Available online at www.sciencedirect.com
ScienceDirect EJSO 40 (2014) 559e566
www.ejso.com
Splenic volume may be a useful indicator of the protective effect of bevacizumab against oxaliplatin-induced hepatic sinusoidal obstruction syndrome K. Imai a, Y. Emi b, K.-I. Iyama c, T. Beppu a, Y. Ogata d, Y. Kakeji e, H. Samura f, E. Oki b, Y. Akagi g, Y. Maehara b, H. Baba a,*, Kyusyu Study Group of Clinical Cancer (KSCC) ancillary study a
Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan b Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan c Department of Surgical Pathology, Kumamoto University Hospital, Kumamoto, Japan d Department of Surgery, Kurume University Medical Center, Kurume, Japan e Department of Surgery, Division of Gastrointestinal Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan f Division of Digestive and General Surgery, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan g Department of Surgery, Kurume University Hospital, Kurume, Japan Accepted 6 December 2013 Available online 20 December 2013
Abstract Aims: The aim of this study was to investigate the relationship between the use of bevacizumab (Bmab) in addition to oxaliplatin (OX), the development of sinusoidal obstruction syndrome (SOS) and the changes in splenic volume as an indicator of the protective effect of Bmab against OX-induced SOS. Methods: Seventy-nine patients who received OX-based chemotherapy with (OX þ Bmab group: n ¼ 48) or without Bmab (OX group: n ¼ 31) for colorectal liver metastases were included in this study. The changes in splenic volume after chemotherapy were evaluated in the two groups. Furthermore, the relationship between the changes in splenic volume and SOS were analyzed in the 55 patients who underwent hepatectomy. Results: A significant increase in the splenic volume was observed in the OX group, but not in the OX þ Bmab group. The increase in the splenic volume relative to baseline was significantly higher in the OX group than in the OX þ Bmab group (39.1% vs. 2.3%, p < 0.0001). The incidence of moderate or severe SOS was significantly higher in the OX group than in the OX þ Bmab group (50.0% vs. 16.0%, p ¼ 0.0068), and the increase in the splenic volume was significantly higher in the patients with SOS than in those without SOS (42.9% vs. 9.9%, p ¼ 0.0001). A multivariate analysis identified the increase in the splenic volume as an independent predictor of the development of SOS. Conclusions: This study demonstrated that the inhibition of splenic volume enlargement might be a useful indicator of the protective effect of Bmab against OX-induced SOS. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: Sinusoidal obstruction syndrome; Colorectal liver metastases; Bevacizumab; Oxaliplatin; Splenic volume
Abbreviations: CRLM, colorectal liver metastases; OX, oxaliplatin; FU, fluorouracil; LV, leucovorin; SOS, sinusoidal obstruction syndrome; Bmab, bevacizumab; VEGF, vascular endothelial growth factor; FDA, Food and Drug Administration; FOLFOX, 5-fluorpuracil/leucovorin/oxaliplatin regimen; XELOX, capecitabine/oxaliplatin regimen; CT, computed tomography; SD, standard deviation; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; HR, hazard ratio; ICG-R15, indocyanine green retention rate at 15 min. * Corresponding author. Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Tel.: þ81 96 373 5211; fax: þ81 96 371 4378. E-mail address: [email protected] (H. Baba). 0748-7983/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.12.009
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Introduction Colorectal cancer is one of the most common malignancies worldwide and its incidence has been rapidly increasing during the past few decades. The liver is the most common site of metastatic spread, and nearly half of the patients with colorectal cancer develop liver metastases at some point during the course of their disease.1e3 In patients with liver-only metastases, liver resection remains the only treatment modality that potentially achieves longterm survival and offers the hope of a cure. Previous studies reported a five-year survival rate of 40e58% after potentially curative liver resection.4e7 These favorable outcomes of patients with colorectal liver metastases (CRLM) are attributed not only to the improvements in surgical techniques and perioperative management, but also to the emergence of more effective chemotherapy. However, only about 20% of patients with CRLM are eligible for liver resection.8,9 In such patients with initially inoperable liver metastases, the recently introduced chemotherapeutic and biologic agents can increase the number of candidates for potentially curative resection.8,10,11 When marked tumor shrinkage is obtained by chemotherapy, an unresectable tumor may become resectable, and in