] L.D. Thompson, C.S. Heffess, Renal cell carcinoma to the pancreas in surgical pathology material, Cancer 89 (2000) 1076e1088. [14] M.N. Wente, J.A. Veit, C. Bassi, C. Dervenis, A. Fingerhut, et al., Postpancreatectomy hemorrhage (PPH): an international study group of pancreatic surgery (ISGPS) definition, Surgery 142 (2007) 20e25. [15] M.N. Wente, C. Bassi, C. Dervenis, A. Fingerhut, D.J. Gouma, et al., Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the international study group of pancreatic surgery (ISGPS), Surgery 142 (2007) 761e768. [16] C. Bassi, C. Dervenis, G. Butturini, A. Fingerhut, C. Yeo, et al., Postoperative pancreatic fistula: an international study group (ISGPF) definition, Surgery 138 (2005) 8e13. [17] Y. Hoshino, H. Shinozaki, Y. Kimura, Y. Masugi, H. Ito, et al., Pancreatic metastases from renal cell carcinoma: a case report and literature review of the clinical and radiological characteristics, World J. Surg. Oncol. 11 (2013) 289. [18] S. Crippa, C. Angelini, C. Mussi, C. Bonardi, F. Romano, et al., Surgical treatment of metastatic tumors to the pancreas: a single center experience and review of the literature, World J. Surg. 30 (2006) 1536e1542. [19] F. Ruckert, M. Kuhn, R. Scharm, H. Endig, S. Kersting, et al., Evaluation of POSSUM for patients undergoing pancreatoduodenectomy, J. Investig. Surg. 27 (2014) 338e348. [20] G. Butturini, C. Bassi, M. Falconi, R. Salvia, E. Caldiron, et al., Surgical treatment of pancreatic metastases from renal cell carcinomas, Dig. Surg. 15 (1998) 241e246. [21] R. Ghavamian, K.A. Klein, D.H. Stephens, T.J. Welch, A.J. LeRoy, et al., Renal cell carcinoma metastatic to the pancreas: clinical and radiological features, Mayo Clin. Proc. 75 (2000) 581e585. [22] S. Yachida, N. Fukushima, Y. Kanai, S. Nimura, K. Shimada, et al., Pancreatic metastasis from renal cell carcinoma extending into the main pancreatic duct: a case report, Jpn. J. Clin. Oncol. 32 (2002) 315e317. [23] A. Zerbi, E. Ortolano, G. Balzano, A. Borri, A.A. Beneduce, et al., Pancreatic metastasis from renal cell carcinoma: which patients benefit from surgical resection? Ann. Surg. Oncol. 15 (2008) 1161e1168. [24] I.T. Konstantinidis, A. Dursun, H. Zheng, J.A. Wargo, S.P. Thayer, et al., Metastatic tumors in the pancreas in the modern era, J. Am. Coll. Surg. 211 (2010) 749e753. [25] T. Yazbek, B. Gayet, The place of enucleation and enucleo-resection in the treatment of pancreatic metastasis of renal cell carcinoma, Jop 13 (2012) 433e438. [26] J.P. Kavolius, D.P. Mastorakos, C. Pavlovich, P. Russo, M.E. Burt, et al., Resection of metastatic renal cell carcinoma, J. Clin. Oncol. 16 (1998) 2261e2266. [27] C. Sperti, L. Moletta, G. Patane, Metastatic tumors to the pancreas: the role of surgery, World J. Gastrointest. Oncol. 6 (2014) 381e392. [28] T. Hirota, T. Tomida, M. Iwasa, K. Takahashi, M. Kaneda, et al., Solitary pancreatic metastasis occurring eight years after nephrectomy for renal cell carcinoma, A case report and surgical review, Int. J. Pancreatol. 19 (1996) 145e153. [29] K. Jingu, K. Watanabe, H. Yamamoto, Y. Fujita, I. Honda, et al., Surgical treatment of a solitary pancreatic metastasis from renal cell carcinoma: report of a case, Surg. Today 28 (1998) 91e94. [30] J.P. Faure, J.J. Tuech, J.P. Richer, P. Pessaux, J.P. Arnaud, et al., Pancreatic metastasis of renal cell carcinoma: presentation, treatment and survival, J. Urol. 165 (2001) 20e22.
