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Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases G. Morris-Stiff a, A.D. White a, D. Gomez b, I.C. Cameron b, S. Farid a, G.J. Toogood a, J.P.A. Lodge a, K.R. Prasad a,* b

a Department of Hepatobiliary and Transplant Surgery, St James’ University Hospital, Leeds LS9 7TF, UK Department of Hepatobiliary and Pancreatic Surgery, Queen’s Medical Centre, Derby Road, Nottingham NG7 2UH, UK

Accepted 10 September 2013 Available online - - -

Abstract Introduction: Sinusoidal obstructive syndrome (SOS) is well associated with the use oxaliplatin-based chemotherapy, and represents a spectrum of hepatotoxicity, with nodular regenerative hyperplasia (NRH) representing the most significant degree of injury. The aim of this study was to determine the prevalence of NRH in patients undergoing resection of colorectal liver metastases (CRLM) and to determine its impact on outcome. Methods: From January 2000 to December 2010, some 978 first primary liver resections were performed for CRLM. A prospectively maintained database was analysed to identify all patients with evidence of NRH in the non-tumour portion of their histopathology specimens. Clinical data of these patients was reviewed and outcomes assessed. Results: Five patients exhibited NRH (four males, one female) with a median age of 69 years (range: 35e74). Three patients presented with synchronous hepatic metastases, and two with metachronous lesions. All received at least 6 cycles of oxaliplatin as either adjuvant or neoadjuvant chemotherapy. Only one patient developed a post-operative complication namely transient hepatic failure that required a 4-day stay in the intensive care unit. The median hospital stay was 6 days (range: 6e14 days). There were no 90-day mortalities. One patient is alive and disease free at 55 months, the remaining 4 died of recurrent disease between 37 and 70 months following diagnosis of their primary tumours. Conclusions: NRH is not an uncommon finding amongst patients with SOS with all patients having received oxaliplatin-based chemotherapy. Data on outcome would suggest no increased morbidity and mortality associated with the presence of NRH. Ó 2013 Published by Elsevier Ltd. Keywords: Oxaliplatin; Colorectal liver metastases; Sinusoidal obstruction syndrome; Nodular regenerative hyperplasia

Introduction The use of oxaliplatin-based regimens in patients with colorectal carcinoma has lead to significant improvements in survival for both primary colonic lesions and for patients with liver metastases, these findings being appreciated for more than a decade,1 and confirmed for stage 3 disease in a recent meta-analysis.2 Oxaliplatin has also been shown to be valuable in the treatment of patients with colorectal liver metastases (CRLM) and has been shown to down* Corresponding author. Hepatobiliary and Transplant Unit, St James’ University Hospital, Beckett Street, Leeds, Yorkshire LS9 7TF, UK. Tel.: þ44 (0) 113 2064890; fax: þ44 (0) 113 2448182. E-mail address: [email protected] (K.R. Prasad).

size previously unresectable lesions thus increasing resectability rates and increasing long-term survival of this cohort of patients.3,4 Although the clinical efficacy of oxaliplatin is clear, there are distinct drug-specific side-effects, one of which being sinusoidal obstructive syndrome (SOS).5e7 SOS represents a spectrum of hepatotoxicity, with nodular regenerative hyperplasia (NRH) the most significant degree of injury. NRH is of interest to the surgeon performing liver resectional surgery as it is associated with the presence of portal hypertension, and so may be expected to adversely affect outcome. Reports of the incidence of NRH following chemotherapy for CRLM and analysis of its affect on outcome are scare, and so the magnitude of the problem is unclear.8

0748-7983/$ - see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.ejso.2013.09.015 Please cite this article in press as: Morris-Stiff G, et al., Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases, Eur J Surg Oncol (2013), http://dx.doi.org/10.1016/j.ejso.2013.09.015

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The aim of this study was to determine the prevalence of NRH in a contemporary cohort of patients undergoing resection of CRLM, and to determine its impact on outcome including morbidity and mortality. Patients and methods A prospectively maintained database of all hepatic resections for colorectal liver metastases performed within our institute was interrogated to identify all patients who had features of SOS on histological analysis of the nontumours portions of their resected specimens. All histological specimens had been evaluated by a consultant pathologist with a specialist interest in hepato-biliary diseases. The patient case notes were reviewed to determine: the diagnosis at primary presentation; primary therapy; and the use of, nature, and duration of chemotherapy. Examination of the radiology database provided details of recurrence patterns following the initial therapy and also identified stigmata of portal hypertension including splenomegaly and varices. The details of subsequent hepatic resections were obtained from the clinical database including: extent of resection; intra-operative findings; intensive care unit (ICU) stay; post-operative stay; the development of post-operative complications and their grading according to the ClavieneDindo system.9 Findings of subsequent imaging studies, associated therapies and outcome were also recorded. Results During the period January 2000 to December 2010, 5 patients were identified in whom NRH was reported in the normal parenchyma of their resection specimens as summarised in Table 1. The classical histological appearance of SOS with NRH is illustrated in Fig. 1. The finding