such cases, a favorable long-term outcome can be expected by hepatic resection with curative intent. In patients with initially unresectable liver diseases that become resectable after preoperative chemotherapy, the five-year survival rates have reached 30%.8 Oxaliplatin (OX), a third-generation platinum compound, is widely used in the treatment of CRC in combination with either 5-fluorouracil/leucovorin (FU/LV) or capecitabine. OX-based chemotherapy has been increasingly utilized in the adjuvant, neoadjuvant and metastatic settings. However, several studies have demonstrated sinusoidal obstruction syndrome (SOS) in the non-tumorbearing liver in patients receiving preoperative OX-based chemotherapy, with an incidence of 19%e78%.12e15 Other reports showed that OX-induced SOS was associated not only with intraoperative bleeding15 and postoperative morbidity,15,16 but also with early recurrence and a decreased overall survival.17 Bevacizumab (Bmab), a monoclonal humanized antibody directed against vascular endothelial growth factor (VEGF), was initially approved by the U.S. Food and Drug Administration (FDA) in 2004 for the first-line treatment of metastatic colorectal cancer based on a survival benefit,18 and has been increasingly used in combination with chemotherapy before hepatic resection in patients with CRLM. Previous studies demonstrated that Bmab may prevent SOS in patients treated with OX-based chemotherapy for CRLM.19,20 In the current study, we investigated the relationship between the use of Bmab in addition to OX, the development of SOS and the changes in the splenic volume after
chemotherapy to demonstrate the benefit of assessing the change in the splenic volume as an indicator of the protective effect of Bmab against OX-induced SOS. Patients and methods Seventy-nine patients with CRLM who received OXbased preoperative chemotherapy with or without Bmab between 2004 and 2012 were retrospectively analyzed in the current study. Thirty-nine patients were treated in the Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University (Kumamoto, Japan), and the remaining 40 were patients who were enrolled in the Kyushu Study Group of Clinical Cancer (KSCC) 0802 ancillary study. The patients treated in Kumamoto University were administrated preoperative chemotherapy with the intent of both neoadjuvant and conversion. KSCC 0802 study was a prospective multicenter phase II trial in Japanese patients, and the aim of this study was to evaluate the resectability and safety of mFOLFOX6 þ Bmab on H2 and H3 liver-limited CRLM. The patients enrolled in KSCC 0802 study were also administrated chemotherapy with the intent of both neoadjuvant and conversion. To elucidate the effects of Bmab, patients were grouped as follows: OX group (n ¼ 31), patients who received OXbased chemotherapy without Bmab; OX þ Bmab group (n ¼ 48), patients who received OX-based chemotherapy with Bmab. In the OX group, 29 patients were treated with a 5-FU/LV/OX regimen (FOLFOX) and two patients were treated with a capecitabine/OX regimen (XELOX). In the OX þ Bmab group, 47 patients were treated with a FOLFOX þ Bmab regimen and one patient was treated with a XELOX þ Bmab regimen. The exclusion criteria were patients with underlying chronic liver diseases, patients who had received previous OX- or irinotecan-based chemotherapy and patients who had received any chemotherapy within six months before initiation of the treatment. Although the patients treated at Kumamoto University received either the FOLFOX (FOLFOX4 or mFOLFOX6) or XELOX with or without Bmab regimen, the patients enrolled in the KSCC 0802 study received only the mFOLFOX6 with Bmab regimen. Thirty of the 31 patients in the OX group underwent surgery, and 26 of the 48 patients in the OX þ Bmab group underwent surgery. In the OX þ Bmab group, one patient underwent exploratory laparotomy because the tumor was not detectable by intraoperative examinations, including ultrasonography. The remaining 55 patients underwent hepatic resection for CRLM. Hepatic resections were performed at least two weeks after the last course of chemotherapy. In the OX þ Bmab group, the last cycle of chemotherapy was usually given without Bmab to establish a gap of five weeks between the last Bmab treatment and surgery. Major hepatectomy was defined as resection of three or more liver
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Figure 1. The splenic volume before and after chemotherapy. The splenic volume before (A) and after (B) seven cycles of FOLFOX in a representative patient with multiple liver metastases from a rectal cancer. The splenic volume before and after chemotherapy were 72 cm3 and 145 cm3, respectively. Therefore, the increase in the splenic volume relative to baseline was calculated to be 101.4%.
