PLACE OF SURGERY IN HEPATIC OLIGOMETASTASES

REJAB Haitham |

La tunisie chirurgicale - 2019 ; Vol 2019

Resumé

The standard treatment for cancer metastases has been systemic management, including cytotoxic chemotherapy, hormonal therapy, and targeted therapy. Emerging evidence has shown an oligometastatic state, an intermediate state between limited primary cancer and polymetastatic cancer, in which local therapy for metastatic lesions results in satisfactory survival comparable to non-metastatic disease. In this review, we purpose to clarify the place of surgery in hepatic oligo-metastases of digestive and extradigestive origin. We conclude with low to intermediatelevel of evidence, that surgery of hepaticoligometastses is proven for colorectal and neuroendocrine liver metastases. It remains to be proved for other cancers especially from gastric, pancreatic and breast cancers.Moreover, The decision ofresection does not depend only on the number of hepatic metastases.

Mots Clés

Oligomestastases;Hepatic metastases;Liver resection;Prognosis.

Introduction :

The standard treatment for cancer metastases has been systemic management, including cytotoxic chemotherapy, hormonal therapy, and targeted therapy. Emerging evidence has shown an oligometastatic state, an intermediate state between limited primary cancer and polymetastatic cancer, in which local therapy for metastatic lesions results in satisfactory survival comparable to non-metastatic disease.

The concept of an oligometastatic state was first proposed by Hellman et al. as an  intermediate state (≤5 metastases) between limited primary and polymetastatic cancers in which local therapy could achieve long-term survival or cure, with no restrictions on primary lesions [1,2]. In 2006, the concept of oligo-recurrence was defined by Niibe et al. as the state that cancer patients have ≤5 metastatic or recurrent lesions with controlled primary lesions [3]. In 2012, the concept of sync-oligometastasis was proposed as the state that cancer patients have ≤5 metastatic or recurrent lesions with active primary lesions [4]. The major difference among oligometastasis, oligo-recurrence and sync-oligometastasis was the status of the primary lesion, which is the most important prognostic factor of oligometastasis, and oligo-recurrence showed better prognosis compared with sync-oligometastasis.

The liver is the site of predilection for metastasis of colorectal, gastric, pancreatic, neuroendocrine (TNE) and gynecological cancers (breast, uterus, ovary). Treatment for hepatic oligometastases is based on surgery and radiofrequency.

In this review, we will try to clarify the place of surgery in hepatic oligo-metastases of digestive and extradigestive origin.

Article

1.Place of surgery in front of the hepatic oligo-metastases:

According to Niibe et al, the most frequent liver metastases occur in colorectal cancer. However, colorectal cancer patients with liver metastases resected by surgery achieve favorable survival. The 5-year overall survival rate is about 40%–50% [5, 6] (Table1). Furthermore, Adam et al. reported that initially unresectable colorectal liver metastasis could be cured by surgery after downsizing chemotherapy [7]. The cure rate was reported to be as high as 19%. Bismuth also reported that initially unresectable colorectal liver metastases could achieve a 5-year overall survival rate of 40% [8]. In the cohort of Parisi A, 170 Patients who underwent liver resections were collected. A subgroup analysis showed the following distribution related to the primary site of the disease: colorectal (77.1%), genitourinary (7.6%), neuroendocrine (NET) (5.3%), breast (4.7%), foregut (2.9%), melanoma (2.4%). Patients with non-colorectal primary malignancies represent 22.9% of the total sample [9].

The disease-free survival rate resulted 40%, 15%, 8% at 1, 3, and 5 years follow-up, respectively. The overall survival rates were 96.2%, 42.8%, and 14.7% at 1, 3, and 5 years, respectively. The survival analysis showed a mean overall survival of 54 months in the colorectal metastases group vs 32 months in the non-colorectal liver metastases group (HR=5.92, P=0.015). The survival of patients with liver oligometastases from NET was better than that of colorectal liver metastases. The conclusion of the authors was that surgery for patients with non-colorectal liver metastases must be considered in the context of a multidisciplinary treatment where chemotherapy plays the main role [9].

  1. Colorectal adenocarcinoma:

According to the European Society of Medical Oncology, treatment strategies for colorectal cancer with liver oligometastases should bebased on the possibility of achieving complete ablation of alltumour masses, using surgical R0 resection (complete resectionwith clear resection margins and no evidence of microscopicresidual tumour), either initially or possibly afterinduction treatment with systemic therapy, for both the primarytumour and metastases. Therefore, the tenth ESMO recommendation for patients with oligometastases was that systemic therapy is the standard of care and should be considered as the initial part of every treatment strategy (exception: patients with single/few liver lesions). Local treatment includes surgery and other toolbox [10].