Figure 1. Histopathological appearance of SOS (sinusoidal dilatation and congestion with atrophic hepatocytes) and NRH in a resection specimen.

was present amongst 65 patients with SOS, representing 7.7% of patients with SOS. Four of 5 patients were male with a median age of 69 years (range: 35e74 years). Three patients presented with synchronous hepatic metastases: 2 undergoing combined colonic and hepatic resection; and the final patient neoadjuvant chemotherapy prior to hepatic resection. The 2 patients with metachronous disease underwent colonic resection with adjuvant chemotherapy. Oxaliplatin was used in combination with 5-fluorouracil (5-FU) as primary first-line adjuvant chemotherapy in 4 patients and also in the patient undergoing neoadjuvant therapy. Four patients received 6 cycles of oxaliplatin, and the remaining patient had 14 cycles, respectively. In one case, there was radiological evidence of portal hypertension associated with SOS (Fig. 2) and in one further case SOS was recognised pre-operatively on cross-sectional imaging. In an additional case, the classical appearance of SOS was seen at the time of surgery.

Table 1 Summary of five patients in whom NRH were reported. Patient Gender Age Primary diagnosis

Primary therapy

Adjuvant chemotherapy

Recurrence

Further chemotherapy

1

70

M

Low anterior resection with non-anatomical resections of segments 2 and 5

6 cycles oxaliplatin þ5-fluourouracil (5FU)

Hepatic recurrence in segments 1, 4 and 6

None

2

74

M

None

3

69

M

Laparoscopic assisted right 6 cycles oxaliplatinþ5FU Hepatic metastases in hemicolectomy segments 4, 5 and 8 Laparoscopic anterior resection 6 cycles oxaliplatinþ5FU Hepatic metastases in with non-anatomical segment 3 resections of segments 2, 4 and 8

4

67

M

5

35

F

Rectal carcinoma with synchronous hepatic metastases in segments 2 and 5 Caecal carcinoma Rectal carcinoma with synchronous hepatic metastases in segments 2, 4 and 8 Sigmoid carcinoma

Laparoscopy sigmoid colectomy

Sigmoid carcinoma with Neoadjuvant chemotherapy with synchronous hepatic 14 cycles of oxaliplatin metastases in segments 2, 4, 5, 6, 7, 8

None

6 cycles oxaliplatinþ5FU Hepatic metastases in None segments 1, 2, 3, 5, 6 and 8 NA NA NA

Please cite this article in press as: Morris-Stiff G, et al., Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases, Eur J Surg Oncol (2013), http://dx.doi.org/10.1016/j.ejso.2013.09.015

G. Morris-Stiff et al. / EJSO xx (2013) 1e5

Figure 2. MRI scan of the liver demonstrating classical features of SOS together with splenomegaly.

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The operative and post-operative course of the patients is summarised in Table 2. The histopathology of non tumour-bearing tissue in the resection specimen confirmed the presence of NRH associated with SOS in all cases. Only one patient spent a portion of their post-operative course in the intensive care unit, and the median hospital stay was 6 days (range: 6e14 days). One patient experienced hepatic impairment that settled with conservative management. The 90-day mortality was zero for this cohort. Four of the patients experienced recurrent disease. In 3 patients, further operative interventions were possible but further recurrence eventually lead to an inoperable state and all patients were palliated with chemotherapy. One patient who underwent synchronous colonic and hepatic resections is still alive 55 months following his initial hepatic resection and 44 months after the diagnosis of NRH during his second resection. The patients who died did so at a median of 38 months (range: 23e63 months)

Table 2 Summary of the operative and post-operative course of the five patients in whom NRH were reported. Patient Subsequent surgery

Histology

ICU Post-op Complications Clavien Post hepatic resection (days) stay grade Progress and further therapy

1

Non-anatomical resections of segments 1, 4 and 6

Sinusoidal obstructive 0 syndrome with nodular regenerative hyperplasia

6

None

0

2

Non-anatomical resection of segment 5, 4 and 8

Sinusoidal obstructive 0 syndrome with nodular regenerative hyperplasia

6

None

0

3

Resection of segment 3

Sinusoidal obstructive 0 syndrome with nodular regenerative hyperplasia

9

None

0

4

Right trisectionectomy and Sinusoidal obstructive 0 non-anatomical resections syndrome with nodular of segments 1, 2 and 3 regenerative hyperplasia