segments. Postoperative morbidity was defined as any complication of Grade II or more according to the classification system proposed by Dindo et al.21 The presence of histological SOS of non-tumorous liver tissues away from the tumor was assessed by a single pathologist (KI.I.) who was blinded to the clinical data.
SOS was graded using a previously established system; grade 0, absent; grade 1, mild (centrilobular involvement of less than one-third of the lobular surface); grade 2, moderate (centrilobular involvement greater than or equal to one-third of the lobular surface, but not the whole surface) and grade 3, severe (complete lobular involvement with or
Table 1 Background characteristics of the patients before chemotherapy with or without bevacizumab.
Gender (male/female) Age Site of primary tumor (colon/rectum) Synchronous/metachronous Largest tumor size (mm) Number of metastases Number of chemotherapy cycles Total bilirubin (mg/dL) AST (IU/L) ALT (IU/L) ALP (IU/L) White blood cell count (/mL) Hemoglobin (g/dL) Platelet count ( 104/mL) Splenic volume before chemotherapy (cm3)
OX (n ¼ 31)
OX þ Bmab (n ¼ 48)
p value
21/10 66.2 10.2 18/13 22/9 50.3 56.9 4.8 6.5 6.7 2.6 0.64 0.26 28.6 21.9 25.8 16.6 369.6 247.4 6261 1876 11.9 2.1 27.6 11.6 120.8 50.5
34/14 63.0 9.2 30/18 37/11 56.5 34.4 6.0 5.5 5.3 2.7 0.64 0.29 33.0 18.7 29.6 19.90 442.9 295.3 6226 1536 12.4 1.7 24.5 7.4 127.2 52.9
0.96 0.16 0.69 0.54 0.062 0.28 0.0016 0.86 0.079 0.53 0.083 0.68 0.26 0.35 0.52
The values are the means standard deviations. OX, oxaliplatin; Bmab, bevacizumab; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase.
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Table 2 The blood biochemical parameters before and after chemotherapy. OX (n ¼ 31) Before chemotherapy Total bilirubin (mg/dL) AST (IU/L) ALT (IU/L) ALP (IU/L) White blood cell count (/mL) Hemoglobin (g/dL) Platelet count ( 104/mL)
0.64 28.6 25.8 369.6 6261 11.9 27.6
0.26 21.9 16.6 247.4 1876 2.1 11.6
OX þ Bmab (n ¼ 48) After chemotherapy 0.67 31.4 29.5 348.0 4831 12.2 16.8
0.21 15.6 25.7 142.2 1629 1.3 6.0
p value
Before chemotherapy
0.63 0.18 0.75 0.88 0.0011 0.34 65a Site of primary tumor (rectum) Synchronous vs. metachronous Largest tumor size >36a mm Number of metastases >1 Number of chemotherapy cycles >6a Decrease in the platelet count >7.3a ( 104/mL) Bmab use Interval between completion of chemotherapy and surgery>34a days Splenic volume before chemotherapy >112a mL Splenic volume after chemotherapy >129a mL Increase in splenic volume relative to baseline >25%
Multivariate analysis
HR
95%CI
p value
0.83 1.72 1.65 1.40 1.11 1.46 2.52 2.69 0.19 1.72 0.90 1.58 20.7
0.25e2.80 0.56e5.29 0.52e5.24 0.41e4.81 0.37e3.38 0.42e5.03 0.80e7.95 0.86e8.49 0.05e0.69 0.56e5.29 0.29e2.84 0.50e5.00 4.44e96.2
0.77 0.34 0.39 0.59 0.85 0.55 0.11 0.091 0.012 0.34 0.86 0.43 0.0001
HR
1.62 0.65
14.4
95%CI
p value
0.36e7.26 0.12e3.52
0.53 0.62
2.48e83.3
0.0029
Bmab, bevacizumab; 95% CI, 95% confidence interval. a Median.