Surgical resection should always be discussed and possibly discussed in a multidisciplinary meeting with at least one surgeon and one radiologist experienced in hepatic pathology. The patient must be compatible with anesthesia and resection of metastases. The surgery should be carcinological with a possible R0 resection of all metastases. The resection must be anatomical. In case of vascular invasion (portal pedicle, suprahepatic veins), the resection must allow to leave a parenchyma with its own vascularization and its biliary drainage.
A residual volume> 25% to 40% of healthy liver is required, depending on whether or not there is an underlying liver disease [11, 12].

  1. Gastric adenocarcinoma:

The review of most scientific surveys leads with certitude to the principle that an aggressive multimodal treatment associating surgery and chemotherapy should be pursued whenever clinically possible, as it offers the best survival results. As regards treatment with systemic chemotherapy alone, the Japan  Clinical Oncology Group 24 reported a 5- year survival rate of only 1.7 % in patients with metastatic gastric cancer confined to the liver, suggesting that monotherapy of that kind is of low utility [13].

The best results are associated with surgery, if a complete resection of the lesions can be achieved, while also preserving adequate postoperative liver function. Regarding the operative risk, most centers report absence of surgical complications with low perioperative mortality [14]. Consequently, surgical removal should be proposed if extrahepatic noncurable tumor dissemination can be ruled out, even when facing multiple lesions spread bilaterally within the organ [15]. Moreover, adjuvant chemotherapy after gastrectomy does not negatively affect survival after hepatic relapse, implying that recurrence does not necessarily reflect more aggressive disease. A trend toward a better survival was also observed in patients with recurrence treatedwith chemotherapy [16]. Variations in the biologic behavior of the metastatic nodule and the host reaction rather than the surgical procedure or adjuvant chemotherapy may affect the prognosis. Results are summarized in Table 2 [14,17, 18,14,19, 20, 21, 22, 23, 24, 25, 26, 27, 28]

  1. Pancreatic adenocarcinoma:

Pancreatic adenocarcinoma is a highly aggressive malignancy with one of the worst prognoses among gastrointestinal tumors. The American Cancer Society estimates that approximately 48,960 patients will be diagnosed with PDAC in 2015 with more than 40,560 deaths due to the disease [29]. The liver is the most common initial location of distant recurrence in part because it is the first major organ reached by portal venous blood draining from the pancreas or lymphatic spread. The most effective treatment for pancreatic adenocarcinoma is surgical resection, but patients with distant metastases are considered unresectable based upon National Comprehensive Cancer Network (NCCN), National Cancer Institute (NCI) and ESMO guidelines [30, 31, 32]. Current literature has shown that pancreatectomy with synchronous hepatic metastasectomy can be performed safely without a significant increase in perioperative morbidity and mortality [33]. However, the potential benefit on long-term survival is less clear. Acoording to Adam et al, the 5 year overall survival (OS) of patients who underwent synchronous metastasectomywas 25% and median OS was 20 months [34].

There is little data on this subject. According to Lu et al, metastasectomy for solitary hepaticmetastases of pancreatic adenocarcinoma should be considered only when a negative surgical (R0) resection can be achieved by pancreatectomy after a good response to neoadjuvant systemic therapy with resecableoligometastasesin a patient with good general health and limited comorbidities. When applied in these situations, surgery may be considered for these selected patients with the primary goal of improving long-termsurvival [35].

 

  1. Neuroendocrine tumor

Gastrointestinal neuroendocrine tumors represent an unusual subset of tumors within the spectrum of malignancies. Unlike many cancers, neuroendocrine tumors grow very slowly and have the capacity to produce hormones. Endocrine activity is a late sign of the disease, and many of these patients present with hepatic metastases. Surgery is appropriate for patients with metastatic neuroendocrine tumors for the following two reasons: many of them still have the primary tumor in place and resection should be undertaken to avoid acute complications and the addition of adjunctive ablative therapies to surgical resection accomplishes the control of greater than or equal to 90% of the bulk of the tumor. If preoperative evaluation indicates that less than 90% of the tumor is treatable, surgical therapy is contraindicated [36]. Prospective randomized data on the outcomes of surgical treatment of neuroendocrine liver metastases are lacking. Surgical treatment recommendations were initially based on single-institution experiences compared with historical controls. Resection of neuroendocrine liver metastases, primary tumour, and locoregional lymph node metastases is thought to positively benefi t long-term survival and quality of life. The overall survival after hepatic resection is 46–86% at 5 years and 35–79% at 10 years. These results should be viewed with caution (complete resection in only 20–57% and local recurrence evident in up to 94% at 5 years) [37]. Candidates for resection include: grade 1 or 2 tumours; when no evidence of non-resectable extrahepatic disease exists; type I or II metastatic growth assessable for R0 or R1 resection with an anticipated liver remnant of at least 30%; when no evidence of advanced carcinoid heart disease exists; and when access to a hepatic surgery centre is possible. Liver metastases of grade 3 NETs are usually not amenable for resection [38].