6

None

0

5

Hartmann’s procedure with extended right hemihepatectomy and non-anatomical resection of segment 3

Hepatic Failure

2

Sinusoidal obstructive 4 syndrome with nodular regenerative hyperplasia

14

Developed widespread pulmonary, hepatic and local recurrence and was commenced on palliative chemotherapy Developed widespread pulmonary recurrence and was commenced on palliative chemotherapy No further evidence of recurrence

Outcome Died 46 months following primary diagnosis

Died 35 months following primary diagnosis Alive 55 months following primary diagnosis with no evidence of recurrence Died 70 months following primary diagnosis

Developed hepatic recurrence on the surface of the remnant and underwent non-anatomical resection. Then developed recurrence on 2 further occasions and underwent non-anatomical resection of lesions in segments 2 and 3. Finally developed a further hepatic recurrence inoperable due to position on IVC and was commenced on palliative chemotherapy Died 37 months Developed hepatic recurrence in segments 2 and 3, a metastasis following primary in the right adrenal gland, and a diagnosis peritoneal deposit. Underwent further chemotherapy followed by a right adrenalectomy, resection of a peritoneal nodule, and non-anatomical resections of segments 2 and3. Subsequently developed further widespread metastases and commenced on palliative chemotherapy

Please cite this article in press as: Morris-Stiff G, et al., Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases, Eur J Surg Oncol (2013), http://dx.doi.org/10.1016/j.ejso.2013.09.015

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G. Morris-Stiff et al. / EJSO xx (2013) 1e5

following their initial hepatic resection, which was a median of 30 months following diagnosis of NRH, as one patient had NRH diagnosed at their second resection. Discussion The primary finding of the study was that NRH accounted for a no insignificant proportion of patients with SOS, with the finding present in 7.7% of cases. Portal hypertension was identified pre-operatively in only one case (20%), was not confirmed intra-operatively in any other patients, and did not appear to have a negative impact on postoperative outcome with only a single morbidity and no 90day mortality in this patient cohort. The advent of oxaliplatin-based perioperative chemotherapy regimens has lead to a significant improvement in outcome for patients with metastatic colorectal cancer.1,3 One histological diagnosis frequently linked with the use of oxaliplatin is SOS. The pathophysiology of this condition was delineated by DeLeve and colleagues who identified its origin from the hepatic sinusoid.5 They described the characteristic histological features of SOS namely: sinusoidal congestion and dilatation; disruption of the sinusoidal membrane; and collagen deposition within the perisinusoidal space, leading to a blue appearance of the liver, and the alternative name for the condition namely ‘blue liver syndrome’.5 SOS was reported in relation to oxaliplatin chemotherapy independently by Rubbia-Brandt and colleagues, and Tisman et al. in 2004.5,6 Rubbia-Brandt and colleagues noted histological evidence of SOS in half of the livers from patients receiving chemotherapy prior to resection, as did Julie and co-workers in a study of specimens from the EORTC trial.7 Likewise, Vauthey et al., noted moderate or severe SOS in 15/79 (19%) of patients receiving oxaliplatin as part of their regimen.10 Recently Vreuls et al. demonstrated a statistically significant correlation between high-grade SOS and a failure to respond to oxaliplatinbased chemotherapy and therefore its identification may have a prognostic value.11 In this current small series, one patient remained disease free at 55 months and the median survival time of the remaining patients was 38 months, and so not dissimilar to patients without evidence of NRH in published series. Sinusoidal injury has been shown to increase morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy.12 In addition Tamandl et al., report that the occurrence of highgrade SOS following chemotherapy for metastatic colorectal cancer is associated with early recurrence and decreased overall survival following potentially curative liver resection.13 NRH, as identified in the cases in this series has previously been reported in relation to oxaliplatin chemotherapy both in the original papers and in an update from RubbiaBrandt’s group.6,7,14 Hubert and colleagues reported NRH