prevention of the development of SOS and decrease in the postoperative morbidity. In the current study, the splenic volume increased significantly in the OX group, however, the addition of Bmab prevented the splenic enlargement (Fig. 2). In addition, the increase in the splenic volume was significantly higher in patients with SOS than in those without SOS (Fig. 3(B)). These results suggest that the improvement of splenic enlargement might be a useful indicator of the protective effect of Bmab against OX-induced SOS. Although it remains unclear whether some of the patients treated with Bmab still developed OX-induced SOS in the liver parenchyma, preoperative and non-invasive prediction of the protective effects of Bmab against OX-induced SOS will facilitate the appropriate management of patients with CRLM in terms of the selection of hepatic resection after chemotherapy. There are some limitations to this study which consisted of two groups, the patients treated in the Kumamoto University, and the patients enrolled in KSCC 0802 study. First, the sample size was relatively small. Second, the patients enrolled in the KSCC 0802 study received only the mFOLFOX6 with Bmab regimen, and in principle, 5 cycles of mFOLFOX6 þ Bmab will be administered. Therefore, some bias could be present between the groups. In fact, there was a significant difference in the total amount of chemotherapy cycles between the groups. In this study, postoperative morbidity did not differ between the groups, in spite of the high incidence of SOS in the OX group. This result disagreed with the previous reports,15,16 and may be influenced by its small sample size and some bias. In conclusion, the present study showed that the development of SOS induced by OX-based chemotherapy was reduced when Bmab was added, and the inhibition of splenic enlargement might be a useful indicator of the protective effect of Bmab against OX-induced SOS.
Conflict of interest disclosure None of the authors has any conflict of interest. Appendix A. Supplementary data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.ejso.2013.12.009.
References 1. Leporrier J, Maurel J, Chiche L, et al. A population-based study of the incidence, management and prognosis of hepatic metastases from colorectal cancer. Br J Surg 2006;93:465–74. 2. Leonard GD, Brenner B, Kemeny NE. Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol 2005;23:2038–48. 3. Manfredi S, Lepage C, Hatem C, et al. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006;244:254–9. 4. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002;235:759–66. 5. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005;241:715–22. 6. Shah SA, Bromberg R, Coates A, et al. Survival after liver resection for metastatic colorectal carcinoma in a large population. J Am Coll Surg 2007;205:676–83. 7. Morris EJ, Forman D, Thomas JD, et al. Surgical management and outcomes of colorectal cancer liver metastases. Br J Surg 2010;97: 1110–8. 8. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004;240:644–57. 9. Scheele J. Hepatectomy for liver metastases. Br J Surg 1993;80:274–6. 10. Bertolini F, Malavasi N, Scarabelli L, et al. FOLFOX6 and bevacizumab in non-optimally resectable liver metastases from colorectal cancer. Br J Cancer 2011;104:1079–84. 11. Saif MW. Secondary hepatic resection as a therapeutic goal in advanced colorectal cancer. World J Gastroenterol 2009;15:3855–64.
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12. Overman MJ, Maru DM, Charnsangavej C, et al. Oxaliplatin-mediated increase in spleen size as a biomarker for the development of hepatic sinusoidal injury. J Clin Oncol 2010;28:2549–55. 13. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004;15:460–6. 14. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006;24:2065–72. 15. Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006;24:4983–90. 16. Nakano H, Oussoultzoglou E, Rosso E, et al. Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy. Ann Surg 2008; 247:118–24. 17. Tamandl D, Klinger M, Eipeldauer S, et al. Sinusoidal obstruction syndrome impairs long-term outcome of colorectal liver metastases treated with resection after neoadjuvant chemotherapy. Ann Surg Oncol 2011;18:421–30. 18. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–42. 19. Ribero D, Wang H, Donadon M, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer 2007;110:2761–7. 20. Rubbia-Brandt L, Lauwers GY, Wang H, et al. Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis. Histopathology 2010;56:430–9. 21. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–13.
22. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313–21. 23. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008;371:1007–16. 24. Soubrane O, Brouquet A, Zalinski S, et al. Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: correlation with posthepatectomy outcome. Ann Surg 2010;251:454–60. 25. van der Pool AE, Marsman HA, Verheij J, et al. Effect of bevacizumab added preoperatively to oxaliplatin on liver injury and complications after resection of colorectal liver metastases. J Surg Oncol 2012; 106:892–7. 26. Ward J, Guthrie JA, Sheridan MB, et al. Sinusoidal obstructive syndrome diagnosed with superparamagnetic iron oxide-enhanced magnetic resonance imaging in patients with chemotherapy-treated colorectal liver metastases. J Clin Oncol 2008;26:4304–10. 27. Klinger M, Eipeldauer S, Hacker S, et al. Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases. Eur J Surg Oncol 2009;35:515–20. 28. Kesmodel SB, Ellis LM, Lin E, et al. Preoperative bevacizumab does not significantly increase postoperative complication rates in patients undergoing hepatic surgery for colorectal cancer liver metastases. J Clin Oncol 2008;26:5254–60. 29. D’Angelica M, Kornprat P, Gonen M, et al. Lack of evidence for increased operative morbidity after hepatectomy with perioperative use of bevacizumab: a matched case-control study. Ann Surg Oncol 2007;14:759–65. 30. Reddy SK, Morse MA, Hurwitz HI, et al. Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases. J Am Coll Surg 2008;206:96–106.
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Splenic volume may be a useful indicator of the protective effect of bevacizumab against oxaliplatin-induced hepatic sinusoidal obstruction syndrome K. Imai a, Y. Emi b, K.-I. Iyama c, T. Beppu a, Y. Ogata d, Y. Kakeji e, H. Samura f, E. Oki b, Y. Akagi g, Y. Maehara b, H. Baba a,*, Kyusyu Study Group of Clinical Cancer (KSCC) ancillary study a
Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan b Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan c Department of Surgical Pathology, Kumamoto University Hospital, Kumamoto, Japan d Department of Surgery, Kurume University Medical Center, Kurume, Japan e Department of Surgery, Division of Gastrointestinal Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan f Division of Digestive and General Surgery, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan g Department of Surgery, Kurume University Hospital, Kurume, Japan Accepted 6 December 2013 Available online 20 December 2013
Abstract Aims: The aim of this study was to investigate the relationship between the use of bevacizumab (Bmab) in addition to oxaliplatin (OX), the development of sinusoidal obstruction syndrome (SOS) and the changes in splenic volume as an indicator of the protective effect of Bmab against OX-induced SOS. Methods: Seventy-nine patients who received OX-based chemotherapy with (OX þ Bmab group: n ¼ 48) or without Bmab (OX group: n ¼ 31) for colorectal liver metastases were included in this study. The changes in splenic volume after chemotherapy were evaluated in the two groups. Furthermore, the relationship between the changes in splenic volume and SOS were analyzed in the 55 patients who underwent hepatectomy. Results: A significant increase in the splenic volume was observed in the OX group, but not in the OX þ Bmab group. The increase in the splenic volume relative to baseline was significantly higher in the OX group than in the OX þ Bmab group (39.1% vs. 2.3%, p < 0.0001). The incidence of moderate or severe SOS was significantly higher in the OX group than in the OX þ Bmab group (50.0% vs. 16.0%, p ¼ 0.0068), and the increase in the splenic volume was significantly higher in the patients with SOS than in those without SOS (42.9% vs. 9.9%, p ¼ 0.0001). A multivariate analysis identified the increase in the splenic volume as an independent predictor of the development of SOS. Conclusions: This study demonstrated that the inhibition of splenic volume enlargement might be a useful indicator of the protective effect of Bmab against OX-induced SOS. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: Sinusoidal obstruction syndrome; Colorectal liver metastases; Bevacizumab; Oxaliplatin; Splenic volume