  1. Breast cancer:

Following a breast cancer diagnosis, 20% of patientsdevelop metastases, and 50% of these metastases involvethe liver and are associated with a shorter mediansurvival. The aim of surgical treatment for liver metastases is to ensure prolonged recurrence-free or metastasis-free survival. In the review of Chua et al., the median 5-year survival rate was 40% (range: 21e80%). Eighteen studies were selected in that review, and only four studies had survival rates equal to or more than 50% at 5 years [39]. In the French multicentre retrospective cohort (41 centres), the overall survival rates after surgical treatment were 41% and 22% at 5 and 10 years, respectively, indicating that the prognosis of liver metastases from breast cancer is better than that of many other metastatic non-colorectal and non-endocrine cancers [34]. Mortality was reported as low across all studies with a median of 0% and a maximum of 5.9% which is interesting given the data spans almost three decades and we know that there have been significant improvements in the perioperative care of patients undergoing liver resection during this time. Mortality was taken as reported in each paper and whilst we aimed to extract 30-day mortality and/or mortality during post-operative stay this was not always clearly stated; for example ‘no intraoperative or early post-operative deaths’or ‘no perioperative death’, thus not defining any specific time frames. However, patients undergoing liver resection of breast cancer metastases are a highly selectgroup with potentially favourable prognostic indicators, so wewould expect a low mortality. It should be noted also that in onepaper the only patient death was excluded from the survival calculations (table 3) [34,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64].

Conclusion:

Definitive recommendations regarding patient selection or the optimal choice of treatment modality cannot be made until results from randomized trials are avail­able. In the interim, treatment decisions should be made in the context of a multi­disciplinary team. Discussions with patients should be balanced, describing the theoretical benefits of surgery, the associated uncertainties, the risks of toxicity, and the likelihood of occult metastases beyond the known oligometastatic lesions.Surgery of oligometastses is proven for colorectal and neuroendocrine liver metastases. It remains to be   proved for other cancers. Randomized controlled prospectivestudies are strongly recommended.

Conflict of interest:There are no conflicts of interest to be declared. No financialsupport was requested or received in the productionof this article.

 

 

 

 

 

 

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Table 1:Prognosis of surgery for liveroligometastases

Authors

Treatment of liver oligometastases

Overall  survival

Choti et al. [5]

Surgery

40%

Pawlik et al. [6]

Surgery

58%

Adam et al. [7]

ChemotherapySurgery

33%

Bismuth et al. [8]

ChemotherapySurgery

40%

 

Table 2:5-year survival of curative surgery in hepatic oligometastases from gastric cancer

 

 

Number of patients

Five year survival

of curative surgery (%)

Wang et al. [17]

30

16.7

Takemura et al. [18]

64

37

Kinoshita et al. [14]

256

31

Tiberio et al. [19]

212

9.3

Qiu et al. [20]

526

24.9

Li et al. [21]

101

0

Tiberio et al. [19]

73

20

Shirabe et al. [22]

36

26

Wang et al. [17]

315

10.3

Cheon et al. [23]

22

23

Nomura et al. [24]

17

30.8

Garancini et al. [25]

67

19

Thelen et al. [26]

24

23

Koga et al. [27]

42

42

Sakamoto et al. [28]

37

11

 

 

 

 

 

 

            

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

    

Table 3:Outcomes of hepatic surgery in case of liver oligometastases from breast cancer

 

Number

Mortality (%)

Morbidity (%)

 Mariani P et al [40]

51

0

19.6

 Her D et al [41]

30

3.3

13.3

 van Walsum GA et al [42]

32

0

34

Abbott DE et al [43]

86

0

21

Hoffmann K et al [44]

41

0

21

Schmelzle M et al [45]

9

0

11.1

Rubino A et al [46]

18

0

11.1

Furkha A et al [47]

17

0

11.8

Caralt M et al [48]

12

0

16.7

Kollomar O et al [49]

23

0

17.4

Thelen A et al [50]

39

0

12.8

 Adam R et al  [34]

85

0

22.44

D’Annibale M et al [51]

18

0

27.8

Okaro AC et al  [52]

6

0

0

 Sakamoto Y et al[53]

34

0

-

Vlastos G et al [54]

31

0

-

Arean E et al  [55]

17

0

29.44

 Elias D et al [56]

54

0

13

Maksan SM et al  [57]

9

0

0

 Kondo S et al [58]

6

0

0

 Yoshimoto M et al [59]

25

0

0

Selzner M et al [60]

17

5.9

0

Pocard M et al [61]

49

0

12.2

 Seifert JK et al [62]

15

0

20

Raab R et al [63]

35

2.9

28.6

Schneebaum S et al [64]

6

0

-