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.journal-surgery.net
Original research
Retrospective analysis of survival after resection of pancreatic renal cell carcinoma metastases Felix Rückert a, *, 1, Marius Distler b, 1, David Ollmann a, Anja Lietzmann a, Emrullah Birgin a, Patrick Teoule a, Robert Grützmann c, 1, Torsten J. Wilhelm a, 1 a
Department of Surgery, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany €t Dresden, Fetscherstrasse 74, 01307 Department of General, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universita Dresden, Germany c Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Krankenhausstr. 12, 91054 Erlangen, Germany b
h i g h l i g h t s Pancreatic renal cell carcinoma metastasis is rare and the best treatment is uncertain. We analysed outcome after resection of those metastasis in two German centers. Due to selection of patients we found no risk factor. Due to lymph node metastases in some patients we advice to perform lymphadenectomy.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 September 2015 Received in revised form 25 November 2015 Accepted 4 December 2015 Available online 29 December 2015
Introduction: Previous reports showed an excellent survival for patients after resection of pancreatic metastases from renal cell cancer (pRCC) and reported several predictive factors. This study aims to give more evidence to reported risk factors by analyzing a large cohort of patients with pancreatic resection due to pRCC. Patients and methods: We retrospectively analyzed all pancreatic resections due to pRCC between January 1993 and October 2014 in two German pancreatic surgery centers. Predictive factors were analyzed using the chi square test. Results: Surgery was performed in 40 patients. Mean survival after resection was 147.9 months (SD 25.6 months). No predictive factors for survival were identified. Pathological examination showed that five out of 21 patients with examined peripancreatic lymph nodes had lymph node metastases. Conclusions: Although our analysis comprised the biggest cohort of patients with pRCC it rendered no significant predictor for survival. This might be due to the overall excellent prognosis of study patients and the relatively rare condition with a limited number of patients. Several patients had lymph node metastases. Therefore lymphadenectomy should be considered in pRCC resection if the health condition of the patient permits this. By this more aggressive approach to pRCC, a better prognosis after resection might be achieved. © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.
Keywords: Pancreatic surgery Renal cell carcinoma Metastases Resection Survival
1. Introduction Renal cell carcinoma (RCC) is a cancer with a high incidence; for example, there were an estimated 64,000 new cases in the US alone
* Corresponding author. University Hospital Mannheim Medical Faculty Mannheim, University of Heidelberg, Germany Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. E-mail address: [email protected] (F. Rückert). 1 These authors contributed equally.
in 2014 [1]. Metastases may occur a long time after resection of the primary tumor [2]. Although RCC is one of only few tumors that spreads to the pancreas, pancreatic metastases are rare. Only 4% of all pancreatic resections account for metastases of RCC (pRCC) and less than 300 cases were reported in the last 60 years [2]. Consequently, there is limited data in the literature concerning the prognosis after resection of pRCC. The European Society for Medical Oncology (ESMO) guidelines for the treatment of metastatic renal cell carcinoma state that metastasectomy may provide a possible survival benefit for a selected group of patients with lung
http://dx.doi.org/10.1016/j.ijsu.2015.12.003 1743-9191/© 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.
F. Rückert et al. / International Journal of Surgery 26 (2016) 64e68
metastases only (i.e., those a long metachronous disease-free interval and a positive response to immunotherapy/targeted therapy) [3]. Recently it was also shown that targeted therapy might be an option for metastatic RCC [4,5]. However, several retrospective and nonrandomized studies with a limited number of pRCC patients suggested that resection of metastases might also lead to a prolonged median survival [6]. After operation, three- and five-year survival rates were 78% and 72%, respectively [2]. RCC is highly resistant to chemotherapy, thus surgery seems to be a better option than chemotherapy in the opinion of the authors [7]. Data from a randomized controlled clinical trial for the treatment of metastatic renal cell carcinoma only showed a survival of up to 11 months under first line chemotherapy [8]. Therefore chemotherapy must be regarded as relatively ineffective and surgery still must be considered as an alternative. Although mortality after pancreatic surgery has recently decreased, it nonetheless has a high morbidity rate and not all patients may benefit from resection of pRCC [9,10]. Predictive factors could facilitate the decision of when to operate. Recent retrospective studies revealed different predictive factors for patient survival after resection of pRCC. These include lymph node involvement [11], multifocal metastases, synchronous metastases, symptomatic metastases [12,13], size of the metastasis [13], and recurrent metastases [2]. The aim of this study was twofold: to evaluate the prognosis after resection of pRCC, and to both analyse predictive factors and identify new predictive factors, in a large cohort of patients with pRCC.