Abbreviations: CRLM, colorectal liver metastases; OX, oxaliplatin; FU, fluorouracil; LV, leucovorin; SOS, sinusoidal obstruction syndrome; Bmab, bevacizumab; VEGF, vascular endothelial growth factor; FDA, Food and Drug Administration; FOLFOX, 5-fluorpuracil/leucovorin/oxaliplatin regimen; XELOX, capecitabine/oxaliplatin regimen; CT, computed tomography; SD, standard deviation; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; HR, hazard ratio; ICG-R15, indocyanine green retention rate at 15 min. * Corresponding author. Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Tel.: þ81 96 373 5211; fax: þ81 96 371 4378. E-mail address: [email protected] (H. Baba). 0748-7983/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.12.009
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Introduction Colorectal cancer is one of the most common malignancies worldwide and its incidence has been rapidly increasing during the past few decades. The liver is the most common site of metastatic spread, and nearly half of the patients with colorectal cancer develop liver metastases at some point during the course of their disease.1e3 In patients with liver-only metastases, liver resection remains the only treatment modality that potentially achieves longterm survival and offers the hope of a cure. Previous studies reported a five-year survival rate of 40e58% after potentially curative liver resection.4e7 These favorable outcomes of patients with colorectal liver metastases (CRLM) are attributed not only to the improvements in surgical techniques and perioperative management, but also to the emergence of more effective chemotherapy. However, only about 20% of patients with CRLM are eligible for liver resection.8,9 In such patients with initially inoperable liver metastases, the recently introduced chemotherapeutic and biologic agents can increase the number of candidates for potentially curative resection.8,10,11 When marked tumor shrinkage is obtained by chemotherapy, an unresectable tumor may become resectable, and in such cases, a favorable long-term outcome can be expected by hepatic resection with curative intent. In patients with initially unresectable liver diseases that become resectable after preoperative chemotherapy, the five-year survival rates have reached 30%.8 Oxaliplatin (OX), a third-generation platinum compound, is widely used in the treatment of CRC in combination with either 5-fluorouracil/leucovorin (FU/LV) or capecitabine. OX-based chemotherapy has been increasingly utilized in the adjuvant, neoadjuvant and metastatic settings. However, several studies have demonstrated sinusoidal obstruction syndrome (SOS) in the non-tumorbearing liver in patients receiving preoperative OX-based chemotherapy, with an incidence of 19%e78%.12e15 Other reports showed that OX-induced SOS was associated not only with intraoperative bleeding15 and postoperative morbidity,15,16 but also with early recurrence and a decreased overall survival.17 Bevacizumab (Bmab), a monoclonal humanized antibody directed against vascular endothelial growth factor (VEGF), was initially approved by the U.S. Food and Drug Administration (FDA) in 2004 for the first-line treatment of metastatic colorectal cancer based on a survival benefit,18 and has been increasingly used in combination with chemotherapy before hepatic resection in patients with CRLM. Previous studies demonstrated that Bmab may prevent SOS in patients treated with OX-based chemotherapy for CRLM.19,20 In the current study, we investigated the relationship between the use of Bmab in addition to OX, the development of SOS and the changes in the splenic volume after