in 3 patients with colorectal liver metastases in whom resection was planned.15 Two of their patients exhibited portal hypertension and the diagnosis of NRH was confirmed by biopsy leading to exclusion from resection. Wicherts et al., demonstrated that patients with colorectal liver metastases who receive preoperative oxaliplatin have an increased risk of NRH and associated postoperative morbidity.16 They postulate that NRH is part of the spectrum of SOS and that portal hypertension occurs as a consequence of NRH. Whilst the pathogenesis of NRH is not fully understood, it has been suggested that it represents a chronic ischaemic injury secondary to disturbance to the blood flow within the liver.17 This would certainly make sense in relation to the observation of NRH developing on a background of SOS. NRH in isolation of SOS has been reported to be linked with a number of systemic conditions, however, none of these associations were present in either of our cases. Furthermore SOS and NRH have also been reported together in patients undergoing treatment with 5-fluorouracil in the absence of oxaliplatin.17 The clinical impact of NRH on outcome is uncertain as numbers of patients reported in the literature are currently too small to try and sub-analyse according to grade of NRH nor in relation to duration or dose of oxaliplatin treatment. A further point that is not clear is whether the SOS and NRH are rare, dose-dependent or ubiquitous complications of oxaliplatin therapy. At present the data is not available to comment on the true prevalence of SOS, NRH and indeed portal hypertension following oxaliplatin therapy. If the rates of these treatment-related complications are significant, then greater efforts will be required to accurately document their presence, in particular portal hypertension prior to attempting resection as this is may otherwise lead to a negative impact on survival. Conclusions This observational study has demonstrated that NRH is not an uncommon finding amongst patients with SOS associated with oxaliplatin-based chemotherapy. Although the cohort is small, the presence of NRH did not appear to have a negative impact on outcome in terms of morbidity or mortality. Conflict of interest The authors have no conflicts of interest to disclose. References 1. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–47. 2. Sanoff HK, Carpenter WR, Martin CF, et al. Comparative effectiveness of oxaliplatin vs non-oxaliplatin-containing adjuvant

Please cite this article in press as: Morris-Stiff G, et al., Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases, Eur J Surg Oncol (2013), http://dx.doi.org/10.1016/j.ejso.2013.09.015

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chemotherapy for stage III colon cancer. J Natl Cancer Inst 2012 Feb 8;104(3):211–27. http://dx.doi.org/10.1093/jnci/djr524. [Epub 2012 Jan 20]. Bismuth H, Adam R, Levi F, et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 1996 Oct;224(4):509–20. discussion 520e2. 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 Oct;240(4):644–57. discussion 657e658. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004;15:460–6. Tisman G, MacDonald D, Shindell N, et al. Oxaliplatin toxicity masquerading as recurrent colon cancer. J Clin Oncol 2004;22: 3202–4. Julie C, Lutz MP, Aust D, et al. Pathological analysis of hepatic injury after oxaliplatin-based neoadjuvant chemotherapy of colorectal cancer liver metastases: results of the EORTC Intergroup phase III study 40983. J Clin Oncol 2007;25(Suppl.). [Abstract 241]. van den Broek MA, Olde Damink SW, Driessen A, Dejong CH, Bemelmans MH. Nodular regenerative hyperplasia secondary to neoadjuvant chemotherapy for colorectal liver metastases. Case Report Med 2009;2009:457975. Dindo D, Demartines N, Clavien P-A. 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.

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10. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in ninety-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006;24:2065–72. 11. Vreuls CP, Van Den Broek MA, Winstanley A, Koek GH, Wisse E, Dejong CH, et al. Hepatic sinusoidal obstruction syndrome (SOS) reduces the effect of oxaliplatin in colorectal liver metastases. Histopathology 2012 Aug;61(2):314–8. 12. 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; 1:118–24. 13. 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. 14. Rubbia-Brandt L, Mentha G, Terris B. Sinusoidal obstruction syndrome is a major feature of hepatic lesions associated with oxaliplatin neoadjuvant chemotherapy for colorectal liver metastases. J Am Coll Surg 2006;202:199–200. 15. Hubert C, Sempoux C, Horsmans Y, et al. Nodular regenerative hyperplasia: a deleterious consequence of chemotherapy for colorectal liver metastases? Liver Int 2007;27:938–43. 16. Wicherts DA, Robbert J, Sebahg M, et al. Regenerative nodular hyperplasia of the liver related to chemotherapy: impact on outcome of liver surgery for colorectal metastases. Ann Surg Oncol 2011 March;18(3):659–69. 17. Shimamatsu K, Wanless IR. Role of ischemia in causing apoptosis, atrophy and nodular hyperplasia in human liver. Hepatology 1997;26:343–50.

Please cite this article in press as: Morris-Stiff G, et al., Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases, Eur J Surg Oncol (2013), http://dx.doi.org/10.1016/j.ejso.2013.09.015

Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases.

Sinusoidal obstructive syndrome (SOS) is well associated with the use oxaliplatin-based chemotherapy, and represents a spectrum of hepatotoxicity, wit...
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