65
Table 1 Characteristics of our patient cohort. (SD ¼ standard deviation; BMI ¼ Body-MassIndex; x ¼ missing data).* Values are mean with standard deviation. Patients n ¼ 40 n (%) Age (years) Male sex BMI Time after primary tumor (months) Age at initial diagnosis (years) Classification of primary tumor T 1 2 3 4 x N 0 1 x G 1 2 3 x R 0 x Metachronous metastases (>6 months) History of other metachronous metastases
65.5 24 28.0 125.4 55.7
(SD 9.0)* (60) (SD 4.5)* (SD 77.4)* (SD 9.6)*
11 (27.5) 11 (27.5) 7 (17.5) e 11 (27.5) 21 (52.5) e 19 (47.5) 1 (2.5) 8 (20) e 31 (77.5) 3 37 39 13
(7.5) (92.5) (97.5) (32.5)
2. Patients and methods 2.1. Patients A retrospective search for patients with a diagnosis of metastases from RCC (pRCC) was performed at the Department of General, Thoracic, and Vascular Surgery of the Carl Gustav Carus University Hospital, Dresden, and the Surgical Department of the University Hospital, Mannheim. The patients were selected from the prospective pancreas databases. Between October 1993 and March 2014 we identified 40 consecutive patients that were resected for pRCC. The final pathological diagnosis confirmed metastases from RCC in all patients. The demographic characteristics of the patients are summarized in Table 1. 2.2. Data collection Patients who had undergone pancreas resection for pRCC were identified from our databases and their medical records were analyzed retrospectively. In accordance with the guidelines for human subject research, approval was obtained from the Ethics Committee at the University Hospital, Mannheim. The data were complemented with clinical notes from the patients' physicians and surgeons. The information regarding deceased patients was obtained from family members or from the respective general practitioner. Patient characteristics and parameters used for statistical analysis are listed in Supplementary information 1. The postoperative events and clinical outcomes were also recorded prospectively and analyzed retrospectively. Tumor stage designation was categorized according to the TNM system of the Union Internationale Contre le Cancer (UICC) 2007 guidelines. Literature search was performed using Pubmed (www.pubmed.com) and the keywords “pancreatic metastases” and “renal cell carcinoma”.
Postoperative pancreatic hemorrhage (PPH) was categorized according to the International Study Group on Pancreatic Surgery (ISGPS) consensus definition [14]. Delayed gastric emptying (DGE) was classified according to the suggested definition by the ISGPS [15]. Postoperative pancreatic fistula (POPF) was defined analogous to the ISGPF criteria [16]. Synchronous metastasis was defined as metastasis within 6 month of initial diagnosis. 2.4. Statistical analysis Statistical analyses were performed using the Statistical Package for the Social Sciences for Windows, version 15.0 (SPSS, Inc., Chicago, IL, USA). All clinical and pathological characteristics were stratified to build categorical or nominal variables. The thresholds used for categorization were based on previously described thresholds in the literature and/or recursive partitioning as previously described [18]. Laboratory values were defined as elevated if values were higher than the normal cut-off value. Continuous data are presented as mean with standard deviation (SD). The univariate examination of the relationship between the assessed criteria and survival was performed with a Chi-square test. For the assessment of the impact of different parameters on survival, we utilized a three-year survival rate. The estimates of patient survival were generated using the KaplaneMeier method. Factors significant (at p < 0.10) at the univariate level were entered into the multivariate model. A Cox regression analysis with stepwise backwards elimination based on likelihood ratios was employed to test for independent predictors of survival (at p < 0.05). 3. Results 3.1. Study cohort
2.3. Definitions Perioperative mortality was defined as in-hospital mortality.
Analysis of the pancreatic databases showed that 2% of all operations at the two centers were performed for pRCC. A total of 40
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cases were identified. 24 (60%) of our patients were male. The patients' mean age at diagnosis of the primary tumor was 55.7 (SD 9.6) years. Data on the initial tumor stage included a high percentage of missing data (Table 1). The mean age of our patients at operation was 65.5 (SD 9.0) years. Mean time between resection of the primary tumor and the diagnosis of the metastases was 125.4 months (SD 77.4). Consequently, 39 (97.5%) of the metastases were metachronous. In 24 (60%) of the patients, the metastases were found during routine surveillance imaging, and 13 patients had symptomatic metastases (32.5%). Of these 13 patients, nine had obstructive jaundice, two had gastrointestinal bleedings, one had hyperglycaemia, and one had abdominal pain. 3.2. Tumor characteristics 13 (32.5%) patients had other metastases at the time of pRCC diagnosis. Singular metastases within the pancreas were seen in 18 (45.0%) of patients, eight patients (20.0%) had two metastases, and 12 had multifocal metastases (30%). Two patients had no data on the number of metastases. 14 (35.0%) of the metastases were larger than 2.0 cm. Parapancreatic lymph nodes from 22 patients were pathologically examined, and of these five had metastases within the lymph nodes (22.7%). Five patients total (12.5%) had an R1 resectional status (Table 1).