chemotherapy to demonstrate the benefit of assessing the change in the splenic volume as an indicator of the protective effect of Bmab against OX-induced SOS. Patients and methods Seventy-nine patients with CRLM who received OXbased preoperative chemotherapy with or without Bmab between 2004 and 2012 were retrospectively analyzed in the current study. Thirty-nine patients were treated in the Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University (Kumamoto, Japan), and the remaining 40 were patients who were enrolled in the Kyushu Study Group of Clinical Cancer (KSCC) 0802 ancillary study. The patients treated in Kumamoto University were administrated preoperative chemotherapy with the intent of both neoadjuvant and conversion. KSCC 0802 study was a prospective multicenter phase II trial in Japanese patients, and the aim of this study was to evaluate the resectability and safety of mFOLFOX6 þ Bmab on H2 and H3 liver-limited CRLM. The patients enrolled in KSCC 0802 study were also administrated chemotherapy with the intent of both neoadjuvant and conversion. To elucidate the effects of Bmab, patients were grouped as follows: OX group (n ¼ 31), patients who received OXbased chemotherapy without Bmab; OX þ Bmab group (n ¼ 48), patients who received OX-based chemotherapy with Bmab. In the OX group, 29 patients were treated with a 5-FU/LV/OX regimen (FOLFOX) and two patients were treated with a capecitabine/OX regimen (XELOX). In the OX þ Bmab group, 47 patients were treated with a FOLFOX þ Bmab regimen and one patient was treated with a XELOX þ Bmab regimen. The exclusion criteria were patients with underlying chronic liver diseases, patients who had received previous OX- or irinotecan-based chemotherapy and patients who had received any chemotherapy within six months before initiation of the treatment. Although the patients treated at Kumamoto University received either the FOLFOX (FOLFOX4 or mFOLFOX6) or XELOX with or without Bmab regimen, the patients enrolled in the KSCC 0802 study received only the mFOLFOX6 with Bmab regimen. Thirty of the 31 patients in the OX group underwent surgery, and 26 of the 48 patients in the OX þ Bmab group underwent surgery. In the OX þ Bmab group, one patient underwent exploratory laparotomy because the tumor was not detectable by intraoperative examinations, including ultrasonography. The remaining 55 patients underwent hepatic resection for CRLM. Hepatic resections were performed at least two weeks after the last course of chemotherapy. In the OX þ Bmab group, the last cycle of chemotherapy was usually given without Bmab to establish a gap of five weeks between the last Bmab treatment and surgery. Major hepatectomy was defined as resection of three or more liver
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Figure 1. The splenic volume before and after chemotherapy. The splenic volume before (A) and after (B) seven cycles of FOLFOX in a representative patient with multiple liver metastases from a rectal cancer. The splenic volume before and after chemotherapy were 72 cm3 and 145 cm3, respectively. Therefore, the increase in the splenic volume relative to baseline was calculated to be 101.4%.
segments. Postoperative morbidity was defined as any complication of Grade II or more according to the classification system proposed by Dindo et al.21 The presence of histological SOS of non-tumorous liver tissues away from the tumor was assessed by a single pathologist (KI.I.) who was blinded to the clinical data.
SOS was graded using a previously established system; grade 0, absent; grade 1, mild (centrilobular involvement of less than one-third of the lobular surface); grade 2, moderate (centrilobular involvement greater than or equal to one-third of the lobular surface, but not the whole surface) and grade 3, severe (complete lobular involvement with or
Table 1 Background characteristics of the patients before chemotherapy with or without bevacizumab.
Gender (male/female) Age Site of primary tumor (colon/rectum) Synchronous/metachronous Largest tumor size (mm) Number of metastases Number of chemotherapy cycles Total bilirubin (mg/dL) AST (IU/L) ALT (IU/L) ALP (IU/L) White blood cell count (/mL) Hemoglobin (g/dL) Platelet count ( 104/mL) Splenic volume before chemotherapy (cm3)
OX (n ¼ 31)
OX þ Bmab (n ¼ 48)
p value
21/10 66.2 10.2 18/13 22/9 50.3 56.9 4.8 6.5 6.7 2.6 0.64 0.26 28.6 21.9 25.8 16.6 369.6 247.4 6261 1876 11.9 2.1 27.6 11.6 120.8 50.5
34/14 63.0 9.2 30/18 37/11 56.5 34.4 6.0 5.5 5.3 2.7 0.64 0.29 33.0 18.7 29.6 19.90 442.9 295.3 6226 1536 12.4 1.7 24.5 7.4 127.2 52.9
0.96 0.16 0.69 0.54 0.062 0.28 0.0016 0.86 0.079 0.53 0.083 0.68 0.26 0.35 0.52
The values are the means standard deviations. OX, oxaliplatin; Bmab, bevacizumab; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase.