preserving pancreaticoduodenectomy (PPPD) and died from multi-organ dysfunction. A 61-year old patient had leakage of the duodenojejunostomy after PPPD and died due to peritonitis in a septic shock. A 64-year old male died after distal resection due to myocardial infarction (Table 2) (Fig. 1). 3.4. Univariate and multivariate analysis Of the remaining 37 patients, four (10.8%) died during the follow-up period due to tumor progression. Of these four patients, two patients died within five years (5.4%). Mean survival after pancreatic resection was 147.9 months (SD 25.6 months) (Fig. 2). We analysed the influence of body mass index (BMI), sex, time point of metastasis (i.e., synchronous/metachronous), symptomatic metastases, resectional status, history of previous renal cell carcinoma metastases in other locations, presence of multifocal metastases within the pancreas, tumor size larger than 2.0 cm, and positive lymph nodes as predictors for survival. However, none of these factors were significant. 4. Discussion Metastases to the pancreas are rare. Only 2% of all pancreatic
3.3. Short term results Most resections were pancreatic head resections (n ¼ 15; 37.5%) followed by distal pancreatectomies (n ¼ 12; 30.0%) and pancreatectomies (n ¼ 9; 22.5%). Segmental resection was only performed in three (7.5%) patients and a broad papillary resection in one patient (2.5%) (Table 2). The mean duration of operation was 325.4 min (SD 135.9). POPF Grade A occurred in four patients (10.0%), Grade B in five patients (12.5%) and Grade C in three patients (7.5%). DGE was infrequently seen. PPH Grade A occurred in one patient (2.5%), Grade B in six patients (15.0%). The mean Intensive Care Unit (ICU) stay was 2.3 days (SD 5.1). Three patients died postoperatively (7.5%). An 83-year old patient had septic shock and myocardial infarction after pylorusTable 2 Data on the intra- and postoperative course. (SD ¼ standard deviation; POPF ¼ postoperative pancreatic fistula; DGE ¼ delayed gastric emptying; PPH ¼ postpancreatectomy hemorrhage; ICU ¼ intensive care unit).* Values are mean with standard deviation. Patients n ¼ 40 n (%) Performed procedure Pancreatic head resection Total pancreatectomy Distal pancreatectomy Segmental resection Papillary resection Duration of operation (min) Blood loss (ml) POPF A B C DGE A B C PPH A B C Stay on ICU (days) Mortality
15 9 12 3 1 325.4 501.3
(37.5) (22.5) (30.0) (7.5) (2.5) (SD 135.9)* (SD 898.8)*
4 (10.0) 5 (12.5) 3 (7.5) e 3 (7.5) 1 (2.5) 1 (2.5) 6 (15.0) e 2.3 (SD 5.1)* 3 (7.5)
Fig. 1. Surgical sample with a pancreatic renal cell metastasis (from R. Grützmann).
F. Rückert et al. / International Journal of Surgery 26 (2016) 64e68
Fig. 2. Survival of patients after resection of pRCC. The numbers indicate “patients at risk”.
resections at the two centers in our study were performed for pRCC. This is in accordance to previous publications that report a range of pancreatic resections due to pRCC from 1% to 3% [13,17,18]. During the last ten years, several retrospective studies have been published that show that radical surgery for pRCC appears to be justified. However, improvements in survival must be examined in relation to the perioperative morbidity and mortality [9,10]. The aim of the present study was to analyze the postoperative course and longterm results after resection of pRCC, and to evaluate possible predictive factors for survival in a large cohort of patients with pRCC. Our database search yielded 40 patients with pRCC. To our knowledge this is one of the largest cohorts of patients with pRCC [2,17]. After resection of pRCC, three patients (7.5%) had POPF grade C and PPH grade B was seen in six patients (15.0%). Three patients died postoperatively (7.5%). Mortality was therefore slightly higher as expected. These results might be due to the fact that these patients had received previous operations. Additionally, most pancreata with metastases have very soft tissue, which leads to a higher rate of pancreatic fistulas and other complications [19]. Of note, prognosis after resection of pRCC was very good. The patients
67
in our cohort had a mean survival of 147.9 months. Several prior studies that focused on surgical resection of the pancreas for pRCC found that five-year overall survival rates range from 75% to 88% [12,17,20e25]. We cannot present three- and five-year survival rates because not all of our patients have completed the five year observation period (Fig. 2). Nearly 50% of the patients of our cohort underwent operations within the last five years. A possible reason for this high percentage might be a rising awareness of the surgical therapeutic possibilities for pRCC. This rising awareness is mirrored by an increase in the number of publications on this subject. A literature search with the keywords “pancreatic metastases” and “renal cell carcinoma” showed that the number of publications nearly doubled within the last five years (Fig. 3). However, the mean survival of 147.9 months suggests that resection might be beneficial for the patients. Previous publications demonstrated that non-surgical therapy for recurrent renal cell carcinoma has a five-year survival rate of 11e47% [23,26]. Chemotherapy, immunotherapy, and radiotherapy therefore appear to be less effective for primary RCC and metastatic disease. However, this lower survival rate could be due to selection bias as most of the patients in these studies may have more advanced disease than that patients that were resected. At the very least, surgery should be considered as a therapeutic possibility for pRCC [27]. It is also possible that an even better prognosis could be achieved through a combined surgical and medical approach. Unfortunately, the low incidence of pRCC will be an impediment for such studies. Due to the excellent survival and the relatively small number of patients in our cohort, we could not validate prognostic markers. Selection bias was a further obstacle to our statistical analysis. We considered the results of previous studies when indicating resection of pRCC, and our cohort thus show low variation in many of the tested parameters. One example is the long disease-free interval from the time of nephrectomy to the diagnosis of metastatic disease (i.e., 125.4 months). Only one patient had synchronous metastasis which is a known negative predictor. This long interval might be a major factor in the good prognosis after resection of pRCC. Such late recurrence after nephrectomy is only seen in 10% of patients after more than 10 years after surgery [17]. Some authors suggest that this long period between primary tumor and metastases might indicate a slow growth that favors local surgical resection [28], whereas synchronous metastasis might be an expression of a widespread and aggressive disease [27]. Yet most of published surgical studies on pRCC only observe late metastases;
Fig. 3. The table shows the number of patients that were operated in our two centers between 1994 and 2013 (grey bars, scale on left y-axis). The line indicates the number of references found in pubmed.com on pRCC in the same time frame (black line, scale on the right y-axis).
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synchronous metastases are far less frequent and only account for 15%e27% of identified cases so there might be statistical bias [27]. Due to the nature of resection, only a few studies report on involvement of regional lymph nodes. 21 of the patients in our cohort received analysis of parapancreatic lymph node samples, and five of these were positive for tumor cells. We consider this an important finding of the present study. Several previous reports found no involvement of lymph node and suggested omission of lymphadenectomy (LAD) [29,30]. One study even reported the feasibility of segmental resection without LAD [25]. With respect to our five study patients with positive lymph nodes, we recommend a lymphadenectomy be performed in each case. In conclusion, our results suggest that resection is beneficial due to the excellent prognosis and acceptable morbidity rates that we observed. However, the high mortality rate should be considered in the perioperative managment. We could not find significant predictors for survival after pRCC, but the literature suggests that metachronous metastases are an important factor. Five of our 40 patients had lymph nodes that were tested positive for tumor cells. Therefore, a regional lymphadenectomy might be beneficial for the patients. However, further studies seem to be necessary to draw general conclusions. Ethical approval Ethical commission II (2015-820R-MA). Funding There was no funding for the present article. Author contribution FR: Study design, statistics, writing MD: Study design, data collection DO: Data collection AL: Data collection EB: Data analysis PT: Data collection RG: Study design TW: Study design, writing Conflicts of interest There is no conflict of interest. Guarantor Guarantor is Felix Rückert. Acknowledgment This study partly contains data of the theses of David Ollmann. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.ijsu.2015.12.003. References [1] R. Siegel, J. Ma, Z. Zou, A. Jemal, Cancer statistics, 2014, CA Cancer J. Clin. 64 (2015) 9e29. [2] F. Sellner, N. Tykalsky, M. De Santis, J. Pont, M. Klimpfinger, Solitary and multiple isolated metastases of clear cell renal carcinoma to the pancreas: an
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