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K. Imai et al. / EJSO 40 (2014) 559e566
Table 2 The blood biochemical parameters before and after chemotherapy. OX (n ¼ 31) Before chemotherapy Total bilirubin (mg/dL) AST (IU/L) ALT (IU/L) ALP (IU/L) White blood cell count (/mL) Hemoglobin (g/dL) Platelet count ( 104/mL)
0.64 28.6 25.8 369.6 6261 11.9 27.6
0.26 21.9 16.6 247.4 1876 2.1 11.6
OX þ Bmab (n ¼ 48) After chemotherapy 0.67 31.4 29.5 348.0 4831 12.2 16.8
0.21 15.6 25.7 142.2 1629 1.3 6.0
p value
Before chemotherapy
0.63 0.18 0.75 0.88 0.0011 0.34 65a Site of primary tumor (rectum) Synchronous vs. metachronous Largest tumor size >36a mm Number of metastases >1 Number of chemotherapy cycles >6a Decrease in the platelet count >7.3a ( 104/mL) Bmab use Interval between completion of chemotherapy and surgery>34a days Splenic volume before chemotherapy >112a mL Splenic volume after chemotherapy >129a mL Increase in splenic volume relative to baseline >25%
Multivariate analysis
HR
95%CI
p value
0.83 1.72 1.65 1.40 1.11 1.46 2.52 2.69 0.19 1.72 0.90 1.58 20.7
0.25e2.80 0.56e5.29 0.52e5.24 0.41e4.81 0.37e3.38 0.42e5.03 0.80e7.95 0.86e8.49 0.05e0.69 0.56e5.29 0.29e2.84 0.50e5.00 4.44e96.2
0.77 0.34 0.39 0.59 0.85 0.55 0.11 0.091 0.012 0.34 0.86 0.43 0.0001
HR
1.62 0.65
14.4
95%CI
p value
0.36e7.26 0.12e3.52
0.53 0.62
2.48e83.3
0.0029
Bmab, bevacizumab; 95% CI, 95% confidence interval. a Median.
prevention of the development of SOS and decrease in the postoperative morbidity. In the current study, the splenic volume increased significantly in the OX group, however, the addition of Bmab prevented the splenic enlargement (Fig. 2). In addition, the increase in the splenic volume was significantly higher in patients with SOS than in those without SOS (Fig. 3(B)). These results suggest that the improvement of splenic enlargement might be a useful indicator of the protective effect of Bmab against OX-induced SOS. Although it remains unclear whether some of the patients treated with Bmab still developed OX-induced SOS in the liver parenchyma, preoperative and non-invasive prediction of the protective effects of Bmab against OX-induced SOS will facilitate the appropriate management of patients with CRLM in terms of the selection of hepatic resection after chemotherapy. There are some limitations to this study which consisted of two groups, the patients treated in the Kumamoto University, and the patients enrolled in KSCC 0802 study. First, the sample size was relatively small. Second, the patients enrolled in the KSCC 0802 study received only the mFOLFOX6 with Bmab regimen, and in principle, 5 cycles of mFOLFOX6 þ Bmab will be administered. Therefore, some bias could be present between the groups. In fact, there was a significant difference in the total amount of chemotherapy cycles between the groups. In this study, postoperative morbidity did not differ between the groups, in spite of the high incidence of SOS in the OX group. This result disagreed with the previous reports,15,16 and may be influenced by its small sample size and some bias. In conclusion, the present study showed that the development of SOS induced by OX-based chemotherapy was reduced when Bmab was added, and the inhibition of splenic enlargement might be a useful indicator of the protective effect of Bmab against OX-induced SOS.
Conflict of interest disclosure None of the authors has any conflict of interest. Appendix A. Supplementary data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.ejso.2013.12.009.
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